Biomedicine's Bionic Man

Robert Lee Hotz is a Times science writer

For a glimpse into the soul of David Baltimore, the curious need look no farther than the scientist's official portrait, which he chose in lieu of the customary oil painting to hang outside the boardroom of the Whitehead Institute for Biomedical Research, here at the Massachusetts Institute of Technology in Cambridge.

The photograph, taken last year as Baltimore's political fortunes turned, is of note both for what the artist saw and what Baltimore as art patron chose to preserve: an off-balance figure in black--shoulders hunched and hands shoved in his pockets--balanced between stark shadow and bright light. It is a portrait of someone who might be emerging from the darkness or, just as easily, being engulfed by it. The eyes are sad, the eyebrows heavy and arched with skepticism. Yet he seems amused, perhaps by the studied ambiguity of his own image.

It could easily be a portrait of Faust, the scholar of legend who sold his soul for the sum of all human knowledge. But the ambitions working within 59-year-old Nobel Laureate David Baltimore, perhaps the most influential biologist of his generation, are more complex than a raw appetite for new information.

Among the youngest biologists--at age 37--to win the Nobel Prize, his formal, somber manner often makes him seem among the oldest. A self-made mandarin of science, Baltimore's practiced elegance frames a fierce pride and a sometimes brutal intellect, softened only by his insistence that professional criticism be leavened by personal respect.

As a scientist, he displays an almost casual brilliance. He takes the broadest possible view of what others might see as narrow questions. A subtle administrator, he is politically adept, with a talent for building unconventional research groups. As a policymaker, he pursues his aims absent self-doubt and with an autocratic intelligence that leads even friends to fret about his arrogance.

Ambitious, pragmatic, aggressive, Baltimore nonetheless appears to prize principle above his own advancement--or even professional survival. He suspended the research that eventually earned him a Nobel prize in order to devote himself to antiwar protests, coming within a hairbreadth of losing his race for the prize. And despite pride in his own rectitude, he more recently weathered the appearance of fraud for almost a decade rather than abandon a colleague accused of falsifying research data.

Now he is assuming the leadership of Caltech--one of the world's most highly regarded research universities--at a time when the university is reassessing its character and Baltimore himself is having second thoughts about his own. The appointment of David Baltimore marks the latest step in the public rehabilitation of a man who, in 1991 resigned from the presidency of Rockefeller University in New York under pressure from colleagues and members of Congress.

For a time, Baltimore faced the ruin of almost everything he valued: his reputation forprobity, his position as an academic leader and the respect of his peers. Then, in barely a year, he was exonerated formally of any stigma of scientific impropriety by a federal appeals board, named to coordinate the federal effort to develop an AIDS vaccine and, most recently, appointed president of Caltech.

It is a breathtaking reversal in public fortunes.

"It is even more breathtaking," Baltimore says, "to live through it."

*

Given his formidable public presence, Baltimore in private is unexpectedly genial. He is a considerate dinner companion with an intimate knowledge of the fashionable restaurants, espresso bars and basement cigar dens of Boston's gentrified Italian North End. He is particular about wines, favors his single malt whiskey with a single ice cube and drives a late-model Audi.

Like a number of his generation's biologists, who benefited from the early 1980s boom in biotechnology stocks, science has made Baltimore a relatively wealthy man. He has been an active consultant.

With his wife, Dr. Alice Huang, he shares a luxury duplex condominium on Union Wharf, which has a commanding view of Boston Harbor and is only a few hundred yards from the berth of the USS Constitution. The meticulous decor of their Boston condo underscores his interest in the arts. A free-standing glass sculpture by Rhode Island artist Howard Ben Tre rises at the top of a spiral staircase. A large scarlet Chinese ceremonial drum, purchased on a trip to Singapore, dominates the living room. The couple also owns vacation homes in Montana and Woods Hole, Mass. At Caltech, they will live in the president's official residence. (Their daughter, Teak, a recent Yale graduate, lives in New York.)

Baltimore is a rare combination of accomplished scientist and experienced administrator, colleagues say. He was founding director of the $135-million Whitehead Institute for Biomedical Research, which today--with 14 senior scientists and an annual research budget of $35 million--is one of the nation's leading science centers. He was president of Rockefeller University in New York from 1990 through 1991. And he is chair of the AIDs vaccine research effort for the National Institutes of Health.

But Baltimore has never run anything so large or diverse as Caltech. Indeed, the Rockefeller, which focuses on biomedical issues, does not even have an undergraduate student body. And he is a stranger to the U.S. space program, which, in the form of the Jet Propulsion Laboratory and its 5,000 employees, is a major part of Caltech. It will be the first time that he will try to manage so many interests and so much expertise beyond his own field of biomedicine.

