THE AIDS WINDFALL

By Barry Werth

New England Monthly June 1988

For two Boston scientists, the epidemic has left a hidden legacy: riches, power, and fame.

It was during the last two months of 1980 that doctors in California and New York began to note that a rash of mysterious illnesses, afflicting perhaps fifty young men, was in all likelihood more than mere coincidence. What was it? For most of the century the great triumphs of medicine had all centered on the discovery of new agents of disease and their eradication by "magic bullets," either drugs or vaccines, Surely the disease we now know as AIDS qualified for such attention. And yet, this time science held back.

Biomedicine generally likes to decide what to study on the basis of what interests it most, and the possibility of this new contagion did not, scientifically at least, look especially interesting. Whatever was killing the young men was unlikely to advance the main line of research. Nor was it likely to yield, in the lovelorn argot of the trade, answers that were "pretty" or "elegant." This new mystery disease looked nothing if not dreary, a routine microbe hunt on the fringes of scientific respectability. "Science," says MIT Nobel Laureate David Baltimore, "is much better at solving problems of its own devising than those it is asked to solve." Most scientists hadn't asked for this problem and had little interest in adopting it now that it had been dropped at their door.

There were, however, a handful of researchers who had, in some sense, asked for it. Because of what they were studying at the time they couldn't help but be intrigued. Dr. Robert Gallo, the head of tumor cell biology at the National Cancer Institute, had been looking for a dozen years for rare human viruses that attacked the blood and were suspected or suppressing immune response. Gallo instantly became the frontrunner in the search for the cause of the new disease. Eventually, he helped find the AIDS virus. He became famous as the country's, if not the world's, leading AIDS expert, and then infamous as the willful researcher whose 1984 battle over credit for the discovery resulted in an international incident between the United States and France.

But Gallo was not the first to envision that AIDS was caused by the kind of virus he'd been pursuing. Dr. Myron Essex, a Harvard virologist and friend of Gallo's, had suggested the possibility much earlier, soon after the first cases were reported. Max Essex, as he is known, was perhaps the first to propose publicly that what was killing gay men was probably a new virus, that it was quite likely spread sexually, and that the profound devastation it wrought was the result of a collapsing immune system. Incredibly, he had even foreseen all this. Essex, unlike Gallo, hadn't only been called to AIDS. He'd called it.

Meanwhile another Harvard scientist, Dr. William Haseltine, found AIDS as the culmination of years of theoretical research. He, too, as it would turn out, had been looking for the very disease itself. "Ask my friends," he would later declare. "I predicted [AIDS] ten or fifteen years ago."

What was it? In the first terrible months of the AIDS epidemic, when it could have been anything, most scientists weren't interested, and even Gallo was unconvinced; Max Essex and Bill Haseltine almost alone appeared to have already guessed. Their assertion of a new virus was an extraordinarily prescient piece of science, the importance of which cannot be overestimated. And, for anyone who knew the culture of high-stakes biomedical research, it was also the break of a lifetime.

If it hadn't been for AIDS, Essex would still be working with cats. Essex is a veterinarian by training who turned to research early in his career. He began studying feline leukemia, which kills more cats than any other illness and is transmitted by a virus. That certain cancers can be "caught" like infectious diseases had long been a controversial notion among researchers. Yet by the time AIDS struck in 1981, Essex was one of a halfdozen virologists worldwide who had transformed the study of cat leukemia into a mainstay of human cancer research. He has been at Harvard since 1979 and is chairman of the department of cancer biology at the School of Public Health.

Essex's first great observation was that cats were spreading the leukemia virus through sexual contact and saliva. Until then, viral cancers were thought to be solely hereditary, running in families as stowaways in the vessel of the genes. But by the mid-seventies Essex and others were asking, If cats can infect each other with cancer through intimate contact, why not people? Essex was also among the first to note that most infected cats weren't dying of the leukemia, but that their immune systems had collapsed. giving way to an onslaught of "opportunistic" diseases. Again, he and his collaborators asked, Couldn't something similar occur in humans? Couldn't there be a cancer virus that decimated white blood cells, making us prey to other infections that normally don't kill?

It was a chilling notion and an extraordinary leap: in effect, a theory in search of a disease. But theoretical maladies are scarcely hard currency in science. Essex was positing these questions during Richard Nixon's War on Cancer. It was a time when many of the country's leading biomedical researchers were being paid to kind some connection between their own work and a cancer cure, all with notoriously limited success. And so, though his cat research was widely respected, his excursions into human viral theory attracted little attention.

It would seem that the progress of science is inevitable, that discoveries follow one another logically and that lines of inquiry are self-selecting. But often that's not the case. Usually, science lurches in a given direction because of what society, or scientists themselves, want from it. The War on Cancer, which dominated biomedical research during the first two-thirds of the seventies, exemplified one way to do science: managing research to achieve a social goal. The idea was that with enough money the federal government could will biomedicine to eradicate a major scourge. But the program failed - no cure for cancer was found. And its most inglorious failure, from a scientific standpoint, was precisely the inability to find the type of cancer-causing virus that Essex, Gallo, and a few others were so assiduously promoting. These viruses were well documented in cats and other animals, but no one could prove their existence in humans, despite perennial claims to the contrary.

