Meet a Whitehead Postdoc: Shawn Liu

In  Whitehead Institute Founding Member Rudolf Jaenisch’s lab, postdoc Shawn Liu is investigating epigenetics — the heritable modification of gene expression — and diseases linked to aberrant epigenetic changes. Liu’s work is supported by the Damon Runyon Cancer Research Foundation, Rett Syndrome Research Trust, and NIH Pathway to Independence Award (K99). We sat down with Liu to learn more about him and his experiences in and out of the lab.

What do you investigate?

I’m interested in epigenetics, and particularly in an epigenetic mechanism called DNA methylation. This is a type of chemical modification that adds a methyl group to DNA, which changes the activity of the gene, often silencing it. DNA methylation is one way in which cells that share the same DNA sequences—like all of the cells in a human body—can come to have different identities and functions, based on which genes are expressed in each cell. However, aberrant DNA methylation can lead to abnormal gene expression and disease.

When I joined Rudolf’s lab, I wanted to develop molecular tools that would allow us to edit DNA methylation in a targeted fashion so we could precisely change the methylation state at a given genomic site but nowhere else. That way we could figure out what methylation at those sites does. My thought was to borrow CRISPR/Cas9, a powerful tool for editing the genome that usually targets the DNA sequence itself, for this purpose. We developed a CRISPR-based tool that can instead be guided to specific loci in DNA sequences where the methylation occurs in order to remove it.

What are the potential medical applications of the methylation editing tool you developed?

Many diseases are associated with abnormal DNA methylation, including some cancers and neurodevelopmental disorders such as fragile X syndrome. To study these diseases, we can use the tool we created to remove methylation at genomic sites linked to the disease in cells derived from patients. Then we observe changes in cell behaviors, which helps us figure out the role or consequence of methylation in these diseases. Looking forward, the tool could serve as a potential therapy. As a proof of concept, we first focused on fragile X syndrome — a common form of intellectual disability in males—in which the FMR1 gene is silenced. By simply removing methylation at specific sites, we were able to reactivate the gene and rescue fragile X neurons from the disease.

When you were a kid, what did you want to be?

When I was very young I wanted to be a basketball player, because at that time in China they had started airing NBA games, and I was influenced by that. When I was in elementary school, I was already as tall as I am now (5’ 9”). However, by high school I was still the same height and had stopped growing. I quickly realized that basketball was only going to be a hobby.

How did you become interested in a career in science?

Both of my parents are physicians, so they thought becoming an MD would be a good career path for me. I wasn’t so sure because every day you have to spend all of your effort to take care of patients and sometimes the options are very limited, which frustrates both patients and doctors. Fortunately, my dad was always interested in science, and he bought me a science experiment kit that got me interested as well. In college I started out majoring in business, but after one year I thought, "This might be like the basketball, not really my thing." I switched to studying chemistry, in part because of the homemade experiments I had done with my dad. Then I turned to biochemistry because I think that while chemistry is very cool, biology is a lot more open ended. In biology there are many mysterious black boxes, and it's quite exciting once you have some tools to begin asking questions and seeing what will come out of them.

What are your favorite and least favorite parts of your job?

My favorite part is that we get to pursue the questions that we think are exciting and interesting. We are given an opportunity to just explore, even if it may not have a direct or immediate value that can be translated into a product or a medical application. The freedom to satisfy our curiosity, that’s the reason I'm still in this business. My least favorite part of this job is that we have to put in a lot of time and effort trying to find answers to questions we're excited about. It can take days, months, sometime years, and even then you may not find the answer. Sometimes I feel bad for the researchers who did a lot of work that didn’t generate an expected result, because their work may not be appreciated by the community, but negative results are actually very useful for us. They narrow down the possibilities. Academic research is time consuming, and sometimes it's frustrating, but the moments when you figure something out are the best moments in your life.

What are your hobbies outside of work?

For a long time I played basketball, but now my hobby is badminton. I think it’s very good exercise for my neck and my back because it counteracts our daily routine in the lab. We do a lot of pipetting crouched forward over the bench in the fume hood. For badminton, you have to look up and lean back. I play almost every week as a way to refresh myself. I think working out and playing badminton, while physically tiring, makes you mentally sharp again. It helps me think in a clearer fashion when I return to work.

What’s the most expensive thing you’ve broken in the lab?

In graduate school, we had to defrost the lab freezer. That's normally done by unplugging the power and then you let the freezer defrost naturally, but I don't have that type of patience. I tried to manually remove the ice from the inside of the freezer. I used a screwdriver, and at the beginning it worked very well, but then suddenly, somehow, I hit the tube inside the freezer that has the coolant in it. After that the freezer never worked again.

What is it like working in the Jaenisch lab?

It's quite exciting to work in Rudolf's lab because we're a big and dynamic group. Our projects are very diverse, and I get to hear about lots of exciting projects during our lab meetings. I'm trained in molecular biology and biochemistry, so my research is always related to molecules. Some of my colleagues study mouse genetics. They try to create human-mouse chimeras to study human diseases. To me, that is crazy! I know little about the subject or the techniques. But it's fun when people studying different topics collaborate. We have learned so much from each other. I think that's the culture of Rudolf's lab: dynamic, diverse, and very exciting.

What questions about epigenetics are you most interested in investigating?

In the field there is a very provocative hypothesis that DNA methylation may contribute to memory storage in our brains. Once I establish my own lab, I would love to look at the role of DNA methylation in long-term memory and find out how much it contributes to memory functions. This has been an open question in the field for several decades, and we don't have a good answer. However, now the memory-encoding neurons have been identified, and with the DNA methylation editing tool we developed, I think we are ready to begin to answer this question.

Where do you see yourself in ten years?

Hopefully I establish my own lab and continue doing exciting research. I hope in ten years my lab will begin to provide answers to puzzles in the epigenetic field, develop new tools to push forward the epigenetic editing field, and depict the role of DNA methylation in memory.