In Science, In India: A Conversation with Infosys Prize 2022 Winner Vidita Vaidya

When Yale faculty and staff recently traveled to India, their first stop was in Bangalore, where Professor Rohini Pande was receiving the Infosys Prize 2022 in Social Sciences for her work.

While in Bangalore, the faculty and staff of the South Asian Studies Council had the pleasure of meeting another Yalie: Vidita Vaidya, PhD ’98, who was receiving the Infosys Prize 2022 in Life Sciences for her research into signals engaged by the neurotransmitter serotonin in causing persistent changes in behavior induced by early life stress and the role of serotonin in energy regulation in brain cells.

Vaidya earned a PhD in neuroscience from Yale and has since made her mark at the frontiers of biomedical. An excerpt from the “Scope of Work” section included in Vaidya’s award hints at the possibilities unlocked by her research: “Prof. Vaidya’s laboratory has shown that an imbalance in serotonin mechanisms, via different receptors with different G-protein based signaling systems, is an important contributor to stress-induced anxiety and depression… Vaidya’s findings demonstrating a role for serotonin signaling in making new mitochondria and enhancing mitochondrial function in neurons establishes a connection between neurotransmitter activity and cellular energy regulation. This work provides a new way to understand the effects of serotonin and has the potential to yield novel approaches to therapeutic treatments for psychiatric or neurodegenerative disorders.”

Vaidya currently serves as Professor and Chairperson for the Department of Biological Sciences at the Tata Institute of Fundamental Research (TIFR) in Mumbai. She is as impressive in person as her research is academically. As intimidating as her CV is, it’s matched by the warmth of her manner and the intense, cheerful candidness with which she discusses topics ranging from serotonergic receptors to New Haven weather and inherited privilege in India. A few weeks after the SASC returned from India, I had the opportunity to sit down virtually with Vaidya and ask her a few questions about her research, leadership, and time at Yale.

Daevan Mangalmurti: To start off, can you talk a little bit about your work and what got you into researching stress and its effects on serotonin and serotonin receptors?

Vidita Vaidya: My interest in early life stress came from the fact that if you look across the spectrum of psychiatric diseases—from anxiety and depression to schizophrenia and substance abuse—a common risk factor is a history of early trauma. There are very few common risk factors for psychopathology, but early adversity is one of them. I was interested in asking mechanistically how early trauma may influence serotonergic receptors, setting up a substratum for the rest of the life of that organism so that when the second hit comes, or a second challenge such as adult stress, you’re not dealing with a tabula rasa, but a prior history which may shape the way you respond in adulthood. That was the driver behind the interest.

For serotonin, the idea that anyone who is interested in neural circuits that regulate emotion might eventually get interested in serotonin is an obvious one. In the popular press, ask someone, “Can you think of a molecule that is associated with your mood?” Most people will pop up with serotonin. It’s got instant recall for a molecule tied up with mood.

I’ve been working with serotonin for a long time. As a graduate student I worked with a molecule called DOI, which is a synthesized serotonergic psychedelic. It’s not one that’s part of street parlance for most people because it’s largely restricted to laboratory settings. But it’s a molecule similar in some sense to LSD and psilocybin in the way it works. As a graduate student at Yale I was already looking at the effects of adult stress on serotonin receptors. I was looking at how receptors, in particular the 5-HT2A receptor, are regulated to modulate plasticity in the brain. 5-HT2A is the major target of serotonergic hallucinogens. Psilocybin, LSD—all of them target this particular receptor. The discovery we made for which we got the Infosys Prize was totally unexpected and surprising: through the 5-HT2A receptor, serotonergic psychedelics and serotonin can directly boost energy production in neurons.

Neurons eat up almost all the energy in your body. Fifteen to twenty percent of whatever you eat is fueling this 1.5 kilo jelly-like organ in your head. Neurons are also the longest-lived cells. They don’t die too easily, and that is a good thing! Unlike your kidney or your skin which can replace itself, with the nervous system what you’ve got is what you want to do your best to keep. So neurons are first energy hungry and then they are long-lived. They are your cellular companions for life. They have to get their energy regulation absolutely optimal to allow them to be both long-lived and also highly electrically active cells. One of the things we discovered is that serotonin, through the 5-HT2A receptor, boosts the production of mitochondria in neurons and increases their efficiency. So say you have a city like Mumbai, and there’s huge energy demand, and everything’s at risk of shutting down unless you generate sufficient electricity. Either you provide more energy plants or you get your energy plants to be more efficient. What serotonin would do in this context for a city like Mumbai is give you more energy-producing plants and then improve the efficiency with which each of those plants works, to drive up energy production.