Now, for the second time in a decade, Baltimore is leaving Boston, where he has spent so much of his career, to take the reins of a major research university. There is an adage that holds there are no second acts in American life, but Baltimore is confident he will prove it wrong.

"The experiment is that here I am--a functioning scientist--taking over the reins of a university," Baltimore says. "I will be, I believe, the only functioning scientist who is running a major university in the United States.

"But if it was not a challenge, why do it?"

In choosing Baltimore, Caltech acknowledged that it is seeking a more prominent voice in the debates over the future of science when, more than at any time in recent memory, the place of basic scientific research in the affairs of the nation is in flux. It also signals the growing importance of biology research.

And the school's choice of president is one way it is bracing for the rapid changes in funding and educational priorities facing all universities, says Caltech engineering professor and former provost Paul C. Jennings, who was on the faculty search committee that selected Baltimore: "Caltech needs to position itself for the future. The relationship that has existed between science and the federal government since World War II has changed.

"We need visionary leadership."

Biologist and search committee member David Anderson agrees: "We can't just simply steer the course and do what we have been doing."

*

They could hardly have picked a more public figure. There has scarcely been an issue of import to biology or biomedical research in which Baltimore has not been involved.

From debates over the safety of genetic engineering and the importance of AIDS research, to more recent bitter public battles over fraud in science, colleagues say Baltimore has never hesitated to use his stature as a biologist, the prestige of his Nobel prize and his skill as an administrator in an effort to shape the course of American science.

At the same time--and perhaps with equal dedication--Baltimore has worked to make himself an arbiter of the high society of science. "David is interested in his national and international persona," says Nobel Prize-winning MIT biologist Phillip Sharp. "His public perception and reputation are important to him."

When, for example, American scientists tried to avert a hunger strike by Soviet dissident and physicist Andrei D. Sakharov in 1981, Baltimore was among those who wrote to Soviet leader Leonid I. Brezhnev. And when Pope John Paul II wanted to caution President Ronald Reagan that same year on the danger of nuclear weapons, Baltimore was one of four scientists the pontiff appointed to carry his message.

But it is as an activist in the policy affairs of science over the past 25 years that Baltimore has left his most indelible mark--and where he hopes to make an impact as president of Caltech.

"No matter how we in the West Coast science establishment pretend it is not true, the East Coast science establishment is really much closer to the centers of money and power," says Stanford University cancer biologist Irving L. Weissman. "David moves easily in those spheres. I wonder how much he can affect the balance of power . . . and how well he can adapt."

In a lifetime of policy jousts, Baltimore has gathered powerful allies, among them Maxine Singer, president of the Carnegie Institution in Washington; NIH director Harold Varmus; Bruce Alberts, head of the National Academy of Sciences; and Stanford University Nobel Laureate Paul Berg. He has acquired influential opponents as well: Nobel Prize-winning Harvard biologist Walter Gilbert and Nobel Laureate James Watson, co-discoverer of the structure of DNA.

Baltimore's public policy concerns often ran counter to his own personal research interests and he sometimes waged his bureaucratic battles in such a way that he ended up in charge of what he opposed.

When, in 1974, for example, the public grew concerned about the potential danger of new gene-splicing techniques, he helped engineer a moratorium on such research, including a ban on genetic engineering experiments he himself was anxious to perform. Then he lobbied to have those voluntary guidelines become federal regulations, heading off efforts in Congress to enact even more restrictive legislation.

And when, a few years later, he became convinced the dangers had been overstated, he worked just as hard--and just as successfully--to have those regulations relaxed.

In the early 1980s, he fought a crash project to map all human genes--the $1-billion Human Genome project--even though it offered new sources of federal funding that would have benefited his chosen field of molecular biology. Though he worried that it threatened more traditional biological research, he eventually chaired the NIH committee that recommended the project. The Whitehead Institute eventually became the flagship of the genome project, with the single largest federal grant today for gene mapping.

He became an early champion of federal AIDS research and chaired a national commission in 1986 that concluded the federal government's response to the AIDS epidemic was dangerously inadequate. The commission called for a $2-billion research effort to avert a public health "catastrophe." Today he is chairman of the NIH advisory committee that effectively oversees the search for a vaccine against what many consider the world's leading public health problem.

Throughout it all, he still found time to continue his own research into the nature of viruses and molecular immunology. So far, Baltimore has published 536 peer-reviewed research papers.

The controversy over one, however, which seemed to embody a power struggle for the public soul of science, almost destroyed his career.

