Season 2, Ep. 3

Shalini Gupta: I don’t like the idea of doing science in isolation. I think it’s really important to me that I’m constantly interacting with people, but also making some sort of difference to people around me.

[“Something Elated” begins]

Raleigh McElvery: Welcome to “BioGenesis,” where we get to know a biologist, where they came from, and where they’re going next. I’m Raleigh McElvery from the MIT Department of Biology—

[“Something Elated” ends]

Conor Gearin: And I’m Conor Gearin from Whitehead Institute—

McElvery: And this season, we’re bringing you stories of converging paths — grad students who are combining diverse interests in their research and beyond.

Gearin: Today we meet Shalini Gupta, who felt she had to choose between many diverging career paths before coming to MIT and learning to blend her interests and sculpt her own grad school experience—

McElvery: Combining her two primary goals: make a difference both inside and outside the lab.

Gearin: While exploring how our cells copy their DNA, she’s also finding ways to become a leader in her community, and to mentor budding scientists.

[“Beignet Interlude” beings]

Gupta: I’m Shalini Gupta. I’m a fourth-year graduate student in biology and I’m in Steve Bell’s lab. So I grew up in Bangalore in India. I’m the oldest of three children. And I grew up on the campus of this, the place where my dad is a professor, it’s the Indian Institute of Science. So he’s a chemical engineer. It’s weird because in some ways it humanized scientists a lot because I grew up with these kids all of whose parents are professors. I didn’t have this reverence for the academia while growing up. I just thought that it’s a normal thing for people to do, to be scientists. My mom was a software engineer. And then she moved up to like managerial positions. I felt more like I wanted to be like my dad.

[“Beignet Interlude” ends]

McElvery: Shalini was drawn to chemistry at an early age, before she fully understood what was transpiring at a molecular level. She was captivated by the vibrant colors of chemical reactions and the eye-catching books her father brought home.

Gupta: I think my dad just like loved collecting these like very pretty textbooks from the campus. And I just would like flip through them. And they were so colorful.

[“Castor Wheel Pivot” begins]

So in like 9th and 10th grade, I just started like really enjoying the chemistry that I was learning at school. And then because I was putting so much time into studying chemistry because I liked that stuff, I just started getting better and better at it.

Gearin: At the public high school that she attended in Bangalore, Shalini was required to choose between 2 tracks at the end of 10th grade: She could take biology as her elective in addition to the core subjects of physics, chemistry, math, and English. Or, she could take computer science.

Gupta: I picked biology.

McElvery: When it came time to select a college, Shalini was once again faced with 2 diverging paths if she wanted to attend one of the top-tier public Indian institutions: engineering or medical school.

[“Castor Wheel Pivot” ends]

Gupta: At least back when I was starting undergrad, there were basically like two options. One was either you become an engineer or you become a doctor. I kind of wasn’t really aware that you could just do science.

Gearin: She decided to apply to the Indian Institute of Technology Kanpur, because it was one of the few public engineering institutions in India that offered biology.

Gupta: If I wanted to take courses in biology, I could actually do that.

McElvery: Everyone applying to the engineering schools had to take an entrance exam, and were then ranked based on their scores. The sheer number of applicants makes the process highly competitive. Shalini’s interest in chemistry helped her stand out. Most people taking the engineering exam ranked computer science as their top choice. Fewer opted for chemistry, and she was accepted into IIT-Kanpur.

Gupta: Not many people really wanted to do chemistry at an engineering school, but they have really good research facilities at the engineering schools because those are the best undergrad institutions. So in general, more resources, more faculty doing actual research in labs and such. And then I had some opportunities to do research outside of Kanpur in the summers.

[“Brass Buttons” begins]

Gearin: She spent one summer at the National Center for Biological Sciences in Bangalore, in the area where she grew up.

Gupta: I worked with Yamuna Krishnan. Her lab at that point was working on in vivo sensors for small molecules and they did this using RNAs that were specialized for sensing. In hindsight, I think, like, I didn’t appreciate how cool it was to be working with a female mentor. And because she was the first person I worked with, I just thought that that’s the norm. But yeah, it was it was really cool to see a woman in science and also her lab was very female heavy at the time also. And just in general, I was around a lot of female scientists, which is not very common in India.

McElvery: When she returned to IIT-Kanpur, Shalini joined a lab that specialized in computational chemistry.

[“Brass Buttons” fades out]

Gupta: This was with Professor Nishant Nair. What we were working on was quantum mechanics simulations of an enzyme.

