THE BROWN, GLEAMING EYES OF THE 4-year-old girl darted between "Sesame Street" on the TV next to her bed and the bearded doctor with the 20-gauge needle in his hand. When he inserted the needle, she made no sound. She did not pull away. She stared down at her seemingly disconnected hand, watching the doctor work. Abruptly, she shifted back to Cookie Monster.

Kenneth Culver, her pediatrician, found the vein, but while trying to connect the clear plastic tubing, he dragged the needle out. Culver stiffened, paused a moment, then switched to her other hand.

She did not seem to notice.

They had both been there before: she sitting on a bed in the National Institutes of Health's high-tech hospital, he with his necessary needles. Again Culver pierced her skin, probing for a vein. This time a rush of crimson filled the needle's clear plastic barrel. "Okay, this one looks like it is real good," Culver said, never taking his eyes off the needle. "Looks like this is the magic hand."

The child didn't smile or cry. She seemed unaware of the historic events about to take place in her body.

In the background, a thin, 53-year-old scientist with gray hair and a white lab coat watched over the proceedings. W. French Anderson, chief of the molecular hematology branch of the National Heart, Lung and Blood Institute, managed the last-minute preparations -- observing Culver, giving orders on the phone, consulting with R. Michael Blaese of the National Cancer Institute as Blaese ran the final safety tests on white blood cells that would soon be given to the girl through the newly installed needle.

More than anyone else, Anderson was responsible for the events about to take place in the room that Friday, September 14, 1990. This was the moment he had worked toward for so long. He and a handful of colleagues were about to open the door to human gene therapy, a radical new treatment that may one day cure thousands of inherited illnesses and attack major killers such as cancer and heart disease.

Just to get to that moment, however, Anderson had waged a fierce public battle with some of the most respected molecular biologists in the country, defending his vision of gene therapy, even as he lobbied federal gene regulators to allow him to proceed. Anderson knew all about winning and losing in bare-knuckle science. When he first came to NIH in July 1965, he'd gone to work in the lab of Marshall Nirenberg. At the time, Nirenberg was racing to beat several other high-powered laboratories to finish deciphering the genetic code -- a three-letter alphabet that is used by genes to direct the production of protein. Nirenberg won the race and the Nobel Prize; Anderson learned about competition in science.

The higher the stakes, the meaner the fight.

He knew the risks too. He was one of the few people who had gotten close to the shy, stoic girl and he worried foremost that she might die as a result of the treatment. But, as a researcher, he also knew that such a result could set the field back for years. In addition, it would be a devastating defeat for Anderson. For most of the last two decades, he had engaged in the highly controversial and heady competition to make gene therapy a reality. He does not like to lose. The Threshold of a New Age

The development of gene therapy has been a horse race with enormous stakes. Whoever wins could end up with a Nobel Prize. And if gene therapy becomes as essential as penicillin -- as many biologists believe it will -- some enterprising private researcher could make millions. Already, biotechnology companies are lining up to market it.

French Anderson's gene therapy experiment is pretty simple. The girl was born with an inherited illness, a single broken gene, that robbed her of a normal immune system. She suffered from constant infections, severe colds, earaches, fevers and pneumonia; without some kind of treatment, eventually one of the maladies would kill her.

Anderson's team wanted to give her a normal copy of the damaged gene in hopes of restoring her tattered defenses. To give her the new gene, the researchers took some of the genetically defective white blood cells from her body and began growing them in the laboratory. As the cells grew, Anderson's team intentionally introduced into them a crippled virus that could not reproduce itself or cause an infection. Genetic engineering had turned the virus into a molecular ferry that could carry a normal copy of the girl's broken gene. When each virus infiltrated a white blood cell, it would deposit one copy of the gene into the cell, healing it.

At 12:52 p.m. on September 14, Ken Culver pushed the plunger of a needle that squirted a test sample of a few million gene-treated cells into the girl's intravenous line.

They waited.

Nothing happened; that was good.

The girl's heart monitor beeped a steady pulse of 101 beats per minute. Culver smiled, hugged his patient and walked away. Anderson stood by the bed, smiling down at the 4-year-old pioneer. She looked back, unsmiling. At first, no one spoke. "That's it," Anderson said to her. "What did you think of that? All this buildup, and that's it. All that will happen now is we will watch you for a while,

and then tomorrow, you will go home. That's it."

With the start of the six-month experimental treatment, Anderson and his gene team had taken a tentative step across the threshold into a new age of genetic medicine. They were now the first to try using genes to relieve a human patient's symptoms -- true genetic therapy.

