Michael Heylin

C&EN Washington

Biotechnology is the molecular, fundamentally chemical, approach to understanding and manipulating life. Will it provide the spearhead in combating the scourges of hunger, disease, human deprivation, and environmental degradation? Will biotechnology be the cutting edge of science-based progress in the 21st century—just as chemistry and physics have been in the 20th?

In the long run—and as the scientific fundamentals of biotechnology become far better understood than they are today—the full answers to these questions will unfold.

Modified soybeans make up about half of the U.S.'s 1999 crop.

USDA photos

Today, however, biotechnology as applied to agriculture is in some disarray. After about a quarter century of gestation, it is surging into the new millennium at a high rate of speed. But it is upsetting untold numbers of customers, consumers, and investors.

The ensuing controversies could delay exploitation of what the advocates of agricultural biotechnology claim to be its enormous potential for helping to feed the world—and feed it better than today—as world population surges from 6 billion to maybe 8 or even 10 billion in the next 50 years.

The promise includes foods of better quality and higher nutritional value, as well as higher crop yields and crops that can be grown with less impact on the ecosystem, with less fertilizer and pesticide, and in colder and drier areas than they can be today.

The key to all this is genetically engineered crops and foods. These are produced by gene-splicing techniques involving the transfer of a few selected genes from one organism to another to produce a specific useful effect with no, or minimal, adverse side effects.

This new method of genetic modification differs in three significant ways from the traditional method of cross-pollination that goes back to the beginnings of agriculture. It is more precise and predictable. It is faster. And it gives breeders, for the first time, the power to cross biological barriers—such as from animals to plants.

The reality

Despite all this potential and the excitement genetically engineered plants and foods are generating in the scientific community, they have run into serious problems in Europe—especially the U.K. The major supermarket chains there won't carry products containing them. Egged on by activist groups and the press, a significant fraction of the public—still traumatized by the mishandling of mad cow disease—is not yet convinced genetically engineered products are safe to eat or to have in the environment.

Reaction in the U.S. has so far been relatively muted. The public seems to be largely either unaware or supportive of genetically engineered crops and foods. Such products already permeate the U.S. food supply. Only 38% of 1,000 respondents to a recent poll conducted by the Washington, D.C.-based International Food Information Council knew that genetically engineered foods were already in supermarkets. Just over half, 51%, said they would likely buy a food genetically engineered to taste better, whereas 43% indicated they likely would not.

However, environmental, health, and regulatory issues related to genetically engineered foods are receiving growing attention. In the U.S. marketplace, within the past few months, a major pet food producer has declared it won't use genetically engineered crops. Two baby food makers, in response to consumer preference, have stated they will not use them either.

U.S. farmers have seen the once considerable European market for their modified corn dwindle to almost nothing—although the overall worldwide demand for U.S. corn remains high. A nasty trade dispute looms over barriers to biotech food products. And some major grain handlers have announced they want genetically engineered corn and soybeans kept separate from unmodified varieties. In some cases, they are paying farmers a premium for the unmodified version. This all raises some questions over which crops—modified or unmodified—farmers will grow next year.

These troubles have come after a seemingly spectacularly successful launch over the past three years of biotechnology as a major actor in food production.

In addition to Monsanto's genetically engineered bovine growth hormone that boosts milk production in cows and is another story in itself, genetically engineered potatoes, tomatoes, melons, beets, and other crops have been approved. But the big volume surge for biotech crops has come since 1996 with soybeans and corn. In 1996, a million or so acres of farmland in the U.S. were planted with genetically engineered food crops. By 1999, this had grown to more than 60 million acres, including about half of the soybean and about a third of the corn crops.

The largest volume biotech soybean is engineered to tolerate direct application of Roundup, Monsanto's powerful but relatively environmentally benign glyphosate herbicide. This simplifies weed control and is attractive to farmers. The genetically engineered corn contains a gene encoding an insecticide from the bacterium Bacillus thuringiensis (Bt) and so needs less protection from chemical pesticides.

What happens next

What will it take to get and keep agricultural genetic engineering onto a sustainable growth track worldwide? Nobody knows for sure. But Monsanto and its chairman and chief executive officer, Robert B. Shapiro, have an outline of the concerns that first need to be answered to the public's satisfaction.

