"HOW ARE YOU DOING, KID?" THE DOCTOR ASKS HIS young patient, hugging and tickling her and trying to make her giggle. The girl looks up at him with huge dark eyes, but since a stranger is in the room today she is too shy to smile. She is a quiet 4-year-old whose solemn gaze can be a bit unnerving. As she drinks chocolate milk and zaps the hospital television with the remote-control device, she seems oblivious to the fact that she is making medical history.

It's a bright blue day, and the child is back at the National Institutes of Health in Bethesda, Md., for another monthly infusion of genetically engineered blood cells. She has adenosine deaminase (ADA) deficiency, a rare inherited condition that makes her unable to manufacture ADA, an enzyme crucial to the immune system. Without ADA, she is as vulnerable to infection as a person with AIDS.

The Band-Aid on her left hand is the only sign that the child, whose family has requested anonymity, is going through any medical procedure at all, much less a trailblazing one. But the doctor hugging her is acutely aware of the significance of every small gesture. Infusing this little girl with the genes she is missing has made the physician, Dr. W. French Anderson, 54, one of the world's first genetic surgeons.

This Thursday, if all goes as planned, the child will be back in Bethesda for her sixth transfusion of genetically engineered cells. The following day, Anderson will give an update of her status before the Human Gene Therapy Subcommittee at the National Institutes of Health, the official Government body that oversees his research. After months of guarded optimism, the physicians caring for her are finally ready to claim the child has been helped. Anderson, chief of molecular hematology at the National Heart, Lung and Blood Institute, will announce that "gene therapy has worked."

THE ERA OF GENE THERAPY OFFICIALLY BEGAN ON Sept. 14, 1990. Droopy-eyed from a night of worried wakefulness, Anderson joined two colleagues from the National Cancer Institute, Drs. R. Michael Blaese and Kenneth W. Culver, in a medical procedure that on the surface looked no more complicated than an ordinary blood transfusion. Over the course of about 30 minutes, the 4-year-old received one billion of her own white blood cells, which had been treated to contain the ADA gene that she was missing -- the absence of which led to her rare condition. An hour later she was wandering around the hospital playroom and eating M&M's.

An important second step occurred on Jan. 29, when two dying patients -- a 29-year-old woman and a 42-year-old man -- became the first to try gene therapy as a way to fight cancer. (Another ADA deficiency patient, a 9-year-old girl, began treatment two days later.) If genes prove useful for cancer treatment, the potential applications for this technique will go far beyond those rare disorders caused by a single defective gene -- disorders such as hemophilia, sickle-cell anemia, cystic fibrosis, muscular dystrophy -- to include conditions that are not strictly genetic at all, such as heart disease and AIDS.

How genes have been manipulated to help these first four patients is largely a story of scientific ingenuity. After years of peering into cells and figuring out how they work, scientists are now able to arrange and rearrange the basic building blocks of life, to maneuver them into more functional configurations. But it's also a story about politics and people. The technology of genetic engineering has been subject to an unprecedented level of public scrutiny because it involves tinkering with the chemicals that define us as human beings. At each stage of a research plan, the molecular geneticist is called before committees of ethicists, physicians and other scientists and forced to defend his work. The scientist who masters this process is the one whose work will be approved.

That is why French Anderson has excelled -- not only because he knows the science, but because he knows all the political players and all the regulatory hoops. He spends all his time thinking about his next move; to Anderson, the whole thing is like a gigantic game of chess. "This is what I do," he says. "I eat and sleep and breathe gene therapy 24 hours a day."

As the nation's leading genetic surgeon, Anderson has been called upon to address many of the fears and uncertainties that surround this brave new technology. Did he rush ahead too early with an experiment before it was fit for humans, just so he could say he did it first? Did he start with the wrong patient, since a less extreme drug therapy for the child's condition already exists? Is he leading us down a slippery slope toward a new era of eugenics, when scientists try to manipulate genes to create a disease-free Master Race?

Anderson answers questions like these with a strained patience. "Of equal importance to having the scientific community accept gene therapy," he says, "is having the public accept it." Like any visionary with a radical new idea, Anderson has applied mule-headed determination to force a sluggish society into its rendezvous with the future. But in a field as technical as genetics, a self-professed zealot like Anderson is not simply a catalyst for change. He is also called upon to summarize for the rest of us its potential benefits and risks.