After 10 minutes, the researchers hooked up a bag with a billion of the girl's treated white blood cells to the intravenous tube and turned on the flow. Then Anderson decreased the speed at which the gene-altered cells poured into the girl's body. The action was cautious and notably out of character. Anderson almost never slows things down. 'The Most Unpopular Boy In School'

Ever since he first thought about attacking human ills at the genetic level nearly 40 years ago, Anderson has been impatient to begin. The urgency intensified in the last decade as the technical means became available and as scientific competition increased. "There is no question that I am driven," he says.

His drive, which borders on compulsion, seems for the most part to come from within, from a childhood characterized by precocious intelligence and social awkwardness. Achievement was always expected of this Tulsa boy, born in the heart of the Bible Belt on New Year's Eve 1936. His parents were well educated; his father was an engineer, his mother a journalist. With their help, he learned to read and write, add and subtract before he entered kindergarten. His ability to focus -- some would say obsess -- on whatever goal he set would become a personality trait that haunted him even as it drove him. "People used to call me a preacher's son," Anderson says, "because I didn't curse. I didn't smoke. I didn't drink. I wasn't interested in sex. I was only interested in science."

From a very early age, he excelled. But Anderson's outstanding academic achievement led to arrogance. He says that even in elementary school, he looked down on classmates who could not keep up. That earned him enemies. "I remember Mary Dunn, we were walking from school in fourth or fifth grade," Anderson recalls. "She said, 'You are the most unpopular boy in school.' " At the time, he says, he didn't care, but today the memory pains him.

Anderson says that during the fifth grade he had so much trouble with other kids that the school psychologist was called in, and, though he pronounced Anderson normal, it was clear the boy needed help with socialization. "I realized I really had to change my life," Anderson says today. "If I was ever going to be

successful in life, I had to get along with

people."

Typically, he did something dramatic. He changed his name. He stopped using his first name, William, and -- in hopes that it would change the way people treated him -- began going by "W. French." To this day the alteration still means a great deal to him. "I will not speak to anyone who accidentally calls me Bill," Anderson says. "Any letter that comes to William or Bill, I throw it away. I don't even open it. It's absolutely irrational."

Eventually, however, Anderson learned to get along with his peers. By seventh grade, he was popular enough to be voted class president.

In 1951, the Anderson family moved to Muskogee, Okla., for a year. At Muskogee Central High School, Anderson decided he had to do something about another problem: He stuttered. He already had tried talking with stones in his mouth like the Greek orator Demosthenes, but that didn't help much. So he joined the debate team.

Debate didn't cure him -- Anderson's stammer still shows up when he gets excited -- but it did hone his competitive skills. So did several summers at camp, where he learned he could run faster than almost anyone. "When I learned that I could outrun people, track became the single most important thing in my life," he says. "I put training for track above everything else, including school."

After his family moved back to Tulsa in 1953, Anderson began winning cross-country races, and even started setting records for shorter events, according to newspaper accounts of the meets. "At my peak I was only a second off the world record in the 440," he says.

Still, track never really made him one of the guys. Larry Oliver, a high school chum who is now a Tulsa criminal lawyer, remembers that while the rest of the high school track team would be roughhousing in the bus on the way to a meet, Anderson would sit in the back, alone, reading.

In 1954 he entered Harvard, and it was there that he became fascinated by biochemical research. Upon graduation in 1958, he delayed entering Harvard Medical School to study genetics at England's Cambridge University. He worked in the laboratory of Francis H.C. Crick, the physicist who just five years earlier had codiscovered the structure of the DNA double helix with American biologist James D. Watson. "It was just an extraordinary time," Anderson says. "The first model of a molecule {hemoglobin} was being built atom by atom. Three of the four people in that little Quonset hut won Nobel Prizes for what they were doing."

During his two years at Cambridge, Anderson started medical school and, over a head and neck dissection in anatomy class, met Kathryn Duncan, who was also a medical student and now is vice chairman of surgery at Children's Hospital. The two married and transferred to Harvard to

finish medical school.

From Boston, Anderson moved into Nirenberg's laboratory at NIH and, three years later, set up an independent lab to study diseases of hemoglobin, the protein that carries oxygen throughout the body and makes blood red.

And he began searching for ways to fix blood diseases at the genes. 'Two Steps Short of Bizarre'

French Anderson's office is a long, narrow room on the seventh floor of the clinical center at NIH. Pink phone message slips litter the side table beneath the wall phone. The blinds are drawn, the fluorescent lights are glaring. All about are photos of his laboratory assistants, his disciples. On the far wall near the corner is a very unusual calendar. For want of a better name, let's call it French Anderson's Personal Scientific Progress Chart.