Monsanto, the longtime St. Louis-based chemical maker, has in recent years transformed itself. Stripping off most of its chemical operations, it has metaphorically bet its own farm on biotechnology as applied to agriculture and health. It has invested billions of dollars to acquire outlets for its genetically engineered seeds and other billions to develop them.

Other major international life science companies, including Novartis and Aventis, have done much the same. DuPont has made a similar investment in agricultural biotechnology but has kept most of its chemical operations.

However, no company has been more aggressive and hard-nosed than Monsanto in developing and promoting genetically engineered foods and food-related products. The company has been tenacious in screening them from what it would consider unnecessary testing, excessive regulations, unhelpful labeling, or negative publicity.

No one is a more passionate and articulate proponent of the special significance of biotechnology than Shapiro. As he put it in an address in San Francisco at a State of the World Forum in October 1998: "In a very important sense, biotechnology is a subset of information technology. . . . It deals with information that's coded chemically in living cells. . . . Perhaps the most important, and to some degree the most troubling, aspect of this is we are also developing tools that enable us not only to decode this information that's encoded in DNA, but also to change it.

"This is something fundamentally new in the world, new in history. It is something like that moment in prehistory in which consciousness became aware of itself. It is the moment when life begins to understand what it is."

He goes on to say that application of this new knowledge creates "wholly new and wholly unprecedented hope" for addressing such issues as "how to feed people without damaging and, indeed, destroying land and forests and water. How to prevent human and animal disease, rather than intervene after it strikes. And how to offer people around the world the prospect of healthy aging as a normal, expected part of life."

Just one year later, in October of this year, Shapiro had a somewhat different message in an interactive video satellite linkup with a Greenpeace Business Conference in London. Commenting on what he describes as the "rather raucous debate" that has erupted over genetically engineered foods, he admitted that Monsanto has "probably irritated and antagonized more people than we have persuaded."

Sergiu Cealic from the Republic of Moldovia works on genetic mapping of eastern gamagrass that may result in improved corn.

Shapiro reconfirmed Monsanto's faith in the benefits of biotechnology for agriculture, nutrition, and human health, as well as the company's commitment to using it to develop "good, safe, useful products." But he acknowledged that a number of concerns about genetically engineered products that Monsanto, in its enthusiasm for the technology, had previously tended to dismiss are of substance, are not trivial, don't have obvious or self-evident answers, and need careful and thoughtful consideration.

He identifies these concerns as follows:

Are genetically modified foods safe to eat?

Is the regulatory process that each nation has in place sufficient to assure consumers of the safety of such foods?

Will consumers have meaningful choices based on the kinds of information they want to have?

Are these products going to be safe for the environment? How are they going to affect biodiversity? How will they affect other plants, insects, and birds?

How will the new technologies affect traditional agricultural practices, rural life, and especially organic farmers?

Will companies like Monsanto gain too much power over agriculture?

Are we playing God? Do we collectively have the wisdom to use these technologies well?

A recent report on the politics and economics of agricultural biotechnology organized by the University of Illinois also expresses the need for greater public understanding about genetically engineered crops and foods. It concludes, among other things, that "it is risky to let technology get too far ahead of consumer acceptance. Technology should not, and ultimately will not, drive the market."

Michael Fumento, a senior fellow at the Washington, D.C., office of the Hudson Institute, who has written extensively on biotechnology, had another slant in the Nov. 1 issue of Fortune magazine: "Monsanto used to have the best science and the worst p.r. [public relations] in the business. It's working on the p.r."

However, as Monsanto itself acknowledges, far more than better public relations is needed. The chemical industry learned this after Union Carbide's disaster in 1984, when a methyl isocyanate leak from an affiliate's plant in Bhopal, India, killed thousands. Very serious problems have to be examined and addressed in very serious ways.

Sen. Richard G. Lugar (R.-Ind.) summed up the current situation when opening a hearing in October before the Senate Committee on Agriculture, Nutrition & Forestry, which he chairs.

As he put it: "Neither the advocates nor the critics of this new technology, nor government officials here or in Europe, have, in my judgment, distinguished themselves in this debate. The proponents have failed to inform the public sufficiently about this new technology or to convince consumers of the benefits that might accrue from it. The opponents have voiced concerns and fears without much apparent consideration of the advantages that society may obtain. Government officials have failed to articulate a consistent and principled framework for public discussion and analysis. The public needs and deserves better."

