David Ho was born in the large city of Taichung, Taiwan. His parents struggled to support their young family, with his dad changing jobs every few months. When Ho was five years old, his father decided to change his luck for his wife and two children. He left them in Taiwan and moved to Los Angeles, confident that it would take only a year until he could save enough money to bring his family back together. Seven years later, the family was reunited when Ho, his mother, and younger sister moved to Los Angeles. He was used to living in a large city and excited to be living in America. He excelled in school, showing a particular aptitude for the sciences.
Ho studied physics at the California Institute of Technology (Caltech), then moved to the East Coast for medical school. His proud parents helped him pack up his belongings and make the cross-country move. At age twenty-six, he graduated from Harvard Medical School and immediately moved back to Los Angeles. It was 1981; Ho was chief resident at Cedars-Sinai hospital. A strange, new group of patients started emerging, patients presenting with unusual opportunistic infections indicating that their immune systems weren’t functioning normally. As it would turn out, these were some of the earliest cases of AIDS in the United States. By chance, Ho saw four of the five first AIDS cases described. A report published by the CDC on June 5, 1981, documented this odd cluster of five homosexual men, all of whom developed a rare pneumonia. It wasn’t known what caused their disease. When Ho recalls that time, he remembers how skewed his perspective was. “I was so focused scientifically on what was happening,” he said, “I could have no idea this was the start of a global pandemic.”
These early cases in his medical career influenced the course of Ho’s professional life. After finishing his residency, he moved back to the East Coast to work at Massachusetts General Hospital in Boston. It seemed that HIV followed Ho. While he’d originally intended to work on another virus, herpes, he was drawn to HIV as the cases of the mysterious new infection rose in the wards of the hospital. Ho became, in his words, the “one and only person playing with samples from HIV-positive patients.” He wasn’t afraid of the risk of the new disease; he wanted to understand the science.
For his first research assignment in Boston, Ho was given a project on Kaposi’s sarcoma (KS). KS is a cancer that leaves blotchy purple lesions all over the skin and mouth. It was the first opportunistic disease associated with AIDS. It’s called opportunistic because it takes advantage of our immune system when it’s down. Although KS is rare, it’s frequently seen in people with AIDS, whose immune systems can’t defend against the herpes virus that causes KS. As Ho studied the cancer prominent on the faces of those with AIDS, he couldn’t help being reminded of another plague that caused spots on the face—“the speckled monster,” or smallpox. The two diseases have radically different origins; AIDS is a retrovirus transmitted through bodily fluids, while smallpox is a large poxvirus that can travel airborne from person to person. Smallpox is one of the biggest killers in history. By some estimates, it is responsible for more deaths than all other infectious diseases combined.
While plagues differ in their details, symptoms, mortality rates, and whom they target, there is one common thread that runs through the history of all pestilences: stigma. This can be seen in such varied diseases as the Black Death in the fourteenth century, cholera in the nineteenth century, and AIDS in modern time. The writer Susan Sontag described this stigma perfectly as “the archaic idea of a tainted community that illness has judged.”
Smallpox carried its own stigma. Although the virus is not transmitted sexually, the disease itself renders its victims repulsive, covered in oozing sores. The bumps build over each other, covering the skin, and fill with a thick white fluid. For those spared by smallpox, the virus left them scarred and disfigured.
On May 14, 1796, Edward Jenner gave the first vaccine against smallpox. The forty-seven-year-old family doctor took a sample from a related virus and inoculated an eight-year-old boy, the son of a man who worked for Jenner. Although hard to believe today, two months and a second inoculation later, he tried to infect the boy with smallpox. It was the first vaccine in history. Thanks to that unethical experiment, the World Health Organization (WHO) was able to declare smallpox officially eradicated from the planet in 1980. The next year, 1981, a new disease, AIDS, would be discovered. David Ho hoped the lessons learned from Jenner and the first vaccine could be applied to HIV. Unfortunately, the same rules didn’t apply. Where smallpox could be prevented by an inoculation with a similar virus, this approach hasn’t worked with HIV because it is a rapidly mutating retrovirus. Where the plagues intersect is the effect they have on a community. Ho says, “If you walked in with an AIDS diagnosis you’d be dead within a matter of weeks. There was discrimination. Patients were not wanted by staff, friends, and family . . . discrimination pushed me to work.”