It's not an easy role. Try as he might to explain gene therapy dispassionately to the people who must judge him now -- his peers reviewing his proposals, the politicians considering laws to restrict genetic tinkering, the patients on whom he wants to experiment -- Anderson's bias is obvious; he can barely conceal his enthusiasm. When he talks about human gene therapy, the trim, silver-haired scientist in the white lab coat starts bubbling over like a little boy.

The theory behind gene therapy is simple: treat a patient whose cells lack a particular gene by giving the missing gene to the cells. But it's harder than it sounds.

The first problem is, how do you get the gene into the cell? The cell has an elaborate defense mechanism, encased as it is in a cell membrane that is all but impenetrable. Fifteen years ago, scientists tried altering the cell membrane with chemicals, electricity, even brute force. Some reasoned that one way to get genes into a cell nucleus would be by mimicking the methods used by nature's own best invader, the virus. In the early 1980's, a young researcher named Richard C. Mulligan, now at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology, developed an efficient way to render a virus noninfectious -- by removing most of its own genes -- and to splice into it the genes he wanted to transport into human cells. The virus, although now harmless, still retained its ability to get inside the cell and to integrate its genetic cargo into the cell's genes.

Mulligan started work on a class of viruses called retroviruses, which are now the most popular tools in gene manipulation. All retroviruses -- the most notorious of which is the AIDS virus -- have in common the ability to penetrate the cell nucleus and insert retroviral DNA into the cell's own chromosomes. They are smaller than most other viruses and, unlike most other viruses, they usually do not kill the cells they infect.

After years of lab manipulations -- in which the virus's inner workings were stripped away bit by bit -- the retroviruses now used in gene therapy have been reduced to shells for carrying foreign genes and getting them into the cell's nucleus. They are called retroviral vectors, from the Latin "to carry." They are little more than stripped-down conveyor belts for genes.

The retroviral vector has the desired gene spliced directly into its nucleus. Then begins the process known as transduction -- Anderson rejects the more common term, infection, as "too emotive" -- in which the cells designated to receive the gene are mixed with the gene-boosted vector in a laboratory culture dish. For most of the cells that are the targets of the retroviral vector, such as the white blood cells called lymphocytes, it takes no more than a few hours for the viruses to get inside.

The choice of target cell is an important one in gene therapy. For the patients treated so far, only lymphocytes have been used. But for a long time, scientists expected that the first target cells would be the stem cells, cells of the bone marrow that mature into lymphocytes.

Unlike lymphocytes, which have a life span of a few months, stem cells last forever. They give rise not only to lymphocytes but to all the other cells of the circulatory system: red blood cells, plasma cells, macrophages. It was thought that insertion of a needed gene into a stem cell would guarantee that all cells derived from that stem cell for the rest of the patient's life would have the new gene, too.

But stem cells turned out to be wily targets. During the mid-1980's, stem cells proved to be all but impossible to find, much less to transduce. Less than one bone marrow cell in 10,000 is a stem cell, and there was no good way to separate stem cells from the others. In addition, transduction occurs only in cells that are dividing, which stem cells rarely do. The odds against a retroviral vector actually getting through to a stem cell seemed to be enormous.

With the science at an impasse, Anderson decided to concentrate on politics. Even though he had no precise plan for inserting a gene into a human being, he wanted practice dealing with the regulatory machinery already in place to oversee gene therapy once it became feasible. This is where the politics of regulation comes in -- where French Anderson removes his lab coat and dons the three-piece suit of the Government bureaucrat.

On the wall of Anderson's cramped office at the National Heart, Lung and Blood Institute are six long rows of framed black-and-white glossy photographs, signed the way celebrities' are, of the people who have worked in his laboratory since 1968. (One framed photo is of a rhesus monkey; a student put it there years ago as a joke.) The young men and women in the photographs came through the lab as technicians, graduate students and postdoctoral fellows, and have risen over the years to senior positions in industry and academia.

Other scientists decorate their offices with photos of themselves shaking hands with famous people. Anderson could have done that, too. He has become a familiar figure on Capitol Hill, on a first-name basis with the lawmakers who will help determine the future of gene therapy. His Congressional appearances are featured regularly on television news shows, and he's so hounded by reporters that he recently asked his agency's press officer to stop granting interviews for a while. Last October, after declining two previous invitations, he and his wife finally went to their first state dinner at the White House.

