We chatted with Professor Jennifer Phillips-Cremins on a fall afternoon that felt more like summer than almost winter. Meeting up with Jennifer in her office, I first noticed the lack of stuff. If you spend enough time around university offices, you notice that professors are very good at creating piles of papers, coffee mugs, books, and trinkets. And the piles exponentially multiply the longer the professor is on faculty. By the time they gain tenure, every surface is covered by a foot-high stack.
So, of course, I had to ask, “Did you just move to this office?” Nope. She is just tidy, and spends a significant portion of her time in lab with her students and post-docs. She even has a second desk in the lab and often does work there. Jennifer joined the faculty at Penn in January of 2014 and is making serious headway into understanding the role epigenetics plays in neurological health and disease. Recently, she was named a 2014 New York Stem Cell Foundation Robertson Stem Cell Investigator. She is one of few people investigating the 3D folding patterns of DNA in the cell nucleus and using this information to understand how epigenetic markers interact with each other over large distances. (Typically epigenetics is studied in the context of linear DNA sequences.)
We were excited to chat with her and ask what inspired her to focus her research on such a challenging, risky, and potentially game-changing topic.
Q. How did you find your way into science?
My primary interest in high school was math. But my uncle is a PhD [scientist] and he ran a cancer lab at George Washington University. I remember we would visit him on family outings and he would show us this museum in the GW medical school with all the cadavers behind the glass cases. The first time I saw it I was 10, 11, or 12, and I just loved it. Everyone else in my family just wanted to get out of there! But, it was absolutely captivating to me to see the skin peeled back and to have a glimpse into the complex systems of the human body that work 'behind the scenes'. However, other than thinking about how cool the human body was and just being amazed by it, it wasn't until graduate school that I took a formal biology course. (Her undergrad major was chemical engineering with a minor in math.)
Q. What did you do after finishing undergrad?
Q. Did you enjoy working in industry?
If anything, it taught me that it was not the right fit for me. It went really well, I got promoted really fast, but within two years I was very unhappy. Just when you get to something interesting that you want to pursue scientifically, it always came down to— is this going to lead to a better formulation that will make us more money? If not, let's move on. And that turning point often happened when I wanted to go deeper into the science. I also didn't like people telling me what to work on! [laughing] I wanted to work on what I wanted to work on. So for me, academia was the right choice.
Q. And you did a medical school program in conjunction with your PhD? What was that like?
Q. When you entered grad school did you know it was the right fit for you right away?
Q. What is your metric or barometer for choices you make? What keeps you on track?
In my case, as I am exploring, I'm always assessing and questioning - is this activity a good use of my time? Is it catering to my passions or what I think that I'm uniquely skilled to do? I think everybody asks these questions, but it's at this critical juncture where one might look at the factors of money or logistics or fear of what other people will think and make a decision to stay [in their current position]. I have been fortunate to have mentors that have challenged me at each transition point to make the hard decision and stay on track toward my purpose.
The idea that each individual has a unique purpose to fulfill on this earth is probably a controversial life view. But I can tell you that all my decisions, especially now as a mentor, come from that core belief. I have found a lot of joy in the process of working with students and helping them find projects and approaches that fit their unique skill set(s).
Q. What did you do during your PhD? How does it relate to what you do now?
By the end of my PhD work, I was quite dissatisfied by our inability to engineer fully functional tissues. At that point in my career, the nucleus was a black box and I only thought about gene expression in a locus-specific manner and in terms of the gene simply being 'on' or 'off'. I was restless and wanted to work on something that [involved] understanding mechanistically how cells chose their fate during development. At the time, my motivation to study the mechanisms regulating gene expression was to use the knowledge to engineer better tissues.
I read about epigenetics during this time of angst where I felt unsettled with the progress in the lab. Even though we published a ton of papers (11 while she was in graduate school!), I felt that I needed to go back to mechanisms before I could move forward.
So I started reading very broadly. I asked the question: where is the biggest area in science where I could use my talents and skills to really make an impact? I just stumbled upon the topic of epigenetics— I was reading a Time magazine article! And then I started exploring it, around 2008 or so. It just seemed like the concept could explain a lot of my unanswered questions. The tension between nature and nurture, the differences between twins in disease susceptibility. The idea that there is an additional layer of information on top of the genome, that is influenced by the environment and developmental signals, a unique signature— from each cell to each person to each behavior. It just resonated with me.
I was fortunate that the technological advances that made deep sequencing tractable for individual labs happened right around the time that I started my post-doc. The timing was serendipity, but it allowed me to use engineering problem-solving skills and quantitative statistical approaches to study biology from a systems perspective. So I took a huge risk and followed my interests and what I thought was my purpose at the time.
