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Disorder in a dish: PhD alum Sundari Chetty uses human cells to study autism and schizophrenia

By April 15, 2020December 8th, 2022No Comments

UPDATE DECEMBER 2022: Chetty has moved from Stanford and is now an assistant professor of psychiatry at Harvard Medical School, and an assistant professor at the Center for Regenerative Medicine at Massachusetts General Hospital.

“I really wanted to do something that was translational — to bridge my interest in science and medicine.”

Sundari Chetty, Neuroscience PhD Program alum (entering class of 2005)

Sundari Chetty

Sundari Chetty

To understand the mechanisms underlying disorders such as autism and schizophrenia, Sundari Chetty first takes blood or skin cells from patients and induces them to become stem cells. Then she coaxes these so-called induced pluripotent stem cells (iPSCs) to produce different types of mature brain cells, allowing her to model the disorders in a petri dish where she can even test potential treatments. 

Chetty is an assistant professor of psychiatry and behavioral sciences at Stanford University, and an alum of the Berkeley Neuroscience PhD Program. She was an undergraduate molecular and cell biology major at UC Berkeley, where she discovered her passion for therapeutically-relevant neuroscience research as a student in Robert Knight’s lab. Knight is a neurologist and a member of the Helen Wills Neuroscience Institute.

Chetty’s exposure to neuroscience at Berkeley inspired her to join the Neuroscience PhD Program. She did her PhD in Daniela Kaufer’s lab, where she studied how stress alters the fate of stem cells in the hippocampus of the adult rat brain and how that may affect learning and memory. She then went on to do a postdoctoral fellowship in Douglas Melton’s lab at Harvard, where she studied the mechanisms regulating differentiation and cell fate choice of human embryonic stem cells and iPSCs. After her postdoc, she started her own lab at Stanford in 2016.

Read our Q&A with Chetty to learn how she uses human cells to search for new treatments for neurological disorders; why she liked the atmosphere of neuroscience at Berkeley; and how being a parent meshes well with being a developmental neuroscientist. This Q&A has been edited for length and clarity.

Rachel Henderson: How did you become interested in neuroscience?

Chetty and her daughter on Halloween.

Chetty and her daughter on Halloween.

Sundari Chetty: I grew up in a family of doctors. My father is a physician as well as my two older sisters and younger brother. So I was always very interested in medicine and the science behind it. I became interested in research when I was doing my undergraduate degree at UC Berkeley. I was in the molecular and cell biology [MCB] department, emphasizing in neurobiology. I was fortunate to get exposure to neuroscience research in Bob Knight’s lab, which really sparked my interest in doing research that has therapeutic relevance. I really wanted to do something that was translational — to bridge my interest in science and medicine together so that I could possibly find new therapies for some of the neurodegenerative disorders or neurobiological issues affecting mental health. 

RH: Why did you choose the Neuroscience PhD Program at Berkeley?

SC: I went to Berkeley for my undergraduate degree and especially in my last few years, I was exposed to a lot of the neuroscience research, both in MCB as well as through cognitive neuroscience by working in Bob Knight’s lab. That had really sparked my interest in wanting to understand how the brain functions and works, and how that can affect normal wellbeing as well as a lot of mental disorders or neurodegenerative disorders. Because I was at Berkeley and I knew the faculty and the atmosphere fairly well, I was very interested in doing a PhD at Berkeley. 

I really liked the Neuroscience Program at Berkeley. It was so new at that time and seemed to have a lot of potential, including opportunities for collaboration with other labs across disciplines. I really liked that atmosphere of the science and it seemed like a very enriching program where you learn a lot, get exposed to new kinds of ways to tackle questions, and are able to integrate with different colleagues, even if you’re in one particular lab.

RH: What was your PhD thesis about?

