Big Shot: Passion, Politics, and the Struggle for an AIDS Vaccineby Patricia Thomas
A veteran journalist dramatizes the controversial search for an AIDS vaccine-the players, the politics, the money-in a vivid, suspenseful story that reveals how science is done, and not done, in America today. When the human immunodeficiency virus was identified in 1984, the competition to create an AIDS vaccine was fierce. Now Patricia Thomas brings the contenders to life in a fast-paced, dramatic narrative: Two biologists rescue precious virus cultures from destruction by a military biohazard team. Other researchers drive hundreds of miles during a heat wave to work in a safe containment lab. And a heroic figure from Randy Shilts's And The Band Played On just might win the vaccine marathon. Thomas shows how the scientists' youthful optimism is honed into gritty determination as they struggle with difficult research challenges, public condemnation of AIDS patients, cautious bureaucrats, conservative executives, hostile activists, and a perennial shortage of money. The lives and complex motivations of the characters illustrate the triumphs and frustrations of the quest for a vaccine. Interwoven with these gripping human stories are lucid explanations of how vaccines aim to block the potentially deadly tango of the AIDS virus and the human immune system. Above all, Big Shot shows how the health of future generations rests on the shoulders of individuals who are as strong, and as weak, as the rest of us. Just as A Civil Action ultimately told us more about human nature than environmental law, Big Shot is about a great deal more than AIDS vaccines.
Author Biography: Patricia Thomas has written about medical research for many years, and from 1991to 1997 she was editor of the Harvard Health Letter. She has been a Knight Science Journalism Fellow at MIT, and in 1998 was awarded the Leonard Silk Journalism Fellowship. Thomas was one of the first healthy volunteers to be injected with an experimental DNA vaccine for AIDS, in a study at the National Institutes of Health.
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WHISTLING PAST THE GRAVEYARD
Paul Luciw was alone in his lab at Chiron Corporation in Emeryville, California, on an August evening in 1984. Rush-hour traffic on the nearby Nimitz Freeway had fallen to a dull rumble, the technicians had gone home, and Paul relished the chance to work without interruptions. Then the call came from Kathy Steimer, his closest colleague at the company. "Paul, I've got a problem," she said. "The ultracentrifuge has stopped."
He could picture exactly where she was, all alone in a spooky P3 containment facilitya place where dangerous microbes could be handled in an isolated, specially ventilated room. This lab, a part of the Navy Biosciences Laboratory (NBL), was less than two miles from Chiron. All summer, Paul and Kathy had been loading the huge, heavy ultracentrifuge with samples of virus that doctors had isolated from AIDS patients in San Francisco. Like other teams of scientists in the United States and France, they were racing to unravel the genetic code of the virus and figure out how this tiny killer is organized. Scientists put a premium on this information because it could open the door to diagnostic tests, treatments, or even a vaccine.
When Kathy called, Paul's first thought was that the ultracentrifuge had thumped and bumped itself off balance like an overloaded washing machine, wreaking havoc with its contents while whirling at up to 20,000 revolutions per minute. If this had happened, whoever lifted the lid would find a jumble of metal racks and broken glassware coatedwith deadly viral goo.
Fortunately, Kathy reassured him, the situation wasn't as serious as that. The ultracentrifuge had simply ground to a halt while she was running a large preparation of virus. What troubled her was the prospect of filing an incident reportrequired any time something goes awry in a labwith the central NBL office. Kathy and Paul had been cleared to work in the lab only because a navy researcher, who happened to be an old friend of Chiron's CEO, had lent surplus lab space to the company three months earlier. This made it possible for the fledgling biotech to work on the AIDS virus; at this point, the company hadn't finished building a place where dangerous organisms could be safely handled. As guests of a military facility, working on a virus that terrified most people, the Chiron scientists had kept their heads down.
As soon as Kathy finished talking to Paul, who agreed they had to reveal what microbe was in the broken centrifuge, she called the duty officer for the Biosciences Lab. He immediately notified the commanding officer of the Oakland Naval Depot, where the laboratory was located, to report that there had been an accident with the AIDS virus on the base. The irate commander demanded to see Kathy in his office that very nightnot in the morning, but ASAP.
