Gene Therapy Safety in Question Again

By Tina Hesman Saey and Amy Maxmen
St. Louis Post-Dispatch
July 27, 2007

A research group led by scientists from Washington University and St. Louis University released a study today showing that a genetically altered virus used in human gene therapy trials causes liver cancer in mice.

The findings follow the announcement Thursday that a patient in Seattle died earlier this week after being treated with the same virus. The cause of the patient's death is unknown, but the Food and Drug Administration is reviewing whether 29 human trials using the virus should be allowed to continue.

The treatment, using a virus called adeno-associated virus, is considered one of the most promising avenues for battling genetic diseases such as cystic fibrosis and muscular dystrophy.

"The bottom line is we need more research so that we can really define the risk," said Mark Sands, a Washington University researcher who led the cancer study.

In 2000, researchers at Washington University noticed that the mice they successfully treated for a liver disease using the adeno-associated virus were developing tumors. The virus had already been approved for use in clinical studies on humans.

Sands relayed the findings to the Food and Drug Administration, which oversees gene therapy trials, said Karen Riley, an agency spokeswoman. The FDA convened a safety panel to discuss those results and other safety concerns in March 2001.

"We decided that the safety profile was acceptable and should continue to be evaluated in clinical trials," Riley said.

Sands then pursued a new study, this time to verify whether the virus was directly responsible for causing cancer. About half of the mice treated with the virus got cancer. The results appear today in the journal Science.

"No one is more disappointed about these data than I am," Sands said. "With gene therapy we can cure this disease in mice. But I can't ignore the data. We were anxious to repeat our findings, hoping that the tumors were an artifact, but it's not," Sands said.

In gene therapy, healthy genes are inserted into a person with a genetic disease. One way to insert the gene is through a genetically engineered virus, which is injected into the patient. The healthy gene then makes proteins that reverse the disease.

The death in Seattle raises new questions about whether the virus should be used in human trials. The patient died after receiving a second injection of the gene therapy virus while being treated for arthritis during a clinical trial by Targeted Genetics Corp. The company has treated about 100 people in the trial without adverse affects, the FDA said Thursday.

While it remains unclear whether the virus played a role in the patient's death, the cancer finding is reason enough to step back from human studies, said Ronald Munson, a medical ethicist at the University of Missouri-St. Louis.

"Safety should be established in animals before it is tried in humans," Munson said. "I think therapy using this version of the virus should not go forward until we understand what has happened."

Still, several scientists, including Sands, say they aren't ready to abandon the virus in human studies, given its potential.

"The problem is that no one else has seen the same thing" as Sands, said Nick Muzyczyka, professor at the University of Florida and scientific adviser at Applied Genetic Technologies Corp. in Alachua, Fla. The company is conducting two gene-therapy trials using adeno-associated viruses and has several gene therapy treatments in development.

Meanwhile, Dr. Valder Arruda of the University of Pennsylvania deliberately attempted to use the virus to cause cancer in mice that were already predisposed to the disease. But the mice remained healthy.

While Arruda said he believes Sands' data, the technique is so complex that the virus alone may not be the problem, noting other complicating factors, such as the age of the animal.

Arruda and his colleagues began treating people for hemophilia with the virus in 2001. They have also been treating 30 dogs for hemophilia with the virus, some for more than five years. Thus far, neither the six humans nor the dogs have gotten cancer.

Medical research comes with a certain amount of risk, scientists say. For some reason, gene therapy is given less room for error, said Dr. Markus Grompe, director of the Oregon Stem Cell Center in Portland.

"In general we have a tendency to not accept any side effects of gene therapy," Grompe said. "If we had that attitude we would have never figured out bone marrow transplants; many people died in those trials. The key is how many other options do you have."

Gene therapy has been used to cure only one disease, an immune system disorder called severe combined immunodeficiency, or SCID. Most people know it as "bubble boy disease." When three children in a French study developed leukemia linked to the virus used in gene therapy, treatment was halted. Now only children with no other alternative are given gene therapy to treat the disease.

The first high-profile death in a gene therapy trial happened in 1999 at the University of Pennsylvania. A young man named Jesse Gelsinger died after his immune system reacted badly to the virus used in the trial.

