The New York Times, May 1, 2000
Altered Salmon Lead the Way
With quaint fishing villages dotting its shores and farming still one of its mainstays, the pastoral landscape of Prince Edward Island seems an unlikely place to encounter one of the most modern creatures on earth. Yet it is in the tanks at Aqua Bounty Farms on the island off New Brunswick, Canada, that hundreds of truly novel fish swim: schools of genetically engineered salmon that await approval for sale in the United States.
These fish look like Atlantic salmon found in groceries around the world, but for their age they are enormous. Endowed with foreign genes that produce growth hormones, they grow to market size -- about seven pounds -- in 18 months, twice as fast as normal salmon.
Experts on the biotechnology industry predict that these fish will be the first genetically modified animal to make it onto American dinner plates, alongside genetically engineered vegetables like corn and potatoes, which have been available for several years.
Elliot Entis, president of A/F Protein Inc., the biotech company that owns Aqua Bounty Farms, said that the company already had orders for 15 million eggs and would be ready to ship them next year, should they receive federal approval. Approval is also being sought to sell the fish in Canada.
A menagerie of other genetically modified animals is in the works, promising what biotech backers say will be advantages like cheaper and more nutritious food. Borrowing genes from various creatures and implanting them in others, scientists are creating fast-growing trout and catfish, oysters that can withstand viruses, and an "Enviropig," whose feces are less harmful to the environment because they contain less phosphorus.
Scientists are also developing a pig that makes a leaner pork chop, one of the first genetically modified animals that would offer direct benefits to consumers and something biotech advocates hope will make the marketing of genetically modified foods easier.
Mr. Entis and colleagues describe their fast-growing fish as part of a blue revolution in aquaculture that could feed more people more efficiently and more cheaply.
But critics and even some Clinton administration officials say that genetically engineered creatures are threatening to slip through a net of federal regulations that has surprisingly large holes.
While food safety issues should be addressed, some scientists say, the bigger concern is the environmental threats posed by genetically modified animals like the salmon. For example, a recent study showed that populations of wild fish could, in theory, be wiped out by mating with certain kinds of genetically engineered fish, should they escape. In addition, there is the possibility of unpredictable environmental disruptions, like those that occur when non-native species invade ecosystems, as the zebra mussels have the Hudson River.
Yet United States regulators interviewed could not point to any federal laws specifically governing the use or release of genetically engineered animals.
"This is a very big hole," said Dr. Rebecca Goldburg, senior scientist at the Environmental Defense Fund, a group that has been highly critical of the biotech industry and the federal regulators. "There's nothing clearly on the books. There are no regulations about what you can and can't do."
Instead, federal agencies seeking to regulate genetically engineered organisms are stretching regulations written for other purposes to what critics describe as surprising lengths.
So far, for example, only the Food and Drug Administration appears to have any authority over the new salmon, which the agency claimed by designating the fish's foreign genes and the growth hormone they produce as a drug for animals.
The Environmental Protection Agency and the Department of Agriculture, the two other agencies overseeing genetically modified organisms, have bowed out of the salmon case, a decision that many with an interest in the issue regret. The F.D.A. is likely to be rigorous in examining food safety, these critics say, but the agency is less experienced in reviewing environmental risks.
"The F.D.A. is not qualified to evaluate the ecological risks of engineered fish," said Dr. Jane Rissler, senior staff scientist at the Union of Concerned Scientists, a watchdog group that is a longtime critic of biotech regulation. "We should be concerned that the environment will be at risk."
John Matheson, senior regulatory review scientist at the Food and Drug Administration's Center for Veterinary Medicine, defended the agency's ability to conduct environmental reviews, saying that it routinely investigates the environmental impact of new drugs.
"We look at the environmental impacts of approving an antibiotic, how much is released into the environment, what does it do," Mr. Matheson said. "I don't have any more discomfort about this than reviewing other animal drugs for environmental impacts."
Yet other administration officials said increasing concern over the handling of ecological risks by the three federal agencies that monitor biotech organisms had prompted consideration of a review of the current regulatory framework.
"We need a system that lets us check things beforehand, that shifts the burden of proof onto those that would introduce them," said Dr. William Brown, science adviser to the secretary of the Department of the Interior. "I don't think the potential impacts on nature have been thought through as well as they should be."
Dr. Choy Hew and Dr. Garth Fletcher were among the first researchers to genetically engineer fish when they inserted two foreign genes into Atlantic salmon in 1989. One gene, taken from a chinook salmon, produces growth hormone. A second gene, taken from an ocean pout, a distant relative of salmon, functions to keep the first gene constantly producing its hormone.