Terminator

Monsanto has quickly moved to help diffuse the most contentious of agricultural biotech issues. This came with the company's public eschewing of so-called terminator technology in an Oct. 4 open letter from Shapiro to Gordon Conway, president of the Rockefeller Foundation. The foundation is a leading sponsor of agricultural research in developing nations. Conway is a distinguished agricultural ecologist, and this July he was asked to advise the Monsanto board of directors.

Shapiro writes that Monsanto's action is based on "input from you [Conway] and a wide range of other experts and stakeholders, including our very important grower constituency." Monsanto's specific commitment is "not to commercialize gene-protection systems that render seed sterile."

With terminator technology, crops would be genetically engineered to produce seed that is infertile. Farmers growing such crops would have to buy new seed every planting season. The same has long been true of high-yielding corn varieties developed by traditional plant-breeding techniques.

However, critics fear that terminator technology would be applied to crops grown in developing countries and would have very negative social and economic impacts on traditional small-farm practice that depends on breeding local varieties and saving seed for the next planting.

The prototype patent on terminator technology is owned jointly by the Department of Agriculture and Delta & Pine Land (D&PL), a Mississippi-based seed company. Since June 1998, Monsanto has been attempting to acquire D&PL. The deal is still pending, awaiting government approval. Shapiro points out that the specific sterile seed technology it would acquire with D&PL is only in the conceptual or developmental stage, and its business utility is speculative.

Monsanto leaves open the option of developing gene-protection systems other than those that render seed sterile. But in his letter, Shapiro assures Conway that "we will not make any decision to commercialize a gene-protection technology until a full airing of the issues is complete and we have responded publicly to the concerns that are raised."

Gene-protection systems, none of which is yet near commercialization, would provide built-in technical—as opposed to contractual or legal—ways to protect the investment that companies make in developing genetically engineered crops.

In a statement applauding Monsanto's decision to disavow the terminator technology, Conway comments that biotechnology is the most powerful tool ever put in the hands of agricultural research.

He points to a genetically engineered rice being developed by his foundation and the European Union. It dramatically improves the dietary supply of vitamin A and iron and could greatly benefit hundreds of millions of women and children in developing countries whose staple diet is rice.

Modified corn accounts for one-third of the U.S. 1999 harvest.

Conway also expresses concern that if the current controversies over genetically engineered food continue, they may "so polarize consumers, producers, industry, and governments in both developed and developing countries that it will be impossible for developing countries to realize benefits from plant technology."

However, these controversies are continuing. For instance, although Monsanto has joined other major biotech companies in backing away from terminator technology, the future of that technology remains uncertain.

Modified potatoes area smaller share.

For instance, in October, USDA Secretary Dan Glickman met with representatives of farm, consumer, and environmental groups to hear their demand that his agency abandon R&D on terminator technology. He made no commitment, but he said he would be personally involved in reviewing the situation.

This event highlighted one element of the controversy over the credibility of the regulation of genetic engineering as applied to agriculture. USDA is a promoter and developer of agricultural biotechnology. It is also a key player in the regulatory system. This problem is far from unique to genetic engineering. It also occurs, for instance, in the regulation of aviation.

Regulation

Proponents of agricultural biotechnology insist the regulatory mechanism in place is comprehensive and ensures extensive testing of any genetically engineered product. They claim that all the procedures involved are based on sound science and have been examined and endorsed by a host of expert and advisory panels—both in the U.S. and elsewhere. They also point out that the system has worked well. It has even identified and headed off a potential problem—a Brazil nut-spliced soybean that turned out to be allergenic.

Regulators stress that the onus is still on producers to put only safe products on the market. They also claim that genetically engineered foods are by far the most extensively tested of all foods.

To those who remain unconvinced, the regulatory process is too diffuse, too loose, and too trusting. It assumes too much from the limited experience to date and is too dismissive of any uncertainties, these critics say.

Critics also maintain that the testing that is done is very incomplete. For instance, they claim more effort should be put into exploring if there is a way to give indications whether a genetically modified food may be allergenic.