The indifference to Essex's hypothetical disease has to be seen in this context. Managed research had become, by the late seventies, anathema to organized science, yielding to a new entrepreneurial system. Those who, like Essex, Gallo, and Haseltine, had found the War on Cancer such a boon were widely discredited. Human tumor viruses were now mocked - human rumor viruses, they were called. It became increasingly hard for those who believed in them to find funding or to get their work published, which for a scientist amounted to being boycotted. By the end of the decade - though what they were doing would turn out to be indispensable for understanding AIDS - in cancer research, where it mattered, their ideas mostly were considered passe.

What they needed was a breakthrough, and in 1980 Gallo provided one by discovering the world's first human cancer virus. He called it HTLV, for human T-cell lymphotrophic virus, which meant it was attracted to the white blood cells that normally lead the charge against infections. The disease it caused was neither major nor widespread, resulting in isolated outbreaks of lymph cancer in the Caribbean basin, Africa, and southern Japan. But suddenly those who believed such a virus eventually would turn up, Essex and Haseltine included, were no longer unfashionable. They were rehabilitated by Gallo's discovery, and by the rules of the game, they were entitled to bragging rights.

"There are a lot of people who take chances," Essex says of the rough-and-tumble of science, "who get fried for it." Sitting in his paper-crammed office in an outsized executive chair that makes him appear small and strangely vulnerable, Essex seems an unlikely oracle. His hard-angled face is framed by a halo of salt-and-pepper hair, giving him the aspect of a rapacious teddy bear. Gallo's discovery reversed Essex's fortunes and sent his stock soaring even before AIDS erupted. Unlike Gallo, he'd suffered the rebuke of his fellow scientists privately, and when it was over, he acted as if it had never touched him, as if he'd always known he would be vindicated. This was typical of Essex. Though he could give an impression of weakness, he had a rare sense of his own scientific preeminence. Now, with the discovery of HTLV, the world had to concede that, too, and for Essex, that meant not having to conceal his ferocity. Behind his chair is a framed close-up photograph of a cat—with the lower half of a mouse's body dangling from its mouth.

Only at the highest magnifications under an electron microscope does the AIDS virus begin to look sinister. An infected human cell will be spattered with hundreds, if not thousands, of black dots - new virus particles - that appear to be spreading outward. As the theory goes, the AIDS virus hijacks a healthy human immune cell by slipping into its gene package and hot-wiring it. The cell, overcome, forgets its role as one of the body's main defenders and starts churning out endless amounts of new virus. Then, when all elements of the virus are assembled, the cell ruptures and the virus particles are extruded into the blood, killing the host along with potentially billions of other cells. Such viruses are called retroviruses because they oppose normal genetic conventions. Genetic information generally flows from DNA, where it is stored, to RNA, which serves as a messenger, to proteins, which are the functional molecules in cells. But the genetic information in retroviruses is in RNA, which can be turned into more permanent DNA once the virus invades a host cell. This ability of the AIDS virus to reverse a host's mission by tinkering with its chromosomes - converting sentinels to assassins through chemistry - is precisely why it's so hard to pin down, and so feared.

Haseltine is a molecular geneticist, which means his job is to go much deeper into the world of viruses than can be seen under the microscope, to the information within the molecules inside genes. There may be more fundamental ways of looking at life, but biological science hasn't found them. The chemical organization of these molecules dictates what a virus, or any organism for that matter, will do, from replication to (as with the AIDS virus) making a Trojan horse of its host. To Haseltine and others like him, the fight against AIDS is a fight to control that process.

Late in 1981, after Gallo discovered HTLV, Haseltine plunged into the attempt to characterize it in his lab. The first step for understanding a new virus is to identify its genes and how they connect with one another - their "sequence" - and Haseltine, who is chief of biochemical pharmacology at Boston's Dana-Farber Cancer Institute, is skilled at the trade. But Haseltine also did what by then had become not only possible, but expected, for a top microbiologist astride a growing field: He started a biotech company.

Not every ranking basic scientist goes into business, but the economics of research surely favor it. Molecular genetics not only revolutionized biological science, but also made that science fabulously profitable. Now, every theoretical breakthrough, every find, is potentially the basis for a new generation of drugs, and enterprising researchers soon see the opportunity to capitalize mightily on the transfer of information.

Haseltine was a born entrepreneur. Aggressively intelligent, he'd been on the fast track from the start: graduate work at Harvard, postdoctoral fellowship at MIT with David Baltimore. Now, with Wall Street's mania for biotechnology mounting, he had little trouble funding capital for a new firm. Nor was there a problem tapping into the most promising new research: Haseltine simply invited several of his friends from human retrovirology's recent dark days, Essex and Gallo included, to be his partners. Gallo, as a federal employee, was barred from joining because of possible conflicts of interest. But Essex had no such constraints, and he gladly took an equity position in return for becoming an exclusive consultant to Haseltine's firm. And so within twenty-four months after the world had its first human retrovirus, it also had a pioneering retroviral company: Haseltine's Cambridge BioScience. Its expectations were modest: Its first project wasn't in human diseases but in the more established area of animal vaccines.

Just as molecular genetics made basic research profitable, it also made it expensive, and Haseltine and Essex both now needed new money to begin working on HTLV in their labs. Long-term funding was the first requirement of any new work, and in recent years, research institutions such as universities and hospitals had increasingly forged so-called strategic alliances with industry to subsidize their basic science programs. The institution got its financing; the company got proprietary rights on any new discoveries. Everyone, presumably, was served.

