Gene Therapy Race : Egos, Prizes on the Line for Scientists

Times Staff Writer

Late in the morning last Monday, two scientists faced each other, one sitting, one standing, in a small conference room here at the National Institutes of Health.

W. French Anderson, 50, director of the laboratory of molecular hematology at the National Heart, Lung and Blood Institute, had been explaining to an NIH advisory committee why he wanted to make the first authorized attempt to change a sick human being's genes. Now he was leaning back in his chair, fielding questions from a committee member, Richard C. Mulligan, 33, an MIT associate professor and lab director at the Whitehead Institute for Biomedical Research in Cambridge.

"I am curious, French," Mulligan said, pacing before a chalkboard. "Do you think it would work if you tried it?"

Anderson chuckled.

"That's the question," he said. "Do we think that it will work? We've asked that ourselves during pizza sessions many times. An even better question is, if it was my own child--"

"Let's keep it to the--" Mulligan began to interrupt.

"No one really knows," Anderson quickly replied.

In that momentary exchange lies a story about science and scientists, politics and ambition, ethics and philosophy.

While most of his colleagues and competitors believe gene therapy is still years in the future, Anderson wants to begin experiments with human beings. His campaign is forcing consideration of questions long simmering in the complicated, hybrid world of scientists, ethicists, lawyers and government regulators.

When is the right time to make a transcendent leap, and how to decide? Must we fully understand the basic science involved and feel certain we will cure the patient, or should we accept uncertainty and view the first attempts as part of the experimental research?

How do we balance the dangers in premature application against the waste of undue delays?

Classic Conflict

Do we have a workable means to settle public policy in this complex field?

These issues involve divisions among many types of people over all sorts of matters--scientific data, scientific philosophy, moral judgments, politics, public opinion. But the conflict at its most basic can be seen as a classic one between two types of lab investigators: the clinicians and the basic researchers--that is, the medical doctors and the molecular biologists.

Making such a distinction risks oversimplifying matters--the differences do not always break along such clear lines--but the two groups do tend to look at issues differently. Anderson is a medical doctor. Mulligan is a molecular biologist.

From afar, scientists in white coats in a lab seem all of a group. Closer up, the differences seem more apparent than the similarities.

The doctor's training in medical school gears him to act, to treat patients, to apply science, to get results. He thumps chests and listens to hearts. The molecular biologist earns his Ph.D. in a lab, amid test tubes and vials and slides. There he learns technique and patience and a distrust for anything the hard data cannot prove. He seeks not results so much as a general understanding into the workings of genes and cells and viruses.

How to do science? This is the eternal tension in the lab between these two groups. This is the present tension coloring the debate about gene therapy.

The story of how Anderson jumped into the race to do human gene therapy, and forced consideration of such issues, provides an unusual look at the world of scientists working on the cutting edge of a historic, pioneering field.

Tortured Lurches

Theirs is a world of conflict and confusion more than consensus and certainty. What seems an unchecked march from ignorance to knowledge most often involves tortured, random lurches in the dark that eventually find the light. Their science is nothing so precise and objective that it can be agreed upon by all. The truth depends on where the scientists stand and who they are and in which direction they direct their gaze.

It is difficult at times to separate the scientists' intellectual differences from matters of ego and ambition and politics. Competition, after all, is the engine that drives the quest.

They compete for grants--funding is their lifeblood, and funding is scarce. Profits from commercial applications also loom, albeit in the distant future. Anderson directs a private lab, Genetic Therapy Inc., funded by a venture capital arm of an investment banking firm. Most other figures in the hot molecular biology field have some sort of commercial connection.

Above all, though, they compete for recognition. The prospect of a Nobel Prize hovers over everything. Altering defective genes promises to provide cures for all manner of disease now considered untreatable, diseases that only recently have been linked to genetic causes. Molecular medicine offers a new way to attack illness. When gene therapy comes it will represent medicine's second great revolution in this century, following the emergence of antibiotics in the 1950s.

Many scientists are in the race and they all want badly to prevail, but Anderson in particular does nothing to hide his abiding passion to be the first to do human gene therapy.

'I Get Bored'

"I want to be the best scientist among my peers," he says frankly. "I get bored when there is no clear goal in sight. I want to win. I don't mind letting my colleagues know that."

Last April, he delivered a 500-page document to the body that must approve clinical trials on humans--the human gene therapy subcommittee of the NIH's Recombinant DNA Advisory Committee (RAC).