The chart is really nothing more than a daily calendar that Anderson uses to keep himself on track: Each half-day, he rates his scientific productivity. If he has spent several hours doing science, he colors in that half-day green for "good." If he has done only a little science, he marks the half-day yellow for "caution." If he hasn't done any science, the half-day is colored red for "danger." He condenses the half-days into monthly colored calendars and even plots his level of scientific activity on a graph. But day in, day out, the calendar is there as a scoreboard.

Above the office door hangs another kind of scoreboard: a photograph of a brother and sister in their teens. They are young and smiling. The young man is wearing a graduation cap and gown, his sister is in a red dress.

Nick and Judy Lambis were Anderson's first patients at the 500-bed NIH clinical center. The siblings suffered from an inherited illness called beta-thalassemia, a lethal form of anemia that occurs when a defective hemoglobin gene is inherited. In the early 1970s, Anderson's blood research group used a number of innovative treatments to keep the Lambises alive for a dozen years, longer than similar patients had survived in the past.

Ultimately Nick and Judy died, unable to tolerate the accumulation of iron in their bodies caused by repeated transfusions. Anderson was not able to save them from their underlying problem, the defective gene. "If we could have done gene therapy in those days, Nick and Judy would be alive and healthy today," Anderson says.

But the techniques for shooting genes into the body didn't exist then, and the frustration of Nick's and Judy's deaths helped spur on the notions of gene therapy already crystallizing in Anderson's mind. He decided it was time to intensify his search for a way to fix diseases at their molecular roots.

Though no one could repair genes in people until the mid-1980s, there were several earlier discoveries that pointed the way. In the late 1950s, Stanfield Rogers, a physician and biochemist working at the Oak Ridge National Laboratory in Tennessee, had discovered that the Shope papilloma virus, which causes warts, carried a gene for producing an enzyme called arginase. When the virus infected skin cells, it turned the cells into tiny enzyme factories, and the enzyme lowered an infected person's blood levels of arginine, an amino acid.

In 1969, Rogers learned of two German sisters with extremely high blood levels of arginine that caused them to be retarded and suffer convulsions. He and the family's German doctors infected the children with the Shope virus in hopes of bringing down their arginine levels, but to no avail. Rogers was severely criticized by other physicians who felt his crude attempts at a gene therapy were premature, even unethical. He abandoned the effort, but his experience foreshadowed the use of viruses to transfer genes into human cells by about 15 years.

In the early 1970s, as Anderson began to consider molecular cures, no one had yet figured out how to engineer a virus to carry a specific gene. The gene engineering revolution was just getting started, and Anderson realized "that all the things we were doing {with hemoglobin research} were not relevant to gene therapy."

But he'd made up his mind what he wanted, and in 1974, in typical French Anderson fashion, underlined his decision dramatically: He gave his blood projects to his colleagues and surrendered most of his lab space so he could refocus on gene therapy. "I was regarded as two steps short of bizarre," Anderson says. "Nobody gives away three-fourths of their

program."

And so began a quirky period for Anderson. Methodically, he went back to basics, learning the new gene-manipulating techniques, searching for a way to use them to treat sick patients. He would try an approach, learn it and then rapidly abandon it when he concluded that it would not lead him to a genetic cure.

Eventually Anderson's personal calendar became a rainbow of yellows and reds. For distraction, he turned his attention to tae kwon do, a Korean martial art in which he has a fourth-degree black belt. He practiced longer and longer hours and began entering competitions. Yet no amount of chops and kicks could obliterate the truth: Because the technology was in its infancy, Anderson's quest for a way to do gene therapy was at a standstill.

In 1976, Anderson had discovered that Elaine Diacumakos, a lone researcher working in the back labs of Rockefeller University, was injecting bits of material directly into individual cells with extremely fine glass needles. Struggling alone with a microscope on a rickety lab bench, Anderson adapted Diacumakos's technique and injected an individual enzyme-producing gene into a cell that lacked that enzyme. In 1979, for the first time, Anderson "cured" a cell growing in the laboratory of its genetic defect by putting in a single copy of the normal gene.

The report caused a sensation, and the number of groups working with microinjection, as the technique was called, rapidly increased. But as the excitement of the initial discovery waned, Anderson realized he was no closer to his goal of human gene therapy. It would not be possible to microinject by hand the billions of cells that would be needed to treat a human patient.

On June 25, 1980, Anderson's 19th wedding anniversary, he chaired a scientific session on gene transfer and gene therapy at the Airlie Conference Center near Warrenton, but his heart wasn't in it. "I was so depressed I could hardly give my talk," Anderson says. "The technology was simply not available to do clinical gene therapy." He tossed and turned in his bed for a couple of hours, got up at 3 in the morning, went home and gave up on microinjection. But there was nothing else to try. His calendar began to turn completely red.

