The tall, bearded figure leaned forward and looked down at his gloved hands working beneath the transparent shield used to protect researchers from deadly substances. He moved his arms in a mechanical routine, drawing up liquid from a tiny vial, reaching over to inject it into a flask, then labeling it. Again: draw, reach, squirt and label. And again.
He eyed the vials carefully and handled their contents with caution: They contained live AIDS virus, the enemy itself, staring him in the face in what is now a daily confrontation for researchers working on acquired immune deficiency syndrome.
Steven C. Josephs, a 35-year-old father of two, a born-again Christian and a saxophone player, sealed the flasks and put them into a heated box. Twenty minutes spent, and a single step was finished in the many hundreds needed to complete one experiment.
He was cutting the virus into pieces -- chemically snipping its DNA, or deoxyribonucleic acid, into bits. Through days of monotonous combining and recombining, extracting and injecting, mixing and remixing, spinning, shaking, heating, cooling and waiting, endless waiting, he was attempting to answer one fragment of the main question about this new, infamous particle of disease: What makes it work? How does it infect, reproduce, hide from the immune system and then kill?
Once these questions are answered, drug treatment and vaccines may follow close behind.
Josephs works in the most prominent AIDS lab in the world, headed by Robert C. Gallo at the National Cancer Institute. He is one of several score of researchers around the country who are working as fast as time and chemistry will allow to break the hold of the perplexing virus.
These people are mostly young, 35 and under. They are from more than a dozen nations. They are paid $10,000, $20,000 or, at best, a bit more than $30,000. Most will get little credit except within their own labs and hospitals.
Among them is Hiroaki Mitsuya, 35, here temporarily from Nagasaki, Japan. Mitsuya became an expert on HTLV-1, a leukemia-causing virus that is part of the AIDS family, because a substantial percentage of the people in his home town carry it in their blood. The phenomenon predates the atomic-bomb attack on Nagasaki in 1945. Mitsuya is now applying his knowledge of this virus to the related AIDS problem.
At the desk next to Mitsuya is Robert Yarchoan, also 35. He said that in the field of biology, he feels time chasing him. "I push myself a lot . . . . As I get older I seem to get more ambitious," he said. For a long stretch, things seemed easy. "Now I have a sense of life running away. Your reputation is on the line every day. You can't sit back and say, 'This is what I have done.' If you don't keep up, you fall behind."
Mitsuya and Yarchoan are two researchers in the National Cancer Institute lab of Dr. Samuel Broder. Their mission is somewhat different than Josephs' -- they work directly on drugs to combat AIDS, and what comes out of their lab sometimes goes directly into patients in drug trials.
All three are linked by a sense of urgency and -- even though no researcher has yet been infected with the disease -- by a faint back-of-the-brain fear. Not long ago, Josephs watched a sore open on his leg. It was raised, red and growing. "My God!" Josephs said, "It looks like Kaposi's!" (Kaposi's sarcoma is a skin cancer often associated with AIDS.)
"It couldn't be Kaposi's, I told myself. This virus isn't spread that way," Josephs said. "But I waited, and it didn't go away." Finally, he went to a dermatologist who said the lesion was nothing important and that Josephs could live with it. Josephs asked him to remove it anyway.
The researchers are linked as well by their willingness to spend the most productive years of their careers on a small part of the fatal enigma that is the AIDS epidemic.
The epidemic has now struck more than 15,000 people with AIDS and another 150,000 with AIDS-Related Complex in the United States alone. Four years after the discovery of the disease, AIDS still appears to be 100 percent fatal, or very near it. There are no known survivors.
It is a disease that masks its own face, appearing in many guises. It destroys the body's defenses, leaving people vulnerable to many fatal infections. It can show itself as a formerly rare and fatal skin cancer, or as a virulent pneumonia, or as a nerve disease that cripples and causes dementia before killing.
The disease is spreading at a high rate on several continents, but solutions seem possible. They lie in knowing the chemistry of the AIDS virus, the long tangled strand of its genetic makeup. They lie at the lab bench, in the hands of a small troop of lab workers at such places as the National Institutes of Health, Harvard University and its hospitals, Duke University Medical Center, the University of California at San Francisco, Memorial Sloan-Kettering Cancer Center, The Wistar Institute in Philadelphia and the Centers for Disease Control in Atlanta.
"One thing never written is the element of quiet courage that a number of men and women were called upon to demonstrate," said Broder, deputy clinical director of cancer treatment at the National Cancer Institute. "In the early days of the AIDS epidemic, little was known about the new deadly disease. Young men and women were being called on to treat a new disease and to evaluate specimens from patients with a new disease. Anything was possible.
"The level of contagion we had to deal with was not known, simply not known. There was an enormous outpouring of quiet courage, for which these people are never going to get credit. In a way it's easy to do if you are in the public eye. But ward staff, lab technicians just did it," he said.