If the base commander was so bent out of shape, what would happen to the viral cultures that she had spent all summer cajoling into lush growth? For all she knew, a hazardous-waste disposal team was already hurtling in her direction, with instructions to confiscate the precious flasks. In a second quick phone consult, Kathy and Paul agreed that it made no sense to wait and see. Within minutes Paul was on his bike, pedaling furiously from Chiron's headquarters in Emeryville, a down-at-the-heels industrial suburb of Oakland, to the navy base. Paul was a short man, only a few inches over five feet tall, but fit in the way of one who shuns cars and walks or bikes wherever he goes.
Once at the Naval Depot, Paul showed his security pass to the armed guards at the gates and pedaled on to the P3 building, a forlorn structure near the base's edge. In the entry chamber, he stripped off his jeans and T-shirt and tossed them into a locker, pulling on a cotton scrub suit, gown, mask, booties, and latex gloves.
As soon as Paul stepped into the ill-lit hallway, lined with derelict freezers and obsolete lab equipment, he began to sweat. His reaction was the same every time he saw the labels on the closed doors of individual labs. The hallway was a rogues' gallery of pestilence: plague, anthrax, slow viruses that eat the brain. God knows what scourges had been handled in this old building and by whom. The only room in use now, however, was the one where he and Kathy had labored fourteen hours a day, six or seven days a week, since May. All that time and they had never seen another person in the corridor.
Kathy had removed the contents of the ultracentrifuge and had lined up the T-150 flasks on the bench. Each contained about one cup of cloudy viral broth, and she was tightening the tops and wrapping them in tape. Working swiftly, the two identically dressed scientists put each flask into a plastic bag, sealed it, then bagged it again. Finally, they loaded the flasks into some of the thick Styrofoam shipping boxes that accumulate in biology labs like coat hangers in a closet. These they sealed with broad strips of plastic shipping tape. The goal was to move the cultures to the small biosafety level-3 room that Chiron had completed only a few weeks earlier. Clearly, they'd have to transport the boxes of virus in Kathy's car, but leaving through the front gate would be too risky: It was now late in the evening, and the guards would surely suspect these civilians of stealing government property. A stealthier departure would be better.
Soon Kathy traded her sterile garb for street clothes, retrieved her car from the nearby lot, and signed out at the guardhouse. A couple of quick turns put her on a service road that hugged the outside of the navy's tall chain-link fence topped with concertina wire. She rolled slowly through the bright pools of the tall security lights, finally dousing the headlights and stopping in a dark patch only twenty yards from the back door of the lab building. She slipped out of the car, taking care not to slam the door.
Paul had been watching, and within seconds he emerged from the lab, looking nervously for the armed sentries who patrolled the base at night. He listened for the crunch of tires but heard only the low whiz of light traffic on the freeway. The air was brackish with the smell of the nearby mudflats of San Francisco Bay. With a box tucked under each arm, he hurried back and forth from the door to the fence until all the shipping containers were out.
Kathy and Paul each took a few steps back from the fence. She was the taller of the two by half a foot, a rangy, flaxen-haired California girl. He was smaller and darker, and his spectacles glinted in the darkness They exchanged furtive whispers and a signal nod before Paul gently lofted the first box, like a square and fragile beach ball, over the fence to Kathy's waiting arms. One by one, she received them. Less than an hour later, all Kathy's precious flasks filled with the AIDS virus were safe on the Chiron campus.
She returned to the Oakland Navy Depot alone to meet with the base commander. He was not a scientist, so Kathy explained calmly and carefully that although a machine had malfunctioned, no deadly organisms had been spilled and nothing had been contaminated. She also explained that she and Paul had been authorized to use the containment facility by the navy scientist in charge of it. The commander did not care what had happened or how it came to be. Only the future interested him. The AIDS virus, he told Kathy, was not the kind of problem he was going to have on his base.
