More Labs Than Patients : Desire to Be First Colors Gene Studies

As the young microbiologist Richard C. Mulligan delivered a speech about human gene therapy before an Institute of Medicine conference here on Oct. 15 of last year, W. French Anderson sat in the audience, listening intently.

Mulligan, after all, was talking about something Anderson had been feverishly pursuing for years.

I want to win, I want to be the first to do human gene therapy, Anderson had often said. Director of the laboratory of molecular hematology at the National Heart, Lung and Blood Institute, he had already managed to put a new gene into monkeys--the ADA gene, which codes for an enzyme that protects immune system cells from deadly poisons. Now he wanted to try the same with humans.

Must Use Stem Cells

Unless you can put a gene into the human bone marrow’s stem cells, Mulligan was saying, the whole game is doomed. Getting into more mature, already developed cells was no good--when those cells died out, so would the transplanted gene. The gene would only proliferate if you got it into the self-renewing stem cells that replenish the entire system.

French Anderson’s lab, Mulligan declared, could not have gotten the ADA gene into their monkeys’ stem cells. The gene’s enzyme activity in the monkeys had lasted only a short time.

We need a test to show we can get into stem cells, Mulligan said. That would be the appropriate final test before going into humans. If we can’t develop that test, a critical decision will have to be made about what to do next.

Anderson stared at Mulligan as he spoke and slowly shook his head.

Anderson did not so much disagree with Mulligan as he viewed the matter from a different angle. Mulligan, an MIT associate professor and lab director at the Whitehead Institute for Biomedical Research in Cambridge, Mass., after all, was a basic researcher pursuing knowledge. Anderson was a medical doctor, a clinician geared to treating sick patients.

Critical Decision Looms

Anderson agreed that without the needed test for stem cell infection, a critical decision loomed. But unlike Mulligan, he was not inclined to search any longer for that test, for he did not think it could be found. He was ready to make the critical decision Mulligan spoke of.

There finally was only one way to find out if you could get into stem cells and stay in: go into a human patient, a human ADA-deficient patient. See there if you got results that lasted.

Others would argue that he should first get those types of results in a monkey. Then the leap to humans would be much shorter.

That’s not possible, Anderson would respond.

You could not do in a monkey what you could do in a sick, ADA-deficient human patient, Anderson reasoned. That was so because only in the human system would your new cells have a selective advantage.

At the heart of Anderson’s impassioned endeavor was his belief in this theory of selective advantage.

Even if they got the ADA gene into only a few cells of an ADA-deficient patient, he reasoned, that would be enough, for those cells would have a selective advantage over all the other cells that lacked the ADA gene. They alone would be immune to the body’s poisons. They would proliferate while the others died out.

Selective advantage could not be tested in monkeys, though, or any other animal. Animals have their own ADA gene, their own ADA enzyme activity. They aren’t sick, as the human patient would be. So the newly inserted cells would have no advantage over the monkey’s own cells.

Others, Mulligan included, thought Anderson’s selective advantage idea was not just a speculative theory, but a poorly thought out one at that, full of basic flaws. How, for example, could Anderson assume the stem cells in an ADA-deficient patient were the defective ones? If they weren’t, newly infected stem cells would have no advantage over all the others.

Everything Anderson was shooting for, though, hinged on the idea of selective advantage. If it wasn’t right, gene therapy was a long way off. For the patients, for his own goals, the theory just had to be right.

It is here, where the pursuit of science turns on matters of theory and what a lab investigator desires, that the differences between the clinicians and the molecular biologists become most sharply apparent.

Trained in Labs

Molecular biologists do not traffic much in theories and desires. Trained in labs amid test tubes, not patients, they talk a complex language, one deeply rooted in the hard nuggets of science. They keep their eyes on the cells.

They see so many unanswered questions.

Which donor cells really get taken up into the body’s system? How can we be sure those cells even existed in the marrow obtained from patients and infected with vectors? What if there is something wrong with the cells the vectors are supposed to infect--maybe there won’t be anything for the vector to hook onto. How do you know you won’t have to kill off some of the patient’s own cells to make room for the ones you were giving him? How dangerous would that be?

Where will the newly added gene land on the host cell’s chromosomes? Might it disrupt the cell’s normal functions, or turn on a cancer-causing oncogene? What if the retrovirus vector or other viral material managed to escape the cell and become infectious?

“Suggestions that we go forward in the absence of the scientific information--I don’t consider that very scientific,” Mulligan argues.