Haseltine, working at Dana-Farber, sought funding from the National Institutes of Health and foundation sources. Essex, at the School of Public Health, turned to Harvard to find support from industry. These were supposed to be straight-up deals. But Harvard, more than most universities, agonized over making them. As a self-appointed guardian of academic principles, it felt it had a mandate to put science in the service of truth and the commonweal, not simply the highest bidder. Nonetheless, it began soliciting major drug companies on Essex's behalf. No one was interested. What the companies wanted were promising leads on ulcers and cholesterol, which were afflicting millions of health-conscious, premium-paying Americans, not an obscure Third World virus. No business was going to divert money from its own mainline research to subsidize Essex's hobbyhorse - no company, that is, except Cambridge BioScience.

It would be hard to overestimate Harvard's chagrin when the only firm even remotely interested in supporting Essex's new work was Haseltine's own fledgling start-up. It was bad enough that any company would have to be involved. But with Cambridge BioScience, Essex and Haseltine would stand to profit from the very work Essex was conducting at Harvard. Harvard would own the patents to anything he discovered, as it did with all its faculty. Yet the company would have the license, which is where the real money was made. Thus it would have a vested interest in what research Essex chose to give priority to and how he assigned graduate students to experiments. It was a blurring of business and education, and Harvard was mortified. "If there'd been anyone else," says Ken Barclay, dean of administration at the School of Public Health and a negotiator for the university, "we wouldn't have given [Cambridge BioScience] the time of day."

Yet Harvard did manage to swallow its pride. It had to. With virtually every other research institution making these deals most of them much more aggressively than Harvard, they had become a competitive necessity. And so it agreed, finally, to let Cambridge BioScience sponsor all of Essex's work in human retroviruses - on HTLV or any other that might be discovered. For its part, Cambridge BioScience got exclusive rights to Essex's discoveries. In the end, the months of tedious negotiating may hardly have seemed worth it. With the HTLV market so small, the agreement was an option on future discoveries, and no one could guess what those would be.

Haseltine, nonetheless, was pleased. The field of human retrovirology was now quickly being rehabilitated, and his company was right there with it, running alongside. If Haseltine was right, retroviruses caused up to a quarter of all human cancers, as well as AIDS. The world was verging on a period when medicine would be battling retroviral diseases everywhere. And he alone was neatly poised to help the world fend off those plagues while reaping the maximum rewards for his effort. He had his research. He had his company. And his company had Essex (and by association, Gallo). This was how modern science worked. If retroviruses were a major threat, somebody was going to profit. Why not him; "The AIDS virus," he once said, speaking generally of the imperatives of science, "does what it does, and so do we."

In June 1982, some eighteen months after the first AIDS deaths in the United States, Essex began testing blood samples from a Japanese infectious-disease ward in one of the first attempts to explain how HTLV worked. As he had expected, patients suffering from pneumonia and other bacterial infections were also three times more likely to be infected with the new virus, suggesting that the virus was weakening their immune systems. Essex was jubilant. Here was precisely what he had predicted - a human analog to feline leukemia. Privately, Essex began filling in the rest of his earlier vision: Maybe Gallo's first human retrovirus was the cause of AIDS.

Essex wasn't the only one excited by this line of inquiry. AIDS, coming from nowhere, had presented science with hardly any clues to help determine its cause. No one had seen anything like it before, so investigators were grasping even the thinnest of leads. New bacterial and toxins were routinely proposed and rejected. Variations on existing venereal diseases were suggested, then dismissed because their pathologies were dissimilar. Linking many of the first cases together through attendance at gay bathhouses, epidemiologists even began doing toxicological tests on Crisco, a preferred lubricant for anal sex, and amyl nitrate, a popular gay party drug. And yet here was Essex, suddenly presenting hard evidence of similarity with a known disease. It was the first truly hopeful breakthrough of the epidemic because it abruptly narrowed the search area. Supported by some promising data from Gallo who had just begun working in AIDS, Essex spent the rest of 1982 studying blood and tissue samples, persuaded that if he wasn't on to the exact cause of AIDS, he surely was close.

Essex's work connecting HTLV with AIDS was published in the spring of 1983, nearly a year before the putative cause of AIDS was identified and the public feud between Gallo and French virologist Luc Montagnier began making headlines. The new virus, later dubbed HIV for Human Immunodeficiency Virus, was not HTLV. That virus, causing cancer, "immortalized" white blood cells, making them replicate uncontrollably. But those dying of the new disease had white counts near zero. Nonetheless, the AIDS virus was a retrovirus, just as Essex had said. He'd been wrong in all the particulars, but right in general, and being half right secured him the undisputed mantle as the prophet of AIDS.

In the case of almost anyone else, being half right on an issue of such critical importance would have meant instant and universal acclaim. But it became clear soon after the discovery of the AIDS virus that not everyone was eager to recognize Essex's contribution. This was more than competitive jealousy, or the bitter residue of the War on Cancer. It had to do with Essex's style of research. Essex tends to make grand leaps, to be an intuitive thinker who sees what others are incapable of seeing, then waits for others to provide proof. He has on occasion believed he was light despite a shortage of evidence, then castigated his critics as slow and unimaginative when they have insisted on more data. Gallo exhausted himself collecting data from four continents to build a case for HTLV, but that's not Essex's style. His faith appears to be not so much in the rigors of science as in himself, and while it has led to great triumphs - with human retroviruses, for instance - it has also resulted in some failures.