* * *
In 1981, the same year that doctors in Los Angeles and San Francisco began reporting puzzling and rapidly fatal illnesses among young gay men, the fledgling Chiron Corporation made history by inventing a new kind of vaccine against hepatitis B. Some cases of this viral infection were chronic, untreatable, and ultimately fatal. And like AIDS, it was commonplace among homosexual men and posed a threat to transfusion recipients and health-care workers who handled human blood.
Chiron's founders, William Rutter and Edward Penhoet, were academic biochemists at the University of California campuses in San Francisco and Berkeley, respectively. Both were experts on hepatitis B and other viruses that prey on people. More important, they were charter members of a small club of genetic engineers. They practiced recombinant DNA technology, which basically meant snipping genetic material out of one organism, inserting it into a different organism, and tricking the host into expressing it: churning out the protein specified by the newly transferred DNA. This enabled them to make a large amount of whatever protein they chose, which might hold promise as a preventive vaccine, a treatment, or a laboratory tool.
On Easter Sunday of 1981, Rutter and Penhoet wrote out a wish list of products that their new company might make using recombinant DNA technology. Their goal was not only to solve some real biological mysteries but also to use genetic engineering to improve human health. At the top of their list were vaccines to prevent hepatitis B, herpes, and influenza, as well as tests that could be used to check blood samples for two types of hepatitisB and the mysterious, newer kind known as "non-A, non-B" (since shown to be several distinct viruses, including hepatitis C).
Rutter's lab at UC-San Francisco had already studied the hepatitis B virus in great detail. At the time Chiron was founded, the East Coast pharmaceutical giant Merck was actively seeking a replacement for its current hepatitis B vaccine, which used a protein derived from the blood of hepatitis B carriers. Making vaccine this way was not only expensive, but the process was also vulnerable to contamination with other blood-borne virusesincluding the scary new pathogen responsible for AIDS. Merck wanted a new kind of vaccine that would cost less to make, could be manufactured in a laboratory, and would be free of contamination. This was a tall order, however, and the best ideas for such a product were being nurtured in young biotech companies or in academic labs. Merck invested in several groups racing for the same goal, and one of them was Chiron.
Chiron's main rivals were hotshot researchers at Genentech, the San Francisco Bay Area's preeminent biotechnology company, and a group of Rutter's former collaborators at the University of Washington in Seattle. But it was Chiron's Pablo Valenzuela who got there first. He figured out how to use recombinant DNA technology to make the hepatitis B vaccine of Merck's dreams.
From hepatitis B virus, Valenzuela removed DNA that coded for a protein on the outside of the virus called HBsAg, short for "hepatitis B surface antigen." Then he inserted the DNA into yeast cells, which are cheap and easy to grow, and voilà! The yeast cells cranked out HBsAg that looked like the protein Merck had been laboriously isolating from blood. This genetically engineered version could be made safely, without any blood or virus involved. By Christmas, tiny Chiron had outdistanced its competitors and licensed this process to Merck. This precedent-setting vaccine, approved for sale by the Food and Drug Administration (FDA) in 1986, does an excellent job of preventing hepatitis B and is used around the world.
* * *
All vaccines accomplish the same thing: Like a self-defense instructor impersonating a mugger, the vaccine teaches the immune system what to do in an emergency. When a real thug appears, the lesson is recalled and a swift immune response immediately overpowers the attacker. Most traditional vaccines consist of disease-producing organisms that have been altered or killed; the Sabin polio vaccine is made from live attenuated (weakened) virus, for example, whereas the Salk formulation consists of killed organisms. Sometimes nature supplies a vaccine: Credit for eradicating smallpox goes to vaccinia, a pox virus that originally infected cows but in humans evokes a protective immune response to smallpox without causing any harm. Today, recombinant DNA technology offers a wondrous alternative, a wholly new generation of vaccines that are safer and cheaper to make than old-fashioned ones.
The first step toward building a genetically engineered vaccine is to identify an antigen that is always part of the attacking virus. Antigens are simply molecules, usually proteins, that the immune system recognizes as a threat and takes steps to eliminate. Finding the right antigen, as it turns out, can be an enormous challenge.