SC: I did my PhD in Daniela Kaufer’s lab, where I investigated how stress affects the brain. In particular, we were looking at how stress affects hippocampal neurogenesis in adulthood. The hippocampus has a region where there are neural stem cells that have the ability to become neurons in adulthood and that has impacts on learning and memory. I was particularly interested in understanding the molecular and cellular mechanisms of how stress regulates that process. We used rat models as well as in vitro cell culture systems, where we isolated the neural stem cells out of the rat brains, cultured them, and exposed them to stress hormones, particularly corticosterone which is a rodent form of cortisol. What we found was that in the presence of high levels of corticosterone, the neural stem cells both in vitro as well as in vivo would turn into oligodendocytes [Ed. note: oligodendocytes are glial cells that produce the myelin sheath surrounding the axons of neurons] over neurons. We suppressed generation of new neurons by supporting the oligodendrocyte path, which impacts myelination of the neurons, and these effects could be reversed if we blocked stress signaling mechanisms through the glucocorticoid receptor.

Chetty and her lab at Stanford.

Chetty and her lab at Stanford.

The way we showed this in vivo was with a few different stress paradigms. We exposed the rats to restraint stress, and that elevates their stress hormones over the span of a week. Then we would isolate the brains and look at the neural stem cells embedded in the dentate gyrus of the hippocampus and examine the cell fate of those neural stem cells. In the in vivo model as well, we saw that the neural stem cells had suppressed generation of neurons and had more generation of oligodendocytes. Then we injected corticosterone directly into the animals and saw the same effects — there was an increase in oligodendrocyte generation over neurons. We began some preliminary studies to look at how this would impact function, or learning and memory. That was still at the early stages, but it seemed to have an effect on increasing long-term learning and memory retention, potentially having implications for disorders such as post-traumatic stress disorder.

RH: Because you had been an undergraduate at Berkeley, did you know Daniela Kaufer before you started in the Neuroscience PhD Program?

SC: No, I didn’t. Daniela actually joined UC Berkeley during my first year, so I only got to know of her work after she had arrived at Berkeley. Her lab was the fourth rotation that I did during my first year, but I really fell in love with it. I liked both the molecular and cellular mechanism aspect of it and how that translated to mental wellbeing or brain function. I really liked having the ability to study basic science and seeing how that might affect human behavior.

I actually did a couple of rotations in imaging and cognitive neuroscience, then moved to a more systems approach where I worked with primate models. Then I ended up in more of a molecular and cellular lab — Daniela’s lab. I did this whole spectrum mostly because I wasn’t sure which area I wanted to go into. But I was glad I got the exposure to all aspects of neuroscience.

RH: I noticed you have a publication with HWNI member William Jagust as well. 

SC: That was from my rotation in Bill Jagust’s lab in the first year of my PhD. Each of my rotations was very fruitful. Even though it’s a short time span that you get in each of the rotations, I had the opportunity to really go deep into many of the projects, which was a very nice exposure to the wide array of techniques in the field.

RH: What was your experience in the Berkeley Neuroscience PhD Program like in general?

SC: I loved the Berkeley PhD program. I still have fond memories of it. The cohorts of students in each class were fantastic. We were a pretty small class of about 10 students and I’ve kept in touch with many of my classmates, who are either still doing academic research or have moved into industry. So it really formed nice connections and friendships that have lasted for a long time. It was a very motivated group of people to be around, who were enthusiastic and passionate about science. They were easy to talk to about ideas or anything that’s going on in your life.

I really liked the exposure to different fields, not just within neuroscience, but also other fields of molecular and cellular biology, mostly because HWNI is very tightly integrated with MCB. You get a chance to see the science behind many areas, and attend seminars and journal clubs. 

We also had something called Neurofriends where the Neuroscience PhD Program allowed us to have these lovely lunches with our classmates. I think that really helped us form tight connections and let us hear about the work that our classmates were doing. Often they were not in the same area — some might be in imaging and cognitive neuroscience, while some were in a more systems area, and some were in more of a molecular and cellular biology area. It was really nice to have those opportunities to interact with your own classmates in a more informal setting.

RH: What did you do after you left Berkeley?

SC: I continued to be interested in stem cell research after my PhD in Daniela’s lab, and I really wanted to bring it more to therapeutic relevance, which is my long-term interest. At that time, human embryonic stem cell work was gaining a lot of momentum. I wanted to do research in induced pluripotent stem cells (iPSCs) and human embryonic stem cells (ESCs) and hopefully bridge it back to neuroscience or neurodegenerative diseases. So I chose to go into a postdoc at Harvard in Doug Melton’s lab, where I studied the mechanisms that regulate cell fate of human ESCs and iPSCs. 

