BioGenesis Podcast: Avi Singer of the Keating lab on the consequences of small chemical changes
From MIT Biology and Whitehead Institute: BioGenesis is the podcast where we get to know a biologist, where they came from, and where they’re going next. In each episode, co-hosts Raleigh McElvery, Communications Coordinator at MIT Biology, and Conor Gearin, Digital and Social Media Specialist at Whitehead Institute, introduce a different student from the Department of Biology, and — as the title of the podcast suggests — explore the guest’s origin story.
Season 2 features stories of converging paths. In our second episode, we hear how graduate student Avi Singer of the Keating lab applies chemistry to biological problems, collaborating with computational biologists to explore how even small chemical changes to our body’s building blocks can have far-reaching consequences.
Avi Singer: I think I've kind of come to accept the fact that I come into lab every day and I mix a bunch of clear liquids that supposedly have molecules in them, but, you know, you can't actually see them. Being someone who does research, you’re kind of like a detective. And even if you can’t see the thing that is happening you see the effects.
Conor Gearin, cohost: Welcome to “BioGenesis,” where we get to know a biologist, where they came from, and where they’re going next. I’m Conor Gearin from Whitehead Institute—
Raleigh McElvery, cohost: And I’m Raleigh McElvery from the MIT Department of Biology—
Gearin: And together, we’re introducing you to the students behind the biology.
McElvery: This season, we’re exploring stories of converging paths. We’re talking to grad students whose research projects or paths in science combine seemingly disparate approaches.
Gearin: Today, we’ll meet Avi Singer, whose research applies chemistry to biological problems, collaborating with computational biologists to explore how even small chemical changes to our body’s building blocks can have far-reaching consequences.
Singer: Hi, my name is Avi Singer. I'm a third-year graduate student in the MIT Biology program in the Keating lab. So I'm originally from Minneapolis, Minnesota. I grew up there and I lived there until I was 14. I'm from an Orthodox Jewish family. I'm one of five children. I have two older brothers, a younger brother and a younger sister. So my mother is a first and second grade teacher at the Jewish school that I went to growing up, and my dad doesn't work. He's not in like perfect health.
I grew up going to a Jewish day school with a dual curriculum education, where you spend part of the day learning Jewish studies, studying the Bible and things like that. And the other part of a day, you know, you take regular classes: English, math, science. So my parents wanted me to continue with an education like that throughout high school. And there was no Jewish high school like that in Minneapolis. So my older brothers, myself, and my younger brother all got shipped off to what's called a Yeshiva in Chicago.
McElvery: In high school, Avi’s attitude toward studying began to change.
Singer: Well, I would definitely say that I wasn't a very good student until partway through my high school career. Like, I was one of those kids that didn't really do their homework and didn't care about school. At least up through eighth grade before I got shipped off to high school. And then my dad put the fear of God into me, saying that you better do well in high school if you want to be able to go to college [laughing].
McElvery: Avi started to get more invested in his classwork. At his high school, he continued with a dual curriculum split between religious studies and secular subjects.
Singer: I was I was studying like Talmud, which is recordings of discussions between Jewish leaders from 1500 years ago about Jewish law. I would study that for like three hours a day.
Gearin: Looking back, these classes had an unexpected benefit.
Singer: Studying those subjects kind of taught me how to think. I'll try to give an example. We spent years discussing the laws of who is responsible to pay whom and how much if your ox breaks free from its pen and it breaks someone else's pot. Now sitting here, it sounds a little silly, like this is not a scenario that's going to arise. Like, why would you spend years studying that? And I guess what I took away from it, looking back, is you would approach this scenario and try to think about it logically given a bunch of different amendments to the scenario.
Maybe if you're responsible to pay for it changes if the ox has done this multiple times and you're not doing your due diligence and locking the ox up. Different little tweaks to the scenario like that. So it taught you how to analyze information and try to think logically given the information that you have. And that's something that is definitely valuable as a scientist, even if oxen and pots are not.
Gearin: While he was learning to think logically and consider all the variables at play in the Talmud, Avi was getting excited about another subject.
Singer: The class that kind of gave me an interest in biology, though, was the AP biology class I took. And that was probably the first time where I had actually been exposed to a lot of different ideas in the life sciences. And there's a lot of material to cover in these AP classes, so I ended up teaching myself a lot of material. And that was a very valuable skill. Learning how to learn.
McElvery: Despite his budding interest in science, choosing a financially safe career was foremost in Avi’s mind.
Singer: I came from a family with one parent who was working to support the family, five kids. So, you know, I was pretty set on having a future where I would be financially stable. So I was thinking about maybe going into business.
Gearin: For college, Avi chose Brandeis University in Waltham, Massachusetts.
Singer: And then during orientation, someone gave a talk about how we should use our first semester to just explore things that we find interesting.