This was the other Max Essex. As a postdoctoral fellow in the early seventies, he and his chief collaborator in cat research, William Hardy of Memorial Sloan-Kettering Cancer Research Center in New York, began speculating about an extraordinary defense mechanism that prevented cats from getting leukemia. They called it FOCMA, for Feline Oncornavirus-associated Cell Membrane Antigen, and it was supposed to do what only foreign microbes were thought to do, that is, direct the body's immune response. The implications were startling. Here was something the body knew how to manufacture that could help ward off cancer. Dozens of scientists went off in pursuit of FOCMA.

But no one could prove FOCMA existed. Essex abandoned the subject, and he refused to pursue the criticisms of those following it up, or to retrace it. He simply let FOCMA hang, and other scientists were understandably incensed. "We'd have figured it out ten years earlier if Essex had only done his homework," complains one researcher.

Essex clung to his HTLV theory even after the discovery of HIV. His reluctance to consider the doubts about his work raised concern over his role in AIDS from the start - and not only his role. Other researchers began suspecting Essex, Gallo, and Haseltine of having their own agenda to promote the particular family of retroviruses first found by Gallo. This was said to explain Gallo's attempt to have the AIDS virus named HTLV-III (a second human T-cell lymphotrophic retrovirus, HTLV-II, was discovered by another virologist in Gallo's lab in 1981) and Essex's lingering support for HTLV. Nonetheless, since they'd been largely right about the central challenge to AIDS prior to 1984 - the search for a cause - they automatically assumed a leading position in the next phase, the search for a cure.

The way a society fights a disease once it finds the cause reflects certain cultural norms. A society united by crisis will tend to marshal its resources and subjugate the interests of individual researchers to the whole; a competitive society in the throes of merger mania is likely to evolve competing conglomerates. Such was the American model for developing magic bullets in the era in which AIDS arose. A basic researcher, using seed money from government and industry and acting through a research institution such as a university or hospital, joins with a biotech firm and drug company in a vertically integrated strategic alliance. The speed, direction, and tenor of research are set by the competition between alliances more often than by any other single factor.

By 1984 the alliance forged by Essex and Haseltine (with Harvard, Cambridge BioScience, and potentially the pharmaceutical companies) was among the most strategically located of any grouping in AIDS. Haseltine loved the whole notion of strategic alliances, seeing in them a hugely efficient system for pushing ahead the pace of discovery by ensuring that scientists got what they wanted: the chance to do critical work, get recognized for it, and make good money at it. And so as AIDS research entered the next phase, Haseltine, perhaps more than anyone else in the field, brimmed with optimism and confidence about where it was heading. "This is the group that played a key role in discovering the AIDS virus," he would announce in 1985, "and it will have a lot to do with bringing you a cure."

The fight against AIDS invites comparison to the crusade against polio. In the spring of 1955, when Jonas Salk's vaccine was about to become one of the most widely disseminated and potentially profitable magic bullets of all time, Edward R. Murrow asked Salk who held the patent. "Well, the people, I would say," replied Salk. "There is no patent. Could you patent the sun?'

That was then. Now, three decades later, as science fanned out in the search for a magic bullet for AIDS, no statement from a leading researcher could have been less likely. The question in 1984 with AIDS was never whether there would be a patent, but how many, and how the royalties would be structured.

Modern researchers don't have to invent anything per se to apply for and receive patents. Advances in molecular genetics meant that the discovery of every gene, every surface molecule, every snippet of DNA had potentially vast commercial uses. As a consequence, in 1980 the U.S. Supreme Court ruled that such discoveries were entitled to full protection under existing patent laws: You could patent life itself. Discoveries were now inventions. Microbiologists were inventors. Getting credit for one's work suddenly wasn't just the main thing, but everything.

Like the shattering of a taboo, this redefinition unleashed a new era of self-interest in basic research. Biologists who once shared ideas and materials freely, who "cloned by phone," became more secretive, more protective of data, and more frantic about getting recognition for their work. Journals sprang up whose sole function was to reduce the lead time for publication so they could rush their findings into print, a published article being Exhibit A in any patent fight. Universities, earning millions of dollars in licensing fees, amassed "war chests" for cracking down on unauthorized use. When a lab at UCLA used a cell from a patient's body to start a cell line for experiments, then licensed it to two companies that used it to produce the drug interferon, the patient sued for compensation.

It soon became clear that AIDS research would not be exempt from the new competitiveness. Where rival researchers once tolerated one another, they now spread rumors. One of the most persistent was about Gallo, though as a federal employee he was entitled to only token royalties from his discoveries. As discoverer of HTLV and titular co-discoverer of HIV, he held the "gold standard" for most AIDS-related reagents - that is, those viral isolates, cell lines, and clones that anyone working in AIDS would need for their experiments. In one celebrated instance Gallo refused to share these. Afterward, he was increasingly said to be hoarding reagents. It was a serious charge - a federal official creating obstacles in a public health emergency - and he denied it strenuously. In fact, Gallo shipped ample materials to most labs freely. In return, he was credited with co-authorship on an astonishing number of research papers - more than two hundred in the eighteen months immediately following the isolation of HIV. Even without a profit motive, Gallo came to exemplify the drive for individual credit in AIDS.

