> How has your Dartmouth experience helped shape your career?
After a great intro bio class in my first-year fall, I asked Lee Witters if I could work in his lab. He was studying a particular protein that regulates metabolism and responds to energetic stress. I was nerdy enough to actually enjoy learning metabolic pathways like glycolysis and the Krebs cycle. And I knew all about energetic stress from my experiences as a distance runner. So working with Lee was a great match in many ways! Perhaps more importantly, though, Lee was a fantastic mentor and model for a student considering a career as a physician-scientist. I’m not so sure I would have wound up applying to MD-PhD programs or going to medical school at all if it wasn’t for Lee’s example and guidance. While in Lee’s lab, I spent most of my time on a collaborative project with Eric Lambie, a C. elegans geneticist. Eric provided another important source of mentorship and a great taste of how exciting it can be to do research that crosses multiple fields.
My Dartmouth experience was also notable for the many hours I spent with the cross country and track teams. Coach Barry Harwick and my teammates instilled in me a keen appreciation for endurance. As I approach the 7th year of an 8-year MD-PhD program, this appreciation for the long view has certainly come in handy!
> What was your path to becoming a graduate student in Craig Thompson’s lab?
After graduating from Dartmouth I spent a year in Cambridge, England on a Churchill Scholarship. I worked with Fiona Gribble, a young scientist studying an intestinal hormone that aids the effects of insulin and is secreted following a meal. The experience was amazing scientifically as well as culturally.
I then started the MD/PhD program at the University of Pennsylvania. A big reason I chose Penn was its strength in metabolism research, and I had a great rotation after my first year of med school with a scientist who focused on metabolism from a diabetes/endocrinology perspective. However, I was becoming more interested in the biology of cancer. I ultimately decided to do my thesis with Craig Thompson, who was approaching the cancer problem as a disease of altered cellular metabolism.
> What has been the focus of your latest research? > How did you decide to focus in on this subject?
My thesis research grew out of my rotation project in Craig’s lab that was supposed to be a longshot. I was studying a branch of metabolism that takes the Krebs cycle on a detour through the cytoplasm. There was essentially no work being done on this pathway in cancer at the time, but Craig and I thought that this pathway might be important for cell growth. We had some promising preliminary data, but then lightning struck: 2 months into my rotation, a paper came out that described a new class of genetic mutations in brain tumors. This new class of mutations was specific to one enzyme in the very pathway I was studying: isocitrate dehydrogenase 1 (IDH1).
I was fascinated by what these mutations could be doing, as there was very little precedent for mutations in metabolic enzymes driving tumor formation. Of the few examples that were previously known, they were understood to promote cancer by the mutations inactivating the enzymes’ normal metabolic activities. Initially, this was the explanation that was proposed for IDH1 mutations as well, and it was published in Science. However, a week before this publication appeared, I had obtained data which directly contradicted it. Moreover, my data suggested that mutant IDH1 was not simply a dead enzyme. We subsequently learned that Agios Pharmaceuticals had also been studying mutant IDH1 and found that it can acquire a new enzymatic activity to produce a metabolite that does not normally accumulate in human cells, 2-hydroxyglutarate (2HG). 2HG was 10-100 fold elevated in human brain tumors with IDH1 mutations. We combined our data with the company’s data and published jointly on this discovery in late 2009.
Since then, my thesis has been one incredible ride. Shortly after the initial work on IDH1 in brain tumors, we decided to test human leukemia samples for elevations in the 2HG metabolite. Based on the published frequency of IDH1 mutations in leukemia, we were expecting 10% of samples to be positive for 2HG elevation. However, I surprisingly found 25% of samples to have elevated levels of the 2HG metabolite. When we performed more thorough genetic sequencing of these samples, we found that 2HG elevation could also be accounted for by mutations in the enzyme IDH2, the mitochondrial homolog to IDH1. This finding provided additional evidence that 2HG production was not just an unimportant side effect of IDH1 mutations, but might actually be an “oncometabolite” selected for in tumors through a variety of distinct IDH1 or IDH2 mutations. Most recently, we have been pushing hard to identify how 2HG may promote tumorigenesis as such an oncometabolite. We are now fairly confident that 2HG’s major effect is to inhibit the activity of multiple enzymes that regulate epigenetics, thereby altering how genes are expressed. The 2HG target enzymes include histone modifying enzymes and enzymes that alter DNA methylation. Ultimately we think that this epigenetic dysregulation mediated by 2HG can impair the ability of cells to differentiate.
In my spare time, I’ve also been continuing to explore my original interest in whether the non-mutated IDH1/2 pathways can be important for cell growth and cancer. We and others have found that cells deprived of oxygen actually use these enzymes to run part of the Krebs cycle in reverse!
> What is the most rewarding part of research?
It is fun to read about science, and it is fun to talk about science. But, I think the most rewarding part has to be the moment in an experiment when one realizes that he/she has found something new and unexpected that no one else has observed before.
Going forward in my career, I hope another “most rewarding part” may be seeing a scientific discovery that I somehow contributed to be translated into a treatment makes it through clinical trials and actually benefits patients. I haven’t gotten there yet, though I’m keeping my fingers crossed that the IDH and 2HG story may turn out to be one of those examples.
> What would be your advice to someone interested in scientific research?
I would suggest finding a mentor whose personality and work excite you, and then find a way to get in his/her lab as soon as possible. Long-term career goals do not need to be decided at this point, and one can even try a few different labs during one’s undergraduate career. The most important thing is to get some exposure to a lab that is doing good science, and a mentor who can help one to start thinking like a scientist. Research is not for everyone, but it is hard to know if it is for you unless you get in there and get your hands dirty.
> What advice do you have for someone interested in graduate school for the sciences?
Ditto the above on getting into a lab while an undergraduate. I would also suggest considering taking a year or two after college to get more exposure or experience before diving right into a long graduate/professional program. It is by no means necessary, but this time can broaden your perspective (on both science and life!) and make you a more attractive applicant for many top programs and labs. For those few thinking of MD/PhD programs, make sure you fully understand what you’re getting into. If I had to do it over again I’d make exactly the same decision, but ideally you should be interested in both medicine and science and the intersection between these two largely disparate modes of thinking. Embarking on a combined MD/PhD just because it seems like “the hardest thing,” because it is a way to get med school paid for, or because it is a way to please your parents when you really just want to be a scientist are all terrible reasons to do it. Both medicine and science can be infinitely challenging on their own and provide plenty of competition and fulfillment for a lifetime. Be brutally honest with yourself.
> Where do you see yourself in ten years?
In ten years I’ll hopefully have finished my PhD, finished medical school, completed some additional clinical and research training, and be a few years into running my own lab. I ultimately want to focus primarily on research, and I see myself continuing to apply what we have not yet learned (or learned but subsequently forgotten) about metabolic pathways to new biological problems. I also hope to develop a clinical perspective that will allow me to recognize the moments when scientific advances are ripe for application to the treatment of human disease.