McElvery: He took that advice to heart, registering for intro courses in psychology, chemistry, and you guessed it, biology.
Singer: Yeah. So after my first semester and taking introductory biology and chemistry, I was pretty set on doing the whole premed track because I enjoyed it and I had done pretty well for myself.
Gearin: Setting his sights on med school, he found one way to work towards a safe financial future: working in a biology lab as a research assistant.
Singer: First of all, I needed a job because I had federal work study. Second of all, my dad pointed out that before my brother had applied to medical school, he had worked in the lab and had made his medical school application much stronger. And then third of all, I would say that in introductory biology there are a lot of questions are left kind of open ended, and that's either because the introductory course is too basic to address them, or we just actually don't know the answers to a lot of questions in biology.
McElvery: Avi emailed a number of different professors to see if he could work with them. As a preliminary screening, one lab quizzed him about frog biology.
Singer: They basically gave me like a five question quiz about frogs. And I'm pretty sure I got all the answers wrong, ’cause I know nothing about frogs.
Only one professor replied positively. Professor Timothy Street.
He was a brand new professor at that point. So I come in to talk with him. And he's in his lab and the lab is kind of dark because it was a brand new space and it wasn't fully set up yet. And he was just there washing his glassware. And we had like a nice 30-minute conversation about what it means to be in a lab, what it means to do research. And he said that if I wanted to join, he'd be open to having me, and he laid out some expectations. I think when I look back on my life up until this point, that was probably one of the most pivotal moments in my life. So I definitely, from my experiences, know how important it is to get undergrads involved in research early, and to take chances on them even if they have no prior experience.
Gearin: As a biochemistry major, Avi began to see that that there wasn’t a hard border at the convergence of biology and chemistry.
Singer: I don't really know if there are any rigid definitions for the difference between biology and biochemistry. I guess I just think of biochemistry as, you know, working with biological molecules as opposed to working with cells and organisms. When I tell people that I'm a protein biochemist, they're like, oh, proteins, those are the things on nutrition labels, but it doesn't mean much to them other than that — especially if they've never seen, you know, a picture of a protein.
McElvery: Of course, proteins aren’t just a food group. They’re complex molecules that have crucial jobs in our bodies.
Gearin: And doing their jobs is dependent on having the right shape and fitting together with other proteins in the correct way.
Singer: So when we talk about protein-protein interactions, we're talking about what are the physical effects that are causing two proteins to come together in a cell. You know, kind of like how opposite charges attract.
McElvery: The Street lab studies a protein called HSP90 —
Singer: Heat shock protein 90. And it's this really weird looking protein.
Gearin: Normally, seeing the shape of a protein helps form a hypothesis about how the protein may work.
McElvery: But for HSP90 —
Singer: just from looking at you basically don't have any sense in how it does what it does.
McElvery: It turns out that quirky shape makes HSP90 great at interacting with other proteins and helping them fold into the right shape to do their jobs.
Gearin: Timothy Street’s lab looks at how proteins like HSP90 interact with other proteins, uncovering the logic of how their structures lead to specific functions.
McElvery: Avi worked in Street lab for most of his time at Brandeis. When college was drawing to a close, he didn’t want to leave research for med school.
Singer: One of my brothers is actually a doctor, and he told me not to go to medical school. And I have another brother who got a PhD. And he told me not to go to grad school. So I was going to disappoint someone no matter what I picked [laughing]. But it was, for the most part, it was my experience doing research in the Street lab that convinced me to go to grad school.
Gearin: While he was still concerned about making a living, his perspective had changed a little.
Singer: I think I came to realize, that you spend so much of your time at work, it's really important that you enjoy what you're doing. And making money isn't your only goal. And to me, research is really enjoyable. You know it's one big giant puzzle that requires you to use your brain a lot. And I when I was looking at grad schools, I mostly applied to programs that are heavy on the biochemistry. The MIT Biology program is actually pretty different from most of the programs I applied to in that it's not a biochemistry program. It's an all-encompassing biology program. One thing I really remember about my experience interviewing at the MIT program is how great the people were here. It's not just that everyone was super friendly, but everyone seemed happy. And the grad students are a good reflection on what the program is like.
McElvery: As a first-year grad student, Avi had to decide on his next chapter in biochemistry, choosing the lab where he’d spend the next several years.
Gearin: His best experience while doing rotations was in Amy Keating’s lab. He liked the environment there, and he would get to continue studying how proteins interact.
Singer: I would say the broadest way to describe the work in the Keating lab is protein-protein interactions. And that ranges from the computational biologist who try to design protein-protein interactions to just the regular run-of-the-mill biochemists who take protein-protein interactions and try to dissect them.
McElvery: It might seem like a niche interest at first, but the mechanisms of how proteins interact can lie at the root of certain diseases.