It is also, the biologists fear, politically unwise.

Essence of Being Human

Scientists and their regulators are not unaware that the idea of changing a human’s genes is startling and frightening to many, in its implications of playing God, and in its potential to alter the essence of being human. They are deeply concerned about being perceived as moving too fast. This is what sets gene therapy apart from other medical frontiers such as cancer chemotherapy or AIDS drugs.

Anderson’s competitors worry that the National Institutes of Health scientist, driven by ambition and ego into a failed experiment, might sour public sentiment and take them all down with him.

They do not want Anderson or anyone to provide ammunition to the outspoken critics of genetic engineering, such as the environmental ethicist Jeremy Rifkin. They also shrink from the specter of Martin Cline, who in 1980 unsuccessfully tried the first gene therapy using recombinant DNA techniques, operating abroad without getting proper approval from review boards. In the furor that followed, Cline resigned as chairman of his division at UCLA and the NIH terminated his two grants.

“Nobody wants to provide a target for the people to say, ‘Gee, it doesn’t work and what are we doing to the environment, and what else is going on here,’ ” said A. Dusty Miller at the Fred Hutchinson Cancer Research Center in Seattle.

If an experiment fails, said the Harvard Medical School and Children’s Hospital researcher Stuart Orkin, “lots of explanations will be needed. It will give ammunition to lots of critics. We would be dead for 10 years.”

These scientists pose a question: Why the rush?

Only About 35 Cases

Gene therapy in general, far down the line once the models can be applied to widespread disease, might eventually help many people but there are only some 35 ADA-deficient cases of severe combined immunodeficiency (SCID) born each year in the United States. Approximately one-third of them will have a properly matched sibling donor, and so will be able to get a regular bone marrow transplant. That leaves about 12 cases a year eligible for gene therapy.

Of those, some might be able to take an unmatched transplant. Others certainly are candidates for an experimental procedure called PEG-ADA just now being tested by Michael S. Hershfield at Duke University, in which the ADA enzyme--not the gene but its product--is injected directly into patients, much like insulin is given to diabetics.

The fact is, there are more labs in the field than patients.

“The only urgency is competition of labs,” said Orkin. “There is not a crying need elsewhere. This is not like AIDS. These are rare diseases. Gene therapy is a stunt. Face it. Our position is to try to understand the science. If we learn enough, it will apply. Intellectually it is more interesting to understand. We are just plodding along right now. We don’t know why or what works.”

Conversations with clinicians unfold in a world that at times seems quite different from all this. They sit across from patients as well as test tubes. They listen to parents beg, sometimes demand, treatment.

“I resent the fact that a few well-meaning individuals have presented arguments strong enough to curtail the scientific technology which promises to give some hope,” wrote one such parent, Ola Huntley, mother of three children suffering from sickle cell disease. “Aren’t they deciding what’s best for me without any knowledge of my suffering? I am very angry that anyone would presume to deny my children the essential genetic treatment. . . .”

Against the Wall

In early 1985, University of Wisconsin clinician Dr. Sheldon Horowitz looked at his 6-year-old ADA-deficient patient, Erin McCarthy, and thought: We can’t wait forever. We have gotten into trouble hearing that gene therapy might be available in six, 12 months, and trying to wait and while we wait the kid gets some terrible infection and then we’re really up against the wall.

There came a day when he felt moved to sit down and compose a letter to the federal panel that must approve human trials. “Gene therapy may have only a small chance of success,” he wrote, “but its risks are minimal compared with certain death.”

You would not at first be trying to cure anybody, Anderson and others say. You would be doing it specifically as part of the experimental research, using a small handful of patients with drastic, terminal illnesses, patients with no alternatives, patients who volunteer. Such Phase 1 clinical testing is not unusual. We test drugs and treatments all the time, when treating terminally ill patients stricken with such diseases as cancer or AIDS.

Accepting and using imperfect science, uncertain knowledge--that, say the clinicians, is what medical therapy is all about.

Anderson’s collaborator, R. Michael Blaese, deputy chief of the metabolism branch and head of the cellular immunology section at the National Cancer Institute, talked recently of why he thinks the science is close to justifying going into humans.

He listed recent hard evidence pointing to more efficient methods and increased safety. But he also talked of something else.

For Terminal Patients

“I go around talking to clinicians,” Blaese said. “Often they are cancer specialists accustomed to throwing new drugs at terminal patients, realizing the chances are slim but the possible benefits so great. They are used to taking desperate chances all the time. That’s how they make discoveries. . . .

