Bruce Walker says he is now doing the most important work of his career as a physician-scientist combating AIDS.
He is leading an international research effort to understand how some rare people who are infected with HIV but have never been treated can fight the virus with their immune system. He hopes such knowledge could lead to a vaccine and new treatments for the disease.
He also has spearheaded the creation of advanced clinical and laboratory facilities at the front lines of the AIDS epidemic in South Africa, where he and his colleagues at Harvard and the Massachusetts Institute of Technology routinely collaborate with the medical, scientific, and support staff.
Walker is motivated today by the same drive that brought him to medicine more than three decades ago. "As a physician you have the chance to make a difference," Walker said, "to be involved in people's lives at really critical junctures…and that is a privilege, honor, and a really precious thing to be able to do."
Walker always knew he was going to pursue a career in science. Both his parents were academics: His father was a geology professor at the University of Colorado at Boulder, where Walker grew up, and his mother was a psychologist and artist.
During elementary school, he collected rock samples on his father's field trips. What particularly "lit him up" one day was seeing, under his father's microscope, life teeming in a sample from the campus pond. He particularly enjoyed biology in high school, where a teacher exposed him to the idea that physicians employ biology in their work. Nevertheless, he majored in chemistry at the University of Colorado at Boulder, with the aim of someday focusing on the molecular aspects of biology.
How biology actually informs the practice of medicine became concrete to Walker when he volunteered at a hospital in Zurich, while spending two years as an exchange student at the Swiss Federal Technical Institute. He saw for the first time physicians "applying the tools of science to try to save someone's life," and wanted to do the same.
He went to Case Western Medical School and, in 1980, began his residency in medicine at Massachusetts General Hospital. The next spring, Walker saw his first AIDS patient. At the time, AIDS had not yet been recognized as a disease. But in hospitals throughout the country, doctors were seeing increasing numbers of previously healthy young people suffering from multiple diseases, such as Kaposi's sarcoma and pneumocystis pneumonia, immune system collapse, and ultimately, death.
By June of 1981, the Centers for Disease Control and Prevention named the new epidemic acquired immune deficiency syndrome, or AIDS. In 1984, Robert Gallo and Luc Montagnier identified HIV, a new retrovirus, as the cause of AIDS. The finding led to a diagnostic test for the virus and an understanding of how it spread. Additional research showed the virus destroys CD4 T cells, immune cells the body needs to fight disease.
During the 1980s, the epidemic rapidly expanded in the United States, and also globally. Currently more than 40,000 new cases of HIV occur in the United States every year. Antiretroviral drugs introduced in the early 1990s and improved over the years have transformed AIDS from a death sentence into a chronic condition for people fortunate to have access to these life-extending medications.
Today, the epidemic has shifted to Africa. In South Africa alone, approximately 5.4 million people currently are infected with HIV.
As a research fellow, Walker was impressed with how research relying on patient and laboratory data could address the problem of AIDS. In the mid 1980s, he decided to try to understand how the immune system in people with HIV tries to fight the virus, but without treatment, usually loses.
The prevailing idea at the time was that a patient's T cells were inactive during HIV infection because the problem with AIDS was the lack of a cellular immune response, one of the major ways the body defends itself against viruses. In 1987, though, Walker showed that T cells from the blood of patients were able to fight the virus in test-tube experiments, but with time the virus vanquishes the immune system.
Since then, Walker has characterized many strategies the virus uses to kill off immune cells. He also has studied, on a small scale, how certain infected people can evade viral destruction. In Boston, he directs the Ragon Institute of MGH, MIT and Harvard, a highly collaborative research initiative established in 2008, designed to bring new scientists and engineers from diverse disciplines to contribute to the development of an effective HIV vaccine. Walker hopes his new multi-institutional research team at the Ragon Institute will generate findings that will allow scientists to replicate the biological processes used by the immune systems in that small number (approximately 1 in 300) of people with HIV who coexist with the virus without drug treatment.
For the study, which began in August 2006 in his laboratory in Boston, he and his colleagues have been working to genetically characterize 2,000 individuals from all over the world deemed to be elite or viremic virus controllers. Elite controllers keep their HIV viral load below 50 virus particles per milliliter of blood; viremic controllers maintain a range between 50 and 2,000 particles. The average untreated patient has a viral load of more than a million particles at the time of acute infection.
"Viral load is what dictates, to a large extent, whether you get sick or transmit the disease," Walker explained. "At a viral load of 2,000 your chances of getting sick and transmitting the disease are much less." If a vaccine or treatment were developed that kept the virus below 2,000 particles, disease progression and transmission might be contained.
Walker's team has recently completed an extensive multigene analysis of nearly 1,000 of these controllers to determine the genes contributing to their survival. A large sample is needed to distinguish relevant genetic factors from normal variations between individuals. The results provide strong evidence that HIV-specific CD8 T cells are the major genetic determinant of viral control, and lay the foundation for ongoing functional studies to define the mechanism of this effect.
Since 1998, Walker also has worked in South Africa investigating how different isolates of the virus contribute to the disease. People can be infected with different strains of the virus, and in any individual the virus changes over time. While working in Africa, he soon realized he needed to improve the care of the people he was asking for blood samples.
So, with a small grant from the Elizabeth Glaser Pediatric AIDS Foundation, Walker helped establish a clinic in Durban, South Africa, which also had a research component.
In time, the project evolved. By 2002, the Doris Duke Foundation awarded two grants to Walker for the Nelson Mandela Medical School in Durban to improve HIV medical research there. One grant led to the construction of the Doris Duke Medical Research Institute (DDMRI), finished in 2003, which performs state-of-the-art biomedical research, focusing in particular on HIV. The other supported the creation of the HIV Pathogenesis Program, an initiative to train the next generation of African scientists to study the evolution of the virus and the immune responses effective in controlling HIV. Walker collaborates on both projects, shuttling between Boston and South Africa routinely. More recently, Walker was involved as one of the founding scientists for the HHMI-funded KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), a state-of-the-art research facility in KwaZulu-Natal dedicated to the study of the dual epidemics of HIV and TB.
After more than 25 years battling AIDS, Walker remains optimistic. He hopes his research will contribute to a vaccine and better treatments. He also hopes his work in South Africa will continue to prevent new infections and allow infected people there to live fruitful lives, lives that otherwise would have ended prematurely.