It is of symbolic importance that Anderson chooses to display photographs of his lab workers rather than of himself rubbing shoulders with the rich and famous. To him, science is a collective enterprise, and any of the success he's had must be shared with those people in his photo gallery. But behind the scenes, rubbing shoulders with powerful nonscientists is exactly what he has learned to do. In fact, his ability to rub shoulders effectively might be why gene therapy was ever able to get off the ground.

"If there hadn't been someone as conscientious and cooperative as French moving this along," says Dr. Henry Miller, director of the office of biotechnology for the Food and Drug Administration, "this line of research might not have taken place at all." Miller, whose agency must join the National Institutes of Health in approving all federally funded human gene therapy procedures, uses words like "saintly" and "fanatical" in describing Anderson. Alexander Capron, a member of the Human Gene Therapy Subcommittee -- the first of several national review bodies that now must approve every gene-transfer experiment involving human beings -- agrees that Anderson almost single-handedly moved gene therapy through the regulatory labyrinth to the point of acceptability. "For a serious scientist to have mastered the bureaucratic review process is extremely unusual," says Capron, co-director of the Pacific Center for Health Policy and Ethics at the University of Southern California.

To Anderson, though, there is nothing remarkable about this skill; it is all part of the elaborate chess match. Since he was 16 years old, long before he or anyone else really understood what genes do, Anderson was determined to become a genetic surgeon. In high-school in Tulsa, Okla., he was such a brilliant student that his teachers took his test scores off the grading curve so his classmates wouldn't hate him. When he applied to Harvard in 1953 -- the same year that James Watson and Francis Crick discovered the structure of DNA -- he already knew what his life's work would be. "I want to understand disease at the molecular level," he wrote on his application.

Along the way, Anderson worked beside some leading lights in molecular biology: with Francis Crick himself, and with Marshall Nirenberg, who helped decipher the genetic code. Now Anderson sees his scientific role in part to serve as a mentor for the next generation of molecular geneticists. The only time he travels these days is to visit labs where scientists are preparing research proposals that are headed for Federal review, trying to guide them through the regulatory hurdles that he has already faced.

At home, Anderson and his wife, Kathryn -- vice chairman of surgery at Children's National Medical Center in Washington -- lead a quiet life. The last play they saw together was in 1967; the last movie they saw was "Amadeus." They have no children, having decided early on to devote themselves to their careers. The only nonscience activity Anderson takes any pleasure in is tae kwon do, a Korean martial art in which he holds a black belt. In 1976, he was the official physician for the United States team at the Olympics in Seoul, and he still teaches a weekly class on the N.I.H. campus.

Dealing with people is a crucial part of Anderson's job, but it's not a skill that comes naturally to him. He describes himself as a "weird" child, who at the age of 8 or 9 preferred reading college textbooks to playing with other kids. "I didn't see the point," he says. "Everyone else was stupid."

When Anderson was in fifth grade, his parents and teachers insisted that he try harder at making friends. So he did. He went into the project wholeheartedly, even switching from his first name, William, to his middle, French, as a way of reinventing himself. By the seventh grade, he was the most popular boy in school and was elected the president of his class.

The ability he cultivated to relate to people has had a political impact. Some of his colleagues say it was his personal shepherding of his proposals through the Human Gene Therapy Subcommittee of the National Institutes of Health that allowed the nation's first experiments in this new field to proceed. Anderson has been directly involved in all three of the experiments approved to date: a gene-transfer experiment involving cancer patients, the gene therapy experiment for ADA deficiency and the gene therapy experiment for malignant melanoma.

The political maneuvering began in March 1988, when Anderson and Michael Blaese approached Dr. Steven A. Rosenberg of the National Cancer Institute with an idea they thought would help them all -- and ultimately further the cause of gene therapy. They wanted to piggyback gene-transfer technology onto Rosenberg's successful anticancer techniques. They wanted, as Anderson puts it, "to start with a target cell we knew we could hit" -- the cells that Rosenberg was working with.

Rosenberg's name was already a household word because of his widely publicized success with "adoptive immunotherapy," a cancer treatment that involves culturing huge quantities of a patient's own natural cancer-fighting cells -- tumor-infiltrating lymphocytes, or TIL cells. Anderson and Blaese's idea was to add a genetically engineered virus to the TIL cells before giving them back to patients. The project would begin by simply tacking on a gene that would tag the TIL cells, to help trace their progress through the body. This would be followed by insertion of a therapeutic anticancer gene.