But some people facing miserable lives and early deaths at the hands of disease may think that taking a chance on developing cancer later is worth the risk, said Ana Iltis, an associate professor at the Center for Health Care Ethics at St. Louis University.

At the very least, patients need to know exactly what risks they face before deciding whether to go through gene therapy, she said.

Gene therapy is a promising technology with frustrating problems, Munson said, adding that once researchers work out the kinks, gene therapy can save many lives.

"I think gene therapy has such significant benefits that the problems it faces, though complicated, shouldn't be enough to stop it," he said. "I don't think this is the end of gene therapy at all. It's just another problem that needs to be examined and resolved."

Without U.S. Rules, Biotech Food Lacks Investors

By Andrew Pollack
New York Times
July 30, 2007

This little piggy's manure causes less pollution. This little piggy produces extra milk for her babies. And this little piggy makes fatty acids normally found in fish, so that eating its bacon might actually be good for you.

The three pigs, all now living in experimental farmyards, are among the genetically engineered animals whose meat might one day turn up on American dinner plates. Bioengineers have also developed salmon that grow to market weight in about half the typical time, disease-resistant cows and catfish needing fewer antibiotics, and goats whose milk might help ward off infections in children who drink it.

Only now, though, do federal officials seem to be getting serious about drafting rules that would determine whether and how such meat, milk and filets can safely enter the nation's food supply.

Some scientists and biotechnology executives say that by having the Food and Drug Administration spell out the rules of the game, big investors would finally be willing to put up money to create a market in so-called transgenic livestock.

"Right now, it's very hard to get any corporate investment," said James D. Murray, a professor at the University of California, Davis, who developed the goats with the infection-fighting milk. "What studies do you need to do? What are they looking for?" he said, referring to government regulators. "That stuff's not there."

But some experts caution that even if the F.D.A. clears the regulatory path in coming months, investors and agribusiness companies might still shy away. Many fear that consumers would shun foods from transgenic animals, sometimes referred to as genetically modified organisms, or G.M.O.'s.

"The companies we have spoken to have gone organic, and they are very concerned, at least up to the present time, of having G.M.O. associated with their name," said Cecil W. Forsberg, a professor at the University of Guelph in Ontario, Canada, who helped developed the "Enviropig" with the cleaner manure. Smithfield Foods, for one, the world's largest hog producer and pork processor, says it is doing no research on genetically engineered animals.

Critics say changing the genes of animals could lead to potentially harmful changes in the composition of milk or meat, like the introduction of a protein that could cause allergic reactions. They say there could also be risks to the environment if, for example, extra-large salmon were to escape into oceans and out-compete wild salmon for food or mates. Some also say that some of the processes used to create transgenic livestock can harm the animals themselves.

The federal guidelines would come after more than 15 years of talks and false starts at the F.D.A., a delay irking not only developers of the transgenic animals but also critics of biotechnology.

"The fact that the agency has sat there for years staring this problem in the face and really hasn't come up with a clear way to regulate this is abdicating its responsibilities," said Joseph Mendelson, the legal director of the Center for Food Safety, a Washington advocacy group.

Even now, the F.D.A. will not say when the rules will be ready.

"We want to get it out, but we also want to get it right," said Julie Zawisza, a spokeswoman for the agency, which declined to make any other officials available for comment.

Some industry executives and former and current government officials say one reason for the delay was that some government officials, in part because of a preference for fewer regulations, wanted less stringent rules than the F.D.A. is considering.

Meanwhile, the biotechnology industry is actually pushing for the tougher standards.

"Our overarching goal is to have public confidence in our products," said Barbara Glenn, the managing director for animal issues at the Biotechnology Industry Organization, a trade group. "We won't have that unless we have a very strong review process."

The F.D.A. is turning to transgenic animals after having tentatively declared in December that milk and meat from livestock that is cloned - but not otherwise genetically manipulated - was safe for people to eat.

The F.D.A. considers clones to be less biologically radical than genetically engineered animals - which instead of being mere replicas of naturally occurring animals are given foreign DNA, usually from another species.

Larisa Rudenko, a senior biotechnology adviser in the F.D.A.'s veterinary drug division, said in a May presentation at the biotechnology industry's annual convention that each new type of genetically engineered animal would require approval for use in the food supply. That will be done, she said, under the umbrella of existing rules for drugs used in treating animal diseases.

