COLUMN ONE : Seeking a Cure: Faith, Frustration : Once researchers found the virus that causes AIDS, they were sure they could soon stop the disease. ‘Find the bug, find the drug,’ they said. A decade later, they are empty-handed and thinking of starting over.

Bob Gallo’s black address book is filled with crossed-out names--the names of the dead.

It has been 10 years since the controversial cancer researcher proudly announced to the world that he had found the virus that causes AIDS, a discovery for which he now shares credit with French scientists. It was a heady time for Gallo, and he was flush with optimism, confident that soon there would be a drug or a vaccine to cripple the galloping plague.

“Find the bug, find the drug,” the theory went.

Now, over a glass of lager in the oak-paneled bar of New York’s Plaza Hotel, Gallo broods about what might have gone wrong. He contemplates the destructive swath of a disease that, like a familiar enemy, he and countless others have spent too many years trying to outwit.

He did not expect it to be this way.

Villages in Africa are being wiped out. AIDS is racing through Asia, where more than 10 million infections are expected by the year 2000. In the United States, 92 people die of the disease each day.

For Gallo, who trained as a doctor before turning to research, there are faces to these numbers. He recalls having dinner last year with Jesse Dobson, a well-known AIDS activist. Two weeks later, Dobson was dead.

Another name crossed out of the black address book.

“I feel like we should have solved problems sooner,” the virologist said somberly. “Would’ve, should’ve, could’ve.”

But didn’t. Thirteen years after AIDS made its first appearance in this country and a decade after “the bug” was found, just a handful of drugs that directly attack the virus--AZT and three others--are on the market. None of them work very well, and doctors are confused about how to use them. Other new medicines have either been slow to emerge from drug company laboratories or abandoned altogether.

The prospects for a vaccine are equally dim. The wizards of genetic engineering have been unable to work their magic into a shot that prevents AIDS neatly and efficiently. The most promising candidates have flunked laboratory tests, and six volunteers who got the high-tech injections became infected anyway, prompting the government to abandon plans for large-scale studies.

The best hope for a vaccine, many scientists now say, lies with an old-fashioned method that uses a weakened but live form of the human immunodeficiency virus--a method that paradoxically may be too dangerous to test in humans. This formula worked with polio.

But HIV is not that simple. It is a retrovirus, meaning it inserts its own genes into the cells of the person it infects. And it mutates rapidly, raising fears that a vaccine containing live virus could transform itself to infect the person it was supposed to protect.

It is no wonder then that the days of talking about a cure for AIDS are long gone. There isn’t a cure in sight.

Instead, as scientists gather in Yokohama, Japan, for the 10th annual International AIDS Conference this week, most use words such as crisis to describe the state of AIDS research.

Among researchers, a consensus has emerged: After 10 years, it is time to go back to the drawing board.

“Over the past decade, ever since the discovery of the virus, there was a great deal of effort put in place to see if we could quickly hit a home run,” said virologist David Ho, director of the Aaron Diamond AIDS Research Institute in New York. “I think, in retrospect, that strategy is not going to work, and did not work.”

Indeed, the silver bullet Gallo once hoped for has not materialized. And although government and drug company scientists have spent the last decade trying to find one, they have yet to answer some of the most fundamental questions about HIV. Those answers may hold important clues to developing just what everyone wants--better treatments and a vaccine.

“We probably know more about this virus than we do most other viruses,” said AIDS researcher Steven Wolinsky of Northwestern University’s Medical School. “But many of the basic issues are still begging to be answered.”

New York AIDS activist Mark Harrington puts it a bit more bluntly. “We are standing,” Harrington said, “at the edge of a scientific black hole.”

Researchers do not fully understand how the AIDS virus crosses the body’s mucous membranes--the linings of the mouth, vagina and anus--to infect cells. They do not know precisely how HIV spreads inside the body. Nor do they know if certain strains of the virus are more deadly than others, nor why some people die quickly while others live for years.

Also lacking is a good animal model that scientists can use to study AIDS--a monkey, perhaps, or a chimp that could be infected with HIV and would develop the disease just as humans do. However, in Yokohama, UC San Francisco researcher Jay Levy is expected to report that he has solved this problem by using baboons.

