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Raul Mostoslavsky talks to us about his research into epigenetics, metabolism and genome stability.
Raul Mostoslavsky studied medicine at Universidad Nacional De Tucuman, Argentina, (1988–1993) before completing his PhD studies in molecular biology at the Hebrew University of Jerusalem, Israel (1994–2001). Following this, he joined Professor Frederick Alt at Harvard University to complete his post-doctoral training (2001–2007), first as a Human Frontiers Science Program Fellow and later as a Lymphoma Leukemia Society Special Fellow.
Raul started his own independent laboratory at The Massachusetts General Hospital Cancer Center-Harvard Medical School in 2007, focusing on the precise role of SIRT6 in modulating glucose homeostasis and cancer metabolism. It was here that he produced research that demonstrated the gene functions as a tumor suppressor by inhibiting the Warburg effect and identified specific SIRT6 point mutations in cancer patients.
He has received numerous awards, including the 2001 Science-GE Prize by AAAS and the Massachusetts General Hospital Research Scholar Award in 2012. Raul’s work continues to focus on the precise role of SIRT6 in cancer metabolism and other tumors.
I was in second year of medical school (in Argentina), and we got a lecture from a scientist who just came back from the UK, where he worked with Cesar Milstein, and gave a fantastic talk on molecular immunology. I was immediately hooked.
Hearing this talk about molecular mechanisms, and facts that could explain how our organism works (rather than just collecting symptoms to make a diagnosis) was inspiring. I decided than that I will do a PhD after finishing med school to try a career in research.
That’s an interesting question. I don’t think I intentionally chose that path. I trained as a chromatin biologist. We were studying the functions of the histone deacetylase SIRT6, and when we generated SIRT deficient mice, the main phenotypes these animals developed were a profound metabolic imbalance and genomic instability.
I had no problem in trying to decipher the genomic instability phenotype, but metabolism was something I never trained on. Despite my fears of going into metabolic research, I knew we needed to, in order to understand how lack of this single chromatin factor caused such major metabolic abnormalities. So, we spent the next 5–7 years working hard on these problems. We were lucky to publish nice studies explaining, at the molecular level, the roles for this histone deacetylase in modulating metabolism and genomic instability.
In the middle of these studies, we realized that there was much more cross-talk between epigenetics and metabolism than previously thought (which is surprising given that every single DNA and histone modification requires metabolites that come from major metabolic pathways). It is nice to see that now many chromatin scientists are working on metabolism and vice versa!
As I said before, basically every metabolite used in cells for chromatin modification (methyl groups, acetyl groups, acyl groups, etc) comes from major metabolic pathways, and multiple studies have already demonstrated that changes in availability of these metabolites cause acute changes in histone and DNA modifications. Therefore, understanding such cross-talk will be crucial to better determine how cells adapt (from an epigenetic perspective) to metabolic stress.
I would love to see epigenetic signatures and adaptations incorporated into the major metabolic pathways that we are so used to seeing in graphs and reviews. And two that are close to my heart: first, given the known metabolic adaptations of cancer cells (Warburg effect, glutaminolysis, etc), it will be important to determine how these metabolic changes affect chromatin dynamics in cells.
Second, we are putting a major effort in the lab to determine whether the communication between metabolic pathways and the nucleus is a two-way street, namely whether the nucleus could serve as a reservoir of metabolites for the cells. We hope we can contribute to that angle in the near future.
Do not despair because of the funding crisis. All you need to have a career in science is passion for what you do, a natural curiosity about things, and being an incurable optimist. With those characteristics, you will do great science! The funds will come.
First, the freedom of pursuing questions that have never been answered before. Second, knowing that some of our discoveries, even if they contribute a small grain of sand, could change in the future the health of people for the better.
As Milstein used to say, I can’t tell, this is an experiment that has never been done!
My wife, my daughter and chocolate! (I know, these are three things…)