This tome, a "preclinical data document," co-signed by three other scientists--two at NIH, one at Memorial Sloan-Kettering Cancer Center--was not a formal proposal to do human gene therapy, but it did include the protocol Anderson would follow if he were to do a human experiment.

Anderson's intent was to force a debate. That is what he got last Monday.

His document, along with critiques of it from competing scientists and Anderson's response to them, was considered that day at a RAC subcommittee meeting in Bethesda.

The reviews from other scientists were critical and dubious. This Anderson expected.

Do Not Have Answers

I agree with my colleague's objections, Anderson has said time and again. We do not have answers to all these questions. But I do not think we will ever get the answers by experimenting with animals. We will never know until we go into humans. So what are we waiting for?

"After listening to all this today," Anderson told the group near the end of its six-hour meeting, "my group will get together and draft a limited, last-chance protocol. Then the committee will have to make tough decisions."

We always operate with uncertainty in medicine, Anderson argues. We don't know how aspirin works, but we use it. It is unethical to withhold treatment that might help. The Ph.D.s don't deal with patients.

"What is the situation if it turns out we go into a patient and it cures him?" asks Anderson. "Then how are we going to justify that we sat on it for two years now? Should we sit on it another two years? What about four years?"

Others, particularly but not only the molecular biologists, shake their heads in dismay at this.

We first need to understand, they reply. We need to do the basic science.

What Are the Facts?

The Ph.D.s ask the same questions over and over: How do you know this? What are the facts?

Talking to his postdoctoral fellows at MIT, Mulligan finds himself at times asking just those questions.

At 33, he is something of a Wunderkind , winner of a MacArthur Foundation "genius award" and head of his own 21-man lab.

Why do you think that will work? How do you know? he asks his postdocs.

Mulligan's tone at these times touches on the sarcastic.

Do you feel it. . . ? Believe it. . . ? Is it a religion. . . ? Is it intuition. . . ? The fact is, you don't know. . . . Where is the science?

"If I were an M.D., I could see why you'd want to try anything," he said one day recently, "but let's just define what we are saying and doing. There is absolutely no shred of evidence that it will work. Maybe French just has faith in miracles."

It is no wonder the competitive tension runs deep between Mulligan and Anderson. The differences are inescapable.

Discussions with Anderson about the science of genes tends at times to veer toward the mystical.

"Nature is a very formidable opponent," he said one day in his lab, when his experiments were faltering. "You must just keep pushing. We all get tired. I really believe that cells get tired. Molecules are the same way. Molecules and cells have a mind of their own and so long as they can beat you they will. The only way you can beat them is just keep going. Sooner or later they get tired."

Anderson likes the dark--the literal dark. He does not usually keep lights on when he sits in his suburban Maryland home. His NIH office is a narrow cave, the window glass covered with black-out lining. The dark, he explains, reduces sensory input and allows meditation.

He is a third-level black belt in tae kwon do, the ancient Korean martial art. For relaxation in the evening, he teaches this art in a gym across Wisconsin Avenue from his NIH lab in Bethesda. Tae kwon do , he explains, is something he can do subconsciously, almost in a transcendental state, the world focused right there in that moment.

Important to Relax

It is important, he told his class one night in the gym, to keep some parts of your body relaxed, some parts tight. He stood perfectly still, barefoot in a white cotton martial arts outfit. Suddenly, his rigid right arm shot out, the knuckles on his closed fist slamming into the gym wall. The sound echoed across the room.

"Well, I guess that makes the point," Anderson said, his face expressionless, inscrutable. "Try not thinking of what to do. Just do it."

The next morning in his lab, he explained: I do science like I do tae kwon do. Science is also something best done without thinking, something transcendent and intuitive.

Told of all this about Anderson some time later, Mulligan looked aghast. He just shook his head.

Anderson is a thin man of medium height, with fine silver hair swept straight back over an angular face. He and his wife of 25 years, a pediatric surgeon, are childless, having decided long ago they lacked the time for parenting. At times, he tends to stammer. In the lab, he favors bedroom slippers and sweat shirts.

Nobel Prize Winners

A pediatrician by training who was graduated magna cum laude from both Harvard College and Medical School, and with honors from Cambridge University, Anderson has worked in the labs of Nobel Prize winners Sir Francis Crick and Marshall Nirenberg. Crick cracked the mystery of DNA, Nirenberg the genetic code.

Anderson can lay claim to several major breakthroughs of his own during a 22-year tenure at the NIH, but those lab triumphs came years ago. More recent efforts have followed blind alleys.

