Q & A with Ragon Institute Director Dr. Bruce Walker

Q: Who is Bruce Walker?

A: I am originally from Colorado, and am the son of a geologist and a sculptor. I went to Case Western Reserve for medical school and then specialized in internal medicine with the goal of taking care of patients as a general practitioner. Upon completing medical school, I did my internship and residency training at MGH beginning in the summer of 1980. My goals changed drastically when we started seeing young people with what was clearly a new and deadly disease for which we had no answers and no treatment. They all died of what was ultimately shown to be AIDS due to HIV infection. It was clear to me that unless we learned from our patients we would see a lot more of them die, so I decided to become a physician-scientist to try to understand how the body fights back against this new disease, and why it usually loses that battle.  I have spent my entire career working on HIV, with the goal of making a vaccine and developing a cure. I am the Director of the Ragon Institute of MGH, MIT and Harvard, and one of approximately 300 scientists nationwide funded by Howard Hughes Medical Institute (HHMI).

Q: What is the Ragon Institute?

A: In 2007, with yet another failure of a vaccine to protect against HIV, my colleagues and I decided that we had to go back to the basics, to study fundamental immunology and to bring people from other disciplines like engineering and physical sciences to work on HIV, to apply all available knowledge to this problem. This was not easy to do since science exists in silos—if you are not already working in a specific area and have a successful track record, it is almost impossible to get funding. At the same time, through our work at a mission hospital in South Africa, I was asked to meet the owner of the electronic medical record (EMR) company that was servicing the hospital.  I was asked to tell him the EMR was saving lives, since there was concern that they would pull out of South Africa given the difficulties in dealing with the government at that time. That owner was Terry Ragon and it was clear that the EMR was saving lives. We met briefly in Cambridge where his main company, InterSystems, is located, and he then traveled to South Africa to see his EMR in action. While there, he was also able to see the other things we were doing to combat the HIV epidemic. This coincidental encounter led to a gift of $100M ($10M per year for 10 years, all to be spent) to establish the Ragon Institute as a joint venture between MGH, MIT and Harvard to “harness the immune system to prevent and cure human disease.” Our organizing principle was to take on challenging medical problems of global importance that had not been solved, and our first goal was development of an HIV vaccine. This year, 2019, marks our 10th anniversary, and we now have a promising candidate vaccine that is being tested in humans for efficacy. At the anniversary, we were given a $278M endowment by Terry and Susan to carry on our mission, which has expanded to include influenza, TB, Zika virus and other diseases. 

Q: What is HIV, and why is it so deadly?

A: HIV is essentially an infection of the immune system. It is a virus, which consists of genetic material surrounded by a sugar coating. It binds to so-called “helper cells” (white blood cells of the human immune system). Upon binding, the viral genetic material enters the cells and programs the cell to make more viruses, and ultimately kills the CD4 helper cells. AIDS is defined by the number of CD4 cells a person has—when that number gets below 200 (normal is 800-1200), then the immune system begins to fail. This failure is due to a lack of sufficient helper cells, which are the central orchestrator of the immune system—the key to coordinating a defense against viruses, cancers and other diseases.  Infection and loss of these cells leads to loss of immune function, so people end up dying of infections and cancers that the immune system would otherwise be able to fight off. There are currently 37 million people worldwide who are HIV infected (UNAIDS, 2017).

Q: How do HIV drugs work and why do they not cure HIV?

A: HIV drugs work by disrupting the ability of the virus to infect new cells and use their genetic material to force the cell to make new copies of the virus to infect more cells. The drugs act by inhibiting key viral enzymes that are needed for new viruses to be made. As soon as someone becomes HIV infected, they are infected for life because HIV inserts its genetic material into the human genetic material and remains there forever. Some of the infected cells make more virus and ultimately die, but some lay dormant with the virus’ genetic material inserted. In this dormant state they are not recognized by the immune system and are not susceptible to drugs, since drugs and the immune system can only kill off virus when it is actively replicating. These dormant cells may be only one in a million cells, but are enough to re-establish a robust infection and destruction of CD4 cells if the drugs are stopped, even after decades of treatment with the antiretroviral therapy (ART, also called the HIV drug cocktail since it is a combination of medications that are more effective in concert that alone).  Thus for anyone infected with HIV, treatment has to be taken every day for the rest of their lives. If not, the virus will return. If doses are missed, the virus develops resistance to the ART and it no longer works, and AIDS develops.