In the three years since then, just about everything has gone according to plan, though sometimes at a slower pace than Anderson had anticipated. In May 1989, the three scientists treated the first of 10 cancer patients with gene-engineered TIL cells -- the gene-tracing experiment. Then, in September 1990, Anderson, Blaese and Culver began the ADA deficiency experiment -- the first time genes were transferred into a human being for a therapeutic, rather than purely informational, purpose. And in January 1991, gene therapy was used for the first time to treat cancer, when two melanoma patients received immune-system cells that had been beefed up with the gene for a potent anticancer substance called tumor necrosis factor. The same month, the 9-year-old girl with ADA deficiency also started treatment. On April 15, she is scheduled to receive her third infusion, but it will be months before anyone knows if it's worked.

The treatment of human beings is, as Anderson is quick to acknowledge, the ultimate test. "If we goof up now," he says, "all our critics will have a field day."

THOSE CRITICS HAVE been waiting in the wings for over a decade, ever since early efforts at treatment -- conducted without official sanction -- erupted into an international scandal.

Dr. Martin Cline, at the time a leading molecular geneticist at the University of California at Los Angeles, applied for permission to insert new genes into patients with beta-thalassemia, a blood disorder whose exact genetic origin was unknown at the time. U.C.L.A. denied permission, saying the animal data were insufficient to justify trying it on human beings. Without informing anyone, Cline went abroad to do the human experiments in Italy and Israel. When his action came to light, Cline was sternly disciplined by the National Institutes of Health and by U.C.L.A.

After the Cline debacle, "people were gun-shy," Anderson recalls. That is why elaborate Federal review procedures, concluding with review by the directors of the National Institutes of Health and the Food and Drug Administration, were put into place: to assure the public that it couldn't happen again.

"The public concern over gene therapy has always been over the issue of playing God," says Alexander Capron. "The fear was that you start by treating a few genetic diseases, but once you have the technology you move on to altering human capabilities and producing inheritable changes."

As a result, almost everyone involved in gene therapy wants to limit its use to the correction of genetic flaws -- and to prohibit experiments involving insertion of new and supposedly better genetic traits. Anderson recoils at the suggestion that this technology could be used for what is called "enhancement engineering," making an individual taller or smarter or blonder. He thinks the procedures now in place to limit which experiments can be done -- at least those using Federal funds -- are sufficient to keep enhancement engineering at bay.

Many critics, including some researchers, want to limit gene therapy even more strictly, to the treatment only of the somatic (body) cells of individuals currently suffering from genetic disease. They want to prohibit manipulations of an individual's germ cells (eggs or sperm), including experiments designed to prevent genetic disease in succeeding generations.

Though germ-cell gene therapy might seem like the ultimate in preventive medicine, critics focus on its darker side. It would permanently change the gene pool of the species -- no doubt with some totally unpredictable results. "Are we wise enough to ignore millions of years of evolution, which has brought us to the point of having these recessive traits?" asks Jeremy Rifkin, president of the Foundation on Economic Trends in Washington and the most visible critic of gene therapy.

By eliminating all problem genes, Rifkin says, scientists may unwittingly eliminate some traits that are actually beneficial. The recessive gene for sickle-cell anemia, for instance, is known to cause problems only for people who inherit it from both parents. A single sickle-cell gene has a surprise benefit: it conveys a resistance to malaria. Similar benefits may account for the existence of other recessive genes as well, which to the untutored eye seem only detrimental.

A few critics think it's too early to begin gene therapy. Richard Mulligan of the Whitehead Institute is the most prominent among them. Mulligan also sits on the Human Gene Therapy Subcommittee, and is the only member to have voted against Anderson's ADA deficiency experiment. He calls it "technically and scientifically a bad idea."

According to Mulligan, Anderson decided to transduce the patient's lymphocytes instead of stem cells for primarily "tactical" reasons, because the subcommittee had already approved a gene-transfer experiment using lymphocytes. But, he says, the only real way to cure ADA deficiency is by transducing bone marrow stem cells. By switching to lymphocytes, Mulligan says, Anderson compromised his patient's chance of a cure. "There's no way they'll ever get the results they say they'll get," he says.