This is apparent from a look at Anderson's calendars.

There are those who might consider Anderson's meticulous calendars the product of an overly obsessed mind. But Anderson takes pride in this form of self-appraisal.

Every half day he measures what he has done and assigns points. Good basic research gets two points, speeches and journal reading get one point, administration and non-science get no points. Then he figures each month's total. Months with 30 or more points on the calendar get colored green, months between 20 and 30 get colored yellow, months below 20 get colored red.

Only Spots of Green

Anderson's calendars throughout the early 1980s feature long bands of red and yellow, interrupted only occasionally by a spot of green.

The colors provide a reminder: There was a time not that long go when French Anderson was not a leading figure in the race to do human gene therapy.

That fact, and the manner in which he jumped into the pursuit, are not the least of the elements that irritate some of his competitors. This part of the story involves a good deal of rancor.

Around the turn of this decade, a handful of scientists--the chief ones being Howard M. Temin at the University of Wisconsin, Robert A. Weinberg at the Whitehead Institute and Edward M. Scolnick, then at NIH--began exploring a method of gene transfer that was both wondrously clever and astonishingly daring.

They were then just coming to understand the nature of a particularly sinister class of viruses called retroviruses. The agent that causes acquired immune deficiency syndrome is a retrovirus.

Own Genetic Material

Unlike more common viruses responsible for such diseases as polio or smallpox, retroviruses do not destroy an infected cell or occupy it only temporarily. Instead, they quietly incorporate their own genetic material into the cell and stay there forever, forcing the cell to make viral proteins along with its own cellular proteins.

The first scientists in this field offered an extraordinary suggestion. Why not harness retroviruses to work for, instead of against, human health? Why not take advantage of the retrovirus's ability to insert genes into a cell?

Why not strip a retrovirus of its own viral DNA and drop into it a human gene--a human gene that someone badly needs because his own is missing or defective?

This gutted and remodeled retrovirus vector would then deliver the needed human gene to a host cell, which would treat it as its own.

Why not, the scientists also suggested, put the gene into the human bone marrow, which generates the cells that populate the bloodstream? In the bone marrow are the basic, self-renewing stem cells from which all the others arise--the cells responsible for replenishing the entire system. If the stem cells take up the new gene, that gene would continue to proliferate in the body forever.

Infect New Gene

The process of actually doing gene therapy on a human would then work much like a traditional bone marrow transplant. Doctors would remove some of the patient's bone marrow cells and combine them in a lab dish with the retrovirus vector, which would infect the cells with the new gene. The doctors would put the altered cells back into the patient's body.

In time, a handful of scientists fixed on a gene that seemed most likely as the first candidate--the ADA gene.

The ADA gene codes for an essential enzyme that inhibits a poison found naturally in humans, a poison that can disable the immune system. Those born without an effective ADA gene suffer from a host of usually fatal immune-deficient diseases, including severe combined immunodeficiency.

SCID was what afflicted David, the well-publicized "bubble boy" in Texas who lived in a sterile plastic tent until 15 days before he died at the age of 12.

ADA and retroviruses--that became the hot field in human gene therapy research.

The early advances at the start of this decade came from the Toronto labs of Alan Bernstein and A. L. Joyner and from the San Diego labs of Theodore Friedmann and Inder Verma.

MIT Connection

Soon after, another team began to stand out, a team based in the Boston area, connected in various ways with MIT, the Whitehead Institute, Children's Hospital and Harvard Medical School.

One member of that collaboration, as it happened, was Richard Mulligan.

First, Mulligan's team designed a particularly nifty retrovirus vector, safer and more effective than earlier versions. Then they used it to put a gene into living mice, a test gene not linked to any disease. In mid-1984, they started playing with a much more critical gene--the ADA gene.

French Anderson was not then fully on the playing field. But he had formed a collaboration with the Princeton biologist Eli Gilboa, who was constructing retrovirus vectors. He also was talking by phone to the leading gene therapy researchers, since he was preparing a review paper for the journal Science, summarizing the state of the field.

On Sept. 28, 1984, while updating his Science article, Anderson placed a call to John Hutton, a clinician at the University of Cincinnati. Hutton had news. He had just finished isolating and cloning the ADA gene--something only one or two other labs had within their reach. Now, on the phone, he seemed unclear about what he was going to do with it.

Anderson drew a breath.

"John, you want to send it to me?"

Sure, Hutton said. Why not?

Being 'Opportunistic'

The retrovirus technology had come from one quarter, the ADA gene from another. Others, searching for the right word, later would suggest that Anderson at the very least was being rather "opportunistic."

