We've seen these visions glinting in the distance for some time--the prospect that one day parents will be able to browse through gene catalogs to special-order a hazel-eyed, redheaded extrovert with perfect pitch. Leave aside for the moment whether scientists actually found an "IQ gene" last week or the argument over what really constitutes intelligence. Every new discovery gives shape and bracing focus to a debate we have barely begun. Even skeptics admit it's only a matter of time before these issues become real. If you could make your kids smarter, would you? If everyone else did, would it be fair not to?

It's an ethical quandary and an economic one, about fairness and fate, about vanity and values. Which side effects would we tolerate? What if making kids smarter also made them meaner? What if only the rich could afford the advantage? Does God give us both the power to re-create ourselves and the moral muscles to resist? "The time to talk about it in schools and churches and magazines and debate societies is now," says bioethicist Arthur Caplan of the University of Pennsylvania. "If you wait, five years from now the gene doctor will be hanging out the MAKE A SMARTER BABY sign down the street."

What makes the conversation tricky is that we're already on the slippery slope. Doctors can screen fetuses for genetic diseases like cystic fibrosis and Duchenn muscular dystrophy; one day they may be able to treat them in utero. But correcting is one thing, perfecting is another. If doctors can someday tinker with a gene to help children with autism, what's to prevent them from tinkering with other genes to make "normal" children smarter? Technology always adapts to demand; prenatal sex-selection tests designed to weed out inherited diseases that strike one gender or the other--hemophilia,

for instance--are being used to help families have the sonor daughter they always wanted. Human-growth hormone was intended for children with a proven severe deficiency, but it came to be used on self-conscious short kids--if their parents could afford as much as $30,000 for a year's injections.

Self-improvement has forever been an American religion, but the norms about what is normal keep changing. Many parents don't think twice about straightening their kids' crooked teeth but stop short of fixing a crooked nose, and yet, in just the past seven years, plastic surgery performed on teens has doubled. As for intellectual advantages, parents soak their babies in Mozart with dubious effect, put a toy computer in the crib, elbow their way into the best preschools to speed them on their path to Harvard. Infertile couples advertise for an egg donor in the Yale Daily News, while entrepreneurs sold the sperm of Nobel laureates.

"What, if anything, is the difference between getting one's child a better school and getting one's child a better gene?" asks Erik Parens of the Hastings Center, a bioethics think tank. "I think the answer has to do with the difference between cultivating and purchasing capacities." Buying a Harvard education may enhance a child's natural gifts, he argues, but it's not the same as buying the gifts.

Every novel, every movie that updates Frankenstein provides a cautionary tale: these experiments may not turn out as we expect. Genetic engineering is more permanent than a pill or a summer-school class. Parents would be making decisions over which their children had no control and whose long-term impact would be uncertain. "Human organisms are not things you hang ornaments on like a Christmas tree," says Thomas Murray, Hastings' director. "If you make a change in one area, it may cause very subtle changes in some other area. Will there be an imbalance that the scientists are not looking for, not testing for, and might not even show up in mice?"

What if it turned out that by enhancing intellectual ability, some other personality trait changed as well? "Everything comes at a price," argues UCLA neurobiologist Alcino

Silva. "Very often when there's a genetic change where we improve something, something else gets hit by it, so it's never a clean thing." The alarmists, like longtime biotech critic Jeremy Rifkin, go further. "How do you know you're not going to create a mental monster?" he asks. "We may be on the road to programming our own extinction."

The broader concern is one of fairness. Will such enhancement be available to everyone or only to those who can afford it? "Every parent in the world is going to want this," says Rifkin. "But who will have access to it? It will create a new form of discrimination. How will we look at those who are not enhanced, the child with the low IQ?" Who would have the right to know whether your smarts were natural or turbo-charged? How would it affect whom we choose to marry--those with altered genes or those without? If, as a parent, you haven't mortgaged the house to enhance your children, what sort of parent does that make you? Will a child one day be able to sue her parents for failing to do everything they could for her?

But just for the sake of argument, suppose raising IQ didn't require any permanent, expensive genetic engineering at all. Scientists are studying brain-boosting compounds. Suppose they found something as cheap and easy as aspirin; one pill and you wake up the next morning a little bit brighter. Who could argue with that?

Some people are worried about the trend toward making people more alike--taller, thinner, smarter. Maybe it's best for society as a whole to include those with a range of needs and talents and predispositions, warts and all "As someone who morally values diversity," says ethicist Elizabeth Bounds of Emory University's Candler

School of Theology, "I find this frightening. We run the risk of shaping a much more mogeneous community around certain dominant values, a far more engineered community." What sort of lottery would decide who is to leap ahead, who is to be held back for an overall balance? At the moment, nature orchestrates our diversity. But human nature resists leaving so much to chance, if there is actually a choice.

The debate raises an even more basic question: Why would we want to enhance memory in the first place? We may imagine that it would make us happier, except that we all know smart, sad people; or richer, except that there are wildly successful people who can't remember their phone number. Perhaps it would help us get better grades, land a better job, but it might also take us down a road we'd prefer not to travel. "You might say yes, it would be wonderful if we could all have better memories," muses Stanford University neuropsychiatrist, Dr. Robert Malenka. "But there's a great adaptive value to being able to forget things. If your memory improves too much, you might not be a happier person. I'm thinking of rape victims and soldiers coming back from war. There's a reason the brain has evolved to forget certain things."

In the end it is the scientists who both offer the vision and raise the alarms. People with exceptional, photographic memories, they note, sometimes complain of mental overload. "Such people," says University of Iowa neurologist Dr. Antonio Damasio, "have enormous difficulty making decisions, because every time they can think of 20 different options to choose from." There is luxury and peace in forgetting, sometimes; it literally clears the mind, allows us to focus on the general rather than the specific and immediate evidence in front of us. Maybe it even makes room for reflection on questions like when better is not necessarily good.

--Reported by David Bjerklie and Emily Mitchell/New York, J. Madeleine Nash/Chicago and Dick Thompson/Washington

-QUOT-

"Every parent is going to want this. But who will have access to it?"

"There's a reason the brain has evolved to forget certain things." --Dr. Robert Malenka

Article 2

Don't look for the southern French town of Montredon on your globe. It isn't even on local road maps, perhaps because it has only 20 inhabitants. But one of them, a Parisian intellectual turned activist-farmer named Jose Bove, may change that. He's the leader of the mobs of farmers who've trashed several McDonald's in France lately. Last week, with 200 supporters chanting outside the jail, Bove declined a Montpellier court's offer of bail and remained behind bars, the better to spotlight his cause. And that would be? "To fight against globalization and advance the right of people to eat as they see fit," he explained.

Grievance No. 1: the U.S. desire to export genetically modified crops and foods. So far, so French, right? But spin that same globe to Peoria, Ill., home of U.S. agribusiness giant Archer Daniels Midland. There, even as Bove's judges readied their decision, the self-styled "supermarket to the world" was demonstrating that the customer is, indeed, always right. In a fax to grain elevators throughout the Midwest, ADM told its suppliers that they should start segregating their genetically modified crops from conventional ones, because that's what foreign buyers want. It didn't matter that GM crops are widely grown by U.S. farmers, and that there's no evidence that the taco chips and soda you're enjoying right now are anything worse than fattening.

ADM had noticed something new sprouting under the bright, warm sun of economic interdependence: a strange hybrid of cultural and economic fears. So it decided to act before the problem got any bigger. Public opposition to GM foods in Europe has been mounting for more than two years, especially in Britain and France. Both Prince Charles and Paul McCartney have come out against the stuff. Now the protests and the tabloid headlines about "Frankenstein Foods" have reached such a pitch that they're reverberating across the Atlantic. Secretary of Agriculture Dan Glickman, a longtime backer of biotechnology, admitted as much in a key speech in July. So did Heinz and Gerber when they announced the same month that they'll go to the considerable trouble of making their baby foods free of genetically modified organisms.

Groups such as Greenpeace, which have long fought biotech on both continents, are crowing. U.S. trade officials, who face a tough fight keeping markets open for American agricultural products, are worrying. And U.S. consumers, who have never really thought much about genetically modified foods, are just plain confused. As well they might be, given the vastly different experiences the United States and Europe have had. In the United States, the FDA issued a key ruling in 1992 that brought foods containing GM ingredients to market quickly, and without labels. Companies such as Monsanto introduced herbicide-resistant soybeans and corn that makes its own insecticide. U.S. farmers loved the products; by 1998, 40 percent of America's corn crop and 45 percent of its soybeans were genetically modified.

In Europe, meanwhile, there was no real central regulator to green-light the technology and allay public concerns, and many more small farmers for whom biotech represented not an opportunity but a threat. Leaders have tried to steer a course between encouraging a new industry and giving the voters what they want, including labeling rules. So, to each his own, right? Not in 1999. If Europe is selling America Chanel perfume and Land Rovers, America will want to sell Europe its soybeans and corn--and maybe even its fervent faith in progress. While European biotech companies such as Novartis avoided the limelight, St. Louis-based Monsanto decided to press its case. The timing was terrible. GM fears were already running high last summer when Monsanto ran an informational campaign; Britain's 1996 bout with mad-cow disease, though unrelated, had weakened European confidence in regulators and industrial-strength agriculture.

Monsanto's PR effort only made the mood worse, as have a string of bad-news food headlines since then: dioxin-contaminated chicken in Belgium last spring; tainted Coke in Belgium and France this summer, and a punitive U.S. tariff on imports of foie gras and other products, imposed in July because Europe won't accept American hormone-fed beef. That last, also nongenetic, dispute actually triggered the vandalism at McDonald's last month. But to many of France's famously irascible small farmers, it's all of a piece. Even among the broader public in France and Britain, the GM-foods issue seems to be intersecting with second thoughts about globalization. French farmers protest American imperialism. But just last week their biggest customers, grocery giants Carrefour and Promodes, announced a $16.5 billion merger that will position them well in a global battle with America's Wal-Mart--and put further cost pressures on farmers.

Britain is a hotbed for Internet start-ups. But Brits still tune in to the BBC radio soap "The Archers" to see if young Tommy will go to jail for helping a group of eco-warriors wreck a GM-crop trial site on his uncle's land. Would an American jury let Tommy go? Probably not. Consumers Union, whose Consumer Reports magazine features a big piece on GM foods this month, has put together an array of poll data suggesting Americans would like to see GM food labeled, but remain interested in its benefits. Of course, if Tommy's trial were held in Berkeley, Calif., where the school board has announced a ban on GM foods, he might walk.

U.S. activists, encouraged by the successes of their European brethren, hope to build on such sentiments. Some of the rhetoric is extreme, and one group--or perhaps it's just one person--has resorted to vandalism, trashing a test-bed of GM corn at the University of Maine last month and crediting the act to "Seeds of Resistance." But there's science going on, too. A Cornell University study published in the journal Nature in May found that half of a group of monarch-butterfly caterpillars that ate the pollen of insecticide-producing Bt corn died after four days. What if the pollen spreads to the milkweed the monarchs lay their eggs in? "The arguments aren't enough to say we shouldn't have any biotechnology," says Rebecca Goldburg of the Environmental Defense Fund. "But they are enough to say we should be looking before we leap." Of course we should, says Gordon Conway, president of the Rockefeller Foundation and an agricultural ecologist. Invited to speak to the Monsanto board in June, he used the forum to talk about the need to go a little slower. But, he adds, don't worry about the monarch. Bioengineers can stop the pesticide (which is supposed to kill caterpillars; they eat the corn) from being expressed in pollen. "There are always problems in the first generation of a new technology," he says. And, he adds, successes.

The foundation just unveiled a genetically modified rice grain it funded to improve nutrition in the developing world. If a shouting match over GM foods should derail such not-for-profit efforts, he says, "that would be a tragedy." Agriculture Secretary Glickman doesn't see Americans growing as fearful as Europeans, mainly because he thinks Americans have more faith in their regulators. He also thinks that labeling of GM foods is a big part of the answer--not mandatory labeling, which industry opposes and activists demand, but voluntary labeling. "I'm not going to mandate this from national government level," he told News-week, "but I believe that more and more companies are going to find that some sort of labeling is in their own best interest." Especially companies that want to export.

Because, as ADM showed with its heartland-stopping announcement on Thursday, it isn't only up to Americans anymore. Brian Kemp, a Sibley, Iowa, farmer, made an urgent call to his elevator on Thursday to see if it would still buy his GM corn. It will--this year. "Europe is so important to the industry that it could mean we'll really have to pull back on growing GM crops in this country," says Walt Fehr, head of Iowa State University's biotech department. "Given the choice, who wants to grow GM?" Glickman says the trade issue--which is sure to generate plenty of heat at the November World Trade Organization meeting in Seattle--will be a tough one to resolve. "But I think over the next five years or so we can get it done." That's a mighty slow pace, considering how quickly the industry came along in the previous half decade. But then, you generally do travel faster when you travel alone. With John Barry in Washington, Scott Johnson in Montpellier, Jay Wagner in Des Moines, William Underhill in London and Elizabeth Angell in New York Mag.Coll.: 100A0624

Organic Gardening, Sept 1999 v46 i5 p16

Article 3

According to a growing number of studies that have been conducted around the world. In Canada, the herbicide 2,4-D was found in rainfall at levels that could harm plants. And Swiss scientists have shown that much of Europe's rainwater is so contaminated with pesticides that it would be illegal to use as drinking water. Don't believe it? Full details on the Swiss research are available in the Summer 1999 issue of the journal Analytical Chemistry.

An international committee has found that use of Monsanto's genetically engineered bovine growth hormone (rBGH) may produce chemicals in cows' milk that could cause breast or prostate cancer in humans who drink the milk, as well as reproductive disorders and other diseases in treated cows. Canadian health officials have refused to recommend approval of the hormone injections, recognizing that more long-term research is needed to assure the hormone's safety. Meanwhile, millions of U.S. consumers are unknowingly drinking milk from cows treated with rBGH, which was approved several years ago in a controversial decision made by the U.S. Food and

Drug Administration.

Genetically engineered (GE) corn pollen contains a toxin that can poison the caterpillars of monarch butterflies, according to a new study from Cornell University.

Millions of acres of corn and other GE crops are now being grown in the United States, but their use is still heavily restricted in most other countries.

The U.S. Department of Agriculture has dropped a policy that had barred organic-meat producers from using the term organic on their products. Look for certified-organic

meats and poultry in stores soon.

Ninety percent of all nonorganic beef raised in the United States contains up to six growth hormones that are banned in Europe because of health concerns. At least one of those hormones, 17 beta-oestradiol, is considered "a complete carcinogen," the European Union's Scientific Committee on Veterinary Measures reported. And all of the banned hormones "may cause a variety of health problems, including cancer, developmental problems, harm to immune systems, and brain disease." The 139-page report added: "Even exposure to small levels of residues in meat and meat products carries risks."

U.S. Secretary of Agriculture Dan Glickman dismissed the panel's concerns as "unsubstantiated." But Samuel Epstein, M.D., a professor of environmental medicine at the University of Illinois, told the Los Angeles Times, "The question we ought to be asking is not why Europe won't buy our hormone-treated meat, but why we allow beef from hormone-treated cattle to be sold to American and Canadian consumers." We've been wondering the same thing. To learn more about this issue, see the Campaign for Food Safety News (item number 19) at www.purefood.org.

Organic groceries and suppliers across Europe were hustling to keep up with soaring demand this summer, after cancer-causing dioxin was found to be widely spread through the nonorganic Belgian food chain. The contamination occurred when fat tainted with dioxin--a by-product of the manufacture of some chemical herbicides and pesticides--was used to make animal feed. According to The Associated Press, initial tests showed that dioxin levels in some chickens were 1,000 times the accepted limit. The poisoned feed also spread to beef cattle and pig farms, and recalled foods eventually included such items as waffles, pork chops, and ice cream.

The British Medical Association has called for the government to require that all genetically engineered (GE) foods be labeled so that consumers can make informed choices, especially until the foods can be proved safe. Britain's chief medical and science officers have called for a special committee to study whether GE foods could cause birth defects, cancer, or immune-system damage. Michael Antoniou, a scientist at Guy's Hospital in London, warned: "Each genetic engineering event holds its own dangers. You could have acute toxicity or something that sneaks up over many years. Any of these things are possible." Meanwhile, a group of government scientists in Britain has issued a warning that some genetically altered plants could unleash antibiotic-resistant strains of meningitis and gonorrhea on the human population. The scientists are looking at modified genes that are already in use on some biotech corn and cotton crops. The genes have proved resistant to antibiotic treatment, and scientists fear that resistance could be transferred to people, rendering established medical treatments ineffective.

The Orkin Exterminating Company has been ordered to pay $2 million to a Florida couple whose home was sprayed in 1993 with the toxic pesticide chlordane. The house was condemned by health officials because of the contamination, according to the Tampa Tribune. Chlordane is a highly toxic and persistent organochloride insecticide that can affect nerve, reproductive, and immune systems. It was widely used in the United States from 1948 until 1988, when it was banned from use on food crops. It has continued to be used in and around homes, and a 1998 study of yard-waste composts found chlordane residues in every sample.

Giant agribusinesses manufacture and market more than 95 percent of the food in the United States, and they also control more than 80 percent of the land around the world that is cultivated for export crops, according to The , Green Guide, the newsletter of Mothers & Others for a Livable Planet. The good news is that organic farming practices continue to grow worldwide.

Corporations are trying to mislead consumers into believing household pesticides are

harmless, according to Marion Moses, M.D., director of the Pesticide Education Center in San Francisco. Take Raid insecticides, marketed by S.C. Johnson Corporation for killing roaches and ants, for example. Dr. Moses points out that the largest words on the Raid label read, "Made With Pyrethrins: Pyrethrin Insecticide Is Made From Flowers." This sounds reassuring, but the fine print reveals that pyrethrins make up only a tiny amount of the product (.08 percent). The dominant active ingredient is actually the controversial pesticide Dursban (.24 percent). In addition, more than 98 percent of Raid's ingredients are so-called inert ingredients, which do not even have to be identified on the label.

Article 4

Dept. of Energy researchers are taking a new approach to plants as pharmaceutical components. They are genetically modifying plants to produce human blood proteins and tissue growth agents.

Researchers at Pacific Northwest National Laboratory, Richland, Wash. (509-375-2561), are using genetic engineering technology to transplant applicable human genes into tobacco plants and produce blood factors. So far, they have produced two blood factors that are used to treat most patients with blood clotting disorders. The first, coagulation factor VIII, is critical to hemophilia therapies. The second, factor XIII and a substance called thrombin, are clotting enzymes that aid in healing wounds and offer an alternative to sutures and other surgical sealants.

Using plants to produce human blood proteins eliminates the possibilities of transmitting disease during lifesaving treatments such as blood transfusions.

PNNL researchers are using a similar technique to grow valuable industrial enzymes in non-edible portions of common agricultural crops. They developed a method to get the desired proteins to express or grow in specific areas of a plant. This can result in two profitable crops in one plant. For instance, potatoes could produce food and cellulases, which are used to produce ethanol.

Article 5

W. Wick and colleagues from the University of Tubingen, Germany, noted that the tumor suppressor gene PTEN (MMAC1, TEP1) encodes a dual-specificity phosphatase and is considered a progression-associated target of genetic alterations in human gliomas. Further analysis revealed that gene transfer of PTEN has therapeutic potential. Results were reported in the journal Oncogene ("PTEN Gene Transfer in Human Malignant Glioma: Sensitization to Irradiation and CD95L-Induced Apoptosis," Oncogene, July 8, 1999;18(27):3936-3943).

"Recently, it has been reported that the introduction of wild type PTEN into glioma cells containing endogenous mutant PTEN alleles (U87MC;, LN-308), but not in those which retain wild-type PTEN (LN-18, LN-229), causes growth suppression and inhibits cellular migration, spreading and focal adhesion," wrote Wick et al. "Here, we show that PTEN gene transfer has no effect on the chemosensitivity of the four cell lines."

Further, upon a correlational analysis of the endogenous PTEN status of 12 human glioma cell lines with their sensitivity to seven different cancer chemotherapy drugs, the researchers found no link between PTEN and chemosensitivity. In contrast, they found that ectopic expression of wild-type PTEN, but not the PTENG129 mutant, in PTEN-mutant gliomas markedly sensitized those cells to irradiation and to CD95-ligand

(CD95L)-induced apoptosis.

According to the researchers, PTEN-mediated facilitation of CD95L-induced apoptosis is associated with enhanced CD95L-evoked caspase 3 activity. They noted that protei kinase B (PKB/Akt), which has previously been shown to inhibit CD95L-induced apoptosis in nonglial COS7 cells, is inactivated by dephosphorylation.

Interestingly, noted the researchers, both PTEN-mutant U87MG and PTEN-wild-type LN-229 cells contain phosphorylated PKB constitutively. They demonstrated that wild-type PTEN gene transfer promotes dephosphorylation of PKB specifically in U87MG cell but not in LN-229 cells. Further, sensitization of U87NG cells to CD95L-apoptosis by wild-type PTEN could be blocked by insulin-like growth factor-1 (IGF-1).

The protection by IGF-1 could be inhibited by the phosphoinositide 3-OH (PI 3) kinase inhibitor, wort-mannin, the researchers found. Although PKB is a downstream target of PI 3 kinase, they found that the protection by IGF-1 was not associated with the reconstitution of PKB phosphorylation.

"Thus, PTEN may sensitize human malignant glioma cells to CD95L-induced apoptosis in a PI 3 kinase-dependent manner that may not require PKB phosphorylation,"

concluded Wick et al.

The corresponding author for this study is M. Weller, University Tubingen, Department Neurology, Hoppe Seyler Str 3, D-72076 Tubingen, Germany.

Article 6

continue to be significant, such as a death

rate of almost 50% for cloned

AFTER THE CIRCUS PROcession of cloned sheep, cows, mice, and goats in the past couple years, humans seemed likely to join the list soon. Now this sobering news: A cloned calf in France dropped dead seven weeks

after its birth.

The calf appeared healthy until days before her death; then she developed severe anemia and collapsed. An autopsy revealed a withered thymus gland, where white blood cells mature, suggesting that her immune system never started working. Jean-Paul Renard of the National Institute for Agronomic Research in Jouy-enJosas, who cloned her, thinks a defective donor cell might be at fault. He points out that the cloning process can work fine--other clones produced with his technique are thriving--but concedes that 30 to 50 percent of cloned calves die shortly before and immediately after birth. "If we want to apply this technique outside of research," he says, "such a high rate of abortion and mortality will not be acceptable."

Failure is actually the norm in the cloning business. Ryuzo Yanagimachi at the University of Hawaii has had perhaps the greatest success, producing five generations of cloned mice. Recently he created the first male clone, also a mouse. Yet Yanagimachi and his team had to transplant 274 embryos just to produce three live male mice, two of which died almost immediately That's not much of an improvement over the 276 failures that preceded Dolly the sheep, the first mammal clone.

There are other signs of trouble. The cloned mice were born with mild breathing problems. More disturbing is that Dolly's chromosomes are worn down at the edges,

possibly showing signs of premature aging. It is not clear if she will die early For now, she appears healthy and has given birth to four lambs, also doing fine. But Margaret

Mellon of the Washington, D.C.-based Union of Concerned Scientists warns: "There are many things that could be seriously wrong with her that would be very difficult to detect."

Article 7

A gene has been identified that allows plants to detoxify heavy metals that are hazardous to human health and the environment, according to newly published research.

It is not a new discovery that plants produce peptides called phytochelatins that naturally bind and detoxify dangerous toxic metals such as lead, mercury and cadmium. Phytochelatins mediate the accumulation of the bonded peptide-metal mix in the leaves of the plant, where they can be safely harvested. Researchers have known and publicized that fact for years.

Low-tech cleanup methods such as mustard plants can suck up toxins. And poplars, willows and cottonwoods can help prevent contamination of water resources and encourage the growth of natural soil bacteria that decompose poolutants.

Now, however, according to the article in the June 15 issue of the European Molecular Biology Organization Journal, researchers from the University of California at San Diego have identified the gene family responsible for producing phytochelatins: phytochelatins synthase, or PCS. They hope to repeat and duplicate its naturally cleansing mechanisms to help clean up places like Superfund sites and certain brownfields.

"We initially identified a PCS gene from wheat roots, but by looking into genome databases, we found a sequence similar to PCS in the mustard plant Arabidopsis," said university biologist Julian Schroeder, quoted in an article by the Environmental News Network. "We then tested the gene in Arabidopsis and, sure enough, it also detoxified the hazardous metal cadmium."

The researchers further used genome databases to successfully locate a PCS homologous sequence in a yeast species, called S. pombe. When the PCS gene was deleted from the genome of S. pombe, yeast growth was much more sensitive to cadmium. Much to their surprise, the investigation also turned up a similar sequence in the genome of a worm, indicating that certain animals might also use PCS genes for detoxification of hazardous metals. Researchers have sought the identities of gene families such as PCS in an effort to ability of plants to detoxify metals at hazardous waste sites, a process known as bioremediation.

Of the 10 leading Superfund toxic site contaminants, four are metals that interact with phytochelatins: lead, arsenic, mercury and cadmium.

"I believe that this gene, together with other genes that help detoxify metals in plants, will optimize the removal of metals in the future," Schroeder said.

"You will never remove the metals completely out of hazardous waste sites, but these genes can dramatically bring down the levels of toxicity, hopefully to below hazard levels determined by the EPA, which will reduce the health and environmental risks at these sites."

Article 8

Peter Lachmann; Alan D B Malcom; Carl

B Feldbaum; H Schellekens; Eric

Brunner; Erik Millstone.

Sir--It is profoundly depressing to follow the public debate on genetically modified (GM) crops. As the passion of the arguments increase, their scientific content diminishes correspondingly. It is a sad day for UK medicine when first the BMA and then The Lancet, in your May 29 editorial,(1) align themselves with the tabloid press in opposition to the Royal Society and the Nuffield Council on Bioethics. It is also disturbing and unusual for

an editorial in The Lancet to be factually so inaccurate.

I imagine the first paragraph refers to maize made resistant to stem boring insects. This crop is not sterile and there is no difficulty in planting the GM seeds. The "Gene Use

Restriction Technology", called the "terminator gene" by the press is so far merely a patent claim and has not yet been produced. This device to prevent the formation of fertile seed from a GM crop, would also prevent the spread of the inserted gene to other plants. Surprisingly, this idea has found no favour with the opponents of GM organisms who concentrate entirely on the rights of the farmer to save seed.

Farmers currently have to use new seed with the conventionally bred F1-hybrid crops that are increasingly used worldwide, because F1-hybrid seeds do not produce F1 progeny. Their yield is so much higher that, in many cropping systems, F1-hybrids are highly advantageous.

There is no experimntal evidence nor any plausible mechanism by which the process of genetic modification can make plants hazardous to human beings. Individual introduced genes may not be a great idea. For example, the use of a nut protein to enhance the protein content of a cereal may be a hazard to people who are allergic to nuts, but this danger would be the same if the nut protein were simply added to the cereal. The practice of leaving antibiotic-resistant markers in the GM plant has attracted criticism from the Royal Society among others since there is a hypothetical risk that antibiotic resistance could spread o gut flora.

The Scottish Crop Research Institute initiated an entirely sensible study to see whether lectins which make some plants unpalatable to insects could be introduced into other plants for the same purpose. The study used potatoes only to make the experimentation easier. These particular potatoes were never intended to be developed as a food crop. Some assessment of the transgenic pota-toes was made at the Rowett Institute. One of their scientists announced on television last autumn that feeding thes transgenic potatoes to rats had caused abnormalities of organ growth and had damaged their immune systems. These remarks were seized upon by the tabloid press and engendered an hysterical reaction that has not died down. The Royal Society produced a careful peer review of all the avilable data on this work and concluded that the experi-ments were badly designed, poorly carried out, and inaccurately inter-preted. Your editorial's comment that it is impertinent of the Royal Society to review the data because they may not be in their final form is incomprehensible. A scientist invites expert scrutiny by making his work public through the media and the worldwide web.

One reason for welcoming GM technology is that intensive agriculture, on which the world's food supply now depends, is in the long term both unsustainable and potentially harmful. It is unsustainable because it relies on the consumption of fossil fuels and consumes more energy than the food produces. The high levels of nitrogen and phosphate fertilisers used are a potential hazard to human health when these ions appe

ar in the water supply. There are also potential concerns about the residues of pesticides and herbicides. Any technology that may enable better yields to be obtained with less external input should be welcomed.

It is also an illusion that there ever was a time when the food supply was entirely safe. All those who, in previous centuries, died of ergot poisoning and those who still develop liver disease from aflatoxin in their food are forgotten, especially by the enthusiasts for organic farming. Bacterial food poisoning always was a serious problem.

It is wrong to regard the introduction of resistance to insects or herbicides as the only long-term goals of genetic manipulation. This is the "horse-less carriage" stage of development of this new technology. Looking rather further into the future, other goals include developing plants that can grow in saline-polluted soil, a major issue in some parts of the world. Similarly, it may be possible to develop plants that need less water input. Finally, there is the pros-pect of developing plants with an in-creased efficiency of the photosynthetic process itself. If this efficiency could be increased several fold agriculture would be able to meet not just the food but also the energy

needs of the world.

The attempt of single interest groups, supported by the tabloid press and now by others who should know better, to declare this whole technology as dangerous and immoral is sad for the UK, but is also absurd. 300 million Americans and a billion Chinese eat genetically modified food with neither ill effects nor hysteria. On the world scale, what happens in the UK may not be of overwhelming importance. However, what this campaign of vilification does to the science base and the prosperity

of the UK may be serious.

Peter Lachmann

UK

Sir--Your editorial(1) on genetically modified (GM) crops would never have passed the rigorous refereeing which you normally use for the contents of the rest of your journal. Of course the motive behind the commercial production of anything is added shareholder value. No farmer is compelled to buy any seed from any company They can always continue to use traditional crops if they feel it is to their benefit. Farmers are just as driven by the profit motive as anybody else, whether in developing countries or not. There are many parts of India where cotton farmers have gone bankrupt through insect depredation, whereas North American cotton growers are now able to guarantee increased yields of cotton accompanied by a 70% reduction of chemical-based insecticides.

Although antibiotic-resistance markers are used for some plant biotechnology products to "select" for the presence of a desired trait, the antibiotic markers in these products were selected on the basis of their frequent occurrence in nature, their efficacy as a marker, and the limited clinical importance of the antibiotics which they inactivate. The potential effect on human health of these markers is carefully evaluated during the safety assessment regulatory review process in the UK and other countries. Further, it is recognised that the increased frequency of bacterial resistance to antibiotics is mainly attributable to the widespread use and misuse of antibiotics in human and veterinary applications, not to genetically modified crops. Experts and regulatory bodies that have assessed the probability that antibiotic markers used in genetically modified plants will impact antibiotic efficacy have concluded that this likelihood is remote. Nonetheless, alternative markers should be and are being developed for use in future genetically modified crops.

It is unusual for the Royal Society to take a judgment on an independent scientist's unpublished data. Unfortunately, it was clear that the mythology surrounding these experiments was having a major impact on public perception of this technology. Although the data were not refereed by the usual channels, they had been made available to the world via the internet. It was therefore perfectly appropriate that any scientist or group of scientists should comment on the false conclusions being drawn.

The British Medical Association did not need to recommend a moratorium on the commercial planting of GM crops. Such a moratorium already exists. No permission for commercial planting has been given nor will it be given until ACRE is satisfied on the various issues which have been widely discussed.

Of course the Government should take an interest in any possible health risks associated with any new food and indeed this is exactly the role which the Advisory Committee on Novel Foods and Processes takes. Nobody, however, has been able to identify any potential health risk associated with consumption of lecithin, or soya oil, or soya starch obtained from a GM crop, compared with traditional crop. In the absence of any

hypothesis, the design of a sensible experiment is impossible.

It is not true that the population of the USA had been eating genetically modified ingredients. The ingredients they have been eating have not been modified in any way whatsoever. It is the crops from which the ingredients were derived that have been modified. There has not been one example of any identifiable medical condition induced in the 250000000 Americans who have consumed such material during the past 3 years.

Alan D B Malcom

Institute of Biology, 20 Queensberry Place, London SW7

2DZ, UK

Sir--Your May 29 editorial(1) misleads readers by saying biotechnology companies and government officials "have paid little evident attention to the potential hazards to health of genetically modified foods". You ignore thousands of scientific studies, environmental risk assessments, and the field trials undertaken worldwide before the com-mercial introduction of transgenic crops.

Before the approval of the first transgenic Bacillus thuringiensis (BT) corn in the USA, the Department of Agriculture (USDA) conducted an environmental assessment in 1995 that analysed data on risks to insects beneficial to agriculture and other non-target insects as risks to endangered organisms--from bobwhite quail to certain species of butterflies. Tests to find out if endangered aquatic organisms were threatened examined

the impact of BT corn pollen blown into water. The USDA concluded the data showed no significant potential to adversely affect organisms other than the targeted pest

that destroys corn.

Scientific inquiry, however, has not ended there. Researchers continued to examine transgenic corn, such as scientists who explored the impact on beetles, flower bugs, and lacewings, all of which feed on corn borers. These predators also eat corn pollen. In a paper published in April 1997, the researchers reported they found no detrimental effects on the beneficial insects. In fact, they observed more of them in BT corn fields than in non-BT corn fields.(2)

As for the safety of transgenic corn and other biotech crops in food, the US Food and Drug Administration (FDA) undertook its own exhaustive studies and concluded in 1992 and again in 1995, "It is not aware of information that would distinguish genetically engineered foods as a class from foods developed through other methods of plant breeding".(3) The fact is, the FDA observed, because recombinant DNA techniques are used to introduce only one or a few genes into a crop, agricultural scientists avoid a major difficulty of conventional cross hybridisation, which is the multiple introduction of undesirable genes.

Results of all studies by the USDA, FDA, and the Environmental Protection Agency--the three US agencies charged with monitoring biotech crops and foods--are produced with public input and available for perusal when completed.

A 1996 report from the Food and Agricultural Organisation of the United Nations and WHO also explored in depth the safety of foods derived from biotech crops. Those two groups concluded: "Food safety considerations regarding organisms produced by techniques that change the heritable traits of an organism, such as recom-binant DNA technology, are basically of the same nature as those that might arise from other ways of altering the genome of an organism, such as conventional breeding."(4) The report also noted, "The presence in foods of new and introduced genes per se was not considered to present a unique food safety risk."

It is one thing for The Lancet to urge caution in introducing genetically modified foods. Everyone agrees continued vigilance is necessary. It is an egregious error however, for you to imply potential health hazards have been overlooked by industry and regulatory agencies. In doing so, it dismisses decades of dedicated scientific work that clearly proves otherwise.

Carl B Feldbaum

20006, USA

Lancet 1999; 353: 1811.

(2) Pilcher CD, Obrycki JJ, Rice ME, Lewis LC. Preimaginal development, survival, and field abundance on insect predators on transgenic Bacillus thuringiensis corn. Environmental Entomology April 1997; Vol. 26, no 2, 446-54.

(3) FDA's policy for foods developed by biotechnology contained in the proceedings of the American Chemical Society Symposium, series no. 605, 1995, by Maryanski JH, Strategic Manager for Biotechnology. Centre for Food Safety and Applied Nutrition, FDA.

(4) Biotechnology and food safety, report of a joint consultation of the food and agricultural organisation of the United Nations and WHO, Rome, Italy, 30 September to 4 October 1996.

Sir--As chairman of the Dutch Committee on Genetic Modification (COGEM), the main adviser to the government in our country on the safety of genetic modifications, I and others stand accused in your editorial of May 29(1) of badly mishandling important health issues.

The safety of genetic modification is a serious topic and the quality of the decision-making process can only improve by the input from as many sources a possible. However, these contributions should be based on the data collected by the cautious step-by-step approach during the 20 years of genetic modification. Although uncer-tainties remain, there is no reason to ignore the information that is available. Your editorial fails to make a continuing argument against the opinion of the US Food and Drug Administration that genetic modification does not constitute a risk in itself.

Phenotypic characteristics such as the presence of an antibiotic resistance in plants may be considered harmful, but you ignore the reports and other scientific evidence on this topic. It would for example, be interesting to know your reaction to the criteria used by the Dutch COGEM to assess the risks of antibiotic resistance gene in crops. Our approach is based on the assumption that antibiotic resistance may spread from plants to microorganisms.

You also fall short of supporting the moratorium on introduction of genetically modified crops, as advocated by the British Medical Association and other organisations. In my opinion there is at present no rationale for a moratorium. Those who argue in its favour have to formulate the specific reasons why and what they want to achieve. They have to quantify the current risks and to what extent these risks have to be reduced to be acceptable and to terminate the moratorium.

Learned societies and journals, mainly in the UK, seem to have lower scientific standards with regard to the genetic modification of plants than other topics. If the assumption is correct that the reasons for this unbalanced approach lie outside science, there is more at stake than the future of genetic modification of plants.

H Schellekens

Nieuwerk, Netherlands

Sir--Peter Mitchell and Jane Bradbury's May 22 news item (p 1769)(1) reports the Royal Society's judgment that Arpad Puztai's study on the potential toxic effects of genetically modified (GM) potatoes is "flawed in many

aspects of design, execution and analysis and that no conclusions should be drawn from it". The society rightly says that research scientists should expose their new results to peer review before releasing them.

The episode at the Rowett Research Institute highlights just how important the integrity of the peer-review process is to the maintenance of high standards in science. Our experience(1) with trial data on recombinant bovine somatotropin (rBST, an injectable hormone which raises milk yield in dairy cows) suggests that increased vigilance, perhaps through some mechanism of formal audit, may be needed to preserve such standards.

