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Lester M. Crawford, D.V.M., Ph.D. - American Enterprise Institute

This text contains Dr. Crawford's prepared remarks. It should be used with the understanding that some material may have been added or deleted during actual delivery.

Speech before
American Enterprise Institute

Remarks by
Lester M. Crawford, D.V.M., Ph.D.

Deputy Commissioner
U.S. Food and Drug Administration,

June 12, 2003

Good morning. I am honored by the invitation to address a conference that deals with the interplay of biotechnology, the media, and public policy. This is a subject with great economic, scientific, and even international implications, and as a scientist and a public servant who has frequently dealt with issues involving genetic manipulation of plants and animals, I want to congratulate the American Enterprise Institute on providing a platform where these topics will be thoughtfully and thoroughly examined by eminently qualified speakers.

The Food and Drug Administration involvement in interplay that's the subject of this conference starts before the genetically modified products are introduced in the market place, and thereby, in most cases, come to the attention of the media and the public. As part of our public health mission, we attend scientific meetings; network with scientists who are developing these new technologies; follow specialized literature; and in addition, we are frequently approached by researchers who request advice about potential regulatory requirements when they begin developing novel products.

This is the beginning of frequently significant exchanges focused on our responsibility for making certain that when these new biotech products enter the market, they comply with the public health standards and policies legislated by the United States Congress. I therefore thought that the best contribution I can make to your discussions is to outline the gate keeper's view of the promise and challenge that biotechnology holds for our future.

I will start with some examples of the array of unprecedented biotechnology products that are in the R&D pipeline or at our doorsteps, and I will largely limit this overview to genetically engineered animals and insects, which represent the cutting edge of rDNA manipulation. This manipulation also poses regulatory questions that frequently differ from those that apply to to the more familiar genetically modified plants, which have been on the market for good many years.

I will next address some of the public health risks that could be involved in the commercialization of these transgenic products. And finally, I will outline the legal requirements and practices that are designed to prevent or mitigate these hazards, and thereby maximize the benefits of a technology that we at the FDA regard as potentially a major contributor to the wellbeing of not just the people of the United States, but all humanity.

I will start with animal biotechnology's most important applications, which include the use of genetically modified animals as laboratory models in medicine; in the production of special foods, human drugs and medical devices; in the development of animal and industrial products; and in insect-based pest and disease control.

Bioengineered animals are now commonly used for the exploration of medical questions that cannot be readily studied otherwise, such as the mechanisms of both normal physiology and the pathophysiology of humans and animals. Pigs, for example, are often chosen as model systems for human disease because the size and function of their organs are similar to humans. They are also readily available, and are relatively easy to work with. One example is the pig model for human retinitis pigmentosa, a progressive disease that begins with night blindness, and affects betwee 100,000 to 400,000 people in the U.S. This pig model is intended to help develop pharmaceutical strategies to slow the onset and progression of the disease.

More traditional laboratory models include rodent systems that have been developed to study the mechanism or mechanisms by which inborn errors of metabolism cause disease. An example is the mouse model used to study Menke's disease, a condition that results in severe mental retardation and other developmental defects caused by extremely limited copper influx and transport. Mouse models have also been developed to study both the mechanism and barriers to the transmission of spongiform encephalopathies, which include human Creutzfeldt-Jakob Disease, Mad Cow Disease, and chronic wasting disease of deer and elk.

Most recently, transgenic mice are being developed to test the safety of the poliovirus vaccine, and they may replace the use of monkeys to test the safety of vaccine batches. Other laboratory models include sensitive detectors of mutagenesis and potential subsequent carcinogenesis that are now commonly employed by commercial testing laboratories. Insects and fish are also employed as laboratory animal models of disease or population dynamics. For example, Drosophila melanogaster, the common fruit fly we all remember from our college days, is often used as a model for developmental studies. Transgenic zebrafish and Amazon Mollies, to mention two other examples, are used to study effects of ultraviolet irradiation on the formation of melanomas.

More familiar -- and, in some quarters, controversial, is the use of bioengineered animals to produce certain human foods and medical products. For example, cows can be genetically engineered to make several kinds of specialized milk. They can produce milk with lower level of the protein beta-lactoglobulin, which may make the milk more suitable for up to 6 percent of U.S. infants and other individuals who are allergic to regular cow milk. They can also produce milk more digestible for people who are lactose intolerant; milk that has more naturally occurring antimicrobial enzyme, which increases the milk's shelf life; and milk with altered relative content of proteins such as caseins, or with lower content of water, which facilitates cheese production.