In October of 1984, Anderson had a conversation with a member of the Boston team, Stuart Orkin of the Harvard Medical School and Children's Hospital, that can fairly be described as strained.

"John Hutton has sent us the ADA gene," Anderson began, "so now we're going to join the ADA field. I appreciate all of the help you've given us in talking about your work for my Science paper, but I won't ask you for anything more, because now that we have the gene, we're competitors."

Orkin said little. He is a serious and intense man, by nature taciturn, given to few words in even the most cordial of situations.

But Orkin thought: I wish the man could be a little more original.

Anderson understood he was arousing some irritation, but this did not give him pause. He knew much about, even embraced, the rougher, competitive side of science. Working in Nirenburg's lab in the '60s, pursuing the genetic code, his group had found it necessary to lock its logbooks in safes each night to keep them from competitors within the same NIH building.

Dived Into the Scrap

So Anderson dived into the scrap headfirst. By early 1985, his lab team had matched the Boston group's early accomplishment--they, too, had put a test gene into living mice.

But both groups were simply refining a method--the test gene was just a marker that did not cure a disease. They needed to get the ADA gene into mice.

Anderson tried this time after time in mid-1985, but it never worked. Other labs also failed.

The entire field seemed blocked. The ADA gene just would not go into a living system.

Anderson's two most trusted young lab lieutenants, Philip Kantoff and Martin Eglitis, felt disconsolate. We do not understand the basic science, they reasoned. We will have to retrace our steps and learn why we failed.

If there is a particular moment that has most fully characterized Anderson's unusually focused drive to change a human being's genes, it came at this point.

Let's think ahead and look at the big picture, he suggested.

Steps You Don't Need

When you do an experiment, you'll get either a yes, a no or a maybe answer, and that will lead to other experiments. But if you look down the road a ways, you might find you don't really need steps 2 and 5. Regardless of what they say, you're going to do steps 3 and 6 anyway. So skip 2 and 5. Just go straight to 3 and 6.

Why try to refine and refine the mice? We want to cure human patients. Monkeys are much closer to humans.

"Let's bag the mouse work," he told Eglitis and Kantoff. "Let's go after the monkeys."

In collaboration with a team headed by Richard J. O'Reilly, head of pediatrics and director of the bone marrow transplantation program at Memorial Sloan-Kettering Cancer Center, he began infecting monkeys with a retrovirus vector containing the ADA gene in mid-1985.

Monkeys represented a much larger and more complex system than mice. Success here would be much more difficult, but it would mean much more. Success here would mean you could go into humans.

The monkeys, it turned out, reacted more favorably to the ADA gene than did the mice.

Monkeys Evaluated

In only one monkey were they ever able to detect the presence of the human ADA gene itself. But they could see that in four of five monkeys evaluated, a few of their cells were producing the enzyme coded by the human ADA gene.

What all this meant has become a matter of considerable debate.

For Anderson, his experiments meant a good deal.

He set about writing a paper reporting the monkey results. He would submit it to Nature, the prestigious scientific journal published in Britain, he told his lab. As soon as Nature accepts it for publication, we'll begin drafting a protocol to go into a human. When the monkey paper gets published, we'll submit the protocol to the RAC. This thing is about locked up.

To the dismay of some colleagues, Anderson also went public. At an NIH press conference in September of 1985, Anderson, answering a reporter's question, said human gene therapy could come within a year. An avalanche of news media coverage followed, including excited predictions and extended reports by virtually every major newspaper and magazine.

There were other scientists, though, primarily molecular biologists, who judged Anderson's monkey results quite differently. They did not simply think his results were weak. They thought the results represented a complete failure.

Richard Mulligan, as it happens, was one of those who held this view.

Many People Involved

By now, Mulligan had become something of a symbol in the Anderson lab. It is misleading to characterize the present conflict as a man-to-man rivalry between these two, for the divisions are more intellectual than personal, and involve many people spread across the country. But Mulligan's name at some point became a form of shorthand in Anderson's lab for all the competition, all the critics.

A full generation younger than Anderson, Mulligan possesses a considerably different approach to the world than does the older scientist. Anderson shrinks from social settings and abstains from drink. Mulligan enjoys beer and martinis and champagne. He enjoys Hollywood parties and attractive women, good food and popular restaurants. His eyes often suggest his bemusement at what he is seeing.