Finally, last year, after a decade of genetic tinkering, researchers had a reliable breeding stock of salmon that could grow up to six times faster than normal.
Company officials are quick to point out that the new fish produces no more growth hormone than normal salmon. The reason the fish grows faster, Dr. Fletcher said, is that the fish produces the hormone year-round, unlike normal salmon, which produce it only in warm-weather months.
In fact, levels of growth hormone in the fish are so low, Mr. Matheson said, that the Food and Drug Administration will not require one particular set of tests -- feeding the salmon to rodents -- that are typical for new drugs for animals.
"You can't choke rats with enough salmon to cause an effect other than choking," he said. Some scientists not involved with the company also pointed out that fish growth hormone was unlikely to have an effect on humans.
The salmon do not even grow to be unusually large, Dr. Fletcher said, as even 7-year-old salmon at AquAdvantage have never weighed more than 17 pounds, large but far from record-breaking for the species.
Mr. Entis also said that the new fish taste just like other salmon grown on farms.
Some scientists not involved with the company also played down food safety concerns but said it would be important to know, for example, if the foreign growth hormone triggered increased production of other compounds, like insulinlike growth factors. Mr. Entis of A/F Protein said the company had been asked to look into that question and others as part of the continuing Food and Drug Administration review.
Salmon are typically grown in enclosures in the sea, known as net pens, renowned for being torn by waves or hungry wild animals. Fish routinely escape, sometimes by the tens of thousands.
If the genetically engineered, or transgenic fish, are grown in such pens, some will eventually slip out into the wild, some researchers say.
If they do, wild fish could be potentially devastated, according to a study published in the journal Proceedings of the National Academy of Sciences in November by Dr. William Muir, a population geneticist, and Dr. Richard Howard, an aquatic ecologist, both at Purdue University.
The two researchers studied mating and survivorship in normal and genetically engineered versions of a fish known as a medaka. Using this information, researchers developed a computer model simulating the escape of a genetically modified fish into the wild. The study showed that if wild females preferred to mate with genetically engineered males and if those matings produced offspring that did not survive well, wild populations could be wiped out, a result they called the Trojan gene effect.
Those, of course, are a couple of big ifs -- no studies have shown whether any fish could create the Trojan gene effect in the real world. But there is evidence of its potential. In many species of fish, females prefer larger males as mates, setting the scene for an advantage for growth-enhanced fish.
In addition, Dr. Muir said the genetically engineered fish he is now studying, the tilapia, could be three times larger than normal tilapia at sexual maturity, providing a possible mating advantage. In addition, in some new fish, including the medaka and coho salmon endowed with foreign growth hormone genes, rapid growth can be harmful, lowering the fish's survival rate.
Whether all these pieces would come into play in the wild, in the AquAdvantage fish or any other, remains to be seen. But even the possibility has jolted some researchers.
"It really surprised me," said Dr. Muir, who has been developing transgenic fish that he hopes to sell. "I went into this thinking that transgenics are not a risk."
Dr. Muir said that while in theory the Trojan gene effect could occur with traditionally bred salmon as well, he believed it was essentially impossible. Traditional breeding tends to result in incremental changes, not the kind of rapid growth that produces radically different size fish or that causes physiological disruptions that are likely to alter a fish's survivorship.
At A/F Protein, Mr. Entis said that he and colleagues did not believe their AquAdvantage salmon could cause a Trojan gene effect. "We don't think that they are bigger," he said.
"They don't seem any bigger."
But he acknowledged that the company had not done the critical experiments to determine whether the fish were larger at sexual maturity or had a mating advantage.
Mr. Entis said the Food and Drug Administration had not specified what studies, if any, would be required that directly addressed such ecological risks. So far the company has done none.
"Lord knows we can't promise total safety for anything," Mr. Entis said.
But, he said, "We believe that our fish are poor survivors out there to start with." Normal fish do not produce growth hormone in the winter, presumably because it is disadvantageous to do so. Mr. Entis reasoned that since AquAdvantage fish produce the hormone year-round, they would not last long enough in the wild to do any harm.
Dr. Anne Kapuscinski, a fish geneticist at the University of Minnesota who has studied potential impacts of the release of genetically engineered fish, said, "Belief is a great thing, but what we need is some risk assessment research."
