A Charizard in the hippocampus! Studying synaptic plasticity and bridging science with industry.
Sadhna recently published a paper titled ‘Tiam1 is Critical for Glutamatergic Synapse Structure and Function in the Hippocampus’ in the Journal of Neuroscience. You can read the article here.
Tell us a bit about your research journey. How did you come to be studying synapses in your PhD program at USC?
I’ve had a sort of circuitous path to graduate school. I’m wondering if when people read this, they’ll maybe relate. Lots of folks out there do undergraduate [study], maybe they do a summer internship, and then they apply to graduate school, or something like that. But I have taken all the years between 21 and 26 to sort of carve my way. I’m from India, down in South India. Where I was living, I didn’t really know anything about graduate school, or research as a career, or even how to begin the path to become a scientist. I was actually in engineering school and a complete misfit! I didn’t want to do it. I was sort of second-guessing. I mean, you’re 19 and you don’t really know why you’re doing anything! (laughs)
I got really lucky. A friend persuaded me to apply for a fellowship that would let me work in a lab for a summer. They actually paid for me to live in a different city, which was really important as it would have been a financial burden on my family to send me somewhere else. I worked in a fly lab. I crossed flies and learned about Hox genes. After what I had learned in high school (and I think a lot of people have this experience), I thought, “Ummm excuse me!… that was awful!” (laughs) “…and this is cool!”.
I remember distinctly this moment. The research institute had a really small library, but they had good, expensive books from the US and from other places. I remember seeing a fly body plan picture, and it just blew my mind. There is so much engineering there. I thought, “Wow, I didn’t know this existed.” I was learning phylum and classifying animal species in high school. It was terribly boring. So, I finished the fellowship, and decided on this idea on having this career in science. I was lucky enough to get into a graduate program that paid for my masters.
I was drawn to developmental neuroscience… I think sort of on instinct. I wasn’t really thinking about all of the [other] disciplines. The lab was studying chicks and mice and using them as models to understand how astrocytes play a role in brain and eye development. So that’s what I did my master’s thesis on. Ultimately I didn’t really like developmental biology as much, I guess. It’s very interesting and fun to learn about, but the actual ‘doing’ of the work was not quantitative enough for me. So, I thought, “OK, I need something where there are numbers and measurements that feel more objective.”
I then worked with Emily Liman at USC. She’s a renowned scientist who studies taste cells and ion channel physiology. She played a really big role in making me a more rigorous scientist. Then, I heard of Bruce Herring’s work. He had just started a lab at USC the year after I had been there. He was studying synapses and it was very quantitative, and I had always wanted to learn physiology. I thought, “Wow. You are plugged in. You are literally recording from the neuron.” There is very little room for error there. I was super excited to get the opportunity to work in his lab. Which is how I got here!
I really like that story. We think that most people take the straight and narrow path to where we are in research at the moment, but the more people I talk to, the more I realize how everyone has quite a unique journey to get to the PhD or the postdoc! It’s often something like that – seeing the engineering of a fly – that sticks in your mind as the moment you realize “this is what I want to do.”
So, you’ve already answered my next question, ‘what made you decide to change your research focus from neurodevelopment to neuroscience?’ It was because you wanted to take a really quantitative look at synapses. Was there anything else more to that? Do you think your previous experience in neurodevelopment gives you an edge coming into this synaptic work?
A lot of things come to mind. I felt guilty. Even ashamed about this, at various points in the last decade or so. I don’t really have a permanent allegiance to a specific subject area or disease where that is all that I study. I’ve noticed that part of the culture in academia, there is almost a requirement that you be very passionate about the one solitary thing, and you stand by it. That’s how it gets talked about sometimes. I understand the instinct to do that, and that it’s part of the culture, but I have just never been like that.
I found it very easy to go, “I don’t want to do that anymore”. I mean, it was fun while I did it, and it has informed how I think, and I wouldn’t have it another way. But even physiology, I may very well move onto something else and explore a different realm of science if and when I do a postdoc after I graduate. I think there is a lot to be said for absorbing information from other disciplines and speaking to folks in other disciplines.
I don’t know about you, but I miss being part of a journal club, five or six years ago, where any paper goes? I love those! It’s kind of great to see how you can really easily read something in a completely different discipline.
I identify with your answer a lot! I did my PhD in the inner ear and now I’m working in the striatum! So… it was a complete change up…. especially because the inner ear is a very tight knit community. When I left, people were like, “gasp! You’re leaving ‘the field?”. I felt like saying to them, I’m still here, I’m still in neuroscience, I’m still doing patch clamping. It’s basically the same job, but I’m just studying different synapses. On the other hand, by staying in a discipline, you develop networks and this unmatched level of expertise. You can always come up with more questions. If you’re open to reading papers outside your area, you’re going to be more creative with the experiments you run.
