Sunday, March 23, 2008

The Glimmering Promise of Gene Therapy

Its history is marred by failures, false hopes, and even death, but for a number of the most horrendous human diseases, gene therapy still holds the promise of a cure. Now, for the first time, there is reason to believe that it is actually working.

Credit: Illustration by Chris Buzelli

By the late 1960s, molecular biologists had erected an overarching explanation of how genes work--their substance, their structure, their replication, their expression, their regulation or control. Or at least they had done so in outline, for prokaryotes, the simplest single-celled organisms (which include bacteria), and for the viruses, called bacteriophages, that prey upon them. The leaders of the field were now looking to a far more difficult problem: doing it all over again for higher organisms.

What this new generation of molecular biology demanded, and what was developed in just a few years, was a set of methods for investigating and precisely manipulating the genetics of eukaryotes, including animals and plants. With reverse transcriptase, which was discovered independently by ­Howard Temin and David Baltimore in 1970, genes encoded in RNA could be read back into DNA. With Daniel Nathans's and Hamilton Smith's work on restriction enzymes, segments of DNA could be snipped out at chosen sites. In a rush, from laboratories chiefly at Stanford University, came ways to link together genetic material from disparate sources. "We will be able to combine anything with anything," one senior scientist told me at the time. "We can combine duck with orange." The initial purpose was to get at the most basic questions of cellular biology, to find out exactly what individual genes do and how they do it. Immediately, though, a shining hope dawned: that this toolbox could be carried from the laboratory to the clinic, to cure hereditary diseases caused by genetic defects. Already, some scientists were dreaming of gene therapy.

By 1970, some 1,500 genetically determined diseases had been identified in humans. Some show up in babies; others surface at puberty; a few emerge only toward the end of the victim's reproductive life. Some can be held in check by dietary restrictions, a few by drugs. But most cannot be cured or even palliated by conventional medicine. Though almost all are rare, some extremely rare, collectively they were coming to be recognized as a burdensome and costly medical problem. Many are marked by gross mental impairment. Victims of Lesch-Nyhan disease, for example, suffer severe mental retardation. They must have their arms splinted, because otherwise they bite their hands and arms. They die in childhood or early adulthood. Though scientists had traced fewer than a hundred of these human diseases to specific genetic deficiencies, they began searching for ways to cure them by safely inserting correcting genes into people suffering from them.

They were still trying nearly two decades later, when on September 29, 1999, the front page ofthe Washington Post carried the headline "Teen Dies Undergoing Experimental Gene Therapy." Jesse Gelsinger was 18, a recent high-school graduate from Arizona who had a potentially fatal genetic disease. He was one of 18 patients taking part in a trial at the University of Pennsylvania. Viruses carrying a new gene had been injected into one of the arteries supplying blood to his liver. In gene therapy, an engineered virus is often used as a "vector," delivering the desired gene to the patient's cells; in this case, however, the virus apparently triggered a series of deadly events.

The New York Times picked up the story the day after it ran in the Post. The National Institutes of Health and the U.S. Food and Drug Administration started investigations, which moved with commendable speed; more details came out. Later, the U.S. attorney general got involved. But with those first newspaper reports, gene therapy seemed dead.

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