Since we stumbled on this finding that serotonin, via this receptor targeted by psychedelics, regulates mitochondria, we want to work on the widest range of psychedelics that we possibly can. We can lay our hands on maybe four or five synthesized psychedelics in Mumbai which are not Schedule I and therefore easy to obtain. But Schedule I drugs are a challenge to import into India. Even though the National Institute on Drug Abuse from the U.S. will actually give us the molecules for free to do research, to get them into the country we need narcotics clearances—not a problem that is easily solved. That has been such a challenge it’s been easier to consider sending my students abroad. You run into some challenges when you’re doing science in a country [like India]. I don’t know anyone else in the country who works on serotonergic psychedelics.

DM: When it comes to your work on stress-induced changes, have you worked at all on reducing the effects of stress on the brain?

VV: We’ve done a fair bit of profiling of what goes wrong and we’d like to see what we can do to fix what goes wrong. We’re interested in environmental and nutritional interventions, and I think in the context of India the nutritional interventions become perhaps the most interesting. We have several hundred million people below the poverty line. We have a very large young population, and early-life stress in this country is substantial. The combined onslaught of poverty mixed with other early onset traumas creates a substantial burden of early childhood adverse experiences. So there might be the possibility of incorporating nutritional supplements or nutritional interventions, for example specific vitamins, which can boost neuronal functions or at least allay some of the trauma-provoked effects. Those would be something we’re interested in. We’re interested in environmental interventions like exercise and how they target circuits in the brain, but our focus so far has been largely pharmacological. We’ve been working on the 5-HT2A receptor and how targeting that receptor can have potent effects on recovery as well.

We are thinking about early adversity in India in a different way from how people in the West may think about early adversity. India is going to provide the young population of the world. In the Indian context we tend to think about this large mass [of people] that we have and how early adversity there can result in consequences which we can’t imagine now but will emerge in the decades to come. One of the things we see with early trauma is an accelerated aging phenotype with higher risk for age-related pathology. If that’s to be the case, a large mass of young people with multiple kinds of early trauma and early adversity could result in challenges that may not just be enhanced risk for psychiatric disorders but also for neurodegenerative and aging-associated disorders decades later. So that’s something we spend quite a bit of time thinking about, because the scale of what we’d be seeing would be large.

DM: What role has Yale played in what you’re doing today?

VV: A huge role. I was part of the Interdepartmental Neuroscience Program (INP) at Yale, and I worked in the Department of Psychiatry at Yale. I spent five years at the Connecticut Mental Health Center (CMHC), which is just behind the Yale New Haven Hospital, and it was absolutely critical in shaping my entire career trajectory. I was surrounded by a very interesting mix of people. My mentor was Professor Ronald Duman, but I also had an additional mentor in Professor Eric Nestler. They were two young guys who had just started a shared lab at CMHC, which was a rather unique and special way of doing science. They shared resources, shared facilities, shared lab meetings, shared journal clubs, shared everything—which is so unusual to see in academia, and so wonderful because it was a rather remarkable way of bringing the best to the fore for the teams they mentored. We were in the basement of the Connecticut Mental Health Center— not a very pleasant place to spend four years. The last year we moved upward and I finally had a view. Otherwise most of my PhD was spent like a tunnel rat down in the basement. But it was very important. I had incredibly generous mentors who continued to play a mentorship role decades later. Lots of independence, lots of ability to take on ideas and fail, no boundary conditions put on what I could try. If I wanted to wander in a different direction it was totally kosher, and that was wonderful. It’s not that common in academia to allow graduate students to do as much free wandering as I had the chance to do, which I think was critical because it’s shaped the way I’ve done science afterwards. As an independent PI at TIFR, I’ve gone into exploring many different new avenues with a greater degree of confidence than perhaps I would have had if I had not been shown the importance of that sort of freedom and been given the facility to have that sort of freedom early on. It was completely okay to fail, and it was totally okay to try new and interesting things. That was something I learned very early in my graduate career, and I’ve used that as something that has fueled my independent journey: take on interesting challenges. Sometimes they will work and sometimes they will fail, but don’t hesitate to explore out of your zone of comfort. We’ve many times gone completely out of our zone of comfort with experiments—especially the findings with the mitochondria—into completely new directions which we would not have normally explored if we were more siloed or restricted in our approach.

DM: Why did you choose to return to India after Yale?