Similar arguments were once made with traditionally bred or normal salmon raised on farms, which were said to be too pampered to survive in the wild. But escapees have since been found thriving and spawning in the same streams as wild salmon.
In fact, environmental groups have long been concerned that salmon from farms might genetically pollute wild salmon or carry diseases into the wild. But little research has been done and it is still unclear what role, if any, these escapees are playing in the decline of wild salmon stocks.
As for the new genetically engineered salmon, the Trojan gene effect is only one possibility should the fish escape. The new fish could also breed with wild fish, genetically polluting dwindling native stocks of Atlantic salmon.
In response to concerns, Mr. Entis has said the company would only sell fish that have been rendered sterile for use in net pens. Then even if the fish do escape, they cannot breed with wild salmon.
A/F Protein employs a standard technique for sterilization that Mr. Entis described as "100 percent effective." But scientists outside the company said that in other laboratories the technique often left some eggs fertile.
In addition, some researchers pointed out that even sterile fish could cause problems by competing with native salmon or otherwise disrupting ecosystems.
f the three agencies that have so far overseen the approval of genetically engineered organisms, only the Food and Drug Administration has sought to regulate the new fish.
Mr. Matheson said the agency had decided to regulate the new salmon as a drug for animals after extensive discussions at all levels at the agency.
Mr. Matheson said it had not been an option to review the fish as a food since the agency did not require approval of new foods before they entered the marketplace. Because the growth hormone is not used to alter the quality of the salmon as food, he said, it could not be regulated as a food additive either. Instead, the hormone is used to change the growth of the animal itself, which qualifies it as an animal drug. In its review of this and other animal drugs, the agency examines human food safety, animal welfare and environmental issues.
While Mr. Matheson defended the decision, some scientists said the handling of the new salmon put a spotlight on the holes in regulation.
"This kind of stretching of the law places the emphasis on the wrong things," said Dr. Kapuscinski of the University of Minnesota, "Plus, it's ludicrous." She urged "a serious revisiting" of the regulation now in place.
So far the Food and Drug Administration has not outlined any explicit policy or process for regulating genetically engineered fish.
Critics point out that because the salmon is being regulated as a drug for animals, it is covered by confidentiality laws that prevent officials from discussing the review without permission from A/F Protein. As a result, there remain many unanswered questions about what steps will and will not be taken to ensure environmental safety.
An additional problem, critics say, is that the Food and Drug Administration is reviewing environmental risks under the National Environmental Policy Act, which requires only that an environmental assessment be done.
Even if the fish should be found to be environmentally damaging, it can still be released.
Noting that the Food and Drug Administration's food safety review is continuing, Mr. Matheson said the agency was keeping all its options open, still considering whether A/F Protein would be allowed to sell fertile fish or only sterile fish and whether farmers would be allowed to grow the fish in net pens or only in tanks on land.
He said the agency would consult with other agencies in making its decision. But the agencies typically in charge of fish have yet to get involved, and it remains unclear what role they will play.
Dr. Brown, the science adviser to the Interior Department secretary, said the department might possess the authority to regulate genetically engineered animals under statutes for controlling injurious wildlife and aquatic nuisances.
If existing authorities should be insufficient, he added, "Congress might need to get involved."
In an interview in March, Edwin Rhodes, aquaculture coordinator for the National Marine Fisheries Service, said he was surprised to hear that the Food and Drug Administration was overseeing the environmental review regarding the new salmon and making decisions on such things as whether fish would be grown in net pens. Mr. Rhodes said the National Marine Fisheries Service, not the Food and Drug Administration, had the expertise to make such decisions, and it would need to be involved.
"We have to have absolute certainty that transgenic fish do not interact with wild stocks," Mr. Rhodes said.
It remains unclear what role the fisheries service will play.
Dr. Eric Hallerman, fisheries geneticist at Virginia Polytechnic Institute and State University, likened the situation with fish to that of genetically engineered plants in the early 1990's when the first crops were being pushed toward commercial use.
"Environmental safety assessments should be done before these fish are stocked out on an industrial scale," Dr. Hallerman said. "It's time we got our policies together."
Anti-biotech organizations around the world are already up in arms over the possible dangers to the food supply and the environment from genetically modified plants, like corn that produces its own pesticide, and the use of a growth hormone in cows. Public concerns over the new crops have even caused a few prominent companies to ban their use.
In Scotland and New Zealand, efforts to develop other salmon using the foreign genes developed by A/F Protein have been abandoned amid cries of "Frankenfish."
