Lab Meeting: Vishva Dixit
“Today there are tools that you can use to attack and study problems, which were never before thought to be solvable.”
Professor Vishva Dixit is a master storyteller.
I recently witnessed Dr. Dixit deliver the keynote lecture at a Gordon Research Conference. Like any great storyteller, he provides only essential information—conveying complex cell death signaling mechanisms with beautiful clarity. His work is rigorous, mapping the precise molecular events that lead to necrotic death in painstaking detail. Yet his goal is not simply to illustrate his findings—throughout his talk he emphasizes the opportunities to explore the “uncharted waters”—the larger questions about the evolutionary principles that govern cell fate. He is also really fun to have a beer with, as I discovered at the reception following his lecture.
By his own admission, Vishva was not always a “thinker” when it came to science and medicine: “I was more of a rote learner.” As a medical student in Nairobi, he first learned to appreciate physiology from a cherished professor: “he illuminated this deep underlying logic to biological systems. That you could view complex problems through this lens [of evolution], and they would suddenly make sense.” Armed with a first principles approach to studying medicine, Vishva secured a pathology residency at Wash U St. Louis. Working in the biochemistry department there, he fell in love with the “pugilistic character” of science, and the exhilarating process of exploration: “one could make discoveries that may be important enough to end up in textbooks and could achieve immortality that way.”
The rest is history. After publishing early work on thrombospondin at WUSTL, he moved to The University of Michigan. In short order, he rose through the ranks to become a full professor, before moving to Genentech in 1997. Starting in the early nineties Vishva initiated a series of studies on cell death that uncovered the mechanisms of TNF-driven inflammation and death receptor signaling, the MyD88-NF-kB axis, necroptosis and pyroptosis. Now, Vice President of Discovery Research at Genentech, he is one of the most highly cited researchers in the world (> 160,000 citations). He is an elected member of the National Academy of Sciences, the National Academy of Medicine, American Academy of Arts and Sciences as well as a Foreign Member of the Royal Society (ForMerRS). Along with Katalin Karikó, he was a 2022 recipient of the Vilcek Prize in Biomedical Science, which honors outstanding immigrant scientists for their work in the US. In 2022, he also received the Dr. A.H. Heineken Prize for Medicine – the Netherlands most prestigious international science prize – for his foundational contributions to the fields of cell death and inflammation.
His work on innate immune signaling and apoptosis are now part of the canon, immortalized in biology and medical textbooks—a fitting plot point in the story of the young student from Nairobi, who dreamed of becoming a great scientist.
Below is an interview with Dr. Vishva Dixit from July 2022:
1. Name an overlooked scientist, whom you feel strongly that every grad student (or med student) should know and be able to describe their major findings. What were the killer experiments?
There are a few people that come to mind—the first are James Till and Ernest McCulloch. They showed for the first time that mammals had stem cells. They performed a series of really classic experiments in the early 1960s. They heavily irradiated mice and injected bone marrow cells into them; they essentially used the recipient spleen as a petri dish, because they noticed small nodules grew on the spleen surface. Within these nodules they could detect the three primary blood lineages—red cells, white cells, platelets. So, they hypothesized that there was a “stem cell” and that these colonies on the spleen arose from a single progenitor. So that was really the first experimental verification of stem cells in mammals, and then the field grew exponentially. They got a lot of awards, but never the Nobel prize. [For the Nobel] they were overlooked for reasons not clear to me, but their work stands out as a testament to original thinking.
Another person who really stands out is the late Al Knudsen, who came up with the ‘two hit hypothesis.’ It was a mathematical framework, and he [Knudsen] was a pediatric geneticist. He hypothesized the existence of tumor suppressor genes, and very clearly stated that both the alleles of these genes had to be inactivated. This was the foundation on which the discovery of tumor suppressor genes occurred. I think he too made transformational contributions, Nobel prize winning stuff, but was not recognized.
There are many such instances that you can find, but the appreciation of the stem cell and tumor suppressor genes—well those are massive contributions to biology and the Nobel prize has been given for less. It is a commentary on recognition and the human condition that a lot of great work gets overlooked.
2. What are you reading in your free time?
I tend to gravitate towards reading journals and science, but the book I am finishing up now is Countdown to 1945 [by Chris Wallace and Mitch Weiss]. It is the story of the atomic bomb. The real decision making that went behind Hiroshima and Nagasaki—the scientists who were involved, the politicians, the generals. It’s a great book because it discusses the tension between the various parties, and why ultimately the decision was made. Of course, the US is the only country that has used a nuclear weapon on a civilian population—so it was intriguing to see: ‘how was this decision made?’ Who were the actors who decided this was the right thing to do? Whether it is right or wrong is hugely debatable, but the book immerses you in that time period. I just bought another book and am beginning to look at it—the name is Elusive [by Frank Close], and it is about Peter Higgs and the search for the Higg’s boson.
I tend to read more about science, even when I do read books.
3. What was your first taste of science? Briefly, what about this initial experience drew you in? Who was your first great scientific mentor?
I loved medicine. I found it very satisfying, but I realized that it was algorithmic and a lot of people could do it. When I was a resident at Wash U in St. Louis, I had the opportunity to work in the biochemistry department. That was a really liberating experience for me. I loved the atmosphere of discussion, argumentation, not taking the written word for granted. The journal club was called the ‘shark tank’ because they really ripped into papers. I thought ‘wow this is amazing you get paid to read and think and criticize and argue.’ It [research] had a certain pugilistic character to it and seemed like an intellectual boxing match. I really enjoyed that atmosphere and thought it [science] was something I would like to do.
I was also amazed at the power of biochemistry—this was the early days of cloning and the magic of genetic engineering. Cutting plasmids with restriction enzymes, engineering them made me think: ‘wow, this is a brave new world.’