I guess we can get to the paper now! What were some of the major findings in your recently published paper in Journal of Neuroscience?
I’ll start with the overarching theme, because it helps to frame the findings better. The community of scientists that study the hippocampus, we are also very tight knit, like what you were saying about the inner ear community. There is a kind of go-to method to determine whether a molecule is important for synapse function, and that is to deplete the protein using RNAi or another method (e.g. CRISPR) in CA1 pyramidal neurons, which are in one of the three subregions in the hippocampus. They are very large, and they are ‘easiest’ to patch. If you see an effect, for example, a reduction in synaptic transmission in CA1 neurons where you depleted the protein relative to a control neuron (we use a dual patch clamp method, so we are always recording from pairs), then you think, “Yes. This protein may very well be important for synaptic transmission” and you can follow up.
When I first joined the lab, I was just curious about this and I went through and looked at all of the RhoGEFs - a class of molecules that are part of the actin polymerization pathway, they are immediately upstream from a molecule that polymerizes monomeric actin to polymeric actin. Why is that important for synapses? Well, you need actin to fill up the spines, which are the postsynaptic end of a synapse. These protrusions are what connect with the presynaptic side. So, we are studying that class of molecules. When I joined the lab I thought, “why don’t we just look and see what’s happening in the other subregions of the hippocampus?” I made a list of the 12 or so GEFs that are expressed in the hippocampus and found that a number of them were expressed in DG and not CA1. DG is the dentate gyrus, which is a very different and very distinct region in the hippocampus – it is structurally different and functionally different. This molecule, Tiam1, one of these RhoGEFs, is expressed exclusively in DG, and if we had just looked in CA1 - which is the gold standard method in our field to determine if a protein is important for synapse function - we would have found that it is not important. Thank goodness we looked, because this molecule is only expressed in DG and it is important for synapse maturation in DG granule neurons but has no role to play in CA1 neurons! We are now thinking there are other molecules like this, that there may be very distinct molecular pathways for synapse maturation and synapse function in CA1 and DG, as far as being different hippocampal regions. If you are treating a disease that plays primarily a role in the dentate gyrus or screening synaptic regulators as disease risk-genes, that’s something to consider.
That’s super cool. I just love that. The hippocampus is such an interesting place to study, and as you say we have these ‘classical’ approaches. You were willing to step outside of that, because you had the curiosity to look, and you have found this completely new mechanism!
What is it like to study and work within the hippocampus, which is such a ‘competitive’ brain area?
It is. I have a specific experience that can speak to this sub-area. There is a small group of people that are interested in questions at the intersection of synaptic molecules, neurodegenerative diseases, and the hippocampus, like our lab does. So, I was at home, it was maybe 9 or 9:30 PM. I want to say that it was towards the end of my second year, and my boss sends me an email saying, “we need to move on this project, ASAP”. I mean, I had already collected a lot of data but, wow! That sent my blood pressure sky-rocketing all of a sudden. We had just found out that another lab was working on the same molecule. We spent the next year expediting our work. We submitted quite quickly and were reviewed and rejected, and that was fortunate, because we then worked on the items listed in the review and sort of fleshed out the paper a little more. We submitted a year later and were fortunate that J Neurosci were willing to take a second look at it. It was an important finding, just very premature when we first submitted! It’s very competitive, and there is that fear of being scooped. I’m sure every graduate student and postdoc knows what that is like.
I think people imagine journalists being scooped all the time but I don’t know that they necessarily think about us competing for the science scoop. It’s a very real and a very anxiety-inducing thing, when you know someone else is working on the exact same thing at the exact same time.
I do appreciate my PI (principal investigator). It is impossible to run a lab for years and to separate yourself from that anxiety. We worked closely and I’m very grateful that I have a PI who wanted to work to make it happen for us.
Do you have a fun science fact that you’d like to share with us?
I mean, the GWIS readers probably know this already, but I was on a road trip with my boyfriend. We were looking at the road ahead of us. I’m not sure he knew what a mirage was really. That is what is cool about the sciences - you can expand that moment! I said to him, “You don’t know what this is? Let me share with you.” Mirages are pretty cool, for those of you who don’t know. It is only happening because light is being made to bend in a very precise way that is resulting from this very, very hot day that you are experiencing. You have a stratification of air, so if you have a large column, maybe a hundred yards wide and a hundred yards long, it is very, very thin at the bottom. There is a density gradient of air. It forces light that is otherwise just hitting the ground and scattering, to focus and bend towards your eyes. So it hits the ground, bounces off and hits your eyes at an angle that makes it so that you’re really looking at a reflection of the sky on the ground. So you really think it’s water, when you are lost in the desert. I think that’s pretty cool, although I suspect I lost him about halfway through my explanation!