“They keep asking me, what are you afraid of, why not try, why not go in. I sort of feel that way too. It’s like Phase 1 cancer drugs, or AZT and vaccines with AIDS. . . . There’s no hard promise it will help, but patients with terminal diseases are willing. . . .

“I remember when I was a student in the 1960s, doing work in a basic research lab. Then Christian Barnard started putting hearts in people, when the labs were suggesting it wasn’t going to work. But it worked. . . . Then came kidney transplants, after the lab tests showed that skin transplants wouldn’t work. I remember the basic lab people being very dubious, skeptical. But it worked.”

It is difficult to reconcile these sharply contrasting worlds.

Robert Cook-Deegan, a medical doctor with postgraduate training in molecular biology, directed a landmark report on human gene therapy published in 1984 by the Office of Technology Assessment (OTA), an arm of the Congress.

He chose to print an epigram at the front of that report. It was a quote from the Austrian philosopher Ludwig Wittgenstein:

“Where two principles really do meet which cannot be reconciled with one another, then each man declares the other a fool and heretic.”

‘Real Sticking Point’

One day recently, he said: “We’re at a real sticking point. There are certain kinds of information you can’t get without going into humans. But at the same time you don’t want to go into kids just for the hell of it, without some hope it will help. People will part company on this. I don’t know how we will grapple with this.”

In recent months, Anderson decided he would simply have to force the issue.

He was tired of the selective-advantage issue just hanging there, unresolved, with no prospects for reaching an answer. The cells that received his new gene certainly would prevail in a body full of cells with defective genes.

He would have to put a proposal on the table, submit something to the panel that must approve clinical trials on humans--the human gene therapy subcommittee of the NIH’s Recombinant DNA Advisory Committee (RAC). He would invite fire from all his competitors. What more do you want to know, he would ask them--and more important, how can we get the answers to your questions without going into a human?

Anderson began talking to his trusted lab lieutenants, Martin Eglitis and Philip Kantoff, about his plans. First they would publish a paper about their monkey experiment results, then they would put something before RAC.

Are you willing to go into a patient and fail? Kantoff, dubious, asked Anderson one day at lunch, as the three shared a pizza in the lab’s conference room.

‘Kids Would Die’

“Sure,” Anderson said. “If we wait until we were certain, lots of kids would die. Also, let’s face it, it’s a big scientific plum we’re after. It comes down to selective advantage. We won’t fail if that’s right, and we can never know if that’s right until we go in.”

Isn’t ambition coloring our plans? Kantoff asked.

“No more so than ambition influences a businessman or an athlete,” Anderson said. “Every Olympian is overly ambitious.”

Why do it now, French? Eglitis asked.

“Because then we will direct the debate. I know everyone on RAC and the subcommittee. I know what they know and what they don’t know. They basically don’t want to make a mistake. But they don’t know what’s right or wrong. Only we sit around and think about these things. So by putting a protocol on the table, finally everyone will understand--here’s what we know, here’s what we don’t know, here’s what we cannot know without going in.”

But Anderson’s plan--the monkey paper, then the RAC protocol--soon hit a sizable roadblock. Near the end of January of this year, the prestigious scientific journal Nature rejected Anderson’s monkey paper. Two anonymous reviewers, other scientists in the field, had savaged his results.

‘Largely a Failure’

“Although the authors naturally wish to put their findings in the best light, most dispassionate observers would conclude that the experiments were largely a failure,” wrote one. “I am left cold by this work.”

What happened next tells a good deal about a world where judgments and perceptions claim as much territory as do hard facts and clear truths.

When Anderson sent his monkey paper to another publication, the Journal of Experimental Medicine, the editors there readily accepted the report. This magazine was not as prestigious or widely read as Nature, but it was a recognized professional journal.

When Anderson’s article appeared in print last July, he had the stamp of legitimacy he so long sought--along with prominent newspaper headlines announcing another step forward in human gene therapy. The present stage was finally set.

Anderson now could try to force to the public table what previously had been a relatively private debate within a corner of the scientific community.

Do you at times leap with incomplete knowledge into the unknown, powered on by faith that discoveries will be made and by a driving obligation to do something for a patient? Or do you progress step by step, keeping both eyes firmly focused on the data and the facts, guided by what is truly known?

Could Trigger Debate

After some consideration, Anderson decided he could trigger this debate by filing something less than a formal proposal.