So, there were two factors that drew me to science. One was the excitement of participating in an activity where you really engaged your fellow colleagues in intellectual discussion. Another, the fact that the tools of genetic engineering in the early 80s were being made widely available. What one thought was impossible was suddenly possible. In the last year of my post-doc work I spent 9 months sequencing a piece of DNA, maybe it was 1200 base pairs. Now with nanopore sequencing that can be accomplished in much less than a second. If you had a background in medicine, it [research] seemed like so much was possible in terms of generating new knowledge. One could make discoveries that may be important enough to end up in textbooks and could achieve immortality that way. I was just attracted to the work and the power of being so impactful. I always gravitated to explorers even as a child, and loved reading about Howard Carter and Tutankhamen’s tomb. I thought to myself that I could be an explorer here, go into uncharted waters and be the first one to see something.
Today, the tools are even better. The questions are large and remain unanswered. There is huge opportunity. If I was in your shoes, training as a physician scientist, I would be excited to be living in this present time. It is a magical time, sort of like the emergence of quantum mechanics at the turn of the last century. Today there are tools available that you can use to attack and study problems, which were never before thought to be solvable.
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 were two stories that were for me, exhilarating. The first is when we were studying the death receptors, such as Fas and TNF receptor. The question was: how do these receptors signal? At that time, receptors were thought to signal either by functioning as ion channels or by altering phosphorylation and dephosphorylation events. We discovered in the mid-90s that the death receptors were neither ion channels nor altered phosphorylation but signaled by an entirely different mechanism. This was the activation of a death protease—in a sense, the death protease was a second messenger. This is the story of the discovery of FADD and caspase-8, which was very exciting personally. There was a lot of apprehension in putting forward an entirely new signaling modality, and so that was certainly a high point.
The other one was the discovery of the non-canonical inflammasome pathway in a series of papers in 2011, 2013 and 2015. The 2015 paper culminates in the discovery of GSDMD, but the earlier papers set the stage for the existence of a dedicated intracellular pathway for the recognition of LPS. This was very surprising because the Nobel prize had been given in 2011 for TLR4 as the receptor for LPS—here we were coming in and saying ‘hold on’ there is another signaling system for LPS that has nothing to do with TLR4. This story continues, and the later discovery of GSDMD, which was also made by Feng Shao at the same time, has set up a cottage industry in the study of these pore forming proteins.
These two discoveries really were high points.
5. What set of research questions or projects has you most excited about coming into lab today?
It is a bit like choosing amongst children. But currently I am really excited about our discovery of Ninj1, which we published last year. There is so much to discover there. Essentially it [Ninj1] violates a tenet of biology that we were taught in junior high: ‘if you lethally perforate a cell membrane then subsequent rapid lysis is driven by mechanical osmotic forces.’ You can imagine our surprise when we found that this is not the case—this lysis is enormously accelerated by a membrane protein, Ninj1. This is a really perplexing question: why would such a mechanism be evolutionarily conserved? Ninj1 is found all the way down to the fly, and structurally similar molecules are found in archaebacteria and prokaryotes. One model [to explain this] is that very rapid lysis is important for innate immunity, which deprives intracellular pathogens of a replicative niche. This is one hypothesis with some experimental support, but really it is an open question. It may be the tip of an iceberg as to why and how this whole family of molecules rapidly mediate cell lysis.
6. Who are a couple up-and-coming scientists (lab < 10yr old) in your area, or more broadly, whom you think we should watch? Why is their work so exciting to you?
For me, the scientist that comes to mind is Andrea Ablasser who is in Lausanne [EPFL] and works on the cGAS-STING pathway. I think she effectively uses technology to address really important questions. She has done everything from structural biology to screening of small molecules to animal models, and really provides an understanding of this very important pathway. She is very impressive.
7. What is one piece of advice for a young scientist aspiring to have a career in academia, and make some important discoveries?
It’s a great question. It is easier said than done, but it is really key to choose an important problem to work on. And that can be very difficult to define because the problem if solved should garner attention, and people should care that you have solved it. But it also has to be solvable with today’s technology. However, it also should be difficult enough that not everyone can do it. You need to find this “goldilocks” zone, and it is worth debating what these [projects] are. This is where argumentation and discussion are really important in science, rather than just going into the lab and doing experiments. What you work on is the most important decision in your research career.
In terms of working on a project, you also need to do experiments that try to disprove your model and not just support it. The papers I am most proud of, are ones where we did lots of experiments aimed at disproving our model; in the end, the results only made our conclusions stronger. Having the benefit of hindsight, I would now say that it is crucial to do experiments that challenge your favorite model.
8. Who was your biggest mentor, and what made them so great?
It was really Professor Hettiarachi, who taught me physiology in medical school. He really emphasized that there was a logic in biology that could be viewed through two basic foundational concepts: one is the importance of feedback and that biological systems are geared towards maintaining homeostasis. He emphasized that this simple logic could be applied to complex clinical problems. He also emphasized the ‘Darwinian’ way to look at things, and the importance of studying problems through the lens of natural selection and evolutionary biology.
Before his influence on me, I was not a thinker. I was more of a rote learner. But he illuminated this deep underlying logic to biological systems, and that you could view complex biological problems through this lens, and they would suddenly make sense. I owe him an enormous debt because he got me thinking about ways to simplify problems, and this was a turning point for me. Now, whenever I come across a problem, I try to simplify it in my mind and break it down.
[Vishva Dixit went to medical school in Nairobi, where he had a Sri Lankan physiology professor, Dr. Hettiarachi. More on Dr. Dixit’s upbringing and early training can be found in this excellent article, published by Cell Death and Differentiation]