By 1995, Ho’s skyrocketing career had led him to New York City as director of the fledgling Aaron Diamond AIDS Research Center. He wrote an editorial that year for The New England Journal of Medicine titled, “Time to Hit HIV, Early and Hard.” The article, which would become famous among HIV researchers, hypothesized that treating HIV early, using multiple HIV drugs, including drugs not yet approved by the FDA, could result in an “ablative therapy.” He compared the strategy to the battle against tuberculosis and childhood leukemia, saying, “It was aggressive combination chemotherapy at the outset that led to cures. Optimistically, we can hope that such an approach will become possible in patients infected with HIV-1.” The hope was that the virus could be eradicated in patients during acute infection, resulting in the desperately needed cure. If not a cure, at least the drugs could stem the virus before it took hold in the body.
Although mass killing of T cells comes later in infection, the virus still kills some cells in acute infection, particularly in our tissues. Once the T cells in our tissues are gone, they don’t come back. This has prompted some researchers, like Ho, to advocate for early therapy. The logic for early intervention, Ho argues, is “infallible,” explaining, “Even when a person is doing very well, virus is churning away, knocking off CD4 T cells. Why let this happen?” Despite the logic behind early therapy, Ho’s theories were not universally accepted. Even now, Ho wishes the medical community had adopted his guidelines for early HIV therapy. He says, “It still bothers me that there’s not greater consideration for the science. It’s always ‘show me the data’ and yet this doesn’t apply to other diseases.”
Ho is referring to diseases like breast cancer. Despite a lack of evidence of the benefit of early screening and treatment, few argue against giving early, aggressive treatment to people whose mammograms have revealed tumors. Ho wishes that physicians would respect the science about what HIV is actively doing at this stage—making billions of copies of itself and crippling tissue immune cells—rather than insisting on large-scale clinical trial data. Ho uses a fitting analogy: “A man falling off a 100-story building feels fine when he passes the 50th story.” So, Ho argues, does an acutely infected HIV-positive person. But this doesn’t mean he doesn’t need a safety net. While Ho’s argument for early therapy wasn’t universally accepted, and today still isn’t, his work developing a new class of HIV drugs, which inhibit the protease enzyme, and his subsequent plan to eradicate HIV infection won him many accolades from both the medical and greater community. In 1996, he was named Time’s “Man of the Year,” and Newsweek ran an article enticingly titled “The End of AIDS?” featuring Ho’s work. Everywhere, people with HIV celebrated the approaching end of a fatal era.
• • •
Bruce Walker came to medicine by a path littered with false starts, roadblocks, and confusion. He doesn’t remember a time when he didn’t love science. His dad, a geologist, inspired his fascination with the natural world. Walker describes him as a “workaholic.” He recalls happy, precious Saturdays accompanying his dad to field sites. After one of these trips, when Walker was only eleven years old, his dad put a sample of pond water they had collected under a microscope. “It was teeming with life,” Walker recalls, smiling. This was a turning point. Those drops of pond water held far more interest for him than all the rocks his dad studied. He felt a draw to biology in a way that geology couldn’t touch.
Like David Ho’s family, Walker’s would move a continent away during his formative years. When he was a junior in high school, his dad got a grant to study red soils in North Africa. So they moved to Switzerland, which served as a jumping-off point for his dad to travel back and forth to field sites. Now enrolled in public school in a foreign country, Walker struggled academically and suddenly had to learn German. But though it was difficult, it brought the family together, and Walker fell in love with the alpine country.
Walker spent time painting houses and driving a fruit and vegetable truck around Switzerland during the years when most of his peers were starting college. But by the time he was finishing school in Colorado, now in his mid-twenties, his feelings were clear. He was desperate to go to medical school. His long road to medical school made his acceptance that much sweeter. Judging by the size of the small envelope he opened at his parents’ home one afternoon, Walker was expecting a rejection letter. But as soon as he read the opening line, beginning with “Congratulations,” he fell back on the couch, tears streaming down his face. “It was one of those situations where you realize how close emotions can be to one another,” he recalls. It was actually going to happen. He was going to medical school. Through all the starts and stops of his undergraduate education, he had come through with a prize that truly mattered to him.
