Engineered Animals

A DRUG that is produced in the milk of a genetically engineered (GE) goat for treating a rare blood disorder is on the verge of approval in the U.S. Although the goat is not supposed to enter the food supply, if the drug gets the green light next month as expected, it could set the stage for the approval of other GE animals, regardless of their intended use.

The U.S. has been a leader in biotechnology since the 1990s, and many countries are looking to the U.S. for guidance on how to regulate GE animals. But so far, no GE animals—those modified by recombinant DNA (rDNA) techniques—that could be consumed as food have been approved in the U.S.

The responsibility for regulating GE animals in the U.S. is divided between the Food & Drug Administration and the Department of Agriculture. FDA is responsible for ensuring the safety of GE animals for human consumption, and USDA is responsible for regulating GE animal imports. All GE animals, regardless of whether they are produced for drugs or for food, must go through the same regulatory process to win U.S. approval.

The benefits of GE animals, which have been under development for decades, could be huge, those promoting the industry say. By inserting DNA snippets from one species into another, biotech developers can introduce new traits into an animal. The possibilities are endless. GE animals could produce proteins or antibodies for drugs or vaccines, an arena sometimes known as pharming. Cows could be made resistant to mastitis or mad cow disease. Pigs could produce high levels of heart-healthy omega-3 fatty acids in their meat or have tissue that is transplantable into humans.

But critics of the technology argue that not enough is known about the risks of GE animals. They want to see more environmental, health, and safety data on these animals and are concerned about the animals' health and well-being. The critics also emphasize the need to address ethical concerns and the need for transparency and public participation when it comes to regulating GE animals.

Getting access to information about the GE animals that FDA is reviewing is difficult because the agency is prohibited from disclosing it under the Federal Food, Drug & Cosmetic Act (FFDCA). A few companies, however, have voluntarily released information to the public.

ONE PROBLEM with the current regulatory framework has been confusion over whether a GE animal that produces a drug must be approved before the drug itself is approved.

In September 2008, FDA issued draft guidance for the biotech industry clarifying its position in this area. It says that all GE animals themselves are considered new drugs and therefore need FDA's approval before they can be marketed. The agency justified its position by saying that the rDNA construct in a GE animal affects the structure or function of the animal and thus meets the definition of a drug under FFDCA. In mid-January, after reviewing about 28,000 public comments, FDA finalized the guidance.

Because the gene constructs and intended uses of GE animals will vary widely, FDA plans to look at the animals on a case-by-case basis, says Larisa Rudenko, senior adviser for biotechnology at FDA's Center for Veterinary Medicine. For GE animals such as mice, rats, and insects, which are not traditionally consumed as food, FDA says it intends to "exercise enforcement discretion," which means the agency will not always require approval before these products are commercialized. For example, FDA opted not to require approval for a line of "day-glo" pet fish.

FDA is currently reviewing applications for at least two GE animals that could end up on dinner plates later this year. One of them, called the Enviropig, is a pig that has been genetically modified to produce less phosphorus in its manure, so more of the waste can be spread on land as fertilizer.

The pig was developed by researchers at the University of Guelph, in Ontario, as a way to help pig famers comply with nutrient management laws, which limit how much nitrogen and phosphorus can be applied to agricultural fields. Phosphorus levels in pig manure are typically one-third higher than those of nitrogen, says Cecil W. Forsberg, an emeritus professor of molecular and cellular biology at Guelph and the lead scientist who developed the Enviropig. "So phosphorus becomes the first component that limits the amount of manure you can spread on land," he explains.

To create the pigs, the Guelph researchers linked a gene from Escherichia coli with a promoter—which facilitates the gene's transcription—from a mouse and introduced the construct into a pig embryo. That small segment of DNA leads to the production of the enzyme phytase in the salivary glands of the pig, Forsberg notes. The enzyme helps the pigs digest phosphorus-rich phytate in animal feed, reducing the amount of phosphorus in their manure.

Pigs are often given supplemental phytase in their feed. The Enviropig makes its own phytase, and thus also would save farmers $1.00 to $1.50 over the course of a pig's lifetime, Forsberg says. That is a marginal benefit, he acknowledges, but for a large operation, it could add up.