"At least several laboratories were reluctant to get involved in studying AIDS," said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. "They were afraid the disease would spread to lab workers. We've been working since 1981 now and there has been no incidence of lab-transmitted infection . . . Still, when dealing with a virus that can kill you, you are not cavalier with it. There have been occasional cases of people who have said they prefer not to work with the virus."
In the past, the time between the first sighting of a new disease and the discovery of its cause and cure has often been counted in decades. The progress made in the AIDS labs, which simultaneously compete and cooperate with one another, has been extremely rapid. AIDS was first identified in 1981, its cause seen in late 1983, and some apparently potent drug treatments now may finish first trials in 1986.
In a windowless room on the sixth floor of building 37 at the National Institutes of Health, Steve Josephs works at his part of the problem -- the basic mechanisms inside the virus.
Several workers are pressed into the small space in the lab where Josephs works. There is one waist-high workbench with a black washable top in the center of the lab. Against two walls is other waist-high work space. But the area is jammed with equipment, so that any work usually begins with time clearing space.
A modern biological laboratory during work on a hot problem is a little like an auto repair garage. Supplies and tools are heaped in stacks around the walls, on shelves, in corners. Wires hang from the ceiling and sprout multiple plugs. The floor is swept but looks marred and dirty. Work spaces are rarely empty -- one or two people are always at work on different jobs, surrounded by a scattering of tools. A radio is always on.
But the engines the laboratory works on are the engines of the cell. Because cells are a thousandth or a ten-thousandth of an inch across, the tools used by biologists must be tiny. In fact, the tools are chemicals that open up cells, allowing their DNA -- their genetic material -- to be worked on. There are chemicals that, like wrenches, can remove or replace DNA. Sequences of chemical reactions can fabricate new parts.
Josephs is extracting the genetic material from the AIDS virus and cleaving it into fragments. He will probe chemically, testing piece by piece for the fragment of genetic material responsible for one bit of behavior seen in the AIDS virus.
The AIDS virus, HTLV-3, is unlike any other virus in several ways. Its special combination of traits makes it seem perverse:
*Its attack is preemptive. That is, it attacks the very cells that are needed to fight off the infection, the T4 cells of the immune system.
*The virus infects the brain, where many drugs cannot reach. The brain is protected by membranes, referred to as the "blood-brain barrier," allowing only a few kinds of chemicals to pass. Any successful drug treatment must ultimately be able to cross this barrier and halt the virus without damaging brain tissue.
*The virus kills the cells it invades, and perhaps can kill nearby cells that it does not attack directly. But its mechanism for killing is unknown.
*Its invasion can be invisible to the immune system. Its genes can infiltrate the victim cell's string of genes. Thus hidden inside the body's own cells, the virus cannot be seen by the immune system looking for foreign material. It can remain dormant up to several years. Then at once it springs out and is reproduced extremely rapidly.
It is this last bit of macabre behavior that Josephs is trying to understand. One of the great surprises of AIDS research is the discovery of one control mechanism that is new to biology. After the virus invades a cell and becomes a sleeper gene, it waits until some unknown trigger sets it off.
Then the virus bursts into production at a level a thousand times higher than normal. This instantaneous response, when it is time for the AIDS "bomb" to go off, is called TAT (for transactivation and transcription.) It was first found at Dana Farber Cancer Institute by William Haseltine's lab. Now Josephs is working in an amicable but fierce competition with the Haseltine lab to locate and define all the gears and levers behind the TAT effect.
One finding is that if the gene for TAT is disabled, the virus cannot reproduce. Its deadly cycle is halted.
Josephs stood beside a small partition in the tiny space that passes for his office. A brown bag with grease spots sits beside a soft drink can, and both are set in a small valley between great mounds of paper, notebooks and X-ray film.
"The days here are normally long, till seven or eight at night," Josephs said. But because of work on TAT, "Recently there have been a lot of even longer hours because of the competition. I will sometimes end up working till three in the morning," he said. "My wife thinks I work too long."
At 35, Josephs is young, but he is a rather senior lab worker in a place filled with people who are a few years out of school. Josephs, who was born in Pennsylvania and went to Susquehanna College there, has worked in the Gallo lab since 1975 -- a long stay -- and now earns more than $30,000.
On a recent Wednesday evening, Josephs was methodically using a modern pipette -- a hand syringe that can draw up small, precise amounts of liquid when a button on its handle is pressed. He drew up fluid, moved his arm over to a tray of 57 ampules and squirted the bit of liquid into one. He repeated the process. After the 57 ampules were filled, there would be another sequence to do.
The phone rang. "My wife wants me home," he said, explaining tht she had something to do and he had to attend a meeting at his church, the Living Word Fellowship. He tried to get back to the tedium of the bench, but soon frowned and stopped. "I'll do this later," he said, and left the lab. It was just after 5 p.m. As he walked out the door, he told a coworker he'd be back by eight that night at the latest.
