Lab Meeting: Bruce Walker
“I think the next 20 years are going to be the age of immunotherapy.”
We live in a dangerous world, awash in a sea of microbes that can hijack our bodies, wreak havoc on our organs and cause devasting disease.
SARS-CoV-2, Ebola, SARS, influenza, polio and HIV, are notorious villains, with more threats certainly looming on the horizon: “To have something as transmissible as COVID, but with the case fatality rates of MERS…[it] would really be a threat to human existence,” explains Dr. Bruce Walker, Director of the Ragon Institute and Professor at Harvard Medical School and MIT.
“We are born alone…” but we certainly live and die by our immune system. The ability of our white blood cells to stop viruses from replicating inside our body, is quite literally a matter of life and death. Pathogens like HIV destroy T cells and impair our ability to mount an immune response. The consequences are devastating: “The early days of the AIDS outbreak were very dark days… [patients] were coming in with very advanced disease, and as physicians we had little to offer. It was just excruciating,” describes Walker, who trained as an infectious disease physician at MGH during the AIDS crisis of the 1980s (#2).
The COVID-19 pandemic has again placed viruses at center stage. Immunology is the lingua franca of daily life—terms like mRNA vaccines, antibody therapies, viral variants, Ro and “super spreader” are practically commonplace. What the public may not realize is that these ideas, concepts and therapies were spawned from responses to earlier viral epidemics: “So much of what we were able to do in the COVID pandemic was based on advances made in combating HIV. There are so many parallels,” reflects Walker (#2). We owe a great debt to physicians and scientists who have studied viral pathogenesis for decades—they have, and continue to, lay the groundwork for effective responses to current and future threats.
Bruce D. Walker was not a born scientist—a reluctant chemistry major at UC Boulder, he yearned to do something relevant to human health: “I came to the slow realization that there were two people in the world that were interested in my [chemistry] experiments…and I was not one of them” (#1). After discovering a passion for taking care of patients in medical school (Case Western Reserve), Walker completed internal medicine residency at MGH: “in residency I saw a patient…who had three infections and three cancers all at the same time. Doctors who seemed to know everything about every disease were saying that they had never seen this before…It turned out to be one of the sentinel cases of AIDS” (#2).
Treating these dying patients was “heartbreaking” and pushed Walker to specialize in infectious disease, and research HIV in the laboratory. His initial foray into bench research was not a success: “I totally flailed around.” After words of encouragement from his wife strengthened his resolve, Walker finally had a breakthrough—he discovered that infected patients mounted a vigorous HIV-specific T cell response, despite eventually losing the majority of their lymphocytes: “People didn't initially believe the data, because the T cell response was so robust” (#3). After a second study proving the existence of an MHC I restricted HIV-specific CD8+ T cell response in persons with HIV (#3), Walker was off to the races.
Over the past several decades, his lab has elegantly mapped how cellular immune responses control (or fail to control) chronic viral infections, with an eye towards leveraging insights from human patients (both in the US and in South Africa). In his role as Director of the Ragon Institute, Walker has played a key role in directing COVID-19 related research—culminating in development of the J&J vaccine (#5). For his efforts, Walker has received the Doris Duke Distinguished Clinical Scientist Award, and been named a member of the Association of American Physicians, the National Academy of Medicine, and the American Academy of Arts and Sciences. He is also a fellow of the American Association for the Advancement of Science and the American Academy of Microbiology. Since 2002 he has been an HHMI investigator.
Walker’s career is a reminder that the impressive science we see splashed across today’s headlines did not happen overnight. Learning from (and improving upon) our response to prior epidemics is crucial. As a longtime physician, Walker also embodies the throughline that caring for sick patients can be one of our greatest sources of scientific inspiration and motivation.
Below is an interview with Dr. Bruce Walker, from January 2023:
1. What initially got you interested in science and medicine?
My father was a geologist, and I would often go with him to his office—I grew up in Boulder, Colorado and he was a professor at the university. We used to go [to his office] on the weekends, probably to just give my mother a bit of a break. In his office he would give me thin sections of rocks to look at under the microscope, which was always really interesting.