Singer: Imagine a scenario where there is, for example, a protein-protein interaction that is really important for cancer, right? And we want to be able to prevent this protein-protein interaction as kind of a way to create a therapeutic for this cancer. So first of all, I should say that we're not very good at that. We can't really create protein-protein interactions that do what we want. And that's partially what the Keating lab is trying to do.
McElvery: Here’s what’s tricky: just knowing that two proteins bind isn’t enough. You also need to know what parts of the proteins actually interact and how they do it — especially if you want to stop an interaction that causes disease.
Singer: So imagine, if you will, a protein-protein interaction as a baseball and a baseball glove. And if you put on the glove, you have one protein and I throw the ball to you, and when you catch the ball, that's the protein-protein interaction.
McElvery: You can block that interaction by placing a different object in the glove and preventing the incoming ball from being caught — in this case, that object could be a drug that binds to prevent the disease-causing protein from making contact.
Singer: But if, you know, if I just walked up behind you and I put my hand on the glove, that could be another example of a protein-protein interaction. But you may still be able to catch the baseball.
Gearin: What he’s saying is that just because two proteins are in contact, that doesn’t mean they are connected in the way that you want. There’s more than one way to connect two proteins.
McElvery: The key to understanding these interactions is the building blocks of proteins, which are called amino acids. A long sequence of amino acids folds into a 3D shape, and that 3D shape lets the protein do its job in the cell.
Gearin: The Keating lab wants to know the amino acid sequences and 3D structures that allow proteins to bind to one another, or allow drugs to intercept those interactions.
McElvery: One of the big questions in this field is how proteins recognize their partners for binding. That’s why the Keating lab is studying protein parts called short linear motifs.
Singer: These short linear motifs are 5 to ten amino acids long, and they somehow contain enough information to seek out and bind to specific protein binding domains. Because you know the cell is basically just a soup. Or like maybe more like a stew, because it's really thick and it's filled with a bunch of different proteins. And the question basically is: How do these interactions occur? What are the important rules for these interactions will make them specific? What make them tight?
Gearin: Testing what makes short linear motifs work was Avi’s first project in the Keating lab.
McElvery: The researchers will actually use software to design new proteins, and simulate how they might interact with the real proteins. They can take out different parts of a structure to see which parts are most important to form a tight bond.
Singer: Yeah, the computational side of the lab is definitely very important. Even if you're not directly involved in it. So there's a lot of working hand-in-hand with people in the "dry lab" and the people in the wet lab.
Gearin: Avi’s one of the “wet lab” people, growing different proteins in bacteria and seeing how they interact to test the predictions from the dry lab folks.
McElvery: Having passed his qualifying exams last fall, Avi now has a new research direction and a new protein of interest.
Gearin: It’s a protein called Mena. It’s part of a group of proteins that regulates cell movement.
McElvery: When there’s a small change to the structure of Mena, adding just 19 extra amino acids, it can turn against the body and actually help cancer spread—
Singer: Which helps cells migrate from the tumor into, you know, blood vessels and the lymphatic system where they can go on and spread to other parts of the body and cause new tumors.
Gearin: Avi’s excited about the new project—
Singer: Yeah, so I think it's a really interesting research question, how such a slight change to the protein can cause such a terrible phenotype.
Gearin: But he still has a long way to go.
Singer: I'm at the very initial stages of that project. I'm, you know, building a bunch of DNA to start making the proteins that I'll be testing to begin the project.
McElvery: But he’s excited to see where merging protein biochemistry with computational techniques will take him next.
Singer: I can't imagine what it was like, you know, working in this field back before computers were as prevalent and we had all this technology available to us. My grandfather was actually a professor of biochemistry at the University of Minnesota. He died before I was born. But, you know, I've tried to go back and look at some of his papers and his notebooks. And it's just wild to imagine a time before they had what's available to us now. You know, you look at this protein structure on the computer and you can try to figure out how it does what it does. You know, look at different parts of the protein and say, if I break that will the protein and still be able to function? And that's a good way of summarizing what biochemists do. If I break this, does this still work?
McElvery: That’s all we have for today. Next time, tune in to hear how one grad student investigates how DNA is replicated in two directions at once.
Gearin: Subscribe to the podcast on Soundcloud and iTunes or find us on our websites at MIT Biology and Whitehead Institute.
McElvery: Thanks for listening.
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, “Tiny Putty” — Blue Dot Sessions, “Beignet” — Blue Dot Sessions, “Awaiting an Arrival” — Blue Dot Sessions, “Palladian” — Blue Dot Sessions, “Turning to You” — Blue Dot Sessions, “True Blue Sky” — Blue Dot Sessions, “Tarte Tatin” — Blue Dot Sessions, “Dusting” — Blue Dot Sessions, “Hundred Mile” — Blue Dot Sessions
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