While the implanted gene is somewhat like a drug, the existing rules would have to be stretched to fit.

But industry executives and some former agency officials said it was unlikely that Congress would enact totally new laws for transgenic animals. And using the drug laws, they say, would provide tighter control than an alternative approach of using the rules governing food additives. Agency officials have said that the veterinary drug rules would be used, and they have already been overseeing some experimental work on that basis. But they continued to debate the issue, and the policy has never been made official.

The regulatory guidelines would indicate how the drug rules would be interpreted for transgenic animals, and what types of data would be needed to prove safety and efficacy. But there are open questions about how the drug rules would actually translate. While a chemical drug must be shown to be consistent and stable, for instance, it is unclear how that standard would apply to a gene passed from generation to generation. Some critics say that while the drug rules do provide fairly strict regulation of food safety, there are drawbacks to adapting that approach. Because applications for approval of drugs are confidential, for instance, there would be no opportunity for public comment before the agency acted.

"In order to create confidence in a new technology, you really don't want behind-closed-door proceedings," said Margaret Mellon, director of the food and environment program at the Union of Concerned Scientists.

Another worry is that the F.D.A. might not have enough expertise or authority to conduct a vigorous review of the environmental impact of transgenic animals. The F.D.A. has dismissed this concern, however, saying it has sufficient expertise and can consult with other agencies.

The biotechnology regulatory branch of the Department of Agriculture created an animal division last December to figure out what its role should be.

Genetically engineered animals are often created by injecting the gene of interest into a single-cell embryo. A more recent technique that is more efficient is to put the gene into a skin cell and create an embryo from that cell by cloning.

In both cases, the embryo with the foreign gene is then implanted into the womb of a surrogate mother. After some transgenic animals are born, additional ones can be made by conventional breeding, because the foreign gene generally will be passed on to some of the offspring, as would any other gene.

The fast-growing salmon is the transgenic animal that has been swimming upstream the longest at the F.D.A. Its developer, Aqua Bounty Technologies of Waltham, Mass., has been working to win agency approval for about 10 years. Aqua Bounty's fish are Atlantic salmon that have been given a growth-hormone gene from the Chinook salmon. They have also been equipped with a genetic on-switch from a fish called the ocean pout, a distant cousin of the salmon.

Normally, salmon produce growth hormone only in warmer months, but the pout gene's on-switch keeps the hormone flowing year round. That enables the Aqua Bounty fish to grow faster, reaching their market weight in about 18 months instead of 30.

Elliot Entis, Aqua Bounty's chief executive, said the company had already given the F.D.A. studies showing that the fish were healthy and that the implanted gene remained stable over generations.

He said the company also had tests done to show that its fish contained the same level of fats, proteins and other nutrients as other farmed salmon and would not set off unexpected allergic reactions in people who eat them. The fish also taste the same as other farmed Atlantic salmon, Mr. Entis said.

"Nobody has ever analyzed salmon as closely as we have had done," he said. But the F.D.A. is asking for more data on safety and potential environmental effects on wild salmon.

Industry executives say the Enviropigs would be the next candidate for F.D.A. approval. The pigs contain a bacterial gene that allows them to produce an enzyme that helps them more fully digest a vital nutrient, phosphorus, in their feed. That means less phosphorus in the manure, which in turn could mean less phosphorus running off into lakes and oceans, where it can cause algal blooms and fish kills.

MaRS Landing, a technology promoting organization in Ontario, is trying to find a corporate partner for the pig, said John Kelly, the agency's executive director.

Less far along in the approval pipeline are pigs that contain a gene from the roundworm allowing them to produce omega-3 fatty acids, a nutrient normally found in fish that is good for the heart. That, in theory, could make eating pork or bacon healthier, although that has yet to be tested.

Jing X. Kang, an associate professor at Harvard Medical School who helped direct the project, said the researchers were looking for corporate backers while also trying to raise the level of omega-3 in the meat.

Carol Tucker Foreman, director of the Food Policy Institute at the Consumer Federation of America, a consumer advocacy group in Washington, said regulations might not assuage consumers, many of whom object to the genetic engineering of animals on humane or ethical grounds, more than on safety concerns.

"The fact that the F.D.A. has a powerful regulatory process for reviewing genetically engineered animals, far greater than they apply to genetically engineered crops, may not make any difference at all," Ms. Foreman said. "Because that's not what it's all about."

