Wednesday, November 01, 2006

The Glimmering Promise of Gene Therapy

Continued from page 1

By Horace Freeland Judson

The trial that Gelsinger had been participating in was tainted by accusations of overconfidence, haste, negligent administration, and conflict of interest. Yet all this diverted attention from acute and fundamental problems with gene therapy itself--problems in the science and technology, problems in clinical exploitation of the technology, problems that were by no means new but that Gelsinger's death made glaringly evident.

I had been following developments in gene therapy for a third of a century, watching as hundreds of millions of dollars were lavished on it, as new hopes cyclically turned to ashes, dramatic claims to sad farce. By 2000, more than 300 gene-therapy trials had been registered with NIH, involving more than 4,000 patients, according to an article printed that year in the Council for Responsible Genetics' magazine GeneWatch. The Gelsinger affair was the most highly publicized failure. There had been plenty of others.

There were two chief reasons for pessimism about gene therapy. As had been plain from the start, although the total societal load of illness and debility caused by genetic defects is considerable, most individual diseases caused by single-gene defects--the kind that seem most likely to be cured by gene therapy--are rare. (Sickle-cell anemia and some other hemoglobin disorders are among the few exceptions.) Everybody in the field acknowledged this. Nobody seemed to face up to the implications. Because these diseases have different genetic mechanisms and affect different types of tissue, each presents a new set of research problems to be solved almost from scratch. As the millions burned away, it became clear that even with success, the cost per patient cured would continue to be enormous. And success had shown itself to be always glimmering and shifting just beyond reach, an ignis fatuus: from the start, step by step, everybody had underestimated the real difficulties the science presents.

The history of gene therapy can be told as the repeatedly frustrated search for viruses that work well as envelopes for gene delivery, paralleled by the increasingly baffling realization that far more than a few simple genes are needed to produce the desired proteins successfully. For the gene-therapy community, the years had been a calendar of failures. "We totally underestimated the fact that the viruses could present so many difficulties," Inder Verma--a molecular biologist at the Salk Institute, in La Jolla, CA--told me in August 2006. "We underestimated the fact that it took billions of years for the viruses to learn to live in us--and we were hoping to do it in a five-year grant cycle!" He went on, "You know, the body is designed to fight viral infections. One hundred percent. Luckily for us! And here we are putting billions of viruses back into people and hoping that if we have a good virus, the body will say, 'It's okay, because we're bringing the good stuff.'"

The first attempt at gene therapy in human patients began with a fortuitous observation. In 1959, the physician ­Stanfield Rogers, at the University of Tennessee, was working with the Shope papilloma virus, which causes warts on the skin of rabbits. He reported in Nature that the skin of these warts contained abnormally high levels of arginase, an enzyme that breaks down the amino acid arginine. He then found that some scientists who had worked with Shope virus, even 20 years in the past, had decreased blood levels of arginine.