With HIV from Gallo, Essex and Haseltine soon were plowing ahead with major discoveries of their own. Haseltine helped locate the gene that makes the virus replicate so furiously. Using a form of chemical scissoring, he was able to snip it out in vitro and deactivate it, stopping replication cold in the lab. But Harvard's big breakthrough in AIDS belonged to Essex. Working under his contract with Cambridge BioScience, Essex found what has so far turned out to be the most commercially important "invention" of the entire AIDS era: a protein called gpl20 extending like a gaff from the virus's outer shell.

Microbiologists had suspected its existence for some time. Something on the outside of the virus was leading it to a cell and getting it inside. If experience was any guide, it was probably the same thing the body's surveillance mechanism keyed in on as it sought to design effective antibodies. Whatever this protein was, "inventing" it would have untold applications in AIDS test kits, vaccines, and antiviral drugs. Perhaps only the discovery of HIV was more critical to the progress of research.

Essex was now not only the prophet of AIDS, but a leader in the attack against it. But the larger prize belonged to Cambridge BioScience. What had looked like a moderately promising deal when the company elected to back Essex with HTLV was now turning into a boon with AIDS. With the rights to gpl20, the firm suddenly had the potential to develop a magic bullet for what was fast becoming a pandemic. Either Cambridge BioScience would develop drugs or a vaccine itself, or it would license gpl20 to whoever did. Either way, it won big, something Wall Street was quick to notice.

Before long, the company would move to a gleaming new glass-and-brick headquarters in Worcester, Massachusetts, the first major tenant in the state's new biotech enterprise zone. It would boost its scientific staff to more than fifty. It would sign manufacturing and marketing agreements with pharmaceutical giant SmithKline Beckman and Institut Merieux, a leading French vaccinemaker, and commission huge, splendidly detailed computer generated lithographs of retroviruses to hang in its lobby. With actual product sales of less than half a million dollars a year, it would raise twenty million dollars in its fourth stock offering in as many years. Ultimately Haseltine, with 350,000 shares of stock, and Essex, with 150,000 shares, would become rich, their stock alone worth $4.7 million and $2 million respectively as of April of this year.

"We see a wave of devastating disease approaching..." The prognosis - careful, measured, authoritative—filled the crowded Senate hearing room as it was meant to, as a clarion call. "The magnitude and nature of the problem is crystal clear." Bill Haseltine had not been a national figure before and was hardly known outside the relatively small community of microbiologists who normally would be the only ones to care about or understand what he had to say. But his speech to the Senate Appropriations Subcommittee in September 1985 urging dramatically increased federal support for the fight against AIDS was as much a breakthrough as Essex's discovery of gpl20. Haseltine, it turned out, had a gift for talking about AID5 in a manner at once both relentlessly dire and upbeat. He could explain the disease in its most depressing details, yet convey such confidence about biomedicine's ability to fight it that he left one feeling exhilarated, even hopeful. He was the ideal spokesman. The media, ever eager for a simple take-home message in the mountains of data and counterdata they were being asked to comprehend, sought him out. Presidential campaign staffs asked his advice. Lay funding agencies coveted his counsel. "That Bill Haseltine," a cab driver at Logan Airport would announce - unsolicited - to another scientist, "that's the guy I listen to."

In less than six years, Haseltine, Essex, and Gallo had gone from relative obscurity to being among the world's leading experts on the number-one public health threat of our time - heirs apparent to Salk's legacy. They had priority now, which with any disease was what a researcher coveted most. And yet this was AIDS. Given the still small number of scientists working in the field, the fact that it was a new area (unlike, say, cancer) with no rigid hierarchy, and given the overwhelming public interest, being on top was not only a measure of one's prestige but an exceedingly rare opportunity to exercise power.

The group's agenda-building extended beyond getting good press. They also were starting to reshape the scientific debate by exercising the prerogatives of their success. Between 1984 and 1987, for instance, Haseltine was appointed to nine scientific committees, three of which allocated money for AIDS research. During the same period, he joined the editorial boards of five scientific journals, two of them concerned with AIDS, and became editor in chief of one of them. Once, he and Essex had been boycotted. Now he was in a position to decide who would be published and funded.

By 1986, the atmosphere in AIDS research was raising deep misgivings among many scientists. Patent fights, credit fights, nomenclature fights, allegations of sabotage within the Centers for Disease Control's AIDS virology unit - all were signs that the research community was aligning itself into hostile camps. It had become nearly impossible for a researcher to remain neutral, and outside scientists were increasingly discouraged from working in AIDS.

So while Haseltine's confidence may have been reassuring to congressmen and cab drivers, other scientists were critical. The magnitude of the AIDS problem, they knew, was not all that clear. Nothing about AIDS was, least of all how many people would get it. Haseltine had been quite prescient, in fact, predicting that 800,000 people would be carrying the virus in this country by 1990, relatively near the one million the National Institutes of Health are now projecting for 1991. But some of his other assertions about AIDS were highly debatable, and many researchers began to view them as ill-considered.