VV: I always ask this of young people when they are considering their scientific career in India. There’s science, and then there’s India. If those two are equal in your mind, if doing science and doing it in India are sort of equal, then you will handle some of the challenges of setting up in a country where the ecosystem is not yet fully flourishing or fully mature. But if science is your numero uno priority, and it’s not necessary that it be in India, then it may be pretty hard because you will run into a bunch of things you will have to do totally from scratch. And if that bothers you then you are better off doing science without the worry about a restriction on where you should be. But for me, the in-India element was very, very important. When I left as a graduate student, India didn’t have too many vertebrate neuroscience labs. There are several now that have come back over the last twenty years. Vertebrate neuroscience is beginning to thrive in the country. Someone or the other needed to start these things. It was not just me, and it was tricky in the beginning, and it gets easier as the community grows. That’s how an ecosystem grows, and it is fun to be part of that process. Sometimes there are days where you’re like, “Oh, this would be so much easier if I were already in a more mature ecosystem.” But there are also advantages to being in an ecosystem that is new. The silos are less; you talk to each other a lot more easily; you’re not in an institute that is an entire building on your campus; and you’re in a department of biology talking to mathematicians, computer scientists, and chemists with much greater ease than if you were in a space that is dedicated only to doing your kind of work. So that’s the advantage of being in a nascent ecosystem. I wanted to run my lab back home in Mumbai. I wanted to give it a shot. I expressed that very early on to my PhD advisors, and everyone was supportive. They didn’t minimize any of the challenges, but they certainly were supportive of the idea. And I look back 23 years later since I came back and I don’t regret it a bit. It’s been a fun ride.

DM: What do you think accounts for your perseverance in India? Because there are people who come back to India for two, five years and then leave if they encounter too many obstacles.

VV: I don’t think I gave myself the alternative option. It wasn’t on the table. I said, “I’m coming home, and I’m doing science back in my country, in the city in which I grew up.” It was going to be hard, and it was not going to be straightforward, but it was what I signed up for. I never spent time looking at an alternative. I just said, “This is what I’ve been given, now I’m going to make it work.” And to be fair, I’ve been given a lot. I’ve been in a remarkable institute with substantial financial support. It was the challenges of how to work things around in a system that isn’t yet mature and doesn’t yet have critical mass. But frankly, otherwise it was a very cushy landing. I think it would be hard if you went to a system that had no financial support. So that really is your privilege. Yes it was challenging, but I was carrying a ton of privilege where I was landing. So I feel like now if I complain beyond a certain extent and don’t attempt to solve those problems I’m not looking at all the advantages that I’ve been given.

DM: When we met in Mumbai, you talked about barriers to entry at places like TIFR. Can you speak to that?

VV: We look at highly selective institutions in the West, but we sometimes forget that the most highly selective institutions are actually in other countries. Something like 10,000 people take [the TIFR] entrance exam nationwide. We will eventually end up selecting somewhere from 25 to 30 from about 200 or 300 who we interview. It’s extremely steep. You’re losing people at each stage who are quite capable and incredible. They do well, I’m absolutely certain, but because you have this absurdly small number that you can accept, you realize the number of wonderfully talented people in the country who you are not going to be able to take. And that’s when you start looking at the challenges associated with your recruitment itself.

Some of your eligibility criteria are that you interview in English, that you take the exam in English. We’ve had situations in our interview committees where we’ve had first generation learners who are incredibly bright but struggle with ease of communication in English. So switching language can change the tone so much in interview settings because it brings ease of communication. And when that happens you have the full available talent emerging because language is not a barricade anymore. But that puts the onus on the interviewer to be able to, first, detect that you need to be able to switch languages, and, second, to have the facility in that language itself to ask appropriate questions. Then you realize that you yourself are not going to be able to ask questions effectively in languages which you are not totally comfortable in. But it’s so important to do this, because as you look at all of these institutions the barricades to entry are still very high. India has a large mass of very talented young kids across the country, many of whom will be first generation in university, and you don’t want to be only providing opportunities to those who already carry substantial privilege. You want to be able to tap into that large mass of amazing Indians in the country.

We do our little bit, but we don’t do enough. It’s a drop in the ocean, and I think it needs systematic addressing to look at equity in your own systems and the awareness of a lack of equity to be able to actually change how you look at recruitment itself. It’s interesting, right: [in the West] we talk about how entrance exams have ended up as a barricade to those who don’t have the ability to take training or have the support to take these multiple times because they’re expensive. In India, that’s not currently a challenge. We make sure that access to all of this is done in a manner where the financial limitations would not be a concern. But we have to look at what would be the barriers to entry. And that requires you to wear a different hat, when you try to put yourself in the situation of someone trying to enter carrying a variety of other challenges. Then for equity to happen you have to actually start saying “Where is the challenge? And what is the barricade you need to look at?” And that I think requires a focus and a systematic consideration at each step, otherwise you will not be able to do much in terms of change. And it’s much needed in all countries, certainly in India. Caste and class are two huge huge barriers which are difficult to surmount in this country, and unless there’s conscious awareness and constant awareness you will always have this problem.

Gender is a barrier and if you look at the intersectionality of it, the women who have made it are women who carry caste and class privileges. So gender is a massive barrier, there’s no question about it. The ones who have actually pushed through are often carrying other privileges that have allowed them to be able to navigate despite the gender challenge. So this becomes something to consider, the intersection of all of these: gender, caste, class. Then each of these layers make it even more and more difficult.

DM: Thank you!

Byline: Daevan Mangalmurti