In that case, official regulatory authorities accepted the manufacturer's unpublished analysis. We previously identified the shortcomings in this analysis, and did our own, but we were unable to publish it because the company concerned withheld consent. Here the peer-review process was compromised, partly by the pressures on the existing regulatory process and partly by the requirement for commercial scientists to deliver th product to market. In general, if preapproval studies are not published, any questionable conclusions may go unchallenged. Put another way, if applicants are able to argue successfully that disclosure would cause commercial harm, then peer scrutiny may be restricted.

A process that bears the hallmarks of these difficulties led to the approval of rBST for farm use by the US Food and Drug Administration in 1994. rBST is unlicensed in Canada and the European Union. The company seeking to market this productivity aid gave us data from eight randomised controlled trials. We did a meta-analysis and found evidence for a pro-mastitic effect due to rBST. The report was sent to the company and to a UK peer-review journal. Although our report passed the peer review, the company refused permission for its publication on the basis that the trial investigators would soon submit their own analysis for publication. In the following 3 years, no such report appeared. We resubmitted our paper to a US journal and then to another UK journal. On each occasion the paper received peer approval but could not be published because the company alleged they had copyright over our analysis of their data. We were eventually able to publish our findings as a response to a public accusation of plagiarism by a company representative, but only after FDA approval for rBST had been given.

There is no method of recourse in such situations. We therefore support the recent recommendation contained in the first report of the Commons Select Committee on Science and Technology2 for further openness in the regulatory process in the UK and elsewhere for new foods, with the rapid publication of papers and data (http://www.publications.parliament. the-stationery-office.co.uk/pa/ cm199899/cmselect/cmsctech/286/ 28602.htm; accessed June 10, 1999).(2) This approach would substantially strengthen the peer-review process.

[*] Eric Brunner, Erik Millstone

[*] Department of Epidemiology and Public Health, University College London Medical

School, London WC1E 6BT, UK; and Science Policy Research Unit, Sussex University,

Brighton

(1) Millstone EP, Brunner EJ, White IR. Plagiarism or protecting public health. Nature

1994; 371: 647-48.

(2) House of Commons Select Committee on Science and Technology. Scientific Advisory

System: genetically modified foods. First Report of Session 1998-99 (HC 286). London:

HM Stationery Office, 1999.

Article 9

game of evolutionary

one-upmanship, plants and

viruses wrangle over gene

silencing. (includes related article on

gene splicing) Elia T. Ben-Ari.

Abstract: Post-transcriptional gene silencing (PTGS) is a mechanism where cosuppression occurs in plants. Studies showed that PTGS supports an antiviral function and that viruses that support nucleic acid sequences homologous to transgenes can promote the silencing of genes.

In a game of evolutionary one-upmanship, plants and viruses wrangle over gene silencing

In a way, it started with petunias. In the late 1980s, plant geneticist Richard Jorgensen and his colleagues at DNA Plant Technologies, in Oakland, California, were attempting to create petunias with more deeply colored flowers by over-expressing the gene coding for chalcone synthase, an enzyme that plays a key role in producing the pigment protein anthocyanin. Because chalcone synthase was known to control the rate of anthocyanin synthesis in purple corn seeds, the researchers reasoned that boosting the levels of chalcone synthase in petunia flowers might lead to increased amounts of anthocyanin and thus to flowers of deeper hues.

To try to maximize chalcone synthase expression, Jorgensen, now at the University of Arizona, and his research team created transgenic Petunia hybrida plants containing a "hybrid" chalcone synthase gene. This hybrid gene consisted of the strong promoter region of cauliflower mosaic virus, which drives high expression of downstream genes, hooked up to the petunia chalcone synthase coding sequences. But the result of these genetic engineering efforts, Jorgensen says, "was the opposite of what we intended." Instead of producing deeper purple flowers, many of the transgenic plants had white, pigment-free flowers, and others had flowers with white patterns on a purple background.

The reason for these seemingly paradoxical results? Further experiments showed that, despite the strong promoter, the chalcone synthase transgene was not expressed; moreover, the researchers were surprised to find, the endogenous chalcone synthase gene was also inactivated, or silenced, in the white flower tissues.

Jorgensen coined the term cosuppression to describe the phenomenon in which two or more homologous gene sequences are specifically silenced. Cosuppression has since been observed in many transgenic plants. Research by several groups has shown that, in many of these plants - including the chalcone synthase-transgenic petunias - cosuppression occurs via a mechanism known as post-transcriptional gene silencing, or PTGS, in which silenced genes are still actively transcribed but the resulting messengerNAs are degraded before they can be translated into proteins. Gene silencing due to the presence of multiple homologous nucleic acid sequences can also occur at the transcriptional level (via homology between promoters rather than between transcribed sequences), through a mechanism whereby a gene's promoter is inactivated, preventing transcription.

The detailed mechanisms underlying PTGS remain to be worked out and are the subject of a great deal of investigation and debate (see box page 435). Nevertheless, plant biologists - not only molecular geneticists but also virologists - have learned a great deal

about cosuppression and PTGS in the decade since cosuppression was first reported in petunias.

Presumably, plants did not evolve the ability to silence homologous genes as a means of frustrating the efforts of molecular biologists hoping to create flowers of a deeper hue or improve food crops through transgenic technology. Indeed, a growing body of evidence suggests that the evolution of PTGS may be related, at least in part, to plants' need to defend against viruses.

The first evidence hinting that PTGS might have an antiviral function came from studies by John Lindbo, William Dougherty, and their colleagues at Oregon State University, and subsequent studies by David Baulcombe and his colleagues at The Sainsbury Laboratory, in Norwich, UK. These researchers all showed that viruses can be the targets of gene silencing. For example, if transgenic plants that were exhibiting PTGS were infected with a virus into which nucleic acid sequences homologous to the silenced gene had been inserted, virus accumulation was inhibited. That is, the plants were immune to infection by the virus.

Furthermore, several research groups showed that viruses that contain nucleic acid sequences homologous to transgenes or to endogenous plant genes can trigger silencing of those genes. In one set of experiments, for example, Dougherty and his colleagues infected transgenic tobacco plants expressing all or part of the tobacco etch virus (TEV) coat protein (CP) with TEV. Several weeks after infection, the new stems and leaves that developed in the transgenic plants were virus free. The researchers found that the CP transgene was post-transcriptionally silenced in these "recovered" tissues, which also turned out to be immune to subsequent infection by TEV.

"Those separate sets of observations - that viruses could be targets of gene silencing and [that] viruses could also induce gene silencing - made one think that maybe this wasn't a coincidence," Baulcombe says. These findings led him and others to examine nontransgenic plants for examples of virus resistance that could be accounted for by a gene silencing - like mechanism.

The search paid off, yielding more persuasive evidence that PTGS in plants is involved in natural virus resistance. In 1997, research groups led by Baulcombe and by Simon Covey, at the John Innes Center in Norwich, reported that infecting nontransgenic plants with tomato black ring nepovirus (an RNA virus) or cauliflower mosaic virus (a. DNA pararetrovirus) can trigger a viral resistance mechanism in the plants that resembles transgene-induced gene silencing. However, in contrast to the cosuppression phenomenon, silencing of these viruses occurs even though the viral genomes are not homologous to any host genes.

Just like in transgenic plants infected by certain viruses, virus-infected nontransgenic plants initially showed symptoms of viral infection, but new leaves that developed after systemic infection were symptom-free and largely lacked virus. The accumulation of viral transcripts was greatly reduced in newly developed tissues in the "recovered" plants. Furthermore, Baulcombe's group showed that recovered tissues were resistant to infection by a second virus if that virus contained nucleic acid sequences that were similar to sequences from the first virus. This work extended the early work of plant virologist R. E. F. Matthews, which had shown that "dark green islands" in virus-infected leaves are immune to superinfection by related viruses.

More recently, Frank Ratcliff, in Baulcombe's group, has shown that the ability to induce a PTGS-like defense is not restricted to nepoviruses and pararetroviruses. Other, more frequently studied viruses, such as potato virus X and tobacco rattle virus (the latter being similar to tobacco mosaic virus) are also able to activate this mechanism, and Baulcombe and his colleagues think that most viruses are activators of a PTGS-like defense.

Although these results indicate that plants can use gene silencing to fight viral infection, it turns out that viruses are not entirely passive in the face

of PTGS. Three independent research groups have now reported that plant viruses encode proteins that can suppress post-transcriptional gene silencing.

These reports, from groups led by Vicki Vance, at the University of South Carolina; James Carrington, at Washington State University; and Baulcombe (and published, respectively, in Proceedings of the National Academy of Sciences 95: 13079-13084; Cell 95: 461-470; and EMBO Journal 17:6739-6746) - and the discovery of other silencing suppressors yet to be reported in the literature-lend further credence to the hypothesis that PTGS is a natural antiviral defense mechanism in plants. "You can postulate that the reason [viruses make these suppressors of silencing] is that the silencing response is likely an antiviral response" and that the production of silencing suppressors by viruses "serves as an effective counter-defensive mechanism," Carrington says. In this sense, he and Kristin Kasschau noted in their Cell article, "plant viruses join their animal-infecting counterparts in being promoters of their own infection through suppression of innate or adaptive host responses."

All three research groups provided evidence that a protein known as viral helper component-proteinase (HC-Pro), which is made by a family of plant RNA viruses known as potyviruses, suppresses PTGS in plants infected with these viruses. In particular, they found that HC-Pro can reverse existing transgene-induced gene silencing and prevent virus-induced silencing in tobacco (Nicotiana tabacum) and Nicotiana benthamiana.

Like many other viral proteins, HC-Pro has multiple functions. Results of earlier studies showed that HC-Pro aids in viral spread and replication. For example, studies by Carrington's lab showed that HC-Pro is necessary for long-distance movement of TEV, a potyvirus, through a plant's vascular system. Studies by Carrington and others also showed that HC-Pro allows TEV to continue replicating in plant cells for relatively long periods of time. By contrast, "in the absence of functional HC-Pro, the plant appears to mount an effective defense response that shuts off [replication of] the virus after a relatively short period of time," Carrington says. The latter finding, he says, suggested that perhaps HC-Pro was not stimulating replication and spread of the virus directly but rather was exerting an indirect effect by suppressing some type of plant defense response.

Strong support for this hypothesis was provided by work from Vance's lab and from collaborations between Vance and Carrington. This work showed that when the HC-Pro coding sequence from TEV was inserted into the genome of a virus that does not encode HC-Pro, that virus was able to replicate for a longer period of time than normal.

Moreover, HC-Pro was found to be responsible for the ability of TEV and other potyviruses to mediate a phenomenon known as synergistic viral disease (or synergistic viral infection). In synergistic viral disease, plants infected with TEV together with an unrelated virus develop much more severe symptoms than plants inoculated with either virus alone. The ability of HC-Pro to suppress PTGS, thereby limiting the general plant defense response, could explain this protein's facilitation of the replication and spread of other viruses in synergistic viral infection.

Baulcombe's group also reported that a second viral protein known to stimulate long-distance movement of viruses in plants acts as a silencing suppressor in N. benthamiana. This protein, the 2b protein from cucumber mosaic virus (which is a cucumovirus), is smaller than HC-Pro and has no sequence similarity to it, and it appears to work by a completely different mechanism. "HC-Pro is able to reverse silencing wherever it's happened, whereas 2b is only able to reverse silencing in the leaves that emerge from the growing point of the plant after the virus starts spreading," Baulcombe says. These findings suggest that, whereas HC-Pro blocks a reversible step in the gene silencing mechanism, the 2b protein blocks an irreversible step.

Carrington notes that the ability of the 2b protein to suppress silencing only in newly developing plant tissues suggests that it may inhibit a systemic signaling mechanism that mediates the spread of gene silencing throughout a plant (see box page 436). By contrast, HC-Pro seems to act at an earlier stage in the establishment of PTGS. For instance, it might interact with a component of the silencing apparatus or with some cellular factor that in turn regulates a component of the silencing machinery.

Silencing suppressors have now been found in several different viruses, and Carrington suspects that "most viruses probably have ways to deal with the silencing response in at least certain hosts." Indeed, he notes, one reason for the limited host range of certain plant viruses may be that a particular silencing suppressor may be effective only in certain plant species.

The finding that HC-Pro enables viruses to suppress PTGS points to an apparent paradox: The first experiments (by Dougherty's lab) demonstrating the ability of silenced transgenes to confer immunity against viruses containing homologous gene sequences and the ability of transgenic plants to "recover" after viral infection through a mechanism involving PTGS were done with TEV - the very same virus in which the HC-Pro silencing suppressor was discovered.

So if the virus produces HC-Pro, how can plants silence the virus? Conversely, if the plant silences the virus, how can enough HC-Pro accumulate to suppress silencing? One possible explanation, Baulcombe says, "is that you get some activation of silencing by the virus, even though it produces the suppressor." Perhaps a signal (see box page 436) carries the silencing response from cell to cell through the plant ahead of the advancing front of viral infection, he says, "so the gene silencing is basically switched on before the virus gets into those cells, and then as a result of the silencing the ability of the virus to accumulate - the ability of the virus to produce the suppressor of silencing - is compromised."

In essence, it seems that plants and viruses are engaged in a sort of tug-of-war, in which the balance between gene silencing and suppression of silencing can shift back and forth. "You can think of [silencing] as a sort of basal defense mechanism against viruses," Baulcombe says. "If the gene silencing mechanism didn't exist...then the virus would just go through the roof and kill its host."

Indeed, Baulcombe's group found that when they inserted a gene coding for HC-Pro or 2b into a virus that contained a different silencing suppressor gene, "these viruses killed the infected plant quite rapidly and spectacularly," he says. And Baulcombe notes that killing the host would not be advantageous for a parasitic organism such as a virus, "because what the virus needs to do is to spread within a plant and also hang out in the plant" until the opportunity to infect another plant comes along.

The discovery of viral suppressors of gene silencing opens new doors for plant biologists. For one thing, plant geneticists may be able to use HC-Pro to prevent gene silencing in transgenic plants, thereby ensuring that transgenes are expressed at high levels. Conversely, researchers might exploit newfound knowledge about the mechanisms of silencing suppression to deliberately silence specific genes.

The silencing suppressor proteins will also be useful in dissecting the mechanism responsible for the plant silencing response. If researchers can identify cellular factors that interact with, or bind to, HC-Pro or 2b, they will almost certainly uncover key components in the PTGS pathway. Identifying these components should shed some light on the mechanisms involved in the silencing response. But to gain further insights into the mechanistic details of PTGS, Carrington notes, "we need genetics to come through on model systems." For example, he says, "we need silencing-defective mutants, and using those mutants we need to isolate the genes and identify components" of PTGS. Indeed, researchers are actively pursuing this tack, and reports identifying some of these genes have begun to appear.

The finding that PTGS is likely to be part of the "immune system" of plants is "a fundamental shift in how we view plants' response to pathogens," Carrington says. One of the main ways in which gene silencing differs from other plant defense systems is that it is adaptive, he says. In other words, "plants can recognize a new invading virus, they can elicit a specific antiviral response to that viral pathogen, and [they can] therefore suppress it specifically." Although radically different in its mechanism, PTGS in plants is analogous to the mammalian immune system in that it can generate a "customized" defense response to pathogens.

In contrast to gene silencing, Carrington says, other plant defense mechanisms are "carried out by pre-existing components that do not change." For example, wild plants have dozens of resistance, or R, genes, each of which is specific for a given pathotype, or race, of pathogen. "If that particular race lands on a particular plant that has a dominant R gene that can recognize that pathogen, then you have a resistance response...that results in limitation of the pathogen," Carrington says. However, other races of that pathogen would be virulent in the plant.

Although it is becoming clear that PTGS serves as a natural defense mechanism against viruses, some researchers think that plants may use gene silencing as a more general mechanism to regulate the expression of endogenous genes. This hypothesis is still speculative, but the petunia may once again offer researchers some clues. Jorgensen notes that when German plant breeders first created the species Petunia hybrida in the 830s from crosses among wild petunia species from South America, "they produced many of these same flower colors or patterns that we see" in the cosuppressed transgenic petunias. Some of the patterns in these hybrid strains have turned out to result from post-transcriptional silencing of duplicate copies of the chalcone synthase gene in the hybrid plants' genomes. Although Jorgensen points out that this lone example of cosuppression amon endogenous plant genes was produced by breeding, not by natural selection, he says that "certainly if you can have that in a breeding population it can happen in nature."

Whether gene silencing indeed serves a broader gene regulatory purpose in plants remains to be determined. It is interesting to note, however, that gene silencing responses similar to the cosuppression phenomenon in plants have also been reported in fungi and, more recently, in nematodes and fruit flies. If these phenomena turn out to be mechanistically similar to gene silencing in plants. PTGS may ultimately be found to be part of a universal gene regulation system.

Researchers have suggested that post-transcriptional gene silencing (PTGS) can be broken down into three phases: initiation, systemic spread (see also box page 436), and maintenance. Several types of models have been suggested for the initiation phase of gene silencing:

* Threshold models propose that gene silencing is a response to inappropriately high levels of expression of the targeted gene(s). These models suggest that the plant can somehow "sense" the levels of specific RNA species and will activate the silencing response when these levels exceed a certain threshold.

* Aberrant RNA models propose that PTGS is activated by the presence of RNA that is qualitatively "different" from most other RNAs. The nature of these "aberrant" RNAs is also a matter of debate, but they might include double-stranded sequences or truncated sequences resulting from premature termination of transcription.

* Ectopic pairing models suggest that PTGS is triggered by pairing between homologous DNA sequences (e.g., between a transgene and a related endogenous gene) or by DNA-RNA interactions (e.g., between introduced DNA sequences and transcripts in the cytoplasm).

The three types of models are not necessarily mutually exclusive. For example, a threshold of aberrant RNA may be required to trigger silencing, or an ectopic DNA interaction might in turn lead to transcription of aberrant RNA species that elicit the silencing response.

Researchers have discovered that, at least in some cases, cosuppression due to post-transcriptional gene silencing (PTGS) can spread through a plant over significant distances. The results of two studies in particular convincingly demonstrated the systemic spread of gene silencing.

In one set of experiments, Olivier Voinnet and David Baulcombe, of The Sainsbury Laboratory in Norwich, England, studied Nicotiana benthamiana plants that were expressing the green fluorescent protein (GFP) from jellyfish. The GFP gene serves as a "reporter gene" that, when expressed, produces a protein that lends plants a green glow under ultraviolet light. When the researchers infiltrated the lower leaves of the GFP-expressing plants with strains of Agrobacterium designed to deliver a second copy of the GFP gene into the leaves, newly developing leaves far from the infiltrated leaf did not show GFP fluorescence. This loss of fluorescence resulted from the post-transcriptional silencing of the GFP genes. Silencing occurred even though the newly introduced GFP DNA apparently did not enter the silenced leaves.

Voinnet and Baulcombe also found that when they inoculated the GFP-silenced leaves with an RNA virus (potato virus X, or PVX) containing the GFP gene, the virus failed to accumulate in the plant - that is, the plant was resistant to the virus. By contrast, GFP-transgenic plants were not resistant to infection by PVX carrying a different reporter gene. The difference suggests that viral resistance was sequence specific.

In another series of experiments, Jean-Christophe Palauqui, Herve Vaucheret, and colleagues at INRA in Versailles grafted the upper, growing shoots from plants expressing a nitrate reductase transgene (as well as the endogenous nitrate reductase gene) onto the lower parts (stocks) of plants whose endogenous nitrate reductase gene was cosuppressed via PTGS. These researchers found that the nitrate reductase gene in the upper shoots (scions) grafted from the non-silenced plants rapidly became silenced as the scions grew on the cosuppressed stocks. Moreover, transmission of silencing in the grafte plants occurred in a sequence-specific manner. That is silencing occurred only in grafted scions that expressed the nitrate reductase transgene; other transgenes were not affected.

Together, these observations suggest that some type of signaling molecule can transmit silencing throughout a plant. The pattern and timing of the spread of silencing seen in these and subsequent experiments are consistent with a signal that travels over long distances through the plant via the phloem and that moves from cell to cell via the specialized intercellular channels called plasmodesmata. The plasmodesmata may play a role in regulating plant growth and development and physiological function by permitting the selective intercellular trafficking of proteins and their transcripts.

This putative pathway of systemic PTGS signaling is similar to that of viruses. Viruses spread via the use of movement proteins that exploit existing routes for molecular trafficking in plants by allowing viruses to squeeze through the narrow plasmodesmata and thereby move from cell to cell and into the phloem for long-distance transport.

Some researchers have proposed that the as-yet-unidentified silencing signal (which is widely assumed to be an RNA molecule) is carried through the plant by an accessory protein that is analogous to virus-encoded movement proteins. Indeed, William Lucas, at the University of California-Davis, and his colleagues recently reported the cloning of a protein that may turn out to be a plant version of the viral movement proteins, and they hypothesize that one function of this protein, which appears to bind to RNA, could be to mediate the spread of a gene silencing signal in plants. Jorgensen and Lucas postulate that plants may have evolved such movement proteins, which travel the same paths as viruses, to track viruses down and stop their spread by turning on the gene silencing response throughout the plant.

Article 10

The Lancet, May 29, 1999 v353 i9167 p1873

Paul R Billings; Ruth Hubbard; Stuart A

Newman.

Abstract: Genetic manipulation of germ cells should be prohibited. Alterations of the genetic code in sperm cells, ova, and fertilized ova could be used to prevent disease or to induce desired traits. In comparison to gene transfer in other body cells, germ cell modification may produce effects that were not predicted, and may not reveal themselves until the child is grown, or in future generations. Germ cell modification not only influence the single offspring, but create unique DNA that will persist into subsequent generations. Prenatal diagnosis permits specific pregnancies to be evaluated for genetic fitness. Manipulation of germ-cell DNA is unnecessary and potentially dangerous.

Human germline gene modification has been foreseen but not yet accomplished.1-6 It can be defined as the genetic manipulation of human germ cells, or of a conceptus, resulting in inherited changes in DNA. With the development of advanced in-vitro fertilisation (IVF) methods, preimplantation DNA analysis, improved techniques for gene transfer, insertion, or conversion, and of embryo implantation procedures, the technical barriers to such an intervention seem easily surmountable. Unintended changes in DNA may occur when gametes are manipulated or stored.7,8 Inadvertent germline mutations. therefore, may have already occurred as a result of reproductive technologies in current use, such as artificial insemination and IVF. There are unpublished reports that researchers in the USA have already carried out a manipulation involving the exchange of a mitrochondrial genome in an IVF protocol. If true, this human experimentation involving intentional hereditary changes was probably conducted without federal oversight of safety, since there are no discussions of this protocol in the available public record.

Tsukui and colleagues9 used viral vectors in somatic gene therapy protocols to infect mouse eggs in vitro, leading to germline transmission of a transgene in the progeny. Although removal of the zona pellucida is a prerequisite for infection of the eggs in vitro, the early oocytes of postnatal ovaries also lack zonas. These experiments thus raise the possibility that modification of gametes may occur in vivo, and constitute a germline hazard in the 200 or more somatic gene therapy protocols now in use. Any such alterations would be difficult to detect. Intentional or inadvertent germline modifications may pose significant burdens. Although there are restrictions on experimentation that might result in human modifications,10 and opposition to its implementation has been voiced,11-15 some leading scientists and other commentators have begun to advocate the development and application both of techniques that may increase the risk of inadvertent alteration of the germline, and of methods that would alter it deliberately.6,16-18

W French Anderson and his colleagues have developed an experimental protocol for the treatment of adenosine deaminase deficiency during fetal development; although their therapeutic intent is directed towards somatic cells, they acknowledge that the technique may modify germ cells as well. They have submitted this proposal to the National Institutes of Health (NIH) for review (panel). By introducing a genetic construct in utero, which knowingly allows for the alteration of germinal tissue, their attempt at a potentially transmissible correction could be used to erode opposition to germline genetic manipulation since germline modification would be achieved, though unintentionally.

Opposition to germline modification is based on several lines of reasoning.19-22 First, as we have already suggested, germline DNA modifications may affect gene function in ways that are not immediately apparent, so their occurrence may not be recognised for a generation or more-for example, germline introduction in mice of an improperly regulated normal gene resulted in progeny with unaffected development but high tumour incidence during adult life.23 Furthermore, interactions among genes and their products are highly integrated, have been refined over evolutionary time scales, and often serve to stabilise developmental pathways and physiological homoeostasis.24-26 Through experimental error, unanticipated allelic interactions, or poorly understood regulatory mechanisms such as imprinting, there is a risk that germline genetic manipulation will alter sensitive biological equilibria. Disruption of these interactive systems is likely to have complex and uncertain biological effects, including some that appear only during the development or functioning of specific cells or tissues.27 Many of these effects could be undesirable.

Second, this sort of intervention is not needed. With available methods of prenatal diagnosis, virtually all interested couples can choose not to transmit specific identifiable genes. Other reproductive options (artificial insemination, egg donation) and adoption are available to those not able or willing to use prenatal or preimplantation selection methods. An exception might be when, rarely, two individuals have the same recessively inherited disorder. If such couples chose to reproduce, it could be argued that they would "need" germline or very early genetic interventions since all their progeny might inherit a disease-associated genotype. Yet, even these children may differ genotypically and phenotypically from their parents and the development of a new mode of treatment for this unusual occurrence does not seem justifiable. Although available alternative procedures are invasive, germline modifications would also require similar interventions since they would probably involve IVF. Moreover, the associated risks with existing procedures are not as serious as those created by introducing a hereditary genetic "error" into a family. People who oppose prenatal diagnosis on philosophical or religious grounds would be unlikely to want to take part in germline modification if they were aware of its intrinsically experimental nature and of the numbers of human embryos that would have to be expended during the development of the technology. No unmet need balances the risks of germline interventions to mothers, fetuses, and future generations. Moreover, the costs associated with the general development and implementation of germline manipulation would be formidable.

If there is no clinical need for germline modifications, the primary reason for using this intervention would be human enhancement.28 Apart from the uncertainties about its ultimate outcome, enhancement is a form of eugenics. Though not a recrudescence of overtly coercive, public-health-based eugenics popular earlier this century, germline manipulations represent an individual or familial form. Seemingly private personal decisions and "choices" about medical or non-medical programmes for enhancement would, nevertheless, reflect prejudices, socioeconomic and political inequalities, and even current fashion. Though enhancement procedures now in use (eg, cosmetic surgery or orthodontics) also change according to fashion, germline intervention would intentionally subject later generations to modifications undertaken on the basis of existing values and conditions. The chance that "desirable" manipulations might later be viewed as disastrous makes germline enhancement "therapies" unacceptable.

Human germline interventions would necessarily alter the lives of individuals who are yet to be born. Informed consent by the affected individuals is not possible. Extension of the parental right to consent for minors would be required.29 Such legal permission to specifically alter the lives of generations of unborn individuals would be unprecedented and unjustified.

If germline manipulation is attempted, there will be mistakes or errors in its application. Neither social acceptance nor the necessary range of protections and care for accidentally damaged individuals can be guaranteed.30 Unexpected alterations in family relationships will occur, and "wrongful life" disputes could arise.31 Irrespective o whether such interventions were to take place in research or clinical settings, these issues mean that germline modifications cannot be approved by existing standards for the protection of human beings.32 No benefits to and future individual would justify abrogating or curtailing these restrictions.

For these biomedical reasons, as well as others based in legal,33 philosophical,19,34,35 cultural, and spiritual/religious traditions,36,37 human germline modifications should be opposed and prohibited. Experimentation that may gradually make human germline modification more feasible is under way; it may require further review. Further study is needed of the safety of somatic gene therapy protocols to ensure that they detect, with adequate sensitivity, germline alterations. Many individuals and groups that monitor developments in human genetics can be expected to mount vigorous opposition to the development of human germline protocols, involving direct action, legal manoeuvres, and organising among interested public groups. Unlike man other countries, including those of the EU, which have prohibited germline manipulation in principle,38,39 restrictions on the procedure in the USA are mainly based on practical considerations (see, for example, the summary of the January 1999, RAC-sponsored conference at http://www.nih.gov/od/orda/gtpcconc.htm. Site accessed March 20, 1999) and are subject to revision as the state of the science changes. Although debate about human germline modifications should continue and, indeed, be broadened to include representation of a diverse cross- section of viewpoints and backgrounds, such discussion should not be construed as suggesting that such a method would ever be appropriate or acceptable.

We thank Jacque Bradley for technical assistance, Jon Beckwith, Felipe Cabello, Suzanne Bodor, Vernon Chong and Parris Burd for helpful suggestions and critical

comments on drafts of this paper.

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Veterans Health Administration, Heart of Texas Health Care System, 1901 North HighwaY

360 Grand Prairie, TX 75050

(P R Billings MD); Biological Laboratories, Harvard University, Cambridge, MA (R

Hubbard PhD); and Department of Cell Biology and Anatomy, New York Medical

College, Valhalla, NY, USA (S A Newman PhD)

Correspondence to: Dr Stuart A Newman (e-mail:newman@nymc.edu)

Article 11

At birth, the female calf appeared blissfully normal, and the French scientists who had nurtured her since her start in a petri dish heaved a sigh of relief. But the celebration was short lived. A month later, tests revealed a sharp drop in the calf's hemoglobin. Iron supplements failed to remedy it. At seven weeks, the calf died suddenly from massive anemia.

This young calf was a clone, the product of a single skin cell from another animal's ear. And her mysterious death, reported this month in the Lancet, is just one of many failures in this dazzling new specialty. Cloned cows are at least 10 times more likely to be unhealthy than their naturally conceived counterparts. No one knows why.

"The problem," says James Robl, a developmental biologist and cloning pioneer at the University of Massachusetts- Amherst, "is the embryos all look fine. We don't see [abnormalities] until eight months of gestation." Still, scientists suspect that something goes awry in the embryos' first days.

One possible culprit is genetic imprinting, a poorly understood process in which maternal and paternal genes ensure that neither predominates in the offspring. With only one parent, the cloned fetus could be left without a balance of genes necessary to thrive. Scientists point to disorders triggered when imprinting goes wrong that resemble those they see in clones. One, Beckwith-Weidemann syndrome, produces an unnaturally large child with an oversized tongue and internal organs.

Clone defects also could be caused by the process itself. With so little known about early embryonic development, handling the embryo, or even creating it--which involves using an electric shock to fuse the donor's cell with an oocyte that lacks a nucleus--could disrupt crucial growth processes. It's also conceivable that scientists simply haven't mastered a complex and novel technology. Indeed, Ryuzo Yanagimachi, a professor of reproductive biology at the University of Hawaii Medical School and the first to clone mice, calls his 1 percent success rate "a rather encouraging figure."

But 1 percent success, coupled with many more disastrous outcomes, means that human cloning can't be considered until the process is almost foolproof. Most scientists are optimistic that a few years of toil is all it will take to make significant improvements. But it could be that without genes from two parents of their own, cloned mammals are largely doomed.

Article 12

Drumsticks, anyone? If you're partial to chicken legs, here's good news for you. Thanks to some clever genetic engineering, scientists at the Salk Institute in La Jolla,

Calif., have come up with a way to grow birds with an extra pair of legs.

The work, described in last week's Nature, centers on so-called T-box genes. Common to all vertebrates. including humans, they're important in the development of limbs in the embryo--determining, for example, whether they become hind- or forelimbs (or in chickens, legs or wings). But, says geneticist Juan Carlos Belmonte, the study's senior scientist, "we didn't know if one of these genes by itself was sufficient to send a limb down one pathway or the other."

To unravel the puzzle, the scientists infected the unformed wing region of day-old chicken embryos with a virus carrying a T-box gene known as Tbx-4. A day later, they transferred the tissue to other embryos still in their shells. The transplanted cells quickly grew into recognizable legs. By contrast, when the scientists transferred wing tissue without first infecting it with Tbx-4 genes, the tissue always grew into wings. That shows that Tbx-4 contains a full genetic blueprint for a leg, says Belmonte.

The scientists hope to learn how T-box genes turn on and off. That could give them clues to human birth disorders like Holt-Oram syndrome, which is characterized by stunted arms and hands and is linked to these genes. As for the chicks, the scientists didn't let them hatch, resisting the temptation to grow drumsticks for KFC.

--By Frederic Golden

Article 13

Eric B. Kmiec.

Abstract: Media reports create the impression that genetic technology has been making rapid progress in recent years. The problem with this portrayal is that it inevitably leads to a disappointed public whose expectations were raised by an almost daily report of genetic breakthroughs. The truth is genetic technology has yet to mature and many fundamental problems still have to be worked out to make the technology clinically valuable.

Investigators have been searching for ways to add corrective genes to cells harboring defective genes. A better strategy might be to correct the defects

In the middle of the 19th century, the now-famous monk Gregor Mendel performed his landmark experiments indicating that certain traits can be inherited, and he postulated a discrete unit of inheritance that we now call a gene. Since then, scientists have come to appreciate how much of an individual's constitution is determined by genes, and, in particular, they have focused on the link between genes and disease. Indeed, over the past 10 or so years, identifying disease-related genes has becom something of a cottage industry within the scientific community.

Any reader of newspapers knows just how fruitful this enterprise has been. Almost daily come reports about the discovery of a new gene that contributes to some disease or another, be it sickle cell disease, muscular dystrophy, familial hypercholesterolemia, Alzheimer's or some form of cancer. Right now, therapies directed toward these conditions can only alleviate the symptoms - the manifestations of the defective genes. Implicit, and sometimes explicit, in stories about genetic discoveries is the idea that new therapies can be created that directly address the source of the problem. These gene therapies seek treatments, even cures, that act at the level of the gene itself.

Most of the gene therapy techniques developed so far are of the gene-addition variety; that is, they attempt to provide a good copy of a gene to a cell that harbors a bad one. The hope is that the good, corrective gene will compensate for the bad one and restore the cell to its proper function. Gene addition has been achieved by a variety of means - not only in test-tube experiments, but in clinical trials involving real patients as well. Yet, to date, the results of these trials have been disappointing. Even the most successful clinical trial has fallen short of therapeutic efficacy.

Unfortunately, many of these trials have been widely publicized - and, in some cases. oversold - in popular books and magazine articles. Having failed to live up to the inflated expectations created by such publicity, these disappointing trial results have left a general impression that gene therapy cannot now or ever fulfill its initial promise. But these clinical trials may have been conducted before the technology was fully mature, driven in part by investor demands on biotechnology companies to rush products to market. Such clinical trials were almost certainly destined to fall short of the mark.

Many of the fundamental problems with gene therapies have not yet been worked out sufficiently to make the technology therapeutically viable. A number of vehicles have been developed to deliver corrective genes into cells. Some are more effective than others, but none is yet exactly right. The greater challenge, however, lies in the problem of how to make the therapeutic gene behave reliably and at clinically beneficial levels.

Making gene therapy a successful endeavor will require careful research to understand why traditional approaches have not produced the hoped-for results and, in turn, to improve them, while exploring new ways to deal with genetic defects. In my own laboratory, we are considering the possibility that inserting an entire gene into a cell and then expecting it to behave as a native gene may be overly ambitious at this point. It may also be unnecessary. Since the defects in many disease-related genes are fairly small, my colleagues and I are exploring ways to repair rather than replace them. Our initial results lead us to be cautiously optimistic that with adequate basic research this or some other approach will ultimately yield fruit. My own feeling is that pronouncements of gene therapy's imminent demise are as premature as were those overly optimistic pronouncements of its imminent success. At its core, the notion of gene therapy or gene correction is scientifically sound.

Abnormal cell behavior is often the result of an altered gene whose expression is either absent or unregulated. A mutation in just one gene can sometimes cause a cell to malfunction. The mutated gene directs the synthesis of a dysfunctional protein, with the consequence that the cell functions marginally or not at all.

In the case of sickle cell anemia, for example, a mutated hemoglobin molecule actually distorts the red blood cell in which it resides, causing the cell to assume a sickle shape instead of its usual disk shape. The shape change prohibits the cell from adequately performing its designated role of carrying oxygen to the body's organs and tissues.

Another example is presented by muscular dystrophy, which is linked to mutations in the dystrophin gene. This gene codes for the dystrophin protein, which is crucial for the strength and movement of normal muscle tissue. People lacking dystrophin experience the muscle weakness characteristic of the disease.

Finally some genetic mutations do not alter a cell's function as much as they interfere with the cell's normal life cycle, specifically its cell-division cycle. Such mutations can lead the cell to divide uncontrollably, as is the case in certain cancers.

The essence of gene therapy, then, is to deliver to a cell a correct version of a mutated gene, the expression of which will produce the normal protein and hence restore normal cellular function. This has been obvious for some time, but how to achieve this goal has not been. An initial problem centered on how to get a gene into a cell. The chromosomes of a mammalian cell are housed inside a membrane-bounded compartment, called a nucleus. It is not enough for a gene-delivery system to deposit the gene into the cell; the gene must be delivered to the nucleus.

This in itself is not difficult. Scientists have been able to do it for decades. Foreign DNA can be injected into a cell, or its entry can be facilitated by various chemical or electronic means. But these methods are not very efficient, and one requirement for gene therapy is that sufficient amounts of corrective DNA be delivered to enough cells to be therapeutically beneficial.

Under the best circumstances, one would also want the therapeutic DNA to become a permanent part of the host's chromosomes. This would ensure its stability and would meanhat the therapeutic gene would be replicated along with the host's chromosomes during each cell division. In contrast, DNA delivered to a cell by physical or chemical means can be placed in the cell's nucleus and can be expressed, but it does not become integrated into the chromosomes.