Farmyard Truths and Industry Lies

AP Coalition in Defence of Diversity
Media Release
July 30, 2007

The Genetic Engineering industry has started a huge campaign on the so called success of Bt cotton to bamboozle public opinion in the country. In the wake of a series of setbacks suffered as a consequence of a spate of refusals by the apex regulatory body Genetic Engineering Approval Committee of the Government of India, the biotech industry had to go for an overdrive for its survival. And it has predictably done so.

Against this backdrop, it is essential for us to consider the realities on the ground both in Andhra Pradesh which is closest to us as well as the reality in the Global South where Bt cotton has tasted a string of reversals: It has been kicked out of many countries; it has been prevented from entering into others; has been losing in popularity in some others and is making an illegal business in some others.

The film A Disaster in Search of Success: Bt Cotton in Global South, an incredible production by a group of peasant women from the Community Media Trust of Medak District, Andhra Pradesh, presents these realities from South Africa, Indonesia, Thailand, Mali in West Africa and of course from India.

This truth has hit Monsanto so badly between the eyes that it has produced 29 short films of its own and has hosted them on its website to counter these realities. While Monsanto can have testimonies from manipulated farmers and paid scientists, the AP Coalition in Defence of Diversity and the Deccan Development Society will soon come out with its own web videos representing the experiences of farmer-victims of Genetic Engineering from different parts of the world and from independent, free thinking, respected scientists who have refused the corporate traps and have been cautioning the humanity about the negative impacts of GMOs.

Within AP itself, evidences are glaringly different from the fools' paradise that Mahyco-Monsanto is creating with its cohorts from the Assocham and Chamber of Commerce and Industries, for whom the foreign direct investment is far more important than the lives of farmers lost in the pursuit of Bt cotton or the Bt-infected toxicity in our soils and plants because of which thousands of animals have died over the last two years.

Many NGOs including the Deccan Development Society and the APCID have presented irrefutable evidence of animal deaths as a result of feeding on Bt Cotton plants This prompted the Government of Andhra Pradesh to start its own investigations. As a result, the Director of Animal Husbandry, Government of Andhra Pradesh wrote a letter to the Chairman, GEAC to arrange for Biosafety studies on the impact of Bt cotton on sheep and goats. But the GEAC has done nothing of the sort.

This leads us to the question of direct or indirect complicity of responsible government institutions who refuse to get out of the trap laid for them by the industry. The AP Coalition in Defence of Diversity, in spite of repeated appeals to National Institute of Nutrition, the apex body of the Government of India on the issues of nutrition and food toxicity has not succeeded in persuading the institute to start the toxicity study of Bt plants on animals. This is in spite of our offer to meet the costs of the study. So is the case with GEAC, which refuses to pro actively study the Biosafety aspects of GM crops and save the citizens and soils of this country from the toxic crops. The only option left to us is to use the RTI Act and force these institutions to take up their constitutional responsibility.

While the public sector institutions are cocooned in their reluctance to explore the truth, the industry spin doctors have started crying from the housetops about the phenomenal success of Bt cotton in India "because of which cotton farmers of India earned an additional income of Rs.7,039 crores after an increase of 50% in yield".[Press Release from ASSOCHAM, July 11, 2007] That such an incredulous lie goes unchallenged by the public sector is extremely tragic.

On July 27th, ASSOCHAM which claims to have done a survey on Bt Cotton farmers came up with a series of embarrassingly false claims. Look at some of them below:

Those who had grown Bt cotton earned higher incomes and their household income and family conditions had improved substantially. Increased maternal care services like anti-natal checkups, access to services by trained paramedical and nursing personnel, larger school enrolment and other such improvements in quality of life were found among the Bt cotton growers as compared to those growing non-Bt cotton. Children in the Bt cotton growers' families had been vaccinated for polio and received complete immunisation. Villages where Bt cotton was being grown had benefited due to increased access to services such as telephone systems, electricity, drinking water, better internet connectivity, banking, and markets and shopping. [from a report in The Hindu, July 27, 2007] Short of saying that people were breathing air in and out because they grew Bt Cotton, the ASSOCHAM publicists gave credit to Bt cotton for everything else.

Then what is the reality from the field? Let us bring a few for your consideration:

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