After graduation from Case Western Reserve medical school, Walker continued his medical training at Massachusetts General Hospital. As in the past, he was a little unsure where medicine was leading him and what he wanted to specialize in. The next spring, Walker began to notice an unusual group of patients, all presenting with very uncommon diseases, such as pneumocystis, a fungal infection of the lungs. Specialists from all over the hospital poured in as they tried to figure out what was wrong with these young men. No one seemed to have an answer. This struck Walker forcibly: There were still mysteries in medicine. Even in a hospital like Mass Gen, full of the best doctors in the country, a disease could baffle the foremost medical minds.
It was 1981 and the mysterious disease was still called GRID, or gay-related immune deficiency. Some called it the gay plague or gay cancer. No one knew what caused it or how it spread. Walker had been undecided about his future medical path, but now, with the rising crisis, he found himself needed.
• • •
In the early 1980s, both Bruce Walker and David Ho were receiving training in infectious disease at Massachusetts General Hospital. Ho was a year ahead of Walker and already a superstar. In 1984, Walker and Ho sat at grand rounds, a ritual meeting that occurs in hospitals around the world, where medical problems are discussed. This grand rounds was special, for it featured Robert Gallo, the codiscoverer of HIV. Gallo had just published his paper in Science identifying the virus as the cause of AIDS. “It was so exhilarating,” Walker remembers. “Finally this thing that had been killing people was identified as a virus.”
Walker decided to pursue a research fellowship, even though it meant giving up much of the patient interaction he cherished. His experience in residency had changed his outlook on medicine. As he watched patient after patient die of AIDS in the crowded infectious diseases wards, he realized it was research that was needed. He felt helpless as a physician, unable to offer his patients anything but supportive care. Walker had done some research in college but hadn’t liked it. This seemed like a good time to give it another try.
He began what would become a long research career in Chip Schooley’s laboratory at Mass Gen. Walker was still something of a naïf. His mentor told him he should research the cellular immune responses to HIV. “I didn’t know exactly what that was,” he remembers. He didn’t have much experience in immunology. Schooley suggested that he start by measuring the response of T cells to HIV, particularly the storm troopers of the immune system: the killer T cells. The hope was that by understanding how the immune system fought off the virus, they could understand why it was losing the battle.
Arriving in the lab, Walker was told not to talk to two researchers: Joe Sodroski and Craig Rosen. These two, Walker was told, “were doing really important work” and couldn’t be distracted. If it sounds childish for lab members to be told not to speak to one another, imagine how it feels for a new researcher trying to gain a foothold in the field. As odd as it may sound, labs like this exist today. Even worse, many high-powered labs take the situation a step further, pitting their lab members against one another, each junior researcher in a battle to get the data first for the sole purpose of putting his or her name at the top of a manuscript. For Walker, it was tough. While he appreciated his mentors, he felt lost at sea. There was little supervision. He had no one to ask for help. The lab environment was tense. None of Walker’s experiments were working. As a year of his fellowship passed without any appreciable results, Walker sank into feeling like a failure.
One Saturday morning, Walker was in the lab, and yet another experiment had failed. This isn’t so unusual; all scientists have many failed experiments. A perfectly planned experiment faced with the chaos of reality often collapses. But, with persistence and experience, some will succeed. Part of maturing as a scientist is recognizing these moments, understanding when to pack it in and when to keep going. Walker, at the very beginning of his career, wasn’t sure which to do. Morose, he sat looking over the botched data. Joe Sodroski, the researcher he wasn’t supposed to disturb, came up to him. “What are you working on?” Sodroski asked, concerned about Walker’s despondent attitude. Walker told Sodroski what he was trying to do and how nothing was working. Much to his surprise, Sodroski had the solution.
Using Sodroski’s suggestions, Walker was able to get a unique model for HIV up and running. From their conversation, he devised an artificial system in which B cells taken from patients are engineered to express individual parts of HIV. He then measured the ability of killer T cells, the storm troopers, to respond specifically to each piece. With this scheme, he was able to dissect the components of the T cell response to the virus, teasing out which parts of HIV initiate a response. Taking the storm trooper cells from their first HIV patient, Walker’s team was excited to finally measure how the body responded to HIV. What they found was dramatic. In people infected with HIV, their storm trooper T cells specifically target and kill HIV-infected cells. These killer cells knew who or what they were looking for. When storm trooper cells were taken from people not infected with the HIV virus, the cells did not know what they were looking for. This data was the first indication that the body can mount a specific response to HIV.