An ideal gene-delivery vehicle would be able to enter a large number of cells and integrate its DNA into the host's chromosomes. As it happens, some kinds of viruses are perfectly adapted to do just that. And, about 15 years ago, Richard Mulligan and Constance Cepko, who were then at Massachusetts Institute of Technology, along with colleagues at MIT and Harvard, made the important technological leap that initiated the modern era of gene therapy. Specifically they demonstrated that members of the retrovirus family could be engineered to carry foreign genes into mammalian cells and splice them into the host's chromosomes.

To create these gene-delivery vectors, Mulligan and his coworkers essentially gutted the virus of its genes, disposing of those that could be harmful to the host. At the same time, they retained those genes that enable the retrovirus to insert DNA into host chromosomes. By attaching this integrative machinery to the therapeutic gene, they created a retrovirus capable of infecting cells and splicing a corrective gene into chromosomes.

Inserting a gene, however, is only half of the problem. The vector must also contain a mechanism for activating the therapeutic gene, since this is not automatic. Genes have evolved a pattern of expression wherein certain levels of their product are required at specific times in the life cycle of the cell. Hence the corrective action of gene therap must include a timing and regulatory "device." Such devices are usually found at the start of a gene and constitute the gene's "on" switch, or promoter. But this leads to another problem.

Promoters are often exquisitely complex and sometimes quite large, so placing them into a therapeutic vector is difficult. When constructing their retroviral vectors, Mulligan and his colleagues opted to use promoters native to the virus, rather than the corrective gene's own promoter. In laboratory petri dishes, these vectors sometimes worked quite well, but not always.

In some cases, the therapeutic genes entered the cells as expected but were expressed at unpredictably low levels. Low levels of expression continue to dog gene-therapy efforts, and improving expression levels remains a major focus of research. Recent vectors include portions of the gene's own promoter. This has the added benefit that the therapeutic gene is expressed as naturally as possible - only during the times when its product is needed.

Other constructions attach promoters that can be externally controlled. For example, certain genes have promoters that are sensitive to the antibiotic tetracycline and are activated when the drug is present. A vector was recently constructed by Herman Bujold and colleagues at the University of Heidelberg that pairs a tetracycline-sensitive promoter with a corrective test gene. The test gene would be activated only if the patient ingests tetracycline.

The initial expectation was that cells would have to be removed from the body in order to be treated. This ex vivo approach would necessarily limit therapy to those cells, such as blood cells, that are easily removed and replaced. But more recently, retroviral vectors have been developed that can be infused directly into an organ, such as the liver, or placed into the lung by inhalation. This versatility is one of the great advantages of retroviral vectors.

There are also some considerable disadvantages to retroviral vectors that have made investigators cautious about using them. The same feature that makes the retroviruses so attractive to gene-therapy investigators has also been one of their greatest drawbacks - namely the ability to integrate genes into chromosomes. The problem is that scientists have no control over how many copies of the gene become integrated or where on the chromosome they insert. Since integration appears to be essentially random, the vector's genetic payload may become inserted within another important gene, disrupting or altering its expression. Or a gene may integrate within the regulatory region of a gene responsible for controlling cellular proliferation, thus putting the cell on the path towards cancerous growth. Although these are remote possibilities, they are real and must nevertheless be considered as a potential consequence of retroviral-based gene-delivery vectors.

Considering some of the safety issues surrounding the use of retroviral vectors, investigators have been casting about for other viruses that can deliver genes to cells without disrupting their normal chromosomal configuration. There has been much interest in the use of adenoviruses for this purpose. The bulk of the early work on adenoviral gene therapy was conducted by Ronald Crystal at Cornell Medical School and James Wilson at the University of Pennsylvania.

Like the retroviruses, adenoviruses deliver their genetic payload to the nucleus, but, except under rare circumstances, the genes do not integrate into the resident chromosomes. This, of course, relieves concern about random genetic integration, but it also means that the therapeutic gene is only transiently active. The adenoviral vectors have to be repeatedly administered in order to maintain a steady therapeutic dose.

Adenoviruses can infect a broad range of human cells, including those of the lung, liver, blood vessels and brain. In fact, brain tumors have been treated with adenoviral vectors carrying "suicide genes," whose expression leads to cell death only when its product interacts with a specific drug taken by the patient. These studies generated mixed results.

Adenoviral vectors have also been used in human trials to correct mutations in the cystic-fibrosis transmembrane receptor (CFTR) gene, which contributes to cystic fibrosis. The success of these trials, however, has been quite low. For one thing, the host's immune system registers the adenoviral vector as foreign and eliminates it from the system. In addition, some of the vectors cause an inflammatory response at the high levels required to achieve therapeutic doses.

One of the most promising vehicles to emerge from recent gene-therapy studies is adeno-associated virus (AAV). This virus infects a wide range of cells, including lung and muscle cells, and it integrates its genes within the host's. In addition, it can infect nondividing cells and does not elicit an immune response both of which are important advantages over retroviral and adenoviral vectors. The work on this virus has been pioneered by three investigators: Kenneth Berns and Nicholas Muzyczka at the University of Florida and R. Jude Samulski at the University of North Carolina at Chapel Hill. Significant advances in the use of AAV for gene therapy have recently been reported by Mark Kay and colleagues at Stanford University and Kathryn High and coworkers at the University of Pennsylvania. Both of these research groups used a modified AAV vector to achieve long-term expression and correction in animals of gene that contributes to hemophilia. This achievement required a detailed appreciation for the basic biology of AAV.

However, as expected, this virus has some drawbacks. First, it can carry only a small genetic payload, which considerably restricts its usefulness. Second, it, too, carries the risk of disrupting functioning genes by randomly inserting itself into the chromosomes. Finally, it is somewhat difficult to manufacture these vectors in sufficiently high quantities. Other viruses under study as potential vector candidates include Herpes simplex, Vaccinia and even the human immunodeficiency virus.

In addition to vital-based vectors, investigators are continuing to explore nonvital delivery systems. One system that holds some promise delivers drugs via liposomes, small vesicles artificially created from lipids that resemble those making up the membranes of mammalian cells. Because they are constructed of virtually identical materials, the liposomes can fuse with cell membranes and empty their contents - which can include drugs or corrective genes - inside the cell. Some of the DNA delivered by liposomes makes its way into the cell's nucleus.

[TABULAR DATA FOR FIGURE 6 OMITTED]

Ultimately, scientists would like to replace a dysfunctional gene with a functional one, within the normal context of the chromosome, an approach that could skirt the concerns about the number of genes delivered, the chromosomal location and the level of expression. Right now, homologous recombination, the only technique that comes close to this, is so inefficient that its success rate is 1 in 10,000. Needless to say, this is not adequate for human use.

But the idea of completely replacing a bad gene with a good one may be overreaching, especially when one considers how small are many of the mutations that contribute to disease. To understand how small, we must first consider a few basic facts about the composition of genes.

The gene is to inheritance what a word is to language; it is the basic trait of meaning.

In the genetic lexicon, the gene is a length of DNA that codes for a particular protein. The alphabet used by the genetic language contains only five letters, or nucleotides, named for the bases. These are adenine (A), thymine (T), cytosine (C), guanine (G) and uracil (U). The nucleotides A, T, C and G are found in DNA. (RNA, a chemical cousin to DNA and an important participant in genetic decoding, lacks thymine, but has uracil in its place.) The average human gene is a little over 1,000 nucleotides long. In many inherited disorders only one or a few of these nucleotides is incorrect.

For example, sickle cell anemia is the result of a single nucleotide substitution, a single letter misspelled, in the gene encoding the [Beta]-globin strand of hemoglobin. Yet this one-nucleotide substitution can cause the structural deformity of the molecule and the characteristically distorted shape of the sickled red blood cell. Over 70 percent of the cases of cystic fibrosis are attributable to the deletion of three nucleotides in the CFTR gene. Why should the entire gene be replaced when the error is so minimal? That strategy seems akin to remodeling the whole kitchen to repair a leaky faucet.

In 1993, while studying homologous recombination in mammalian cells, members of my laboratory began experimenting with ways to repair damaged genes, rather than replacing them. The cell's own repair mechanisms are extremely efficient, as evidenced by the simple and continual inheritance of normal genes through generations of cell divisions. If we could harness the cell's own power of DNA repair, we reasoned, we might be able to correct mutations.

Normal human chromosomes are actually made up of two strands of DNA complexed to each other in an interesting way. It turns out that the nucleotides of DNA can bind with each other in a specific pattern. Except in very rare cases, adenine always pairs with thymine, and guanine always pairs with cytosine. Each DNA strand carries a nucleotide sequence exactly complementary to the other, such that every adenine nucleotide on one strand is matched up with a thymine on the partner strand, and every guanine is matched with a cytosine on the complementary strand. A sequence of GATC on one strand would therefore bind to the sequence of CTAG on its partner, or so it should be.

Occasionally the wrong nucleotide is inserted into a spot, so that the corresponding nucleotide on the partner strand cannot properly bind in that position. In that case the mismatched nucleotides form a bulge. Usually this is not a problem, since the cell contains DNA repair mechanisms that actually scan the DNA and detect such bulges. When one is discovered, the repair systems work to remove the incorrect nucleotide and replace it with the correct one. But if the mismatch is overlooked by the cell's repair machinery, the error is retained, and the gene remains defective.

It was our idea to alert these repair mechanisms to the error. The principle is quite simple. We artificially create a short string of nucleotides, called an oligomer, that, with one exception, is exactly complementary to the section of the gene in which the error is located, the exception being at the site of the error. Here we insert the nucleotide complementary to the one that is supposed to be in the DNA sequence of the normal gene. The oligomer binds to its complementary sequence on the DNA, and by design creates a bulge at the site of the mismatch. This bulge is eventually detected by the cell's internal DNA-repair mechanisms. Repair enzymes remove the erroneous nucleotide and replace it with a nucleotide complementary to the one in that position in the oligomer, which happens to be the correct nucleotide. This scenario for targeted gene repair has been experimentally confirmed in my laboratory by Allyson Cole-Strauss.

Our work builds on earlier studies from Fred Sherman's laboratory at the University of Rochester, who used a similar technique to change a single nucleotide. But th e oligomers used by the Sherman group were unstable, and the team never extended its work. It turns out that mammalian cells contain enzymes that either degrade the ends of DNA molecules, or link them in long arrays called concatamers, which essentially destroys the integrity of the oligomers. We discovered that we could increase the stability of an oligomer by attaching segments of RNA to each of its ends. Like DNA, RNA is also composed of strings of nucleotides and therefore can bind to DNA in the same complementary manner as can another strand of DNA. (RNA contains no thymine. Instead, the uracil in RNA pairs with the adenine in DNA.)

In the past two years, we have successfully corrected seven chromosomal targets with this approach. Cole-Strauss and others in my lab have demonstrated the feasibility of using gene repair to correct the sickle-cell mutation in vitro, and Clifford Steer's laboratory has reproduced and extended those results in certain animal models. Vitali Alexeev and Kyggeon Yoon have shown that the correction is maintained through successive generations of cell division, suggesting that gene repair may have long-term benefits. Only continued studies will be able to determine whether this approach will be useful for human gene therapy.

In the clinic, gene therapy has enjoyed few successes and many failures. But within these failures lessons have been learned. In some cases, scientific rigor was sacrificed in order to bow to financial pressures to rush gene therapy into clinical trials. In other cases, the goals were too lofty, and the expectations were unrealistically high.

Limited success in animal models all too often leads directly to clinical trials. But a mouse is not a small human with four legs, and the positive results in mice do not necessarily portend a positive outcome in people.

Even at their best, the results of trials with human gene therapy are equivocal. For example, let's consider a gene therapy trial to treat familial hypercholesterolemia (FH). People with this inherited condition have dangerously high blood levels of cholesterol, in spite of their body weight or diet. The condition results from a defective gene that encodes a receptor found on the membranes of liver cells specific for low-density lipoprotein (LDL), what many call "bad cholesterol." Normally LDL enters liver cells via this receptor, after which the liver clears the body of LDL. But people with FH have too few functioning receptor molecules and cannot remove LDL from their blood. As a result, blood serum levels of LDL are too high in people with this condition, and many FH patients develop coronary artery disease.

In animal models, investigators demonstrated some success when corrective copies of the receptor gene were transferred into liver cells via a retroviral vector. Blood levels of LDL in the treated animals were significantly reduced and remained so for over six months. These experiments were done carefully, in several animal models and with rigorous controls. All the models produced similar, encouraging results. based on these results and the fact that patients with this disease have few good treatment alternatives, a human gene-therapy trial for FH was approved.

Figure 11. Overwhelming majority of gene therapy protocols currently approved to enter clinical trials are for cancer. Today's clinical trials are likely to point out areas that basic researchers must address before gene therapy truly fulfills its promise.

protocol type number approved

cancer therapy 56

cystic fibrosis 11

AIDS 9

Gaucher's disease 3

familial hypercholesterolemia 1

rheumatoid arthritis 1

The experience of one 28-year-old woman represents one of the better outcomes of this clinical trial. The patient lacked any detectable functioning LDL receptor becaus she lacked the gene for it. At the start of the trial, she had 482 milligrams of LDL in each deciliter (mg/dl) of blood, well over twice the normal level of 160 to 210 mg/dl. Her liver cells were then treated with a retroviral vector containing the LDL-receptor gene. Within a few days, her serum cholesterol dropped by 180 mg/dl to about 300 mg/dl. With additional cholesterol-lowering drugs, her LDL blood levels stabilized at around 356 mg/dl and remained there for about two and a half years. These levels, although lower than they were originally, are still higher than they ought to be.

Herein lies the quandary of human gene therapy: It "sort of" works. This trial demonstrated the feasibility and safety of gene therapy for treating FH. But the results hardly constitute a ringing endorsement for this approach as the definitive therapy. In fact, it would be difficult to name a clinical trial to date that does, a situation that prompted review of the approval process for clinical trials.

Decisions on clinical applications of gene-therapy approaches fall under the auspice of the federal government. Originally, the Recombinant DNA Advisory Committee (RAC) was charged with the duty of making suggestions for approval or disapprovalto the director of the National Institutes of Health (NIH). The RAC was empowered t consider somatic gene-therapy protocols only; that is, the RAC considered protocols that did not involve the so-called germ line cells, such as eggs and sperm. In addition to submitting protocols to the RAC, investigators submitted new gene-therapy protocols to the Food and Drug Administration for Investigational New Drug (IND) approval. More than 100 protocols have been approved by the RAC to date.

In 1996, Dr. Harold Varmus, the director of the NIH, amended the procedure because

of rising concerns over the rate of failures among approved clinical trial protocols. The

fallout of this effort has been an enhanced oversight role for the NIH through three mechanisms. First, the office of Recombinant DNA Activities Advisory Committee (OAC) evaluates protocols. Next, gene-therapy conferences are held to promote public discussion of scientific merit and ethical aspects of proposals for human clinical trials. Finally, the public is informed about the progress of ongoing trials. The genetherapy policy conferences have already helped to improve the oversight of the approval

process. They also encourage continued review of the ethical aspects of each trial.

Although in most cases, increasing government involvement is viewed as an invasion

into scientific enterprises, gene therapy will stand to benefit by such heightened control.

In spite of the increased government scrutiny of previous gene-therapy protocols, the pressures to bring gene therapy to the clinic do not seem to abate. This is in part

because of the formation of ventures aimed at commercializing products and techniques. Financial pressures and constraints often force biotechnology companies to forgo basic research in favor of application-driven development. Unfortunately, this means that promising but technically difficult approaches may never be adequately developed for lack of research funding.

Increases in public funds for research may well be part of the answer to improving the technology, since it is the basic level of investigation that will in the end broaden

understanding of gene-therapy techniques and increase the probability of clinical

success. What is clearly needed is the development of molecular analysis and rigorous

testing at the level of basic science, with an eye towards application in clinically

appropriate targets. Only then will gene therapy have a hope of fulfilling its promise.

Acknowledgments

I wish to thank current and former members of my laboratory for their hard work on

gene repair, the NIH for funding these projects and Michelle Hoffman for editorial advice.

Bibliography

Anderson, S. F. 1992. Human gene therapy. Science 256:808-813.

Cohen-Haguenauer, O. 1997. Gene therapy: regulatory issues and international

approaches to regulation. Current Opinion in Biotechnology 8:261.

Cole-Strauss, A., K. Yoon, Y. Xiang, B.C. Byrne, M. C. Rice, J. Gryn, W. K.

Holloman and E. B. Kmiec. 1996. Correction of the mutation responsible for sickle

cell anemia by an RNA-DNA oligonucleotide. Science 273:1386-1389.

Edgar, H., and D. Rothman. 1995. The Institutional Review Board and beyond:

future challenges to the ethics of human experimentation. Milbank Quarterly 73:489.

Gorman, C. 1998. DNA therapy. Time (March 16) p. 37.

Hall, S. J., S.-H. Chen and S. L. C. Woo. 1997. The promise and reality of cancer

gene therapy. American Journal of Human Genetics 61:785-789.

Kay, M. A., D. Liu and P. M. Hoogerbrugge. Gene therapy. Proceedings of the

National Academy of Sciences 94:12747-12748.

Kmiec, E. B. 1999. Targeted gene repair. Gene Therapy 6:1-3.

U.S. General Accounting Office. 1996. Scientific Research. Continued vigilance

critical to protecting human subjects. Health Education and Human Services

Division Report #B259279.

Shuster, M. J., and G. Y. Wu. 1997. Gene therapy for hepatocellular carcinoma:

progress but many stones yet unturned! Gastroenterology 112:656-658.

Verma, I. M., and N. Somia. 1997. Gene therapy-promises, problems and prospects.

Nature 389:239-242.

Links to Internet resources for further exploration of "Gene Therapy" are available

on the American Scientist Web site:

http://www.amsci.org/amsci/articles/99articles/kmiec.html

Eric B. Kmiec received his Ph.D. in molecular biology and microbiology at the

University of Florida School of Medicine. He is currently an associate professor of

microbiology in the Kimmel Cancer Institute at Thomas Jefferson University in

Philadelphia. He is also head of the section on experimental therapeutics and

genetic medicine at the Jefferson Center for Biomedical Research. He has

published extensively in the basic science of genetic recombination and repair.

In 1994, he was the scientific founder of Kimeragen, Inc., a biotechnology

company formed to develop commercial applications for targeted gene repair.

Address: Jefferson Center Thomas Jefferson University, 700 East Butler Avenue,

Doylestown, PA 18901. Internet: kmiec@lac.jci.tju.edu.

    Article A54517248

Article 14

Sondra Wheeler.

One of the obvious but decisive facts about parenting is that prior to embarking upon the relationship, we don't know who is coming. We receive and live out our responsibilities toward our children, whoever they turn out to be, simply because they are ours and we are theirs, and most of the time that is enough to bring us to welcome and cherish and protect them. We do it whether they are beautiful or homely, brilliant or ordinary, cheerful or fretful. Even when they grow into adolescents with strange haircuts who, it seems, can hardly stand us, by and large and with varying degrees of struggle, we continue to welcome and cherish and care for them. Parenting is the most routine and the most socially essential form of welcoming the stranger.

It is this unreserved and uncalculated commitment to accept and love the children we are given that makes the relationship between parent and child so central a metaphor for our relation to God, who welcomes and receives and cares for us, whoever we are. In this most fundamental and natural of all social relationships, we see the nearest analogue for the divine charity which loves each of us in her or his particularity, but universally and without conditions.

It now seems likely, due to certain recent advances in scientific technique, that soon we will develop the capacity to make changes in the genetic makeup of human beings, including changes that they will pass to their descendants. The challenge this presents is, how much should we try to determine about our offspring?

The possibilities go all the way from that offered by cloning--which would allow us to select a complete genome (the total complement of chromosomes of a species) as long as we had an existing "template" to reproduce--to much more modest alterations in a single gene designed to prevent the development and transmission of a particular genetic disease.

Among the myriad questions forming around these technologies is a fairly broad and basic one: What will it mean if we move from a social practice of welcoming the children who are born to us to a practice of selecting them and their characteristics, either by cloning or by modifying the genome in vitro before implantation? In particular, it is important to address what for. Christians and Jews (at least) defines and limits the senses in which human beings may be said to belong to each other, and what this suggests about the terms on which we ought to intervene in the genetic makeup of another human being.

WHAT ALL THIS HIGHLIGHTS is the very different moral posture between that of simply accepting the child we are given vs. a decision to engineer the genetic endowment of a child to replicate a desired genome or to select for personally desired or culturally valued characteristics. What will it mean to us, and to our children, if we embrace practices that make a child so decisively the project of its parents' will?

Certainly to seek such control involves abandoning a certain kind of reservation grounded in the fellow-humanity of our children, a respect based in religious awe for the child as a creature whose source and destiny are in God and who does not ultimately belong to us. It means shifting from a position in which we discover and foster the nature and flourishing of the children we receive, to one in which we determine the nature of the children whom we will accept. It is a kind of embodiment of all those corruptions of parenting in which the child is viewed primarily as the means of the parents' fulfillment and forcefully created in the image of their

There are, of course, many much more serious and compelling reasons to seek the power to intervene in the genetic makeup of human beings. About 2 percent of all live births are of children with genetic disorders, some of them imposing severe sufferin and early death. To have the power to prevent such misery or to heal its effects is indeed a worthy goal, and an appropriate exercise of human powers to intervene. But it is not too soon to begin asking whether we can even hope to exercise so vast a power with the caution and deep self-scrutiny that wisdom would demand.

SONDRA WHEELER is professor of Christian ethics at Wesley

Theological Seminary in Washington, D.C., and the author most

recently of Stewards of Life: Bioethics and Pastoral Care

(Abingdon Press, 1996). Glen Stassen, the Lewis B. Smedes

Professor of Christian Ethics at Fuller Theological Seminary in

Pasadena, California, serves as consultant and adviser for this

Ethics page.

Article 15

They loom still, just over the horizon of my imagination: donor eggs. Every time I read another article about them, another article about another forty- or fiftysomething woman having a baby courtesy of some younger woman's eggs, I think: "Hey, that could be me. It's not too late, even as menopause is just around the corner. No matter. Donor eggs will cure what ails me--the womb ache of loneliness that haunts me still."

The problem is: I can't do it and I know I can't do it and it makes me crazy. It's not a physical issue. It's a moral one, and I hit up against it every time I'm tempted to run out of the house and get back in the stirrups.

Let me be clear. I've been down this road before. I was first offered donor eggs seven years ago. I was 42, still childless, and had spent the previous half decade trying to beget a biological baby with my husband. We had tried it all, every high-tech and low-tech procedure then available. My body was whipped, my humor gone, my marriage frayed, our bank account depleted.

Just then, as I was nearly off the baby-making treadmill for good, one last doctor offered me the new solution for us aging infertiles: donor eggs. For a mere $2,500, he said, I could buy the eggs of a younger woman, a high-IQ college coed (translation: you don't need to traffic in adopted children with their sometimes fraught backgrounds). Those eggs would be extracted from her, put in a dish with my husband's sperm, and I would then carry the resultant embryos to term. I could be pregnant; I could give birth--the whole shot.

But could I meet the donor? No, no, I was told. This was an anonymous donation. I would fill out a questionnaire with my vital physical and mental statistics (hair color, height, hobbies schooling), and the fertility clinic would match a donor to my traits. That way I could physically pass the baby off as my own, as the doctor told me most of his other patients were doing, as couples who had used donor sperm over the years had routinely done. I would be given a medical history of the donor and her family so I could rest easy in my soul about the baby's genetic inheritance. Listening to him, I swooned with hope, fast- forwarding myself into the carpool line with the other SUV-driving soccer moms.

But with the swoon came a swift moral reckoning: How did you do that? How could you bring a child into the world and not tell the truth--or outright lie--about his or her true origins? How did you look him or her in the eye if you did that? After all, no matter how you sliced it, this was, in effect, an adoption--if a pre-emptive one. There are differences with normal adoption. Giving up an egg is less traumatic to all parties involved than giving up a baby. Then, too, an egg-donor child would still have a biological parent in the house: the dad.

But that child would be unalterably and inexorably linked to another woman and therefore, in my moral universe, entitled to know that fact-- even to know the woman herself. If I were the de facto birthmother and hands-on mother, I would still not be the genetic mother and no pregnancy or self-deception or maternal love on my part could alter that fact.

And what if I told the truth to my child? What would keep him or her from later looking for that genetic mom just as thousands of adoptees have gone looking for their biological mothers--not to mention half siblings and grandparents and the whole familial line? Was this young donor ready for any of this, the possible knock on the door 15 or 20 years down the road, or even just the emotional repercussions to her own soul when she got married and pregnant and reckoned finally with the reality of being tethered to another child--or children--out there somewhere? Were we older, richer, infertile women just duping such younger, poorer women into a blithe commercial egg exchange, the fallout of which they could not possibly yet understand?

Maybe I'm just hopelessly unhip. Maybe feminism these days--certainly the updated, acquisitive version--means never having to say you're sorry to another women for waltzing off with her eggs in your womb, especially if you pay her handsomely. (One couple just offered $50,000 for the eggs of some choice, high-IQ donor). All I know is, I couldn't do it. If it was all aboveboard, all parties getting together, the donor agreeing to be available should the child later want to meet her, hang out with her--whatever--maybe then I could have done it, a kind of open egg adoption, as it were. Anything short of that was a nonstarter for me--which doesn't mean I begrudge anyone else's choices in the matter. As I learned firsthand, in the babymaking world we all have to make our own complicated decisions. Given my enduring baby-longing, I wish mine could have been different.

Taylor Fleming lives in Los Angeles and is author of the book

"Motherhood Deferred."

Photo: 'It's not a physical issue. It's a moral one, and I hit up

against it every time I'm tempted to run out of the house and get

back in the stirrups.'

Copyright 1999 Newsweek Inc. All rights reserved. Any reuse,

distribution or alteration without express written permission of

Newsweek is prohibited. http://www.newsweek.com

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    Article A54305179

Article 16

Abstract: Agricultural methods in the 20th century have not been sustainable. One example that proves this theory is that as incomes increase, people improve the quality of the food they eat and this burdens the farmers. However, with biotechnology and information technology, sustainability could be achieved.

Unless we find better ways to grow food, we'll need to find ourselves another planet, warns the CEO of the Monsanto Company.

Today there are more than 5.9 billion people in the world. About 1.5 billion of them live in conditions of abject poverty - a subsistence life that simply can't be romanticized as some form of simpler, preindustrial lifestyle. These people spend their days trying to get food and firewood so that they can make it to the next day. As many as 800 million people are so severely malnourished that they can neither work nor participate in family life. That's where we are today. And, as far as I know, no demographer questions that the world population will continue to grow by several billion during the next 50 years.

Without radical change, the kind of world implied by those numbers is unthinkable. It's a world of mass migrations and environmental degradation on an unimaginable scale. At best, it means the preservation of a few islands of privilege and prosperity in a sea of misery and violence.

Simply doing better what we've done in the past won't work. In industrialized countries, the economic system evolved in an era of cheap energy and careless waste disposal, when limits seemed irrelevant. None of us today, whether we're managing a house or running a business, is living in a sustainable way. It's not a question of good guys and bad guys. The whole system has to change, and there's a huge opportunity for reinvention.

Facing the implications of what sustainability requires is no easy task, but we can't avoid it. Here's why.

In the twentieth century, we have been able to feed people by bringing more acreage into production and by increasing productivity through fertilizers, pesticides, and irrigation. But current agricultural practice isn't sustainable. We've lost something on the order of 15% of our topsoil over the last 20 years, irrigation is increasing the salinity of soil, and the petrochemicals we rely on aren't renewable.

Most arable land is already under cultivation. Attempts to create new farmland are causing severe ecological damage. So in the best case, we have the same amount of land to work with and billions more people to feed. It comes down to resource productivity. We have to get significantly more yield from every acre of land just to maintain current levels of poverty and malnutrition.

This is only part of the story. As incomes increase, people's diets change. For example, while Asia's gross domestic product has grown by about 10% annually for the last decade, a substantial part of the extra personal income has gone to improving what people eat. Instead of the largely cereal diet of the poor, these newly prosperous people want higher quality food, including meat, dairy products, and cooking oil. In China, total meat consumption rose by nearly one-half between 1991 and 1995.

Producing these foods places an even heavier burden on the world's farming resources and uses up more land. For instance, cattle not only need space for themselves,but land is also needed for the hay, corn, and feed to get them ready for market. Producing a calorie of cooking oil takes twice as many resources as a calorie of cereals; a calorie of meat takes three to five times as many.

This is why, if the world's population goes up by 75%, the demand for food won't simply go up by the same amount. Some estimate that rising standards of living, fueled by growing personal incomes, will cause it to triple.

Now, even if we wanted to boost food production in an unsustainable way, no technology today would let us double, let alone triple, productivity. With current best practices applied to all the acreage in the world, we'd get about a third of the way toward feeding the whole population. The conclusion is that new technology is the only alternative to one of two disasters: not feeding people - letting the Malthusian process work its magic on the population-or ecological catastrophe.

We all know the effects of starvation. Here's a sense of the ecological implications: Since virtually all the world's good farmland already is under cultivation, most of the new acreage that will be converted to agriculture will be of marginal quality - and consequently crop yields will be lower. This marginal land is often fragile or erodible or supports animals and plants that are part of the earth's rich biodiversity.

Technology will be needed to make sure the yields on all agricultural lands are as high as they can be: The experience of recent decades shows its potential. It's estimated that if we tried to produce the food we grow today using 1960s agricultural techniques, our planet would lose to farming nearly 10 million square miles of wildlife habitat.

How can we double or triple food output in a sustainable manner without destroying large parts of the living systems and soil on which we depend? We don't have 100 years to figure this out; at best, we have decades. In that time frame, I know of only two viable candidates: biotechnology and information technology. I'm treating them as though they're separate, but biotechnology is really a subset of information technology because it is about DNA-encoded information.

Using information is one of the ways to increase productivity without abusing nature. A closed system like the earth's can't withstand a systematic increase of material things, but it can support exponential increases of information and knowledge. If economic development means using more stuff, then those who argue that growth and environmental sustainability are incompatible are right. And if we grow by using more stuff, I'm afraid we'd better start looking for a new planet.

But sustainability and development might be compatible if we create value and satisfy people's needs by increasing the information component of what's produced and, in so doing, diminish the amount of stuff.

With biotechnology, we know how to genetically code a plant to repel or destroy harmful insects. This means we don't have to spray the plant with pesticides - with stuff. Up to 90% of what's sprayed on crops today is wasted. Most of it ends up on the soil. If we put the right genetic information in the plant at the outset, we waste less stuff and increase productivity. It's not that chemicals are inherently bad, but they are less efficient than biology because of the raw materials and energy it takes to make, distribute, and apply them.

I offer a prediction: The early twenty-first century is going to see a struggle between information technology (including biotechnology) on one hand and environmental degradation on the other. Information technology is going to be our most powerful tool.

About the Author

Robert B. Shapiro is chairman and chief executive officer of the

Monsanto Company, 800 North Lindbergh Boulevard, St.

Louis, Missouri 63167. Telephone 1-800-325-1224; Web site

www.monsanto.com.

This article is adapted from his CEO Series essay "Trade,

Feeding the World's People and Sustainability: A Cause for

Concern," published by the Center for the Study of American

Business, Washington University, Campus Box 1027, One

Brookings Drive, St. Louis, Missouri 63130. Telephone

1-314-935-5630; Web site http://csab.wustl.edu.

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    Article A54349266

Article 17

Mike Holmberg.

Abstract: Monsanto Co's Roundup Ready corn successfully hurdled obstacles in its first year of commercial use and will likely be accepted by a substantial number of farmers in 1999. There will also be new suppliers and three Roundup ready hybrids offered in 1999.

After the first year of commercial use, it seems obvious that Roundup Ready corn will fly. The question now is how high and how fast. DeKalb was the only seed company to offer hybrids with the Roundup Ready trait last year. DeKalb now has competition in the Roundup Ready corn business - but not from Pioneer.

This year there will be new suppliers, several new Roundup Ready hybrids, and the option of applying up to 64 ounces of Roundup to a crop. DeKalb will have the Roundup Ready trait in three hybrids with new, elite genetics. The other 14 DeKalb hybrids are existing products that had Roundup Ready added to the genetic package.

Monsanto recommends three different weed management systems with Roundup Ready corn. One option is use of a residual herbicide followed by a postemergence application of Roundup Ultra. A second choice is use of a residual herbicide with the postemergence application of Roundup. And the third option is two postemergence applications of Roundup.

Brad Karlen, Reliance, South Dakota, planted about 1,400 acres of DK493RR last year but would have preferred to have the trait in DK477. He's studying the university test plots before making plans for this year.

On most of those acres, he used Roundup alone. Karlen used atrazine down on fields where he had manure coming out of the feedlot and knew he had more weed pressure. Karlen says the atrazine took the early weeds out so he didn't need to be in spraying the Roundup as quickly in those fields.

"Overall it was a bit cheaper, and we were getting better weed control." Karlen says. He also raises Roundup Ready soybeans, and doesn't want to rely on the same herbicide for both. In the long run, he expects to stick with more Roundup Ready beans than corn.

C.J. Farms planted almost 3,000 acres of Roundup Ready corn near Oxford, Nebraska, says Clyde Lueking. Some followed corn, and the rest was planted in ecofallow treated with atrazine the previous summer.

Lueking says they used a Roundup burndown at planting, then followed with 24-32 ounces of Roundup when the corn was 20-24 inches tall on about two-thirds of these fields. They tankmixed 4 ounces of Banvel on the other third to help control triazine-resistant kochia, their worst weed. With the option of a second Roundup application, Lueking says they will skip the burndown this year.

The Roundup Ready corn was all planted on dryland fields at 18,000 seeds per acre. That spread the technology fee over 4.44 acres.

Lueking says they are not as demanding in hybrid selection for dryland fields as for those being irrigated. He thinks the selection may be better suited for irrigated corn this year.

Article 18

Abstract: Genes now being developed will cause the plant seeds to be unable to reproduce as soon as they mature to protect the company's intellectual property rights. Protests have been formed and are rapidly expanding on the Internet, where the patented technology is called "Terminator." The grass roots protesters predict that this plan will cause planters be under Monsanto's control as to the prices and other demands before they can plant a crop. Even more dangerous situations could occur when Terminator plant pollen crosses with ordinary and wild plants. The result could be sudden and irreversible sterilization around the world.

For farmers hoping for a healthy harvest, the best place to turn for help these days is the Monsanto Corp. One of the world's leading biotechnology companies--and lately a pioneer in genetically engineered seeds--Monsanto has been incorporating flashy traits like herbicide and pest resistance into everything from canola to corn. But such supercrops don't come cheap. Farmers pay a premium for Monsanto seeds, and to make sure they keep paying, the company requires them to sign an agreement promising not to plant seeds their crops produce. If farmers want the same bountiful harvest next year, they must return to the company for a new load of seeds.

While this arrangement makes sense for Monsanto, it works only if farmers honor it--something that's difficult to police in the U.S. and almost impossible in the developing world. Now, however, Monsanto hopes to enforce biologically what it can't enforce contractually. With the help of clever genes currently in development, future Monsanto crops may be designed with a new feature in mind: sterility. No sooner will the company's plants mature than the seeds they carry will lose the ability to reproduce.

From Monsanto's point of view, the set of new genes--which others have dubbed Terminator--is a perfectly legitimate way to protect their intellectual-property rights. Not everybody agrees. And in the 10 months since the patent for the seed-sterilizing technology was issued, Terminator has become the focus of a grass-roots protest that is spreading through the Internet like, well, wildfire.

Let the new science take hold, opponents warn darkly, and farmers could find themselves coming to Monsanto, seed cup in hand, paying whatever the company demands before they can plant that season's crop. Worse still, some doomsday scenarios suggest, pollen from Terminator plants could drift with the wind like a toxic cloud, cross with ordinary crops or wild plants, and spread from species to species until flora all around the world had been suddenly and irreversibly sterilized.

No serious scientist thinks anything so dire will come to pass. For Monsanto, however, with a technology in its pocket and a fight on its hands, the situation is about as grim as it can get--at least in terms of public relations. "From a marketing perspective, the technology is brilliant," says biotech critic Jeremy Rifkin. "From a social perspective, it's pathological. This is a question of who controls the seeds of life."

To get a feel for the p.r. beating Monsanto is taking, check out the Web. Activist groups like Rural Advancement Foundation International are using the Net to rally Terminator opponents, urging them to flood the U.S. Department of Agriculture with letters of protest. At least 4,000 people from 62 countries have responded--an anti-Monsanto army raised by the electronic vox pop alone. "The group R.A.F.I. masterfully called this Terminator," says Gary Toenniessen, deputy director for agricultural science at the Rockefeller Foundation in New York City. "It's not what Monsanto would call it."

For all the heat Monsanto is taking, the company did not create Terminator. The technology was developed by the USDA and a Mississippi seed company known as Delta and Pine Land, and the patent was awarded to both of them. Monsanto later made a $1 billion-plus offer to buy Delta--an offer that was quickly accepted.

Opponents don't care who made Terminator. To them the idea is Frankensteinian on its face. After tweezing out a toxin-producing stretch of DNA from a noncrop plant, gene scientists managed to knit the lethal genetic material into the genome of commercial plants. They also inserted two other bits of coding that would keep the killer gene dormant until late in the crop's development, when the toxin would affect only the seed and not the plant. But because the seed company needs to generate enough product to sell in the first place, the scientists included one more DNA sequence--one that repressed all the sterilizing genes they had just inserted. Once they had grown all the seeds they needed, they would soak them in an antibiotic bath that neutralized the genetic repressor--rendering them infertile. "This is the most intricate application of genetic engineering to date," says Margaret Mellon, a senior scientist at the Union for Concerned Scientists.