Fish can also be modified to provide better, more nutritious food. One example is the transgenic modification of rainbow trouts to increase the amount of their omega-3 fatty acid, which can help prevent heart attack. Incidentally, some of these food products are on the near horizon with respect to regulatory review. Several manufacturers have started a process that's necessary to receive the FDA approval for their product, and others have come in for preliminary discussions or are in the proof-of-concept phase.

But within the next few years, we're likely to see many more of these products. Genetic engineering can also develop animals capable of producing therapeutic proteins. In general, these proteins will be produced in the milk of cows, sheep, or goats; in chicken eggs; in the semen of swine; or in blood of various large farm species. The advantage of producing these proteins in animals -- rather than cell or tissue culture, plants, or microorganisms -- is significant: for one thing, in general, the yields are high, and the proteins tend to be glycosylated in a manner more consistent with human patterns. This decreases the potential for allergic reaction, or loss of function due to inappropriate post-translational modification.

In addition, the post-development costs tend to be lower, because raising a herd of dairy goats or cows is cheaper than building and maintaining a bioreactor facility. An example of therapeutic products from bioengineered animals includes the production of the protein alpha-1-antitrypsin in sheeps' milk. This is a human blood protein used to treat hereditary emphysema, cystic fibrosis, and chronic obstructive pulmonary disease, which are thought to affect more than 200,000 people in the U.S. and Europe. This product is in clinical trials in Europe.

Another human drug that can be produced by transgenic animals is human lysozyme. This is an antimicrobial protein that has been genetically engineered into cows' milk at levels 3,000 times higher than in mother's milk. Use of this protein can enhance the health protection of infants, and increase product shelf-life by limiting spoilage. Human tissue plasminogen activator; Factors VIII and IX; antithrombin III; protein C; and cystic fibrosis transmembrane conductance regulators have all been introduced into genetically engineered animals for synthesis and secretion in milk.

Monoclonal antibodies to treat rheumatoid arthritis, which are now synthesized in tissue culture, are currently being developed as products in the milk of ruminants. In addition to providing a necessary therapeutic function, these milk-derived products, which are normally purified from human blood, can be significantly safer because they won't be potential carriers of infectious diseases such as HIV or hepatitis. At the same time, as I will discuss later, the potential for transmission of animal-borne diseases remains to be addressed, especially given the emergence of apparently new spongiform encephalopathies, such as BSE, the Mad Cow's Disease, which has been associated with a version of Creutzfeldt-Jakob disease that has caused the premature death of more than 100 people in Europe.

Xenotransplantation is another area where transgenic animals could be used to greatly benefit human health. The field of xenotransplantation covers many procedures, ranging from implantation of single cells to treat Parkinson's disease, to implanting tissues such as pancreatic islets to treat diabetes, and to the transplant of organs to treat organ failure. Because of their physiological similarities to humans, pigs are attractive as a potential organ donor species, and have been genetically engineered to remove 3-galactosyl transferase. This is a protein that's linked to acute tissue rejection, which appears to be the primary medical barrier to the use of pig organs in human patients.

Incidentally there have been predictions of a $6.5 billion market for organ transplants within a decade, but scientific obstacles make that a highly optimistic estimate. Transplants of smaller tissues and individual cells are currently under clinical investigation, and skin autografts co-cultured with mouse cells have been successfully tested for burns and other skin injuries. Transgenic animal organ transplantation, howewver, has yet to be successfully carried out in humans.

There is one more type of medical products that could be manufactured with materials supplied by bioengineered animals, and that's medical devices. For example, transgenic goats have been produced that secrete spider silk proteins in milk. These proteins are easily isolated, and depending on the spinning process, can be used to create a multitude of very strong and resilient medical products including sutures and replacements for tendons and heart valves.

I've mentioned some of the human benefits that could be derived, or are being derived, from genetically engineered animals. The same or similar technology could be or is being used to improve animal production. The best known products in this category are those that incorporate growth hormone genes into the genomes of the same or other species. Aquaculture provides several good examples. By using genetic material from such sources as the Pacific salmon, scientists have developed transgenic salmon, catfish, and tilapia that grow faster and more efficiently than their non-transgenic counterparts. Shrimps have been successfully treated with bovine somatotropin to increase their growth rate and improve resistance to diseases.