Science, as David Baltimore says, doesn't "proceed from truth to truth, but from suggestion to suggestion." Yet Haseltine was dogmatic. He spoke in gospel tones. Asked to speculate on some controversial aspect of AIDS, he would begin his response with a staunchly declarative, "We are certain . . ." and go on to cite as fact what others considered supposition. Like Essex, he implied that if other people didn't agree with him, it was their inadequacy, never his. One of the most troubling questions about AIDS was why there were so few infected cells relative to the number that were killed. Haseltine and others theorized it was because of a process called fusion. The diseased cell supposedly gathers a clump of healthy cells about it and kills them all in one murderous spasm. When others doubted the theory, or asked for data, Haseltine would simply brush them off by saying there was "no question." The theory still has not been proved.

Even those who worked closely with Haseltine and respected him found his boastfulness irksome. "I am certain," he began saying by mid-1987, "that by the year 2000 we'll have a curative therapy for AIDS, wherein through a daily regimen of antiviral drugs in low dosages the course of infection will be stabilized and asymptomatic individuals will live full normal lives without infecting anyone else." It was an exceedingly bold claim, and doctors at Harvard with far more experience with antiviral drugs found themselves suddenly having to maintain a safe distance from it, lest the world come to believe it. To believe Haseltine, as much of thc lay public had begun to, AIDS was well understood. But other researchers, who were looking at it just as hard and found it enigmatic and elusive, were increasingly troubled.

In the end, the underlying issue was much what it had been for a decade: human retroviruses. The argument favoring HIV as the cause of AIDS was now, if not irrefutable, remarkably strong. Yet there were those who refused to concede the fact, or the new hegemony of those who'd established it. Largely these were people who'd seen their own work in AIDS eclipsed and were resentful, but at least one, a Berkeley biochemist named Peter Duesberg, had no such motivation. Duesberg, though he had never done a single experiment in AIDS and had only a glancing knowledge of immunology, was nonetheless highly credentialed, a member of the prestigious National Academy of Scientists who in the seventies did pioneering work in oncogenes, or cancer-causing genes. Exploiting the well-recognized gaps in knowledge about how HIV worked in the body, he began debunking HIV as a myth - a creation, he said, of those who needed a powerful human retrovirus to redeem themselves. Duesberg also charged that the science of two of the leading proponents of human retroviruses - Essex and Haseltine - was suspect because of their vested interests. To make his point, and no doubt to garner publicity, Duesberg offered to be injected with HIV to prove it didn't cause AIDS.

The controversy between Duesberg and supporters of human retroviral theory quickly became personal, bitter, and well publicized. "Peter," says Haseltine, "has lost his respectability. His arguments are based on misrepresentation of reported information, avowed ignorance, and confusion. He's wasting our time." But responses like Haseltine's also documented something else: that in the contentious climate of AIDS research, most skepticism tended to be treated dismissively. Duesberg - may be wrong, but he has a point. While the evidence supporting HIV is overwhelming, there's still much more to be known. If Haseltine, Essex, and Gallo all could make mistakes, did it not behoove them to consider the weaknesses in their arguments? Their refusal to do so drew criticism from various members of the scientific community. Says prominent New York AIDS doctor Michael Lange, assistant head of infectious diseases and epidemiology at St. Luke's Hospital, whose own work has been overshadowed: "We've lost three years in AIDS drug development ... because of the Gallo/Essex/Haseltine axis boycotting other ideas."

Essex, for his part, always tried to overpower such attacks with new discoveries, knowing that scientific priority is determined ultimately in the lab, not in the press. After recovering from the damage over FOCMA and its echo - his persistent defense of HTLV - he launched into some of the most promising work of his career. He began investigating two AIDS-related viruses: one in African green monkeys, the other in apparently healthy prostitutes in Senegal. As the first known relatives of HIV, these viruses were invaluable. They were close enough in structure to help explain where AIDS might have come from and how it evolved, but because they apparently didn't cause disease, each was a critical genetic reference for finding the molecular variations that made the AIDS virus so virulent. A related virus might well be the basis for a vaccine - the ultimate magic bullet - the way cowpox virus is for smallpox. Essex even began calling the monkey virus the missing link.

The new work had the potential to be the great achievement of Essex's career, which by late 1986 was beginning to rival even Gallo's. He'd just received the Lasker Award, often a precursor to the Nobel Prize, along with Gallo and Montagnier. (Haseltine had been appointed to the jury the previous year.) His gpl20 was the basis for practically all vaccine development going on in the United States. And the media were beginning to recognize him as a star - his African work provided a focus for a highly flattering story in The New York Times Magazine about AIDS research at Harvard. At last, Essex was attaining the priority that had always seemed his right.

Except that eleven labs around the country, including Gallo's and Haseltine's, were furiously trying to clone and sequence Essex's monkey virus, and so far no one could.

Jim Mullins, a young colleague of Essex's at the school of Public Health, was intrigued. Inspired by Essex's early work in HTLV, Mullins had been working increasingly in AIDS, doing valuable genetic characterizations on new viral discoveries by Essex and others. Mullins had once been a protege of Essex's, lured to Harvard by the chance to collaborate with him when Essex was still working with cats. Now, at thirty-three, he was a recognized expert in precisely the sort of technical analysis Essex needed, and he saw a chance to help. The monkey virus didn't interest him, but the second, human virus, possibly relating more closely to his own work, did. So Mullins offered to try to clone the simian virus if Essex would give him the human virus to work on as well. Essex readily agreed.