These issues are the nitty-gritty of AIDS research. If AIDS had been cured by now, there would be no need to address them; after all, who cares about the intricacies of a disease that can be rendered powerless with drugs?

But that is not the case. And so, researchers say, they will have to learn a lot more about HIV--perhaps the cagiest, most formidable of viruses--before they come up with a way to conquer it.

To that end, the federal government is shaking up its AIDS research machine. Officials are planning to revamp the $1.3-billion annual AIDS budget to devote more money to laboratory studies--basic research, in the lexicon of science--and less to clinical research to test new treatments.

It will be a plodding process, and--barring any silver bullets--it will probably take decades.

The Activists

Faced with this grim outlook, AIDS activists--once spitting out fire and rage--are downtrodden, more tired than angry. Most of the movement’s fathers are dead, and their work has been turned over to a younger generation.

Marty Majchrowicz typifies this new breed--articulate, well educated, more realistic than optimistic. The first time he heard about AIDS he was in the eighth grade and already aware of his sexual identity. He saw the disease featured on the cover of Time magazine, saw pictures of people dying. He remembers feeling scared. He remembers thinking: “I am going to die from this one day.”

That was in 1981, when AIDS was still called “gay cancer.” Majchrowicz obtained an undergraduate degree from USC and a master’s degree in public health from UCLA. He puts his knowledge to good use, working as a treatment advocate at AIDS Project/Los Angeles. The slender, fair-skinned activist gives advice from a dimly lit office in APLA’s cavernous Hollywood headquarters.

Sometimes he thinks the approved AIDS drugs--AZT, DDI, DDC and D4T--are no better than herbal remedies; the only difference is that these nucleoside analogues, designed to cripple the virus by keeping it from copying its genetic blueprint, have been tested. Looking back, he said, maybe the activists themselves are to blame.

“We forced them into a corner,” Majchrowicz said, referring to scientists and politicians. “We told them, ‘We want a drug.’ They gave us AZT. They put the fastest thing on the market that they could. We pushed them again and we got DDI. So here we are screaming, ‘We need drugs, we need drugs, we need drugs.’ We screamed for something and we got it. But it wasn’t good enough.”

Although the expected survival time for someone diagnosed with AIDS has doubled since 1986--to 24 months--this falls short of the five-year survival rate by which most diseases are measured. Rather, the longer survival time is mostly the result of better treatments for the various infections, such as pneumocystis carinii pneumonia, that kill people whose immune systems have been destroyed by AIDS.

By contrast, government tests have failed to demonstrate conclusively that the nucleoside analogues prolong life for more than a few months, alone or in combination with one another. They work for only so long and then people develop resistance.

One day, Majchrowicz knows, he will have to turn to these medicines. Like so many AIDS activists, he is HIV-positive. He is especially hopeful about an up-and-coming class of drugs--”protease inhibitors,” which attack a crucial enzyme that enables HIV to reproduce inside the body. It has not yet been approved by the Food and Drug Administration.

Still, he worries that his adolescent nightmare, that he is “going to die from this one day,” may come true before his own work does him any good.

“I feel old,” he sighs. He turned 26 in March.

The Researchers

In a sense, the story of AIDS research is a product of a uniquely American belief: Science can do anything. Doctors have all the answers.

“For decades, and maybe even half a century, the American medical machine has tried . . . to put a myth over the public that everything is within our ability to control,” said Dr. Michael Wilkes, a UCLA professor of medicine.

This myth has been debunked before, but faith runs deep. When President Richard Nixon declared a “war on cancer” in 1971, some said the cure would be found within five years. And when, with a beaming Gallo at her side, U.S. Health and Human Services Secretary Margaret Heckler announced in 1984 that the AIDS virus had been isolated and a vaccine would be produced within two years, people believed that too.

Today, significant strides have been made in preventing and treating certain types of cancers. Some childhood leukemias, for instance, have a cure rate of more than 80%. The advances have come as doctors learned how to put seemingly ineffective drugs together to work wonders. Even so, cancer remains the nation’s second-leading cause of death. Nobody expects there will be a single “cure for cancer” anymore.

Many scientists think AIDS may follow the same pattern.