Research from the Chetty lab.

Research from the Chetty lab.

One of the main challenges in the stem cell field is to efficiently and effectively guide different stem cell lines into a lineage of choice. Many barriers prevent ESCs and iPSCs from readily differentiating, greatly limiting their applications for disease modeling and therapy. During my postdoc, I focused on understanding the mechanisms that regulate ESC/iPSC differentiation and found that if you modulate cell proliferation and the cell cycle by enriching cells in the early G1 phase of the cell cycle, there was increased propensity for differentiation into any lineage of choice following directed differentiation. The reason this is important is because ESC/iPSCs have a truncated cell cycle with short gap phases that promote amplification over differentiation. However, by enriching cells in the G1 gap phase and allowing the cells to pause from cell division, ESCs/iPSCs were significantly more responsive to the differentiation signals in a dish. This work was along the lines of what I had done in Daniela’s lab looking at neural stem cells and how environmental triggers can alter cell fate. But here, I was focused more on unleashing the differentiation potential of embryonic and induced pluripotent stem cells into any lineage in the body for therapeutic applications.

Then I moved to Stanford to start my own lab. I’ve been using human iPSCs to study psychiatric disorders, particularly autism and schizophrenia. We’re using human iPSCs for disease modeling approaches, in the hopes that we can understand disorders like autism and schizophrenia using humanized models and also identify new therapeutics by screening for drugs in an in vitro system. 

Some of our ongoing projects focus on studying autistic children, who have and do not have brain enlargement. As you know, autism spectrum disorder is quite heterogeneous. There are a lot of different subtypes of autism, typically affecting boys more than girls. About 20% of autistic children have an enlarged brain relative to their body height, and this has been associated with poor outcomes. They have more severe behavioral deficits, lower IQ, and they don’t seem to be as responsive to the standard therapeutic interventions. Even though one may try to treat these kids at higher intensity — because they are so severe on the spectrum — they still don’t seem to respond to the therapies that are currently available.

What we wanted to do was understand the basic mechanisms that may be contributing to this brain overgrowth in autistic children. We have an NIH-funded grant with UC Davis, where we are collecting blood samples or skin fibroblasts from kids with and without autism, who have normal brain volume or enlarged brains. My lab is currently generating iPSCs from those kids and differentiating the iPSCs into different brain cell types — microglia (the immune cells in the brain) as well as cortical neurons and cortical oligodendrocytes. This is because in the kids who have the brain enlargement, imaging studies have shown that there are increases in gray and white matter. We wanted to model these effects in vitro, so we’re generating both neurons for gray matter as well as oligodendrocytes that may model the changes in white matter.

Schematic showing the Chetty lab’s approach of using peripheral blood mononuclear cells (PBMCs) from blood samples of patients and control subjects to reprogram them into expandable populations of iPSCs that can subsequently be differentiated into neural progenitor cells (NPCs), oligodendrocyte progenitor cells (OPCs), and microglia following directed differentiation. The cellular and molecular mechanisms are correlated with brain imaging and behavioral testing data obtained on the same individuals to gain deeper understanding of the underlying mechanisms contributing to psychiatric and neurodevelopmental disorders and ultimately identify more targeted therapeutics.

We’re working with over fifty iPSC lines in the lab from different kids and patients with these types of neurodevelopmental and psychiatric disorders (with and without brain enlargement), differentiating the cells over a span of a month or two months to generate the different neural and glial cell types, and looking at what is contributing to the differences. We perform a lot of RNA sequencing, gene expression studies, protein analyses, and functional assays to gain understanding of the mechanistic insights.