Mullins seldom did his own benchwork anymore, but he knew that several labs, especially Gallo's, were already ahead of him. Either you won, Mullins knew, or it wasn't worth the effort. And so in early January 1986, he and three other researchers started working full-time on the simian virus, purifying it, extracting its genetic material, and beginning the complex series of experiments that would yield its genetic code. By early March they were through, finishing first. They hurriedly wrote up their results with Essex's group and, of course, they applied for the patent.

The euphoria was short-lived. When Mullins tried to isolate the human virus, he found it indistinguishable from the simian one. Initially he was startled, but he continued working anyway, knowing that it was possible, at least, for a monkey virus and a human virus to have the same genetic blueprint. Throughout the summer, though, he began to realize that he couldn't overlook the more obvious explanation: that the viruses were contaminated, that they looked alike because they were alike.

The beauty of science for Mullins lay in its exacting precision. Through rigorous and painstaking analysis, one could prove or disprove any assertion. He was not at all prone to the sort of intuitive long jumping favored by Essex and Haseltine. "All I ever wanted," he says, "was for everything to be absolutely precise." And yet he was jittery about confronting Essex with his hypotheses. Mullins knew Essex; he had been at his side with HTLV. Moreover, Essex was his department head, which gave him considerable say over Mullins's future.

Essex, understandably, chafed at Mullins's initial suggestion. There was no possibility of contamination, he said, and if there was, it must have occurred in Mullins's lab, not his. But Mullins, anticipating this, had spent weeks double and triple-checking his work, and by then there was no question. What Essex and researcher Phyllis Kanki had isolated and were sending around were not new viruses at all, but a previously known monkey virus first found in a colony of Asian macaques at the New England Regional Primate Research Center, an arm of the medical school twenty-five miles away in Southborough. Essex and Kanki had been working on the macaque virus upstairs. Someone, it appeared, must have inadvertently got some of it into the newer cell lines, where it overpowered Essex's African viruses and outgrew them - if indeed they'd been there in the first place. What Essex had been touting as the "missing link" wasn't from Africa at all, but from a domesticated group of Indian monkeys living in cages in a wooded Boston suburb.

There are those who would have loved to embarrass Essex for this, but Mullins wasn't one of them. Still, he was anxious to publish his findings. He wanted to set the record straight and save precious time and energy for everyone who was still following Essex's lead. But one had to be extremely politic in challenging Essex: His career was in a near-vertical ascent.

When Mullins went to Essex after writing up his initial results, Essex insisted on additional research, which delayed submission of Mullins's article by five months - months when other researchers increasingly debated the importance of Essex's African work; months when Montagnier began saying the second, human virus did, in fact, cause disease; and when characterizing it was considered paramount for determining whether there might be a second contagion emerging, a second wave of AIDS. Then Essex declined the customary courtesy of being listed as a co-author, in effect disowning not only the work but his own contribution to it. Finally, the article was published, but with the delicate subject of contamination only hinted at. Mullins was distraught. He'd tried to satisfy everyone, especially Essex, and ended up satisfying no one. "Everyone hated us then," he recalls. "Those people who thought Essex was wrong were pissed at us for not saying so. Those who thought he was right thought we were just out to get him."

Mullins had also talked with Gallo, who was furious that he was working on the human virus. He contends that Gallo told him he had a prior agreement with Essex that he alone would work on it.

Essex did finally try to resolve the contamination issue after others - not Mullins - started attacking him publicly. He still refused to believe his work was tainted, but he started developing new isolates for others to test. He maintains that he and Kanki even wrote a letter to a leading scientific journal - oddly, rejected - detailing their efforts. He finally issued a partial retraction last February, nearly two years after Mullins first raised doubts. Despite his inability to isolate them, he continued to insist that the importance of the viruses remained unchanged (which may yet prove to be true). And what of the charge from Mullins and others that he discouraged them from their own pursuit of the truth, that by not trying to get to the bottom of the matter himself he misled others, costing them valuable time? "Total bullshit," Essex says.

Not to Mullins. Grappling with Essex and Gallo had been the most demoralizing experience of his life, violating everything he believed about science. He'd lost sleep, he was tense. Worse than that, he was starting to feel distrustful. The precision of science, its rigorous honesty and dauntless pursuit of truth, were what he loved most in the world, and if he couldn't trust them, what was left? As much as Mullins wanted to work in AIDS, he decided it wasn't worth the harassment. And so he would work in human retroviruses only when there was a specific problem he was sure he could solve. But it seemed crazy. All he had done was what any true scientist would do. and now he was having to quit the very research where he was needed most. Meanwhile, he and Essex had stopped speaking, and his future at Harvard had begun to look uncertain.

"Our suggestion of the possibility of contamination," he says, "was consistently perceived as an unfriendly act."

And was it?

"No," Mullins groans. "No... no. It was just science."

There are scientists, and there are Men of Science. David Baltimore was a thirty-two-year-old researcher at MIT when, searching for the gene that makes retroviruses replicate so furiously, he discovered something far more elemental: reverse transcriptase, the enzyme that enables them to mimic, then enslave, the cells they infect. Baltimore's discovery won him the Nobel Prize in 1975 at the improbable age of thirty-seven, and ever since, he's been a leading champion of the new order in biomedicine.