For the next two years, Anderson did little science at the lab bench. Instead, he spent more time on tae kwon do and practiced sports medicine, often acting as the official physician at international tae kwon do tournaments. 'I Will Do Whatever I Have To'

Despite his seeming disenchantment with the whole process, Anderson kept one eye on the scientific literature for hints of new lab procedures that might open a passageway to gene therapy. To many of the biologists struggling to make these molecular tools, Anderson's approach was opportunistic. He seemed to simply hang back, wait for new ideas to emerge and then seize on them to advance his goal instead of plunging into the lab to do the hard work of creating the tools himself.

In the early 1980s, several scientists who had been working with an unusual virus family called the retrovirus -- which includes the AIDS virus -- discovered that its genes could be scooped out and replaced with any other gene. What's more, when the retrovirus infects a cell, it doesn't kill it. Instead, the virus unpacks the genes it carries and permanently entwines them with the genes of the host cell. Scientists realized that the retrovirus might be able to carry genes into human cells for therapeutic purposes.

The idea caught Anderson's imagination, and in 1984 he set up a collaboration with Eli Gilboa, a retrovirus expert now at Memorial Sloan-Kettering Cancer Center in New York City, who genetically engineered several of the now-classic systems used to carry genes into cells. For Gilboa, it was an intoxicating time. "I was a very junior faculty member at Princeton," he says. Anderson "was a well-known researcher with a lot of resources who could help me survive in this difficult, competitive profession."

They had plenty of competition. A major group already had formed around Theodore Friedmann at the University of California at San Diego, and another around Stuart Orkin at Harvard and Richard Mulligan at the Massachusetts Institute of Technology. Both teams were well into the race to build better viruses to put genes into mice and show that the systems worked.

As Anderson started gearing up in 1984, he began working on a review article for Science magazine and interviewed all of the leaders in the field. Since the other scientists did not yet view Anderson as a competitor, they reported to him their up-to-the-minute results. The discussions convinced Anderson that retroviruses were the way to go and that, for a variety of technical reasons, the first disease likely to be attacked with gene therapy was a rare disorder often called ADA deficiency, a gene defect that damages the immune system. "I was convinced it was ADA," Anderson says, "but I wasn't in the ADA field."

Only three research teams in the world had isolated the ADA gene. Two of them -- one led by Orkin and one led by Dinka Valerio at the Institute of Applied Radiobiology and Immunology in Rijswijk, Netherlands -- refused to share their copies of the gene. So Anderson called the third team, led by John Hutton, now dean of the University of Cincinnati School of Medicine, to talk about Hutton's work for the Science paper. Hutton told Anderson about his ADA gene and said he didn't plan to use it for gene therapy.

"So I said, 'Will you send it to us?' " Anderson recalls.

Hutton said sure. A few days later, a white Styrofoam box packed with dry ice arrived from Cincinnati with the ADA gene inside. Anderson was ecstatic. continued on page 36 ANDERSON continued from page 26

"I couldn't believe that Hutton would just sort of hand it over," Anderson says. After thanking Hutton and offering a collaboration, Anderson knew that he had to call Orkin, who had been feeding Anderson the latest results from his lab. Anderson explained that Hutton had sent him the ADA gene and that Anderson was now going into direct competition with Orkin in ADA gene therapy research and he wouldn't be asking him any more questions.

Anderson remembers Orkin as being upset. "He spent two years cloning the gene," Anderson says, "and I got it in two days by making a phone call."

Orkin remembers the episode a little differently. "It is sort of in character for him to suggest that doing that {ADA gene therapy} experiment was so important in our minds, which it never really was," Orkin says. Today Orkin's group continues basic research with the ADA gene, and others, but concentrates more on what turns genes on and off, rather than searching for ways to cure ADA deficiency with gene therapy.

But if Orkin didn't care about the way Anderson conducted himself, other groups did. Anderson was accused of not doing his own work and merely taking advantage of the work of others.

"The opportunist charge is a valid charge," Anderson says. "Anything that will help accomplish the goal, I will do it, within a fairly rigid personal and ethical framework. I don't steal things. But whatever obstacle is in the way scientifically, politically, I will do whatever I have to do to get around it."

One of Anderson's more vocal critics, MIT's Richard Mulligan remains unimpressed. "The key question," Mulligan says, "is looking at the track record and the contributions to the field. If you look at his {Anderson's} contributions, in technological development, there is nothing there." Neutralizing the Critics

Even with the ADA gene in hand and the virus revealed as the way to get it into cells, Anderson and the other groups still had to figure out how to put the two together and show that gene therapy could work. But all the groups ran into technical problems while trying to get the transplanted genes to function in mice.