Then one day, he took me to the pond on the campus where we got some pond water to take back to his office. He had an inverted microscope, which he set up for me. I started looking at the water and it was just this amazing moment where there was all this stuff [microbes] looking back. It was so different than looking at thin sections of rocks—I just got really mesmerized by it. This was my “Introduction to Biology” course in a way. Then it was it was really through my 10th grade biology teacher [and his encouragement] that I got much more into it. I took a class in high school where we dissected a cat and did the whole anatomy thing. And that was just amazing—I didn't know what liver was or a spleen or where any of those things were, but just to see how it all fit together was amazing. So that was kind of how I ended up thinking about medicine—as a way to study applied biology.
2. What was your first taste of experimental science? Who was your first great scientific mentor?
When I was in college, I majored in chemistry. Even though I was interested in biology, I was also interested in chemistry.
I decided to transfer to the Swiss Federal Technical Institute in Zurich—I had spent a year there in high school when my father was working in North Africa on an NSF fellowship. We lived in Switzerland, so he [father] could use an electron microscope there. I'm one of four siblings, and my parents gave us each a German-English dictionary and sent us to public school, where we initially sank and then slowly learned to swim. By the end of the year, I spoke German and Swiss-German fluently. In college [Colorado], I decided that I would go back to Switzerland to really focus on chemistry, math and physics. But I decided soon after I got out there that I really wanted to pursue a medical career. When I went back to the University of Colorado [after three semesters in Switzerland], I had enough credits and decided I would go ahead and try to graduate with honors in chemistry. But I had to do a research project in chemistry to graduate with honors. I ended up investigating some organic compounds with gas chromatography.
I came to the slow realization that there were probably two people in the world who might be interested in the outcome of my experiments, and that I was not one of them. So it was a tough situation to be in. When spring break came up, I had the option to spend the entire time in the lab trying to finish the chemistry project, or to go backpacking with my girlfriend in Rocky Mountain National Park. I decided to go backpacking and forego graduating with honors [settled for distinction]. When I went to medical school, I just knew that research was not for me—I wanted to take care of patients. So I graduated from medical school at Case Western Reserve in Cleveland, and in 1980 went to Mass General for residency in Internal Medicine. I fully expected that I would do some kind of primary care, and maybe some clinical research, but certainly no bench research.
But during my first year of residency I saw a patient, a young man, in the emergency room who had three infections and three cancers all at the same time. Doctors who seemed to know everything about every disease, were saying that they had never seen this before, in an otherwise healthy young guy. Despite our efforts, he rapidly died. He turned out to be one of the sentinel cases of AIDS.
[All the doctors] said: “you'll probably never see another case like it.” But a couple of weeks later, another case just like it came in. It was just horrific to watch these people die, and we had nothing to offer them. We had no idea what the cause of this thing was, but it was clear to us on the front lines that this was some kind of new disease, as we started seeing more cases.
This experience made me decide to specialize in infectious disease and learn from patients so that we'd have something to offer them. Suddenly research seemed relevant, though it had always seemed very esoteric in college. I then trained in infectious disease and sought out a laboratory where I could work, even though I was completely green. My classmates and friends were looking for Nobel laureates to work with. I was looking for somebody who would understand that I didn't know anything about research and would be supportive.
I picked a young physician-scientist [Robert “Chip” Schooley], becoming the second postdoc to ever work with him. We started trying to understand how the body fights back against HIV. He suggested that I look to see if people who are HIV infected mount T cell responses specific to HIV. I didn't really know what a T cell response was at the time, but I started in the lab and wrote a training grant proposal—most of which my professor dictated to me because I just didn't have any background.
We submitted the grant, and I got a terrible score. Essentially, the review was saying: “don't you understand HIV is immunosuppressive disease? The problem is that people don't make T cell responses.” That was depressing to see that it didn't get a good score. But my research mentor, Chip Schooley said: “no, this is a good project. Let's resubmit the grant.”