One of our recent findings is that the brain overgrowth in some forms of autism (e.g. 16p11.2 deletion syndrome) is associated with overexpression of CD47, which is a ‘don’t eat me signal’ that’s upregulated in a lot of cancer cells, leading to suppressed engulfment by immune cells. We had hypothesized that perhaps the brain enlargement is due to improper elimination of cells early in development, and that may be contributing to the brain overgrowth. So we specifically looked at this protein called CD47. We see that in neural stem cells as well as oligodendrocyte progenitor cells derived from the autistic kids with brain enlargement, there is overexpression of CD47. That leads to reduced engulfment by the immune cells in the brain called microglia. We’ve found that if you block CD47 with blocking antibodies that have been developed for cancer, we can restore phagocytosis [Ed. note: engulfment by immune cells] to normal levels.

What we ultimately hope to do is look at these pathways in other psychiatric disorders that are associated with changes in brain size, and also correlate our iPSC data back to brain imaging and behavioral data from the same individuals so that we have a deeper understanding of the relationship between the cellular phenotypes to the neuroimaging and clinical/behavioral measurements (a more personalized medicine approach). Our ultimate goal is to find more targeted therapeutics that could potentially help alleviate some of the symptoms in the kids who have autism by understanding these underlying mechanisms. One can potentially intervene at an early stage if the mechanisms are well-known.

RH: You mentioned that you work on schizophrenia too — is that related to brain growth?

SC: There is one psychiatric disorder called 16p11.2 duplication syndrome which is often associated with schizophrenia, where individuals can have a microcephalic, or a very small brain. We are planning to study these individuals as well, and see if similar mechanisms are underlying reduced brain growth. One idea that we have is that there is potentially too much elimination of cells, either through the complement system that activates the immune system or through changes in the balance between ‘eat me’ and ‘don’t eat me’ signals (such as CD47) as we’ve found to play an important role in the brain overgrowth models. In the long run, we will investigate if these imbalances in the neuroimmune system may be more generally involved in regulating brain size.

RH: How are you finding life as an assistant professor?

Chetty getting ice cream with her lab and daughter.

Chetty getting ice cream with her lab and daughter.

SC: It’s been a lot of fun, I really enjoy it. In the early years, it definitely takes some time to build up. In the first year, you’re waiting on new equipment to arrive, waiting for the right personnel to join the lab, and it takes some time to get your name out there so that students and postdocs know about you. But it definitely picks up within a year or two. The momentum has picked up a lot, and there are many different projects ongoing in the lab, which is a lot of fun. I also enjoy mentoring students and postdocs and seeing them do well. It’s really nice to attend and present our work at conferences, form new collaborations, and get feedback from others, and often my whole lab (including students, postdocs, and research technicians) gets the chance to go and present on their work as well. It takes time initially and you don’t know when you’ll reach that stage when it starts to just flow, but once you do reach it, after a year or two, it’s very nice to see the work getting published and rewarding to see your students and postdocs do well.

RH: Do you have any advice for prospective or current graduate students?

SC: I would say that choosing a lab where you’re really excited about the research questions is probably most important. You want to be in an environment where you’re excited to go into work every day, and keep working with the cellular or animal models, or whatever the techniques and the systems are in that lab. You want to be really passionate and excited to go in at any time to do the work. And ideally, it wouldn’t feel like work to you — it feels like you’re just having fun. The research questions have to be aligned with your own interests, and your long-term interests. I think that helps keep you motivated and keeps you asking new questions. Even after you’ve answered one, you will be eager to improve it and tackle the next question.

Finding good mentors and collaborators is very important as well. At Berkeley, Harvard, and Stanford, I’ve been really fortunate to have wonderful mentors and collaborations, both within the lab and outside the lab. With new collaborations, you have opportunities to learn new techniques and skill sets that are outside of your own space that may help you address a scientific question in a new way. I would say: seek good mentors and collaborators, and make sure you’re excited about the science that you are working on.

RH: What do you enjoy doing outside of work?

Chetty with daughter

Chetty and her daughter.

SC: My husband and I have a four-year-old daughter. Spending time with her is very enjoyable. It’s so fun to watch her grow, especially being in the neurodevelopmental field. When she was a baby, I could see all those things happening so quickly — the brain is developing so fast — and how important environmental enrichment can be for a young baby’s brain development. I like spending time with our daughter and family, being outdoors at parks or taking long walks, and exploring restaurants in the Bay Area.

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