That is when Anderson decided to sidestep the mouse problem and shift his focus to monkeys through a collaboration with Gilboa, Blaese, Richard O'Reilly, chairman of pediatrics at Memorial Sloan-Kettering, and others. Some of the initial results were disappointing, but in the end, his group reported that the virus could carry the gene into the blood cells of monkeys.

Other scientists looked at the same results and reached a different conclusion. The gene's activity in the monkey's blood "was so small, so transient and at so trivial a level that one could argue the opposite," Orkin says. There were even disagreements among the collaborators. Says Gilboa: "We considered those studies as failures."

The problem was the stem cells. These are the bone marrow cells that give rise to all other blood cells. Anderson had hoped to put the genes into the stem cells, which would provide a permanent cure, but scientists have yet to find a way to selectively identify stem cells, let alone selectively infect them with a gene-carrying virus.

Anderson, however, looked on the bright side. The monkey experiments had problems, but they also showed the promise and the safety of the approach. None of the monkeys were harmed by the gene-carrying virus.

Even as the scientists haggled over the meanings of individual experiments, Anderson looked down the road and saw a new hurdle, a regulatory obstacle called the Recombinant DNA Advisory Committee, or RAC, and its human gene therapy subcommittee. The RAC is a group of experts that was first assembled by NIH in the 1970s to allay the fears of Congress and the public about the emerging techniques of genetic engineering. The gene therapy subcommittee was set up to regulate the application of gene technology to people.

The subcommittee was established after Martin Cline, a hematologist at the University of California at Los Angeles, tried using a crude form of gene therapy on two thalassemia patients in Israel and Italy. The treatment had no effect on the patients, but because the experiment was conducted without peer approval, Cline lost most of his federal research grants.

The RAC subcommittee is chaired by a thoughtful bioethicist named LeRoy Walters from Georgetown University's Kennedy Institute of Ethics. Walters, a mild-mannered minister used to long-winded academic debates, recognized that gene therapy would arrive sooner or later and that the best the subcommittee could do was build a consensus about the review process so the work could continue in a safe and orderly fashion. Walters and the group began by drafting a list of questions scientists would have to answer to receive the subcommittee's blessing.

Anderson helped the process along, giving advice, answering technical questions and, some say, positioning himself to put in the first application for gene therapy. On April 24, 1987, he submitted a preclinical document about the size of the D.C. phone book, basically a treatise stuffed with facts about how his group would do gene therapy with sick children. Politicians call such documents trial balloons.

Anderson also sent the document to his competitors, almost daring them to find something wrong. Mulligan and Orkin each got one. So did more sympathetic gene researchers, such as UCSD's Theodore Friedmann and Dusty Miller of the Fred Hutchinson Cancer Research Center in Seattle.

The reviews were blistering: All but one concluded that an ADA experiment in a sick child should not go forward. But Anderson proceeded unfazed.

"One approach is to ignore critics," says Arthur Nienhuis, chief of clinical hematology at the National Heart, Lung and Blood Institute and a longtime Anderson friend. "French draws them out. If you get people to commit to their criticism, then eventually you are going to neutralize them."

On November 20, 1987, Anderson sent a seven-page letter to the RAC and the subcommittee. Even as he agreed with the criticisms, he offered the group a middle course called a "limited protocol." In it, he argued, he would be justified in trying the experimental therapy on children who had no chance of recovery with emerging treatments, such as bone marrow transplantation or a new drug treatment called PEG-ADA.

In December 1987, the subcommittee met to go over Anderson's answers, and by the end of the meeting, the limited protocol proposal convinced the regulators that Anderson's idea was worth a try, though Mulligan and others still disagreed. "Scientifically, there was just no data to suggest that it would work," Mulligan says.

Buoyed by the subcommittee's encouragement, Anderson agreed to file an ADA proposal for the next meeting. But the proposal never came. Between the December meeting and the next time Anderson would come before the RAC subcommittee in the summer of 1988, the NCI's Blaese came up with a brand new idea.

Blaese, an expert in the immune system, was still struggling with the problems involved in getting the gene into the blood cells of monkeys. While looking over the data one day, it occurred to him that it would be much easier to put the ADA gene into T cells, the specific type of white blood cells that were killed by the gene defect. What's more, the world's expert in growing T cells, Steven A. Rosenberg, NCI's chief of surgery, was four floors below in NIH's clinical center.