The “preclinical data document” his team instead composed this past spring was Anderson’s own hybrid invention, not called for under any formal procedure. The thick volume included a detailed roundup of the state of the science, along with a draft version of a protocol for human trials--one that followed, essentially, the protocol he had used on the monkeys two years before.

Send this to all my competitors, Anderson told the RAC’s executive secretary, William J. Gartland Jr. Here are their names.

Mulligan got a copy. So did Stu Orkin, Dusty Miller, Ted Friedmann. So did six others, among them Howard Temin at the University of Wisconsin, Hershfield at Duke, David Martin at Genentech, and Cook-Deegan at the OTA. Anderson knew he was walking into a clearing and willfully drawing the fire of his critics.

If they’re correct, he reasoned, then I say so, and I haven’t lost anything. If it turns out there are hidden agendas, which there will be, or just simply concerns . . . they can be answered.

This would also be a dry run for the policy-making process itself. A “bellwether,” Anderson called it, showing how the process handles all this. Can a system of government committees and regulatory bodies reach answers in this sort of matter?

Some Withering Reviews

The softest of the reviews that arrived on Gartland’s desk this past summer and fall were merely negative in tone toward Anderson’s document. Some were withering. Noting the low ADA enzyme levels, the risk of viral contamination and the emergence of the alternative therapy involving PEG-ADA enzyme, all but one firmly agreed the time was not right for human trials.

Anderson, in turn, responded on Nov. 20 with a letter to Gartland that can fairly be likened to the sort of long-planned move a wily chess master might make just when he appeared cornered.

“Overall we agreed with essentially all of the concerns raised by the reviewers,” he began.

But by the time the letter reached its conclusion on page seven, Anderson was writing, “We now think, based on all the information that is currently available, that it would be appropriate to prepare a limited clinical protocol.”

Soul of a Clinician

In the leap from the opening to closing thoughts soars the soul of a true--some would say fevered--clinician.

Our decision, Anderson wrote, hinges on the following consideration:

In specific cases where all available therapies, including bone marrow transplants and PEG-ADA, have failed and there is nothing else to offer, “would it be ethical to deny the potentially life-saving gene therapy protocol in the face of certain death?”

We would certainly be more comfortable if we understood the gene transfer procedure better, had higher enzyme activity and less risk of viral contamination, he continued. But a clinical decision in this setting, as in other complex medical situations, should be based on an assessment of the risk/benefit ratio for the patient, which in this case involves the threat of impending death.

We are aware of three infants who may soon fall into the last hope category, Anderson concluded. Because of that, we feel a limited clinical protocol should be submitted in the near future.

At NIH Headquarters

It was against this backdrop that the RAC subcommittee gathered in Conference Room 9 of Building 31C at the NIH headquarters in Bethesda, Md., on Monday morning, a week ago.

If is fair to say the day offered its share of unspoken undercurrents and subtexts.

By design, the 15-person panel includes three each from the fields of basic lab science, clinical medicine, ethics, the law and public policy. Because the committee’s highly respected consultant, Nobel Prize winner Howard Temin, could not attend, the panel decided to add what they called an “ad hoc consultant” to the panel for the day, someone who could deliver the expertise in retrovirology that Temin normally provided.

As it happened, the ad hoc consultant they selected was Richard Mulligan.

Anderson that morning had traded his customary sweat shirt and slippers for a tailored gray suit. Mulligan had found a gray herringbone sport coat to wear over beltless khaki jeans, a pink striped shirt and a red bow tie. Anderson sat with members of his lab in chairs along the room’s wall, amid some two dozen other observers. Mulligan sat at the long rectangular table with the other committee members.

Answer Shapes Discussion

At first, Anderson’s answer to his critics shaped the discussion.

Anderson’s response of Nov. 20 shifts the idea from a full-blown clinical study to the idea of a limited, last-hope protocol, suggested James F. Childress, an ethicist in the University of Virginia’s religious studies department. Do the standards for approval change? Childress thought so.

Is there a “boomlet for last chance” here? asked Alexander Capron from the University of Southern California Law School.

Mulligan was taken aback. What was this talk of last hope? He thought all candidates for this experiment were last hope patients. That’s what this therapy was for.

“Excuse me,” he said out loud. “As I understand it, French (Anderson) never was going to do more than two patients. So what’s the difference? I don’t see how the issue has changed.”

Most likely, it had not.

‘See 2 Situations Differently’

“Let me set your mind at ease,” Maurice J. Mahoney from Yale University said to Capron. “I don’t think many here see the two situations differently.”