Regulation of genetically modified plants and foods is split among three federal agencies. USDA is responsible for ensuring that new varieties are safe to grow. The Environmental Protection Agency is responsible for ensuring they are safe for the environment. And the Food & Drug Administration is charged with ensuring that new varieties are safe to eat.

The regulatory process is focused primarily on the characteristics of the plant or food itself, not on the method of its creation. This is based on the belief that there is no conceptual distinction between the genetic modifications of plants by classical breeding methods and by gene transfer. As a 1989 National Research Council report puts it: "Crops modified by molecular or cellular methods pose risks no different from those modified by classical genetic methods for similar traits. As the molecular methods are more specific, users of these methods will be more certain about the traits they introduce into the plants."

Under the current regulations, food producers are not required to seek premarketing approval for a genetically engineered variety of food that is "substantially equivalent" to foods already on the market. And it is up to the producer to decide if its new product meets this equivalence criterion. FDA has guidelines for genetically engineered foods but no regulations specific to them.

Testifying in an October hearing of the House Science Committee's Subcommittee on Basic Research, FDA's James H. Maryanski explained that the agency had been studying genetic engineering techniques for two decades and has "carefully developed policies to accommodate the evolving world of biotechnology. The evidence shows we are meeting our goal of ensuring that these new products meet the same safety standards as traditional foods." Maryanski is biotechnology coordinator for FDA's Center for Food Safety & Applied Nutrition.

In concluding her remarks at the same hearing, Janet L. Andersen, director of EPA's Biopesticides & Pollution Prevention Division, stated: "EPA believes that our regulatory program is based on the most rigorous scientific information available, is credible, is defensible, and will serve to protect the environment and public health as we address the challenges associated with biotechnology."

Taking the other side was Mark Silbergeld, codirector of the Washington, D.C., office of Consumers Union. In his opinion, the development and marketing of genetically engineered food products "are well ahead of the policies needed to ensure public health, environmental safety, and the rights of consumers."

He admitted that "there is no evidence that the genetically engineered foods now on the market present safety problems." But he insists the regulatory framework is too fragmented and too reliant on industry self-regulation to ensure that they are safe. The issues he sees as unresolved include the potential for genetically engineered foods to be allergenic, toxic, of lower nutrient value than unmodified varieties, and harmful to the environment in a variety of ways, especially in the evolution of pesticide-resistant insects and weeds.

Rebecca Goldburg expressed similar reservations at the same hearing. She is a Ph.D. biologist, senior scientist at the Environmental Defense Fund, and a member of the National Research Council's Committee on Genetically Modified Pest-Protected Plants.

Goldburg made three points at the hearing:

There are real risks associated with the development of genetically engineered plants. Additional research would help scientists and regulators to handle and even obviate some of them.

The environmental benefits from some bioengineered crops are more limited than what is claimed by those with an economic stake in them.

Genetic engineering should be assessed in a realistic way. It is not a high-tech panacea, and its advantages and disadvantages should be weighed relative to those of other agricultural technologies and practices.

Dialogue

Any consensus on the need for extensive and far more open dialogue, especially with the public, before agricultural biotechnology can really blossom will have to evolve out of today's highly polarized situation.

At one extreme are scaremongers, mostly in Europe, of the killer tomato and "Frankenfood" school of thought. They see nothing but disaster from an agricultural biotechology imposed on society by greedy seed and chemical conglomerates intent on clamping a patent-protected, iron-fisted grip on much of the agriculture worldwide. They claim that application of agricultural biotechnology is dangerously ahead of knowledge about its impacts.

At the other extreme are those who immediately dismiss anyone who raises a question about agricultural biotechnology as a Luddite or an agent of an antiscience conspiracy that will eventually lead to massive chronic food shortages and even starvation if biotechnology is not given free rein.

In the middle in the U.S. is a somewhat bemused public. It is not yet unduly alarmed as in Europe. But Americans may not yet be entirely comfortable with big corporations manipulating their food in, to them, mysterious ways. This is especially so when it is done to no perceptible advantage to them as consumers—as has been the case so far.

The concept of genes from animals, bugs, bacteria, viruses, or any other living thing being inserted into corn or other foods is inherently not an easy one to swallow, especially for nonscientists. In addition, there is sentiment that people have a right to the information they need to make an informed choice about eating transgenic foods or not—something that has so far been denied them.