That is awesome.
What are some of your tips for staying motivated as a research scientist, especially in the current climate?
It’s tough right now. I’m saying no to a lot of things. I can speak to parts of the audience, this is a newsletter that is read by women in science, so we already know that it’s very different for us, even at the outset, even outside of these circumstances, in a field that is mostly male-dominated. If I had to offer one piece of advice, or something that I’m working on right now, it is to say no to things that don’t work for you. Say: “no, I can’t do that right now. Let’s talk about maybe when we can resume that in the future, or another way that we can do it.” That was a hard-won lesson for me in graduate school.
Another thing would be to really reach out and find role models, people that you can actually identify with. I’m still struggling with this, so if anyone has any advice for me please let me know. A lot of the time, when I have felt a struggle, it’s because I just can’t picture myself being successful. I’m sort of in a moment where I don’t see anyone else that looks like me or that has come from my circumstances that has made it there. Reassurances from people, while they are very nice… there is a difference between a lived experience versus someone that is sympathizing with you and wants you to do well. I think reaching out and finding those people that are powerful role models for you and also creating visibility for yourself, which is part of that.
So… saying no to things. Recognizing your powerlessness and still saying no to things, finding your power and reaching out to people, and making yourself visible. Setting boundaries and finding your power are an inside job.
Definitely. That’s why I really like being part of something like GWIS, because it provides a bit of a meeting place for both junior and established scientists who have taken many different paths to get to their position.
You mentioned that in your free time you work with a non-profit networking company, Biotech Connection L.A. Can you tell us a bit about what you do there and whether you think basic scientists should be networking and partnering more with industry?
I’ll answer the second part first, which is yes, absolutely! I want to say about two years ago, it was slowly dawning on me. I wonder if other graduate students and postdocs have a desire to move in a direction that is outside of their advisors’ experience. Our PIs either are or have been tenure-track, and that’s what they wanted to do, and it’s worked out for them which is great. Then, you mention something about an industry job or consulting and they’re like, “whoa? you want to give up science?!” It hits a panic button. Not to say that they aren’t supportive, there are plenty of PIs that I have met that say “I have had so many students go to industry” and they are proud of it. I realized, for many, that’s just outside their experience and that’s not where to go for help. So, you go to other places, and I highly encourage that if you have any way to build that resource to go and do that. I have been working as the lead for the outreach wing of our organization. I’m very new, I started in December last year. I was just this week in fact, asked to interview for the Vice President role!
Oh wow, congratulations! That’s so exciting.
Thank you. I’m excited and I’m even more excited about the fact that it was the same day Kamala Harris announced her potential Vice Presidency!
I was like “Hello Kamala, do you know?! I might be VP like you!”
(Laughs) Yes! Yes to the VPs!
I’m pretty excited. I like the experience of working with other people on the same thing, I realized. Maybe even more than in my graduate career of working more individually on something that I care about. I wonder if other people sort of have that yearning, and that experience?
It’s certainly something I have no experience with. I know a lot of neuroscientists in general just have no idea, and as you say it’s a bit of a ‘panic button’ moment. As soon as someone from industry comes in, we panic because we are in foreign territory. We often don’t know the language, or how to relate to people in industry. When actually, we have a lot of shared experiences and similar goals long term with people in industry. Too often, we have this weird attitude towards people graduating from a PhD and going into industry, as if it’s some kind of compromise, when it’s really not. It’s an issue with academia. We need to blend those borders a little more, even just to do better science?!
Yes, I agree! I mean, how old do you think the academic institutions are? The thesis, the graduate student, the professor… I mean hundreds. I was even thinking of how when you do your dissertation, or you do your meetings. It struck me all of a sudden, we do the presentation, then they maybe give us a little feedback, but then they send you out of the room to discuss you when you’re not there. I always thought… I would like to hear the feedback. It’s so archaic! You send me out, then you give me a yes or no, like a verdict. (laughs) It’s a holdover from a very long time ago. I think all of that comes from a long time ago, maybe a little evolution is overdue?
Whereas now, to be a successful scientist at a certain level, you really have to have these partnerships. You have to be able to speak with medical doctors and with people in industry, it has to be a skill.