*

For much of the past decade, it has been impossible to discuss the issue of integrity in science without considering the matter of David Baltimore.

In one of the country's most celebrated investigations of alleged misconduct in science, Baltimore was condemned and then dramatically cleared, when the government's case abruptly collapsed last year.

The controversy involved a research paper published in the April 25, 1986, issue of the research journal Cell on immunity cells in genetically engineered laboratory mice. The researchers analyzed the way the altered mice produced antibodies against simple chemical compounds, and concluded that by inserting a foreign gene into the mice, they had prodded the immune system into producing antibodies that mimicked those of the new gene. If true, the finding offered the possibility that, through genetic engineering, researchers could take command of the body's defenses against disease.

Baltimore's own technical contribution was never in question. But, wrote Harvard biologist Paul Doty in an acerbic letter to the journal Nature, another co-author's work was at best "so sloppy as to insult the scientific method," and at worst raised troubling allegations of fraud.

Baltimore defended the honesty of his problematic co-author. Although it was never suggested that Baltimore himself had falsified data, he came to symbolize for many the unwillingness of the powerful to admit error or give proper weight to concerns raised by junior scientists, such as the postdoctoral student who first questioned the research paper.

No one ever duplicated the experiment, and a debate raged within the scientific community on how best to handle doubts about the research. There were internal reviews, apologies, corrections to published data and retractions, but to critics they always seemed grudging or too limited. They seemed to exemplify the unwillingness of science to police itself or accept public oversight of the billions in tax dollars spent on research.

The dispute culminated in contentious congressional hearings, chaired by powerful Michigan Rep. John D. Dingell, about alleged fraud in federally funded research projects. Four federal investigations and a grand jury probe ensued.

And when Baltimore's own integrity was directly challenged, the bearded biologist with the unwavering blue eyes responded with a complete heedlessness to consequence.

"Dave is a very proud guy and he can be very obstinate as well," says Stanford's Berg. The accusation "just inflamed Baltimore. He was not contrite. He was like a red cape in front of a bull."

The political coup de grace to Baltimore's reputation was administered through the leak in 1991 of a harshly critical draft federal report that was made available to reporters--and sent to his most prominent academic critics--before any of the accused had an opportunity to see it. Again, the report did not suggest Baltimore himself had been party to fraud, but castigated his behavior in defending his colleague as "deeply troubling."

"I knew the report was all wrong but I could not convince most other people of that. They saw it as a condemnation," Baltimore says.

Under growing pressure, he resigned as president of Rockefeller University and returned to MIT.

"It was the first rough spot in David's road," says one longtime Cambridge colleague who asked not to be identified. "He did not have the experience of being wrong about something. He is not someone who could easily say he made a mistake. I think the experience acquainted him with fallibility--perhaps for the first time. He had his comeuppance, you could say."

Still, Baltimore's research never flagged.

During the decade he wrestled with the Cell controversy and the power struggles at Rockefeller, he published 194 papers, including several of the period's more interesting findings in molecular biology.

But those who have known him the longest say the affair had a lasting--and perhaps chastening--effect.

"For me, he became a more accessible human being," says Whitehead biologist Rudolf Jaenisch.

Then, in one of the remarkable reversals in American public life, an NIH review panel handed down a 200-page decision last June that completely repudiated the federal investigation as politically motivated and its evidence as deeply flawed.

Indeed, the evidence of the appeals panel--6,500 pages covering six weeks of testimony and a review of 70 original laboratory notebooks--suggests that Baltimore appears to have been singled out for censure because, like a Puritan elder unwilling to join a witch hunt, he was guilty of insufficient zealotry. (The colleague he defended was able to pick up the pieces of her research career.)

Baltimore today acknowledges that his own actions may have, in part, prolonged the controversy, but he believes much of the criticism was aimed not at the experiment in question but at him personally: "I do not accept insults lightly. John Dingell revels in insulting people. He wants them to squirm and take it. And I would not.

"That has to do with my feeling about my own self, and I think there is a real sense that, had I been willing to accept whatever he wanted to dish out, I might have had less trouble. But I am willing to put up with that.

"If, in being true to myself, I have to take a bath, I am willing to take the dip. I think that, in the end, by standing up to Dingell and helping the scientific community to see what he represented, I did something that was important."

*

Baltimore's third-floor office in MIT's building 68 is a warren of unfiled papers. Pictures of his wife and daughter dot the walls. Awards crowd the top of the corner file cabinet. A photograph of Steven Spielberg and the filmmaker's mother--by Mariana Cook, the same person who took Baltimore's official portrait--is propped against the desk lamp.