During this time, I was able to read a lot more about viruses and immunology. I basically got to the point where it actually made sense to me. And I thought: “wow, it really does make sense from reading about other retroviruses that T cells really may be doing something important in HIV. We finally resubmitted the grant and it came back with an even worse score. Again, the reviewers basically said: “don't you understand T cells don't exist in this disease. That's the problem.” But I had made a copy of the grant and had also submitted it not to the NIH, but also to the American Cancer Society [ACS]. Somehow it miraculously got funded through the ACS, and I could start working on trying to look at these HIV-specific T cell responses. I needed to have some way to express HIV envelope protein, and so I went over to Bill Haseltine’s lab at the Dana Farber to learn how to put HIV envelope on the surface of target cells. I worked on the project for about nine months, and Bill told me I wasn't allowed to talk to anybody in the lab because they were all doing important work—I wasn't supposed to bother them. I totally flailed around. And after nine months, I was in on a Saturday, and was completely depressed because I gotten another negative result. A postdoc said: “what's up? What are you doing?” I started to explain it to him, and he said: “why are you doing that, we did that a year ago, and we know it doesn't work.” I went home, and I told my wife: “I'm done. I tried research twice.” She talked me down off the ledge and said: “you planned to commit a couple of years to this [research]. Don't be daunted, do what you said you were going to do, and really give it a try.”
Joe [postdoc] then pointed me to a paper that had just come out in Nature from Bernie Moss’s lab, where they had use recombinant vaccinia virus to express HIV envelope. He said: “you should look at that article. So I went down to the library—it was before the internet [late ‘80s]—and found that the article said in the last sentence: “this methodology could be useful for looking at cellular immune responses to HIV.” We were able to get the vaccinia virus vectors from Bernie, and actually showed that not only do people with HIV infection make a T cell response, but they make an enormous T cell response. Nobody believed our results initially. I've since spent my entire career trying to understand that T cell response to HIV and other viruses.
3. Besides your wife’s encouragement, what made you keep going in research despite the two early setbacks?
There was just clearly an incredible need. The early days of the AIDS outbreak were very dark days—clinically, we were rounding on patients in the hospital, knowing every one of them was going to die.
They were coming in with very advanced disease, just so agonizing to see when we had so little to offer. Some would go blind from CMV retinitis, some were disowned by their families because they were gay. It was just awful. Seeing these patients was clearly a motivating factor. I was always more linked to the clinical side of things. That’s why the project with Chip was so compelling, it involved obtaining blood specimens from patients, going back to the lan and trying to figure out what the white cells were doing.
A few years ago I was invited by Bob Gallo to be on a panel at Cold Spring Harbor, where I tell the whole story of those early days. The first paper I ever published [from this time] was a first author Nature paper—I didn’t even really appreciate what Nature was at that time. I still had a very rudimentary knowledge of immunology. Many people didn't believe the data from this initial paper, which I can understand in retrospect. We didn't conclusively show that it the T cell responses we were detecting were HLA class I restricted. The critical experiment to show class I restriction was done in a second paper, which was published in Science—that really nailed it. But there's an interesting story about the moment I realized what I was claiming was correct. You can see me discuss that moment in the Cold Spring Harbor talk.
4. What has been your scientific high point? — What do you consider to be the most exhilarating discovery or set of discoveries you have been involved in throughout your career?
There have been many great moments. I've stayed connected clinically, and continued to see patients on the ID clinical service at MGH until just a few years ago. One stands out in particular. In 1994, before we had effective therapy, I was asked to see someone in clinic who was supposedly HIV infected. When I went down to see him, he was the one person in the waiting room who looked healthy. I took him into the exam room and asked him what was up, he said that he'd been HIV infected for 16 years, and they kept telling him he was going to die. But he had a normal CD4 T cell count, and he felt entirely well, and had never taken any anti-HIV medications.
