Fellows Feature: Janet Song

Janet is a graduate student in David Kingsley’s lab,song7468_forweb where she is investigating genetic regions that might be involved in the evolution of the human brain. She received her B.A. in Chemical and Physical Biology from Harvard University in 2009.

Can you tell us a bit about yourself, personally and professionally? 

I grew up in the suburbs outside of Philadelphia where I had a pretty normal childhood – attending our local Chinese church and cheering rabidly for the Philadelphia Eagles. As a high school student, I was fortunate to do summer internships at Drexel University, where I worked with Dr. Timothy Block on the early detection of cancer, and later with Dr. Gordon Harris and Dr. Marlene Oscar-Berman at Massachusetts General Hospital on brain volumetric differences in alcoholics. These early exposures to research drove my interest in genetics and molecular biology.

In college at Harvard, I worked with Dr. Jeffrey Macklis. His lab studies the development of the cerebral cortex. I focused on genes that control axon extension in corticospinal motor neurons, which reside in the brain and extend long processes into the spinal cord. These neurons control voluntary movement and are often damaged during spinal cord injury.

After college, I came to Stanford to pursue my PhD with David Kingsley. My early experiences with research had made me very interested in gene regulation: How do the same set of instructions encode all the cells in the body? How do mutations in the genetic code affect these instructions? As I entered graduate school, I was particularly interested in asking these types of questions in relation to evolution. I wanted to understand how a relatively small amount of change to the genome – most of which is not in the genes themselves, but rather in non-coding regions – can distinguish one species from another.

How did you end up here? How did you first become interested in genetics and science?

My parents, who both got PhDs in biology in the early 1990s, talked about PCR so much that one of my first words was actually “PCR”. Because of this, I like to say that I was destined to be a biologist from birth. However, the truth is that I was not that enamored with science as a kid. That all changed in sixth grade, when my science teacher announced that students could do science fair projects for extra credit. I promptly informed my mom that I would be participating in this endeavor and needed to buy some plants. She was horrified at the thought of our house besieged by sunflower plants grown under different conditions for months (the de facto sixth grade project) and suggested instead that I come to her lab for a few days. To sixth grade me, a few days of work sounded way better than growing plants for months, and I agreed.

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Images courtesy of Janet Song

There, I UV irradiated DNA at different wavelengths and for different amounts of time to see how much DNA damage it would cause. That was my first exposure to “real” science and I was hooked. I went on to do more science fair projects (Question: Which brand of sunscreen is the best at protecting against UV irradiation? Answer: Rite Aid) and later, participated in multiple summer research internship programs in high school. I went to college certain that I wanted to run my own research group one day and have not wavered from that path since.

Can you tell us about your current research and what you want to achieve with it? What kind of responses have you gotten to your research/findings?

I study a human-specific element in the third intron of the calcium channel gene, CACNA1C. We discovered that this genomic region is misannotated in the human reference genome and is composed of hundreds to thousands of 30 bp repeats, expanded from a single 30 bp sequence found in chimpanzees and other primates. Intriguingly, this human-specific tandem repeat is also variable within humans. We found that different sequence variants on the 30-mer motif are linked to nearby SNPs that have been repeatedly associated with bipolar disorder and schizophrenia.

Using enhancer reporter assays, we showed that the expanded human tandem repeat arrays drive significantly higher enhancer activity than the single 30-mer found in chimpanzees, and that human repeat arrays associated with psychiatric disease risk have decreased enhancer activity compared to other human repeat arrays. These results suggest that changes in the structure and sequence of these repeat arrays may have contributed to changes in CACNA1C function during human evolution and may modulate neuropsychiatric disease risk in modern human populations. (See our recently published manuscript for more details: https://www.cell.com/ajhg/pdf/S0002-9297(18)30238-6.pdf)

This tandem repeat may provide a key example of how genetic regions are involved in both evolution and in disease. Previously, hallmarks of human evolution, such as bipedalism or smaller jaws, have been linked to lower back problems and impacted wisdom teeth present in adult humans.

