Battler for Gene Therapy

By LEON JAROFF

* The 1990 Acura Legend pulls into the garage in San Marino, California, and out steps a slightly built man with graying hair, in suit and tie, just back from work. He calmly surveys the workout equipment he has set up in the adjacent parking slot: two heavy bags and a pair of rigs, one supporting a stack of five 1-in.-thick pine boards, the other a stack of three. Suddenly he explodes into violence. His right foot lashes out, delivering a blow that cleanly severs the five stacked boards. Without missing a beat, he slams his right fist into the stack of three, also sundering them.

With a satisfied smile, he heads for his backyard retreat, a small walled orchard interlaced with pathways and featuring a central karate ring, and sinks into a lounge chair. He relaxes and begins ruminating, not about his athletic prowess, which is formidable, not about his critics, who are vociferous, but about his lifelong obsession.

That obsession is gene therapy, and W. French Anderson, 57, more than anyone else, has brought it from the realm of science fiction to reality. It was Anderson who campaigned single-mindedly for the first approved test of the technology in 1990, who organized and supervised the trial, and who last year was able to announce that the subjects of the experiment, two young girls with a debilitating disorder called ADA deficiency, had been relieved of virtually all symptoms of the disease.

Having given gene therapy a jump start, Anderson, if anything, has become even more obsessed with the subject. After 27 years with the National Institutes of Health, where he advanced the art of using genes to treat disease, he departed in 1992 to join the University of Southern California. There, while serving as a professor of biochemistry and pediatrics, and director of the Gene Therapy Laboratories, he hopes to produce a new generation of delivery systems, or vectors, that will enable doctors to give patients therapeutic genes much as they administer drugs today.

Anderson himself seems to have inherited a remarkable collection of genes. "I was rather a weird little boy," he admits. A child prodigy in Tulsa, he could read, write, add and subtract before kindergarten, and was devouring college science books when he was eight -- skills, he says, that "did not endear me to the other schoolchildren of Oklahoma." He was also a stutterer, which made him a target of taunts. But that didn't bother him, he says, "because I considered everybody else in the world stupid."

And certainly not as determined and multifaceted as he was. To overcome his stammer, he talked with pebbles in his mouth ("like Demosthenes") and joined his high school debating team. Also a track star, he won a scholarship to Harvard.

There he audited a chemistry course taught by John Edsall, an expert in proteins. Edsall soon took Anderson under his wing, as author Larry Thompson recounts in Correcting the Code, a forthcoming book about the pioneers of gene therapy. At one of Edsall's seminars, Anderson became intrigued by a visiting British scientist's talk about the hemoglobin molecule, which transports oxygen in the bloodstream. A thought occurred to Anderson, and he blurted it out. "If you could determine its structure," he reasoned out loud, "then you could do the same with sickle hemoglobin and determine what the defect is." And because that structure is determined by genes, he went on excitedly, "you could actually change the genes and correct sickle-cell anemia."

The British scientist cut him off. "What a stupid thing to say," he chided. "This is a serious scientific session." Anderson was humiliated, but as he slunk out after the session, John Edsall came by. "Interesting idea," he said, and walked away.

That incident inspired Anderson. "If Edsall thought it was an interesting idea," he recalls, "then by God it was an interesting idea. I decided to figure out how to cure sickle-cell anemia by changing genes."

After graduating from Harvard Medical School, he landed a job at the NIH, excelled and soon had his own laboratory. As early as 1968 he predicted in a speech that "the first attempts to correct genetic defects will take place within the next few years."

But Anderson's optimism was not matched by the state of the art, and in 1981, discouraged by the lack of a reliable technique for inserting genes into the nuclei of mammalian cells, he temporarily abandoned gene therapy, turning to other research. As balm for his disappointment, he relentlessly practiced the Korean martial art Tae Kwon Do, won a fourth-degree black belt and was eventually appointed team physician for the U.S. Tae Kwon Do squad at the Seoul Olympics.

During Anderson's gene-therapy hiatus, however, Richard Mulligan, an M.I.T. researcher, showed that genetically engineered mouse-leukemia retroviruses were effective vectors for inserting human genes into mouse DNA. To Anderson, this meant one thing: gene therapy was now possible, and he was back in business.

Knowing he needed help, he began collaborating with retrovirus researcher Eli Gilboa and Dr. Michael Blaese, an NIH pediatrician and expert in immunology. Over the next few years, Anderson submitted proposals for human gene-therapy trials to the NIH's Recombinant DNA Advisory Committee (RAC), which must approve such tests.

Turned down time and again, Anderson persisted, diplomatically adding to and revising his telephone-book-size protocols to meet RAC demands. In 1989 he finally won approval for a nontherapeutic test that would transfer bacterial genes into immune cells of terminal cancer patients to serve as markers in trials conducted by Dr. Steven Rosenberg of the National Cancer Institute. Those experiments established the safety of using retroviral vectors.

Having put his foot in the door, Anderson doggedly went on to win approval in 1990 for the historic and eventually successful gene-therapy trials of the two girls with ADA deficiency. The final committee vote was 16 to 1, the only opposition coming from Mulligan, who has been Anderson's most vociferous critic, and who called the proposal "bad science."

But Nelson Wivel, who is the head of the NIH's Office of Recombinant DNA Activities, defends the experiment. Anderson's detractors, he notes, "call him a zealot. But if it weren't for his zealotry, we probably wouldn't be doing gene therapy." Indeed, it was the ADA trial by Anderson, Blaese and Dr. Kenneth Culver that opened the floodgates for dozens of gene-therapy efforts.

And to no one's surprise, Anderson will be involved in several of them. In 1986, while he was still at the NIH, he and venture capitalist Wallace Steinberg established Genetic Therapy Inc., a biotech company in Gaithersburg, Maryland, dedicated to producing retroviral vectors. Under an arrangement with the NIH, the first of its kind, GTI would have the initial rights to technology developed in Anderson's lab in return for the NIH's receiving payments and royalties from sales of GTI products.

While Anderson became eligible for royalties, as a government employee, he could receive no salary or stock options. Indeed, he so meticulously hewed to federal financial regulations that he paid for his own chocolate doughnuts at meetings with GTI's board.

Since arriving at U.S.C., Anderson has assumed the post of director of GTI's scientific advisory board. While he still draws no GTI salary, he is eligible for stock options -- which could soon be valuable. GTI is spending $5.5 ; million to tool up for the production of therapeutic retroviruses to treat victims of brain cancer.

As Anderson pushes for more and more gene-therapy trials, he is often asked, "What's the rush?" To that question, he says, "I would respond, Ask the cancer patient who has only a few months to live. Ask the AIDS patient whose body is shriveling . . . the 'rush' arises from our human compassion for our fellow man who needs help now . . . The sooner we begin, the sooner patients will be helped."