21 January 2002

LAB STUDY RAISES NEW QUESTIONS OVER GENE "WONDER" THERAPY / BIOTECH BOOSTS BIO-WAR

1. Lab study raises new questions over gene "wonder" therapy
2. biotechnology and biological warfare

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1. Lab study raises new questions over gene "wonder" therapy

Agence France Presse, PARIS, January 20, 2002

Laboratory tests involving cancer cells have raised fresh questions about the safety of gene therapy, an area of research that has stoked huge expectations that a generation of miracle cures is on the way. The treatment entails slotting in a healthy gene to replace a defective one, with the idea of preventing or even reversing an inherited illness. To deliver the new gene, researchers tuck it like a Trojan horse inside a disabled virus, called a vector. The virus is modified so that it retains its ability to infect cells but, ideally, has no pathogenic effects. In a handful of cases since it was first tried experimentally in 1990, the experimental treatment has wrought dramatic progress, but these have also contrasted with setbacks, most notably the death in 1999 of Jesse Gelsinger, an 18-year-old American.

Gelsinger, who hoped for a cure to a chronic liver disease, died from a massive immune reaction, apparently triggered from the vector itself, a disabled cold virus.

His death caused a major reassessment of vectors, notably prompting interest in a smaller and, it is hoped, harmless alternative called the adeno-associated virus (AAV).

Several clinical trials using AAV are now underway, but researchers at the University of Washington in Seattle warn caution. In a study published online Sunday by the specialist journal Nature Genetics, the team infected cancer cells with an AAV vector that carried a gene which is resistant to the antibiotic neomycin. The cells, after they were infiltrated by the vector, showed a number of unusual DNA abnormalities, including deletions and rearrangements of some chromosomal sequences.

"(The results) have consequences for gene therapy, as these phenomena may influence both transgene and cellular gene expression," the authors say, adding that further work is needed to investigate whether the same thing could happen in normal human cells. "Given the increasing popularity of AAV vectors for human gene therapy, it will be important to address these issues in clinical trials," they warn.

The University of Washington study is not the first to raise questions over the safety of AAV. Last year, a study discovered that among older mice which had been given gene therapy to correct Sly syndrome, a rare enzyme syndrome that can cause mental retardation, several developed liver tumours. That research prompted the US Food and Drug Administration (FDA) and National Institutes of Health (NIH) to order a halt to early human trials involving AAV. However, other researchers reported no similar side effects, and the trials were reinstated while experiments were repeated.

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2. biotechnology and biological warfare

Biotech companies fighting threat of 'superbugs'
By PAUL ELIAS, AP Biotechnology Writer
The Associated Press, January 20, 2002

SAN FRANCISCO: Genetic engineers who have spent years fighting diseases face a dismaying paradox in the post-Sept. 11 world: many of their impressive breakthroughs can also be used for sinister purposes.

Genetic maps of many disease-causing viruses and bacteria are now available to anyone with an Internet connection.

Techniques that can make pathogens more deadly are publicized in scientific journals. Some scientists fear that information made public with the most altruistic of intentions may also help terrorists create biological weapons laced with genetically modified superbugs. Such germs are created by splicing drug-resistant genes into diseases normally defeated by vaccines. "This is the double-edged sword of biotechnology," said Dr. Vito Del Vecchio, a University of Scranton researcher who this month published the genome, or genetic blueprint, of the Malta fever pathogen, which can cause severe flu-like symptoms.

Del Vecchio and an international team of scientists deciphered the bug's genome in order to understand what makes the microbe virulent and to possibly create a vaccine. But no vaccine yet exists, and meanwhile, that same information could be used to engineer a drug-resistant biological weapon. While researchers like Del Vecchio scramble to devise ways to detect and defend against biological weapons, others may be working to genetically engineer around these efforts. At least six countries - Britain, France, Germany, Iraq, Japan and the United States - plus the former Soviet Union, either have or once had major biological weapon programs. It's never been easier to tweak a bug's genes to make it antibiotic-resistant or more potent, or to transfer a germ's deadly properties to a normally benign microbe. "It's a fairly straightforward process," said Stanford University microbiologist Steve Block. Dr. James Baker Jr., a University of Michigan bioterror expert, said most microbiologists suspect that someone somewhere is trying to use these genetic engineering techniques to make biological weapons more deadly. "I think Ken Alibek gave that 'gift' to the world," Baker said. As second-in-command of the Soviet biowarfare program, Alibek did more than dabble with genetically engineered diseases, the blackest of biotechnology's black arts. His genetic tinkering improved the virulence and antibiotic resistance of a variety of diseases, from anthrax to smallpox. Alibek's goal was to make merely debilitating diseases deadly, and deadly pathogens resistant to vaccines. Now, he's working to undo his legacy, joining other U.S. researchers in a frantic biological arms race against an unknown enemy. Their task is made more difficult by the wealth of publicly available biological warfare information. Alibek says obtaining superbug recipes could be as easy as digging up old Russian scientific journals where his colleagues published a few of their findings. "If somebody is capable of reading Russian, you would find information in scientific journals on how to develop some of these techniques," he said. Ignorance of Russian may not even be a hindrance. Last year, two Australian researchers published a paper detailing how they accidentally engineered a super potent mousepox, a close cousin of smallpox. They said they published their accident to warn that the same techniques could harm humans by strengthening the virulence of smallpox. Years earlier researcher Willem Stemmer published news of his creation: an E. coli strain 32,000 times more resistant than conventional bugs. Of course, genetically engineered "superbugs" aren't the only threat. Baker, for one, is more concerned about things found in nature, like anthrax, that can be made into biological weapons. Another setback for biowarfare defenders is the easy availability of declassified documents from the decades-old U.S. germ warfare program, which was discontinued in 1969. Since Sept. 11, the government has been re-evaluating public access to such documents. Even before the terrorist attacks, the U.S. government was funding research to combat potential misuse of biotechnology in biological warfare.

The Defense Advanced Research Projects Agency spends about $58 million annually on a program that develops countermeasures to unconventional pathogens, said agency spokeswoman Jan Walker. Walker said the program's main goal is to find vital elements common to all pathogens. The hope is that a single vaccine or detector could work against myriad microbes, genetically engineered or otherwise. At least three biotechnology companies - including Alibek's firm, Hadron Advanced Biosystems of Alexandria, Va. ­ also are trying to create "universal" vaccines and detection devices against all pathogens. Such universal immunity is the only way to defend completely against biological attack, Alibek says. He fears that too many scientists now have the knowledge to genetically engineer old diseases and create new diseases not yet in the human lexicon.

 "Theoretically any scientist from any country who needs money could do this work," Alibek said. "There's no smoking gun. But I believe this business does exist."