This was for me, the first so-called “elite controller” I encountered: a person who was actually controlling the virus on his own. I didn't initially believe that he was infected and retested him just to be sure, and confirmed he was infected. We had access to an early-stage viral load assay that we applied, and he had an undetectable viral load by the cut offs in those days. The reason we knew he had been infected for so long was because he was a hemophiliac, and had frozen blood samples. He had a severe viral-like illness in 1978, when he was studying in the seminary at Yale and over two weeks slowly got better, without a diagnosis ever being made. In 1985, when a blood test for HIV became available, they went back and looked at his frozen blood samples from years prior. He seroconverted at that time [‘78], and so that was his acute HIV infection syndrome [at Yale]. But then he was entirely well, and subsequently had an undetectable viral load. It was just this amazing moment where I realized: “Oh my God, not everybody dies of this disease.”
We really pounced on that discovery to try and see if we could find anybody else who was an “elite controller,” and try to understand what was going on. And studying him provided new insights: what we found in this patient was that he had an enormous HIV specific CD4 T cell response—we had looked in other individuals and never found any evidence of this type of response, which is critical for providing help to CD8+ T cells. We did this study figuring that if this patient really was controlling [HIV] on his own, then he must have CD4 help for his CD8 T cells. In fact, he had the strongest CD4 and CD8 T cell responses we'd ever seen. So, it all fit together.
What has been so amazing to me about the HIV field is just to see how HIV has slowly revealed its secrets over time—and it all makes biological sense. Now most recently, we’ve done work where we think we have figured out how these “elite controllers” actually clear virus. We think this mechanism is actionable, and that it has to do with the specificity of the response, which we figured out by applying network theory to the HIV structure—we showed that highly networked amino acid residues are preferentially targeted by elite controllers, such that if the virus mutates these residues it leads to a fitness cost for HIV. But we made other discoveries along the way through things that we were doing in South Africa. I was collaborating with Rafi Ahmed on a project, when he told me about this new molecule they just identified called PD-1 in mice that was associated with T cell dysfunction. He wondered if it was something relevant in human disease, and I said: “wow this sounds like HIV is the next place to look for this [PD-1].” We went on and identified PD-1 as a negative immunoregulatory molecule in HIV infected individuals—we used the antibody from Rafi and Gordon Freeman to study this molecule in our South African cohorts.
5. What was it like being the Director of the Ragon Institute and a virologist, during the COVID pandemic? Any parallels to the AIDS crisis, and how what long-term changes has COVID made to the practice of science?
In January of 2020 I was in South Africa with 25 Harvard and MIT undergraduates, teaching a course called “Evolution of an Epidemic,” about HIV. It is a course that we teach that tries to link the biology, immunology, vaccinology and treatment of HIV. Where did HIV come from? How does it cause disease, and what are all of the social determinants and policy that influence the course of a pandemic? One of the students had just returned from visiting her family in a city in China I'd never heard of, called Wuhan. She started getting text messages saying: “there's something really bad going on here. Everybody's coming down with pneumonia and they're building new hospitals.” And then we'd see it come out in the newspaper a few days later. I was also with one of my former trainees—Diana Brainard, who I had invited to come as a teacher in the course. She was at the time, the Senior Vice President at Gilead for emerging infectious diseases. She had developed a drug that I'd never heard of called remdesivir. And so we felt like we were right in the center of all of this, and we pivoted the course to talk about this emerging virus in China. As I was flying back, I thought we had to get involved in this. Dan Barouch is one of the founding members of the Reagan Institute, and I called Dan as soon as I got back. He said: “well we're both thinking the same direction [studying SARS-CoV2]. But we need funding.” I got in touch with Mark Schwartz, who had given us lots of funding in the past. He gave us the money to jumpstart the studies that the Dan did, which led to the J&J vaccine.
There are many differences between the AIDS epidemic and COVID-19. It took about five years from the first cases of HIV appearing, until we had isolated the etiologic agent, and developed a blood test that could actually be used. It took about five weeks for the same thing to happen with COVID. It’s really extraordinary what science has accomplished. But so much of what scientists were able to do was based on things that had been done related to HIV. So I think there are also a lot of parallels: COVID has an immunosuppressive aspect to it that causes destruction of lymph nodes, in a way that makes it harder to mount immune responses. There are also disparities in terms of the people that are most affected by COVID; this parallels HIV, which disproportionately affects more marginalized people with poor access to health care and medications. So this is true for both viral outbreaks.