I do follow some people on Twitter that have done that. They have built start-ups, and how cool! I’ve seen in synthetic biology and I’ve seen it in neuroscience too, start-ups that have come out of academia. In fact, Boston, one could argue, there are academic institutions making very strong connections within itself and with industry. They grew the biotech hub there from a few old-school academic institutions to a thriving billion-dollar hub.
Why do you think the US is such a highly regarded place to train as a young scientist? Maybe this is something that we think about more, coming from outside the US. It’s something that I think about a lot, why did I feel drawn to come here? Do you think that’s something that will persist, that it will always be “we have to go to the US to get the best training”?
Can I just say that I have developed more than a little bit of admiration for you, in the way that you have raised these questions, that you’re so thoughtful. That question is so timely, and I love that you’re asking that, because I could not think of another place to go. I think Germany crossed my mind. I remember conversing with some PIs there. But at least when I came here, there was a healthy acceptance of ‘foreign’ human resources. I felt like it was an exchange that was profitable for both parties, and more than just a transaction. It felt exciting, because academia is a community that’s trying to uncover the unknown and there’s not many places in the world where it is happening at this scale. It’s cool. That’s why we are all in science, you know? I get chills! More recently, I have personally experienced a week in July where I had the hardest time getting myself to work and back. I felt so unwanted. It was the F1 student visa ban. It sort of got me on Twitter, I had some rage tweets that I feel like I probably need to go back and delete now (laughs). So upsetting! It was harder to persist in my dream of keeping this going, and to head in more meaningful directions with my career. We could all be working together. I feel hopeful that we will still be able to do that. I did have a brief moment where I was plotting an escape to Canada! (laughs)
We will find a postdoc in Canada, we will free ourselves from this! (laughs). I don’t know. I think it is still a highly regarded place, and I am grateful for everything that I’ve been able to learn here. It’s invaluable the training that I have. I would not have gotten that in India. I hope that I get to give back and to keep learning. We will see!
Yeah, it has not been easy for people on visas the last couple of months. I mean, when I go to work, I work in a really diverse lab, and a lot of us are on visas. That’s part of what I love about going to work every day. We are all coming from different places and we’re working together, we’re all highly motivated, and that is what makes the science here so strong. When that is threatened, it’s kind of like they are saying about your very existence and your happiness, “Oh , so we can take this away from you at any time, and with very little notice”.
It’s an existential threat. I have experienced it at a low grade for this whole four-year period, and it’s just been dialled up a little bit, especially now.
Even with all of this going on, it’s still an incredible place to be for science. It’s so interesting to talk about all of the reasons why that is, but I just don’t think that we can find what we get here anywhere else at the moment.
No! Have you heard of the phrase, ‘economies of scale’? I’ve been thinking about this a lot, and I’ve been in some business classes at night. It’s sort of a virtuous cycle. The idea essentially being that you have something that is unique, and then something that amplifies and motivates the production. For example, a company that is making stents, only it’s a very innovative design, so that’s the unique part, and then you have really great marketing and distribution, so a lot of people hear about it. You get a lot of the market share, your profit margins go up, and you have R&D. You have momentum going. I think that already happened here. you have the virtuous cycle in academia and the economies of scale dictate that we are part of it.
That might collapse. If you kicked out all of the F-1s, J-1s and H1-Bs.
Where are all the papers gonna’ come from? How will this work? (laughs)
This is a big question, and it’s specifically related to the mission of GWIS. How do you hope to see the scientific landscape change for women in the future?
That’s a hard one. I’m trying to think of my experiences and where it has been especially challenging. I think I can speak a little more to being a female immigrant, than just being female. My experience has been equally hard because I’m not from here.
I’m thinking of the default decision. This happens quite a bit in group decision making. Both with the students, as well as with the faculty. Picking a new PI in a department or picking a [representative] for the graduate student association. We are actually very lucky here - there are actually more female than male graduate students! But we have far more white male PIs than of any other race or sex. So, I might be completely missing the mark here, but it feels like the collective comfort may lie in electing someone that is white and male.
My general experience is that academia as a culture is already set up to allow white men to thrive, and great. I don’t want white men to not thrive. I just have found it difficult to find my voice. A lot of the gatherings that happen around SfN, for us as a community, predominantly were male PIs hanging out and getting to know each other. I have the sort of personality where I might just go butt in, like “I will join you, you can reject me later”. It’s harder on a day when I’m not feeling as brave.