Scientists are also experimenting with genetic modification of shellfish that would control their rate of molting, and thereby make them grow faster. Another attempt to improve animal growth -- in this case, of piglets -- has been the introduction of various proteins into sow milk. For example, bovine lactalbumin and insulin-like growth factor-1 have both been employed as transgenic growth enhancers. The "Enviropig" is another example of a transgenic modification that affects the nutrition of the pig. In this case, the enzyme phytase is introduced into pigs to allow them to make better use of the phosphorus in their feed.

This not only allows the farmer to decrease phosphate supplements, but more importantly, it significantly decreases the amount of phosphorus in pig manure. Phosphorus in the environment has been associated with eutrophication of fresh water and estuaries, leading to decreased fish and shellfish viability in breeding grounds such as the Chesapeake Bay.

Transgenesis can also be used to enhance disease resistance in animals. For example, lysostaphin, a bacteriocidal enzyme, has been introduced into cows to decrease the incidence of mastitis caused by Staphylococcus aureus. Moth cecropin, a broad spectrum antimicrobial peptide, has been transgenically incorporated into catfish to decrease their susceptibility towards a broad range of bacterial diseases.

The intrinsic allergenicity of certain food animals is another trait that scientists are trying to mitigate using biotechnology. For example, scientists are attempting to decrease the allergenicity of shellfish by altering the structure of one of the key proteins thought to be the cause of shrimp allergy. One biotechnology company is trying to produce an "allergy free" cat by transgenically blocking the expression of a key salivary protein that's thought to be responsible for allergies to cat dander.

Finally, I want to briefly mention couple of other potential uses of biotech animals in industrial production and farming. Perhaps the best known example of genetically engineered animals providing a manufacturing material is the transgenic goats that I've already mentioned as producing spider silk proteins in their milk. In addition to medical devices, these proteins could be used in the manufacture of body armor, bulletproof vests, or puncture-proof canoes -- all light-weight products that require exceptional strength.

Biotechnology can also be employed in insect-based pest and disease control. Several approaches are being investigated to modify mosquitoes so that they do not spread diseases such as malaria, and hemorrhagic fevers such as dengue. Another interesting idea is using selective breeding techniques to enhance the predatory behavior of certain mites against other species of mites that infest and harm plants. Letting these predatory mites control low-level plant disease could reduce the use of pesticides.

Although I have by no means covered all of the potential uses of transgenic animals, I hope I have given you an idea about the great benefits this technology and its products could bring for human and animal health, as well as our economy. I have said less about the hazards that these products might present for humans and animals, and they need to be fully investigated.

We are familiar with many of biotechnology risks from informal reviews of the more than 50 genetically modified plants that the FDA has conducted -- at the product developers' requests -- in the past 10-11 years. In addition, we have a 97 year-long record of determining human food safety. This experience leads us to believe that transgenic animals are less likely to contain harmful substances than transgenic plants, because humans and animals share more of the same physiology than plants. For example, one major concern with the FLAVR SAVR tomato, the first transgenic food product to come on the U.S. market, was that its alkaloid levels would be increased as a result of the random insertion of the gene that delays ripening. Because food animals do not need to produce such substances for protection, our concerns about this type of adverse event involving transgenic animals are much lower.

Having said that, we are aware that the creation of new proteins in transgenic animals used for food raises potentially serious safety concerns that must be addressed through the development of rigorous, science-based analysis. Bioactive compounds are a good example. These substances, which have the intrinsic ability to affect the physiology of an organism, include growth hormones; proteins that aid in resisting disease; and even proteins of pharmaceutical interest. If these proteins are present in edible tissues of transgenic animals, they might pose a food safety risk, depending on the nature of the compound and its pharmacological properties.

Another type of risk could be presented -- particularly given the emergence of apparently new spongiform encephalopathies -- by drugs and biologics derived from the milk of transgenic animals. The degree to which these or other infectious animal diseases can be transferred by injection or inhalation is not known, but it presents an important risk for drugs that cannot be administered orally. In addition to the known toxicity of the bioactive compounds for individuals exposed to them, another significant risk issue is their potential effect on the producing animal.