Late in the morning, the conversation eventually turned to matters of hard science. It was Mulligan’s turn to talk retrovirology. He rose and walked to the head of the table, holding a single sheet filled with notes.

“I think I will involve French (Anderson) in this if I may,” he said.

Mulligan had questions.

I am curious, he said to Anderson. Do you have data that shows infection of stem cells?

That is a crucial point, Anderson allowed. We have no evidence with the monkey or with ADA.

“So. . . “ Mulligan said, drawing out his words. “It appears you’re infecting . . . something. “

Busy With Grease Pencil

Mulligan by now was busy with a grease pencil working on a board set before him on an easel. Soon it was covered with circles, arrows and cells. He continued.

Anderson was assuming he would not have to kill off a patient’s own bone marrow cells before adding the newly infected ones.

“What’s the evidence for that?” Mulligan asked.

Anderson began citing several studies, but eventually stopped. Pointing to Mulligan’s chart, he said: “I have to admit there are black boxes up there.”

What level of efficiency would he need to get selective advantage?

That’s also a critical question, Anderson said. There are data and studies, but they still don’t answer the question. We don’t really know.

‘Would It Work?’

Mulligan took two steps, digesting these responses, then stopped and bit off his next question: “I am curious, French. Do you think it would work if you did it?”

“That’s the question. . . . No one really knows. . . . I don’t think it is likely.”

Then what would we learn from this experiment? Mulligan inquired.

This, finally, was the heart of the matter. Scientists are quite familiar with failed experiments, but they like experiments to provide answers whether or not they succeed.

If there is any improvement, any selective advantage, we learn that that happens, Anderson said.

And if nothing happens? Mulligan asked.

That’s a good question, Anderson answered. That is why we changed course in the Nov. 20 response to a last hope protocol.

Both Seem Satisfied

It is telling about the nature of their differences that both men seemed satisfied as the meeting drew to an end near 3 p.m. Mulligan felt he had made it clear that there was no data or evidence to support a human trial. Anderson felt the issues were now sharply framed, the committee prepared to evaluate proposals.

“After listening to this today,” Anderson told the panel, “my group will get together and draft a limited last case protocol. Then the committee will have to make tough decisions.”

The first human trials will in the end also need approval from an institutional biosafety committee, the full RAC, the director of NIH, and the FDA, but the front-line deliberations will come from this RAC subcommittee. The next meeting is scheduled for late March. It is not clear when they will face the decision Anderson intends to force upon them.

We want to approach this rationally, the panel’s members said in interviews. We want a reasoned process, a legitimate procedure.

But most on the panel also say they are generally inclined to rely on the critiques sent in by the 10 reviewers. We must look, they explain, to what the scientists tell us.

Judgments Colored

That the experts’ judgments are colored by matters of training, philosophy and politics as well as by the hard facts is a condition that the panel must accept.

It is partly an epistemological question, said the bioethicist LeRoy Walters, the RAC subcommittee chairman: “How do you know the truth? There is no alternative but to listen to the experts. Who are the experts? The experts are those who are acknowledged by experts to be experts. At a certain point, it gets to be a circle.”

“There may be gray areas,” Gartland said, “but at least we can agree that there are these gray areas and go ahead anyway. We can at least agree about what we are basing our decision on.”

The type of question less likely to be agreed upon has more to do with the scientists than the science.

Is the clinician French Anderson’s fiercely willed drive toward a finish line a danger to science, or what’s required in order to make transcendent leaps?

How do you reach the landmark discoveries?

Intuitive Advances

It is true that the history of science abounds with sudden, intuitive advances. Yet it is also true that many of those came not from acts of directed will, but rather, from unplanned, unexpected random twists of fate in a lab.

One morning recently, a member of the RAC leafed through the critical reviews of Anderson’s preclinical data document. He could not hide his puzzlement. The RAC had received not a single piece of paper, not a phone call, from any other scientist interested in filing a protocol.

So he had a question. What was it with French Anderson? Was he a visionary, that far ahead of the others? Or was he something else? Was he off the wall?

That question was put to Anderson the same day.

“I don’t know who is right,” he said. “I don’t know if I’m right or not. Was Lindbergh right? If he crashed into the Atlantic he would have been wrong. The simple issue is that if you’re a pioneer, most pioneers by definition flame out. They fall off cliffs, their ship sinks, their plane crashes, something else happens. Were they right or were they wrong? If they were lucky and they got there, they were right.”