However, the U.S. public is apparently sensitive about its food supply when it believes it is being pushed too far. USDA learned this last year when it proposed that genetically engineered foods be allowed to fall within a formal definition of "organic foods" it was developing. The agency quickly dropped the idea in the face of spontaneous and ferocious public response.

For the public, there is also the contradiction of biotechnology defined as "something fundamentally new in the world, new in history"—as Monsanto's Shapiro refers to it—but also described by regulators as not really different from plant-breeding practices that go back through the millennia.

Much of the heightened biotech debate in recent months in both the U.S. and Europe has swirled around three papers published in prestigious peer-reviewed journals. They concern the central and most sensitive issues facing transgenic foods: the basis of their regulation, substantial equivalence; their potential for affecting health; and their potential for impacting the ecosystem.

Equivalence

The commentary on substantial equivalence comes from Erik Millstone, a senior lecturer at the Science Policy Research Unit at Sussex University, England [Nature, 401,525 (1999)].

Millstone does not mince words: "Substantial equivalence is a pseudoscientific concept because it is a political and commercial judgment masquerading as if it were scientific. It is, moreover, inherently antiscience because it was created primarily to provide an excuse for not requiring biochemical or toxicological tests. It therefore serves to discourage and inhibit potentially informative scientific research."

Application of pesticides should be cut back with increased use of modified seeds.

He points to what he sees as the anomaly. The chemical composition of glyphosate-resistant soybeans is different from antecedent varieties; otherwise they couldn't be patented and couldn't withstand the herbicide. However, for regulatory purposes, they are deemed substantially equivalent to other soybeans.

Response to Millstone has been equally vigorous. Stephen L. Taylor, head of the University of Nebraska's department of food sciences and technology, presented the major arguments at the House Subcommittee on Basic Research hearing in October.

He pointed out that the concept of substantial equivalence has been endorsed by the Organization for Economic Cooperation & Development (OECD), the World Health Organization, the International Life Sciences Institute, and government authorities in the U.S., the U.K., Japan, Canada, and the European Union.

Taylor explained that substantial equivalence is not a means to avoid testing. Rather, it appropriately focuses testing on the unique, novel components of transgenic products. He stated that the extensive animal toxicity testing that Millstone advocates would be "tremendously unfocused, wasteful of laboratory animal resources, and unlikely to detect any harmful substances, even if they were present."

Health, rats, and potatoes

The second article reports findings that a genetically engineered potato fed to rats causes a thickening of the wall of part of their digestive tract [Lancet, 354,1314 (1999)]. The publication of this article comes only after months of raging controversy and near hysteria in Britain.

The principal author is Arpad Pusztai. He is recently separated from the Rowland Research Institute in Aberdeen, Scotland, where he did the work. The coauthor is Stanley Ewen, senior lecturer in pathology at Aberdeen University Medical School.

The potato involved contains a gene from a snowdrop plant. It produces a lectin, a natural insecticide. Two control groups of rats in the test were fed unmodified potato—either straight or spiked with lectin. The aberration in the digestive tract occurred only in the rats fed the genetically modified potato.

The uproar started when Pusztai talked about his then-unpublished work in a television interview in 1998. He said, among other things, that he would not eat genetically engineered food himself and that is was unfair to use the public as guinea pigs.

The Royal Society reviewed what it could of Pusztai's still-unpublished evidence this May, finding it "flawed in many aspects of design, execution, and analysis," and stating that "no conclusions should be drawn from it."

This unusual intrusion by the most prestigious scientific organization in Britain upset Lancet Editor Richard Horton. In his May 29 editorial, he described it as "a gesture of breathtaking impertinence."

Horton's decision to publish Pusztai's paper—it was submitted to Lancet late last year—has brought great criticism from scientists who still maintain it is unworthy of publication and damaging to Lancet's standards and standing. It has also brought Horton continued confrontation with the Royal Society, which preempted publication of the paper by a few days with a critical public rebuttal. It repeated the society's earlier charge that the experiments described in the paper are flawed and that there is "lack of rigor in the experimental design and statistical interpretation."

In an accompanying editorial, Horton defends publication. He writes that it is not vindication for Pusztai's television claims, which Horton had criticized earlier. "On the contrary," he writes, "publication of a paper after substantial review and modification provides a report that deserves further scientific attention."