Walker’s advisor knew this would be a big paper. He suggested they submit it to Nature, the field’s preeminent academic journal. Walker had never written an academic paper before and found the process intimidating. Indeed, the paper came back with an ambiguous letter. It wasn’t clear if the journal wanted to publish it. The reviewers wanted another experiment done. Specifically, they wanted HLA typing to be done on the patients being tested. HLA, which stands for human leukocyte antigen, is a cluster of genes that govern how our immune system functions. This cluster, located on chromosome 6 in our DNA, varies widely from person to person and gives us, as a species, an evolutionary advantage. With a wide variety of genes among us, we have a broad range of disease defenses. This makes it more likely that if a pandemic occurs and many die from a fateful disease, there will still be some of us who survive.
The journal wanted Walker to HLA-type the patient samples to be sure there wasn’t a hidden genetic advantage influencing the strong response of the killer T cells to HIV. The problem was, no one who did HLA typing would touch samples from HIV-positive individuals. These technicians, like many people in the late 1980s, were afraid of working with HIV-positive samples at a time when it was still unclear how the virus was transmitted. So Walker decided to do it himself. He learned the procedure and then ran the HIV-positive samples. The data were, as Walker puts it, “equivocal.” It seemed there was some pattern, but it wasn’t clear whether this cluster of genes exerted influence. Walker sent the paper back to Nature with the new data.
While the paper was in review at the prestigious journal, Walker traveled to Washington, DC, for the third International AIDS Conference, in 1987.
Walker and his wife had just welcomed their first child, a son. Now he was also reveling in the excitement of sharing the new HIV data. His excitement was short-lived, however. As he sat through the opening talk by none other than Anthony Fauci, a prominent AIDS researcher and director of the National Institute of Allergy and Infectious Diseases, he was shocked to see his own data looking back at him. Walker, a self-described “lowly postdoc,” was crushed. He assumed Fauci had been shown his data by a colleague looking for advice; it seemed Fauci had replicated their experiments.
Desperate, Walker called his mentor with the bad news. He told Schooley that T cell experiments very similar to theirs had been presented with no acknowledgment of their work. “Don’t worry about it. Nature just accepted your paper,” Schooley announced. In that moment, Walker’s mood changed from depression to delight. His work had paid off.
As Walker finished his fellowship in Schooley’s lab, his mentor sat him down to discuss his future. “Chip told me that one day I would be a famous immunologist, and I laughed. I was so sure he was wrong,” he remembers, smiling widely. By the 1990s, Schooley was proven right. Walker was the director of the AIDS Research Center at Massachusetts General Hospital and Harvard Medical School in Boston.
Now that Walker had a way to compare storm troopers of various people infected with HIV, he wanted to see if the personal genetics of an individual’s HLA affected the storm troopers’ ability to target HIV. By chance, just as Walker was investigating the role of these killer T cells, he came across a few, rare individuals. These were people who, for reasons no one understood, controlled HIV without taking any drugs. Because they were such a rare group, they became known as elite controllers. Walker discovered that the secret behind why this group of people is special lies in the ability of their T cells. Unlike the defeated army of cells in most people with HIV, in elite controllers, the T cells survived and were able to coordinate an effective strategy of targeting and killing the virus. But how did the army maintain the ability to target and kill the virus? The answer seemed to lie in their genes.
Walker had discovered a fundamental truth about how the immune system responds to HIV and what is necessary to overcome the virus. Somehow, he and his colleagues had to figure out a way to replicate this preservation of the commanders and storm troopers of the immune system in people infected with HIV. But how could scientists re-create such a complex system of immune control without the genetic advantage?
Walker had a theory, intimately connected with the work David Ho was doing. He believed that early therapy might initiate the immune response seen in the elite controllers. He hypothesized that the use of antiviral drugs, if given early enough in HIV infection, would convert a typical person’s storm trooper T cells into the elite squad that the HIV controllers maintained. But how could he find a patient given early therapy and then whose therapy was stopped? No physician could ethically stop therapy in a person infected with HIV. By chance, Walker was about to learn about a patient who fit these criteria—a young man given an unusual combination of antiviral drugs very early in infection: Christian Hahn, Berlin patient #1.