By Sydney Stanley, published in our 2016-17 issue
Dr. Garnett Kelsoe is a James B. Duke professor of immunology. His major contributions to the field include his groundbreaking work on T-follicular helper cells and germinal centers. Dr. Kelsoe shares his experiences and insights (along with his humor and personality) in the following interview.
What sparked your interest in research and/or science?
[Laughing] I’m so old it’s so hard for me to remember that but as a kid I really wanted to be a scientist. And I don’t know why, scientist were famous back then and I grew up on a farm and it just seemed to me to be very exotic and cool. I didn’t quite know what a scientist was, but when I was 11 or 12 this cinematographer named Jacques Cousteau had a big motion picture about water stuff and fish and I decided I wanted to become a marine biologist. And I actually got a job one summer working to count phytoplankton in a lake. And for 8 hours a day I categorized phytoplankton samples into 4 or 5 different types. And this sort of broke me of wanting to be a marine biologist [laughs]. By the time I was older, I was very interested in trying to be useful. I was interested in parasitic diseases and it seemed to me to be absolutely amazing that you could have people with huge burdens of big parasites and the parasites were stably living in their hosts for long periods of time. And that seemed to me to be an immunological question. So that's why I became an immunologist.
Who did you admire most as an undergraduate, or who had the most influence in shaping you as a researcher?
Do you mean besides Jacques Cousteau? [laughs]. Jacques doesn't count, he was not a scientist. But although, when I got my doctoral degree finally, Cousteau received an honorary doctor of science at the same graduation. I thought it was fun, my mother thought it was fantastic that my boyhood hero and I both got a degree at the same time. Which must mean I was a quicker learner than he was, right? It took him a lot longer [laughs].
So when I was an undergraduate, I was still very naive. But I did have two or three heroes. Because I was a chemistry minor, Linus Pauling was a great hero because at the time organic chemistry was simply a mass of rote memorization. And it was Pauling who first began to come up with molecular rules that could sort of order the reactions we memorized, that could sort of make sense out of them. And although I can't say I ever would have been a great chemist, he was a great guy. The two guys I admire the most of course were James Watson and Francis Crick, and that's because all of us read the The Double Helix, the little autobiography by Watson. It never occurred to us that you could be so chatty and fun and clever and meet so many interesting people and spend so much time in the club and still win a Nobel Prize. And I said “gosh, maybe this is a job I could certainly bear” [laughs].
When did you know you wanted to pursue a PhD in biomedical science, and what advice do you have for undergraduates who are considering this as an option?
When I was an undergrad, I knew. I can't tell you why, but I knew with absolutely certainty that I wanted to be a scientist and a scholar when I was an undergraduate. I suspect many of my professors thought that was not a very rational wish given my skills but I had made up my mind absolutely.
Getting a PhD and actually earning a living with a PhD is hard. The vast majority of us don't make a lot of money. It can be boring, it can be a grueling job. So if you don't think you absolutely love doing science and thinking about science, then there are millions of jobs that are equally fulfilling, perhaps more fulfilling [laughing] and pay more and people should chose those instead. Don't enter a PhD program because you don't know what you want to do. That is actually a recipe for disaster. The hard part of doing a PhD is not learning methods. Good plant biologists, good evolutionary biologists, good molecular biologists, we all basically think the same way. We just have a mental construct we use to identify important parts of nature. We use the same tools, we just use them on different products if you will. And that is really what you should learn during your PhD project, more than anything else.
What is the most fascinating aspect of your current research?
We have three things going on, and it's like choosing among your children, so I can't really pick. I like all three of my scientific kids equally. The first is in the issue of immunological tolerance. And my colleague who has been with me for some time discovered that this same pathway has been recognized independently by a guy at Yale. It is that innate immune signaling pathways, in our case toll-like receptor pathways, are absolutely crucial in establishing the so-called first checkpoint of B-cell tolerance. So I find it fascinating that the innate and adaptive immune systems are so closely woven together that actually the innate system controls the first tolerance checkpoint of the adaptive system. And we have been working on how that works, and genetically we know it’s required but I find that really really fascinating.
The second is the work we are doing on HIV and influenza. One of the questions that people used to ask when I was a graduate student is: “if tolerance removes the ability of the immune system to recognize all self-epitopes, how is it that there is anything left to react with foreign antigens?” And basically that question was never answered, people just said “well it does and that it is kind of a philosophical question so let's get on with life”. With our work with the Duke Human Vaccine Institute and Bart Haynes what we are finding is that HIV and an increasing number of human pathogens mimic host antigens or are selected to mimic host antigens. By doing so, they get to hide behind tolerance, at least for a while, to increase their transmissibility. So in other words, they are evolving to enhance their transmissibility as we have evolved to minimize their transmissibility. It is a great evolutionary game. This thing that everyone sort of ignored, we think at the moment there is a great number of pathogens that have used this pathway to escape host control.
And finally, there are these special cells, and actually our laboratory is the first to point them out. They are called T follicular helper calls. They leave the T-cell zone and go around and go to germinal centers. Like the B-cells, they are antigen specific and they collaborate with B-cells. We showed a long time ago that if you stop that collaboration, the whole germinal center falls apart. So you get directed evolution in germinal centers. So B-cells get better and better at binding antigen. And there are several models for how that works. One model is that the antigen receptor signaling strength tells the B-cell whether it is a good B-cell or a bad B-cell. And that is almost certainly not the case. A lot of people, including us, has shown that is not true. But there is another hypothesis, which is a good one from a guy at Rockefeller. He says it is really competition for T follicular helper cells. So the better the antibody is at virtually removing antigen, taking it and processing it and presenting it, the higher the density of MHC peptide is on the surface, and the better the interaction with the T follicular helper cells. So we have actually done an experiment to test that within certain limits. And when we do it, we don't see any evidence for this hypothesis at all. And it could be that the effects are outside the limits of our experiments. But it reminds me of the famous quote that every beautiful theory can be destroyed by one ugly fact. I am fascinated by this because it brings up a lot of contradictions. There is this wonderful wave of evolution yet we don't know how it works. Gosh, I hope I can stay around long enough to find out.
What is the most rewarding part of being a professor/principal investigator?
Truthfully, for being a professor as opposed to being a scientist, is my students and post docs. And you know, this is a great job. I met so many people that I admire. To get into a graduate program, you clearly are at one extreme of a certain set of abilities. Even within that sample, there is a distribution of ability. But for the vast majority of my trainees I have had, (I had a few bad apples but not many) I truly admire these people for their innate interest in things. I had a woman whose husband had a chronic illness and she would commute between here and Washington D.C. Sometimes she would break down crying...she was the strongest person I have ever met in my life. I learn more from my students than they do from me.
Anything you would like to add?
I think kids at Duke have remarkable opportunities. I told this to my kids, I graduated high school in 1968 (some time before you were born) and then 1972 from college. I didn't really notice it at the time but clearly opportunities for women and minorities were much much much reduced. And at my university peer group, for the girl I was dating and her friends, the major job for all of these bright college graduates was to become a flight attendant for the airlines…but my younger daughter is an archaeology student and spends time in middle China and Mongolia and my younger daughter is studying history at Cambridge University. I have all these kids and students that are everywhere and have done all of these things... the future is in your hands and you just have to grab it.