* * *
Pablo Valenzuela's hepatitis B vaccine was a cosmic home run for Chiron. Suddenly, anything seemed possible. In order to keep the company's streak going, Bill Rutter and Ed Penhoet drew up lists of scientists they wanted to hire, and most said yes when they were asked. "We were looking for people with a high energy level, dedicated to their work, and who wanted to make a difference," Penhoet recalls. In 1981, the scientists who joined Chiron and other biotech start-ups were turning their backs on stodgy academic tradition and offending many of their mentors.
During the late 1970s, the world of biology was split over the legitimacy of patenting discoveries made in the course of tax-supported research. Old-guard academic scientists saw university-based research as a gentleman's game and looked down their noses at scientists who went into trade by joining a biotechnology company. Today, when professors at elite universities and medical schools race to patent discoveries as soon as they are made, this snobbishness seems as outmoded as the idea that all telephones must have cords. But this attitude was entirely real in 1981. "So we put people on our list that we thought we could actually recruit, and they were all young people," Penhoet recalls.
Virologist Paul Luciw (pronounced "loo-shoo") was thirty-three when he joined Chiron in July 1982. He had just completed postdoctoral training in a UCSF lab whose leaders would win the Nobel Prize seven years later. Rutter, Penhoet, and Valenzuela were a tremendous lure for Paul. Not only were they respected as top-notch scientists, but "they were adventurous, broad in their thinking, yet able to define goals and get things done," he says.
Hiring Paul was a smart move for Chiron because he was an expert on retrovirusesbizarre little organisms that were just beginning to seem relevant to human health. Although doctors weren't worried about retroviruses in the pre-AIDS era, veterinarians were all too familiar with the damage these unusual organisms caused. Feline leukemia virus, known as FeLV, caused many thousands of fatal cancers in domestic cats. There would be a lucrative market for a vaccine against FeLV, and this was Paul's first project at Chiron. He explored two possible approaches at once. One was a classic vaccine strategy, in which protection would come from immunization with a weakened version of FeLV itself. The other, and far more exciting, idea would be to mimic the recombinant hepatitis B vaccinesplicing FeLV genes into yeast cells, so that these cells turn into vaccine factories.
Kathy Steimer had just turned thirty-four when she decided to write to Pablo Valenzuela and ask for a job at Chiron. She and Martin Wilson, a young neuroscience professor she had been dating during the previous year, drafted the letter beside a swimming pool in Davis, California. They had been introduced the previous Christmas by a mutual friend and had since become inseparable. Their lives had begun quite differently, with Kathy growing up as the daughter of a firefighter in Los Angeles, and Martin in a cultured British household where he was immersed in classical music. Both families valued education, however, and each produced a scientist absorbed in the challenges, frustrations, and satisfactions of laboratory research. In addition to falling in love, Kathy and Martin gave each other tremendous professional support. So it was natural for Martin to help her write a job-hunting letter to Chiron.
Like Paul, Kathy was a skilled retrovirologist. Earlier, she had left a biotech company because she was impatient with managerial incompetence, then moved to an immunology postdoc at Stanford, where she grew tired of being patronized by male physicians who were sure they were smarter than any woman with a Ph.D. At this point in her career, Kathy wanted to be respected for who she was and what she knew. During her first biotech job, she'd worked next door to Chiron and had seen Rutter, Penhoet, and Valenzuela in action. Observation told her that they were the kind of people she wanted as colleagues.
The feeling was mutual, and Chiron needed a scientist with exactly Kathy's strengths. An earlier postdoctoral stint at a famous Harvard lab specializing in growth factorsnatural substances that signal cells to grow or dividehad made her an artist when it came to growing temperamental cells. At Stanford, which had not been a happy experience on a personal level, Kathy had worked on the cutting edge of immunology. In Chiron's view, she was exquisitely prepared to create new assays for determining how the human immune system responds to experimental vaccines.
Kathy started at Chiron in September 1983. She promptly devised several methods for detecting viruses that proved useful for research purposes, had less success with a crotchety system for automating certain lab tests, and figured out how to synthesize interleukin-2, usually called IL-2, a cell growth factor that was fun to tinker with in the laboratory but didn't appear to have any immediate medical value.