Tall, bearded and lanky, clad usually in worn jeans, he looks more like a graduate student from the 1960s than the world-class scientist he is. To some, he appears smug. He does not hesitate to suggest that another scientist is "nothing," if that is his judgment.

"Arrogant" is a term sometimes mentioned in the same breath with Mulligan's name.

His comments on a PBS "Nova" program broadcast two years ago particularly irked some doctors.

We molecular biologists are responsible in the technical sense for the whole method, he said. One should not leave some of the scientific issues to the physician. I would feel very, very much more responsible than the physician for the patient if someone used a method I worked on.

Takes Exception

Ted Friedmann was on that same "Nova" program. The UC-San Diego clinician responsible for some of the earliest breakthroughs took exception to what the microbiologist said. After all, Friedmann, like Anderson, had augmented his medical degree with years of work in several prestigious labs.

Mulligan's comments, Friedmann thought, revealed his inexperience with the world of medicine.

"Brilliant," though, is another word invoked often when describing Mulligan.

Mulligan tends to work not by grinding out the lab hours, but by relying on "conversational science"--talking and thinking over concepts with others. This at times irritates some of his more traditional elders.

After their initial successes, Mulligan's team like all the others had encountered critical roadblocks. There might be a biological block, they came to believe, that we just do not understand.

To Mulligan, Anderson's work was just touching on this basic biology in a peripheral, shallow fashion. He resented Anderson's whole approach. He objected even to being grouped in the same field with him. He did not think they were so linked.

Scientifically Unimaginable

It made him uncomfortable to say so about another scientist, but the fact was, he could not imagine Anderson's position scientifically.

Mulligan--and others--saw several fundamental problems with Anderson's monkey results.

The levels of ADA enzyme activity Anderson found were, after all, just faint traces, certainly not enough to cure a patient lacking his own ADA.

In only one of the monkeys could Anderson detect the presence of the human ADA gene itself.

Having failed at this, Anderson had tried to test indirectly for the gene's enzyme activity. Even there, he had found nothing when he used the standard test. He had been forced to rely on a far rarer type of assay.

To Mulligan, though, there was an even bigger problem with Anderson's work.

Would Limit Effect

Gene therapy would require that they get the new gene into the replenishing stem cells in the bone marrow. Only then could they provide a patient with a continuing source of the new gene. That much was certain. If you just got the gene into the more mature, already developed cells, the effect would be quite limited--when those cells died, so would the transplanted gene.

It was clear to Mulligan that Anderson could not have gotten into the stem cells.

Cells Soon Died

The enzyme activity in Anderson's monkeys had begun declining after 60 to 80 days, and had disappeared altogether by day 170. The effect lasted only a brief time. Anderson must have hit some late, mature cells--cells that soon died.

The fact was, the whole business of stem cells was rapidly becoming the chief obstacle for all those pursuing the goal of gene therapy.

They all just might be running up against a brick wall, Mulligan reasoned.

No Way to Separate Them

The stem cells, after all, have been estimated to make up only a fraction of bone marrow cells, 1 in 10,000. There is no way to separate them from the rest. They look like the other cells and behave like them. You can't test for them or select them out. So how do you show you can get into them?

Anderson had to be called on this.

Mulligan's opportunity came on Oct. 15 of last year. The Institute of Medicine, an arm of the prestigious National Academy of Science, that day opened a special conference in Washington about gene therapy. Mulligan was a featured speaker.

The first morning of the two-day conference, at a breakfast reception, he moved about the hall at the newly opened J. W. Marriott Hotel, three blocks down Pennsylvania Avenue from the White House. Anderson approached him at one point. They chatted briefly, their tones cordial.

Then Mulligan climbed the podium and began his talk.

The stem cells have to be infected, he said. You've got to see results long after transplantation--at least four months. And instead of testing for a gene's enzyme activity, they should be looking for the presence of the gene itself.

Couldn't Detect Gene

Anderson's lab couldn't detect the ADA gene, Mulligan declared. The enzyme activity they did see came only in a short window of time.

Clearly, Mulligan argued, a test for stem cell infection needs to be developed.

"In my opinion, such assays would constitute the appropriate final test prior to clinical testing in a human," Mulligan said. "If no such assay becomes available, a critical decision will have to be made as to how to proceed."

With that, Mulligan left the podium. After this, he thought, there is no way researchers can claim breakthroughs unless they address the issues I raised.

He had set the terms.

The next day, the other scientists had questions for Mulligan. But he was no longer there.

The Red Sox were facing the Mets that day at Fenway Park in the World Series. Mulligan had tickets.

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