Anderson's supporters accuse Mulligan of professional jealousy. He works in the same small field of research that Anderson does; maybe he wishes he had been first. Mulligan laughs at the suggestion. "I don't feel as though I'm a scientific competitor," he says. "The joke going around my laboratory is that French isn't even the first to do gene therapy; Martin Cline was the first. To be the second and to fail is no big deal. I'd rather be the fifth or sixth or seventh, and be the first to succeed."

CONTEMPORARY scientists not only have to deal with the gritty realities of public debate and bureaucratic regulation, many of them are also getting involved in a world that is even more alien to them than politics: the world of business.

Anderson is now negotiating that hazardous terrain. Two years ago, he entered into a formal affiliation with a new biotechnology company, [Genetic Therapy Inc.] -- familiarly known as G.T.I. -- that had been started by [Wallace Herbert Steinberg (born 1934)], a venture capitalist from Edison, N.J. This type of public-private partnership between Government scientists and private corporations had been encouraged as far back as 1986, when Congress passed the Technology Transfer Act to facilitate the marketing of Government inventions. At the time, the feeling in Congress was that many potentially useful discoveries were languishing in Government labs because no one could make a profit from a Government-held patent. Without a profit motive, what company would be willing to invest the millions usually required to bring a new invention to the marketplace?

The solution was the CRADA (an acronym for Cooperative Research and Development Agreement), which allows companies to hold licensing rights to patents held by Government agencies. Anderson was the first scientist at the National Institutes of Health to have a major CRADA with a private company; now, more than 150 others do as well.

[Genetic Therapy Inc.] has its headquarters 15 minutes from Bethesda, in a newly remodeled building with spacious laboratories housing 35 scientists. Anderson spends every Wednesday there, meeting with G.T.I. scientists, executives and board members. Someday this affiliation could make him, if not a rich man, at least a more financially secure one. Government regulations prohibit him from owning stock in the company, or from serving as a paid consultant or a corporate officer. But under the CRADA, Anderson can receive 15 percent of the royalties on patents he co-owns with Genetic Therapy, up to $100,000 a year.

Such financial payoffs are all far in the future, though. To date, the company has provided Anderson with little more than chocolate doughnuts and tea for his Wednesday meetings. (Recently Anderson decided even that looked bad, and started paying, retroactively, for his own doughnuts.) In November, the company wrote its first check to the Government under the CRADA agreement, in the amount of $10,000 for exclusive licensing rights on three patents the company will co-own with the National Institutes of Health. Anderson's share on that payment came to about $400.

The company's value will no doubt increase enormously if it can meet the next challenge to gene therapy: building a better vector. G.T.I. scientists are now working to develop an injectable viral vector, a sort of "smart bomb" for gene delivery that heads straight to the spot on the chromosome where the new gene belongs.

"When you have to remove cells and treat them in the lab and return them to the patient," Anderson says, "you can only do gene therapy at a handful of medical centers. The ideal will be when a nurse can grab a syringe down from the shelf and inject genes into whoever needs them."

Once an injectable vector is perfected, says Anderson, the possibilities for gene therapy expand. He and other molecular geneticists are conducting experiments that would broaden its use beyond the treatment of genetic diseases to the treatment of some of the nation's leading killers. Among them:

• Cancer -- Anderson envisions a time when scientists will use a "suicide gene" to make cancer cells more responsive to treatment. If a gene for drug sensitivity can be inserted into tumor cells, then exposure to that drug may cause the gene-engineered cells selectively to self-destruct.

• Cardiovascular disease -- Current surgical treatment of blocked blood vessels may involve insertion of a tiny stent, a piece of metal that physically holds the vessel open. An alternative treatment is bypass surgery, in which a new vessel, known as a vascular graft, is inserted to replace a clogged one. But in a significant number of both these implants, blood clots eventually develop. Scientists in Anderson's lab are trying to coat both types of implants with cells containing the gene for TPA, a natural clot dissolver, to avoid this complication of surgery.

• High cholesterol -- Anderson's colleagues are also trying to develop neo-organs, structures made of artificial material that can receive gene-engineered cells. Among the most promising are neo-organs placed near the liver, into which are inserted liver cells containing a gene that attracts cholesterol. Connected to the liver by a network of new blood vessels, this neo-organ could pull excess cholesterol from the bloodstream -- where it does its cardiovascular damage -- into the liver for excretion.

