Kristian Helin is Chair of the Cell Biology Program at the Sloan Kettering Institute and Director of the Center for Epigenetics Research at Memorial Sloan Kettering. He came to MSK in 2018 from Copenhagen, where he was Director of the Biotech Research and Innovation Centre at the University of Copenhagen and Director of the Danish National Research Foundation’s Centre for Epigenetics. We spoke to him in October 2018 about his scientific interests and what attracted him to MSK.
It was a very natural progression for me to come to Memorial Sloan Kettering. I’ve been a basic scientist my whole career, since I was a graduate student. As a cell biologist, I’m always trying to understand: What’s the mechanism? Why would it work like that? But at times I’ve also wondered about how my research might be therapeutically useful. Over the years, I’ve gotten more and more interested in that question.
You might think that translating basic science into therapies would be straightforward. It’s not. There is a huge gap between basic scientists and doctors. Quite often, they’re working in different institutions.
MSK is one of the few institutions in the world where you have top-level basic science and top-level clinical science at the same place. That’s the main reason I came here.
There’s a very strong understanding at MSK that it is important to support basic science. Big new things in treatment can emerge from basic science discoveries. And of course, cell biology is especially relevant in this regard. If you don’t understand normal cells, you can’t understand cancer.
On the Term “Epigenetic”
I remember being at one meeting at Cold Spring Harbor Laboratory in 2008. There were some heated discussions about how epigenetics should be defined. In strict terms, “epigenetic” refers to something that is inherited across cell divisions, and perhaps even from one generation to another, but not encoded by DNA. That’s the original definition.
But I would say most people working on epigenetics today are not concerned with that strict definition. In fact, many of the things we’re working on — post-translational modifications of histones, for example — are not inherited from one cell cycle to another, let alone from one generation to another. At least as far as we know. These days, the term refers more generally to things that are related to transcription but are not transcription factors themselves.
And it’s convenient shorthand. You can’t call it the Center for Chromatin-Associated Proteins — you’re not going to sell a lot of tickets that way.Back to top
From Politics to Science
I never thought I was going to be a scientist. I grew up in a small town in the countryside of Denmark, the youngest of four children. My father was a veterinarian. My mother was a pharmacist.
Discussions were always very important in our house. My father liked to discuss politics in particular. I actually thought that I would study political science until the day I sent my application to university.
I ended up studying chemical engineering. During my time in university, however, I figured out that the technical part of chemical engineering was somewhat boring to me. It was formulaic: Multiply this number by this number. I did really like organic chemistry and biochemistry. And then I got hooked on molecular biology. This was back when people were just figuring out how to splice genes and do recombinant DNA technology. That area was fascinating to me and, ultimately, the direction I took in graduate school.Back to top
For my PhD, I was studying EGF receptors, which play an important role in cell signaling and growth. When I finished my degree in 1991, I moved to Ed Harlow’s lab at Harvard for my postdoc. The reason I joined Ed’s lab was that he had published a wonderful paper in Nature in 1988 looking at how the adenovirus transforms cells to make them cancerous. Ed worked on understanding how two adenovirus proteins, E1A and E1B, transformed cells. One of the proteins to which E1A binds is the retinoblastoma protein (Rb). At that time, Rb was the first known mammalian tumor suppressor protein. But no one knew how it worked.
When I went to Ed’s lab, I wanted to work on tumor suppressors, to understand them better. I began trying to identify other proteins that bind to Rb, and in this way, I identified and cloned the transcription factor called E2F1. This work was published in Cell in 1992.
I continued working on the E2F family of transcription factors when I started my own lab. We developed some cell lines in which we could activate the E2Fs and look for changes in gene expression. When we did that, we found gene expression changes in 1,200 genes. That was a big surprise. We never expected so many genes to be regulated by this family.
Among those genes were several encoding polycomb group proteins. We knew at the time that polycomb proteins were mainly studied in Drosophila [fruit flies], where they are important for normal development. They are essential for specifying the anterior-posterior axis of the fly body, for example. Polycomb proteins do this by maintaining transcriptional patterns through a mechanism that involves modifications of chromatin. That was very interesting to us.Back to top
Cancer as a Problem of Development
We decided to shift the focus of our research away from cell cycle control and toward development and differentiation. We were coming to see that cancer is not only about the cell cycle and proliferation but also very much about development and differentiation.
We’ve been trying to understand how these chromatin-associated proteins regulate transcription. Our model is that these proteins maintain a stable gene expression program and, in this way, help preserve cell identity. That’s very relevant to cancer, since cancer cells can be thought of as being in the midst of a kind of identity crisis.
Research by many laboratories has found that the genes encoding chromatin-associated proteins are frequently mutated in cancer. This finding has led to efforts to develop epigenetic therapies that will steer cancer cells back on track by normalizing their gene expression patterns. This is one of the main goals of the Center for Epigenetics Research at MSK.Back to top