Gearin: But her most exciting research experience yet came the next summer, when she went to the University of California San Francisco to work with Bill DeGrado and Michael Grabe.

[“Brass Buttons” fades in]

Gupta: That was the summer that just made me want to go to grad school.

Gearin: She spent the first part of the summer simulating a zinc ion transporter, and the second portion focused on crystalizing part of a prion protein.

McElvery: Prions are toxic proteins that wreak havoc with healthy proteins, leading to neurodegenerative disorders.

Gupta: And so I just like started reading about what does it mean to be a prion? Why are there these hypotheses as to how it’s toxic? And it was just like very broad literature reading. And it was all new to me. Back then, it was it was kind of eye-opening that like you don’t really have to be the, like the biggest person working in the field for the field to be accessible to you. So just the fact that the ideas have so much power and you can actually test them. So that was so nice about that summer. And Bill and Mike were the most supportive advisors ever. They wrote me really nice letters for grad school. More than the science, actually, it was personally a great experience.

[“Brass Buttons” ends]

McElvery: As her time at IIT-Kanpur drew to a close, Shalini felt torn in 2 directions once again. Should she continue to pursue chemistry, her undergraduate major, or try biology — a related field but a virtual unknown?

Gupta: I thought that maybe I would have a better chance getting into chemistry programs. I was surprised to have interviews at biology programs, but I was like, well, let’s go.

McElvery: Most of the chemistry programs she was considering didn’t include an in-person interview as part of the application process, and some didn’t permit lab rotations once the program started.

Gearin: MIT Biology had both. Shalini attended the accepted students’ weekend in March 2016.

[“Coulis Coulis” begins]

Gupta: It already started out great because a graduate student came to pick me up from the airport, which is just like, why are you taking the time out to do this for me? But it was great. And I stayed at her place that weekend because there is this option in the MIT recruitment process, you can stay at someone’s house.

Gearin: During her interviews, faculty members offered to walk her from one appointment to the next.

Gupta: And I was just like completely floored at that point. I’m like, what? Now I know that this is something MIT faculty do, but it was not the case in any other place that I visited. They actually care enough to look at you on an equal footing.

[“Coulis Coulis” ends]

McElvery: When Shalini met professor Amy Keating, though, she still had some concerns about whether a biology program was really the best fit for a chemistry major.

Gupta: Yeah, that was my concern. I think Amy really like put those concerns to rest. She was just talking to me about like how she was a physicist by training. And then she is like this person who has completely switched fields and is now a professor in a biology department. And that kind of really resonated with me.

Gearin: Shalini began at MIT in the fall of 2016. She joined Steve Bell’s lab, which investigates DNA replication — when a cell makes a duplicate copy of its genetic blueprint so it can split into two identical daughter cells.

Gupta: And this division process of cells is necessary to make more cells. So every day in your body a number of cells are dying and new cells are being created. Your blood is being replaced constantly. Your skin cells are being replaced constantly. And the way that all of this happens is that DNA is being replicated in these cells, and these cells are dividing.

McElvery: The Bell lab is working to understand what exactly gets the entire process going.

Gupta: The DNA is kind of marked as you are going to be a place where DNA replication will begin

[“The Cornice” begins]

McElvery: In eukaryotic organisms, there are two steps to replication. First, the cell marks the places where replication will begin, called origins. Then, in a later phase, the cell recruits special proteins known as the “replication machinery” to those origins, and begins copying its DNA.

Gupta: We’re interested in this fact of how are these origins decided? How is the machinery placed on those sites? And then a second part of the lab is working on how are those sites where the machinery is placed, then activated to do their function, which is to replicate.

Gearin: During his postdoc several decades ago, Shalini’s advisor, Steve Bell, discovered a complex of proteins called the Origin Recognition Complex, which is called ORC for short.

[“The Cornice” fades out]

ORC is the first piece of molecular machinery to bind to the place on the DNA where replication is about to begin.

McElvery: Shalini studies an enzyme, known as a replicative helicase, which binds after ORC does, and works ahead of the replication machinery to unwind the DNA double helix so each strand can be copied.

Gearin: And to make things trickier, the replication machinery — including the helicase — is unwinding the DNA in two opposite directions, moving outwards from the origin of replication. Picture a backpack zipper with two zipper sliders that start out next to each other, right in the middle. You have to move the sliders in two opposite directions to open the whole zipper.

McElvery: That’s basically what’s going on at the DNA origins. If one of the two DNA zipper sliders, the helicases, aren’t loaded correctly, then the DNA won’t be unzipped and it won’t get copied during replication.