But clever science isn't necessarily popular science, and Terminator has made a lot of enemies, particularly in the developing world. The USDA and Delta and Pine Land have filed Terminator patent applications in dozens of countries. In many of those countries farmers can't afford to buy top-of-the-line seeds every year and must rely on saving a portion of each crop in order to plant their fields the following year. Monsanto insists that weak patent protection in many of these countries makes a technology like Terminator especially important. But that argument carries little weight in parts of the world where food bowls are going empty. "This technology brings no benefit to farmers," says Hope Shand, research director of RAFI.

Monsanto disagrees--and not without reason. Say what they will about Terminator, even some detractors admit that the company designs a hell of a seed. The maker of one of the world's most popular herbicides, Monsanto has created crops that are resistant to the toxin. With it, farmers can spray away weeds without spraying away their harvest. The company has also developed plants with a built-in toxin that is harmless to humans but lethal to insects. If farmers in the developing world use these muscled-up crops--even with Terminator genes--their harvests might increase enough to cover the cost of buying seeds each spring. Says Delta and Pine Land vice president Harry Collins: "It will help them become more production-oriented rather than remaining subsistence farmers."

Despite the doomsday alarms being sounded by environmentalists, genetic engineers at Monsanto argue that there is no real risk of pollen from Terminator plants causing widespread sterilization in other plants--and they're probably right. Gene drift does occur, but nature doesn't make it easy. Many crops, like rice, are mostly self-pollinated. As for crops that are pollinated by wind or insects, precautions like planting border fields to keep crops isolated help confine genes. What's more, crops tend to mature at the same time--sending out a great puff of pollen all at once--while wild plants reproduce over a longer period. During the brief time Terminator pollen is in the air, relatively few wild plants would notice. "The concern over widespread escape is overblown," insists Toenniessen.

None of this has deterred Monsanto's detractors. Activists are turning up the pressure on the Internet--supporting the "Cremate Monsanto" campaign in which protesters in India have set fire to company test fields. At the same time, a lawsuit is set to be filed charging that the USDA, by supporting Terminator technology, has violated its mandate to help American farmers. Monsanto will probably respond that without Terminator genes to guarantee seed sales, the company has no incentive to develop better crops. But while such a stop-me-before-I-kill-again argument may work in a business seminar, it may not play well before a jury.

For the next few years, things should remain unsettled. Although genetic technology is progressing rapidly, it could be years before a seed containing Terminator genes is ready for market. Lawsuits challenging the technology are likely to advance more slowly still. All this gives Monsanto a chance to rethink its marketing strategy. It may decide to limit the number of Terminator crops it develops or sell supercrops to the developing world without Terminator genes. Says Terminator critic Mellon: "There are many, many opportunities for this thing not to work." What worries critics is what happens if it does.

--Reported by David Bjerklie/New York, Meenakshi

Ganguly/New Delhi and Dick Thompson/Washington

Related Article:

1 Borrowing a seed-killing toxin from another plant, genetic engineers insert it into the genome of a crop plant. In order to breed enough generations of the crop to produce a supply of seeds, the scientists also insert blocker DNA that suppresses the production of the toxin

2 Before the seeds are sold, they are immersed in a solution that induces the production of an enzyme that removes the blocker

3 After the seeds are planted and the crop matures, the toxin is produced, killing the new seeds the plants carry. Farmers who want the same crop line the next year must thus buy new seeds

COLOR PHOTO: WILLIAM MANNING--THE STOCK

MARKET [Field of crops]

COLOR ILLUSTRATION: TIME DIAGRAM BY JOE

LERTOLA [Diagram of life cycle of "Terminator" seed]

COLOR PHOTO: ROBERT NICKELSBERG FOR TIME

BOWL OF GOLD: Farmers in the developing world rely on this

year's seeds to produce next year's, and could be hurt by

Terminator [Hands holding bowl of seeds]

Article 19

A team of South Korean researchers claim to have made a step forward in cloning human cells. The researchers say they created a cloned human embryo that was a genetic replica of a 30-year-old woman. If their claim is accurate, their work would fuel debate about the controversial technology.

According to the scientists, they destroyed the cloned embryo very early in its development. They intend to grow human cells for therapeutic purposes, but do not have plans to transfer cloned embryos to a woman's womb without a consensus about the ethics of doing so, they said. Still, their announcement, which was not accompanied by any scientific evidence, promted a range of responses from various participants in the bioethics debate. "Oh my!" said R. Alta Charo, a professor of law and bioethics at the University of Wisconsin and a member of the National Bioethics Advisory Commission. "This is certainly going to make the debate surrounding cloning and the debate surrounding embryo research ever more urgent."

The Korean researchers report that they injected genetic material, or DNA, from an unidentified fertility patient's ovarian cell into one of her eggs whose DNA had been removed. The resulting embryo divided twice, into a total of four cells, before they halted the experiment in accordance with a 1993 national ban that prohibits research on embryos that are developed more fully.

While some scientists questioned the credibility of the research, several said it demonstrates that cloning work cannot be stopped. "It makes it perfectly clear that this is a worldwide phenomenon, and whatever happens in one country by passing a law or something is not going to keep people from forging ahead," commented Princeton University biologist Lee Silver. Separately, Judie Brown, president of the American Life League, warned that the news about the research in South Korea, whether scientifically accurate or not, is cause for alarm. "This report should send shock waves down the spines of all Americans who have thus far remained blind to the consequences of man's insistence that he is God," she said. --RNS

Article 20

Walter Isaacson.

Ring farewell to the century of physics, the one in which we split the atom and turned silicon into computing power. It's time to ring in the century of biotechnology. Just as the discovery of the electron in 1897 was a seminal event for the 20th century, the seeds for the 21st century were spawned in 1953, when James Watson blurted out to Francis Crick how four nucleic acids could pair to form the self-copying code of a DNA molecule. Now we're just a few years away from one of the most important breakthroughs of all time: deciphering the human genome, the 100,000 genes encoded by 3 billion chemical pairs in our DNA.

Before this century, medicine consisted mainly of amputation saws, morphine and crude remedies that were about as effective as bloodletting. The flu epidemic of 1918 killed as many people (more than 20 million) in just a few months as were killed in four years of World War I. Since then, antibiotics and vaccines have allowed us to vanquish entire classes of diseases. As a result, life expectancy in the U.S. jumped from about 47 years at the beginning of the century to 76 now.

But 20th century medicine did little to increase the natural life-span of healthy humans. The next medical revolution will change that, because genetic engineering has the potential to conquer cancer, grow new blood vessels in the heart, block the growth of blood vessels in tumors, create new organs from stem cells and perhaps even reset the primeval genetic coding that causes cells to age.

Our children may be able (I hope, I fear) to choose their kids' traits: to select their gender and eye color; perhaps to tinker with their IQs, personalities and athletic abilities. They could clone themselves, or one of their kids, or a celebrity they admire, or maybe even us after we've died.

In the 5 million years since we hominids separated from apes, our DNA has evolved less than 2%. But in the next century we'll be able to alter our DNA radically, encoding our visions and vanities while concocting new life-forms. When Dr. Frankenstein made his monster, he wrestled with the moral issue of whether he should allow it to reproduce: "Had I the right, for my own benefit, to inflict the curse upon everlasting generations?" Will such questions require us to develop new moral philosophies?

Probably not. Instead, we'll reach again for a time-tested moral notion, one sometimes called the Golden Rule and which Immanuel Kant, the millennium's most meticulous moralist, gussied up into a categorical imperative: Do unto others as you would have them do unto you; treat each person as an individual rather than as a means to some end.

Under this moral precept we should recoil at human cloning, because it inevitably entails using humans as means to other humans' ends--valuing them as copies of others we loved or as collections of body parts, not as individuals in their own right. We should also draw a line, however fuzzy, that would permit using genetic engineering to cure diseases and disabilities (cystic fibrosis, muscular dystrophy) but not to change the personal attributes that make someone an individual (IQ, physical appearance, gender and sexuality).

The biotech age will also give us more reason to guard our personal privacy. Aldous Huxley, in Brave New World, got it wrong: rather than centralizing power in the hands of the state, DNA technology has empowered individuals and families. But the state will have an important role, making sure that no one, including insurance companies, can look at our genetic data without our permission or use it to discriminate against us.

Then we can get ready for the breakthrough that could come at the end of the next century and is comparable to mapping our genes: mapping the 10 billion or more neurons of our brain. With that information we might someday be able to create artificial intelligences that think and experience consciousness in ways that are indistinguishable from a human brain. Eventually we might be able to replicate our own minds in a machine, so that we could live on without the "wetware" of a biological brain and body. The 20th century's revolution in infotechnology will thereby merge with the 21st century's revolution in biotechnology.

But this is science fiction. Let's turn the page now and get back to real science.

COLOR ILLUSTRATION: ILLUSTRATION FOR TIME BY

JERRY LOFARO COVER SPECIAL ISSUE

How genetic engineering will change us in the next century [Drawing, suggesting caduceus, of snake spiraling around stick crossed by test tubes of DNA]

COLOR ILLUSTRATION: PHOTO-ILLUSTRATION FOR

TIME BY JOHN STILL [Digital montage of items and icons of

cloning and biotechnology]

Michael D. Lemonick; Alice Park; Clare Thompson.

Gene therapy and gene-based drugs are two ways we could benefit from our growing mastery of genetic science. But there will be others as well, including new kinds of vaccines, new sources of transplant tissue, even techniques doctors may someday use to stave off the aging process. Here are just a few of the remarkable therapies on the cutting edge of genetic research that could make their way into mainstream medicine in the coming years:

While it's true that just about every cell in the body has the instructions to make a complete human, most of those instructions are inactivated, and with good reason: the last thing you want is for your brain cells to start churning out stomach acid or your nose to turn into a kidney. The only time cells truly have the potential to turn into any and all body parts is very early in a pregnancy, when so-called stem cells haven't begun to specialize.

Yet this untapped potential could be a terrific boon to medicine. Most diseases involve the death of healthy cells--brain cells in Alzheimer's, cardiac cells in heart disease, pancreatic cells in diabetes, to name a few. If doctors could isolate stem cells, then direct their growth, they might be able to furnish patients with healthy replacement tissue.

It was incredibly difficult, but last fall scientists at the University of Wisconsin managed to isolate stem cells and get them to grow into neural, gut, muscle and bone cells. The process still can't be controlled, and may have unforeseen limitations. But if efforts to understand and master stem-cell development prove successful, doctors will have a therapeutic tool of incredible power.

The same applies to cloning, which is really just the other side of the coin. True cloning, as first shown with Dolly the sheep two years ago, involves taking a developed cell and reactivating the genome within, resetting its developmental instructions to a pristine state. Once that happens, the rejuvenated cell can develop into a full-fledged animal, genetically identical to its parent.

For agriculture, in which purely physical characteristics like milk production in a cow or low fat in a hog have real market value, biological carbon copies could become routine within a few years. This past year scientists have done for mice and cows what Ian Wilmut did for Dolly, and other creatures are bound to join the cloned menagerie in the coming year.

Human cloning, on the other hand, may be technically feasible but legally and emotionally more difficult. Still, one day it will happen. The ability to reset body cells to a pristine, undeveloped state could give doctors exactly the same advantages they would get from stem cells: the potential to make healthy body tissues of all sorts, and thus to cure disease. That could prove to be a true "miracle cure." --By Michael D. Lemonick

We all know that eating fruits and vegetables is good for us, but within the next decade we could be eating broccoli not just to make Mom happy but also as a way to deliver drugs that stave off infectious diseases or that treat various chronic conditions. "The idea of vaccinating people with edible plants is very new," says Dwayne Kirk of the Boyce Thompson Institute for Plant Research in Ithaca, N.Y. "But it's a lot friendlier than injections."

Because their cells naturally produce large quantities of protein, potatoes and tomatoes seem for now to be the most efficient vehicles for the new approach. Instead of mixing viral or bacterial DNA in a formula for injection, for example, scientists could insert it into soil bacteria. When the bacteria are taken up by the plant, therapeutic DNA material is stitched into the plant's genome. Another method of getting genes into plants is to coat tiny particles of tungsten or gold with foreign DNA, then shoot the particles directly into plant cells. Either way, the plant's cells start to produce whatever proteins the new genes are designed to make. Immunization begins when the plant or its fruit is eaten, prompting the body to churn out the appropriate antibodies.

Plant-based vaccines are particularly attractive for Third World countries, where storage and distribution of drugs are a problem. Eventually, people in these areas may inoculate themselves against diseases simply by growing a crop of genetically engineered fruits or vegetables and eating a few several times a year.

The technique does not have to be limited to infectious diseases, however. It may even be useful for conditions such as Type I diabetes, in which a patient's own immune system destroys essential insulin-producing cells in the pancreas. For diabetics, eating insulin-bearing tubers could eventually train the body's defenses to stop reacting to insulin as if it were a foreign material, all without the bother--or risk--of a needle.

A SHOT FOR AGING BODY PARTS?

Eight years ago, scientists discovered that the tips of chromosomes in tissue cells shorten each time the cells replicate--until a point is reached where the cells stop dividing altogether. That point, called the Hayflick limit, comes after about 50 replications, and may be at the heart of the process we call aging.

Scientists have tried ever since to reactivate the enzyme that lengthens the tips, known as telomeres. Last January they succeeded: Andrea Bodnar and colleagues from the Geron Corp.in Menlo Park, Calif., activated the enzyme telomerase, extended the telomeres and lengthened the life-span of cells in culture by at least 20 divisions past the Hayflick limit. In November, Geron scored another first by reconstituting the telomeres of embryonic stem cells, which are renowned for their ability to turn into any type of cell, making it theoretically possible to rejuvenate parts of any organ with a simple injection.

Not everyone is convinced. Leonard Guarente, a specialist o aging from the Massachusetts Institute of Technology, observes that "telomeres seem to be important in getting cells to divide in vitro, but the onus is to show that short telomeres affect aging in vivo. I don't think we know that yet." --By Clare Thompson

Most of us can't remember our first vaccination, but chances are, it was a shot filled with a crippled microbe or perhaps parts of the bug's proteins--just enough to produce a mild infection but not the full-blown disease. Immunizing people against a host of infections in this way has worked reasonably well for more than a century, but geneticists think they can do better.

The vaccines of tomorrow are likely to be far more sophisticated concoctions, made up of snippets of raw DNA from the genome of a virus, bacterium or parasite. Using DNA, as opposed to proteins made by a microbe, elicits a more vigorous, aggressive response from the immune system. While most of the current vaccines do a good job of marshaling antibodies against an invading marauder, they often don't reliably coax the body into churning out killer T cells, the smart bombs of the immune system that strike at the offending microbes with great specificity. In early tests, DNA-based vaccines triggered both responses. For example, immunologists reported last fall that patients injected with an experimental DNA-based malaria vaccine showed not just malaria antibodies but also significant levels of killer T cells.

The potential goes beyond bugs. Because gene-based vaccines can easily be manipulated by adding or deleting DNA, doctors are applying the technique to treat various forms of cancer. The work is still limited to animals, but researchers have developed inoculations made up of tumor cells that act as a red flag to rally an animal's immune system against the tumor. "There is a long

road ahead" for these cancer vaccines, says Duke University's Dr. Eli Gilboa. "But it's very promising." --A.P.

COLOR PHOTO: ANDREW

LEONARD--PHOTORESEARCHERS RAW MATERIAL: Stem

cells like this may soon be used to grow new tissue that could

restore diseased organs

COLOR PHOTO: COURTESY DR. P.M. LANSDORP,

TERRY FOX LAB, B.C. CANCER RESEARCH CENTER,

U.B.C., VANCOUVER, CANADA KEY TO YOUTH? The

telomere tips, yellow, on chromosomes, blue, allow cells to

divide again and again

Article 22

James D. Watson.

There is lots of zip in DNA-based biology today. With each passing year it incorporates an ever increasing fraction of the life sciences, ranging from single-cell organisms, like bacteria and yeast, to the complexities of the human brain. All this wonderful biological frenzy was unimaginable when I first entered the world of genetics. In 1948, biology was an all too descriptive discipline near the bottom of science's totem pole, with physics at its top. By then Einstein's turn-of-the-century ideas about the interconversion of matter and energy had been transformed into the powers of the atom. If not held in check, the weapons they made possible might well destroy the very fabric of civilized human life. So physicists of the late 1940s were simultaneously revered for making atoms relevant to society and feared for what their toys could do if they were to fall into the hands of evil.

Such ambivalent feelings are now widely held toward biology. The double-helical structure of DNA, initially admired for its intellectual simplicity, today represents to many a double-edged sword that can be used for evil as well as good. No sooner had scientists at Stanford University in 1973 begun rearranging DNA molecules in test tubes (and, equally important, reinserting the novel DNA segments back into living cells) than critics began likening these "recombinant" DNA procedures to the physicist's power to break apart atoms. Might not some of the test-tube-rearranged DNA molecules impart to their host cells disease-causing capacities that, like nuclear weapons, are capable of seriously disrupting human civilization? Soon there were cries from both scientists and nonscientists that such research might best be ruled by stringent regulations--if not laws.

As a result, several years were to pass before the full power of recombinant-DNA technology got into the hands of working scientists, who by then were itching to explore previously unattainable secrets of life. Happily, the proposals to control recombinant-DNA research through legislation never got close to enactment. And when anti-DNA doomsday scenarios failed to materialize, even the modestly restrictive governmental regulations began to wither away. In retrospect, recombinant-DNA may rank as the safest revolutionary technology ever developed. To my knowledge, not one fatality, much less illness, has been caused by a genetically manipulated organism.

The moral I draw from this painful episode is this: Never postpone experiments that have clearly defined future benefits for fear of dangers that can't be quantified. Though it may sound at first uncaring, we can react rationally only to real (as opposed to hypothetical) risks. Yet for several years we postponed important experiments on the genetic basis of cancer, for example, because we took much too seriously spurious arguments that the genes at the root of human cancer might themselves be dangerous to work with.

Though most forms of DNA manipulation are now effectively unregulated, one important potential goal remains blocked. Experiments aimed at learning how to insert functional genetic material into human germ cells--sperm and eggs--remain off limits to most of the world's scientists. No governmental body wants to take responsibility for initiating steps that might help redirect the course of future human evolution. These decisions reflect widespread concerns that we, as humans, may not have the wisdom to modify the most precious of all human treasures--our chromosomal "instruction books." Dare we be entrusted with improving upon the results of the several million years of Darwinian natural selection? Are human germ cells Rubicons that geneticists may never cross?

Unlike many of my peers, I'm reluctant to accept such reasoning, again using the argument that you should never put off doing something useful for fear of evil that may never arrive. The first germ-line gene manipulations are unlikely to be attempted for frivolous reasons. Nor does the state of today's science provide the knowledge that would be needed to generate "superpersons" whose far-ranging talents would make those who are genetically unmodified feel redundant and unwanted. Such creations will remain denizens of science fiction, not the real world, far into the future. When they are finally attempted, germ-line genetic manipulations will probably be done to change a death sentence into a life verdict--by creating children who are resistant to a deadly virus, for example, much the way we can already protect plants from viruses by inserting antiviral DNA segments into their genomes.

If appropriate go-ahead signals come, the first resultine gene-bettered children will in no sense threaten human civilization. They will be seen as special only by those in their immediate circles, and are likely to pass as unnoticed in later life as the now grownup "test-tube baby" Louise Brown does today. If they grow up healthily gene-bettered, more such children will follow, and they and those whose lives are enriched by their existence will rejoice that science has again improved human life. If, however, the added genetic material fails to work, better procedures must be developed before more couples commit their psyches toward such inherently unsettling pathways to producing healthy children.

Moving forward will not be for the faint of heart. But if the next century witnesses failure, let it be because our science is not yet up to the job, not because we don't have the courage to make less random the sometimes most unfair courses of human evolution.

James Watson and Francis Crick won a Nobel Prize for Medicine for their 1953 discovery of the structure of DNA. Watson was the first director of the Human Genome Project; he now serves as president of Cold Spring Harbor Laboratory

B/W PHOTO: CORBIS-BETTMANN THE PIONEERS:

Watson, left, and Crick pose with a model of DNA in 1953,

shortly after deducing its structure [James Watson and Francis

Abstract: Scientific and medical advancements in the latter stages of the twentieth Century have allowed for genetic engineers to tamper with the genetic makeup of organisms. Though it might seem like a novel idea to alter undesirable traits, many take a stance that it is morally and ethically wrong.

Full Text: COPYRIGHT 1999 Society for the Advancement of

Education

Scientists seeking ways to produce enhanced size, strength, intelligence, or resistance to toxic substances are being accused of "playing God."

GENETIC ENGINEERING involves directly altering the genetic structure of an organism to provide it with traits deemed useful or desirable by those doing the altering. Genetic engineering of plants and animals has been going on since the 1970s, though attempts to introduce such traits through selective breeding has been going on for centuries.

The most straightforward use of genetic engineering involves producing a plant or animal with "improved" characteristics. In the case of agriculture, for example, genetic engineering has produced crop plants resistant to lower temperatures, herbicides, and insect attack, as well as tomatoes with a longer shelf life. A completely different type of genetic engineering involves transplanting a gene, usually human, from one species to another in order to produce a useful product. A patent already has been applied for to mix human embryo cells with those from a monkey or ape to create an animal that might have kidneys or a liver more suitable for transplantation to human beings. There seem to be no limits to the creatures made possible by genetic engineering--e.g., creating edible birds and mammals with minimal brain functions, including no consciousness, so as to avoid protests about the cruelty involved in raising and killing conscious animals for food.

Although particular instances of genetic engineering of plants and animals have caused some controversy, mostly because of environmental or health concerns, genetic engineering is a generally accepted practice. The major moral controversy concerns whether to allow directly altering the genetic structure of human beings. Genetic engineering done by altering the somatic cells of an individual in order to cure genetic and non-genetic diseases has not been controversial. Indeed, what is known as somatic cell gene therapy is becoming a standard method for treating both kinds of diseases. Unlike the genetic engineering used in plants and animals, somatic cell gene therapy alters only the genetic structure of the individual who receives it; the altered genetic structure is not passed on to that individual's offspring. However, now that large mammals such as cows and sheep can be cloned, it may be possible that genetic engineering done by altering somatic cells in human beings may be passed on to future generations of human beings.

Presently, somatic cell genetic engineering is limited to therapy--there has not even been a proposal to use it for enhancement. Clinical trials using human patients have demonstrated the feasibility of somatic cell gene therapy in humans, successfully correcting genetic defects in a large number of cell types. In principle, there is no important moral distinction between injecting insulin into a diabetic's leg and injecting the insulin gene into a diabetic's cells.

The most serious moral controversy concerns the application to human beings of the kind of genetic engineering used on plants and animals. This type of human genetic engineering, usually referred to as germ line gene therapy, is regarded by some as the best means to correct severe hereditary defects such as thalassemia, severe combined immune deficiency, or cystic fibrosis. Many believe, though, that genetic engineering to treat or eliminate serious genetic disorders--the practice of negative eugenics--will lead to the process being directed toward enhancing or improving humans, or positive eugenics. This slippery slope argument presupposes that there is something morally unacceptable about positive eugenics, but that has not been No one yet has provided a strong argument demonstrating that genetic engineering to produce enhanced size, strength, intelligence, or increased resistance to toxic substances is morally problematic.

Eugenics properly has a bad connotation because, prior to the possibility of genetic engineering, eugenics only could be practiced by preventing those who were regarded as having undesirable traits from reproducing. Genetic engineering allows for positive eugenics without limiting the freedom of anyone. The moral force of the objection that genetic engineering, especially positive eugenics or genetic enhancement, is "playing God" is that we do not know that there are no risks. A proper humility and recognition of limited human knowledge and fallibility is required for reliable moral behavior. A strong argument for concluding that genetic enhancement and perhaps even genetic therapy is morally unacceptable is that it risks great harm for many in future generations in order to provide benefits for a few in this one.

Two standard arguments have been put forward that even negative eugenics should not be practiced. The first is that it will result in the elimination of those deleterious alleles (alternate forms of a gene) which may be of some future benefit to the species. The argument is that the genetic variation of a species affords evolutionary plasticity or potential for subsequent adaptation to new and perhaps unforeseen conditions. To eliminate a deleterious mutant allele, like those responsible for cystic fibrosis or sickle cell anemia, could have some risk. It generally is agreed that the recessive gene responsible for sickle cell anemia evolved as an adaptive response to malaria.

This argument is false for two different reasons. The first concerns the nature of genetic maladies. For those based on the inheritance of recessive alleles, it is not the presence of two mutant alleles that causes the malady, but the absence of a normal allele. As long as a normal allele is present, the mutant ones do not cause a genetic disorder. In the case of sickle cell anemia, gene therapy for recessive disorders will work, even though the mutant and non-functional alleles remain. When it is possible not merely to add a gene, but to replace a non-functional mutant allele, the latter no longer will remain. No evolutionary problem is caused by eliminating dominant genes that cause serious genetic disorders such as Huntington's disease.

Almost all genetic disorders are caused by recessive genes, and it seems quite unlikely that there will be any serious attempt to eradicate these genes from the human gene pool, even if it becomes possible and desirable. The technology required must be applied on an individual basis with rather limited accessibility Because it is a surgical procedure, germ line gene therapy would be done in a medical setting and on a voluntary basis. Although many couples might qualify for gene therapy, just a small number likely would elect to participate. For example, if germ line gene therapy involving gene replacement could be developed for Tay Sachs and was used to treat all embryos showing the disease, the frequency of the Tay Sachs allele in the entire population merely would decrease from 0.0100 to 0.0099 over a generation.

The second argument is an iatrogenic (produced inadvertently in a medical procedure) one. The claim is that, since it is impossible to draw a non-arbitrary line that distinguishes positive from negative eugenics by defining what a genetic disorder is, genetic therapy may cause more serious maladies in future generations than it prevents for the present one. However, genetic conditions like hemophilia, cystic fibrosis, and muscular dystrophy all share features common to other serious diseases or disorders, such as cancer. An objective and culture-free distinction can be made between genetic conditions that everyone counts as diseases or disorders and those that no one does. Even if there are some borderline conditions, it is theoretically possible to limit genetic engineering to those conditions about which there is no disagreement. The topic of what counts as a malady--in particular, what counts as a genetic malady--is important for it may affect not only what conditions will be covered by medical insurance, but which ones are suitable for gene therapy. If genetic engineering is used just to cure serious genetic maladies such as Tay Sachs, it is extremely unlikely that more serious genetic maladies will be created in the future.

While there is no theoretical reason for not using germ line gene therapy, there is a persuasive argument which concludes that all forms of germ line genetic engineering involving humans should be prohibited. This argument, similar to the one against genetic enhancement, claims that even genetic therapy risks great harm for many in future generations, and that there is not sufficient harm prevented to justify these risks. Genetic therapy, like genetic enhancement, not only is permanent during the entire lifetime of the affected individual, the transgene becomes inheritably transmitted to countless members of future generations.

New facts about basic genetic phenomena are being discovered--e.g., five human genetic disorders have been found that are based on mutations involving expandable and contractible trinucleotide repeats. This baffling and novel mechanism for producing mutations was unpredicted, and there currently is no complete explanation for its cause. Similarly, geneticists have discovered another novel and unpredicted phenomenon--genetic imprinting. For a small, but significant, fraction of genes, in humans and other species, the expression of the gene during early embryonic development varies according to its paternal or maternal origin. The biological role of imprinting and th molecular mechanism responsible for selective gene expression remain mysteries. Nevertheless, the effect of genetic imprinting and trinucleotide expansion may be critical in terms of carrying out germ line gene therapy. Problems might not be discovered until the third or fourth generation. Moreover, it seems likely that unpredicted future facts about basic genetic phenomena will be discovered which carry similar risks.

Given even this small possibility of significant harm to many, an analysis of risks and benefits indicates that germ line gene therapy would be justified just in cases of severe maladies, and then only if there were no less radical way of preventing them from occurring. Pre-implantation genetic screening, whereby embryos first are produced by in vitro fertilization, does provide such an alternative. At an early blastocyst stage of development, when the embryo is at the eight- or 16-cell stage, a single embryonic cell is removed and screened, genetically, for the presence of defective alleles. If analysis reveals that the fetus would develop a severe genetic malady, the embryo would not be implanted. If the embryo has no severe genetic malady, uterine implantation would be carried out so that normal development could occur.

Pre-implantation screening can eliminate essentially all severe genetic maladies that could be eliminated by genetic engineering. For those with religious or metaphysical beliefs that prohibit destroying any fertilized human egg, it should be pointed out that genetic engineering usually involves creating more fertilized eggs than one plans to use, since implanting of any fertilized egg, including a genetically altered one, often is not successful.

Consequently, pre-implantation screening eliminates the need for germ line gene therapy. The number of cases whereby both parents carry the genes for a rare deleterious recessive allele, such as cystic fibrosis, are microscopically small. Genetic engineering, then, is necessary only for improving or enhancing people by adding new genes for strength, intelligence, or resistance to pathogens or toxins. Genetic engineering to add improvements, rather than to eliminate defects, may give rise to serious social and political problems.

Moreover, gene therapy will be, for the foreseeable future, a very expensive procedure, so only the wealthy will be able to afford it. Germ line gene therapy probably comes as close as is humanly possible to guaranteeing that those families who can afford it will be able to perpetuate their social and political dominance. Thus, together with cloning, it may give rise to a genetically stratified society, as envisioned in Aldous Huxley's novel, Brave New WorM. Once this technology is well-developed, it can be used by societies in which those in power are not governed by ethical restraints. Individuals may be genetically engineered to provide various tasks--e.g., as warriors. Imagine a group of people engineered to be resistant to various poisonous gases. Still, these concerns, although genuine, are speculative.

On the other hand, scientists know from experience that cutting-edge technology generates pressures for its use. Consequently, it is likely that, if genetic engineering were permitted, the technology would be utilized inappropriately, employed even when a comparable outcome could be accomplished using a less risky method. There is justified concern that genetic engineering advocates will make claims that the risks are less than they really are and the benefits are greater than will be realized. It is at least disconcerting that proponents of germ line gene therapy do not talk at all of the far less risky alternative of pre-implantation screening.

If every scientist, administrator, and venture capitalist involved in applying and commercializing genetic engineering were appropriately thoughtful, there would be much less reason to prohibit development and application for those rare cases in which it could be the therapy of choice. However, based on the cited risks, there is insufficient potential benefit to justify any human genetic engineering. Until certain knowledge of the real risks and benefits associated with human genetic engineering has been obtained, the potential risks to all of the future descendants of the patient outweigh any benefit to a very small number of persons who might benefit. In the event of an unanticipated harmful outcome of genetic engineering using mice or corn, the transgenic organisms can be killed, but clearly this option can not be used with humans.

It takes just a few scientists who have convinced themselves that they know the risks are imaginary and the benefits are real for human genetic engineering to become a field in which researchers compete to be first. National and international recognition, prizes, awards, patents, grants, and other measures of status, wealth, and power are potent incentives to overstate successes and benefits, take unacceptable risks, and dismiss valid objections. The extraordinary loyalty of scientists to one another, resulting in their reluctance to interfere with any research project that their colleagues wish to pursue, makes it very likely that some misguided projects will be carried out.

Technology can not justifiably be used to provide benefits to only a few, even if such benefits are great. In cases where no great harm is being prevented and a large number of people may be put at significant risk, caution must prevail. Even if there is no chance of completely stopping germ line gene therapy, it may be possible to delay it long enough that the technology is developed that enables scientists to repair a gene, rather than replace it. Similarly, it might have been better if the building of nuclear power plants had been delayed until they were designed so that there would be virtually no chance of a nuclear explosion. Indeed, it might have been better to postpone building them until acceptable plans for disposing of nuclear wastes had been developed.

The Human Genome Project involves mapping the entire genome--that is, showing where each gene is located, not only which chromosome it is on, but where on that chromosome. This project was sold to Congress in a somewhat misleading way, its proponents claiming that, by finding the genes responsible for major genetic maladies like cystic fibrosis, as well as those that provide dispositions for standard maladies like cancer and heart disease, scientists better would be able to prevent and cure these conditions. That was true, but the whole Human Genome Project was not needed for this purpose. Most scientists were not so optimistic about it, and there was difficulty in lobbying Congress to appropriate all that money. The solution was to pick just those scientists who were on the optimistic fringe to testify before Congress

The Human Genome Project also involves sequencing each gene--that is, showing how it is built up out of the base pairs that make up a gene. Most defective genes involve a change in a few of these base pairs, often merely one. Gene repair involves changing the base pair causing the problem. This form of geneti engineering has far less potential for disaster or misuse than the kind being considered. Further, the concept of gene repair reinforces the difference between gene therapy and gen enhancement. It would be inappropriate to regard making any change in a gene as repairing it unless that gene is both different from the standard form and results in some genetic malady. Limiting human genetic engineering to the repairing of genes dramatically would lessen the risks of such engineering while no preventing any of its therapeutic benefits.

Application of common moral reasoning to the question of human genetic engineering--both gene therapy and genetic enhancement--thus seems to lead to a natural solution. The present lack of knowledge should restrict genetic engineering to genetic repair. Such a limitation allows the prevention of all the evils of more expansive forms of genetic engineering while not incurring any of the risks. Given this alternative, allowing any more expansive form of genetic therapy or genetic enhancement does not seem morally acceptable.

Dr. Gert is the Eunice and Julian Cohen Professor for the Study of Ethics and Human Values, Dartmouth College, Hanover, N.H.

Article 24

Don't look for the southern French town of Montredon on your globe. It isn't even on local road maps, perhaps because it has only 20 inhabitants. But one of them, a Parisian intellectual turned activist-farmer named Jose Bove, may change that. He's the leader of the mobs of farmers who've trashed several McDonald's in France lately. Last week, with 200 supporters chanting outside the jail, Bove declined a Montpellier court's offer of bail and remained behind bars, the better to spotlight his cause. And that would be? "To fight against globalization and advance the right of people to eat as they see fit," he explained. Grievance No. 1: the U.S. desire to export genetically modified crops and foods. So far, so French, right? But spin that same globe to Peoria, Ill., home of U.S. agribusiness giant Archer Daniels Midland. There, even as Bove's judges readied their decision, the self-styled "supermarket to the world" was demonstrating that the customer is, indeed, always right. In a fax to grain elevators throughout the Midwest, ADM told its suppliers that they should start segregating their genetically modified crops from conventional ones, because that's what foreign buyers want. It didn't matter that GM crops are widely grown by U.S. farmers, and that there's no evidence that the taco chips and soda you're enjoying right now are anything worse than fattening. ADM had noticed something new sprouting under the bright, warm sun of economic interdependence: a strange hybrid of cultural and economic fears. So it decided to act before the problem got any bigger.

Public opposition to GM foods in Europe has been mounting for more than two years, especially in Britain and France. Both Prince Charles and Paul McCartney have come out against the stuff. Now the protests and the tabloid headlines about "Frankenstein Foods" have reached such a pitch that they're reverberating across the Atlantic. Secretary of Agriculture Dan Glickman, a longtime backer of biotechnology, admitted as much in a key speech in July. So did Heinz and Gerber when they announced the same month that they'll go to the considerable trouble of making their baby foods free of genetically modified organisms. Groups such as Greenpeace, which have long fought biotech on both continents, are crowing. U.S. trade officials, who face a tough fight keeping markets open for American agricultural products, are worrying. And U.S. consumers, who have never really thought much about genetically modified foods, are just plain confused.

As well they might be, given the vastly different experiences the United States and Europe have had. In the United States, the FDA issued a key ruling in 1992 that brought foods containing GM ingredients to market quickly, and without labels. Companies such as Monsanto introduced herbicide-resistant soybeans and corn that makes its own insecticide. U.S. farmers loved the products; by 1998, 40 percent of America's corn crop and 45 percent of its soybeans were genetically modified. In Europe, meanwhile, there was no real central regulator to green-light the technology and allay public concerns, and many more small farmers for whom biotech represented not an opportunity but a threat. Leaders have tried to steer a course between encouraging a new industry and giving the voters what they want, including labeling rules.

So, to each his own, right? Not in 1999. If Europe is selling America Chanel perfume and Land Rovers, America will want to sell Europe its soybeans and corn--and maybe even its fervent faith in progress. While European biotech companies such as Novartis avoided the limelight, St. Louis-based Monsanto decided to press its case. The timing was terrible. GM fears were already running high last summer when Monsanto ran an informational campaign; Britain's 1996 bout with mad-cow disease, though unrelated, had weakened European confidence in regulators and industrial-strength agriculture. Monsanto's PR effort only made the mood worse, as have a string of bad-news food headlines since then: dioxin-contaminated chicken in Belgium last spring; tainted Coke in Belgium and France this summer, and a punitive U.S. tariff on imports of foie gras and other products, imposed in July because Europe won't accept American hormone-fed beef.

That last, also nongenetic, dispute actually triggered the vandalism at McDonald's last month. But to many of France's famously irascible small farmers, it's all of a piece. Even among the broader public in France and Britain, the GM-foods issue seems to be intersecting with second thoughts about globalization. French farmers protest American imperialism. But just last week their biggest customers, grocery giants Carrefour and Promodes, announced a $16.5 billion merger that will position them well in a global battle with America's Wal-Mart--and put further cost pressures on farmers. Britain is a hotbed for Internet start-ups. But Brits still tune in to the BBC radio soap "The Archers" to see if young Tommy will go to jail for helping a group of eco-warriors wreck a GM-crop trial site on his uncle's land.

Would an American jury let Tommy go? Probably not. Consumers Union, whose Consumer Reports magazine features a big piece on GM foods this month, has put together an array of poll data suggesting Americans would like to see GM food labeled, but remain interested in its benefits. Of course, if Tommy's trial were held in Berkeley, Calif., where the school board has announced a ban on GM foods, he might walk.

