By Alycia Lee, CURJ Associate Editor
1. What motivated you to study neural crest cells?
I first became interested in developmental biology when I was a graduate student at Johns Hopkins. As an undergrad, I had taken a curriculum that was similar to the curriculum of physics students here at Caltech, and so I hadn’t had much biology. As a consequence, when I was in graduate school, I had to take some undergraduate courses, one of which was developmental biology. I was absolutely blown away by the concepts presented in the course, and decided that was what I wanted to study for my thesis research. In fact, the questions I starting examining then in developmental biology are what I’ve been working on ever since. Learning about the neural crest—the cell population that we investigate—was an epiphany. I knew that was what I wanted to investigate and I’ve been doing it ever since.
I became interested in evolutionary studies only much later in my career. For many years, I taught in a course for graduate students and postdocs at the Marine Biological Laboratory in Woods Hole and became the course director in 1997. I organized the course, invited all these incredible researchers, and for six weeks, sat through their lectures and participated in the lab. The course went over several topics, starting with the development of creepy crawly organisms that live in the sea, and moving up the evolutionary tree all the way to highest vertebrates. I’d been working on the neural crest, which is a vertebrate-specific cell population, and I started wondering, “where (evolutionarily speaking) did these cells come from and why?” That’s how I got interested in evolution. I came to Caltech in 1996, and shortly after arriving here, decided I wanted to work on the evolutionary aspects of neural crest development.
2. What are the importance and applications of neural crest cells?
The neural crest is a cell population that is implicated in many types of birth defects and cancers. These cells are prone to birth defects, because they give rise to a large portion of the facial skeleton so defects in their migration or proliferation can result in cleft palate, heart defects, and other abnormalities. We primarily focus on basic science issues to help understand the mechanisms underlying neural crest development, specifically examining how they form, migrate, and differentiate. The long-term applications of this research are far-reaching: perhaps leading to early diagnosis and recognition of therapeutic targets. By understanding the role of genes involved in neural crest development, we may understand how mutations in these genes result in some of the most common human birth defects.
Regarding cancer: Neural crest derived cells are very prone to metastasis. For example, all the pigment cells in the human body come from neural crest cells, and abnormalities in these cells can result in melanoma. We think that some of the events occurring during metastasis recapitulate the programs that were active during embryonic development. So by understanding the normal function of these programs, we may understand why cells become cancerous.
3. Where is developmental biology headed?
We live in a very exciting time. The tools that we have now are amazing—for example, our ability to perform gene sequencing of cell types and even whole organisms at the population and single-cell level. Now, one can do a gene knockout in any organism, because of CRISPR/Cas9. Because of these advances, we can answer questions that have been around for a long time, but previously were too difficult to tackle. While the questions haven’t changed, the depth with which we can understand them has steadily increased with time. My goal is to revisit classical questions, and get answers to them in a way we never could before. The fundamental questions have not changed, but the technology has advanced to make it possible to answer those questions.
4. Which of your experimental results have surprised you the most?
That’s a hard question. Everything I work on always surprises me. Usually, if I formulate a hypothesis, and then have one of my students or postdocs test it, we find that the original hypothesis was wrong but the new answer leads us in an equally exciting direction. That’s what I love about science—it doesn’t work the way you think it would but new discoveries make it ever more intriguing. When you try to figure out how things work, you formulate a hypothesis, but you can’t be wed to it. You have to try to understand and change it as you go along.
In our studies of evolution, we study a basal vertebrate called lamprey. These animals look like eels, but are jawless vertebrates (whereas eels have very good jaws!). Lampreys are the most primitive animal that has a neural crest, but they do not have all neural crest derived cell types present in humans. In a paper that we published last year, we were looking for a population of neural crest cells in lamprey that contributes to the nerves that control movement in the gut, called the “enteric nervous system.”
During embryonic development, after the formation of the central nervous system (CNS), neural crest cells are initially contained within the CNS, but then leave as single cells that migrate into the periphery. In fact, neural crest cells that arise in the hindbrain undergo the longest migrations of any embryonic cell type. They migrate from the neck region into the foregut (esophagus), then continue down the entire length of the gut and contribute to neurons that innervate the gut. These are important because they cause peristalsis, and without them, an organism would die.
We decided to look for this population of neural crest cells in lamprey. Lampreys have neural crest cells that contribute to the face, and structures in the trunk. However, when we looked for these “neck” neural crest cells, we couldn’t find them—there were no neural crest cells that invaded the gut and migrated down its length. My hypothesis was that lamprey lacks an enteric nervous system. Much to my disappointment, the postdoc working on this project found that lamprey have perfectly good enteric neurons, but we couldn’t find where they came from. Eventually, we found that they came from a different source than the neck neural crest. It was very exciting for us, because the neurons are there, but this enteric population of neural crest cells have yet to exist in primitive vertebrates, and also are only found in jawed vertebrates. It’s as if the neural crest “took over” new cell types during the course of vertebrate evolution.