Rosenberg was having troubles of his own. A novel experimental therapy he had developed for melanoma, an especially deadly type of skin cancer, wasn't working well enough to become a standard treatment. Rosenberg was surgically removing clumps of a patient's cancer and then, in the lab, growing the white blood cells found inside the tumor. Once there were billions of these white blood cells, apparently primed to attack the tumor, he would give them back to the patient to fight the cancer. About 10 percent of the time, the technique worked spectacularly well. Half the time, it worked a little bit, and the rest of the time the patient died. Rosenberg couldn't figure out what was going on because he could not track the cancer-killing white blood cells through the body.

Blaese realized that Anderson's team could put a bacterial gene into Rosenberg's cancer-killing white blood cells, tagging them so they would be easy to track in the body. This experiment had political as well as scientific advantages: It would be carried out in dying cancer patients trying a last-ditch experimental treatment instead of in children, and it wasn't actually therapy since it was just a gene-tracking experiment -- all of which reduced the pressure a little. It also put Rosenberg in the Anderson camp. Highly intelligent and personally imposing, Rosenberg was not afraid to push for what he wanted, even if it meant leaning on a federal committee.

The debate before the gene therapy subcommittee opened in June 1988, but the gene experts on the committee were not happy with the information initially submitted by Anderson's team and deferred a decision. The review battle ebbed and flowed until early 1989, when the NIH team won full approval.

At 10:47 a.m. on May 22, 1989, the first genetically engineered cells flowed into a 53-year-old man who had skin cancer. It wasn't gene therapy, but it was gene transfer. The experiment went uneventfully, with the marker gene causing no harm to the patient, though he eventually died from his disease.

After the cancer trial was launched, Anderson returned to his original idea: fixing the ADA gene in children. By February 1990, he had a plan in motion. The ADA project would be a Blaese and Anderson collaboration. Rosenberg, who cared only about cancer research, would apply for an experiment designed to use gene therapy to turn the white blood cells into delivery trucks that dumped toxins on the tumors.

The review process for the two experiments began in March 1990 and proceeded in parallel without the rancorous debate that characterized the first gene-tracking experiment. The human gene therapy subcommittee, and then the RAC, approved the experiments in July 1990.

Unresolved questions remained about the ADA experiment, but most of the experts concluded that Anderson and Blaese had reasonable answers. When the key subcommittee finally voted, it was 15-1 in favor, with only Richard Mulligan voting no.

Mulligan says he did not consider the experiment well-designed. He voted "no," he said, "to point out that the scientific standards were beginning to go downhill." The Juggler

Now that Anderson has pushed open the door on gene therapy, more than a dozen research groups around the world are hot on his heels, each seeking to test its own version of a genetic cure. Meanwhile, even as the members of the NIH gene team plan to add more children to the ADA study, they continue to give the 4-year-old girl monthly doses of gene-enhanced white blood cells to see if they produce a permanent cure. A preliminary report to the Food and Drug Administration in December was promising, but in mid-December there was a contamination problem with the growing cells that caused Anderson's team to skip a treatment.

Still, Anderson says, "the odds are really strong in our favor that we are helping this child."

The girl, of course, doesn't understand the significance of the things happening to her. "She just knows she is not well," says her father, "and that she is being treated by Dr. Anderson."

When she comes in for her next round of gene therapy, she will stay with her family at the Children's Inn on the NIH campus. Probably first thing in the morning, she and her parents will walk up the hill to the clinical center, where they'll be greeted by gene team members. The little girl will walk into the pediatric intensive care unit and lie down on a bed.

If she is true to character, she probably won't be smiling. But at some point, French Anderson will likely enter the room and, as he's done many times before, begin to juggle three spongy yellow balls, the kind given to blood donors to squeeze. "She is very shy," says her father. "He juggles balls to make her smile. And she smiles for him, which she does not do for many people."

It's an odd image, but an appropriate one. For if French Anderson can juggle enough balls -- medical, ethical and political -- he may yet win the race of his scientific life. Larry Thompson is the science editor of The Post's Health section.

"I couldn't believe that Hutton would just sort of hand it over," Anderson says. After thanking Hutton and offering a collaboration, Anderson knew that he had to call Orkin, who had been feeding Anderson the latest results from his lab. Anderson explained that Hutton had sent him the ADA gene and that Anderson was now going into direct competition with Orkin in ADA gene therapy research and he wouldn't be asking him any more

questions.

Anderson remembers Orkin as being upset. "He spent two years cloning the gene," Anderson says, "and I got it in two days by making a phone call."

Orkin remembers the episode a little differently. "It is sort of in character for him to suggest that doing that {ADA gene therapy} experiment was so important in our minds, which it never really was," Orkin says. Today Orkin's group continues basic research with the ADA gene, and others, but concentrates more on what turns genes on and off, rather than searching for ways to cure ADA deficiency with gene therapy.