Baltimore accounts for Spielberg's picture by explaining that he attended a benefit premiere of "The Lost World" in Great Falls, Mont.

With Weissman at Stanford and molecular biologist Leroy Hood at the University of Washington, Baltimore owns a 160-acre fishing camp near Hamilton, Mont., where he often vacations to fly-fish the Bitterroot.

The social and psychological distance between prewar Manhattan and modern Montana is one telling measure of how far Baltimore has come in his life. He wheels his chair to the only clear space in his MIT office, settles himself and considers his origins.

David Baltimore was born four days before Hitler invaded Austria, in New York Hospital, next door to Rockefeller University, where, in 1964, he would receive his PhD and later briefly lead. He was the first of two sons. His brother, Robert, is a pediatrician on the Yale faculty.

Their father, Richard, was the only son of poor Orthodox Jewish parents and was orphaned at age 14, his older sisters working to support him because "the one boy in the family had to at least graduate from high school," Baltimore recalls. His father entered the garment business, and by the time David was born, he owned a small company manufacturing women's suits and coats.

"His best years were during the Depression," Baltimore says. "He was a very smart, intellectually very interested man, who with more opportunity might have done something very different in his life. He never wanted me to continue in his footsteps. Not for a second did he think I should be in that business or, for that matter, any business."

His mother Gertrude was a tailor's daughter who grew up in a more secular Jewish household and became a tolerant nonbeliever who saw the high holidays as important family events. She worked in the retail end of the garment business.

After Robert's birth, she went back to school, earning advanced degrees in psychology from, and then joining the faculty of, the New School for Social Research. At age 62 she became a tenured professor at Sarah Lawrence College.

"She got a master's and did everything she needed to do to get her PhD except her thesis. For reasons that were never clear to me, she did not do a thesis," Baltimore reflects. "I suspected, but never was sure, that she held herself back because she had gone so much further than my father in her intellectual life."

When David was still in high school, his mother arranged for him to take a summer course at the celebrated Jackson Laboratory in Bar Harbor. There Baltimore met Swarthmore College senior Howard M. Temin, with whom he would one day share the Nobel Prize. Amid the lab mice, cell cultures and summer research projects, Baltimore had his defining encounter with the spirit of science, which he would vigorously pursue as an undergraduate at Swarthmore.

"It was the process of research. I discovered that I could investigate the unknown as a high school student, that the frontier of knowledge was actually very close and very accessible," he remembers. "That is something we almost never realize as a high school student.

"You think of the frontier of knowledge as being someplace in a very abstract place. This made it very concrete and very near."

*

It says something about the mind of David Baltimore that, as the son of a Gestalt psychologist, he settled on biology.

For all its precision tools of molecular genetics and biochemistry, biology remains an intuitive science that in some ways still resists the objective weights and measures that rule physics and engineering. Biology is full of oblique, indirect experiments--intellectual bank shots that carom off the truth that nature has so artfully hidden in living things.

Whether it is Darwin divining the process of natural selection or the team of Crick and Watson discerning the molecular structure of DNA, the science of biology often progresses by inference and inspired guesswork, illuminated by flashes of informative experiment.

It is wet work, messy, an exercise in loose ends.

"When you are a scientist, and you are trying to prove or disprove a notion, you work at the bench doing the dullest, most routine things over and over and over again," Baltimore explains.

"You can't believe how tedious scientific research can be. Getting the answers that are half answers and trying to massage the system so it will behave better and dealing with the contaminations that come along and the machines that don't work and the reagents that are mislabeled. . . . I can't tell you how many ways things go wrong. All the time you are doing this because there is an idea behind it."

The same is true, he says, in building an institution, be it a large research institute such as the Whitehead or major universities such as Rockefeller or Caltech:

"You can, as an administrator, have a vision. I had a sense of what I wanted to do building the Whitehead Institute. I did not have a blueprint all worked out, but I had a sense of what I wanted to do and where I wanted to go, and I was able to realize that.

"In order to realize that, I had to be a politician. But all of that was in the service of a larger vision, which I never lost sight of."

Baltimore expects Caltech to benefit from his own past mistakes as a university president.

When he became president of Rockefeller University in 1990, he arrived on campus intent on shaking up a venerable institution that, by general agreement, was financially troubled, top-heavy with senior scientists and seriously adrift. He arrived with a considerable faction of the faculty set against him.

He lost no time in dealing with the fiscal crisis by imposing a salary freeze. He acted quickly to break up academic gridlock. He moved to phase out the physical sciences, coaxed $20 million from a private benefactor and brought in his own administrative cadre to carry out his reforms.