5. What projects that your lab is currently working on are you most excited about?
I’m always excited about whatever we’re doing. One project is again an evolutionary project using the lamprey. In the 1980s, there was a hypothesis formulated that suggested that the invention of the neural crest is what made vertebrates so successful, because it enabled the head to elaborate and for jaws to form, making vertebrates excellent predators. This was referred to as the “New Head” of vertebrates. We have been testing whether this new head already existed in primitive vertebrates like lamprey. We’ve done a lot of genomic work and what we found is that lamprey don’t actually seem to have that new of a head. Still, they are perfectly good vertebrates. So we think that the new head might not have arisen at the base of vertebrates, but rather with jawed vertebrates. This is surprising, because this hypothesis had been around for forty years, but now we are not sure that it is correct.
The other project is more medically relevant. We’re interested in a population of neural crest cells that migrates into the heart. In the heart of lamprey and other fish, there are two chambers whereas, in birds and mammals, there are four chambers. We’ve been studying neural crest cells that migrate to the heart. By labeling these cells with fluorescent markers, one of my graduate students has found that some of these neural crest cells form part of the muscle of the heart—the myocardium—which was not known before. The reason I’m excited is that these cells have stem cell properties. Whereas the hearts of salamanders and fish can regenerate, the hearts of higher vertebrates fail to do so. So we wonder if this neural crest population may be involved in helping damaged heart tissue regenerate.
6. How is computation used in your research?
All the transcriptome analysis we do involves computation. For example, one of my graduate students is profiling cardiac neural crest cells by single-cell RNA sequencing (RNA-seq), which is a new, cool technique. We’re getting interesting and exciting results. An issue is that we get a huge amount of data from these single-cell RNA seq experiments as well as from whole population transcriptome analysis. We are often not sure what to make of this “embarrassment of riches.” Computation enables us to sort through the data, pick the wheat from the chaff, and try to understand what differences there are between cell populations and what the differences mean.
In the single-cell RNA seq, we have hundreds of single cells. We are focusing on the ones we are most interested in, like these cardiac neural crest cells. One of the questions I would like to address is if there is something special about these cells, and what genes are important for giving this population of neural crest the ability to go to the right places and contribute to the right cell types in the heart. That’s where computation will be really critical.
7. What aspects of Caltech do you treasure the most?
I love that it’s small, and filled with brilliant students and colleagues. As a consequence of the small size, I know many of the other faculty. Therefore, there are no barriers to collaborating with people. Collaborations sometimes emerge via interactions between my postdocs and other postdocs, and sometimes between me and other faculty. These interactions are ongoing and really fun, and take us in directions that we wouldn’t otherwise go. That’s wonderful—being around so many bright people here makes it a very exciting place to be.
The other thing is that at Caltech, you’re allowed to think out of the box and do things that are crazy. When I decided I wanted to work on lamprey—that was pretty crazy. I went to my division chair and said, “Can I have a room to set up some tanks?” And he said, “Sure.” He gave me a room and we set up some large fish tanks, and we got animals sent from the Great Lakes. Then, we started growing them in the lab. Now people come from all over the world to our lamprey facility to work on these beasts in the summertime. We’ve become—in a way—the lamprey center of the world. Being at Caltech enabled that. I don’t know if I could have done it at any other place.
8. What do you enjoy doing in your spare time?
I like to swim, I like to hike—I’m an exercise freak. I play with my dog, I like to cook. I go to the theater a lot. I have a subscription to the Pantages theatre, because I saw Hamilton and really enjoyed the show. I think having other things to do outside of science is really important, because it allows you to step back and think about things and reflect.
9. What advice would you give to yourself as a college student?
The advice I would give myself would be to take life less seriously and have more fun. I think I was much too studious. It’s really important to have balance in life. And you are a better scientist if you step back every once in a while and view the “big picture.” I also think it’s really important to take more writing and literature classes. As a scientist, I spend so much of my time writing. I would tell my younger self to take more courses to hone my writing skills. I didn’t spend enough time writing when I was a student. I see a lot of scientists struggle when it comes to writing a paper or grants.
10. What advice would you give to young female students aspiring for a successful career in STEM?
Have confidence in yourself. One of the worst problems women (and some men) have, and I had this in spades, is a complete lack of confidence. We all have imposter syndrome. We all think we shouldn’t be here—that we’re not smart or good enough. And that continues forever. If you can develop that mindset that you can do it and you do belong in STEM, it’s really important and takes you a long way.
Also, women worry so much about how to balance family and career to the point that it can be debilitating. I always knew I wanted to have a family. If I had to choose between having a family and having a career, I probably would have chosen having a family. But I didn’t have to choose. And I think that having children has been enormously helpful in my career. It sounds counterintuitive, but as a mother and a scientist, you become super organized. I found that once I had kids, I became very focused. In eight hours, I could get as much done as somebody who was spending fourteen.
To be a successful scientist, it takes a very complicated set of skills. We always focus on—in biology, at least—being a good bench scientist. As graduate students and postdocs, people are always at the bench. But there are other skills you need to master if you want to be successful in this career—skills that higher education does not teach you. When you transit from being in someone else’s lab to a faculty position, you are often totally unprepared for the next step. All of a sudden, you have to go from being a bench scientist to a manager. I think people skills are more important than some realize. Learning how to get along with and manage people is an incredibly important skill.
This applies to all young people: Find your passion. The most important thing is to find something that you want to do. Do what you really love. If you can find that special passion that inspires you, it can keep you going for a lifetime. In my case, I feel I get paid to do a job that I would do for free! It’s so much fun. That’s what makes life enjoyable.