Horton goes on: "Ewen's and Pusztai's data are preliminary and nongeneralizable, but at least they are now out in the open for debate." Horton points out he had the paper reviewed by six reviewers, instead of the usual three. One flatly and publicly stated it shouldn't be published. According to Horton, the others went along with publication after a number of changes and clarifications—with various degrees of enthusiasm.

Monarch butterfly

Cornell University entomologist John E. Losey set off a storm when he reported that in laboratory tests monarch butterfly larvae sickened and died when fed milkweed leaves dusted with pollen from Bt transgenic corn [Nature, 399, 214 (1999)]. Milkweed is the larvae's only food, and it can grow near corn fields.

Losey acknowledged that his findings, although raising an important issue, were preliminary and should not be used to draw conclusions about any danger to the monarch population in the field. In spite of this caveat, antibiotech activists exploited his paper.

Sensing the possibility of a public relations field day for biotech opponents, the Biotechnology Industry Organization released a statement a day before the issue date of the Losey paper.

It pointed out that in the natural setting, most monarch butterfly larvae would never encounter any significant amounts of corn pollen, and so the real danger was negligible. It also stressed that it had already been shown that insect biodiversity and population densities in Bt corn fields are significantly higher than in fields of unmodified corn treated with chemical pesticide sprays.

The statement also said the industry would follow up on Losey's findings. This is being done through several industry-funded initiatives. EPA is also following up.

The longer term

Gerald C. Nelson, who coordinated the University of Illinois study of the politics and economics of agricultural biotech, says the technology's future cannot be predicted at this time. He is a member of the university's department of agricultural and consumer economics.

However, he tells C&EN that the most likely scenario includes another five or 10 years of continued debate. He believes this will be a disorganized period as corporations and pressure groups continue their play for public opinion and for the ear of regulators.

According to the report, this scenario also includes the introduction of genetically engineered products that are accepted by the public as safe and of clear benefit to the consumer and the environment. In addition, best practices will be developed to minimize environmental impacts, and regulations on labeling will be resolved to give consumers meaningful information.

The report also stresses the central role of testing. "Whether it is strictly necessary to conduct further widespread testing on the safety of genetically engineered foods is questionable. But to address food safety issues, it would seem wise to conduct toxicology and other tests to evaluate more carefully the properties of genetically engineered and non-genetically engineered foods. Many traditional foods contain ingredients that are harmful at high doses; subjecting genetically engineered foods alone to extensive testing would not present a balanced picture. Disinterested parties should undertake the research rather than organizations with a stake in the outcome."

The conclusions of the report state that if the most likely—and eventually positive—scenario is to be plausible, "the current task is to develop the regulations, tests, and procedures that will smooth passage through the uncertainties ahead. This would suggest that the industry, including food retailers and farmers, join in a dialogue with [moderate] consumer and environmental groups to set up monitoring and evaluation processes that increase the comfort level for all. This outcome argues for cool heads . . . searching for ways for governments to collectively manage trade conflicts and avoid projecting commercial and other differences on the genetically engineered food debate."

The beginnings of the broader dialogue being called for are already in the works. For example, in September, USDA Secretary Glickman announced an agreement for the National Academy of Sciences to undertake an independent, ongoing scientific review of USDA's regulatory process for genetically engineered plants. Also, FDA is holding three public meetings to explain how it determines that a genetically engineered food is safe and to get the public's reaction.

In addition, Monsanto is encouraging much more open discussion. According to Shapiro, "We're listening, and we'll seek common ground whenever it's available and to the extent it is available." DuPont says it will engage and listen to critics who question biotechnology's safety.

And on the international front, OECD is intensifying its work on biotechnology and food safety and will report to the heads of state of the eight major industrial nations, known as the Group of Eight, at their next meeting in July next year.

The challenge for the biotech industry is to realize that any scientific development, however spectacular, has its limitations, won't solve all the world's problems alone, and needs to be applied with care and discretion. And, above all, it has to have a mandate from the public.

Keeping that mandate for agricultural biotech in the U.S., and getting it back in Europe, will be no easy task.

[Building A Sustainable Industry][Medical Frontiers]

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