Our research provides a genetic example of how the rapid evolution of larger brains with increased complexity could have led to susceptibility to psychiatric disease.

We are now studying the effects of adding or removing this tandem repeat from CACNA1C on neural development, calcium signaling, and gene expression in mouse models and in human cultured cells. We hope that further study of this tandem repeat can clarify treatment options for individuals with bipolar disorder or schizophrenia and further characterize how novel DNA insertions can alter neural function both in evolution and in human disease.

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Briefly, what’s the coolest thing about your work?

My research has provided an example of how the same genetic regions involved in human evolution may also play a role in human disease. From my anthropocentric perspective, I often think of the regions in the genome that are unique to humans as “better” than other regions of the genome because they are responsible in aggregate for improved cognition in modern humans. However, it also makes evolutionary sense that regions under selection during human evolution may have inadvertently contributed to human disease. Compared to ancient genetic regions, regions diverged between humans and chimps have had less time to be refined in response to negative selective pressure and would be selected for if they have beneficial effects that outweigh the negative effects.

Were there people (or one person) in particular to whom you would attribute your professional success?

There are so many people who have helped me along this path. My parents have been instrumental to my development as an individual. From them, I gained a moral compass and learned the importance of hard work and determination. I have also had a variety of scientific mentors throughout the years, including my mother, Dr. Timothy Block, Dr. Jeff Macklis, Dr. Vibhu Sahni, and Dr. David Kingsley. They imparted and nurtured my passion for genetics and provided me with different examples of creative and rigorous scientists.

What advice would you offer to other grad students or postdocs who are considering pursuing a similar educational and career path as you?

I still have a long way to go in my scientific journey, but here are some things I have learned so far:

  1. The most important attribute in research is perseverance, especially as an experimentalist. Many experiments will fail technically or give uninteresting results, but it is important to never lose that desire to try and try again.
  2. Science should be communal. Working with others can help you to avoid reinventing the wheel and allow you to iterate through scientific questions more quickly.
  3. Don’t be afraid to try new things! The best way to answer a question is not always with tools with which you are already familiar.

What are your future plans? Where do you see yourself professionally in the next 5 or 10 years?

In a decade, I hope to be an assistant professor running my own research program centered on gene regulation. I have remained endlessly fascinated by how almost every living thing is encoded by the same molecule, DNA. Like many other geneticists, I am driven by the desire to understand how this deceivingly simple code can produce such a wide variety of complex organisms and how the same exact code can be interpreted differently within a single organism to produce neurons, T cells, bone, and all the other kinds of cells in the body.

CEHG’s core values include “interdisciplinary research” and “collaboration.” Can you speak to the ways your work has embodied these values or to their importance to your future work or past experience?

Collaborations combine the expertise of different individuals to best address a scientific question. I have been fortunate to collaborate both within the Kingsley lab and with other labs. The main project I am working on (see earlier answers) started as a collaboration with Craig Lowe in the Kingsley lab. Craig performed a screen for regions of the human genome that are unique to humans and overlap chromatin marks indicative of regulatory activity. One of the regions he identified was the human-specific repeat element that we then went on to study further. As this project evolved toward approaches outside of our areas of expertise, we began collaborations with a number of other labs at Stanford – including Sergiu Pasca’s lab to differentiate stem cells into 3D brain organoids, Paul Khavari’s lab to identify the transcription factors that bind to different repeat variants, and Alistair Boettiger’s lab to probe the chromosome structure at our region of interest. These collaborations have allowed us to use a variety of approaches to more efficiently answer questions about the function of this repeat element.

Tell us what you do when you aren’t working on research and why. Do you have hobbies? Special talents? Other passions besides science?

When I’m not working on research, I enjoy cheering for my hometown Philadelphia Eagles, playing cards and board games, and attending musicals. I recently bought a pair of rollerblades and have been slowly learning to rollerblade around Stanford. I’m still very much a beginner, but I hope to be able to rollerblade to and from lab one day!

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