Among them is Dr. Harold Varmus, the new director of the National Institutes of Health. With an annual budget of $11 billion, NIH is the seat of medical research in this country. Its 17 institutes and six scientific centers and divisions are spread over a hilly campus in Bethesda, Md.

Varmus, a soft-spoken, slightly rumpled man who favors Oxford-cloth shirts and argyle socks, has been in charge for eight months. He speaks thoughtfully and candidly when asked about AIDS.

“Right now,” he said, “it’s hard for me to be optimistic about feeling that AIDS will disappear in 20 or 30 years.” But, he adds, “I do think that we will have drugs that are reasonably effective and that people who develop the disease AIDS will live a lot longer than they live now, but I think it is fair to say that it won’t be so different than (cancer).”

But there is a crucial distinction, he notes, between the two diseases. The causes of cancer, with the exception of environmental factors such as smoking, diet and radon, are largely unknown. But there is nearly universal agreement that HIV causes AIDS. “If you could eliminate the virus, you could eliminate the disease,” he said. Translation: “Find the bug, find the drug” should have worked.

“That,” Varmus said, “is haunting us.”

Under his watch, NIH is shaking up its AIDS bureaucracy. Four months ago, Varmus ousted the well-known scientist who has been the government’s point man on AIDS since the epidemic began--Dr. Anthony M. Fauci--and brought in Dr. William E. Paul to head NIH’s Office of AIDS Research. Paul is a highly regarded immunologist, but he has no experience in AIDS.

“I was looking for somebody who would inspire a lot of confidence, who would do new things, who was well liked,” Varmus said. “I was very much attracted by the idea of his being somebody who was interested in AIDS but not in the middle of it.”

Paul has a big job ahead. He is re-creating the Office of AIDS Research from the ground up; the tiny agency never had any real power until last year, when--in one of the many remarkable twists that characterize AIDS research today--Congress reconstituted it at the urging of activists who charged that the federal research program was a mess.

A Litany of Complaints

This was nothing short of a revolution.

It was orchestrated by a tiny band of activists/dissenters in New York. Their leader was a 33-year-old former Wall Street bond trader named Peter Staley. Several years ago, he and his friends broke away from ACT UP, the group known for in-your-face protests.

Figuring they could accomplish more from the inside, they formed their own group, Treatment Action Group, or TAG. They buddied up to researchers, read grant abstracts and learned about funding streams. Then they issued three reports that caught the attention of Sen. Edward M. Kennedy (D-Mass.) and his colleagues in Congress.

The reports contained a litany of complaints: Money was being spent on studies that were redundant or failed to bear fruit. No one person was in charge of the federal AIDS budget. Top scientists in immunology and virology--fields that have relevance to AIDS--were not encouraged to join the fight. Promising young researchers were staying away.

The AIDS Clinical Trial Group, the arm of the NIH that tests AIDS drugs, had studied AZT and the other nucleoside analogues nine ways to Sunday and had yet to come up with good guidance for doctors, the reports said. (The best AZT news to come out of the government studies is that it helps prevent transmission from pregnant women to their infants.) The research effort, the group asserted, lacked coordination and direction.

“It’s written off as, ‘Well, that’s the way science works,” Staley said. “I don’t see why it has to be that way.”

To Staley’s astonishment, Congress agreed.

A New Game Plan

As a result, for the first time, one central authority--the Office of AIDS Research--controls federal AIDS research purse strings. With this new power, Paul is drafting a plan that will put more money into basic research and less into clinical trials.

The NIH spends about twice as much on clinical tests as it does on basic science. About 42% of the government’s AIDS budget is spent developing and testing new drugs, and 9% is spent on vaccine research. Just 25% is devoted to basic laboratory work. (The remainder goes toward prevention, education and other activities.)

Paul’s plan has not been made public, and in an interview, he declined to provide specifics, although he may do so in Yokohama. But he and Varmus acknowledged that change will take time. Much of the government’s AIDS budget is locked up, committed through grants that will remain in place for the next three to five years.

In the meantime, he is struggling to build up his staff--a job fraught with obstacles because of an NIH hiring freeze--and to familiarize himself with the disease he is supposed to help conquer. He has sought counsel from the great minds of science, among them Dr. Bernard Fields.