Forsberg is anxiously awaiting FDA's decision on the Enviropig, which has been under review since mid-2007. "We feel that we have demonstrated that these pigs are as healthy as conventional pigs," he notes. The real benefits of the Enviropig are that it addresses nutrient pollution, and, he emphasizes, it improves the growth and development of the pig. "Introducing phytase actually gives the pig improved health. These pigs don't need something added to their food for good growth," he says.

Another product awaiting FDA approval is a transgenic salmon called AquAdvantage, created by Aqua Bounty Technologies, in Waltham, Mass. The fish is an Atlantic salmon that contains a growth hormone gene from a Chinook salmon and a gene promoter from a coldwater fish called the ocean pout.

AquAdvantage salmon grow faster than conventional salmon, but they do not grow bigger, says Ronald L. Stotish, chief executive officer and president of Aqua Bounty. They have a shorter life cycle and therefore are exposed to fewer environmental contaminants and pathogens, he notes. And unlike conventional salmon, which are grown in sea cages, transgenic salmon, because of their shorter life spans, can be grown in containment facilities like trout.

Stotish won't disclose how long Aqua Bounty has been trying to get FDA approval for the AquAdvantage salmon, but he says "it's been a long time," noting that the initial salmon was developed more than 10 years ago. "We have submitted extensive characterization data showing that our fish has a single copy of the gene in a unique location that has not changed in more than seven generations. It is a very stable construct," he adds.

Environmental activists who are concerned that the transgenic fish will escape and reproduce with wild salmon can rest assured, Stotish says. All of Aqua Bounty's fish are sterile. "We are a genetics company, and we will sell eggs that will produce salmon that are sterile to people who are in the business of growing fish," he says. It makes sense to sell sterile fish from a business perspective, too. "We don't want to put a fish out there that people could breed because we'd only sell the first one," Stotish notes.

If FDA approves the Enviropig or the AquAdvantage salmon, consumers will have no way of knowing whether the pork or salmon that they are eating has been genetically modified. U.S. law does not require companies that sell GE food to label their products as transgenic, and that has many consumer advocacy groups concerned.

"Consumers have increasingly intense interest in the origin and production of food and a right to know this information," Margaret Mellon, food and environment director at the Union of Concerned Scientists, wrote in comments submitted to FDA regarding the agency's GE animal guidance. If FDA's hands are tied on the matter, "new authority is needed to allow the agency to require the disclosure of how products were made," she continued.

Mellon and others say that denying consumers a choice to avoid GE animal food will ignite consumer opposition to the technology. They emphasize that consumers don't know enough about the benefits or risks of the technology to prevent the kind of public backlash that occurred, particularly in Europe, in the 1990s with GE crops. Transparency and public participation in the regulatory process is critical for consumer acceptance of GE animals, they warn.

EXPERTS PREDICT that consumers will be more likely to accept GE animals used to make life-saving drugs than GE animals intended for food. Thus, the biotech industry is hoping that FDA will quickly approve the first drug derived from a GE animal and therefore be obligated to approve the animal itself as a source of the drug. And once consumers get used to GE animals developed to supply drugs, GE animals for food will likely be an easier sell.

The scenario is already unfolding. In early January, an FDA advisory committee voted overwhelmingly in favor of approving a drug called ATryn, which is produced in the mammary gland of GE goats and is being developed by Massachusetts-based GTC Biotherapeutics. The drug is used to prevent clots in patients with a rare blood disorder. It is intended as an alternative to antithrombin derived from human plasma, which is in short supply.

FDA is expected to make a final decision about the drug next month. If the drug is approved, it will put pressure on the agency to also quickly approve the GE animal that makes the drug.

Critics of the technology fear that once one animal is approved, many more will quickly follow. "The first product from a GE animal to be up for approval will likely serve as a test case for future approval of GE animals," says Nina Mak, a research analyst at the American Anti-Vivisection Society, a nonprofit organization that opposes all uses of transgenic animals and aims to eliminate experimentation on animals.

