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2019 Nobel Laureate in Physiology or Medicine,
Sidney Farber Professor of Medicine at
Dana-Farber Cancer Institute and Bringham & Women's Hospital,
Howard Hughes Medical Institute Investigator
In the first of a series of interviews covering the most significant scientific discoveries, Param and Dr. Kaelin's conversation discusses remarkable new discoveries in cancer metabolism, the current landscape of oncology research, and advances that are shaping the field.
Param: In 2019, you received the incredible Nobel Prize in Physiology or Medicine for your research on how cells sense, adapt, and respond to varying oxygen levels and its implications in tumor suppression. This oxygen-sensing mechanism involves tumor-suppressing proteins that are often mutated in kidney cancer. You and your team discovered that very sensing mechanism. Would you mind going into a little more depth into what your research entails and how you were able to make this discovery?
Dr. Kaelin: So I was trained as a clinical doctor when I was younger, specializing in medical oncology, and I knew about Hippel-Lindau Disease (VHL), a hereditary cancer syndrome where patients generation after generation are at a high risk of developing certain cancers, in this case kidney cancer. I knew from my clinical training that these tumors were notorious for tricking the body and providing themselves with robust blood supply, through inducing the growth of new blood vessels (angiogenesis) and the production of more blood cells (hematopoiesis).
One thing that [angiogenesis] and [hematopoiesis] have in common is that both are often a response to low oxygen levels, and are processes designed to deliver oxygen through blood more effectively. This was a clue that whatever gene was responsible for Hippel-Laundel Disease must be involved in oxygen sensing. Now, the gene was isolated by another group in 1933, but you could see each child generation of an infected family had a 50-50 chance of inheriting a defective version of this VHL gene, and such people would develop cancer.
Once the gene was isolated, we decided to research the functions of the protein that this gene would normally encode. If we could understand this then we could also learn something about both kidney cancer and oxygen sensing. We carried out many experiments that later confirmed our suspicions that the VHL protein was an integral part of the mechanism that you and I use to respond to oxygen at a cellular level. In the course of our research we learned that one of the most important functions of VHL protein is to suppress another protein, HIF (Hypoxia Inducible Factor. HIF protein regulates certain genes important for new blood vessel formation and is a protein that generally acts when there is less oxygen.
My fellow laureates and I figured out the actual biochemical mechanism that allows cells to know whether or not they are receiving enough oxygen, and hence whether the VHL protein should interact with the HIF protein. What normally occurs is that if you have enough oxygen available, VHL would actually target HIF for destruction. On the other hand, if oxygen levels were lower, VHL would leave HIF alone, and HIF would turn off the genes I just alluded to. Of course in cancers such as kidney cancer where the VHL protein is defective, you have too much HIF, which gets hijacked by the cancer cells so the tumor can get more blood supply. Once we understood this molecular circuit in great detail, we could intervene with drugs to either make HIF more active or less active. So in cancers that have hijacked HIF, we wanted to make HIF less active. On the flip side, in a condition like anemia where you need to produce more blood cells, there’s a new class of drugs that can make HIF more active.
Param: That’s fascinating. Do you think your research is complete or is there still a long way to go? And what are some of the implications of this research?
Dr. Kaelin: I would say research is never finished because there are always new questions to be asked. We don’t yet know everything there is to know, so that’s largely why we’re doing new experiments everyday and trying new things to gain new knowledge. We now know that a critical step to prevent kidney cancer is to inactivate the VHL protein, a consequence of that is that you deregulate HIF, and then HIF gets corrupted or hijacked by cancer cells, but that’s not the whole story. There are other genes that play important roles in kidney cancer, so we are trying to understand how these genes work, we’re trying to understand some of the other vulnerabilities in kidney cancer that we would target therapeutically, and we are also trying to target the HIF protein.
Param: In your perspective, how much has been accomplished in cancer research and what areas do we need to focus on in the future? In other words, what questions about cancer are still unanswered, and where in this field do you recommend researchers focus their attention?
Dr. Kaelin: I think there’s almost an infinite amount of questions you can ask in biology in general, especially in cancer biology, so part of the trick in science is to find a question you find interesting and where pursuing the answer is like a fun, detective story. But again, different people find different questions interesting. Part of the magic is finding the right lab and the right question that interests you. I also say one of the fun things about science is that it's often difficult to predict what the next big discovery will be or what it would teach us, so oftentimes when I make presumptions in my research I hope I would be wrong. I think in general, if someone is interested in working in cancer science, I’m a firm believer in genetics, in the sense that we have learned a lot about what genes are mutated and affected in certain cancers, and these are really good clues as to the different biological pathways that cancers utilize, and we want to understand how that mechanism works, why a specific mutation results in a certain type of cancer, and we want to understand what role specific proteins play in cancer. We want to essentially reset our knowledge to think of smarter ways to approach cancer research.
Param: As a physician scientist, in your opinion, what are the benefits of treating patients while simultaneously making scientific discoveries? Has treating patients intellectually benefited your research in any way or provided a new perspective?
Dr. Kaelin: I think it was really my clinical training that allowed me to understand what Hippel-Lindau Disease was really telling us, and it was telling us that the responsible gene had to be involved in oxygen sensing somehow. I think my clinical training there was really useful, but that’s not the only time. I think when you're a clinician you sometimes see clinical observations or clinical conundrums that you then want to go back into the laboratory and understand further through research. You’re really motivated because it reminds you that this is why you do what you do. You can see how research is not entirely abstract, and that your patients rely on the work that you’re doing. So it’s not about the prestige, the prizes, the awards, the journals, or the accolades, it's ultimately all about how we can actually start to improve the care of our patients.
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Note: The full interview may be read in the Fall Issue of Academy SciJournal.
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