Fields is a Harvard University virologist who was a candidate for Paul’s job but withdrew for health reasons. Like Paul, Fields has no experience in AIDS. At 56, he has spent three decades studying reovirus, a member of the family of viruses that causes diarrhea. He never got into AIDS, he said, because he did not want to abandon an established career.

In May, Fields published a commentary in the scientific journal Nature that brought the crisis in AIDS research to public attention. Titled “AIDS: Time to Turn to Basic Science,” the piece reads like a blueprint for Paul to follow.

Ten years ago, Fields said, it was reasonable for AIDS researchers to shoot for the moon--a drug, a vaccine, a cure. After all, it worked with polio: The first vaccine was developed by Jonas Salk long before scientists fully understood the virus that causes the disease. With a vaccine in hand, basic research into polio was all but abandoned. It wasn’t necessary anymore.

That approach, Fields said, hasn’t worked for AIDS. He argues that it is time to broaden AIDS research. Scientists must learn general principles about the immune system, he said, if they are to fully understand how AIDS attacks the body.

And the way to glean such insights, Fields said, is not necessarily to study HIV. Other viruses--rotovirus, which infects the intestines, herpes virus and perhaps even reovirus--might yield equally important nuggets, helping scientists to understand, for instance, how antibodies and other molecules work together to regulate immune responses.

He notes that it is easier to get grants for AIDS than any other disease. At the National Institute of Allergy and Infectious Diseases, which conducts most of government-funded AIDS research, 14% of basic research grant requests in AIDS are approved. Only 8% of grant requests in other diseases are funded.

The Skeptics

Not everyone thinks Fields, Paul and the Treatment Action Group activists are on the right track.

Dr. Robert T. Schooley is the incoming chief of the AIDS Clinical Trials Group. He thinks the criticisms of the AZT studies are too harsh. He worries that his program will be gutted just when it is on the verge of studying new and better classes of drugs, as well as gene therapy and other innovative approaches to treating AIDS.

“If they kill this system . . . we may end up killing trials that many of us think have a lot of potential,” Schooley said. “Then, three years from now you’ll have people saying, ‘Why didn’t we study this?’ ”

Schooley is also skeptical of Fields’ argument that AIDS money should be given to scientists who don’t work with HIV.

“Bernie Fields is a reovirologist,” he said. “Bernie’s thesis all along has been reovirus is a great model for AIDS. Well, HIV is a great model for AIDS. Reovirus is reovirus. I worry a lot about this back to the basics (philosophy) coming from people who would like to have funds used on what they were doing all their professional lives. . . . I think a lot of this is kind of self-serving.”

Larry Kramer is another skeptic. The playwright and AIDS activist wrote a prologue to one Treatment Action Group report, calling it “one of the most important documents about the AIDS plague.” Now he is furious with the organization and other activists, saying they “have become so bureaucratized as to be embarrassing.”

Kramer is pushing for a “Manhattan Project” for AIDS--a highly focused scientific effort like the one used to develop the atomic bomb. Cloister the nation’s best minds out in the desert, this argument goes, and they will undoubtedly come up with the answer. He calls the appointment of Paul “a bad joke” and said the NIH is unfit to guide scientific research.

Although many AIDS researchers--with the notable exception of Gallo--think the “Manhattan Project” is unworkable and unnecessary, they do worry that the public will begin to think of AIDS as a chronic, incurable problem that goes on the back burner. And with it, they fear, will go the urgency--and funding--that characterized the first decade of research.

“This has to be viewed as a national emergency,” said Ho of the Aaron Diamond institute. “Everyone senses there is a complacency setting in, a willingness to accept the situation. But this is a transmissible disease that could get worse if we take that attitude.”

An Insider’s View

Standing outside the fracas, watching with bemused detachment, is the consummate AIDS insider: Anthony Fauci.

He has played several crucial roles in the battle against AIDS. He is director of the National Institute of Allergy and Infectious Diseases, which conducts 40% of government-funded AIDS research. (The remainder is spread over the other institutes.)

He is a respected laboratory scientist who performs the kind of basic research Paul advocates. Thanks to Fauci, the theory that the AIDS virus was inactive after infecting people has been debunked. His research proved the virus can “hide” for years in the lymph nodes, multiplying rapidly before waging its ferocious attack.