Every action stiffened faculty opposition to his tenure. The controversy over the Cell paper only made matters worse. He retreated into a "shell," according to one former trustee. And Baltimore today acknowledges that he exacerbated matters by simply moving too quickly to make major changes:

"What I learned--and what I hope will hold me in good stead in going to Caltech--is that you can only move so fast at a university, and I was trying to move too fast. I was trying to do too much. I had an image of what I wanted Rockefeller to be, and instead of helping that image to develop in other people's minds and to help it along, I tried to force it too much."

For now, he plans to be open to the promise of Caltech. He hopes to be adept and adaptable enough to steer himself and the university around shoals of change. Baltimore has no sense of impending crisis, and he will come with no entourage of handpicked aides.

"I have the sense of an institution that is, in fact, moving along very effectively, where there are opportunities to move in new directions," he says.

There will be, however, at least one new hire on his administrative staff: His wife will likely take a role in external development and government relations. Huang, a distinguished scientist in her own right and a former medical school professor at Harvard, resigned as dean of science at New York University to accompany Baltimore to Pasadena.

He says they hope Caltech can take advantage of her talents without creating the tensions a husband-wife management team sometimes generates among employees. "We have to define that [working] relationship carefully," he says. "We are both conscious of it."

While Baltimore would like Caltech to become more engaged in policy issues and the surrounding Southern California community, he is wary of changes that may tamper with what he sees as its unique academic character.

"Caltech historically has been a pretty insular institution," he says. "I worry about messing with that very much because Caltech has been so extraordinarily effective. I think its insularity may have been part of its greatness.

"I don't want to see us lose that. We will move cautiously."

*

One clue to the ambitions that animate Baltimore can be found in the events of a turbulent week 27 years ago last April, when American troops unexpectedly invaded Cambodia.

It was a moment of spontaneous national combustion, when differences over the Vietnam War ignited on campuses nationwide. At MIT, where the young biologist was already a professor, antiwar protests were especially passionate because the school and its graduates had engineered so much of the war's high technology.

So it may not have been surprising that Baltimore locked his laboratory and, for a week, joined thousands of students and other teachers crowding Massachusetts Avenue in protesting the government's Vietnam policy.

What made his action noteworthy, however, was that he suspended research on the day he had completed a deceptively simple experiment in the genetics of viruses, which--when confirmed--would revolutionize molecular biology and win its discoverer the Nobel Prize.

Baltimore does not volunteer this story and, when reminded of the incident recently, he discounts it: "[Protesting] was clearly of transcendent importance, more important than a scientific experiment, which could and did go on the following week. [The invasion] was probably the greatest insult to right-thinking people that one could imagine."

He did indeed return to the experiment a week later, speedily confirmed it, and wrote up his findings. His finished research paper arrived at Nature on June 2, only 13 days ahead of a manuscript detailing the same discovery from Temin, his friend and research rival.

In 1975, they shared the Nobel Prize for medicine for the work, along with Salk Institute biologist Renato Dulbecco.

The Nobel Prize itself, arriving at the threshold of middle age, left him with a certain sense of isolation, even as it created opportunities, he recalls:

"I don't see it as a burden, but you can't get away from it. I know that when I talk to young scientists, they are looking at me and saying: 'God, I am talking to a Nobel Prize winner.' I try to break that down with the people in my own laboratory and think I do. It gets harder every year."

Indeed, Baltimore prides himself on being especially responsive to young scientists. At the Rockefeller, for example, he appointed or promoted 45 junior faculty members in his first year.

Robert A. Weinberg, a prominent cancer biologist at the Whitehead who was awarded the National Medal of Science in May, says Baltimore "always took pains that people in his shadow acquired their own identity. A junior person can easily be perceived as an appendage."

Nonetheless, younger colleagues say, Baltimore also is unsparing in his demands for excellence.

Peter S. Kim, an expert on the structures of virus proteins who serves with Baltimore on the AIDS vaccine committee, was hired as a Whitehead fellow in 1985. Kim says that Baltimore personally reviewed every grant application before it was allowed to leave the building: "I remember getting my first grant application back with red ink all over it."

And Richard Young, among the first young scientists Baltimore hired when he organized the Whitehead Institute, says his mentor was "utterly unforgiving." Still, Baltimore "had a way of offering the most brutal criticism to young faculty and then going out of his way to have you out for a beer or over to his home, so you would know that it was not personal."

Baltimore will continue that approach at Caltech, remaining convinced that new opportunities in science come from the thinking of young people:

"It is difficult. You have to find people when they are less obvious. You have to help them through sometimes difficult times in molding their careers.

"But in the end, the rewards are greater."

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