Likewise, many salmon farming groups, motivated by a fear of consumer rejection, have already declared that they will not use genetically engineered fish, whether governments approve them or not. So far, none have.
The International Salmon Farmers Association, which represents the vast majority of salmon farmers worldwide, has taken a strong stand against the new fish.
"Genetically engineered salmon is a solution looking for a problem," said Joseph McGonigle, executive director of the Maine Aquaculture Association. "Virtually everyone in the world has taken a position against them."
But while salmon farmers deny any interest, Mr. Entis said, "There's not a salmon company in the world that hasn't talked to us privately."
As adamantly against the new fish as anyone, Odd Grydeland, a salmon farmer in British Columbia, said, "If the rest of the world's salmon farming industry moved to adopt this type of technology and we were left behind, obviously we'd have to reconsider our position."
Scientists say genetically modified carp may already be in commercial use in China and genetically engineered tilapia may be in use in Cuba.
"There's going to be more," Dr. Kapuscinski said. "These fish are just the beginning."
If It Walks and Moos Like a Cow, Then It Must Be a Drug Factory
The power of genetic engineering is providing scientists with the ability to create animals that confound the imagination. The most striking of the new creatures being concocted by plucking a gene from one organism and inserting it into the DNA of another are what are known as pharm animals. These domesticated beasts -- cows, pigs, goats, sheep and chickens -- have been given the ability to produce pharmaceuticals and other valuable substances in their milk, eggs or semen.
Endowed by scientists with foreign genes, often taken from humans, these animals, or bioreactors, as they are also known, earn their keep as living chemical factories.
Two companies, the Genzyme Corporation of Cambridge, Mass., and PPL Therapeutics, a Scottish company, already have products from pharm animals being tested in clinical trials supervised by the Food and Drug Administration.
Many other animals are still in the development stage. For example, Nexia Biotechnologies in Canada is working on a goat that carries a gene from spiders allowing it to produce spider silk in its milk. When the spider silk, which consists of extremely strong, light proteins, is extracted from the goat's milk, the substance, potentially, can be used in applications like bulletproof vests.
Scientific competition is fierce. Some compounds of interest, like the human blood protein erythropoietin, which has not yet been produced by a pharm animal, command prices of more than $15 million an ounce.
"There is no limit to what can be done," said Dr. Francois Pothier, reproductive biologist at the University of Laval in Canada, who is working on a pig that is genetically engineered to produce a drug. Dr. Pothier declined to name the substance.
But because research required to create these animals can take years, the drugs they produce, he said, have to be "very interesting and very expensive." Dr. Pothier said his pigs would produce a drug in their semen, which the pigs could be trained to donate regularly in voluminous quantities.
Dr. Ann Gibbins, molecular geneticist at the University of Guelph, in Canada, and her team are trying to create chickens that make antibiotics in their eggs.
Researchers say pharm animals are the only way to produce some of the more complex proteins needed for use as drugs. Some very simple proteins, like insulin, can be churned out by genetically modified bacteria. But some proteins require being folded in particular ways or having sugars added before they can be used. Bacterial cells cannot carry out these advanced tasks but animal cells can, making pharm animals the producers of choice.
Pharm animals are also of interest because some therapeutic proteins otherwise have to be collected from blood donated by people, which can be tainted by viruses.
Because they are domesticated and are so valuable, pharm animals are extremely unlikely to escape or pose any environmental threat. But they may still pose risks. Animal tissues and fluids can contain other disease-causing contaminants, like prions, a poorly understood class of molecules associated with maladies including mad cow disease.
In addition, while animal rights groups have remained relatively quiet on the issue of genetically engineered animals, some say that the use of animals as living factories raises troubling ethical issues.
There are also food safety issues.
"Those goats are not going to just get a decent burial after they grow old and stop producing silk," said John Matheson, senior regulatory review scientist at the Center for Veterinary Medicine at the Food and Drug Administration, "so we have to look at them as potential food and as potential feed ingredients."
In fact, Mr. Matheson said some genetically engineered animals had already been approved for use in animal feeds. He said he was unable to disclose what kinds of animals had been approved for such use or what animals they might be fed to as these genetically engineered animals are still experimental and under confidential review within the Food and Drug Administration.
But to prevent the spread of prion-associated maladies, Mr. Matheson said, cows would not be given feed made from cows, genetically engineered or not. Noting that animal feed often contains ingredients like rotting animals killed on highways and parts of slaughtered animals, Mr. Matheson said, "Transgenics should be the least of your worries, frankly."
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