Basic understanding: Q&A with Yang Shi

Prior to joining Ludwig Cancer Research, what were your most exciting discoveries and research accomplishments?
The one that stands out is the discovery of LSD1—the first histone methyl eraser, which showed that histone methylation is dynamically regulated. This overturned a 40-year dogma that these modifications were static and irreversible. In addition to LSD1, we and others have also identified many other histone demethylases, which have critical roles in development, differentiation and diseases like cancer. We’ve recently become interested in epigenetic regulation in antitumor immunity and tumor responses to immunotherapy. We were excited to find that inhibiting LSD1 may make tumors more susceptible to checkpoint blockade immunotherapy. In addition to scientific discoveries, what makes me very proud is the fact that my lab has contributed to the training of new generations of scientists who have gone on to start their own labs in academia or who have successfully transitioned to the pharmaceutical and biotech industry.

What motivated you to join the Oxford Branch?
Ludwig Oxford is a fantastic place to do science, and Oxford is a lovely town. But to be honest, it wasn’t an easy decision to make because Boston is my home. I was initially attracted to Oxford because of the opportunity to forge close interactions with clinicians. My understanding is that due to the UK National Health Service (NHS), there are unified treatment protocols for all cancer patients across the country. This allows clinical-related studies to be conducted at multiple centers countrywide to speed up patient recruitment and to expand clinical sample collection. I’m a basic scientist, but I have a lot of interest in seeing how some of these basic findings can be translated to the bedside. In practical terms, my decision was also based on the fact that core funding is provided by Ludwig. This will give me more free time to think about problems and how I can move the science forward in an efficient and expeditious way. There are so many questions waiting to be addressed and no time to lose.

Has your vision of what you would like to accomplish in the next 10 years changed now that you have joined a cancer research organization?
Yes and no. No, because I am still fundamentally interested in the basic underpinnings of how things work biologically. And yes, because now I will  be even more focused on cancer.

Could you elaborate on being more focused on cancer?
In my Boston lab, in addition to cancer, we are also working with mouse models and patient cells to understand the epigenetic mechanisms underlying intellectual disability. But after moving to Oxford, we may have to re-prioritize to allow my lab to focus more on cancer.

Will acute myeloid leukemia and glioma still be a priority in Oxford?
Yes. Our lab is studying the role of epigenetic modifiers in Diffuse Intrinsic Pontine Glioma (DIPG) and acute myeloid leukemia (AML). Epigenetics has been shown to play a crucial role in both DIPG and AML. We are interested in identifying epigenetic regulators whose inhibition induces differentiation of cancer cells that can potentially be therapeutically beneficial.

We’re also exploring epigenetic regulators in order to find ways to turn ‘cold’ tumors ‘hot’ and ways to generate sustained responses to immune checkpoint blockade therapy. We are interested in understanding what role epigenetic factors play in the tumors and the host immune system, which both impact patients’ response to checkpoint blockade therapy.

How will your research impact cancer patient care?
We are a basic science lab, and our goal is to understand these pathological processes by addressing the role and mechanisms of action of epigenetic regulators in cancer. In so doing, not only will we learn more about the fundamental mechanisms, but also uncover new targets for cancer therapy. And I firmly believe that forging closer interactions between basic science researchers the clinicians in Oxford will translate to greater impact on patient care.

What breakthroughs are needed in epigenetics in order to advance cancer research and patient care?
We need to have a solid understanding of the basic mechanisms that control the different processes that lead to cancer. But at the same time, we need to enhance the interactions between scientists and clinicians to really understand cancer. We know that cancer is many diseases, so we need to understand them at the level that will allow us to design better treatment strategies.

If you could talk to the 10-year-old version of yourself, what would you tell yourself about your career?
Things happen in life that are often not by design. I did not initially plan to pursue a career in research. But the more I do it, the more I like it. Although I have had my lab for many years, I feel as if I have only started. I would tell my younger self that research is a career that has satisfied my curiosity but it’s also one where I think I’ve been able to make a small difference. I’ve uncovered some basic biological processes that have implications for understanding cancer and other human diseases and hopefully opened some doors for developing specific, targeted therapies against cancers. I hope what I do will ultimately help humankind by contributing to the development of new therapeutic strategies.

Was there something in particular that inspired you to follow this career? How did you end up with a career in research?
Many people who go into research may tell you that they loved science from a very young age or spent their early years doing science experiments in the basement. None of that happened to me. But I’m really very lucky to have landed in research. I wouldn’t trade it for anything else.

What has been the most satisfying part of your research?
First, it has really satisfied my curiosity. Research is a very free career and has allowed me to pursue important questions and find ways to address those questions. You never feel restricted. You can read papers, listen to talks and say, those are really important and interesting questions, and I should go ahead and look into some of them. Second, you always work with young people who are creative and passionate about what they do. They allow me to be a part of their career development, part of their years either as a PhD student or a postdoctoral fellow just coming out of their PhD training. I get to play an important role in their world.

What is your guiding philosophy for running your lab?
I want my lab members to be free to develop their research interest and passion. I work with them to find out what they are truly interested in and passionate about. But it’s a balancing act. While giving them the freedom to develop their research interests and directing their projects, we have ongoing discussions to help them form their interests, so they have a solid blueprint for initiating and completing a research project.

Do you have any hobbies outside science?
When you’re in science, science is your hobby. That’s first and foremost. I want to be able to do and enjoy other things as much as science once I stop doing science, which seems almost unthinkable at this moment. I like to read, and I enjoy music. But I am completely illiterate when it comes to music, and I may want to spend time on learning music, and possibly picking up an instrument to amuse myself.

What has changed for you during the COVID quarantine?
I’ve actually had an opportunity to learn more. I attend more meetings, virtually. For example, I attended several Cold Spring Harbor meetings that are outside of my field because I didn’t have to travel. It’s really amazing. From the comfort of your home, you can also just click and listen to really cool talks in another state or in another part of the world. And, since I’m not at the bench, I can work anywhere. I don’t have to be in the office all the time, although I still try to go in regularly. And even though I can’t meet with people in person, my lab knows I’m there if they need me. We Zoom from separate rooms in the lab all the time. I could do those meetings from home but just walking up and down the hallways at work and knowing I’m close by makes us all feel connected.