But if Orkin didn't care about the way Anderson conducted himself, other groups did. Anderson was accused of not doing his own work and merely taking advantage of the work of others.

"The opportunist charge is a valid charge," Anderson says. "Anything that will help accomplish the goal, I will do it, within a fairly rigid personal and ethical framework. I don't steal things. But whatever obstacle is in the way scientifically, politically, I will do whatever I have to do to get around it."

One of Anderson's more vocal critics, MIT's Richard Mulligan remains unimpressed. "The key question," Mulligan says, "is looking at the track record and the contributions to the field. If you look at his {Anderson's} contributions, in technological development, there is nothing there." Neutralizing the Critics

Even with the ADA gene in hand and the virus revealed as the way to get it into cells, Anderson and the other groups still had to figure out how to put the two together and show that gene therapy could work. But all the groups ran into technical problems while trying to get the transplanted genes to function in mice.

That is when Anderson decided to sidestep the mouse problem and shift his focus to monkeys through a collaboration with Gilboa, Blaese, Richard O'Reilly, chairman of pediatrics at Memorial Sloan-Kettering, and others. Some of the initial results were disappointing, but in the end, his group reported that the virus could carry the gene into the blood cells of monkeys.

Other scientists looked at the same results and reached a different conclusion. The gene's activity in the monkey's blood "was so small, so transient and at so trivial a level that one could argue the opposite," Orkin says. There were even disagreements among the collaborators. Says Gilboa: "We considered those studies as failures."

The problem was the stem cells. These are the bone marrow cells that give rise to all other blood cells. Anderson had hoped to put the genes into the stem cells, which would provide a permanent cure, but scientists have yet to find a way to selectively identify stem cells, let alone selectively infect them with a gene-carrying virus.

Anderson, however, looked on the bright side. The monkey experiments had problems, but they also showed the promise and the safety of the approach. None of the monkeys were harmed by the gene-carrying virus.

Even as the scientists haggled over the meanings of individual experiments, Anderson looked down the road and saw a new hurdle, a regulatory obstacle called the Recombinant DNA Advisory Committee, or RAC, and its human gene therapy subcommittee. The RAC is a group of experts that was first assembled by NIH in the 1970s to allay the fears of Congress and the public about the emerging techniques of genetic engineering. The gene therapy subcommittee was set up to regulate the application of gene technology to people.

The subcommittee was established after Martin Cline, a hematologist at the University of California at Los Angeles, tried using a crude form of gene therapy on two thalassemia patients in Israel and Italy. The treatment had no effect on the patients, but because the experiment was conducted without peer approval, Cline lost most of his federal research grants.

The RAC subcommittee is chaired by a thoughtful bioethicist named LeRoy Walters from Georgetown University's Kennedy Institute of Ethics. Walters, a mild-mannered minister used to long-winded academic debates, recognized that gene therapy would arrive sooner or later and that the best the subcommittee could do was build a consensus about the review process so the work could continue in a safe and orderly fashion. Walters and the group began by drafting a list of questions scientists would have to answer to receive the subcommittee's blessing.

Anderson helped the process along, giving advice, answering technical questions and, some say, positioning himself to put in the first application for gene therapy. On April 24, 1987, he submitted a preclinical document about the size of the D.C. phone book, basically a treatise stuffed with facts about how his group would do gene therapy with sick children. Politicians call such documents trial balloons.

Anderson also sent the document to his competitors, almost daring them to find something wrong. Mulligan and Orkin each got one. So did more sympathetic gene researchers, such as UCSD's Theodore Friedmann and Dusty Miller of the Fred Hutchinson Cancer Research Center in Seattle.

The reviews were blistering: All but one concluded that an ADA experiment in a sick child should not go forward. But Anderson proceeded unfazed.

"One approach is to ignore critics," says Arthur Nienhuis, chief of clinical hematology at the National Heart, Lung and Blood Institute and a longtime Anderson friend. "French draws them out. If you get people to commit to their criticism, then eventually you are going to neutralize them."

On November 20, 1987, Anderson sent a seven-page letter to the RAC and the subcommittee. Even as he agreed with the criticisms, he offered the group a middle course called a "limited protocol." In it, he argued, he would be justified in trying the experimental therapy on children who had no chance of recovery with emerging treatments, such as bone marrow transplantation or a new drug treatment called PEG-ADA.

In December 1987, the subcommittee met to go over Anderson's answers, and by the end of the meeting, the limited protocol proposal convinced the regulators that Anderson's idea was worth a try, though Mulligan and others still disagreed. "Scientifically, there was just no data to suggest that it would work," Mulligan says.