6. What do you think the next pandemic response will look like? Perhaps 15 or 20 years from now?
I think the next pandemic is going to come sooner than 15 or 20 years from now. But this question brings up some interesting philosophical questions. If you draw a straight line in terms of knowledge and the advances that are being made, you have to wonder at some point, are we going to figure it all out? I mean, are we going to understand what causes aging and have an antidote for ageing? This gets into interesting territory. In terms of pandemics, you know, we know that coronaviruses can be a lot more lethal than SARS-CoV-2. To have something as transmissible as COVID, but with the case fatality rates of MERS, which was like 34% would really be a threat to human existence.
We need to put a lot of effort into rapidly making drugs for new viral threats. I don't think we did all that well with COVID. We ultimately got drugs, but Paxlovid is not what we're looking for—you see these rebound cases, etc, and molnupiravir was also kind of a bust. So there's a lot of room there for science to make contributions that are really going to be critical.
7. Which areas of science are you most excited about seeing develop in the next 5-10 years?
I think the next 20 years are going to be the age of immunotherapy. Immunology is really at the center of human disease in one way or another—either through function [protection], dysfunction or aberrant function. Areas that I think are ripe for clinically relevant advances are places like neuroimmunology, where it's very clear that there's an inflammatory component [in disease]. I think inflammation in a broad context is critical for us to understand better because I think it drives so much disease.
8. Who are a couple up-and-coming scientists (lab < 5 yr old), whom you think we should watch? Why is their work so exciting to you?
Jake Lemieux at MGH is one person that deserves to be highlighted. I think he's done amazing work trying to understand the evolution and proliferation of variants in the COVID space. He’s a really brilliant guy who I think it's going to have a major impact over the course of his career. There are advantages to joining a lab of somebody who's more junior, particularly in the Harvard ecosystem. If you are a hired as a professor at Harvard or MIT, chances are you're well qualified and that you've done well. These new hires are looking for PhD students and will be totally invested in the success of their grad students. The younger faculty are also going to be there in the lab a lot, which can be a really good thing. I think people shouldn't shy away from more junior mentors, I think that there's an incredible amount of creativity there that that can really benefit their careers.
9. What is one piece of advice for a young scientist aspiring to have a career in academia, and make some important discoveries? Any advice specific to physician-scientists?
If you are a physician-scientist, you can do something where your clinical and research synergize. I always wanted to work on something that really used my position as a clinician to actually advance what I was doing—it worked out really well in the HIV arena, because I would see outlier patients. The best ideas—in terms of what we ended up doing in the lab—I got were actually from seeing patients. I think it's really important that you surround yourself in life with people who are supportive, in terms of your relationships outside the lab. I think my wife believed in me more than I believed in myself, and that was really important to me both when I was wavering in thinking about if I could actually make it in research, but also throughout the ups and downs of my career. Perhaps it also goes without saying that it's important to have outside distractions that take you away from the vortex of research. I think it's also really important to be a voracious reader of the literature, which I'm not. But I think I think that's really a critical aspect of science.
[What specific hobbies do you have?]
I make ice cream, which I find very fun. I love ice cream. I do a lot of mountain biking and more recently, road biking as well. But mountain biking is something that you really have to pay attention to while you're doing it, and also is a great workout. Mountain biking also kind of cleanses your mind, because it's hard to be ruminating about an experiment while you're going down something that's tough. I'm also a bird watcher, and I find that really engaging.
10. What are you reading in your free time?
I just read In Sickness by Barret Rollins, who was the chief scientific officer at the Farber. He's, also the person that introduced my wife and me to each other. It’s a book about his wife, who was an oncologist, and her breast cancer diagnosis. It is a fascinating book. I'm just starting a book called This Is Happiness by Niall Williams.