For example, if clotting factors should "leak" from the udder, or if they should be inappropriately expressed in other tissues, the health of the animal would be extremely compromised. Despite what I said about the difference between transgenic plants and animals, allergenicity is another safety concern. The risk of allergenicity is raised whenever foods contain new proteins from transgenic organisms, regardless whether their source is an animal, plant, or microorganism such as yeast or bacteria.

For susceptible populations, any protein has the potential to cause allergenic responses. Adding moth proteins to fish, for example, raises a red flag, because it introduces a brand new substance to human diet. Incidentaly, potential allergenicity of new proteins remains one of the most difficult problems in the safety assessment of foods, and we are working with the World Health Organization and other scientific and regulatory bodies to develop and standardize protocols for testing allergenicity.

When it comes to technologies that use viral sequences for introducing new genes, we have to consider the possibility that a viral vector used to introduce some desired trait can recombine with existing viruses in the animal and create a new pathogen. Yet another hazard may arise when the insertion of a gene produces unintended adverse outcomes collectively called "pleiotropic effects." These result from the disruption of a cell's normal function, and may lead to cell death.

And to mention just one more hazard, there is always the possibility that biotech products will be mishandled through human negligence or error. This was illustrated last year by the accidental mixing of some stems and leaves of genetically engineered corn with soybeans intended for human consumption, and by our discovery earlier this year that university researchers had violated the rules by marketing, instead of destroying, more than 380 experimental pigs. These incidents are a very real concern. We are facing the possibility that biotechnology will generate many thousands of transgenic animals, including non-transgenic offspring, surrogates and donor animals, whose milk and other tissue by-products will have to be disposed of in a safe and potentially costly manner, and prevented from being sold for food or feed.

Now, how is the FDA going to cope with the many issues inherent in the large-scale introduction of products as technologically advanced, highly beneficial, and yet potentially risky as are transgenic animals? We have, by now, a wealth of experience in examining more than 50 food and feed products of transgenic plants under consultation procedures established in 1990 by the FDA and the food and feed industries. Since in the eyes of the law traditional human food and animal feed are GRAS -- generally regarded as safe -- the goal of our food safety evaluation is to ensure that the new product, regardless of the process by which it is achieved, is as safe as its GRAS counterpart.

In general, our approach to the assessment of new food products has included ensuring that the introduced genetic material has been well characterized; that it is incorporated in the genome of the recipient organism in a manner that is stable from one generation to the next; that the composition of the new food is not likely adversely affect health; and that its nutritional value has not been decreased. The same or similar regulatory framework would appear to be suitable for food produced by transgenic animals -- for instance, low-lactose milk from genetically engineered cows.

The FDA has also ample experience, as well as legislated authority and guidance, for ensuring the safety and effectiveness of drugs, biological medications, and medical devices, and it would use all of these resources in evaluating such products manufactured with the help of transgenic animals. But what about other concerns, including the critical question whether, and to what extent, the safety of the environment would be put at risk by genetically altered animals? And what about risks that may be posed to the genetic animals themselves?

The FDA is yet to answer these questions by approving or disapproving the application for marketing of any transgenic animal, and I am not in a position to discus specific decisions and policies that may be currently under consideration. But I can address this issue in general terms on the basis of existing laws and practices. I can also examine the provisions that would protect the public health and environment from harm that could result from the commercialization of one transgenic product that has repeatedly prompted media comments, as well as concerns among environmental and consumer groups. That product is an Atlantic salmon genetically engineered to contain additional fish hormone gene to make it grow faster and use feed more efficiently.

One variety of this salmon has been reported to reach the market weight of 7-9 pounds in about 18 months, as against 24-30 months for non-transgenic salmon. As you will hear from Mr. McGonigle, the Vice President of Aqua Bounty Farms, his firm has been preparing for more than a decade to put a hybrid salmon on the market. To avoid environmental damage, Aqua Bounty plans to raise brood stocks of this transgenic fish in conventional inland hatcheries, and treat them to produce 100 percent genetically female eggs. The eggs in turn would be treated to cause reproductive sterility. The reproductively sterile, all-female offsprings would be grown initially in hatcheries, and then would be transferred to ocean net pens, to mature and be harvested for food.

What are the hazards associated with this sort of enterprise? Although current methods provide high ensurance of reproductive sterility, they are not 100 percent effective. This raises the possibility that fish that would almost inevitably escape from the net pens would include some females capable of reproduction. This in turn could lead to interbreeding with wild Atlantic salmon, hybridization with the closely related brown trout, and disturbance of habitat as a consequence of competition for resources, predation, or mis-mating.