U.S. activists, encouraged by the successes of their European brethren, hope to build on such sentiments. Some of the rhetoric is extreme, and one group--or perhaps it's just one person--has resorted to vandalism, trashing a test-bed of GM corn at the University of Maine last month and crediting the act to "Seeds of Resistance." But there's science going on, too. A Cornell University study published in the journal Nature in May found that half of a group of monarch-butterfly caterpillars that ate the pollen of insecticide-producing Bt corn died after four days. What if the pollen spreads to the milkweed the monarchs lay their eggs in? "The arguments aren't enough to say we shouldn't have any biotechnology," says Rebecca Goldburg of the Environmental Defense Fund. "But they are enough to say we should be looking before we leap."

Of course we should, says Gordon Conway, president of the Rockefeller Foundation and an agricultural ecologist. Invited to speak to the Monsanto board in June, he used the forum to talk about the need to go a little slower. But, he adds, don't worry about the monarch. Bioengineers can stop the pesticide (which is supposed to kill caterpillars; they eat the corn) from being expressed in pollen. "There are always problems in the first generation of a new technology," he says. And, he adds, successes. The foundation just unveiled a genetically modified rice grain it funded to improve nutrition in the developing world. If a shouting match over GM foods should derail such not-for-profit efforts, he says, "that would be a tragedy."

Agriculture Secretary Glickman doesn't see Americans growing as fearful as Europeans, mainly because he thinks Americans have more faith in their regulators. He also thinks that labeling of GM foods is a big part of the answer--not mandatory labeling, which industry opposes and activists demand, but voluntary labeling. "I'm not going to mandate this from national government level," he told News-week, "but I believe that more and more companies are going to find that some sort of labeling is in their own best interest." Especially companies that want to export.

Because, as ADM showed with its heartland-stopping announcement on Thursday, it isn't only up to Americans anymore. Brian Kemp, a Sibley, Iowa, farmer, made an urgent call to his elevator on Thursday to see if it would still buy his GM corn. It will--this year. "Europe is so important to the industry that it could mean we'll really have to pull back on growing GM crops in this country," says Walt Fehr, head of Iowa State University's biotech department. "Given the choice, who wants to grow GM?"

Glickman says the trade issue--which is sure to generate plenty of heat at the November World Trade Organization meeting in Seattle--will be a tough one to resolve. "But I think over the next five years or so we can get it done." That's a mighty slow pace, considering how quickly the industry came along in the previous half decade. But then, you generally do travel faster when you travel alone.

With John Barry in Washington, Scott Johnson in Montpellier, Jay Wagner in Des Moines, William Underhill in London and Elizabeth Angell in New York

Article 25

Abstract: Cloning has presented an ethical challenge to US policymakers. While cloning offers significant scientific and medical benefits, its social implications are unclear. Several solutions can maximize benefits and reduce unethical applications. These include a ban on cloning for reproducing human infants, without prohibiting other human-based procedures that can provide important discoveries.

The announcement by Wilmut, et al., in February 1997 that a lamb had been produced by transferring the nucleus of a cell from an adult sheep into an enucleated egg cell and implanting it took most people by surprise [1]. This largely unanticipated development demonstrates that asexual reproduction of mammals can be brought about, with the possibility it may also work in humans. This development has many implications that need to be thought through so that sensible and ethical policy can be put in place. This paper outlines the technology, explores possible applications and their social and ethical consequences, and suggests what reasonable and acceptable policy in this area might be.

The term cloning is used by scientists to describe different processes that make duplicates of biological material. Growing cells in culture so that cell lines are produced, or making multiple copies of particular DNA sequences by inserting them into bacteria and growing them, are both referred to as cloning. These uses of cloning do not produce individual organisms, but there are many uses of cloning in the production of plants and agricultural products where new organisms are produced--for example, taking cuttings from one plant and propagating these genetic copies of it. However, it has not been possible to make copies of vertebrates in this asexual way until recent years. There are two cloning methods that can be used to produce copies of higher organisms asexually: embryo splitting and nuclear transplantation (transfer) from somatic cells.

The first method has been possible for some time and is used in animal husbandry for commercial purposes. It is usually termed "embryo splitting" but may also be called "blastomere separation." Within several cell divisions after fertilization of the egg, when the developing organism is still a small cluster of undifferentiated cells (blastomeres), the cells making it up can be disaggregated. At this early stage, each cell is still capable of giving rise to a complete embryo (that is, it is totipotent) if it is implanted.

Embryo splitting was used for the first time to produce additional human embryos in 1992, when investigators divided 17 chromosomally abnormal human embryos (which they therefore would not have implanted in a woman, and so which were not going to survive). From these embryos, they obtained a total of 48 developing embryos in vitro [2].

The second kind of cloning to produce an animal--the one that made headlines with the birth of Dolly--was done quite differently. A genetic copy of an adult animal was made, by-passing the usual reproductive process. An egg cell from one sheep was emptied of its nucleus and then fused with a somatic cell containing the nucleus of another adult sheep. This was then implanted in the uterus of yet another ewe. Dolly doesn't have two genetic parents, rather her genomic DNA is a copy of the DNA in the nucleus of an adult animal. In other words, she is a clone of that adult.

Many researchers have tried in various species of animals to clone individuals from somatic cells, but have had little success. In amphibians, using a donor nucleus from an adult in an enucleated egg produced developing individuals, but these all died at the tadpole stage [3]. The key to Wilmut's success, where so many others had failed, seems to have been in using a method that made the donor nucleus and the cytoplasm of the recipient oocyte able to work together. He starved of nutrients those cells that would be used to provide the nucleus, to induce the nucleus into a quiescent phase of the cell cycle where many genes are shut down--the GO phase [1]. In the GO phase, cells contain only one complete set of chromosomes, whereas in later cell cycle phases the DNA is replicated in preparation for cell division (mitosis) so that cells have a duplicate copy of each chromosome (one copy will go to each daughter cell). If a nucleus were transferred in this later phase and then instructed by cytoplasmic factors in the egg to duplicate for cell division, the new cell would end up with too much DNA and chromosomal abnormalities [4]. The approach using a GO phase donor cell seems to facilitate reprogramming of the new DNA by factors in the egg cytoplasm so that cell division and further development occur normally.

There is another aspect that may also have been important: the timing of when the DNA is "turned on" (transcribed) in the sheep. This event marks the transition from maternal to embryonic control of development. Until the genes are turned on, proteins and m RNAs already in the egg cytoplasm carry out the work needed for the early cell divisions to occur. Transcription from the DNA of the embryo doesn't begin in the sheep until the 8 to 16 cell stage. Because the genes do not turn on until then, it may give time for the transferred-in DNA to receive signals from the cytoplasm of the recipient oocyte so that they work in harmony at cell division. In some other species where the genes in the DNA are turned on and transcribed at an earlier stage, there may not be the chance for this "reprogramming" of DNA to occur [5]. This may be a reason why cloning by nuclear transfer has not worked until recently in the mouse, since in mice transcription from the DNA occurs by the late two-cell stage [6]. In humans activation of the embryonic genome occurs at the four-cell stage [4].

In theory, large numbers of genetically identical individuals could be produced by nuclear transfer cloning, followed by splitting the embryo into constituent totipotent cells. In practice, there is a limit to the number of individuals that can be produced in a given period of time from one originating embryo, as beyond a certain number, cells in an embryo lose their totipotency. Because the cells taken to produce the cloned lamb were from the mammary gland of a sheep that was pregnant, the theoretical possibility was raised that they may have been undifferentiated fetal stem cells, but experiments to evaluate this possibility have shown this is not the case [7]. A Japanese group recently reported that they had produced two calves by nuclear transplantation cloning from adult somatic cells of a cow [8], and an American group have now cloned mice from adult somatic cells [9]. In addition, an Oregon group has used nuclei from cells of rhesus macaque monkey embryos (at the eight-cell stage) transferred into enucleated oocytes and has produced liveborn animals, so the techniques are in place to do this in primates [10].

There is an important difference between the embryo splitting and nuclear transfer methods of cloning. In outbred species (such as humans), if the embryo is split one has no way of predicting what the characteristics of that embryo will be, whereas if nuclear transfer is used, the nucleus may come from an adult whose characteristics can be known. This enables selection by known characteristics. As discussed later, this feature raises serious ethical and social issues. In essence, the new technique of nuclear transfer allows the asexual replication of a particular human being, the ability for the first time to predetermine the full complement of nuclear genes of a child, and the possibility of making many genetically identical individuals.

It is worth noting that we need new vocabulary to deal with this area. For example, the National Bioethics Advisory Committee in the United States refers to Dolly as a "delayed" genetic twin of an adult sheep. Although a clone and its source are genetically as similar as identical twins are, identical twins are not produced by deliberate human agency, and they always have developed simultaneously. Given Dolly was a deliberate copy of an adult animal, brought into being after her genome source had fully developed as an adult, this seems an inappropriate use of the term twin. Dolly is a deliberate genetic replica by asexual means of an adult animal. Replicand seems a more accurate term than "delayed twin."

Agricultural animals.--Multiple copies of particularly useful or valuable livestock could be made (gestating them in less valuable animals) so that a herd of high-yield animals would be produced. Either cloning method could be used, as in inbred species the likely physical characteristics (for example, milk, wool, or meat yield) of offspring are known, so it can be determined which embryos should be split to achieve this goal.

Biopharmaceutical production in animals.--Currently it is a difficult and slow process to produce transgenic animals which have useful traits, such as producing human clotting factor or insulin in their milk, yet such proteins may be useful in the treatment of people who have a variety of diseases [11]. Once such an animal is produced, it theoretically would be possible to make many copies of it by nuclear transfer, thus facilitating the production of biologicals for medical purposes. Not only that, in future nuclear transfer might also allow a more efficient production of transgenic animals in the first place. For example, a human gene could be introduced into cultured cell lines which could be screened for expression of the transgene, and those cells expressing it could be used as the source for nuclear transfer into a recipient egg.

Disease research using "knockout" animal models.--There are now techniques whereby a particular gene can be "knocked out" in an animal, thus producing a model of a particular genetic disease. In theory, multiple copies of such animals would be more efficiently obtained by nuclear transfer, gestating the new animals in stock animals. The availability of these genetically identical animals could facilitate research into the mechanisms of genetic disease, with better understanding leading to treatments.

Transplantation of organs or tissues.--Nuclear transfer cloning might also be used for making multiple copies of transgenic animals which have been altered so that their organs have human tissue antigens and could be used for organ transplantation.

Basic research on differentiation and development.--In the long term, understanding of many diseases will be facilitated by the availability of the genetically identical animals described above, but in addition, over time nuclear transfer is also likely to prove useful as a tool to study many biological processes such as aging, control of gene expression, gene imprinting, and the interaction of cytoplasmic factors with nuclear genes. What controls interaction between genes in the nucleus and the constituents in the cytoplasm--will it be possible to use an oocyte from one species and a nucleus from another? Such studies may lead to an understanding of how the cellular environment and factors in it interact with DNA to bring about gene expression in an appropriate way in differing tissues. The fact that Dolly was born shows that even inactive genes in adult differentiated cells can be switched on again (to direct development). An understanding of this may make it possible to activate or turn off almost any gene, and thus allow cells to be reprogrammed to divide and produce tissues with desired characteristics. There are hopeful prospects for repair and regeneration of damaged or diseased human tissues or organs from this approach. It is possible it could lead to many useful applications--getting injured spinal nerve cells to regenerate, for example. It may even be possible in future to guide differentiation along a path to produce specific tissues directly, not via a stage of producing a complete embryo. Much research in animals would be needed before it would become clear if this would be possible using human somatic cells and enucleated egg cells.

Conservation of endangered species.--Cloning by nuclear transfer is not all simply for human benefit and exploitive of other species--it may have some benefits to animals as well. It is theoretically possible that existing collections of frozen somatic cells from endangered species might be used to produce additional individuals that could help preserve these species. Cloning could even be used to increase the genetic diversity of a threatened species by reintroducing "lost" genes, present in the frozen collections, back into the population [12].

In summary, there are many potential uses of cloning animals which may provide therapeutic benefits and be acceptable to most people if done humanely.

As a preamble, it is worth noting that it is simplistic and misinformed to think that making a genetic copy of someone will mean that person is completely identical. Although those characteristics that are monogenic or very strongly genetically determined will be identical--for example, HLA haplotypes--those characteristics that are the outcome of a complex interplay between genetic endowment and the rearing, social, emotional, physical, chemical, and nutritional environment will differ. Both genes and environment are always necessary to develop a person, and they interact and modify each other for many characteristics. As well, the resulting human person would have different mitochondrial genes, unless a nucleus from a woman's somatic cell were put into one of her own eggs.

Cloning used to produce a human individual is rejected by the overwhelming majority of people, but there may be some who would wish to pursue cloning because they see potential advantages to themselves. Although polls on new scientific developments clearly have limitations, it is of interest that the Economist reported in April 1997 that 6 percent of Americans liked the idea of cloning themselves [13]. Some foreseeable situations where individuals may want to pursue cloning include:

* Couples where both have no gametes, or where the male produces no sperm. These situations are extremely rare, given new treatment techniques using immature spermatids and even earlier stem cells [14]. In the first case, an oocyte would have to be donated, and the male's somatic cell could be fused with it. A couple may wish this because both then participate in producing the child--she to carry the pregnancy, he to provide DNA.

* A woman who has few oocytes. Cloning by embryo splitting might give a better chance of conception because more embryos would be implanted.

* A lesbian couple. A couple could use one partner's somatic cell and the enucleated oocyte of the other, to produce a child together.

Even though there are options (sperm donation, egg and embryo donation, adoption) available to people in the three scenarios above, the growing trend in some sectors of society of seeing a genetic connection to offspring as being of central importance may mean they would want to use cloning to produce a child.

Other situations might also arise. For example, a couple's beloved child is dying, and they wish to replace him by using one of his cells in nuclear transfer cloning so they may raise an "identical" child. To clone a child who dies because it is thought the clone will be a replacement is disrespectful of human individuality and devalues the individual brought into the world this way. Such individuals would be simply "substitutes," not valued for themselves. In another scenario, a wealthy individual wishes to have a clone of himself so that a compatible organ donor is in his employ if he ever needs one. In theory, any individual who wished to have a clone of himself (or of another individual) made could pay a laboratory to do so. He would have to obtain eggs for enucleation, and a woman to carry the pregnancy to term, and hand over the baby. However, it is already possible in the United States to buy eggs and to hire women to carry a pregnancy to hand over the baby, for a fee. While few women are prepared to do this, if people are needy, money can buy many things--certainly, body organs have been bought in some countries. The limitations and obstacles to cloning by nuclear transfer mean that it is unlikely for it to be pursued for this purpose--although not impossible.

By and large, the prospects of making human beings by the technique of cloning have elicited deep concern. Since Wilmut's announcement, there have been calls for a worldwide ban on human cloning by many political leaders (such as the French president and Germany's research minister) and by religious leaders, including the Vatican. In the United States, federal funding for research on human cloning has been banned by President Clinton [15]. He also immediately asked the National Bioethics Advisory Commission to study the issue and report back within 90 days [16]. When they did so in June 1997, they unanimously recommended legislation "to prohibit anyone from attempting, whether in a research or clinical setting, to create a child through somatic cell nuclear transfer cloning" in both private and public laboratories, on the grounds of harm to the resulting child in the present state of knowledge. They did not agree on whether the ban should be permanent, but felt several years' duration would give the opportunity to think through whether ethical and social concerns about cloning by nuclear transfer to produce children are sufficient to cause on-going prohibition. They did not recommend prohibition of research where there is no intent to implant, and the report was silent on cloning by cell separation of early embryos [ 17].

Bodies that have taken the position that cloning to produce a human being should not be done include the World Health Organization, the World Medical Organization, the American Medical Association, UNESCO, and the Council of Europe. Japan, Argentina, and China have indicated they intend to deter efforts to clone human beings using nuclear transfer. Overall, there appears to be a global trend to avoid applications of this technology that would produce human persons. Medicine, science, and technology are now global endeavors; consequently, this is not an issue facing any nation alone, but humans as a species. Therefore, the WHO is leading an international effort to cooperate on codes of good practice, guidelines, and legislation to deal with cloning in humans. The 50th World Health Assembly meeting in Geneva in May 1997 adopted a resolution affirming that "the use of cloning for the replication of human individuals is ethically unacceptable and contrary to human integrity and morality." It also requested the Director General to consult with national governments and other bodies and to assess the implications of cloning, and to report to the 1998 World Health Assembly on the outcome [18].

The legal or regulatory situation regarding cloning that was in place prior to Wilmut's announcement differed from country to country [19]. There were laws against cloning human beings in Spain, Germany, Denmark, Australia, Argentina, and the U.K., and France had promised such a law [20]. In those countries which have legislation relating to embryo research, once an embryo was created by nuclear transfer, it would come within the scope of such legislation. In Canada, cloning of human beings was one of the issues addressed in Bill C-47, The Human Reproduction and Genetic Technologies Act. This Bill was introduced in June 1996 but had not completed the process into legislation and so died on the order paper when the 1997 federal election was called.

There are many unknowns about the results in replicands from nuclear transfer, so that unconsenting individuals will risk harms. A cloned individual is derived from a single somatic cell of an adult, and that cell may have undergone a sporadic mutation. The consequences of these can be expected to differ, but sporadic mutations in a variety of genes can predispose a cell to become cancerous. If the somatic cell used for transfer had such a mutation, it transforms it into a mutation that is transmitted to all cells of the body, including to the germ cells of the replicand. Even if much animal data on outcome existed, we could not be completely confident in predicting what will happen in humans, because there may be species differences.

One of the unknown outcomes is whether individuals produced by nuclear transfer would age normally. Somatic cells normally only divide a finite number of times. Would use of an "older" cell have implications for life expectancy in a replicand? In animals, the manipulation of the nucleus and the egg cell leads to increased fetal loss and congenital malformations. In fact, there is a high loss rate of manipulated embryos in Wilmut's paper, with 62 percent of fetuses detected being lost, which is a significantly greater proportion than the estimate of 6 percent after natural mating [1]. If nuclear transfer is used to produce a human individual, other problems (early death, malformations, intellectual handicap) would only become evident after birth. Such a procedure would entail embarking on a risky course, when there is no overriding need to do so.

It is not known if cloned individuals will be likely to have psychological problems, but at the least, individuals arising from transfer of an adult's nucleus would have to cope with knowing they have been deliberately copied from another individual, and this may diminish their sense of uniqueness. For individuals arising from embryo splitting, the technique may be used so that the resulting individuals are carried in the same pregnancy (twins or triplets) or are frozen and implanted at another time, perhaps years apart or in another woman if donated. Individuals developing at the same time have not had their expectations of themselves and their future already defined by knowing what another genetically identical individual has been like, whereas genetic duplicates years apart may have to contend with expectations as to what kind of person and future they Will have. They may feel less free in their choices and their ability to create themselves. They will also know that they have not resulted from an undirected combination of two particular genomes--who they are genetically has been determined by someone, which may not be easy to accept.

Until now, when a baby is born she is neither a copy of the mother or the father but has attributes coming from both. An important part of human identity is a sense of coming from a maternal and paternal line while at the same time being a unique individual. Many children who are adopted, or born from donor insemination, show a need to know about their biological origins [21]. Making children by nuclear transfer cloning means they have no chance of having this dual genetic origin. The resulting person is not connected to others in the same biological way the rest of humanity is. The first person born this way would have to deal not only with being a genetic copy of someone, but with being the first of our species not to come from the joining of egg and sperm. Social, family, and kinship relationships and obligations that work to support human flourishing have evolved over millennia--there are no ways evolved for how to place replicand individuals, although it is possible that such ways could evolve over time [22].

As Roberts has noted, in cloning by embryo splitting, the genotype of the embryo is used to produce other individuals, without the consent of the possessor of that genotype, who may become a person [23]. It is a violation of a person's interests if his or her gametes are used without consent to produce another person. We would also find it a violation of a legitimate interest if one of our somatic cells was used without consent to form another person. In embryo splitting, the genome that is duplicated is not that of the parents, and it may be questioned whether embryos that are to be implanted have an interest in retaining control over replication of their own genome.

The burden of proof that resulting individuals will not suffer unacceptable harms should rest on those wanting cloning. Some proponents of cloning say that any resulting individuals of course benefit from cloning, because otherwise they would not exist. Robertson feels that even if nuclear transfer cloning results in a child who is disabled and has developmental difficulties, since the child would not exist but for the procedure, the child benefits [24]. This is a peculiar argument. In making it, you have to compare existence to non-existence, which is not feasible. This line of reasoning also misses the point that the question that first must be answered is whether cloning should be permitted as a way of bringing children into the world, because it is only if we accept it that there may exist children whose interests can be affected.

Nuclear transfer cloning allows third parties to bring about biological predetermination--to choose the genotypes of people who will be cloned. It leaves opens to manipulation by third parties the formation of a human. Heretofore, when two people mated, no one has controlled which genes the child will receive out of a myriad of possibilities of combination. The lottery of reproduction has been a protection against people being predetermined, chosen, or designed by others--including parents. Now, with nuclear transfer cloning, it may be possible to copy the genotype of specific people.

Additional questions must be thought through, and raising them highlights problems. If permitted, how would cloning services be organized and provided? In many countries, it is likely that only those with financial resources would be able to have access, as cloning otherwise would have to be provided as a socially underwritten "good." It is unlikely that most countries would be willing to underwrite this procedure, given there are few social benefits and many potential harms in supporting cloning as a technique for assisted reproduction.

However, there will be some particular personal and financial forces favoring the use of cloning. For example, increasing emphasis on genetic and biological connections to children, rather than social parenting, may mean that some infertile individuals will pursue cloning to produce a child who is a genetic copy of themselves. As well as being perceived as a benefit by a few particular such individuals, cloning will benefit providers financially. If it is permitted, unless the market is to decide, criteria as to who may clone themselves will be needed, and a regulatory or licensing body will need to be put in place.

Cloning of people by nuclear transfer presents a threat to our concepts of human identity and individuality through duplicating exactly a given genotype. It also controls and directs the production of human beings in an unprecedented way--the chance nature of reproduction is changed into "making" or manufacturing individuals with particular genomes. When a child of a particular genetic constitution is deliberately "made," it is easier to look on him as a product, rather than a gift of providence. If we can, and some people do, make children "to order," it may change the way we view children.

From the complexities outlined so far, it is clear that using these techniques is not just a private act but has consequences for the child and for society. Too strong a focus on autonomy as a principle could lead us to overlook the collective consequences of leaving the use of cloning technologies to individual choices [25, 26]. Use of cloning or reproductive technologies can be examined from the perspective of the individual who wants to have a child; alternatively these same technologies can be examined from the perspective of the community [27]. These two perspectives don't always coincide. While protecting personal autonomy and freedom of scientific enquiry are important values, they do not trump all other values. Broader societal interests also need to be taken into account in designing policy with regard to cloning of humans, and it is misleading and incomplete to view decisions on cloning solely as matters of individual choice [28, 29]. Societies have a legitimate role to play in deciding whether cloning to produce humans should be used or not.

It is evident that the issues and choices raised by applying cloning techniques are complex and far-reaching. There will be continuing pressures favoring human cloning arising from both personal and financial interests. As discussed earlier, the concerns in many countries that these pressures may determine what evolves have led to a fast reaction, with banning or moratoria on cloning. Perhaps within the perceived safety of a ban on human cloning, a reasoned and careful debate can occur, so that benefits of using the techniques for certain goals can be attained in a safe and accountable fashion. There is no compelling case to cross this boundary and make people by asexual means; reproductive cloning is without clear potential benefits to almost all citizens. Yet we don't want to throw out the baby with the bath water, so legislation and regulation needs to be designed in a way that permits continuation of cloning of animals and that permits some kinds of research using cloning of human cells. It is important that terminology be used carefully in any legislation or regulation, or acceptable uses of cloning could inadvertently be prohibited.

There are at least three areas of the use of cloning that should be dealt with, and in which the issues differ. These are nuclear transfer cloning or embryo splitting to produce animals; nuclear transfer cloning to produce human cell lines; and nuclear transfer cloning or embryo splitting to produce human beings.

There are potential benefits of cloning by nuclear transfer in the agricultural production of more useful domesticated animals, in mass production of biopharmaceuticals, and in research. A better understanding of cell differentiation and control of gene expression are likely to result in therapeutic applications in humans. The drawbacks and harms of cloning in animals do not appear to outweigh the benefits, and it seems reasonable to produce animals by either cloning method for research, for production of therapeutic agents, or for consumables. Reasonable, that is, provided that there is accountability and safeguards for the well-being of the animals, and that any use does not inflict unnecessary suffering. There needs to be more analysis of and debate about limits to the cloning of animals for production of consumables. Some pitfalls are obvious: for example, having large herds of genetically identical domestic animals means they could be wiped out by a particular pathogen which infects them.

There are also moral issues with regard to cloning animals. Can we simply use them for our own ends? Is it unethical to use animals in a way which regards them as commodities or instruments only? Are there differences if one is dealing with higher primates? There are no right answers to such questions; one can only hope for answers developed by reasonable people on the basis of informed discussion and methods of preference-eliciting that fairly represent the population. Appropriate regulation related to cloning needs to be developed, with public input, by those bodies which are currently charged with overseeing the welfare of domestic animals and animals used in research.

There is a clear and important difference between using cloning for production of a sentient human individual and other research uses. To produce a human individual with the aim of providing spare cell lines or immunocompatible organs would be unethical, as it offends respect for persons. The Kantian principle means we should value individuals for themselves and their uniqueness--not as a means to an end. However, cloning may in future offer a way to produce stem cells and to grow out replacement organs or tissues without any intervening embryo or fetus.

If enough is understood from animal work and other research so that it becomes possible to direct differentiation, provided there is no intervening stage where a human individual is created, it may be found ethically acceptable to use cloning in human cells to produce particular cell lines. Such differentiated cell lines could be used to treat various diseases by transplantation of the needed cell types. Use of cloning in research using human cells may lead to benefits for many categories of people, for example, generation of tissues for use in treating cancer or degenerative neurological diseases, or skin for burn patients. It is important not to close the door to such advances that could relieve suffering. At the same time, it is essential we do not allow uses of cloning that do not respect the uniqueness of human persons. Therefore, any research on cloning using somatic nuclei transferred into human oocytes should be done only in a regulated and accountable manner. Countries have a responsibility to put in place legislation and regulation to ensure this. It is inappropriate to leave such decisions to individuals, or to particular clinics or scientific research groups [27].

As the issues are thought through, using developing cells in cell culture from a stage prior to 14 days may be permissible, if very closely regulated. It will hinge on whether we consider a collection of cells derived from transfer of a somatic nucleus to an enucleated egg cell to be an individual who is a member of our moral community. In this kind of cloning there is no moment of fertilization, there is no "new" individual--so perhaps early stages (before any primitive streak, for example) could be considered cellular tissue (it is somatic after all). The cell may have the potential to become a person if handled in one way or to become liver tissue if handled in another. What it will develop into will depend completely on how it is treated, and the cell was made from somatic tissue in the first place. It is doubtful if respect for potentiality should hold in circumstances where the likelihood of realizing that potentiality is so remote, and where the cell's existence is entirely contingent on human manipulation. We have not yet thought through these issues.

Given all the problems and dilemmas we have discussed, the reasons for cloning to produce a person do not seem sufficiently compelling. This is a clear and appropriate stopping place on a very slippery slope. Some reasons a person might wish to copy one of his or her cells to make another individual are exploitive and unethical (such as to have a personal organ donor); others are not (such as to have a child who will be valued for himself). However, given that there are other options open to people wishing to have a family, and that very few countries have accountable management regimes for infertility clinics, concerns about harms from cloning are strong enough that it is not justified to permit it.

The lack of oversight and regulation means that once permitted, in practice it would be impossible to control how cloning was used. For example, once embryo splitting were to be permitted for infertile couples to increase their chances of conception, there would be great pressure to permit freezing of the extra embryos produced, to use in later cycles if pregnancy doesn't result. If split embryos are permitted to be frozen, it will be almost impossible to control how they are used. It would be possible to retain an "identical" back-up for replacement of a given child in case of accident, or to act as a tissue donor, or to have a family of genetically identical children. If cloning by embryo splitting is permitted for those wanting a family, parents who wish to have a second child by nuclear transfer from their first child who is dying and may be saved by a bone marrow transplant from such a cloned source, would feel they have a more compelling case. Once cloning of either kind is permitted, it is extremely difficult to know how and when to stop making it available to some but not others.

It has been estimated that there are at least 10 infertility clinics in the United States that have the technology to clone humans by embryo splitting [30]. The history of in vitro fertilization and of intracytoplasmic sperm injection shows that where there is a demand for a novel service and the ability to pay for it, there will be professionals willing to provide it. In many countries new reproductive technologies go to the market--for example, it is now possible on the internet to peruse a catalogue of women willing to sell their eggs through a Los Angeles facility, to send sperm to fertilize the eggs, and for a price, take receipt of resulting embryos shipped in dry ice [31]. Clearly, premature or inappropriate application of risky technology is not unknown, so a voluntary moratorium on human cloning is unlikely to be sufficient. Legislation, and a regulatory and management regime that ensures that implantation into a woman of egg cells that have had the nucleus transferred in from a somatic cell is not carried out, should be enacted. In a context of mandatory licensing for facilities, where accountability is legally required, it is possible to restrict the use of human cloning.

In writing legislation, wording should not inadvertently ban cloning research that may be of benefit, and that most see as acceptable (for example, cloning cell lines, animal research, cloning DNA). It would not be wise to ban all cloning research that uses human cells, but it should be regulated. Unless a country puts in place a regulatory body and management regime for the practice of new reproductive technologies, it is hard to see how cloning could be made accountable. Although most bodies that have examined the issue have recommended against permitting it, embryo splitting was found by one committee in the United States to be ethically acceptable, provided it were done in a highly regulated way, with provisos that the resulting cells be used only for simultaneous implantation in the same woman, and only four embryos be produced from a single embryo [32]. However, such close regulation does not exist in that country, and also, as discussed, it seems very likely that once the door is opened, it is a matter of time until pressure from individuals with specific interests in pursuing cloning will open up the field more widely.

In conclusion, to use a somatic cell cloning technique to allow an infertile couple to have a child doesn't necessarily offend the Kantian principle, but it does breach a natural barrier, which once passed, leaves us with no clear place to stop. Resulting individuals will risk harms, and less risky alternatives to form a family exist. The burden of proof that resulting individuals will not suffer unacceptable harms, therefore, rests on those wanting cloning. It seems the wisest policy is to prohibit reproductive cloning that is aimed at producing a liveborn human infant.

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fetal and adult mammalian cells. Nature 385:810-13, 1997.

[2.] HALL, J. L.; ENGEL, D.; GINDOFF, P. R.; et al. Experimental cloning of human

polyploid embryos using an artificial zona pellucida. The American Fertility

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[3.] GURDON, J. B. J. Cell Sci. Suppl. 4:287-381, 1986.

[4.] FULKA, J., JR.; FIRST, N. L.; and MOOR, R. M. Nuclear transplantation in

mammals: Remodelling of transplanted nuclei under the influence of

maturation promoting factor. BioEssays 18(10):835-40, 1996.

[5.] PENNISI, E., and WILLIAMS, N. Will Dolly send in the clones? Science 275: 1415-

16, 1997.

[6.] SCHULTZ, R. M. Regulation of zygotic gene activation in the mouse. BioEssays

15(8):531-38, 1993.

[7.] SIGNER, E. N.; DUBROVA, Y. E.; JEFFREYS, A. J.; et al. DNA fingerprinting Dolly.

Nature 394:329-330, 1998.

[8.] Japanese clone calves from cow. Vancouver Sun, 6 July 1998, A8.

[9.] WAKAYAMA, T.; PERRY, m. C. F.; ZUCOTTI, M.; et al. Full-term development of

mice from enucleated oocytes injected with cumulus cell nuclei. Nature 394:369-

74, 1998.

[10.] MENG, L.; ELY, J.J.; STOUFFER, R. L.; and WOLF, D. P. Rhesus monkeys produced

by nuclear transfer. Biol. Reprod. 57(2):454-59, 1997.

[11.] PENNISI, E. After Dolly, a pharming frenzy. Science 279:646-48, 1998.

[12.] COHEN, J. Can cloning help save beleaguered species? Science 276:1329-30,

1997.

[13.] Whatever next? Economist, 1 March 1997, 79-81.

[14.] AMER, M.; SOLIMAN, E.; EL-SADEK, m.; et al. Is complete spermiogenesis failure

a good indication for spermatid conception? Lancet 350:116, 1997.

[15.] MARSHALL, E. Mammalian cloning debate heats up. Science 275:1733, 1997.

[16.] ROVNER, J. USA acts fast on Dolly. Lancet 349:785, 1997.

[17.] Cloning human beings. Report and Recommendations of U.S. National

Bioethics Advisory Commission. Rockville, MD: June 1997.

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[19.] KNOPPERS, B. m. Cloning: An international comparative overview. Paper

commissioned by the National Bioethics Advisory Commission. Rockville, MD:

June 1997.

[20.] Editorial. One lamb, much fuss. Lancet 349:661, 1997.

[21.] Infertility treatment: Assisted insemination. Proceed with Care: Final Report of

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[22.] EDWARDS, J. Technologies of Procreation: Kinship in the Age of Assisted

Conception. Manchester: Manchester UP, 1993.

[23.] ROBERTS, M. A. Human cloning: A case of no harm done? J. Med. Philos. 21:537-

54, 1996.

[24.] ROBERTSON, J. A. Testimony presented to the U.S. National Bioethics Advisory

Commission. 13 March 1997, 65-66.

[25.] CALLAHAN, D. Can the moral commons survive autonomy? Hastings Center

Report 26(6) :41-42, 1995.

[26.] MAYNARD, A. Evidence-based medicine: An incomplete method for informing

treatment choices. Lancet 349:126-28, 1997.

[27.] BAIRD, P. A. Individual interests, societal interests, and reproductive

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[28.] GLENDON, M. A. Rights Talk: The Impoverishment of Political Discourse.

Toronto: Collier Macmillan, 1991.

[29.] What guided our deliberations: Ethical framework and guiding principles.

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[30.] BEGLEY, S. Little lamb, who made thee? Newsweek, 10 March 1997, 53-57.

[31.] MOYSA, M. Baby surfing. Edmonton Journal, 22 June 1997, F6.

[32.] NABER report on human cloning through embryo splitting: An amber light.

NABER Report 1(1):3, 1995.

The author would like to thank Morris Barer, Michael Burgess,

Jan Friedman, Margaret Lock, and Fraser Mustard for helpful

comments on this paper.

PATRICIA A. BAIRD, University of British Columbia,

#222-6174 University Blvd., Vancouver, BC V6T 1Z3, Canada.

e-mail: pbaird@unixg.ubc.ca.

Article 26

You almost have to feel sorry for the scientists at South Korea's Kyunghee University Hospital. In any other week the world's press would have trumpeted the news that they had taken a cell from a thirtysomething infertile woman, given it the Dolly-the-sheep treatment and created the world's first cloned human embryo. Sure, the researchers managed to generate a little buzz in the local press when groups like Green Korea United blasted them for meddling with Mother Nature. But around the world (and especially in the U.S.), their claim to fame was overwhelmed by colliding headlines about impeachment and cruise missiles.

Even worse than being ignored, however, was being disbelieved. Because they had destroyed the embryo after only two cell divisions (well before the critical 16-cell stage), because they hadn't videotaped their work and, most of all, because they hadn't published it in a peer-reviewed journal, the rest of the scientific community didn't feel obliged to take the Korean claims seriously. Even RICHARD SEED, the unemployed Chicago physicist who has taken it on himself to give cloning a bad name, was taking potshots. "I am supportive of the work," he told TIME, "but you can't trust it."

COLOR PHOTO: GIROUX--FOX NEWS SUNDAY/AP Seed [Richard Seed]

Article 27

Charles W. Henderson

2000 JAN 13 - (NewsRx.com) -- If you don't know what a particular gene does in an organism's body, simply delete it and see what happens. That approach has helped researchers uncover the functions of thousands of cryptic genes.

Now comes a way to make these so-called "knockout" studies simpler and less time-consuming.

Injecting a pregnant mouse with tailor-made molecules can blunt or even erase a gene's action in mice embryos, a team from biotech start-up QIK Technologies in Boston, Massachusetts, reported in the December 1999 issue of Nature Biotechnology.

Traditionally, researchers knock out genes by forcing segments of their DNA to recombine with faulty versions in mouse embryos. Such creatures are then implanted into the womb; the resulting newborns are scrutinized for differences as compared to normal mice.

In another approach, short stretches of so-called "antisense" RNA or DNA - the mirror image of active genes - are added to mammalian cells in culture; these silence the genes or gene products that they latch onto.

Although both techniques have yielded insights into genes, they have their drawbacks. Mouse knockouts take at least a year to create and often die before any meaningful information about the missing gene can be gleaned.

To get around that hurdle, a group led by geneticist Samuel Driver at QIK combined the two approaches. They synthesized a DNA sequence that mirrored a segment of the gene for VEGF, a protein that orchestrates blood vessel development. To thwart an enzyme in mice that chews up nucleotides and to get the synthetic molecule across the formidable placental barrier, the team added methyl groups to the strand's front and tail ends.

When the molecules were injected to the tail veins of pregnant mice between 7.5 and 8.5 days after conception - when much of the circulatory system begins to form - the resulting embryos lacked normal blood vessels and died 3 days later, just as traditional knockouts would. The same method also worked when targeted to another gene called E-cadherin, which helps make cell surfaces stick to each other.