Buoyed by the subcommittee's encouragement, Anderson agreed to file an ADA proposal for the next meeting. But the proposal never came. Between the December meeting and the next time Anderson would come before the RAC subcommittee in the summer of 1988, the NCI's Blaese came up with a brand new idea.

Blaese, an expert in the immune system, was still struggling with the problems involved in getting the gene into the blood cells of monkeys. While looking over the data one day, it occurred to him that it would be much easier to put the ADA gene into T cells, the specific type of white blood cells that were killed by the gene defect. What's more, the world's expert in growing T cells, Steven A. Rosenberg, NCI's chief of surgery, was four floors below in NIH's clinical center.

Rosenberg was having troubles of his own. A novel experimental therapy he had developed for melanoma, an especially deadly type of skin cancer, wasn't working well enough to become a standard treatment. Rosenberg was surgically removing clumps of a patient's cancer and then, in the lab, growing the white blood cells found inside the tumor. Once there were billions of these white blood cells, apparently primed to attack the tumor, he would give them back to the patient to fight the cancer. About 10 percent of the time, the technique worked spectacularly well. Half the time, it worked a little bit, and the rest of the time the patient died. Rosenberg couldn't figure out what was going on because he could not track the cancer-killing white blood cells through the body.

Blaese realized that Anderson's team could put a bacterial gene into Rosenberg's cancer-killing white blood cells, tagging them so they would be easy to track in the body. This experiment had political as well as scientific advantages: It would be carried out in dying cancer patients trying a last-ditch experimental treatment instead of in children, and it wasn't actually therapy since it was just a gene-tracking experiment -- all of which reduced the pressure a little. It also put Rosenberg in the Anderson camp. Highly intelligent and personally imposing, Rosenberg was not afraid to push for what he wanted, even if it meant leaning on a federal committee.

The debate before the gene therapy subcommittee opened in June 1988, but the gene experts on the committee were not happy with the information initially submitted by Anderson's team and deferred a decision. The review battle ebbed and flowed until early 1989, when the NIH team won full approval.

At 10:47 a.m. on May 22, 1989, the first genetically engineered cells flowed into a 53-year-old man who had skin cancer. It wasn't gene therapy, but it was gene transfer. The experiment went uneventfully, with the marker gene causing no harm to the patient, though he eventually died from his disease.

After the cancer trial was launched, Anderson returned to his original idea: fixing the ADA gene in children. By February 1990, he had a plan in motion. The ADA project would be a Blaese and Anderson collaboration. Rosenberg, who cared only about cancer research, would apply for an experiment designed to use gene therapy to turn the white blood cells into delivery trucks that dumped toxins on the tumors.

The review process for the two experiments began in March 1990 and proceeded in parallel without the rancorous debate that characterized the first gene-tracking experiment. The human gene therapy subcommittee, and then the RAC, approved the experiments in July 1990.

Unresolved questions remained about the ADA experiment, but most of the experts concluded that Anderson and Blaese had reasonable answers. When the key subcommittee finally voted, it was 15-1

in favor, with only Richard Mulligan voting no.

Mulligan says he did not consider the experiment well-designed. He voted "no," he said, "to point out that the scientific standards were beginning to go downhill." The Juggler

Now that Anderson has pushed open the door on gene therapy, more than a dozen research groups around the world are hot on his heels, each seeking to test its own version of a genetic cure. Meanwhile, even as the members of the NIH gene team plan to add more children to the ADA study, they continue to give the 4-year-old girl monthly doses of gene-enhanced white blood cells to see if they produce a permanent cure. A preliminary report to the Food and Drug Administration in December was promising, but in mid-December there was a contamination problem with the growing cells that caused Anderson's team to skip a

treatment.

Still, Anderson says, "the odds are really strong in our favor that we are helping this child."

The girl, of course, doesn't understand the significance of the things happening to her. "She just knows she is not well," says her father, "and that she is being treated by Dr. Anderson."

When she comes in for her next round of gene therapy, she will stay with her family at the Children's Inn on the NIH campus. Probably first thing in the morning, she and her parents will walk up the hill to the clinical center, where they'll be greeted by gene team members. The little girl will walk into the pediatric intensive care unit and lie down on a bed.

If she is true to character, she probably won't be smiling. But at some point, French Anderson will likely enter the room and, as he's done many times before, begin to juggle three spongy yellow balls, the kind given to blood donors to squeeze. "She is very shy," says her father. "He juggles balls to make her smile. And she smiles for him, which she does not do for many people."

It's an odd image, but an appropriate one. For if French Anderson can juggle enough balls -- medical, ethical and political -- he may yet win the race of his scientific life.

Larry Thompson is the science editor of The Post's Health section.