I think there is a lot of systemic change that needs to happen. It’s not just saying it or being on Twitter and saying it. We are having this conversation which is great, but I think the decisions really need to flow from top down. Even just hearing about successful moments for my boss have been bittersweet, where I hear about how it happened and I wonder if that would happen for me, because sometimes it sounds like a back-slapping boys’ club moment where they made a deal. I don’t know if there is a back-slapping man/woman moment where I would get a deal like that! I don’t know. My interactions have not been like that - nor have they been all singularly bad and terrible. But it does make me feel more discouraged when I hear that. I don’t think I’d be drinking beers with someone on the beach and we’d have a cool collaboration that came out of it. Maybe I would!? I don’t know.
The resistance is there. Like there are less channels and it’s a little tougher to proceed for us.
Yeah, a lot of connections that I see happening are from when they were postdocs. I’m looking forward to that next phase too, to see how that opens up for me. It is part of my inclination to maybe not stay in academia because it is mostly white and male faculty members. I’m female, I’m brown, and I am an immigrant, so I don’t necessarily see myself making a reasonable choice and being in a faculty position in a very red state or red city. I sometimes wonder. Maybe I should think about that more, but there is definitely a healthy and oftentimes very justified fear of not putting myself in those places. I have lived in a red state and lived in a city that wasn’t inclusive like L.A. So that’s the female piece and the immigrant piece.
There’s that whole intersection of things that leads you to second guess things that you ultimately really want for yourself, which I think really needs to change.
While I’m often looking for things to grasp at and to help myself move forward, I have had conversations with other graduate students that are younger, and perhaps somewhere in that intersection. I notice how our experiences are mirrored. There is a kind of beauty in that. As much as it is frustrating sometimes, like, “I have been in this scenario”, I definitely feel a sense of community in that there is a collective and we are moving in the right direction.
Following on from that, what would you say to a young person thinking about following in your footsteps to become a neuroscientist?
I’ve noticed this, because I have struggled with this myself. Picking someone to work with. I’m grateful that I had the insight and the wisdom with my graduate program to make a decision that was based on the working relationship between you and the PI. I have found that it can be confusing when you’re picking a lab and you think you should pick a subject that you really love. I have seen how things have transpired in the last 5 years or so, you can love something very dearly but if the person you are working with is not someone you can work with, that’s just not going to work out. So yeah, I’m grateful that I was flexible on the subject area, and more interested in someone that was willing to work with you and perhaps even change themselves a little along the way. My PI is very young and had just started his lab. I’ve noticed with [more established] PIs, they have found a way that works for them, and if it’s not a fit for you then just go and find someone else to work with. That will make your life better.
One other thing I might say is: learn to trust your own instincts and judgement over time. It will not come at first, and you might rely on your PI. With any industry or any job that you might have, you don’t know a lot in the beginning, so you have a surrogate instinct and that’s the person that you’re learning from. But they don’t know everything, and they can be wrong. In fact, they are wrong a lot of the time! So learning to step up. I mean, you are a postdoc now, so you are a more evolved Pokémon than I (laughs). So you have probably learned this a while ago. You’re a Charizard, and I’m like a Charmander. I realized that I need to step up and let you know when I disagree with you. Not even all PIs are comfortable with being challenged. Defer the discussion. That’s something I’ve learned. If it’s not going well right now, pick another Tuesday to have that conversation (laughs). If it’s not going well, just move it to another day.
I think that is fantastic advice. Honestly, I couldn’t give better advice to somebody coming into this than to trust your instincts and to pick a good environment. So important. As a postdoc, you do find yourself stepping up a little bit more. For example, when I know that I’m not being encouraged to pursue something, but I think there’s something there… in the past I would have dropped it, but now I think “I’ll just analyze the data and show them, and then see what they say”!
Nothing better to end a disagreement than a bar plot or a graph!! (laughs)
(laughs) Instead of a mic drop, it’s a data drop!
Is there anything else you would like to add?
I want to thank you first. Personally, I love that this is happening. I have gone many days and months feeling a bit disconnected from the neuroscience community, or from other immigrants, or other women. The whole breadth of people out there who have similar experiences. But this is helping me also, I think, stay connected to my story and where it fits in our community and within a larger landscape, so thank you. I came into this with gratitude and now I feel even more grateful now that we have done this.
I also want to thank my boss. We have been working together for five years now and I have had experiences working in science that have been unpleasant, and the power structure is so severely stacked against an incoming technician or student, even perhaps a postdoc. My professional experiences here have felt like my voice has been heard, so I’m really grateful to him for that. We have had a really good working relationship, and we have put out a paper in record time!
I have a whole community of friends and extended supporters here in LA that I’ve met and that have encouraged me. I love non-scientist friends, because they just think you’re the coolest! I love that support. It has kept me going.