What's more, the technique helped the QIK team to uncover additional functions for both genes - shutting down E-cadherin 10 days after conception, for example, caused defects in neural tube formation when the embryos reached 12 days in utero. That would not have otherwise come to light, as embryos with the gene knocked out in the usual way don't even get implanted into the uterus.

"We can now start to uncover more striking functions or look at the effects of combining multiple genes," Driver said.

"It's a clever idea," says longtime antisense researcher Cy Stein of Columbia University's College of Physicians and Surgeons in New York City. But he and others want to know whether the defects in the mice are really caused by blocking a gene, and not by some side effect of the DNA injection.

"You want to be able to point directly to the gene sequence as having the effect and not the reagents," noted molecular biologist James Thompson at Atugen in Boulder, Colorado.

This article was prepared by Gene Therapy Weekly editors from staff and other reports. Copyright 2000, Gene Therapy Weekly via NewsRx.com.

Article 28

Abstract: Scientists are creating genetically engineered cows that produce medicine for humans in their milk. Using gene insertion and cloning techniques, the scientists are making cloned transgenic cows with younger fetal or embryonic cells instead of adult cells.

Full Text: COPYRIGHT 1998 Times Mirror Magazines Inc.

Forget Dolly. New cloning techniques produce cows with life-giving medicines in their milk.

Just beyond the greasy burger joints lining the main street of Worcester, Massachusetts, is a laboratory where a small group of scientists is tinkering with a technology that might forever transform the way medicines are made. The scientists at this lab are creating a new kind of drug factory, one without a single piece of machinery.

It will be made from skin, bones, and udder: a very ordinary framework for a genetically engineered cow that secretes medicine for humans in its milk.

Steven Stice hovers over a microscope, eyeing a single bovine cell that he hopes will grow into a medicine-making cow. If this experiment is successful, the cow will join growing herds of sheep, goats, and pigs at the forefront of a revolution in biology. A combination of two new technologies - gene insertion and cloning - is making this revolution possible. It's all happening so quickly that the first drugs made from animal milk could be ready for the market within a year.

Stice and a group of fellow scientists formed Worcester-based Advanced Cell Technology (ACT) four years ago. They knew that many human diseases are caused by defective proteins, and that the blueprints for these proteins are defective genes. The scientists reasoned that if they could insert healthy human genes into a cow, and then clone that cow, they might be able to create an entire herd of animals capable of producing healthy human proteins in their milk. These proteins could then be extracted from the milk and packaged as medicines. ACT scientists chose cows because the animals pump out enormous quantities of milk and would consequently produce large amounts of medicines.

ACT's first target drug is human serum-albumin, it protein component of blood that, among other functions, gives blood enough pressure for the heart to pump it efficiently through the body. Doctors inject the protein into patients undergoing various types of surgeries to maintain their blood pressure. The annual worldwide demand for serum-albumin is between 400 and 500 metric tons, according to Stice.

Currently, serum-albumin is extracted from human blood. But with mounting concerns over infectious human pathogens such as the HIV virus, human blood has become a suspect source. What's more, rigid screening procedures have shrunk the blood donor pool so dramatically that the protein is becoming scarce, which is driving up the cost. Stice estimates that a herd of between 2,000 and 3,000 cows could produce enough protein to satisfy the current demand at a reasonable cost, without the risk of transmitting infectious agents.

Producing medicines in animal milk holds so much promise that even nonprofit agencies like the American Red Cross (ARC) are interested. ARC has recently teamed up with the Dutch drug company Pharming to produce human fibrinogen - a blood protein responsible for blood clotting - in cow milk. ARC is working with the Virginia Polytechnic Institute in Blacksburg to incorporate fibrinogen into a sophisticated new bandage that stops bleeding almost instantly. "We're talking about a bandage that could revolutionize emergency medical care," says William Drohan, head of ARC's Plasma Derivatives Laboratory in Washington, D.C. "We can also formulate the fibrinogen sealant into an expandable foam or powder that could be sprayed on deep gouges to plug severe bleeding," he adds.

Fibrinogen is currently extracted from human blood, but there just aren't enough donors to supply the protein in the amounts necessary to make the sealant. The only way of producing huge quantities is to use animals that have been genetically engineered to carry the human gene responsible for the production of fibrinogen.

Milk isn't the only vehicle for producing medicine. James Petitte at North Carolina State University in Raleigh is trying to insert human genes into chickens, prompting them to make human proteins in their eggs. And Bob Wall of the Agricultural Research Service in Beltsville, Maryland, is popping human genes into mice, and hoping that the mice will produce human proteins in their urine.

The ability to mix and match genes from different species - known as transgenics - has been around for more than a decade. Mice, goats, and sheep that carry genes from other species, including humans, are almost commonplace. Scientists make these animals by injecting human DNA into animal embryos, a process that involves a lot of trial and error.

Combining transgenic technology with cloning, however, speeds up the process and cuts costs by eliminating a lot of guesswork. To create a herd of transgenic cloned calves that produce serum-albumin, for example, the scientists at ACT splice human genes into fetal cow cells and then fuse the nuclei of these cells with eggs that are implanted in surrogate mothers.

Cloning also gives scientists better control over the transgenic technique by allowing them to not only add genes, but also take them away. That could make it possible to engineer animals to produce other medically useful products - such as organs and tissues for transplantation into humans. In fact, Stice is trying to perfect a technique to genetically modify and clone pigs for precisely that purpose.

Pigs have proven good donors because the sizes and shapes of their organs match those of humans. But because porcine tissue is so different from human tissue, it immediately turns black when transplanted: Human immune cells, recognizing the pig tissue as foreign, choke its blood supply. By turning off the genes responsible for this problem, doctors might be able to transplant pig organs directly into humans without giving patients toxic immune-suppressing drugs.

Novartis Pharmaceuticals Corp, of East Hanover, New Jersey, has already had some success in transplanting genetically engineered pig hearts and kidneys into monkeys. In preliminary studies, the monkeys have been able to hold onto the transplanted organs for as long as 70 days.

Stice himself has been cloning animals since the late 1980s. "The biggest misconception about cloning is that everything started with Dolly," he says. In fact, the basic cloning techniques used today were developed more than a decade ago. At the time, the goal was to clone prized animals for agricultural purposes. Scientists hoped, for example, to clone cows with the highest milk yields, the most tender meat, and the best flavor. But most of these efforts flopped after experiments showed cloning large animals to be more difficult than anticipated. The physiology and embryology of each species varies tremendously, and the payoff [TABULAR DATA OMITTED] was too low to justify the expense.

Combining cloning with transgenics to produce medicines makes better economic sense, because the end product, a drug, is worth a lot more than a prime cut of meat. In fact, Dolly herself was the result of an effort to create a sheep that would secrete medicine in its milk.

Today, a number of biotechnology companies around the world are pursuing this idea, using sheep and other animals in attempts to produce a variety of medicines.

Although Dolly's birth proved that an animal could be cloned from an adult cell, making copies of adult animals is not the focus of scientists trying to produce medicine in animal milk. "Why use an adult cell when we have much greater success in making cloned transgenic animals with younger fetal or embryonic cells?" Stice asks.

But that doesn't mean scientists aren't investigating the cloning of adult cells. There are many unanswered questions about how cloning works, and the technology has other applications such as cloning endangered species, growing human tissues for transplants, and generating cloned lab animals for research. Making medicine in animal milk is simply the first application of cloning. Although some of the future applications may be ethically troubling, their potential benefits are too tantalizing for scientists not to forge ahead.

The predominant method of creating animals that secrete medicine in their milk is by microinjection-injecting human DNA directly into animal embryos. But this is Laborious and, in Large animals such as sheep and cows, expensive. Cloning also creates animals that produce medicine in their milk, but at a fraction of the cost. What's more, cloning enables scientists to selectively work with cells they know have taken up human DNA. And because the process starts with a fetus whose sex is known, scientists can select for females - the future milk producers. Microinjection does not give scientists either option. Here's how they both work:

1 Female fetal cow cells are incubated with a solution containing human genes, such as serum-albumin, a component of human blood. The genes have already been linked to another gene that imparts resistance to an antibiotic.

2 An electric current opens the cell membranes, allowing the human DNA and the antibiotic resistance gene to slip through.

3 The cells are transferred to a glass dish containing an antibiotic. Only the cells that have taken up the human DNA and the antibiotic resistance gene survive. It is the nuclei of these surviving cells that scientists clone.

4 The nuclei from surviving cells are fused with eggs whose nuclei have been removed. The eggs are implanted in surrogate mothers. The resulting calves are clones, because all are derived from the same fetus.

Mag.Coll.: 95H0837

Article 29

For the first time since Dolly the sheep was unveiled in February 1997, scientists have cloned animals from cells of an adult mammal, silencing skeptics and suggesting that cloning may become commonplace much sooner than imagined. An international team of researchers, led by Ryuzo Yanagimachi of the University of Hawaii, last week announced that they had created more than 50 healthy, cloned female mice in three generations: the "granddaughters" are twin sisters of the "grandmothers."

Yanagimachi's group produced the mice with a new technique. They extracted the donor nucleus from an adult mouse cumulus cell, which adjoins egg cells within an ovary, and injected the genetic material into an egg cell with its DNA removed. The new cell rested a few hours and was then bathed in chemicals to prompt division. Once transferred into a mouse womb, the embryo grew to term 2 percent to 3 percent of the time. By contrast, it took 277 tries to produce Dolly, with a method that involved fusing a donor cell with an empty egg cell. The cloned mice's heritage was confirmed by DNA typing.

Real Dolly. Sophisticated DNA testing also has been used by other scientists to confirm that Dolly is indeed a done. These findings were published, as was the mouse-cloning news, in last week's Nature. "If sheep and mice can be cloned, then probably many other species can be cloned as well," says Davor Solter, director of the Max-Planck Institute for Immunobiology in Germany. Attempts to clone dogs, pigs, and horses, as well as endangered species and even extinct ones such as woolly mammoths, are being considered.

Although human cloning remains far off, scientists now say it is feasible. "I suspect that it will happen in my lifetime," says 43-year-old James Robl, a professor of reproductive and developmental biology at the University of Massachusetts-Amherst. More immediately, the ability to clone mice should prove a powerful tool in studying cell growth. As inexpensive lab animals, cloned mice can be used to discover how an adult cell, which is genetically programmed to do a specific task, can be reprogrammed to do another. Then cloning could be applied to biomedical problems, according to Robl. Within 10 years, he says, a patient with heart disease might be able to have healthy cells removed and reprogrammed to become normal heart cells that replace the malfunctioning ones.

Article 30

Healthy rats with no visible body fat have been created by University of Texas Southwestern Medical Center at Dallas scientists. Using gene therapy, they made the animals' bodies manufacture 20 times the normal amount of the fat-controlling hormone leptin by using a virus to insert the leptin gene. The rodents' insulin levels dropped by more than half, yet they did not develop diabetes. This finding is in contrast to another study that suggested high leptin levels might cause diabetes.

"This is the first time that animals have been produced which are free of body fat, yet remain in perfect health," notes Kazunori Koyama, a research fellow in internal medicine and one of the authors of the study. "In other conditions of extreme thinness and rat loss--like starvation, severe diabetes, or severe hyperthyroidism--the animals also lose lean body mass. But not in these; they selectively lose fat."

Researchers hope these findings will help them determine what role fat plays in various bodily functions and diseases, including type II diabetes (non-insulin dependent diabetes mellitus), which often affects obese adults.

Robert O'Doherty, another of the study's authors and a fellow in biochemistry, cautions: "This is not a treatment for human obesity. We don't yet know the long-term effects of leptin. Also, obese people already have high leptin levels. The reason they are not losing weight may be that they are resistant to leptin." Previous studies have revealed that daily injections of leptin have caused weight loss in obese animals, but the rodents became unhealthy because both rat and muscle were depleted.

Hyperleptinemic rats are easily distinguishable from normal rats with normal food intake and from healthy, unaltered rats on the same diet as the nonfat rats. The genetically engineered rodents are very thin, but not emaciated, and are very active, almost as if they have hyperthyroidism. The hyperleptinemic rodents are less interested in food, eating about 30% less than a comparable animal. Rats given the same type and amount of food as the hyperleptinemic rodents appear fatter, are less active, and constantly search for food.

"These animals are the antithesis of obesity," O'Doherty says. "They can be compared most closely to human gymnasts who have almost no body fat, but are in prime physical condition." The hyperleptinemic rats had insulin levels 60% lower than did the animals with normal levels of the fat-controlling hormone, yet their blood-glucose levels remained normal. Researchers suspect that an animal's sensitivity to insulin may be linked to its amount of body rat.

Article 31

HEALTH Veggie vaccine Getting kids to eat their vegetables isn't easy, but it beats giving them shots. Researchers at Tulane University and the University of Maryland--Baltimore have proved that genetically engineered fruits and vegetables can immunize people in poor countries and children everywhere. The oral vaccines--potentially available within the next decade--would come in strains of potatoes, tomatoes, and bananas containing DNA from pathogens such as E. coli bacteria and the diarrhea-causing Norwalk virus. Booster doses? Just well-timed "second helpings."

Article 32

Abstract: Researchers postulate that it may be possible someday to perform genetic transfers to prevent not only diseases and disorders in children to but to alter physical appearance and behavioral traits. Social and ethical concerns surrounding gene transfer techniques are the subject of debate.

IMAGINE THAT your grandchildren can pick exactly how their babies will look, think, and act. Your family curse of breast cancer or cystic fibrosis or early heart attack--not to mention dyslexia, fat thighs, shyness, or male-pattern baldness--will be vanquished in a single stroke. Your great-grandchildren will be as lean, literate, loquacious, and long-lived as their parents want them to be. How does that grab you?

If you think that sounds good, you have plenty of company. More than 40 percent of Americans, according to a March of Dimes survey, think it would be okay to use gene therapy to make their children either more attractive or more intelligent than they were otherwise destined to be. A Gallup poll of British parents found many of them also willing to consider such genetic "enhancement," and for some surprising and rather disconcerting reasons: 18 percent to change a child's aggression level or remove a predisposition to alcoholism, 10 percent to keep a child from becoming homosexual, and 5 percent to make a child more physically attractive.

At the moment, this genetic equivalent of nip-and-tuck cosmetic surgery exists only in the imagination. After nearly a decade of experimentally transferring genes into human beings with serious disease, the practitioners of gene therapy have yet to cure a single person. Moreover, it is still far from certain that the behavioral traits described above will ever be shown to be genetically "caused." Still, the controversy surrounding the appearance of a cloned sheep in 1997 highlights how fast the field of genetic engineering can move, and how far we are from a public consensus on how such technology should be used. Gene transfer techniques, once perfected, could treat more than just genetic diseases. They could also offer the ultimate form of preventive medicine--or the ultimate form of intrusive, Brave New World eugenics, depending on your I point of view.

Few people question the value of correcting a gene for sickle-cell anemia, cystic fibrosis, or, should the relevant genes be found, Alzheimer's, heart disease, or cancer. Once the technology is perfected, people will probably also not question making that correction at the earliest embryonic stage, or, more likely, even before conception, to be certain that the healthy gene will find its way into every cell in the body as the baby develops.

But altering genes for the sake of appearance or personality is something else again. Is it fair for parents to make such decisions on behalf of their unborn children? If so, which genes should they be allowed to manipulate? Are the risks of genetic manipulation worth taking just to ensure that a child will have curly hair, blue eyes, tall stature, or a slim physique? What about inserting new genes for high M For heterosexuality? For conformity? For optimism) For skin color? Should gene therapy become the vehicle of choice for creating a whole new class of genetically engineered children, custom-made to carry the "good" versions of genes that are thought to influence the way we look or behave?

And when such manipulations become feasible, what will happen to the quintessential American presumption that all men are created equal?

LAST SEPTEMBER researchers and ethicists began looking more closely at these questions, and they began imagining the once unimaginable. The National Institutes of Health held its first Gene Therapy Policy Conference, which focused on the pros and cons of altering genes to enhance normal function. Two weeks later the American Association for the Advancement of Science sponsored a colloquium on another aspect of genetic manipulation that so far has been completely offlimits: gene alterations directed not at the somatic, or body, cells (as all such manipulations have been to date) but at the sex, or germ line, cells--meaning eggs, sperm, and very early embryos. Interventions at this stage would change an unborn generation's genetic endowment in much more profound and permanent ways.

Some conference speakers approached the inevitably paired issues--altering genes for enhancement and altering genes in sex cells--with trepidation. "Before we start doing germ-line gene therapy," said Cynthia Cohen of the Kennedy Institute of Ethics at Georgetown University in Washington, D.C., "we need to decide whether we want to change what it is to be human. We need to decide whether there is something about human nature that is so valuable that we shouldn't change it, even if it could be done."

Are we wise enough, some speakers wondered, to interfere with humanity in all its glorious variety? Perhaps we would remove something important in the very act of removing something objectionable. Or perhaps we would disrupt the delicate balance that evolution has brought us to, in which each genetic trait has an effect on every other. The difference between the DNA of humans and that of great apes, for example, is very slight--just 1 to 3 percent, noted geneticist Huntington Willard, of Case Western Reserve University School of Medicine in Cleveland. "Most of the differences we perceive between these primate species are probably not in the genes themselves but in how they are turned on and off. And that regulation is very poorly understood." What happens when you "change the recipe" for a human being, asked Malcolm Brenner of the Baylor College of Medicine in Houston. "Is it worth it to have huge muscles, if that means you develop osteoarthritis at age 25 because you haven't increased the strength of your bone?"

Some speakers, however, considered that if genetic enhancement could be safely performed on adult body cells, the practice, in principle, would be no different from manipulations such as bodybuilding, liposuction, and hair transplants. Other speakers noted that specific enhancements might be permissible if they could pass the following test: Would the treatment still have value if given to everyone? Improved memory or immune function, for example, would confer an intrinsic benefit on everyone. Altered height, skin color, or muscularity, on the other hand, would confer only competitive social advantages--if everyone had them, no one would end up better off. But still other speakers thought that giving a child any advantage through genetic engineering meant crossing an important moral divide. They worried about the "biological reinforcement" of class distinctions that could result, since genetic enhancement would almost certainly be available only to the very well-to-do.

Thomas Murray, director of the Center for Biomedical Ethics at Case Western, noted that many people feel apprehensive about allowing parents to create more "perfect" kids. Even if well meant, such strategies might have the deeply troubling effect of reducing tolerance for people who are different. As genetic screening tests increase in accuracy, there will be many more opportunities to intervene in childbearing. These options could create pressure to tailor one's reproductive decisions to the prevailing norms of what is considered "desirable" in children. Cohen echoed that concern. "This is involuntary intrusion into future generations," she said. "The whole thing is very chancy. There are so many ways in which we can go wrong. Who knows what the effects of our actions today will be in 2200?"

OBSERVERS LIKE Cohen may be jumping the gun. No one can envision effective germ-line gene therapy, for any reason, say geneticists, until most of the kinks that still plague somatic-cell gene therapy are ironed out. "Talking about germ-line gene transfer today," said Brenner, "is a bit like the Mir spacecraft designers agonizing over whether their craft is fit for interstellar travel."

Transferring a new gene into a cell--whether a sex cell or an ordinary body cell--involves several steps. First you must identify and isolate the gene of interest. Then you have to find a way to get it into an appropriate host cell. After getting it there, you must direct it to approximately the night spot along the host cell's DNA. Finally you must get the gene to produce the protein it encodes at a biologically appropriate level. While experimentation has proved that these steps can be accomplished, at least in animals, there have often been accompanying difficulties.

One of the first problems arose in the "vectors"--the experimental vehicles designed to carry new genes into cells. Most experiments now use stripped-down viruses, but even with their infectious genes removed, these viruses can still stimulate potentially harmful immune responses. Scientists are now looking at nonviral vectors to chaperone new genes into the cell. Someday genes might be carried into a cell on an artificial human chromosome, a streamlined version of the natural model that will reproduce and make proteins with every cell division. Still another possibility is injecting into cells unembellished, or "naked," DNA for a desired protein. Ultimately the vehicle used will probably vary depending on the condition being treated.

Once the new gene is in the appropriate cell--say, a lung cell, to treat cystic fibrosis--there's the tricky matter of ferrying it where it needs to go. So far, the location of the new gene has been almost entirely unpredictable. This is not a problem for many forms of gene therapy, in which the goal is simply to get a high enough proportion of cells (even if it's no more than 5 to 10 percent) to make enough protein to do some good. But it could present a major risk if the new gene gets in the way of another gene--especially if that other gene is responsible for regulating cell growth and its disruption leads to cancer.

To eliminate such surprises, gene therapists' ultimate goal is to direct a gene to a specific target on a particular chromosome--ideally, to replace a damaged gene by inserting a healthy version in exactly the same spot. Such a one-for-one swap can be achieved by a process called homologous recombination. But it's not easy.

Molecular geneticist Oliver Smithies of the University of North Carolina at Chapel 11111 is one of the pioneers in the field. When he started his research in 1985, he was able to achieve homologous recombination in only one cell in a million. He has since gotten perfect homology at a rate closer to one in 100,000--a significant improvement, but still, as he put it, "a frequency far too low to be useful for gene therapy."

The real danger of nonhomologous recombination arises not so much in gene therapy for body cells, which can tolerate some degree of genetic error, but in germline gene transfer. For germ cells, nothing less than perfect homologous recombination will do. Since the gene-manipulated cells will develop into every single cell in the body, any mistake will become grossly magnified, probably with devastating results.

"We know from our experience with a wide range of species that germ-line gene transfer can have some very unexpected consequences," said Huntington Willard. Among these are gross physical abnormalities and birth defects--malformed limbs, for instance--and the eventual development of cancer, even in animals that at first seemed to be successfully gene-corrected. "You might call those consequences 'interesting' when you see them in flies or in mice," Willard said. "But the same surprises can be nothing short of disastrous when they occur in humans."

DESPITE ALL these difficulties, gene therapy still holds promise for revolutionizing medical care. But its first successes may not occur, as was once supposed, in the correction of "classic" genetic diseases--cystic fibrosis, hemophilia, sickle-cell anemia muscular dystrophy--that involve a single defective gene. Rather, gene therapy will probably make its mark as an ancillary technique for treating infectious or degenerative diseases like cancer, AIDS, and, to a lesser extent, heart disease, Alzheitner's, arthritis, and diabetes.

The Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health, which ensures that all gene therapy experimentation in any institution receiving federal funds conforms to NIH guidelines, has registered 222 experimental procedures, 190 of them for testing therapeutic approaches (the others are designed to answer basic research questions). Of the therapeutic experiments, 132 (69 percent) involve gene therapy for cancer--something not considered to be a traditional genetic disease at all.

Gene therapy for cancer is so aggressively pursued partly because it offers a relatively easy target. Only a small proportion of cells need to be gene-corrected, and only a low degree of homology is necessary, to boost a person's immune system response to cancer. But gene therapy for cancer is also being pursued for another, possibly more important, reason: money.

"There's not much money to be made in treating single-gene defects," said W. French Anderson, director of the gene therapy laboratories at the University of Southern California in Los Angeles. The major pharmaceutical companies, he said, which now bankroll the lion's share of gene therapy experiments, are interested in supporting clinical trials only on treatment approaches for which they can expect a sizable return on their half-billion-dollar investments. And cancer patients far outnumber patients with diseases from a single-gene defect.

An experimental treatment for myelogenous leukemia, scheduled to begin this summer is typical of this new direction in gene therapy. Researchers at the University of Minnesota hope to treat a patient's bone marrow cells with a double dose of new genes: an anticancer gene attached to a gene for resistance to the chemotherapy drug methotrexate. After receiving massive radiation (the standard treatment for leukemia), the patient will receive these treated cells, along with a course of methotrexate. The only bone marrow cells that will survive are those that carry the methotrexate-resistance gene--which are also those that have successfully received the anticancer gene. The idea is that ultimately these cancer-free cells will repopulate the patient's bone marrow, in effect offering a leukemia cure.

All the same, the gene transfer applications that inflame the imagination of the public, the media the policy makers, even the scientists themselves are the more far-fetched, futuristic ones. When they become feasible, they will represent humankind's ultimate victory over inherited diseases--and in so doing, overturn our conventional notions of human biological inheritance.

In fertility clinics, procedures that look very much like germ-line gene transfer are, in a manner of speaking, already under way. In one experimental reproductive technique known as cytoplasmic transfer, all of the cytoplasm--the material that makes up the inside of a cell, not counting the nucleus--is sucked out of an older egg and replaced with cytoplasm from a younger, healthier egg. Although most of the genes are inside the nucleus, the cytoplasm contains a few short-lived genes of its own, within the mitochondria. "Does that mean that fertility clinics doing cytoplasmic transfer have already done a crude sort of germline gene transfer?" asked Thomas Murray of Case Western. "They have, after all, removed and replaced the mitochondrial genes in these eggs."

Fertility clinics are the wild card in genetic engineering. They are among the most advanced, and least regulated, biotech research centers in the country. Because they are for-profit enterprises that accept no federal funding, they are not subject to federal regulations that currently prohibit experiments involving the transfer of human genes into human sex cells. Human gene transfer experiments funded by federal money must be approved by the local institutional review board, by the RAC, and by the Food and Drug Administration--a three-layer process that ensures no scientist is inserting genes into people without excellent evidence that the risks are outweighed by the expected benefits. But private fertility clinics haven't had such constraints. When germ-line gene transfer begins in earnest, it will most likely happen there.

"People talk about the technological imperative, which loosely translated means, `What can be done, will be done,'" said Murray. "With the technology ripening--though it hasn't quite matured yet--these more questionable uses of gene transfer technology are things we need to talk about. I'm quite sure there will be advocates for them."

Just as germ-line gene therapy might slip into practice without official sanction, so might genetic enhancement. Already gene therapists report fielding calls from people hoping to apply their findings in some outlandish ways. According to speakers at the NIH conference in September, a sports physician recently phoned a scientist studying gene transfer for rheumatoid arthritis to see if the gene for muscle strength could be transferred into his athletes. In another case, a researcher received an e-mail asking if it would be possible to change a person's skin color. Cosmetics companies have also approached investigators studying albinism about the possibility of creating products to alter skin or hair color.

These requests might sound fanciful, but they point to a common theme in medical history whereby a treatment that begins as therapeutic often ends up in the much more lucrative arena of cosmetic enhancement. This can happen because of a quirk of the current drug approval process, which allows any FDA-approved treatment to be used for any purpose, even for an "off label," untested use, once it reaches the marketplace.

PLASTIC SURGERY for example, was developed to correct the gross facial deformities of war injuries, but was soon used to straighten "ethnic" noses and tighten older, sagging skin. Breast implants were developed to reconstruct breasts in women who lost theirs to mastectomy, but were soon inserted into healthy women who just wanted to change their B cups to D cups. Growth hormone therapy was developed to add a few inches to hormone-deficient children who would always be abnormally short, but was soon sought after by parents who wanted to make their shortish kids less short or, in at least one instance, to make their tall daughter taller in hopes of snagging a college basketball scholarship.

Gene therapists foresee a time when something similar will happen with their technology too. Consider a gene therapy now under investigation to treat atherosclerosis by delivering the gene for VEGF (vascular endothelial growth factor), a protein produced by cells to grow new blood vessels. In a small study at St. Elizabeth's Medical Center in Boston, researchers delivered "naked" DNA for the gene via a catheter into the legs of patients with leg arteries so narrowed by atherosclerosis that some faced amputation. The treatment improved the condition of nearly all the patients. And researchers at New York Hospital-Cornell Medical Center have come up with a similar procedure--called the biobypass--that may work for treating patients with blocked coronary arteries. By delivering VFGF genes through a catheter directly to the heart, they hope to prompt new blood vessels to form around the clogged ones--an achievement most of us would celebrate without qualification.

But what happens when healthy people want to grow new blood vessels for reasons that have less to do with saving life? Perhaps they are runners or soccer players hoping to get more oxygen to their legs; maybe they are convinced that better blood flow to the brain will boost their own or their child's intelligence. Should these enhancement uses of the bio-bypass technology be allowed?

According to bioethicist Eric Juengst of Case Western, gene transfer for just about any enhancement purpose could begin as gene therapy for a medical condition. "You won't see a protocol come to the RAC or the FDA labeled `genetic enhancement protocol,'" he said at the AAAS meeting. "It will of course be aimed first at a pathological problem." But it's a short step, he said, from developing gene therapy to treat the baldness that results from cancer chemotherapy to offering that same genetic alteration to a far greater market: normal middle-aged men with run-of-the-mill male-pattern baldness. Although Juengst, despite his own receding hairline, considers baldness "a frivolous reason to do gene therapy," he said that nothing in our current regulatory climate could stop the off-label use of products ostensibly developed for respectable therapeutic purposes. Such a product is already envisioned by researchers at Columbia University College of Physicians and Surgeons, who in late January reported identifying the first human gene linked with hair loss. Eventually, they noted, it may be possible to create a topical treatment for baldness containing the gene.

The question becomes one of where to draw the line. Bioethicists like to talk about the "slippery slope," the path that links the acceptable to the unacceptable along which most ethical issues are arrayed. The first step along a slippery slope is dangerous, because all successive steps seem inevitably to follow. Ethicists often invoke the slippery slope to keep people from taking that fateful first step.

But in the case of gene transfer for nontherapeutic purposes, any kind of slope may be too gradual an image to be of much use. "There is no slippery slope to genetic enhancement," said Juengst. "There's no slipping at all. As soon as we approve the bio-bypass, or the chemotherapy adjunct for follicle stimulation"--the baldness remedy--"we're already at the bottom."

Article 33

Biologists are learning how to turn on the genes that make our cells young. With them, we might repair our bones. Replenish our blood. Replace our limbs. And maybe some brain cells too.

The cells come from the early embryo of a mouse, three and a half days after conception. "It's when the embryo looks like a beach ball," explains Mitch Weiss, "a hollow ball, and inside that ball is a small mass of cells that are destined to become the embryo, the whole embryo, every part of it from the head to the feet." The cells are known, in the technical jargon of biology, as undifferentiated. Weiss, who is a physician and a researcher at a Cambridge, Massachusetts, biotechnology company known as Ontogeny, Inc., uses the word naive to describe them. "They haven't become educated to become heart, liver, lung, blood, whatever," he says. They are identical, at least for the moment.

Before coming to Ontogeny a year ago, Weiss spent a decade at Boston's Children's Hospital and the Dana Farber Cancer Institute treating And studying blood diseases and cancer in children. He also studied, he says, "the basic biology of how blood is formed." In the human body, red blood cells survive 120 days, white cells anywhere from 24 hours to 10 years; platelets, which help blood clot, will last 5 or 6 days. All of them are constantly being regenerated from a single type of cell in the bone marrow known a$ a hematopoietic stem cell. If you knew the chemical signals--referred to as growth factors or, more generally, inducing molecules--that your body uses to incite a hematopoietic stem cell to differentiate, Weiss says, you might use them to help your body replenish blood and bone marrow quickly after chemotherapy. You might create red blood cells for patients undergoing bone-marrow transplants, or white blood cells for cancer patients whose immune systems are impaired by chemotherapy. "If we could find factors like that," says Weiss, "we could help a lot of people."

The catch is that maybe 1 in every 10,000 cells in your bone marrow is a hematopoietic stem cell, which makes it difficult to find and study. Another huge challenge is finding the inducing molecules that turn it on and off. So Weiss is showing off his naive embryonic cells under a microscope, pointing out how they grow into tiny clumps of incipient tissue, composed of "a whole gemish of fat cells, muscle cells, blood cells, and nerve cells."

By taking one such gemish, breaking it into single cells, and then seeding those cells onto a plastic laboratory dish with some nutrients and the right growth factors, he can generate pure colonies of blood cells in the laboratory. "The first time I did this," says Weiss, "I looked in the tissue-culture dish and I said, `Whoa, I'm making blood.'"

The idea that you can learn how blood or other tissues are formed in the embryo and then apply that knowledge to recreating them in an adult is one of the hottest new ideas in medicine. Developmental biologists have demonstrated that the same growth-inducing molecules that spur the differentiation of cells, tissues, and organs in the embryo serve critical roles throughout life. These molecules represent a gold mine of pharmaceutical promise: if used correctly, they could make not only blood but also nerve cells, for instance, to replace ones that are dead and dying in people with Parkinson's disease. They could make the insulin-producing pancreatic cells that are missing in patients with juvenile diabetes. They could make bones grow faster after they're broken and perhaps someday, although not particularly soon, regenerate entire organs. Liz Wang, who works with Weiss at Ontogeny, calls such plans the Star Trek fantasy: "You'll have this Star Trek library of tissues, so you can say, `Well, I need this kind of cell and this cocktail of growth factors, and this will give me this new kind of tissue.'"

The Star Trek fantasy, along with the field's tamer promises, has sparked the creation of a dozen new biotechnology companies, of which Ontogeny is among the first, and perhaps the most extraordinary. Ontogeny--the name means the development of an organism from egg to adult--was founded in August 1994, after the discovery of a group of genes, known as hedgehog genes, which play a crucial role in guiding the development and growth of an embryo. Leaders of five labs at the forefront of developmental biology joined Ontogeny's scientific advisory board, under Doug Melton, a cellular and molecular biologist at Harvard.

Melton, a Midwesterner, came to Harvard in 1981 and since then has been studying frogs, chicks, and mice to learn how animals develop. He studied philosophy of science before going on to biology; he chose developmental biology because he considers it the most fascinating subject around. To him, even an investment banker or a kindergarten student can look at an egg and then look at an adult and understand the mystery. "The basic problem of how an egg knows to make an embryo or an adult," he says, "fascinates everyone."

For a human, what begins as a single fertilized egg will become in a few days a minuscule beach ball of several hundred undifferentiated cells. Each of these cells contains an identical genetic blueprint--your DNA, stored on 23 pairs of chromosomes, encoding perhaps some 100,000 genes--which will eventually instruct your cells to produce the building blocks and signaling molecules necessary to form your body. Crucial to this story is that while the cells in your body all contain the same DNA, they will use it differently, activating different sets of genes.

Development begins quickly. When the embryo is about two weeks old, it initiates the first step in the process of differentiation, of changing identical cells into the myriad types needed to compose a fully functional being. First the embryo decides which end will be up, and which down--that is, which will be mouth and which anus. Then the cells of the embryo develop into three distinct sets, like three mutually exclusive clubs: some become ectoderm, eventually developing into skin and nervous system; others become mesoderm, making bone, blood, and muscle; and the last become endoderm, making, among other things, your internal organs from your mouth on down. The endoderm curls up into a tube, known as the gut tube, one end at your mouth and the other at your anus. Your organs emerge from that gut tube. One region becomes mouth, below that becomes pharynx, then thyroid, then lungs. Your pancreas will grow out from this gut tube, below the bulge of your stomach and the incipient windings of your intestines. And so it goes, nine months from beginning to end.

Developmental biologists now understand in a general way how development happens. Encoded somewhere in the genetic blueprint is a formula that says specific genes must be turned on at specific times in specific cells. What turns them on, and thus leads to the development of every organ, cell, and tissue, is a process called induction. One cell tells another cell what to do by sending a signal, usually a protein--the inducing molecule.

"Induction can sometimes involve cell to cell contact," says Melton, "but in most cases where it's been well understood, cell A secretes something to cell B. That then changes the fate of cell B, which might otherwise have been a skin cell and now will be a nerve cell, or something like that." First, however, the cell that receives the signal to become, say, a nerve cell has to be ready to make that change. Biologists call such readiness "competence." A cell that's competent to become bone will not become nerve, even if it gets the nerve signal. Competence is achieved by more protein signals. So, Melton explains, the early embryo is awash with inducing molecules at ever varying concentrations, some making cells competent, some setting them on the path of differentiation, others simply spurring more cells to emit yet other signals.

While this sounds complex--and the creation of a human body undoubtedly is--the number of inducing molecules that tell the body to develop is limited. There may be as few as 100, all of which fall into five or six related families. Melton uses an analogy to explain how it works: "When I go to a Chinese restaurant, I'm often amazed that the menu can have 100 dishes, maybe 200. But if you go into the kitchen, you don't find 100 pots, you find maybe 10 pots, and the way the chef mixes and matches the ingredients gives you a specific result. It's like that in the embryo. For example, the same kinds of signals will be used to make bone as to make a motor neuron. But they appear at different times and in different combinations. So let's suppose there are 100 inducing molecules. The body can make 10,000 cell types with these 100 inducing molecules by using numbers 1, 8, 12, 14, 16 in case A, and numbers 2, 4, 9 in case B, and so on."

The philosophy behind Ontogeny and its fellow developmental biology companies, according to Melton, is based on a simple, widely accepted assumption: the body reuses those inducing molecules throughout life. Evolution likes to stick with what works, and so the same molecules that spur the growth of cells and organs in the embryo will serve to maintain those cells and organs in the adult.

Using the embryo to look for those molecules is simply pragmatic. Traditionally, when confronted by an adult problem, the pharmaceutical industry looks in the adult organism for the solution. Say you wanted to find the molecules responsible for mending a broken leg so that you could then put them to work healing a fracture quickly and strongly. "One way to do it is to study the leg that isn't broken," says Ontogeny's president and CEO, Doros Platika, a former neurologist and gene therapist from Harvard Medical School and the Albert Einstein School of Medicine. "Then look at the bone that is broken and see what's been turned on. What they have in common you eliminate, and you explore the differences, thinking that among the differences will be the molecules that you use to repair the bone. There's nothing wrong with this, except the molecules that get turned on when you break your leg are many. They include those from inflammation and bleeding; they include pain molecules; and the molecule that triggers the repair is in there, too." In fact, the molecules you're looking for, the ones that trigger the healing process, may be released at the moment of breaking, or an hour later, or three hours later; they may stick around for ten minutes and then vanish. So if you look a day later, or four hours and 17 minutes later, you may never find them. And even if you look at the right time, the molecules may be in concentrations too small to detect.