But many observers aren't expecting to see a deluge of GE animal approvals. They say that the industry is struggling at best, and federal research funding for GE animals, particularly from USDA, has dried up. There are no animal genetics companies funding research, leaving many experts to question the viability of the industry.

"At this point in time, we don't have any investors interested in the Enviropig," Forsberg says. "We don't expect anyone to show interest until we have regulatory approval in the U.S."

While waiting for the U.S. to move in this area, Forsberg is looking ahead to determine what will be needed to get the Enviropig approved in other countries. The team hopes to market the Enviropig in Asia. "We hold a patent for it in China," Forsberg tells C&EN. "Our impression is that the Chinese requirements are going to be similar to those of FDA." However, the Chinese may require that additional testing be done in China, he adds.

Aqua Bounty also hopes to eventually sell its transgenic salmon worldwide. But the company has decided to pursue U.S. approval first. "We've basically made the assumption and developed a strategy that approval in the U.S. is the benchmark against which the safety of this product will be measured," Stotish says.

AS COUNTRIES around the world figure out how to regulate GE animals produced in the U.S. and abroad, the U.S. is becoming increasingly concerned about how to regulate GE animals that are imported into the U.S. In September 2008, USDA's Animal & Plant Health Inspection Service sent out a request for information on research being conducted on GE animals, as well as the importation of GE animals.

USDA is still trying to determine how best to use its existing authorities under the Animal Health Protection Act to regulate GE animal imports. But the regulatory picture is murky, observers say.

Early last year, former secretary of agriculture Ed Schafer asked a USDA biotechnology advisory committee to identify the regulatory issues that the government should consider with respect to GE animals and the products they produce. The committee met in four plenary and numerous workgroup sessions over 10 months but could not reach a consensus, says committee Chair Patricia A. Layton, a professor of forestry and natural resources at Clemson University.

The fact that FDA released its draft guidance near the end of the committee's deliberations only "muddied the mudhole," Layton says. In the final days of the Bush Administration, the committee sent a memo to Schafer, saying that "in view of the richness of the issues and evolving regulatory landscapes, the 10 months proved inadequate to complete the charge," Layton notes.

In its memo, the committee highlighted issues such as the safety of food and feed derived from GE animals, the health and well-being of the animals and their environmental impacts, and the safety of imported GE animals and GE animal products. The committee also listed as being important global marketing considerations—such as information exchange and facilitation of international trade—ethical considerations, and incorporating transparency and public participation into the regulatory process.

If the committee had had more time, it would have deliberated more about international regulatory coordination and the future competitiveness of U.S. animal agriculture, Layton says. Some of the committee members were concerned that regulatory hurdles in the U.S. could drive the GE animal industry overseas.

In general, the European Union is not as far along as the U.S. in bringing GE animals to market, particularly those intended for food. However, ATryn, the drug produced in GE goats awaiting FDA approval, is already approved in the EU. The area to look out for is Asia, Layton says. "There is a general sense that some Asian countries are further along than the U.S.," she adds.

According to an audit report from the inspector general of USDA that was released in mid-January, China is planning to invest $500 million in biotechnology by 2010. The IG report finds that USDA has no import-control policy for GE animals and no strategy for monitoring the development of new GE animals in other countries.

The Japanese government recently hinted about what is in the works in Asia in a comment it submitted to FDA. "Japan would like to confirm whether FDA will establish an import tolerance to enable import of live GE animals as well as food derived from animals inoculated/exposed with recombinant-live vaccines (GE microorganisms) which are not approved for use in the United States," the Japanese government wrote.

The GE animal industry still is in its infancy, but it has the potential to solve many global health and environmental problems. Champions of the industry say it could help strengthen the economy by creating new jobs. Aqua Bounty thinks its fish may revive salmon cultivation in the U.S., which largely disappeared more than 20 years ago, Stotish says.

But for consumers to ultimately accept the technology, a range of social, ethical, and religious questions need to be addressed, all of which are well beyond FDA's scope. Some experts predict that Congress will need to step in and give FDA additional authority to require labeling of GE products so consumers can choose for themselves whether to purchase the products.