Two months after Kathy started work at Chiron, a thirty-one-year-old molecular biologist named Nancy Haigwood came to the company from another, less-successful biotech in Maryland. At this point there were biotech start-ups on every corner, but in Nancy's mind, Chiron and Genentech were the only two destined for success. A military brat, Nancy grew up on overseas bases where cholera, yellow fever, and the like were commonplace. These early experiences sparked her interest in biology, and in human disease in particular. She joined a biotech company immediately after her postdoc at Johns Hopkins, feeling that the private sector was the place to be if you wanted to develop products that helped people.
On that first job, Nancy met and married a protein chemist who also joined Chiron when she did. Nancy was ambitious, and, in her own words, "I wanted to work in a really high-powered place because I thought it would be fun." She brought important skills to the company. She was expert at site-directed mutagenesis, a technique for introducing deliberate mutations into genes. Another major interest was splicing genes into animal cells, so that they could be turned into protein factories. Although Chiron made its successful hepatitis B vaccine in yeast, some scientists believed that future vaccines should be made in mammalian cells that more closely resemble human cells.
The first generation of molecular biologists thought there was no disease they couldn't conquer, and their dreams were paid for by investors besotted with biotechnology. Dozens of other bright young scientists cast their lot with Chiron in the early 1980s, and they were backed by executives and investors brave enough to risk the time, money, and space needed to tackle major medical puzzles. But it was mainly the brains and determination of Paul, Kathy, and Nancy that enabled the company to create one of the first experimental vaccines for AIDS.
* * *
The New York Times wrote in November 1983 that AIDS cases had been identified in thirty-three countries and on every inhabited continent. By Christmas that year, epidemiologists at UC-San Francisco estimated that one of every three gay men in the city was already infected with the virus that causes AIDS. San Francisco was hit early and hard by the new epidemic, and although cases had been identified among hemophiliacs, transfusion recipients, IV drug users, and a few prostitutes, most people saw it mainly as a gay disease.
AIDS was an ugly way to die. The virus decimated the immune system, leaving the patient vulnerable to opportunistic infections by microbes that aren't normally a problem for healthy people. AIDS patients were disfigured by the purple lesions of Kaposi's sarcoma, wasted by intractable diarrhea, and suffocated by a vicious pneumonia. Microbes swarmed into every orifice; mouths turned mossy with yeast infections and bowels were lacerated by bacteria. Some patients went mad with dementia as malignant lesions swelled in their brains. Doctors prescribed antimicrobial drugs for opportunistic infections, but this was like trying to halt a locomotive with bare hands.
Rutter and Penhoet and their scientists knew about all this. Part of Chiron's business strategy was to maintain close working relationships with UC-San Francisco and UC-Berkeley, where they still had strong ties. The human catastrophe of AIDS was all too evident at UCSF and its crosstown teaching hospital, San Francisco General, which was on the front line of the epidemic. Many of the previously healthy young men who were dying of AIDS were the same people who had earlier been infected with hepatitis B. And this, after all, was the disease that had already made Chiron famous.
Although it would be romantic to think that scientists throw themselves at a new infectious scourge because it vexes their curiosity or stirs pity and terror in their hearts, that isn't how it works. In fact, researchers tackle problems that they believe they are equipped to solve. Rutter and Penhoet figured that they had at least some of the tools needed to study whatever virus might be causing AIDS. At the very least, Chiron might come up with a blood test that could confirm the diagnosis in patients or screen donated blood for signs of virus. The company already had a test for detecting hepatitis B in donor blood, and if it also had a similar one for AIDS, it could package the two and sell the product to blood banks. More important, detailed knowledge of the hepatitis B virus was what enabled Chiron to make the world's first genetically engineered vaccine. If Chiron put its best scientists to work on the AIDS virus, who could say? Back-to-back homers are not unheard of.
Excerpted from Big Shot by PATRICIA THOMAS. Copyright © 2001 by Patricia Thomas. Excerpted by permission. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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