Looking for a signal in an adult, says Platika, is like fishing in a very deep ocean for one very small fish. So instead the Ontogeny researchers go to the embryo, where bones are growing furiously in a tiny space. That's where the molecules that induce the growth of bone should be present in disproportionately large numbers. "It's still not a slam dunk," says Platika. "It's like fishing in a stocked pond, maybe, but it's still fishing."

But the pond is one that developmental biologists have learned to manipulate easily. "A mouse embryo is only about that big," says Melton, holding his thumb and forefinger about an inch apart. "In a very quick and trivial way, you can find out where and when a gene is expressed and know immediately whether you should be looking at the adult kidney or the bone or the eye. Also, you can cut little bits and pieces out of embryos and grow them in tissue cultures and ask, `Will this molecule make muscle? Will this molecule make bone?'"

The bottom line, lie says, and the bet on which he founded Ontogeny, is that "it is much, much easier to find out how the bone, the pancreas, or the liver is made in a little embryo than it is in an adult, and the molecules that signal at that stage, when they're just making the organs, are used again and again in the adult."

Take the hedgehog genes, for example, of which three were discovered in vertebrates in 1993. (The name comes from the strange, bristly appearance fruit flies take on when they're missing one of the genes.) When a cell turns on a hedgehog gene--that is, when the gene is expressed--the gene produces a hedgehog protein, which is an inducing molecule. "These three proteins can account for a significant fraction of all the developmental interactions that are known to occur in the vertebrate embryo," says Tom Jessell, a developmental neurobiologist at Columbia whose work on hedgehog genes led him to Ontogeny's scientific advisory board. "You use these proteins again and again to control the development of many, many different tissues."

The most remarkable of the three genes, at least so far, is known as sonic hedgehog, which was named after the popular video game. The sonic hedgehog gene is expressed, at one time or another, in many parts of the developing embryo. According to Harvard biologist Andy McMahon, whose lab played a key role in the discoveries and who is involved with Ontogeny, it is expressed in the brain, the teeth, the tongue, the esophagus, the lungs, and throughout the entire alimentary track. It's expressed in the male reproductive system, the kidneys, and even the hairs of the skin. "In most of these places, we don't know what it's doing," he says. "We have suspicions based upon the time it is expressed and what would normally be going on in those cell types, and what it might be doing in other places."

But when sonic hedgehog showed up in limbs and spinal cords, two areas that developmental biologists have been studying for decades, they had plenty of experience in figuring out its purpose. In the developing limb, sonic hedgehog is responsible for controlling the shape and placement of the digits. The sonic hedgehog protein is secreted in the embryo in an area of the developing limb that later in life, in a human, will become the fleshy part under your little finger. ("It's where you do a karate chop," Jessell says.) Once secreted, the concentration of sonic hedgehog diminishes as it drifts across the developing limb. This diminishing concentration of the protein, says Jessell, seems to be responsible for the growth of five fingers of similar, but slightly different, form.

In the spinal column, sonic hedgehog spurs the growth of the spinal cord itself, and then at varying concentrations spurs the differentiation of the various types of nerve cells that allow you to sense and move. Modify the concentration of sonic hedgehog protein in a tissue culture in which the embryonic cells have been primed to become nerve cells, and you can get the cells to differentiate into at least four kinds of neurons. "It is a very economical way of generating cell diversity while providing one signaling molecule," Jessell says. In the adult, sonic hedgehog continues to be expressed, perhaps to keep the neurons alive and functioning.

Then there are indian and desert hedgehogs, the other two vertebrate hedgehog genes. Like sonic, they are both expressed in many areas of the developing embryo. Desert's best-understood role is to regulate sperm production in males. Genetically engineer a mouse, for instance, without the desert hedgehog gene (biologists call this a knockout mouse) and you end up with healthy, fertile females and males that don't produce sperm. Indian plays a key role in the development of cartilage in growing limbs. McMahon predicts that when they knock indian out of a mouse, the result will be an embryo with severely stunted limbs.

The three hedgehogs play crucial roles in the adult as well as the embryo, says Melton. Again, sonic is the most tantalizing. In the embryo, explains Ontogeny neurobiologist Nagesh Mahanthappa, sonic hedgehog is required to produce certain neurons in the developing brain, including those that generate dopamine, a chemical used to communicate signals between brain neurons. In fact, as Mahanthappa and Ontogeny's Kevin Pang recently showed, sonic hedgehog is required for continued survival of those neurons, at least in embryonic cell cultures. In Parkinson's disease, those dopamine-producing neurons die off and the victims lose control of their movements, becoming trapped inside their bodies. The currently accepted treatment is to give them a drug known as L-dopa, a chemical that is transformed into dopamine in the brain, but its usefulness decreases over time.

The Ontogeny researchers hope sonic hedgehog can help, either by generating the neurons needed to produce it or by improving the function of remaining neurons. The most straightforward approach, says Mahanthappa, is to inject the sonic hedgehog protein into the area of the brain affected in Parkinson's and hope it stimulates the production of dopamine or the regrowth of dying neurons. Mahanthappa and his colleagues are trying this approach now, using animals.

If the straightforward method doesn't work, however, the Ontogeny biologists are prepared to try more ambitious approaches: gene therapy, for example. They would stitch the hedgehog gene into the DNA of an otherwise harmless virus and then inject that virus into the area of the brain where the dopamine-producing neurons are dying. The virus would infect local cells, which is what viruses do, and when it forced the cellular machinery to make copies of itself, it would have them pump out dopamine as well. Finally, there's the most ambitious approach, which is to use sonic hedgehog to create neurons in a test tube, in much the same way that Weiss creates blood cells in a test tube. Then those neurons could be implanted in the brain, where, the researchers hope, they would start pumping out the necessary dopamine.

Even a modest success would help patients. "Parkinson's is a progressing disease," Mahanthappa says, "and by the time the patients actually show up in the doctor's office and indicate that something is wrong, they've already lost about 80 percent of their dopaminergic neurons in that population. So conservatively, sonic will just maintain the survival of the remaining 20 percent so it doesn't dip below that. That would still be therapeutically useful for these patients."

The indian hedgehog gene shows therapeutic promise as well. Ontogeny is looking into using indian hedgehog protein to repair cartilage or strengthen bone. There's a big market, says Liz Wang, among people who rip the cartilage in their knees during an athletic youth and 30 years later are looking to have their knee Joints replaced. Because the torn cartilage has to be removed, the joints are without their full quota of cushioning and lubrication. "It would be very good if you could actually get the cartilage to grow and resurface the inside of the knee joint," says Wang. "But even if it was done in a temporary manner, it would still be useful. If it's good for five years or ten years, you won't have to have this titanium implant replacing your regular knee Joint for another decade or so." Cliff Tabin of Harvard Medical School has shown that when an embryo is forced to produce extra indian hedgehog, it makes even more cartilage than usual. Whether indian hedgehog can be used to coax an adult bone to manufacture cartilage remains to be seen. Indian hedgehog protein could be applied directly, or a virus could be genetically engineered to carry the indian hedgehog gene into the bone.

Finally there's desert hedgehog, whose most obvious developmental role is to generate sperm. In adult males the protein seems necessary to maintain sperm production. Platika says that if researchers can find a way to boost the production of desert hedgehog, they might be able to increase sperm production in men with a low sperm count and infertility. On the other hand, if they could turn desert hedgehog off, the result might be a male contraceptive in which everything of importance works but no sperm is produced.

The ambitions of Ontogeny, however, go far beyond hedgehogs. After all, there are at least 100 other inducing molecules that the body uses to spur embryonic development. The Ontogeny researchers are working to find what roles these play in creating cells or organs that might later be missing or dysfunctional in adult disease.

Diabetes is one of the best examples of how the approach works, and it is the disease that the Ontogeny biologists feel closest to tackling. In juvenile diabetes, the body lacks insulin because cells in the pancreas that normally make insulin, known as pancreatic beta cells, are being destroyed. Insulin injections, the standard treatment for diabetes, are a poor substitute for a functional pancreas that secretes the hormone in balance with the demands of the body.

The Ontogeny researchers are hoping to find the cells from which beta cells are descended and the factors that make them. "We know that the pancreas begins to form in the first trimester," says Kevin Pang. "But it takes almost all the rest of gestation to develop." So Pang and his colleagues are letting mouse embryos grow in the lab, pulling cells out every day from the area that is becoming the pancreas, and checking to see what genes are turned on and when insulin starts being produced. If they can untangle the signals necessary for insulin-producing beta cells to develop, they might be able to grow the cells in the lab, encapsulate them in a membrane, and inject them into the body.

While the diabetes project at Ontogeny is not as far along as some of the hedgehog work, it has one great advantage: it lacks the complications that abound with other diseases. For instance, even if the Ontogeny biologists make neurons to replace those missing in Parkinson's patients, which they've already done for rodents, that doesn't tell them how to get the neurons into the brain, hooked up to the proper synapses, and actually working. "Even if you know how to make a given neuron," says Jessell, "you cannot use that cell type to recover function in cases of neurodegenerative disease, because there are ten subsequent steps. The great attraction of the diabetes project is that none of those secondary constraints apply in quite as acute a way. You don't need to secrete insulin in any given place. If you can make a beta cell and put it back in the body, it doesn't matter where. The body and the circulation will take care of that. Those secondary problems are much more solvable."

If the Ontogeny researchers find ways to solve these secondary problems, the next question will be how far they can take the developmental approach. The obvious step, says Melton, is to go from creating new cells--such as nerve, bone, or pancreatic beta cells--to growing tissues and eventually entire organs. With the right progenitor cells and the right cocktail of growth factors, the Ontogeny researchers could theoretically grow any organ they want. Taking knee ligaments from cadavers or waiting for heart transplants would be things of the past. The researchers believe Wang's Star Trek fantasy is possible, but they also know the obstacles all too well. Melton emphasizes that the idea of growing something like a new heart is decades down the road, not years.

"I would start at trying to make heart muscle cells," he says, "then see how you would fashion them into heart muscle tissue, and then see about making organs. There are people who like the idea of trying to make organs straightaway. I don't want to say it's crazy to think about organ development. I don't think it is. I just think the challenge now is to start with cells."

Article 34

Abstract: Transgenic crops hold the promise of being resistant to pests and diseases and producing high yields. But critics point out that these crops could usher in evolutionary and ecological catastrophes, such as growing too aggressively and overtaking other plant life.

The seed companies say the plants they've created are safe. But who's to know what will come from a romp in the field with an untamed weed?

Contemplating world hunger from the vantage point of a well-laden breakfast table is certainly comfortable, if odd. One morning last January, executives of Iowa-based Pioneer Hi-Bred International, the "world's largest developer, producer, and marketer of genetically improved seed," gathered at the Friend of a Farmer cafe in downtown Manhattan for a discussion about global food security. Amid the restaurant's rustic decor--dried hydrangeas in earthenware pots, autumn gourds tumbling from rush baskets, exposed brickwork--the three officials and a group of journalists sat dining on maple syrup-soaked buttermilk pancakes, muffins, corn bread, omelettes, and apple butter as Pioneer's chairman and CEO, Chuck Johnson, outlined his vision of the future. "The business we're in is ensuring that the world has the capacity to have the food it needs to survive," he explained. That future capacity, he is convinced, can come only from the crops that companies such as Pioneer are producing: high-yield, insect-resistant breeds of corn, soybeans, sorghum, and sunflowers.

Pioneer makes some of its seeds conventionally, by creating hybrids. Back in the 1920s, though, the conventional was radical, and the typical farmer looked upon the newfangled seeds, in Johnson's words, as "witchcraft and Satanism--until he got his first taste of the Yield." For the past few years, however, Pioneer has been offering genetically engineered seeds, which have genes spliced into their chromosomes that make them more resistant to insects and weed killers. Johnson told the journalists about herbicide-resistant soybeans and a variety of corn that produces a toxin normally made by a bacterium known as Bacillus thuringiensis, or Bt. Last year, he said, a million acres of the Bt corn were planted in the Midwest, with an increased Yield of 10 to 15 percent, thanks to the way the Bt toxin discourages corn-eating insects.

Pioneer's vice president for marketing, Mary McBride, then chimed in, claiming that these "transgenic" crops have the power to increase food production in the developing world with minimal environmental impact. The world's population, she noted, is continuing to rise and must somehow be fed. And with the growing affluence of Asia, much of that increasing population will be eating more meat--thus demanding even more crops to feed the pigs and cows they will consume. By using high-yield transgenic crops, farmers will be able to harvest so much food that they won't try to cultivate fragile, marginal lands. Pioneer, as McBride put it, is creating "virtual acres."

Outside the comfortable confines of the Pioneer breakfast, this sort of unmitigated optimism is harder to find. The public is generally wary of the transgenic crops that are landing in American fields, and there are many vocal critics. As of last October, 24 genetically engineered crops had been approved by the Food and Drug Administration for sale in the United States, a further 8 are awaiting approval, and thousands more are being tested. Many are similar to Pioneer's crops, engineered to carry Bt toxin or to survive dousing by herbicides that kill the weeds infesting their fields. Others have been made resistant to various viruses, while still others have genes that delay their ripening or thicken their skin.

Opponents of transgenic crops claim that ecological and evolutionary forces could turn these crops into disasters. Perhaps the plants will prove so robust that they will grow aggressively, like weeds, and invade other environments--including a neighboring farmer's fields. Virus-resistance genes could escape into weeds and make them so hardy they'd outcompete endangered plants in the wild. Antibiotic-resistance genes (which botanists insert into transgenic crops as supposedly harmless markers) might escape into soil bacteria and from there into those that infect humans. Crops engineered to carry Bt-toxin genes might trigger the evolution of ever adaptive Bt-resistant bugs.

Is all this worry just more witchcraft and Satanism? The only way to know how seriously to take such doomsday scenarios is to run experiments. Researchers have only begun to do this work, setting up experiments to see how readily transgenic genes and proteins can escape the crops they were meant to help. The results thus far are proving that the doomsday scenarios are not pure fiction. But the researchers are split over whether the results should be cause for anxiety.

Much of the concern over transgenic crops stems from the promiscuous sexual habits of plants. Sperm are found within pollen grains released by the stamens of flowers. The grains are carried by wind or by insect. If the pollen should land on another flower's female organ, or carpel, it delivers its sperm to the egg hidden inside. Once the sperm fertilizes the egg, an embryo forms and a seed is produced. Not only can pollen from one breed of plant fertilize another, but different species can sometimes mate and produce hybrids that can reproduce. Genes in one population of plants (crops, for example) can thus seep into another population (neighboring weeds).

In the late 1980s geneticist Norman Ellstrand at the University of California at Riverside began warning of the dangers of this genetic escape. One could, for example, imagine an herbicide resistance gene getting into weeds and making superweeds that could take over a field. Yet this possibility hinged on how likely it was for crops and weeds to hybridize, and for the transgenic genes to establish themselves in the wild population. Ellstrand decided therefore to measure the likelihood, and in 1996 he reported that domesticated sorghum, Sorghum bicolor, could readily form hybrids with a weed called johnsongrass, Sorghum halepense. (Domesticated crops are often surrounded by their close weedy relatives, since both flourish under the same conditions.) Using harmless gene markers rather than actual transgenes, Ellstrand found that wind-carried pollen could create hybrid seeds over 300 feet away from the original crop. These hybrids produced pollen and seeds as viable as the johnsongrass, meaning that they could spread just as aggressively.

Ellstrand thinks that the implications for transgenic crops are quite disturbing. "The take-home story is, if you engineer herbicide resistance into sorghum, and johnsongrass is growing within a couple of hundred meters, then you're really asking for trouble, because then the genes will get into one of the world's ten worst weeds--johnsongrass--and as soon as you apply herbicide, you're going to be favoring it," says Ellstrand. "Here in the United States, where we use sorghum largely as a forage crop, the worst scenario would be a few million dollars' worth of damage." But in a place like Africa, where sorghum is a staple crop for humans, an escaped transgene could be disastrous. "In Africa, the wrong genes falling into weeds could actually end up creating massive crop failure. There are so many weed relatives in Africa because that's where sorghum was domesticated."

More recent experiments with actual transgenic crops also show that inserted genes can move between species. Plant geneticist Rikke Bagger Jorgensen of Denmark's Riso National Laboratory in Roskilde studied the yellow-flowered crop called oilseed rape, known in the United States as canola and in Latin as Brassica napus. Oilseed rape is a cultivated cross between a weed called wild mustard, or Brassica campestris, and Brassica oleracea, the cabbage plant.

Jorgensen planted a version of oilseed rape engineered to survive a weed killer called Basta alongside its wild ancestor (and weedy neighbor) B. campestris. Fertile hybrids easily formed, and when Jorgensen sowed the hybrids together with the original weed, a second generation of seeds was produced. These seeds grew to adulthood without any fuss and turned out to be impervious to Basta as well. Jorgensen returned to her fields the following spring and discovered that this second generation had produced offspring of their own, which continued to be herbicide resistant.

These same genes for Basta resistance, it turns out, can also hop into more distantly related plants. French cytogeneticist Anne-Marie Chevre of the National Institute of Agronomic Research at Le Rheu, found that these transgenic oilseed rape plants could donate their genes to wild radish (Raphanus raphanistrum). But their effects on the radish are not clear; the genes were carried into the wild radish population over the course of four generations, yet by that point only a quarter of the plants descended from the hybrids were resistant to the herbicide. The problem seems to be that the herbicide-resistance gene wasn't firmly integrated into the genome of the wild radish. Chevre, who doubts that the plants will be able to maintain their resistance, is watching to see whether a stable integration may come about in a future generation. If it does, she says, "it will be very difficult to manage because the transgene will be spreading in the wild population."

Yet despite these results, Jorgensen and Chevre remain sanguine about the prospects of transgenic crops. "If you can put in genes that give the plant itself a better resistance, for instance, to fungal pathogens or to insect pests, then you can minimize your use of pesticides, and that would be beneficial to the environment," says Jorgensen. And she believes that as long as transgenic oilseed rape is carefully managed, it can be safe. "If you spray very early, before the campestris flowers, you minimize its potential to hybridize," she explains. But it would be unwise to grow Basta-resistant oilseed rape alongside a crop resistant to a different herbicide. "Then what you'll have is Brassica campestris plants with multiresistance in very few generations," she says. A weed with only one herbicide-resistance gene would, however, still be manageable. According to Chevre, "You can always destroy the plants with another herbicide."

The prospect of herbicide-resistant crops creating the need for spraying still more herbicides doesn't fit well with the environmentally friendly image offered by companies like Pioneer. Yet some critics think that biotech corporations are actually comfortable with that prospect because they can make transgenic crops as well as herbicides. (Monsanto, for example, makes Roundup Ready cotton, which is resistant only to the herbicide Roundup--also made by Monsanto.) "The biotech companies, since they make the herbicides, don't see it as a big problem, because it forces them to make a new herbicide," says botanist Hugh Wilson of Texas A&M University.

Wilson has been studying transgenic gene flow and its possible effects not on the struggle between weeds and crops but between weeds and rare or fragile wild plant species. Herbicide resistance isn't so much of a problem in this regard, since weed killers are found only on farms. Of far more pressing concern to him is the possibility that genes for resistance to insects, viruses, and fungi can be just as important in the wild. It's conceivable that a spread of genes from transgenic crops into wild plants could allow them to outcompete other species. Transgenic crops could do the most damage, according to Wilson, in places where crops originated and where there are many wild relatives still thriving. For corn, the center of diversity is Mexico; for potatoes, it is Peru; for sunflowers, it is the United States.

"We've got to retain genetic diversity," says Wilson. "You can look at the potato blight, a situation where you take a subset of genetic diversity, put it in Ire land--boom--it's hit by something and it's obliterated immediately. The only way to resolve the problem is to go back to the point of origin, find a gene in wild potato that's resistant, and fix it" by conventional plant breeding. "But if that wild potato's not there, or if that wild potato is genetically uniform because of a weird transgenic interaction, then you're a loser."

Researchers have indeed shown that virus-resistance genes can escape from some crops into wild relatives. But whether this newly resistant wild relative can outcompete other native wild plants is still an open question because research has been so sparse. The lack of work is not for lack of interest. Plant ecologist Allison Snow of Ohio State University in Columbus is trying to start an investigation into whether virus-resistance genes inserted by the biotech firm Asgrow into a squash called Freedom II can persist in the wild and provide a competitive edge. But she's having trouble getting the necessary funding for the experiment from the U.S. Department of Agriculture. "I put in a proposal twice to study this, and both times I was tamed down," says Snow. "It could be because my proposal had some scientific flaws in it, but I think part of it could be--possibly--political. People don't want to study this thing. The squash is already deregulated. So the USDA has already said that this is safe." The USDA claimed it was safe because a different company has used conventional breeding to create a resistant hybrid squash. "They didn't use genetic engineering, so the USDA could say that this is really not very different from what's happened in the past."

Defenders of transgenic crops frequently argue that genetic engineering is in essence no different from the hybrid breeding that farmers have conducted for decades, with no ecological calamity. "For 50 years they have been breeding virus-resistant plants, and they behave the same as these transgenic plants," maintains plant pathologist Dennis Gonsalves of Cornell. "The wild relatives have the same ability to pick up resistance genes whether they came from natural breeding or whether they came from genetically engineered squash." Yet apparently in all this time wild relatives still haven't become resistant to viruses (although no one has carefully studied this interaction between weeds and crops).

Unlike Snow, Gonsalves has been able to study the Freedom II with a USDA grant. He hand-pollinated transgenic virus-resistant Freedom II squash with pollen from wild Texas gourd, producing hybrids which he then planted in a field three feet apart from nonengineered wild gourd. The experiment produced a mix of results. When he inoculated the plants with viruses, only the transgenic squash managed to produce viable fruit with viable seeds. Elsewhere in the field, however, a different result occurred. Where the virus was scarce--and the wild plants could thus thrive--the transgenic hybrids bred with wild Texas gourd. A small proportion of the offspring carried the transgenes and were resistant to the virus.

But Gonsalves isn't too worried by his results. "You've got to be careful to look at the big picture," he says. Among the wild gourd, the virus isn't much of a menace, while it is a major problem for the cultivated gourd. This presumably is because of the way squash is grown close together, making it easier for the virus to spread from plant to plant, while wild gourd is far more scattered. So even if the virus-resistance gene were to get into the wild gourd, Gonsalves contends that it would hardly make a difference since the weed is unaffected by the virus.

Snow is familiar with this argument but not persuaded. The USDA, she says, "thinks that these diseases are not really that common in the wild, and they've never seen a wild plant with viral disease, so they think maybe that's not having any effect on the wild population. But no one knows how many diseases are regulating wild and weedy plants. It's a very difficult thing to study, and there hasn't been much effort in that area."

These questions are moot when a crop plant has no weedy relatives in its vicinity. One possible way to contain the threat of transgene escape might be to bar certain genetically engineered crops when weedy relatives already exist in a given place. "There are no weeds related to maize in Europe," says Chevre. "But we have a lot of wild species more or less related to oilseed rape in the field everywhere." Therefore France has permitted transgenic corn to be grown on its soil. The United States could similarly allow transgenic maize, soybeans, and potatoes to be farmed, since they have no wild relatives with which they are sexually compatible here. On the other hand, squashes and sunflowers do.

There are ways that this policy might go wrong, however. A desperate farmer might ignore the law and plant a transgenic crop that can breed with local weeds. And crop-to-weed gene exchanges are only one kind of change that transgenic crops can bring. Researchers have been developing a transgenic potato, for example, that can fight off the aphids that feed on it. The new potato produces a protein called lectin that ruins the aphids' digestion. Greenhouse tests have shown that this transgenic potato can reduce populations of the peach-potato aphid by half. That's impressive but not quite good enough to allow the potatoes to survive on their own. To fully protect their crop, farmers would need to introduce aphid-devouring ladybugs.

But as entomologist Nick Birch of the Scottish Crop Research Institute in Dundee has shown, the lectin in the potato makes ladybugs ill: after eating transgenic potato-glutted aphids, ladybugs produce far fewer offspring and live much shorter lives. Yet even though he has shown how transgenic crops can have harmful effects that spread through a food chain, Birch doesn't think his results are cause for alarm. If ladybugs can also find aphids in the wild that are unaffected by transgenic potatoes, the plant's harmful effects will be diluted. In general, Birch thinks that with careful tests of their potential effects, transgenic crops can prove safe--and useful in reducing our dependence on pesticides.

To critics, this sort of cautious optimism is not yet warranted. They view what's happening now as a vast uncontrolled experiment with consequences we cannot predict--and promises that may never be met.

When the California-based biotech firm Calgene began selling the slow-ripening Flavr-Savr tomato--the first transgenic crop to be introduced in the United States--in 1994, it promoted the launch with a flurry of shiny tomato-shaped leaflets boasting "Summertime Taste ... Year-round!" For more information, the public was urged to dial a handy number: 1-800-34TOMATO.

Call the number now and you'll hear an anonymous voice telling you it's been disconnected. Alas, the Flavr-Savr tomato--which incorporates a transgene that allows it to grow red on the vine without getting squashy--has been withdrawn from sale. Monsanto, which bought Calgene last May, cites production and distribution problems. Apparently the tomato just wasn't tough enough to survive a bumpy ride down a conveyor belt.

The failure of the Flavr-Savr highlights a problem that has nothing to do with safety or gene escape: it's not clear if transgenic crops will actually live up to corporate claims. Some crops have done modestly well, while the performance of two closely watched transgenics--both produced by Monsanto--have proved embarrassing. One crop, Roundup Ready cotton, was designed by Monsanto to hold up against the company's herbicide Roundup. Last fall, in its first season, it ignominiously dropped its bolls all over the fields of some Mississippi farmers who had paid to try it out. In February the company began compensating them for their losses. Another kind of cotton, called Bollgard, was designed to ward off bollworms by producing Bt, the insecticidal bacterial toxin. In its trial season in 1996, the Bollgard plants did produce Bt as promised--but not enough Bt to fight off that year's particularly bad outbreak of bollworms. Some disgruntled farmers had to spray their transgenic crops with old-fashioned pesticides.

Even if Bollgard should be able to produce higher levels of Bt, some critics still think it is doomed to eventual failure thanks to the evolution of resistance. Of ten a conventional pesticide kills all but a few insects that by chance carry a gene for resistance to the toxin. The survivors then reproduce quickly until they reach former levels, and most of them are now impervious to the pesticide. Some farmers have sprayed Bt on their crops in the past, but insects weren't able to evolve resistance to it because the chemical broke down rapidly in sunlight. "But if you put Bt into the crop, then the pest will be exposed to it from the moment the seed comes up until the plant dies," says Margaret Mellon, director of the Union of Concerned Scientists' Agriculture and Biotechnology Program. That will create a powerful force for the selection of resistant insects, and Mellon suspects that it would make Bt a useless pesticide in less than five years.

Monsanto counters that resistance can be avoided by preserving refuges of plants that lack Bt. These islands will allow susceptible insects to thrive, and by breeding with the insects exposed to the Bt-engineered cotton, they will dilute any growing resistance out of the gene pool. But Mellon questions whether every farmer would voluntarily set up these refuges, which would presumably be devastated by the pests and produce no profits. If the insects should evolve resistance, crops such as Bollgard, despite all their high-tech armor, will be useless.

Article 35

Abstract: Biotechnological research studies involving genetic engineering are expected to flourish in the US because of widespread public acceptance. Surveys show that US scientists believe that informing the public about the studies on cloning and gene splicing offer benefits for their works. However, surveys in the European community reveal that studies on gene splicing or genetic engineering are not accepted by the people. Thereby, public attention can become harmful for such scientific studies.

Modern biotechnology - specifically, recombinant DNA research - holds enormous promise. Recently the popular press has been filled with excitement, and much anxiety and confusion, about mammalian cloning. This discussion is being played out against a complex backdrop of public attitudes about biotechnology, and perceptions of those attitudes among scientists. Many applications soon may be made possible by recombinant DNA technology, popularly called genetic engineering or gene-splicing. It is no wonder, given the rapid advances in this field of research, that genetic engineering is widely seen as the science of the next century. But the risks involved in gene-splicing, let alone gene therapy or cloning, have led to controversy, activist pressures and litigation. Given the complex social climate that is developing around genetic technology, what glimpses can we get of the future of this, the most rapidly growing of the sciences?

Over the past decade I have conducted a series of surveys in the U.S. and in Europe, attempting to get a scientist's-eye view of this question and detect trends in the context in which scientists are working. I have examined my colleagues' perceptions of several questions: How do societal and political factors affect the work of recombinant DNA scientists? Are things getting better or worse? What does all the controversy mean for the future of biotechnology? And what are the main threats that must be overcome in order to realize the promise of this new field? I found a mixed picture: an assessment of public perception that differs sharply from one side of the Atlantic to the other, growing optimism about public acceptance of biotechnology in the U.S. (and support for that optimism in surveys of the public) but pessimism in Europe, and some signals that a number of challenges and dangers lie ahead for those working in this field.

Public attention is the ultimate driving force behind science and technology funding - but also behind regulation, political opposition and drawn-out court battles. Looked at through the eyes of genetic-engineering investigators in the U.S., the public-opinion pendulum appears to be swinging in a direction beneficial to their field.

In a 1988-89 survey of 430 U.S. scientists, almost one-quarter saw more harmful than beneficial effects from public attention. However, almost twice as many perceived public attention as more beneficial than harmful in its effects. In 1995 I surveyed 1,257 scientists and found them to be even more optimistic, with more than half viewing public attention as beneficial to their field overall, and fewer than one-fifth seeing more harmful than beneficial effects.

In Europe, however, the perception is far more negative. In my 1992 survey of European genetic-engineering scientists, one-third perceived more harm than benefit, and only one-quarter saw public attention as beneficial overall. The picture was bleakest in Germany, where almost two-thirds view public attention as harmful.

What explains the optimism in the U.S.? Clearly, investigators were not feeling more optimistic because their funding was increasing. Almost two-thirds of my 1995 survey respondents said they had personally experienced a reduction in government funding of their research. This is significant in that government was by far the largest source of funding for our survey population, accounting for 69 percent of their support; only 16 percent came from industry, 8 percent from private foundations and 3 percent from universities.

If more money was not one of the benefits of public attention, what gains did scientists perceive? One was in the area of the reasonableness of regulations and regulators. Although surely people like to complain about government agencies, roughly half of my 1995 respondents rated the performance of regulatory agencies (the Food and Drug Administration, U.S. Department of Agriculture and Environmental Protection Agency) as excellent or good. This is not to say that they saw no problems. Many wished for greater efficiency and more relevant product or research approval criteria, for instance. However, fewer than one-fifth thought that federal regulations were endangering U.S. competitiveness in genetic engineering.

This is a far more positive picture than the one found in my 1992 European survey. Even in the United Kingdom, now Dolly's home, more than one-third of the respondents worried about the loss of their nation's competitive edge because of controversy and regulation. In Germany that figure was a staggering 92 percent.

It would be easy to conclude that the future must be bright for U.S. biotechnology, if those working in the field express such optimism about public acceptance. But some survey findings indicate otherwise.

To begin with, there is the funding question. With government funds becoming more elusive, investigators must look for alternative financing. For many in academia, this means collaborating with industry. In my 1995 U.S. survey, more than one-third of academics were involved in such collaboration. Furthermore, university-industry collaboration seemed so obviously necessary that 96 percent approved of it. However, of those who approved, 65 percent did so with serious reservations about the commercialization of recombinant DNA research.

The first of the reservations had to do with the sharing of knowledge. More than half of my respondents saw commercialization as breeding secrecy rather than scientific openness. This concern is corroborated by other studies and surveys (Blumenthal et al. 1996, OTA 1995), which show that industrial sponsorship of academic research does indeed lead to reduced sharing of research results. For instance, almost three times as many industry-supported scientists (15 percent versus 5 percent of noncollaborating scientists) reported that their work had resulted in trade secrets, and almost twice as many (11 percent versus 6 percent) said they had refused requests from colleagues to share biological materials or research results.

Second, half of the scientists in my survey felt that commercialization shifts the focus too much away from science and toward financial gain. In particular, in their comments, they showed a great deal of worry about erosion of the quality and status of basic research. Again, independent studies confirm that, as one would expect, collaboration with industry makes scientists gravitate toward research topics that promise patentable or practical results rather than basic scientific insight. For instance, David Blumenthal and his colleagues reported that more than one-third of industry-sponsored (versus 14 percent of nonsponsored) scientists said they picked research topics with an eye to commercial applicability.

I am concerned about the perceived trend toward secrecy and neglect of basic research in genetic engineering. Biotechnology is still in its infancy, still working on its foundations. Imagine if early chemists had thrown their energies into developing profitable household products before the periodic table was discovered, or physicists had kept their discoveries of subatomic particles secret. The situation in recombinant DNA research is similar: Universities, laboratories and companies are patenting or keeping secret fundamental gene sequences and data bases. As my respondents note, one certain outcome is massive duplication of key research. An even greater cost is the loss of the scientific dialogue essential for solid progress.

Possibly the greatest promise of medical biotechnology is its ability to reduce human suffering by eliminating genetic diseases such as Huntington's disease, cystic fibrosis or sickle-cell anemia, not just for a given individual but for successive generations. Genetic repair that would have such an effect is called germ-line therapy. Although such therapy is controversial and at best a long-term goal of biotechnology, it was advocated by the scientists in my 1995 U.S. survey by a margin of 2:1, provided a technique becomes available.

Yet consider the obstacles to achieving this goal. One is purely financial. Progress on germ-line therapy surely depends on broad advances in basic biomedical research, but basic research is exactly the area suffering most from loss of funding. Even if one could imagine early applications, what industry would be a likely sponsor of the research? Successful germ-line therapy might well be against the interests of the pharmaceutical industry, for example, since it would threaten its profits from therapies for chronic diseases. (Such issues already have arisen in agricultural biotechnology, where, for instance, techniques to reduce pests by using genetically engineered seed lines might be seen to threaten future demand for pesticides.)

The outlook becomes even dimmer in view of the shift to managed health care, which my respondents expected by a margin of 3:1 to reduce funding for recombinant DNA research. As some investigators noted, managed-care companies want to pay only for care and tend to neglect the costs of medical education and scientific research. Perhaps specific cost-saving bioengineered vaccines or drugs could stand up to such a short-term cost focus, but something as remote as germ-line therapy must fade into the dim future.

Another obstacle to germ-line therapy is, of course, the science itself. Most of the detective work remains to be done; also, much effort will have to go into understanding possible long-term side effects on individuals and the species, as well as any selective benefits of inherited diseases. But perhaps the greatest barriers are public resistance and the lack of rational public debate. It is in this area that scientists can make valuable contributions to help society reach well-balanced decisions.

Ignorance of the public is a tremendous obstacle to the acceptance of biotechnology advances. In their comments, scientists expressed great concern about the extent of this ignorance, which was illustrated by public reactions to the movie Jurassic Park, for instance. Surveys back up this picture: For example, in a 1993 New Jersey telephone survey of the public, more than half of the respondents (including medical practitioners and food growers) said they had heard little or nothing about genetic engineering, whereas 80 percent believed they had adequate understanding of general science and technology (Hallman 1996).

Some scientists view the public not just as uninformed but as uninformable. But the experience of some of my respondents contradicts this: They describe the "everyday public" as eager to learn, understand and evaluate, and quickly coming up with the same questions the scientists ask of their research. Even in the views of many scientists working in the field, then, the prospect of educating the public to improve decision-making on biotechnology is not at all hopeless.

Clearly the scientific community itself must play an educational role if accurate information about DNA technologies is to be conveyed. But are scientists not viewed as biased by the public, so that efforts at education or scientific involvement in public debate would be a waste? (In fact, some respondents worried about the public's perception of scientists as devious, smart and evil!) Interestingly, this does not seem to be the case. The New Jersey survey mentioned above showed that university scientists, at least, are seen by the public as the most reliable source of information (ahead of environmentalist groups and far ahead of government and biotech companies) about biotechnology.

In other words, public-attitude surveys do not suggest that scientists should be reluctant to engage in public debate over applications of biotechnology. Many of the ethical and social issues obviously are outside the realm of science and engineering and must be addressed with the help of specialists from other fields, including philosophy, sociology, political science, law and theology. Nonetheless, the impetus to resolve them has to come from the scientists who are most interested in pursuing advanced research.

A comment from one investigator expresses well the enthusiasm that should go into communication with the public: "Perhaps if more people understood how rudimentary medicine is today and the potential gene therapy has to overcome so many problems, there would be more public enthusiasm. One day the physicians will cringe at the thought of having to prescribe daily insulin injections for diabetes or chemotherapeutics for some cancers. The public should know this!"

Acknowledgments

The author wishes to thank the members of the American Society

for Microbiology for participating in the surveys, and the Richard

Lounsbery Foundation for its support of the work.

Bibliography

Blumenthal, D., E. G. Campbell, N. Causino and K. S. Louis.

1996. Participation of life-science faculty in research

relationships with industry. The New England Journal of

Medicine 335:1734-1739.

Hallman, W. 1996. Public perceptions of biotechnology:

Another look. Nature Biotechnology 14:35-38.

Krimsky, S. 1991. Biotechnics and Society: The Rise of

Industrial Genetics. New York: Praeger.

Office of Technology Assessment. 1995. Federal Technology

Transfer and the Human Genome Project. Washington, D.C.:

Government Printing Office.

Rabino, I. 1991. The impact of activist pressures on recombinant

DNA research. Science, Technology, and Human Values

16:70-87.

Rabino, I. 1992. A study of attitudes and concerns of genetic

engineering scientists in Western Europe. Biotech Forum Europe

9:636-640.