Q: Why do you work in South Africa?

A: Twenty years ago, we wanted to understand why babies born with HIV (because their mothers can transmit infection to them) did so much worse than adults who became infected. We sought out collaborators in Africa, where we heard that there was a high incidence of mother-to-child transmission because there were no drugs provided to the mothers or the babies. In fact, the South African government at that time was claiming that HIV was not the cause of AIDS and that the drugs were deadly. We planned to bring blood samples back to the US to study them, but the collaborators we found asked if we could do the studies there and at the same time train them to become physician-scientists. We did, and rapidly realized how much we could accomplish. This led us to brainstorm with our African collaborators about how to do more, and decided to set an ambitious and likely unachievable goal: to build a world class research institute and put it right in the middle of the worst part of the HIV epidemic. Against all odds, we were able to convince the Doris Duke Charitable Foundation (DDCF) to support this vision. The DDCF gave a grant to me at MGH to build what became the Doris Duke Medical Research Institute (DDMRI), the first dedicated medical research institute to ever be built at an African university. A collaborator of mine encouraged me to also ask my employer, Howard Hughes Medical Institute (HHMI), to support us, and despite my doubts that they would be interested in this project, I approached them. Although it took some time and lots of effort, in the end they gave $150M to build a grand addition onto the DDMRI, which would be used to do world class TB and HIV research. This new building is called AHRI (Africa Health Research Institute) and is owned by the Nelson Mandela School of Medicine. Rather than planting an MGH, MIT or Harvard flag in South Africa, we have tried to support local leadership and ownership for long term sustainability. 

Q: What is FRESH and why is it at a shopping mall?

A: We realized that understanding why the body fails to defend against HIV had something to do with the very earliest events when the battle first begins—just after exposure to the virus. The HIV incidence rates in KwaZulu-Natal (the province that is home to Durban) is 8-10% per year, particularly in young women. We realized we could potentially enroll young women at risk of contracting HIV, and if we followed 100 of them for a year, 8-10 would become infected. This meant it was feasible to study them twice a week before they became infected, to catch those that did become infected at the earliest possible time. To enable frequent monitoring, address issues of poverty that enhance HIV risk, and provide a benefit to the participants, we created the FRESH (Females Rising through Education, Support and Health) Study. It was designed by Krista Dong, an MD from the Ragon Institute who has been living in South Africa for nearly 20 years now.  The program acts in part as a pathway out of poverty by providing participants with a twice-weekly curriculum aimed at empowerment, life skills, job readiness and HIV prevention education. This novel design links benefit to the participant to basic science discovery. To avoid stigma, we established FRESH in Umlazi, a former township, at a shopping mall, converting a retail store into clinic space and classrooms. Concurrently, we monitored for incident HIV infection in recruited participants by finger prick for HIV detection at each twice-weekly visit. The scientific discoveries that have come from this have been remarkable, and the empowerment program has been incredible— it has transformed the lives of these women. Over 80% of the more that 1,200 persons to complete the program have been placed in jobs, internships or school.

Q: Who are the traditional healers and why do you work with them?

Traditional healers, also called Sangomas, are deeply rooted in the South African culture, and much of this has to do with connecting to one’s ancestors. The majority of South Africans will go to a traditional healer before they go to a western doctor if they become ill. We have developed a program that builds on their strong connections to the community to expand HIV testing. Through a program developed by Krista Dong, we have been able to license them as accredited HIV counselors and testers. They also help to teach HIV prevention at the FRESH site in Umlazi.