There are several federal and state agencies that would take measures to minimize the involved environmental hazards. They include the National Marine Fisheries Service, Fish and Wildlife Service, Army Corps of Engineers, and Environmental Protection Agency, all of which probably would be involved in regulating various aspects of this enterprise, such as the location and security of the ocean pens. In addition, the FDA is authorized to exercise oversight of transgenic animals under the Federal Food, Drug and Cosmetic Act, which makes our agency responsible for the safety of drugs, and defines drugs as "articles...intended to affect the structure or any function of the body of man or other animals."

Because the genetic modification affects the structure and function of the salmon, and because it may produce a protein that is not generally recognized as safe for human consumption, the biotech salmon is, in the eyes of the law, a "new animal drug," and as such is subject to the FDA's science-based review and approval before it can be marketed. As part of this review, the FDA routinely considers evidence of a new animal drug's effect on, among other factors, animal health; diseases susceptibility; zoonotic potential; animal welfare; impact on domestic and wildlife populations; and the environment.

I am skipping a lot detail, but I want to emphasize that the FDA takes environmental issues seriously, and takes action when appropriate. For example, a few years ago, when our agency was considering the approval for bovine sematotropin for dairy cows, it required evidence on three types of environmental impact that could be associated with the use of the drug: how it might affect land-use patterns and water quality; how it might affect carbon dioxide emissions; and whether it could present a problem in safely disposing of syringes used to administer the hormone. The first two areas did not prove to be significant, but the disposal of a large number of syringes raised a risk to human health. The FDA therefore required the manufacturer to sponsor a syringe collection system for customers.

If I can inject a personal note: in the 1980s, when I served as director of FDA's Center for Veterinary Medicine -- which regulates animal drugs and feed -- I used to note with some displeasure that the media never paid sufficient attention to the work we did to keep America's livestock and pets healthy. Since then, veterinary issues have undergone a substantial change, but I am afraid that the FDA's animal-health programs still don't get much black ink, let alone TV coverage.

As a result, not much is known about our vigilant and vigorous efforts to help ensure the safety of rDNA-based technology. For example, two years ago we requested producers of animal clones to withhold any food products from such animals and their progeny until the FDA evaluates potential safety issues. Just as human twins who share the same genome, animal clones are not exact phenotypic copies, and we need time to collect data for informed decisions about the potential risks these animals may pose to other animals or, as a source of food, to people. We are now finalizing food consumption and animal health risk assessments for animal clones, and are planning to make them available for public comment.

We've also commissioned the National Academy of Sciences to review potential risks associated with the marketing of products of transgenic animals. The NAS report, issued last year, reflected the same concerns that we have considered. At present, we are hard at work at developing a draft guidance describing the FDA's approach to conducting environmental assessments of the genetic construct contained in transgenic salmon. The document, which will be relevant to all new animal drug applications involving transgenic salmon, will describe the issues sponsors need to address in order to demonstrate that the use of the drug in the transgenic salmon line is safe for the environment.

We are also preparing a draft guidance on how the requirements of the Federal Food, Drug and Cosmetic Act pertain to all transgenic animals, and on procedures by which companies can comply with these provisions. And we insist on compliance with the rules affecting biotech products, and respond with firmness to their infraction. For example, as soon as the mixing of the transgenic corn and soybeans in Kansas was discovered, the FDA and the state authorities made sure that the soybeans were secured in a warehouse, and that none of them were used for human consumption.

The marketing of pigs that were part of a University of Illinois experiment conducted with FDA's approval triggered several strong FDA measures, including a letter sent to all Land Grant universities to remind them that one of their obligations, when conducting a research involving transgenic animals, is to document their plans for the disposition of these animals when the study is completed.

These are just a few examples of our agency's many efforts to ensure that products of biotechnology are safe, and that alarming talk about "Frankenfood" remains just that -- an idle talk that can only do damage. I believe that one of the ways we can increase the acceptance of transgenic products by the media and the public is by getting the word out that the FDA is on the job, and that it has the expertise, the experience, and the determination to do it well. I hope that spreading this message will be one of the many positive outcomes of this conference, and become yet another of your contributions to the success of biotechnology in the years ahead. Thank you.