[“The Cornice” fades in]

Gupta: I’m most interested in understanding how is it that helicases, which have a very specific polarity, how are they positioned such that they’re opposite to each other so that when they go on to lead the replication forks they’re moving in opposite directions.

McElvery: Even though the two helicases are moving in different directions, they start out bound to a single ORC — the protein complex that Shalini’s advisor discovered.

Gupta: The question is as to how does it coordinate the two helicases being positioned opposite to each other. And to study this I have been working on studying the interactions between that origin recognition complex and the helicase by labeling the two at the places where they interact.

Gearin: Originally, the lab thought that ORC only interacts with one helicase, and that helicase recruits the second one. But, Shalini’s work suggests something else.

Gupta: What I observed was really different than what the model that we had going in. So the model was that ORC and the first helicase remain interacting. But what I saw is that that interaction is short. It ends. And then when the second helicase arrives on the DNA, ORC also interacts with that helicase. So instead of this picture where ORC just remains interacting with one helicase the whole time as the second one arrives on the DNA, ORC is interacting with both the first and the second helicase. So through a lot of experiments, I’ve shown that it’s only one ORC molecule that’s doing this. So it’s kind of some kind of crazy flipping of ORC happening on the DNA.

McElvery: ORC has to load one helicase and then flip around to recruit the second one.

[“The Cornice” endss]

Parsing out the details of this molecular ballet is the current focus of Shalini’s PhD research.

Gearin: But, Shalini is gleaning more from grad school than intricate knowledge of how cells copy their DNA.

Gupta: It’s also a little bit about growing up, I guess that you’re while you’re younger and your whole world is centered around you somewhat and you’re like, oh, I’m getting into grad school, I’m so great like all of that. But then you come here and then you realize it’s not just about you. You’re like in a team of people and you it’s kind of on you also to help them and for them if you expect them to help you also.

McElvery: She began to realize that research careers doesn’t always follow a clear-cut path: there are more possibilities than a linear trajectory from undergrad, to PhD, to postdoc, to faculty position.

Gupta: I thought that like the life that that would give me is basically the life that my dad has, for example, just like the academic life. But when I came to grad school I think that’s when I really realized how many options exist.

Gearin: Testing out those options required stepping outside the lab.

[“A Palace of Cedar” begins]

McElvery: MIT Biology grad students are required to serve as teaching assistants in at least two classes. The first time Shalini TA’d was the fall of 2017, teaching biochemistry to fellow grad students.

Gupta: Since then, I like I kind of started seeking out teaching opportunities. Then I did this high school program, it was called the Innovation League. I was teaching high schoolers at the Cambridge Rindge and Latin School. That was a really fun experience because it was a very different set of people there, much younger, much more willing to question like the very basics. Like you’re teaching them about DNA for the first time. It’s so cool to be the person to tell someone A pairs with T and G pairs with C.

Gearin: Shalini has also served as the president of the Biology Graduate Student Council, which aims to improve the quality of life for grad students, facilitate professional development, and promote a strong sense of community. The BGSC also acts as a liaison between the Biology department and the larger Graduate Student Council.

Gupta:  I think that there should be something we all do to make something different around us because it’s really easy to sit back and say nothing changes with time. With BGSC I really appreciated the fact that we got to talk to the graduate community and represent graduate student issues to the graduate committee, which was something that I didn’t know that graduate students could do until I was in that position where I’m the person who is reporting to the graduate committee. And like the fact that you’re here to do research doesn’t mean you can’t do anything else. Graduate school is 100 percent what you make of it.

[“A Palace of Cedar” ends]

Gearin: That’s all we have for today. Next time, tune in to hear about an MD-PhD student who studies how cells tie together nutrient sensing and their metabolism.

[“Something Elated” fades in]

McElvery: Subscribe to the podcast on Soundcloud and iTunes or find us on our websites at MIT Biology and Whitehead Institute.

Gearin: Thanks for listening.

[“Something Elated” fades out]

Produced by Raleigh McElvery and Conor Gearin.

Music for this episode came from the Free Music Archive and Blue Dot Sessions at www.sessions.blue. In order of appearance:

• “Something Elated” — Broke for Free
• “Beignet Interlude” — Blue Dot Sessions
• “Castor Wheel Pivot” — Blue Dot Sessions
• “Brass Buttons— Blue Dot Sessions
• “Coulis Coulis” — Blue Dot Sessions
• “A Palace of Cedar” — Blue Dot Sessions