Near the end of months of work on TAT, Josephs met with his immediate supervisor, Flossie Wong-Staal, to tell her what he had found. Grinning as he collected his notes and large sheets of film showing flares of chemical activity, he said, "This is exciting. This is the best part -- when I get to show people my data."
Before the meeting he explained a few freshly discovered facts that were, in a manner of speaking, his alone -- as if he were in the wilderness and parted some branches to look out on a bit of Earth never before seen by humans.
While Josephs works with the molecular mechanisms inside the virus, across a stretch of lawns and parking lots, in the lab of Dr. Broder, researchers are working more directly with patients, developing new drug treatments for the disease.
Broder's lab is relatively new and is tidy compared to most of its kind. Mitsuya and Yarchoan, both young medical doctors, are now working the opposite ends of the lab's job. Mitsuya is testing drugs, analysing them biochemically. Yarchoan is in charge of giving a new drug, found by the Broder lab, to 22 AIDS patients.
Mitsuya created a "cell line" -- a group of cells that can be made "immortal" and live outside the body if carefully kept. His cell line is especially useful for testing drugs because it reacts quickly to AIDS.
Mitsuya holds up test tubes in front of the window to demonstrate. One tube has a large white spot of healthy cells. In another tube the spot is almost gone after being infected and killed after AIDS virus was added. In a third tube is the news: When cells have AIDS virus and a new drug mixed together, the drug protects the cells. They remain healthy despite the presence of AIDs.
Mitsuya has tested 180 possible drugs this way, to see if they fight off the virus. About 10 have been potent, and two of those are being tested on AIDS patients.
Experiments can go bad. The AIDS virus may have lost vitality while in the freezer, or the nutrient medium may have been defective. "Many things might make an experiment go bad," Mitsuya said. "I worked one and a half years on that screening system and made many mistakes before it worked." He said it has been frustrating and embarrassing at times -- when he got results that others, using his method, could not reproduce, or when he got wildly differing results without apparent cause.
While explaining this, he interrupted for a phone call. It was a conversation about such a technical failure. "I'm sorry," he said. "Some died outright. I should have called sooner but I was too shy to call again about this . . . . "
Mitsuya went back to the bench work. At this, he is unusually graceful. Though making precisely the same motions with pipettes and test tubes that he has made hundreds of times per day for years, he does it with unusual speed and economy of movement, as if making the work a dance of the hands makes it less boring.
During that same morning, another experiment of Mitsuya's suddenly produced a clean result. Lab chief Sam Broder stopped by the lab and looked over the graphed data on Mitsuya's desk.
"Mitch, there's something here!" Broder said loudly.
"Yes," said Mitsuya from the other room.
"This is a real difference. This is very exciting," Broder said.
"Yes" was heard again from the other room.
They were reacting to an experiment in which Mitsuya was testing a certain part of the AIDS virus to see if it was the killer gene, the one responsible for destroying the body's immune cells. Finding that lethal gene would at once give researchers a target: If it could be chemically immobilized, perhaps the effects of the disease could be stopped.
Yarchoan, sitting near Mitsuya, has waited most of the day to hear results from his patients undergoing drug testing. This is the day he gets data back. By the early evening he had called twice to find out when he could get test results.
The worst part of his work is seeing patients. "Quite frankly, I hate it. It is the most unpleasant part of my day. I just don't have much to offer people," he said.
The chief object of the first round of tests in people is to determine whether the drug can be safely administered and at what doses. Second, researchers watch for positive signs from the dying.
The placebo effect compounds problems. Because the patients tend to be depressed, a new therapy may give them too much hope. They may react positively to anything for a time.
"The problem is that the things we are following can fluctuate up and down normally," Yarchoan said. There is a danger of getting too excited at positive indications and too depressed when there is no change. "We call it the Chinese water torture," Yarchoan said.
Beyond the caveats of Yarchoan and Broder, a visitor can hear hope and perhaps even confidence. The drug now being tested is the best-looking one they have had in lab tests. Called AZT, or azido-deoxythymidine, it was developed by Burroughs Wellcome and Broder's lab, and is designed to foul the mechanism by which the AIDS virus multiplies in the cell.
In the lab, it protects cells and completely prevents viral reproduction. It also is not toxic to cells, in the lab work at least. In patients, it has apparently stopped the virus, though how much patients will ultimately gain is undetermined. Full trials of AZT's ability to reverse the disease are expected to begin in January at NIH, Duke and UCLA.
Just as Yarchoan was getting ready to leave, the phone rang. There was a pause and everyone glanced at the phone. Yarchoan finally picked it up and gave it to Broder briefly.
Broder began the ribbing: "We are in bad shape, we're data deprived, standing here without our data. We're obsessive-compulsive guys here. Do you know what happens to us when we don't have our data?"
Broder passed the phone back and Yarchoan started repeating numbers out loud. After hanging up, he stared at the numbers for a minute, then began checking them against earlier measurements. The view is generally encouraging, but there are some ring with some of his work.