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Then, in 1990, an NIH research physician named ­William French Anderson announced to heated publicity that he was launching a gene-therapy trial, treating two young girls for a form of severe combined immune deficiency, or SCID. People with this disease completely lack a normal immune system. The precursor cells in their bone marrow that should make white blood cells are defective, so patients catch all the infectious diseases that white blood cells should fight off. Mild infections become grave; serious ones kill them. They die in early childhood. Anderson said the two girls were suffering from a form of SCID caused by a lack of the enzyme adenosine deaminase (ADA). He was injecting them with correcting genes carried in murine-leukemia virus.

Anderson was a flamboyantly effective publicist of gene therapy and of himself. He announced that the two little girls had been cured. In September 1994, he brought one of them to testify before the Science Committee of the U.S. House of Representatives. She was eight years old by then, lively and apparently well. The chairman of the committee reportedly called her “living proof that a miracle has occurred.” Anderson made sure he was known to the public as “the father of gene therapy,” even displaying the title on his website.

Yet his scientific colleagues and competitors became exasperated, even contemptuous. In point of fact, the trial with the two girls had failed. All along, the girls had also been treated with injections of a synthetic ADA. And Verma and Friedmann had already shown the failure of mouse leukemia virus to introduce genes in vivo. “There was never production of the ADA protein–there never was,” according to Verma. Even before the girl appeared in front of the House committee, the failure was known throughout the medical community.

Since retroviruses presented difficulties in vivo, attention turned to the adenoviruses–which include the viruses that cause certain types of severe upper-respiratory infections in humans. They worked. “They were wonderful,” Verma says. “First of all, you could make billions of virus particles.” Secondly, wherever the particles were introduced, the imported genes would be expressed. Many researchers switched to adenoviruses. But they turned out to be highly immunogenic: they are difficult to use safely because they can provoke strong immune reactions. Next came adeno-associated viruses, AAVs. Because they have only two proteins, AAVs provoke the immune system less than adenoviruses do.

In the fall of 1994, Harold Varmus, the director of NIH, became increasingly skeptical about the quality of gene-therapy research. The agency’s Recombinant DNA Advisory Committee (RAC) was reviewing all protocols for human trials of gene therapy funded by NIH. The committee’s first concern was safety. But as its recommendations passed across his desk for final approval, which was normally routine, Varmus realized that the committee was not systematically evaluating the trials’ scientific merits.

It turned out that Anderson’s were only the most egregious of many extravagant and unsupported claims surrounding gene therapy. Although NIH was giving out $200 million a year for gene-therapy research, and big pharmaceutical firms and swarms of biotechnology startups were thought to be spending as much again, not a single success with humans had been reported in any peer-reviewed journal. In May 1995, Varmus convened a panel headed by Stuart Orkin, a professor at Harvard Medical School, and Arno Motulsky, a geneticist at the University of Washington, Seattle, to review the state of gene-therapy research and assess how funds should be apportioned among gene-therapy research areas.

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Credit: Illustration by Chris Buzelli

Tagged: Biomedicine

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