• AIDS -- Anderson is collaborating with Dr. Robert C. Gallo of the National Cancer Institute to treat AIDS patients with the gene for soluble CD4, a protein that lies on the surface of the lymphocytes. The AIDS virus ordinarily attaches to the CD4 protein as a first step in its destruction of the immune system cells. If enough mock CD4 can be kept circulating in the bloodstream, these decoys may snare the AIDS virus and keep it from getting to the lymphocytes at all.

It is too early to tell whether the first gene therapy patient is "cured." Indeed, "cure" isn't even the goal of gene therapy for this child, or for the other ADA deficiency patient. At best, Anderson expects to put them on the schedule of gene-boosted infusions every few months. Since the experiments began, both children have continued to receive standard care for ADA deficiency: weekly injections of ADA itself, which generally keeps the immune system functioning at about half its normal level. Ultimately, if all goes well, the girls will be able to rely on gene therapy alone and eliminate the weekly shots.

The first patient's father says she's smiling more. This winter, her whole family came down with the flu -- and she was the first to recover. Immune function test results are so encouraging that Anderson believes all these improvements can be traced to the gene therapy. "She has developed antibodies she never had before," Anderson says. "She now has normal, functioning immune cells -- and they are producing human ADA." The number of such cells in the child's bloodstream is far greater than the number of gene-corrected cells she has been given in the last six months. In other words, the ADA-boosted lymphocytes are producing more lymphocytes, and they are functioning normally.

In the spring, Anderson's team will test the child's immune function by giving her some ordinary vaccinations. She has received vaccines before, but her immune system has failed to respond. As for the two cancer patients, they are receiving only very low doses of TNF-producing cells, which are increased incrementally in their twice-weekly infusions. Anderson had not expected to see any improvement yet, and he has not.

ON THE WALL IN FRENCH ANDERSON's all-purpose meeting room, crammed with a photocopier, fax, computer, coffee maker, journal collection and conference table, is a framed quotation of some lines from "Hamlet": Diseases desperate grown By desperate appliance are reliev'd, Or not at all.

The definition of "desperate" is a matter of opinion. One thing is sure: Anderson has proved himself willing to devote every waking hour to figuring out how to reverse genetic disease, no matter how "desperate" it seems.

"Should we have waited?" he asks rhetorically about his ADA deficiency experiment. He says it will be years before people can say, in hindsight, whether this was the right time or the wrong time to begin. "If Sept. 14 marks the beginning of successful gene therapy treatments, then we were right not to delay. If patients are harmed and a public backlash occurs, then we were wrong. I believe that we were right."

A correction was made on March 31, 1991: An article in The Times Magazine today about Dr. W. French Anderson, a genetic surgeon, misstates the date of the Olympics in Seoul, South Korea. They were held in 1988.

[...]

But the therapy cannot prevent the coma that is often the first sign of OTC and ravages the affected infant. By the time Batshaw joined the faculty at Penn in 1988, he was dreaming of a cure -- gene therapy. Patients were dreaming, too, says Tish Simon, former co-president of the National Urea Cycle Disorders Foundation, whose son died of OTC deficiency three years ago. ''All of us saw gene therapy as the hope for the future,'' Simon says. ''And certainly, if anybody was going to do it, it had to be Mark Batshaw.''

Gene therapy became a reality on Sept. 14, 1990, in a hospital room at the National Institutes of Health, in Bethesda, Md., when a 4-year-old girl with a severe immune-system deficiency received a 30-minute infusion of white blood cells that had been engineered to contain copies of the gene she lacked. Rarely in modern medicine has an experiment been filled with so much hope; news of the treatment ricocheted off front pages around the world. The scientist who conducted it, [Dr. William French Anderson (born 1936)], quickly became known as the father of gene therapy. ''We had got ourselves all hyped up,'' Anderson now admits, ''thinking there would be rapid, quick, easy, early cures.''

Among those keeping a close eye on [Dr. William French Anderson (born 1936)] debut was Jim Wilson, a square-jawed, sandy-haired Midwesterner who decided to follow his father's footsteps in medicine when he realized he wasn't going to make it in football. As a graduate student in biological chemistry, Wilson had taken a keen interest in rare genetic diseases. ''All I did,'' he says, ''was dream about gene therapy.''