Rabino, I. 1996. What U.S. researchers think of regulations and

regulators. Nature BioTechnology 14:147-150.

Isaac Rabino received his Ph.D. in cellular and developmental

biology at the State University of New York, Stony Brook, and

has published in that field. He has a scholarly interest in the

social and political implications of genetic-engineering research.

He is professor in Biological and Health Sciences at Empire State

College, State University of New York, 225 Varick Street, New

York, NY 10014-4382.

Article 37

Consider the versatile potato. Even most children consume it in at least some form--baked, mashed, French fried, the list goes on. Now, molecular biologists predict that through genetic engineering they can turn spuds into the darling of the medical world: low-cost, nutritious vaccines.

William H.R. Langridge and his coworkers at Loma Linda (Calif.) University School of Medicine say they have inserted into potatoes a gene that enables the tuber to make a nontoxic component of the cholera toxin. The research could lead to protection against a scourge that afflicts 5 million people annually, they assert.

Moreover, because the toxins produced by the bacterium that causes cholera and by the more common Escherichia coli are nearly identical, Langridge says, vaccines against one germ may head off or ameliorate disease caused by the other.

Cholera locks open crucial pores in cells lining the gut. "So water pours from the blood into the intestines and then out of the system," Langridge notes. People with this diarrhea can quickly become dehydrated and die.

Langridge's team added the cholera toxin's B-protein to potatoes. This portion of the toxin not only binds to cells in the gut, it also triggers the production of antibodies against cholera.

Mice ate the altered potato raw once a week for 4 weeks and downed a booster meal some 40 days later. The scientists then removed pieces of intestine from the animals and added cholera toxin to the tissues. In the March Nature Biotechnology, Langridge's team reports that tissue from the treated mice leaked about half as much as tissue from mice that ate only regular potato.

Because people seldom eat potatoes raw, the scientists cooked the medicinal spuds and found that at least half of the vaccine survived in biologically active form--a donut-shaped ring of five linked B-protein molecules. Taking into account the fact that to develop immunity, people need far less of the vaccine than mice do, Langridge calculates that one cooked potato a week for a month should provide enough active B-protein to immunize against the cholera toxin. However, because immunity falls over time, periodic booster spuds would be required.

Langridge plans to refine the potato further, adding genes to make its vaccine target not just the toxin but also the bacterium that produces it. Such potatoes would constitute a medicine, he emphasizes, and should not be eaten too often. Overexposure to their vaccine could suppress a person's production of disease-fighting antibodies.

Charles J. Arntzen of Cornell University's Boyce Thompson Institute for Plant Research was one of the first scientists to engineer a potential vaccine into potatoes, but the E. coli protein he uses breaks down at high temperatures. He says he is especially interested in the results from cooked potatoes in the Loma Linda project.

Concern that heating would inactivate vaccines had led to an expectation that any useful ones would eventually need to go into foods eaten raw, such as bananas, observes Carol Tacket at the University of Maryland's Center for Vaccine Development in Baltimore. "But now that we know you can cook them, maybe potatoes will become the ultimate vehicle."

Article 38

Abstract: Biotechnology has raised a lot of moral issues which affects the public at large. Moral questions which need immediate answers should be framed in an ethical perspective of genetic engineering. Taking risk into account is also a relevant addition on the discussion of biotechnology.

Improving Nature: The Science and Ethics of Genetic Engineering. Michael J. Reiss and Roger Straughan. Cambridge University Press, Cambridge, UK, 1996. 288 pp. $24.95 (ISBN 0521-45441-7 cloth).

Biotechnology, one of the major scientific and technological breakthroughs of this century, is unique in the degree of controversy and scrutiny that it has stimulated since the first report of recombining genes appeared over two decades ago. Even though genetically engineered products are increasingly entering the marketplace, the public remains uneasy about such products. For example, a Swiss company recently had to recall 500 tons of chocolate bars when they were revealed to contain legally allowed, genetically engineered soybeans (Anonymous 1997}.

The authors of Improving Nature, Michael J. Reiss and Roger Straughan, identify and examine the moral questions raised by the science of genetic engineering and its applications. Many of these moral issues are at the core of public concern. The book is directed at nonbiologists, but those readers who are already familiar with genetic engineering will also find the ethical analysis of interest. The text would be ideal for a college ethics class because it would stimulate discussion on the morals and ethics of science and technology. The authors generally succeed in their aim to "provide a balanced overview of the practice and potential of genetic engineering, exploring the scientific and philosophical principles involved" (p. 8). They are willing, however, to state their own opinions about general issues, such as patenting and labeling, as well as about the specific genetically engineered products presented as case studies.

Improving Nature is easy to read. Each chapter is organized logically and ends with a helpful summary or conclusion that pulls together the ideas in the chapter. The authors' use of numerous headings to separate topics within each chapter enhances readability. The book is divided into three parts. Part 1 provides background information on genetic science and moral philosophy; Part 2 presents a variety of case studies in four general application areas of genetic engineering (microorganisms, plants, animals, and humans); and Part 3 is a single chapter exploring the role of education in public involvement with genetic engineering.

Part 1 begins with a clear, well-constructed chapter for the non-biologist that describes what DNA is, what it does, how it is transferred between organisms in nature, and how the barriers to transferring genes between unrelated organisms have been overcome by molecular geneticists. The next chapter, which focuses on morals and ethics, will be of interest to biologists trying to develop a framework to evaluate the opposing philosophical claims of proponents and critics of genetic engineering.

Moral views, beliefs, and concerns, as defined by Reiss and Straughan, include the understanding that "certain things are right and wrong and that certain actions ought or ought not be performed" (p. 45). Although moral judgments may be made after careful analysis, we often possess, based on our upbringing, a well-defined sense of whether something "feels" right or not. Both ways of arriving at moral judgments are valid, but both are open to examination. The authors define ethics more narrowly, as a set of standards by which moral concerns can be analyzed and critically investigated. Ethics can be used as a mechanism to "uncover and probe the underlying principles" (p. 48) that are used to make moral arguments. The authors identify the moral concerns associated with the cases presented in Part 2 and subject those concerns to ethical scrutiny. The goal of ethical scrutiny is not to determine right or wrong but to show if moral statements are rational and informed.

The authors note that facts alone may not resolve differences over moral judgments but are essential to inform an ethical analysis. For example, to assert that genetic engineering plants for herbicide resistance is morally wrong because the use of such plants will increase the use of certain herbicides presupposes that these herbicides should not be used. Analysis of data can help to clarify this issue but may not resolve it. For example, suppose it can be shown that a particular herbicide has no known adverse effects. One can still not be certain that adverse effects will not be discovered in the future. Thus, someone analyzing these facts could find support for the moral judgment that using any herbicide is wrong, whereas another observer could feel morally secure knowing that all available evidence shows no ill effects.

Some moral concerns about genetic engineering are based on intrinsic factors. For example, some people may feel that exchanging genes between unrelated organisms is inherently wrong; other moral concerns are extrinsic in that they relate to the consequences of genetic engineering rather than to the process. Improving Nature analyzes both intrinsic and extrinsic moral concerns, but the authors favor a case-by-case approach that emphasizes ethical scrutiny of the consequences. The authors dismiss two frequently cited intrinsic objections to genetic engineering - that it is "unnatural" and shows "disrespect" for life - as lacking "clarity and coherence."

Risk is an important extrinsic concern that is relevant to several of the cases discussed in Part 2, especially for applications that involve releasing genetically engineered organisms into the environment. Some scientists may consider risk to be a technical issue, but the authors correctly point out that taking irresponsible or unjustified risk becomes a moral issue as well. The authors engage in a substantive discussion of several risk issues. For example, should research that entails risk be avoided? Should research that might have catastrophic consequences be banned? What is the risk if research paths entailing risk are not pursued?

The case studies focus on products that are currently available or far along in research, rather than on hypothetical future applications. The wide range of cases highlights a variety of ethical issues. The authors present the cases clearly and concisely for the nonexpert. The conclusion of each chapter in Part 2 allows the authors to sum up the "ethical arithmetic" for the products discussed. As might be expected, for many of the products it is difficult to make any extrinsic moral judgments at the present time. However, the greatest strength of the book is in giving readers the framework of analysis for making up their own minds.

A provocative issue not addressed by Reiss and Straughan involves the evolution of resistance to Bacillus thuringiensis (Bt) among pest insects due to the engineering of this bacterial toxin gene into cotton and several other crops. Bt, applied as a spray, has been used by organic farmers in the United States for over 40 years. In 1996, approximately 12% of the cotton crop grown in the United States expressed transgenic Bt genes. Recent experiments suggest that the incidence of Bt resistance alleles in a cotton pest species may be higher than anticipated, leading to fear that resistance to Bt may evolve rapidly (Gould et al. 1997). Is it ethically acceptable to deploy transgenic insect-resistant crops if their use results in the loss of a safe and effective biopesticide?

Improving Nature succeeds in presenting a framework for the ethical analysis of genetic engineering that is accessible and valuable for both scientific and nonscientific readers. It is a welcome addition to the literature of the "new biotechnology."

ROGER WRUBEL Undergraduate Environmental Studies Program University of Massachusetts Boston, MA 02125

References cited

Anonymous. 1997. "Chocolate less sweet as a symbol for

Swiss." The New York Times. 6 August, p. A11.

Gould F, Anderson A, Jones A, Sumerford D, Heckel DG,

Lopez J, Micinski S, Leonard R, Laster M. 1997. Initial

frequency of alleles for resistance to Bacillus thuringiensis toxins

in field populations of Heliothis virescens. Proceedings of the

National Academy of Sciences of the United States of America

94: 3519-3523.

Article 39

Abstract: Development of gene chips has rapidly increased due to improvements in fabrication methods and their great economic potentials. New techniques allow the production of better and inexpensive biochips. Several commercial uses for these chips have been discovered since the first gene chip was produced.

Use of existing fabrication techniques and the promise of important commercial applications are driving rapid development of biotech-based microchip devices.

A great amount of information has been collected from the Human Genome Project and other genetic research. Nevertheless, no "killer application" has emerged to efficiently make use of it. Gene chips may change all that.

Gene chips are being compared to semiconductor chips in that they also may have the ability to reshape our economy, create vast fortunes for those involved in their development, and change the way we live. President Clinton recognized that possibility in this year's State of the Union address: "Within a decade, gene chips will offer a road map for prevention of illnesses throughout a lifetime."

The term gene chip is beginning to stand for a category of miniature biological DNA (deoxyribonucleic acid) probes, just as the terms Scotch tape and Kleenex came to mean adhesive tape and facial tissue.

But GeneChip is a registered trademark of Santa Clara, Calif.-based Affymetrix, the developer of the first photolithography-based gene detection system. A number of similar products are becoming available, so terms like DNA chip, biochip, DNA arrays, chip arrays, microarrays, and others are often being intermixed to describe similar technologies.

Many of these devices make some use of semiconductor fabrication techniques, which are largely responsible for the promise of low-cost and high-reliability detection.

The economic promise of these probes derives from capabilities that will arise from continued mapping of the human genome. Identification of an individual's genetic pattern will provide scientists with the information they can use to effectively treat illnesses and physical disorders. Gene chips will give scientists that information.

Imagine, for example, the possibility of taking a handful of $5 apiece throw-away gene chips and determining immediately at birth (or maybe even before with amniocentesis procedures) what ailments, diseases, and growth possibilities your newborn son or daughter might be prone to for the rest of their lives. Immediate medical actions could be taken to correct or even prevent potential problems later on in life.

Or imagine walking into a doctor's office and using just one of these chips to determine which drug prescription will work best in protecting you against this year's influenza variant. Multiply these and many other examples by the number of people that might use them each year on a global basis and you begin to see the economic potential of the technology and how volume production could lead to low-cost fabrication of gene chips.

On the research side, these same devices can be used to accelerate and dramatically cut the costs of drug discovery and development. An Affymetrix GeneChip with only 135,000 probes - 400,000 is the current design target - could decode human DNA about 25 times faster than current gene sequencing instruments.

Affymetrix has been the leader in this area, with products already being sold and established partnerships and collaborations with the Genetics Institute, Hewlett Packard, Hoffmann-La Roche, Incyte Pharmaceuticals, Merck, OncorMed, bioMerieux Vitek, Roche-Palo Alto, Glaxo Wellcome, Hoechst, Parke-Davis, Pfizer, Pioneer Hi-Bred, and Progenitor.

Its system consists of disposable DNA arrays containing selected gene sequences on a chip, reagents, appropriate fluidic application systems to process the arrays, fluorescence scanners to image the complex gene patterns, and software to manage and evaluate the information.

Affymetrix GeneChips use photolithography processes similar to those used with semiconductors to apply light in a predetermined pattern to a small glass plate or chip less than 1.28 cm square.

Once areas of the chip have been light-activated, a process, termed VLSIPS for very large scale immobilized polymer synthesis, immerses the chip in a solution containing one of the four nucleotides present in DNA - adenine, cytosine, guanine, and thymine.

The nucleotides react only with areas of the chip that have been light-activated. No reactions occur on areas that were shaded by the photolithographic mask.

Performed several times with different masks and different nucleotides, this synthesizes large numbers of known DNA strands or probes in an array format. Each probe contains artificially constructed genetic sequences identical to a normal or known gene segment, since each pattern is known and each nucleotide used with each mask is known.

As in semiconductor manufacturing, developing this initial template for a particular gene chip may cost a few thousand dollars. But it is reusable, which lends itself to high-volume, low-cost economies.

Gene chips or probe arrays contain from tens to hundreds of thousands of different oligonucleotide probes, whose sequences, lengths, and locations within the array are known. The HIV PRT GeneChip probe array from Affymetrix, for example, contains over 15,000 different probes for performing sequence analyses on portions of the HIV virus.

The HIV PRT probe array was introduced in 1996 and uses 100-[[micro]meter] feature sizes. "The demonstrated p53 gene chip uses 50-[[micro]meter] features," says Brian Brown at Affymetrix-partner Hewlett Packard, Palo Alto, Calif. p53 gene malfunctions are thought to be key contributors to most of all human cancers.

"Next generation chips which are being developed now will use 20-[[micro]meter] features," says Brown.

In the Affymetrix system, the prepared gene chip is mounted in a black plastic case or microcassette.

To analyze DNA obtained from a subject, a researcher extracts and purifies the target nucleic acid obtained from the subject's blood sample or other tissue. Fluorescent dyes are then affixed and the sample is fragmented into small pieces. The subject material is usually tagged with one dye and a normal sample tagged with a different dye. Both samples are put into a fluidics station containing the gene chip microcassette.

The fluidics station performs automated sample introduction, mixing, and washing of the probe. During the mixing operation, sample DNA segments bind only to probes holding complementary nucleotide sequences. The remaining sample material is washed off.

The chip then is placed into a scanning analyzer where a laser shines on the chip. Hewlett-Packard has collaborated with Affymetrix to produce the HP G2500A GeneArray Scanner for this step of the process.

DNA attached to the probes fluoresces and the optical scanner reads the fluorescent patterns and analyzes which nucleotide sequences in the subject's DNA have attached to the probes. The GeneArray Scanner does this by focusing its argon-ion laser beam onto a 4-[[micro]meter] section of a 20-[[micro]meter] or larger probe array feature.

The GeneArray Scanner takes less than 15 min to scan a 20,000-cell probe array. It has the optical ability to scan a 400,000-cell probe array of the same overall size. The scanner is priced under $100,000 and the cost per assay is estimated at about $90.

PC-based software is used to collect and analyze the fluorescence intensity and location information from the scanning analyzer to provide sequence data, genotyping, and gene expression monitoring.

While Affymetrix was the principal developer and is the current market leader in gene chip technology, other organizations are following its lead. Hyseq, Sunnyvale, Calif., a producer of gene sequencing modules and gene databases is applying its proprietary DNA array technology to create a universal DNA sequencing chip.

Both Hyseq and Affymetrix gene chip systems use probes of known sequence to determine the gene sequence of an unknown sample through a hybridization, or binding, process. Hyseq, however, claims it can sequence many bases with each probe, while the Affymetrix system is said to sequence one base at a time. Both companies align the sequences encoded in the probe array to obtain a unique DNA sequence.

As an aside, Hyseq sued Affymetrix last year for infringing on its patented sequencing-by-hybridization (SBH) method, which Affymetrix uses in its GeneChip. Hyseq also began a five-year collaboration with Perkin-Elmer, Norwalk, Conn., in 1997 to commercialize its DNA array chip technology.

Recently, Affymetrix sued Incyte, Palo Alto, Calif., and Synteni for infringing on its patents covering arrays of 1,000 or more pieces of DNA in a square centimeter of area. Incyte recently agreed to acquire Synteni and announced its intention to commercialize Synteni's spotted DNA arrays for monitoring gene expression.

Gene expression monitoring is one of three major areas of application for Affymetrix's GeneChip technology.

Affymetrix and Incyte currently have a joint venture to commercialize five Affymetrix arrays in the expression monitoring field. Two devices, LifeChip 1 and 2, are currently available, and three additional devices are under development.

Affymetrix is licensing its technology for use in making low-to-medium density spotted arrays for expression monitoring and has entered into one such license with Molecular Dynamics, Sunnyvale, Calif.

Genetics Institute, Cambridge, Mass., and Affymetrix also recently announced an expanded program for development of gene expression monitoring chips based on GeneChip technologies, following completion of their initial three-year collaboration demonstrating innovative use of DNA chips for gene expression monitoring.

Pharmaceutical supplier Pfizer also recently announced that it too has entered into an agreement with Affymetrix to gain access to GeneChip technology for gene expression monitoring applications.

While many organizations see the value of gene chip technology for its miniaturization and shorter analysis times than conventional sequencing techniques, the method is not yet applicable for clinical settings due to the difficulty of applying quality control steps during the manufacturing processes. Due to the low-definition signals and the need for sophisticated algorithms to interpret the signals, high redundancy is required to get to a statistically validated data set.

Currently available chips still cannot be used to analyze more than a single patient's sample.

Sequenom, San Diego, Calif., has developed a DNA analysis system that improves on the accuracy and reproducibility of existing gene chip techniques. Its DNA MassArray system uses robotically generated nanoliter quantities of DNA that are applied to a 6-[cm.sup.2] SpectroChip and analyzed with a matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDITOF-MS). Multiple analyses can be performed in rapid succession on as many patient samples as elements on the chip.

In either case, genetic identification methods are becoming available as fast as genetic determinations are being realized, which will continue to drive realization of human genome applications.

Article 40

The biotechnology world received a reminder last week of Wall Street's fickle love of new researcH results--and researchers got a lesson in how that passion can play havoc with efforts to orchestrate the release of scientific information. On Tuesday, 13 January, the price of shares tin Geron Corp., a California-based biotech company, rose 44% after news leaked that scientists there and at the University of Texas Southwestern Medical Center (UTSW) had managed to stem the aging process in cultured human cells. By week's end, however, as it became clear that income-gener-ating products of the research are distant, Geron's share price had glided back down.

The research, which confirmed that the enzyme telomerase can affect cellular aging, was scheduled for publication in the 16 January issue of Science. Following what has become standard practice for many journals, Science had sent information on the upcoming paper to reporters on 9 January, under a strict news embargo until 4 p.m. on Thursday, 15 January. A group called the Alliance for Aging Research (AAR), which promotes research on age-related diseases, also scheduled a news conference with some of the authors and other experts on aging to help explain the findings. The news conference was originally set for 1:30 p.m. on Thursday, with the information also embargoed until 4 p.m. But Geron's lawyers asked that the event be pushed back to 4 p.m. so that company officials couldn't be accused of trying to hype the company's stock price before publication.

This careful choreography began to fall apart on Monday, however. AAR sent an embargoed media advisory offering some details of the study to a newswire service that distributed copies not only to news outlets but also to investors. The entire advisory was published online by a database service late Monday afternoon. And on Tuesday, the same advisory was reportedly published on America Online's popular "Motley Fool" investment chat page. Reports that telomerase had been identified as a possible "fountain of cellular youth" were soon all over the Internet, and Geron's stock price took off on Tuesday morning. At that point, Science lifted the embargo on the paper, and stories appeared in most major media on Tuesday evening and Wednesday morning.

David Molowa, a biotechnology stock analyst with Bear Stearns in New York City, notes that biotech stocks are particularly prone to wide price swings because most companies don't have any products or make money, so their stocks trade largely on hopes of future earnings. "Investors get really excited and don't realize [any product] is decades away," he says. Indeed, investors caused a similar spike in Geron's stock price last August following publication of another paper in Science that identified key segments of the human telomerase gene (Science, 15 August 1997, p. 955).

But even scientists at Geron and UTSW downplayed immediate commercial implications of the company's research. The idea that the research will lead to new drugs "is clearly going out on a limb," says Woodring E. Wright, a cell biologist at UTSW, who helped lead the new study. "What [the latest] study shows is that we can control the process of cellular aging, not in the body but in tissue culture." It's a long way from there to affecting the body, he says. Even so, for a short time, it managed to add some youthful vigor to Geron's stock.

Article 41

Charles W Henderson

Pioneering British scientists who cloned Dolly the sheep - the first cloned adult mammal - are rearing cows and sheep to produce blood plasma for use in surgery and transfusions, The Observer said.

The researchers in Edinburgh, United Kingdom, are using their cloning technol- ogy to engineer animals which will generate the key proteins and antibodies in human plasma.

The technique provides a steady stream of cheap, safe blood products worth up to 1.5 billion pounds ($2.5 billion) a year, the newspaper said.

Surgeons and hospital administrators, struggling to overcome blood shortages, have welcomed the breakthrough, saying it could save lives and help prevent the spread of blood-born viruses such as HIV and hepatitis.

PPL Therapeutics, Edinburgh, United Kingdom, has been creating cows and sheep with human DNA. When the animals lactate, their milk contains key elements of human blood plasma.

Dr. Ron James, PPL, said, "We know from our work with Dolly that we can create genetically engineered animals from a single cell. Now we want to use that technology to produce one of the fundamental constituents of the human body. We are 99.9 percent certain we can do it," he said.

The first plasma could be produced within months, he added.  

Article 42

Consumer response to genetically altered foods has been mixed in the United States. While transgenic crops have entered the, food supply with little comment, other foods, such as the bioengineered tomato, have caused considerable controversy. Objections to genetically engineered food are varied, ranging from the religious to the aesthetic. One need not endorse these concerns to conclude that food biotechnology violates procedural protections of consumer sovereignty and religious liberty. Consumer sovereignty, a principle especially valued in this country, requires that information be made available so each individual or group may make food choices based on their own values. And as yet, there is no policy provision for informing consumers about the degree to which food has been genetically engineered.

Speculation about cloning human beings or transforming them through germ line therapy or molecular eugenics programs has given rise to many ethical critiques of biotechnology. When these critiques take up issues of informed consent or raise questions about the moral limits of human ingenuity they connect to a well-established bioethics literature addressing problems such as physician-patient confidentiality, euthanasia, or new reproductive technology. In this literature, the moral problems arise primarily when individuals (whether physicians or patients) must make tortuous choices, and policy issues concern when and whether it is appropriate for institutions such as hospitals or governments to regulate individual choice. An entirely different group of biotechnologies raise issues in public health and individual consent as well, though in a manner that requires a new analysis of the conditions for consent, publicity, and the acceptability of risk. University of Wisconsin sociologist Frederick Buttel has stated that medical biotechnology accounts for about 90 percent of the products from genetic engineering, while food biotechnology accounts for 90 percent of the controversy. Though genetically engineered foods seldom involve the life and death issues that make debate over biomedical technology so compelling, they pose challenges to our conventional thinking on risk, consent, and their role in public health policymaking.

Transgenic crops are being tested in many countries and have entered food supplies in the U.S. and China with little comment, but the introduction of genetically engineered corn and soybeans into European markets caused a firestorm of controversy in 1996. At present, European oilseed buyers are seeking supplies from regions where transgenic crops are not grown, but it is unclear that this practice will be permitted under World Trade Organization phytosanitary and environmental regulations. However, European resistance to transgenic crops is not strictly a cultural or regional phenomenon. Surveys reveal that many adults associate ethical issues with genetic engineering applied to food, and that adults who identify themselves as religious are significantly more likely to express the view that genetically engineered food raises ethical issues.[1]

Though few people have given explicit thought to the ethical principles that govern food choice, consumer sovereignty provides a reasonable interpretation of the implicit ethics in traditional norms for buying, selling, and consuming food. This principle presumes that food consumers give informed consent to the purchase or consumption of food in normal market transactions, and that food suppliers have discharged the bulk of their ethical responsibilities merely by providing information. Ingredient labels inform consumers of the constituents in processed foods, permitting consumers to choose or avoid foods based on health, aesthetic, religious, or even purely idiosyncratic considerations.[2]

In the past, challenges to informed consent in the food system centered on the marketing of unsafe food or on misleading health and nutritional claims. Food safety regulations preserve consumer sovereignty by protecting consumers from risks that would be difficult or impossible to detect without special training. Recent legislation in the United States places restrictions on the health and nutritional claims that food companies can make for foods. However, biotechnology challenges informed consent in a new way because it has the capacity to introduce new constituents into whole foods such as ordinary fruits, vegetables, grains, and meats. Since current policy includes no provision for informing consumers of these new constituents, consumers who find food biotechnology ethically, aesthetically, or religiously questionable have no capacity to avoid recombinantly transformed foods.

Plants and food animals are being genetically engineered to introduce disease resistance, to improve nutritional quality, to provide resistance to agricultural chemicals (allowing farmers to poison weeds without harming crops), to introduce natural pesticidal properties, and to reduce fats in meat. Defining genetically engineered food itself requires several interpretive judgments that may be controversial. A broad definition includes plants and animals that have been transformed through recombinant DNA technology, plus food that utilizes products from transformed microorganisms during an important stage of the production process. Recombinant rennet is an example of the latter. Rennet is an enzyme crucial to cheese-making. Once harvested from the entrails of slaughtered calves, rennet may now be produced by a genetically engineered bacterium. Food industry sources estimate that between 60 and 80 percent of U.S. cheese is now produced using recombinant rennet. Whether the use of recombinant rennet makes ordinary cheese into a genetically engineered food is unclear.

In most instances genetic engineering involves the insertion of foreign genetic material into the DNA of a plant, animal, or microbe. Here, "foreign" means that the inserted DNA is derived from a source other than plants or animals of the same species. At present virtually all inserted DNA has been isolated from plants or animals of another species, but it is possible to insert synthetic sequences of DNA, too. If food scientists identify synthetic sequences having useful functions, transgenic plants and animals of the future will certainly contain bits of genetic code never occurring before in any species.

Cloning represents a form of food biotechnology that does not involve transfer of genetic material. Cloning of plants is routine and is done on an industrial scale. Cloning of animals is more controversial. In the wake of Ian Wilmut's announcement of the cloned sheep, "Dolly," two Newsweek reporters discussed the potential for cloned animals in the food chain, noting that food retailers regard the prospect with horror, and concluding that it will be a long time before consumers are presented with the opportunity to eat "a cloned chop."[3] The Newsweek article implies that consumers are morally and legally entitled to information indicating whether a meat product is derived from cloned animals. Yet small quantities of meat and dairy products derived from embryonic clones have been on grocery shelves for several years, and no provisions for labeling them as such currently exist.

These facts raise a series of philosophical questions. Are animal clones developed from embryonic cells clones in the morally relevant sense of the word? Does inserting genes from one species into another constitute the mixing of species proscribed by religious food purity rules? It is in fact chemical copies of genes that are inserted, rather than physical constituents of plants and animals. Yet whether a chemical copy of a pig gene is still a pig gene, or is still a part of the pig when it has been inserted into a tomato is a question that has received little discussion. As such, these must be regarded as open questions, questions on which reasonable people can be expected to disagree.

It is useful to distinguish two levels of analysis for discussing the ethical issues raised by food biotechnology. At the most basic level are substantive concerns that any given individual or group might have about the consumption or production of genetically engineered foods and food products. Each of us may ask whether we want to eat genetically engineered foods, and some people may bring ethical and religious considerations to bear on their decision. These concerns will be reviewed in the next section, but the main point of this paper is to raise procedural concerns that are associated with the social rules for making food choices at any given time. In short, such procedural issues arise in connection with the question, Who decides when and whether substantive concerns will be taken seriously?

If substantive concerns reflect reasonable cultural and religious beliefs that are widely held or traditionally accepted within Western cultures, we should conclude that practices which threaten a person's ability to act on these beliefs violate liberties of conscience. It is thus not necessary to endorse the substantive concerns discussed below in order to conclude that food biotechnology violates procedural protections of consumer sovereignty and religious liberty. It is necessary only to show that substantive concerns represent reasonable beliefs.

Religious beliefs provide the most obvious and one of the most important reasons for wanting to avoid cloned or genetically engineered foods. Three general patterns of religious reasoning might be deployed in objecting to food biotechnology. First, it is certainly possible to object to any movement of genes from one species to another on religious grounds, without regard to whether the application is in food, medicine, or pure scientific research. Those who feel that altering the configuration of species violates God's handiwork, or implies a human arrogance, an unwillingness to recognize humanity's limits, might draw such a conclusion.

Second, many religions have dietary laws that proscribe certain foods or the eating of foods in certain combinations. Observant Jews must decide whether all or any application of food biotechnology is consistent with the rules of kashrut. Can these laws be violated at the gene level? This is a question that can only be answered by combining thorough knowledge of the traditions for interpreting dietary laws with an adequate knowledge of what actually occurs when genetic engineering takes place. Virtually all people recognize the moral proscription of cannibalism, for example, but it is far from clear that eating a food in which a gene derived originally from the DNA of a human being constitutes cannibalism. Similar kinds of inference will be required to decide whether genetically engineered foods violate dietary laws, but if religious believers do decide that their dietary rules prohibit the eating of such new foods, it can scarcely be doubted that they have a reasonable basis for concern about food biotechnology.

Finally, some object less to genetic technology itself than to what they perceive as the profaning of a sacred domain through the alienation of genes into private property rights and the commercialization of life processes. This is a complex form of religious reaction that depends upon a theologically or traditionally based understanding of life, food, and reproduction as at least partially sacred, and that sees the economic changes wrought by biotechnology as a transformation and violation of that sanctity. It is less clear that this argument can pass the test needed to deserve procedural protection in a democratic society. Some forms of this view are probably not reasonable in virtue of the fact that food and food production are quintessentially commercial processes, having been given over to regimes of private property and market exchange since antiquity. Nevertheless, there may be some version of this concern for the sacred that can draw a line between ownership of plants and animals, on the one hand, and the commercialization of life processes, on the other. To the extent that such concern is based on deep religious convictions and theological commitments, it too deserves respect.

There are a number of nonreligious bases for questioning resisting consumption of cloned or genetically engineered foods as well. Food safety -- the concern that comes first to mind for most people -- is probably not one of them, however. There is an unusually high degree of consensus among toxicologists, nutritionists, and applied biologists that properly conducted gene transfers pose considerably less risk to consumers than conventional chemical and breeding techniques for developing or modifying foods. In the U.S., the Food and Drug Administration has stated that regulatory review of genetically modified foods should take place only when a substance not previously present in the human food chain is introduced, or when genes are derived from plants (such as peanuts) or animals (such as shellfish) known to cause allergic reactions.

Nevertheless, there has been a high degree of scientific consensus in the past on technologies that have turned out to be harmful or to create significant risks. In light of this experience, it is quite reasonable for consumers to be wary of food biotechnology. This is not to say that genetically engineered foods are risky in the sense that there is reason to think that a significant probability of harm exists, but rather to say that an individual's lack of trust in science and technology provides a sufficient reason to prefer traditional foods. Clearly this distrust will be held differentially by members of society, but those who do not trust science have reasonable grounds for their attitude.

A similar but more pervasive distrust might be associated with a dislike of novelty. While this attitude is often derided among progressives, it must be acknowledged as one of those personality characteristics that can be expected to be found among a significant number of people in any large social group. However much one disapproves of such dislike, it is clearly characteristic of many reasonable people. William Bains's Biotechnology from A to Z, a dictionary of terms used in biotechnology and molecular biology, notes a more specific sort of intuitive aversion directly associated with genetic engineering. Dubbed the yuk factor, Bains identifies this as the impulsive or emotional reaction often felt in response to particularly distasteful applications of genetic engineering such as the mouse with three ears, or one in the middle of its back.[4] Clearly people will differ with respect to the extent that they associate the yuk factor with a product of food biotechnology. Nevertheless, such aversion is quite typical of attitudes deemed important in food choice. A similar aversion is felt by most Americans to the eating of dog or cat, and it hardly seems reasonable to require that people eat (knowingly or not) foods that cause such aversion when there are plentiful alternatives available.

One need not agree with or endorse any of these forms of concern in order to agree that food biotechnology challenges cultural integrity and individual consent. In normal circumstances, we would recognize that groups or individuals who shared any of the concerns noted above would be perfectly within their rights to make food consumption decisions that reflect the values which give rise to these concerns. The standard approach, in other words, is that each individual or group makes food choices based on their own values, and that they may reasonably expect to be provided with (or be able to obtain at a reasonable cost) the information needed to make that choice. This is the principle of consumer sovereignty: each individual or group decides based on their own assessment of substantive ethical concerns.

We so readily accept the principle of consumer sovereignty that we hardly think that there are any alternatives. Yet we might stipulate a principle of technological determinism: no one "decides." What happens is just the result of whatever technology happens to be used in food production and processing. Clearly, one would expect technologies to be regulated with respect to food safety, but within the scope of safe foods, consumers would only be able to exert such discretion as was fixed by the technology. I do not want to offer extensive development of what such a principle would entail in other cases, for the point is simply to note that changes in food technology can undermine consumer sovereignty. Food biotechnology is just one of many examples. Consumers may prefer to avoid tropical oils, for example, or may prefer soft drinks sweetened with cane sugar. Food technologies now permit the intersubstitution of many different oils, as well as the substitution of corn sweeteners for cane sugar. In both these instances, consumer sovereignty has given way to technology.

Is the loss of consumer sovereignty in food choice always a bad thing? I wish to bracket a full consideration that question in what follows. Clearly, individuals with food sensitivities or strong aesthetic preferences may regret technology's challenge to the expression of their preferences regarding tropical oils or soft drinks, but these changes in technology have not foreclosed their dietary options altogether. Until now, the ultimate recourse for those who wish to control their diets has been to eat a diet consisting only of whole foods. Whole foods are fruits, vegetables, grains, and animal products that have not been prepared by combining them with other foods or food ingredients in the process of cooking, canning, or manufacturing. Though few of us do so, one could control one's diet by purchasing only whole foods and by cooking, baking, or otherwise preparing everything "from scratch."

Though seldom exercised, the whole food option is crucially important from an ethical perspective because it has, until the advent of biotechnology, protected the principle of exit. Those who did not consent to a broad pattern of practices in the food system could withhold consent by exiting the system altogether, purchasing whole foods only. Clearly our current technology is not consistent with every value that might be held, but as long as those who have intensely held beliefs about dietary control have had the option of preparing meals themselves from vegetables, meats, flour, and other whole foods, they cannot be said to have been coerced into involuntary dietary choices. Prior to the introduction of cloning and genetic engineering, our food policies have been consistent with consumer sovereignty rather than technological determinism.

Transgenic foods challenge the principle of consumer sovereignty because there are a number of reasons why one might prefer not to eat genetically engineered foods (reasons ranging from emotion and aesthetics to religious conviction), and because it will be impossible for consumers to tell whether most foods have been genetically engineered or not. Consumers will not necessarily be able to avoid cloned or genetically engineered foods by purchasing whole foods (not prepackaged or partially prepared), or perhaps not even by growing foods themselves. Tomatoes and vegetable oils are two whole food products currently on world food markets that may well have been genetically engineered. Though there is no current threat to the availability of nongenetically engineered seeds, one can envision a future in which this is not so. Such information will not be "evident"; it must be supplied.

All these considerations weigh in favor of public policies that preserve consumer sovereignty by ensuring that relevant information can be obtained at a reasonable cost. Mandatory labels are often suggested. However, mandatory labels have been opposed by the food industry and by many scientists. Their opposition is in part spurred by the specious claims about the safety of genetically engineered foods that fueled the political debate. The arguments in this paper demonstrate the ethical basis for demanding a restoration of consumer sovereignty. These ethical considerations do not depend on risks that are alleged to be associated with cloned or genetically engineered foods.

Yet I would stop short of claiming that mandatory labels are the best way to restore consumer sovereignty. Food industry representatives fear that such labels would stigmatize good products, and would encourage baseless apprehension on the part of the food consuming public. Such labels would also involve costs that are, from a public health perspective, needless. Other policy mechanisms have been discussed, including a "no biotechnology' type of label that would protect exit, while leaving most foods unlabeled.[5] A complete discussion of the specific policy mechanism for protecting consumer sovereignty thus demands consideration of social and technical variables, as well as ethical principles.

[1.] Thomas J. Hoban and Patricia Kendall, Consumer Attitudes about Food

Biotechnology (Raleigh, N.C.: North Carolina Cooperative Extension Service,

1993).

[2.] Jeffrey Burkhardt "Evaluating Lower-Fat Meats from an Ethical Perspective: Is

Good for You Always Good for You?" in Low-Fat Meats: Design Strategies and

Human Implications, ed. H. D. Hafs and R. G. Zimbelman (San Diego: Academic

Press, 1994), pp. 87-111.

[3.] L. Reibstein and G. Beals, "A Cloned Chop? Anyone?"Newsweek, 10 March 1997,

pp. 58-59.

[4.] William Bains, Biotechnology from A to Z (New York: Oxford University Press,

1993), pp. 337-38.

[5.] Paul B. Thompson, Food Biotechnology in Ethical Perspective (London: Chapman

and Hall, 1997).