Q. Can you tell us a bit about your post-doc? Four labs, three institutions— did you set out knowing that was what you wanted to do?
Jennifer then attended a Keystone conference on epigenetics during the first month of her post-doc and learned about new techniques of deep sequencing that were being performed at the Broad Institute. The talks were on classic histone modifications (methylation, acetylation) and DNA methylation — big breakthroughs at the time (2008).
I was quite disappointed at that conference. I was thinking about studying genome-wide epigenetic marks in stem cells but, well, people were already well on their way to making this happen. I thought - I can either catch up on their game or make my own path. I began reading and searching more broadly and started thinking about the higher-order folding of the chromatin fiber in the 3D nucleus. This problem was poorly understood and also appealed to my engineering side. It's quite a challenging problem in the sense that you have this hairball of DNA, with millions of fragments spatially connected to each other in three dimensions. The analytical skills and engineering thought processes are essential to think through the topological configurations. I suppose I gravitated toward the complexity and the importance of the problem, but I was also quite deliberate in not going where everyone else was going.
Very soon (after the Keystone conference), Job Dekker came to Emory and Victor had asked me to go sit at lunch with him with a few other postdocs and grad students. Job Dekker is a pioneer in the development of methods to analyze chromatin architecture - he invented the Chromosome Conformation Capture (3C) technique, which he was applying to study individual genomic loci at the time. In his lab, but still unpublished, he was pioneering new ways to scale up 3C technology to map chromatin architecture on a genome-wide scale. I suppose it was again serendipity that Job came to Emory after I figured out that I wanted to study genome folding. I pitched him the idea and he said “let's do this!”. I was very fortunate that Job agreed to take me on - and that Victor was willing to give me so much creative freedom. For the rest of my post-doc, I went back and forth between Job's lab (in Worcester, Massachusetts) and Victor's lab (in Atlanta). It was just a fantastic opportunity to train simultaneously in the two labs and apply the most high-tech, innovative genomics tools to study mechanistic chromatin biology.
Once we had the cells and the molecular biology worked out, we then needed to analyze the Terabyte of data that we generated. So there was a guy named James Taylor at Emory (now at Hopkins) who was a computer scientist. His specialty was in writing bioinformatics software. I wanted to learn how to write code to find patterns in large biological data sets. So I just camped out in the Taylor lab! If I wasn't in Victor's lab or Job's lab, I was in James' lab writing code. It turns out that my very favorite part of the creative process, now, is analyzing the data.
Jennifer also worked in Todd McDevitt's lab at Georgia Tech to turn embryonic stem cells into neuronal progenitor cells for this project. Talk about a lot of collaborators!
Because of all the risk, my post-doc took a bit longer, but I don't regret any of it because now [my lab is] unique in that we can do the cellular, the molecular, and the computational work all under one roof. I find it very rewarding to see my students collaborating with each other and working as a team. It shows me that the traveling and the challenges that I faced in my postdoc were worth it because now we can do better science in a more efficient manner.
Q. With such a multi-disciplinary research area, do the students and staff in your lab come from very diverse backgrounds?
Q. What is your approach to a new problem? When do you ask others for help?
Then I start talking to people to get their advice. I try to seek wise counsel from at least three or four people more senior than myself, or more experienced. And then I stay on the look out for collaborators. In the end though, I think you have to do a lot of it on your own. No one else is going to care as much as you do about your problem.
Now, in the lab, we can't get too diffuse. I have to pick projects that will help students be successful in the future. That's my job and I take that very seriously. I read a lot behind the scenes to make sure they're not going to get scooped, they are working on important questions, and they are things we can do in a reasonable timeframe. So I give everyone a safe and a risky project. The risky one will make their career. The safe one will make sure they don't lose their career. We define the projects together.
Q. Do all the projects in the lab feed into a single major question?
My underlying theory is that epigenetics matters in the brain and epigenetic modifications become causally disrupted in disease. That could be wrong.It's a hypothesis that I'm willing to bank on, but we don't know for sure. So now we have to systematically start to test the hypothesis. We might discover that it's not the right path. But I want to do what I can to help brain disorders. If we find out that epigenetics doesn't matter at all, we better be willing to change the direction of the lab.
Q. In addition to your research question, what other things in your life are important to you?
One advantage of doing both is that one makes me better at the other one. I'm more compassionate and in-tune with my students because I look at them as an extension of my family. Which maybe (actually, I'm certain that) I wouldn't have been in my younger days. [By working,] maybe I'm just more alive as a person, so I'm happier around him [my son].
But, I don't think you can have it all. I've had my time [to do other things], when I was in grad school, when I didn't have a family. I'm making the choice to give my best to just two things: my family and my lab. Prioritize and put all your energy into your top 2 things has been my strategy. Of course the balance is hard, but it's the hard that makes it good.