Today, as director of the Institute for Human Gene Therapy at the University of Pennsylvania, Wilson is in an excellent position to make that dream a reality. Headquartered in a century-old building amid the leafy maple trees and brick sidewalks of the picturesque Penn campus, the six-year-old institute, with 250 employees, state-of-the-art laboratories and a $25 million annual budget, is the largest academic gene-therapy program in the nation. In a field rife with big egos, Wilson is regarded as first-rate. ''Present company excluded,'' [Dr. William French Anderson (born 1936)] says, ''he's the best person in the field.''

Batshaw was banging on Wilson's door even before Wilson arrived at Penn in March 1993, and within a month they were collaborating on studies of OTC-deficient mice. Their first task was to develop a vector. Adenovirus seemed a logical choice.

[...]

IT has been nine years since Dr. W. French Anderson performed the first gene therapy experiment, on a 4-year-old girl with an immune system disorder. In those days, the idea that diseases could be treated, or even cured, by infusing patients with healthy DNA was the bright light of medicine, offering hope to patients and the promise of profits to investors. But the light has dimmed considerably.

In September, an 18-year-old Arizona man, Jesse Gelsinger, died in an experiment at the University of Pennsylvania after receiving a dose of corrective genes encased in adenovirus, a weakened cold virus; his was the first death directly attributed to gene therapy. Then came word that other scientists had failed to report safety data to a National Institutes of Health oversight committee.

The committee met last week to review Mr. Gelsinger's death and the safety of adenovirus, and to debate a proposal opposed by the biotechnology industry that would force researchers to disclose all patient deaths, whether or not related to gene therapy.

But not all the headlines have been gloomy. Avigen, a biotechnology company in Alameda, Calif., has reported good results using gene therapy to treat a form of hemophilia.

Last week, Dr. Anderson, director of the gene therapy program at the University of Southern California and the founder of a pioneering gene therapy company now owned by Novartis, discussed these developments and the prospects for commercial gene therapy. Here are excerpts from the conversation. 

• Q. What impact has the death at Penn had on interest in gene therapy?

  • • A. I don't think it has affected it much. The whole field of biotech has had a bit of hard times, but gene therapy particularly, because the fact is there haven't been any products. We are probably still a minimum of three years away from anybody having a product out there. This definitely throws some cold water on investment.

• Q. Why are marketable products taking so long to emerge?

  • • A. The human body has much better defenses against manipulating its DNA than we thought it had. We can do miracles in a tissue culture dish. You can cure cancer in mice with gene therapy. But then you go to the human body, and we face three major problems. The first is, how do you get a gene into enough cells to make a difference? The second is the body's defense mechanisms, which basically shut down the genes once they get there. And then the third is figuring out how to get genes into cells at the right place, at the right time, making the right amount of product to treat a given disease.

• Q. In 1995, you sold Genetic Therapy, the company you founded, to Sandoz, now part of Novartis. Now there are reports that Novartis is scaling back, and has abandoned its largest study, for treatment of glioblastoma, a brain cancer. What happened?

  • • A. We still don't have a product.  The glioblastoma data hasn't been made public yet, but it's so widespread on the grapevine that it isn't confidential anymore. The survival curve between those who received the gene therapy and those who did not was basically no different. Even though individual patients were helped, and there are patients alive now who would have been dead, it was not a product that a major pharmaceutical company would want to go forward with.

• Q. In retrospect, did Novartis pay too much for your company?

  • • A. I think the jury is still out. The total investment was around $315 million. At the time they bought it, I got annoyed by some people at Sandoz. They told us that the things we thought were so exciting would probably not work right away. So, Sandoz, they had their heads on right -- they bought it as a long-term investment.  Now, if it takes another 10 years before gene therapy comes up with a major product, then they will have paid too much.

• Q. Look into your crystal ball. Is the business outlook for gene therapy still exciting?

  • • A. All around the world, there is progress being made. The first indications that we might be tipping over the hump are in cardiovascular disease, cancer, AIDS and hemophilia. We are seeing signs that there are potential products, real products. Over the next two or three years, if we don't hit another brick wall, and several of these products get into Phase 3 trials and things look encouraging, the business outlook for gene therapy will brighten again and money will flow back into the field.