And, until Paul’s appointment, Fauci headed the Office of AIDS Research.

If anyone can take the long view of the epidemic, it is Fauci. The walls in his spacious office are covered with photographs that speak to his spot in the AIDS limelight. There is Fauci with George Bush, who once hailed him as a hero. There he is with Elizabeth Taylor, well known for her AIDS fund-raisers. And there he is peering from behind a collection of test tubes, in People magazine, which named him one of the “25 most intriguing people of 1990.”

In the business of laying blame for the failures of AIDS research, Fauci has become an easy target. Staley, the founder of the Treatment Action Group, calls him “a brilliant scientist and a miserable manager.”

Gregg Gonsalves, a founding member of the Treatment Action Group, said: “When Tony walks in the room, you feel like the king is here. It’s like Frank Sinatra, the chairman of the board. Bill Paul is very collegial. Tony never pulled in people and said, ‘OK, tell me what’s wrong and how we should fix it.’ He was stubborn and driven. . . . ‘This is my epidemic and what I say goes.’ ”

Fauci has heard the criticism before, and he shrugs it off.

“There is a natural tendency to blame,” he said. “You blame the Reagan Administration, you blame the Bush Administration, and now people are blaming Bill Clinton. Except that I have been at it longer than all of them.”

He said he pushed years ago for more basic science. But nobody wanted to hear it.

“I wish someone would go back to my congressional testimonies when I was saying that we need to do more to understand how the virus works, and I was getting beaten up by the activists as well as the congressional committees. . . . Now those same people are . . . saying, ‘Ah, I have seen Jesus. What we really need is more basic research.’ No kidding.”

Slow Progress

As these debates continue, science grinds forward, step by agonizingly slow step.

On the drug frontier, pharmaceutical manufacturer Hoffman-LaRoche is seeking FDA permission to market its protease inhibitor under a special program that allows AIDS drugs to be made available to patients before they are proven effective. The Treatment Action Group is fighting against the approval, arguing that it is unfair to put another drug on the market until the company can show that it works.

Although tests of another new class of drugs--the “tat inhibitors”--have been shelved permanently, some scientists believe it will be possible to develop yet another type, called “integrase inhibitors.” All these drugs, like AZT, are antiretrovirals, designed to stop the AIDS virus from multiplying inside the body. Each targets the virus at a different stage of its replication process.

Meanwhile, research continues on more innovative therapies. Among the most promising work is that being conducted by UC San Diego researcher Flossie Wong-Staal, who is exploring the possibility of gene therapy. In San Francisco, a think tank called Project Immune Restoration is bringing scientists together to examine ways of repairing HIV-damaged immune systems.

At the National Cancer Institute, Gallo and his colleagues are studying everything from the composition of HIV’s genes to new treatments for Kaposi’s sarcoma, a cancer that is common among AIDS patients. He is also working on an HIV vaccine that is being tested in France--one of 29 vaccines in various stages of experimentation here and in Europe.

There is no telling where this effort will lead. The miracle breakthrough, the magic bullet, may still be just around the corner. Then again, it may not.

Gallo puts it this way:

“You could know everything about the Himalayan mountains--evolution, caves, grounds, geography--but you might not be able to climb them until somebody developed a new technique called a helicopter. Knowing everything there is to know about AIDS may not make us solve the problem. It may be unsolvable. I don’t believe that, but that is possible. Maybe we need a whole new technological development from elsewhere, maybe not even from biomedical science. God knows from where.

“For some things, knowing everything may not be enough.”

In the meantime, Gallo is planning his annual fall lab meeting, a seven-day retreat that functions as a mini-AIDS conference and is attended by the world’s greatest scientific minds. The title of the opening talk, to be given by Nobel laureate and molecular biologist David Baltimore, is “AIDS Research in Crisis.”

Each year, Gallo also invites a guest lecturer, someone from outside the scientific community, to deliver a provocative speech. This year’s speaker is Pulitzer Prize-winning author Richard Rhodes.

He wrote “The Making of the Atomic Bomb,” the definitive book on the Manhattan Project.

NEXT: The deadliest virus of all.