Recently, though, Baltimore, who is director of the MIT-affiliated Whitehead Institute, in Cambridge, hasn't been defending biomedical enterprise but assailing it. Working to some degree in AIDS himself; he's taken to publicly beseeching other researchers to overcome their aversion to managed research, put aside their obsession with credit, and sublimate their own urgent career choices and business imperatives to "a sense of responding to a national need." In short, he's been urging a national crash program on AIDS - a Manhattan Project, in which the federal government spends whatever it takes and Big Biomedicine joins in with all hands to effect a speedy cure, just as Big Physics and the federal government managed to build an atomic bomb during World War II. Hardly revolutionary, Baltimore's notion stems from an established wartime practice: the temporary suspension of business as usual.

Scientists tend to show their disapproval in an odd way. Something considered promising or important will be questioned vigorously, even harshly. Something deemed uninteresting, and therefore unworthy of pursuit, will be met with silence. Crows ostracize each other by cackling raucously, scientists by turning to whisper something or staring at their shoes. Such has been the reaction to Baltimore's plan.

In 1986, for instance, he was appointed by the Institute of Medicine to co-chair a panel to review the nation's AIDS initiatives. The institute is the biomedical division of the National Academy of Sciences, and thus the nearest thing to a national reference panel on research. Yet when he raised the Manhattan Project idea in committee, almost no one supported him. The Reagan administration would doom such a project from the start. Top researchers wouldn't join. It would become a boondoggle, a fiefdom. It wouldn't work. It would no more find a magic bullet for AIDS than the War on Cancer had for cancer. And if it did, who'd get the credit, the patent, the royalties? Who'd market it? In the end, the group's final report recommended a steep rise in spending for research - to a billion dollars a year - but no War on AIDS. The idea wasn't even mentioned.

The message other scientists have been giving Baltimore is clear. Sometime after the War on Cancer, after discoveries became "inventions" and researchers became entrepreneurs and Big Biology got too expensive to run without Big Business, biomedicine passed the point of being marshaled. The self-interest of the researcher, of the research institution, of the biotech company and the drug company, is now inviolate. In this view, the helter-skelter of the patent fight and the dominance of strong alliances over weaker ones are preferable to any coordinated system for determining what science does and how it does it - even for something as cataclysmic as AIDS.

To be fair, the system of research that elevated Essex and Haseltine has produced astonishing peaks in our knowledge of AIDS. Science has learned more about HIV in five years than it knows about the polio virus; to the extent the world is not in utter panic, it owes its composure to science. The fact that the rewards are so great has driven individual researchers - Essex and Haseltine included - to perform brilliantly.

And yet it is also clear that the hyper-competitiveness of that system and its dominance by a well-positioned elite have dragged down the pace of discovery overall; the scientific process itself has been distorted. Science is collaborative. No scientist has ever discovered anything of value without the necessary groundwork - and follow-up - that can only be achieved when other researchers devote their work to a common cause. Yet AIDS has made a mockery of that. When priority-obsessed researchers refuse to share what they know and throw roadblocks at those who might disprove them, the system breaks down. It fails completely when those forces drive promising young researchers like Mullins from the field.

There is no telling whether a Manhattan Project would yield a magic bullet for AIDS any sooner than may be possible at the present discouraging pace. Yet the tragedy is that we'll probably never know if it could. With resistance among scientists so high, it's unlikely - short of a breakout of the disease into the general population - that any constituency would be powerful enough to compel biomedicine to do what it is so overwhelmingly disinclined to do on its own.

Science's stock answer to this line of criticism is that the process is essentially self-correcting, and that research money, not management, is all that is needed to rectify the abuses of the past. In theory, more money induces wider participation, which in turn elevates the level of cross-collaboration, which is what ultimately moves science ahead. There's some truth in that. NIH funding for AIDS research began to swell in 1985: from $63.7 million then to more than $400 million this year. The new money, as intended, has attracted more scientists, which has accounted for more diversified and thorough research. And because the tasks are now more challenging, more top researchers have begun apportioning lab time to AIDS. Scientifically, AIDS has become respectable.

But money and respectability are not enough. Among those recruited to AIDS research in the past year is Yale biochemist Tom Steitz, one of five Yale scientists now trying to develop new AIDS drugs under an NIH grant program that also funds Haseltine, Cambridge BioScience, and Agouron Pharmaceuticals, a California drug firm, as well as several other alliances. Steitz has an ample fellowship from the Howard Hughes Medical Institute. He received his first money last summer and immediately began inquiring about getting reagents, particularly reverse transcriptase. He soon found, however, "that the only way you can get anybody to do anything [in AIDS] is to make a deal." One commercial lab denied him reagents outright. Steitz was appalled. Biomedicine was supposed to be rushing to do everything it could to fight AIDS, and he was going to have to waste up to six months generating his own reagents. "There are a lot of people willing to work on these problems," Steitz would say months later, still infuriated, "who are just sitting on their hands."

Haseltine was unsympathetic. Apprised of Steitz's problems, he dismissed his progress as "trivial," an assessment that, given what had yet to change in AIDS research and Steitz's paralysis, was sadly and undoubtedly correct.

If Haseltine is right, and those who are fighting AIDS are proceeding as they must, then some scientists must sit on their hands while others barge ahead, making millions. Big Biomedicine is doing its best. But if he's wrong, if science could, in Baltimore's words, suspend "business as usual," then time - the one factor that wholly favors the disease - is being wasted. "I believe we are in a national emergency," Baltimore has said, "and the biomedical community will be judged in the future by how we respond." *