Season 4, Ep. 4

Keene Abbott: Well it’s super important to have research ongoing in fundamental biology, because it leads to a lot of discoveries you’re not necessarily looking for.

[“Something Elated” begins]

Eva Frederick: Welcome to BioGenesis, the podcast from MIT Biology and Whitehead Institute where we get to know a biologist, where they came from, and where they’re going next. I’m Eva Frederick from Whitehead Institute—

[“Something Elated” fades out]

Raleigh McElvery: And I’m Raleigh McElvery from the MIT Department of Biology. In this season, we’ve met researchers whose fundamental biology research could have an impact on society down the line.

Frederick: For our final episode of the season, we’re talking with Keene Abbott. He’s a cancer researcher, but the way he goes about it might feel counterintuitive at first glance. In order to find new ways to fight the disease, Keene studies what makes cancer cells feel more at home in the lab.

McElvery: This might mean tailoring the medium they grow in, or figuring out what exactly they need to thrive in different environments — which can then be used against them in therapies.

Frederick: By creating more life-like systems for studying cancer cells, Keene is paving the way for research to translate more smoothly from the bench to the bedside.

[“Hardsider” begins]

Abbott:My name is Keene Abbott. I’m a fifth year Ph.D. student in Professor Matthew Vander Heiden’s lab at the Koch Institute and in the Department of Biology at MIT.

McElvery: Keene’s parents are both from Texas, and he spent much of his childhood in Dallas before moving to Chico, California when he was 11.

Abbott:My father is a mechanical engineer and my mother is a garden teacher and educator. I take a lot from my father in that he’s very rational and detail-oriented. And I think I take some aspects of that in shaping the work that I do. And then my mother is one of the most empathetic and compassionate people I know. My mom just cares very deeply for everyone around her and wants to do her best to help other people. I guess I would say I’ve also taken some of those principles for myself with the goal of trying to help others through my work.

[“Hardsider” fades out]

Frederick: Keene first became interested in science through reading science fiction books as a child.

Abbott: I would say that science fiction let me down the path to where I was more interested in the great unknown, that being space.

Raleigh: He was so fascinated with the mysteries of the cosmos that he decided to major in astrophysics during college.

Abbott: Since I was more interested in astrophysics, that’s basically how I selected the schools that I applied to. And of those that I was accepted to, UC Santa Cruz is pretty well-known for its astrophysics program.

Frederick: The culture of the school felt like the right fit for Keene as well.

Abbott: The students are very chill and relaxed. I felt like I fit in a little more with that, where I’d still devote a lot of time to studies, but it wasn’t because I felt super pressured to — it was because I wanted to.

[“Vegimaine” begins]

McElvery: When he arrived at UC Santa Cruz, Keene began taking astrophysics classes. But he branched out into a different field almost immediately, when he found a position working in the environmental studies department as a research assistant in the lab of Carol Shennan.

Frederick: Her lab studies alternatives to a toxic fertilizer called methyl bromide used by strawberry farmers in California.

Abbott: This chemical is toxic both to the environment as well as people. And so the purpose of all of the research that I associated with was to develop this alternative method called anaerobic soil disinfestation. As a result of working on this project, I thought it was really interesting to learn more about biology and chemistry. And also I saw that I was having a more direct impact on both the environment and other people. And I really enjoyed that aspect of that research. And so basically, soon after starting up that position, I decided that I want to switch majors to biology.

Frederick: His next venture into research was in the lab of Fitnat Yildiz. Yildiz and her group study the pathogenic bacteria Vibrio cholera, which, predictably, causes cholera.

Abbott: The purpose of my research there was to basically understand how Vibrio cholera transitions from forming these like plaques called biofilms. It’s when the bacteria aggregate to get her. They’re observed to be in this state in more aquatic environments. But when you ingest these bacteria, they will transition from a biofilm state to a more motile state. This motility allows the bacteria to more successfully colonize your gut. I found one gene that was basically completely uncharacterized that, when deleted, increases the motility of Vibrio cholera by over 100 percent. And I thought it was super interesting. It was just going on to show that there’s so much about biology we just don’t understand, even within this one bacterium.

[“Vegimaine” fades out]

McElvery: Based on these research experiences, Keene knew he wanted to pursue a career in biology. But he wasn’t quite sure what that meant just yet.

Abbott: Grad school definitely crossed my mind, but I didn’t have a ton of solo research experience at the time and I wanted to gain some more experience, solidify my interest in science and research. I also wanted to try working on mammalian cells and like cancer biology as well. So I just wanted to try something different and make sure I liked it before I committed.

Frederick: So instead of going straight to grad school, Keene found a job at Stanford, working in a research lab that studies cancer in mammalian cells.

Abbott: I picked cancer biology, because cancer is a common disease. Almost everyone knows someone who is afflicted with cancer at some point. And even though there’s a ton of research going on in the cancer biology field, there’s still so much we don’t know and there are no great treatments at the moment.

McElvery: Much of his work there focused on a protein called KRAS, which would theoretically be an excellent target for cancer drugs. But finding drugs that can actually inhibit this protein has been a long-term challenge.

Abbott: One of my projects was basically, looking at what other proteins interacted with KRAS, what proteins like bound to KRAS. So finding proteins that bound and then validating those interactions and trying to understand how this new protein binds to KRAS, how does this lead to cancer?

McElvery: He also juggled several other projects — a theme that would continue in his graduate work.

Frederick: Keene spent nearly three years working at Stanford before deciding to apply to graduate school.

Abbott: A lot of people take two years off, and within the first year they then decide to apply for grad school. I was just loving working in the lab so much that I waited until two years in the lab to actually apply to grad school. It was also more when I felt ready, when I felt like I had learned a lot of new techniques and how to be a better scientist. And I was also very sure that I wanted to go on to a career in science. And also I really wanted to have my own project that I pushed forward as a grad student.

During my application process, I applied to a lot of schools. I basically only applied to schools on the West Coast and the East Coast. There were too many good places. I could have imagined myself at any of these schools, really. But I needed some way of narrowing it down. So my first way of narrowing down my school was just saying, “OK, I want to live somewhere else other than the West Coast,” because I’ve lived there for many years.

McElvery: Of the East Coast schools he applied to, Keene determined that MIT was the best fit; he liked the small program size, and was interested in the cancer research going on in the biology department.

[“Talltell” begins]

Frederick: His first year, he rotated in three cancer research labs, the last of which was run by professor Matthew Vander Heiden. It was this lab that he chose to stay in for his PhD — even though the lab’s primary research focus, metabolism, was outside his comfort zone.

Abbott: I decided to work in professor Vander Heiden’s lab because the science excited me. I also really felt at home in the lab as well, like the people there were extremely friendly, collaborative, nice. And it felt like a great place to spend many years of my life working on finding answers to exciting biology questions.

McElvery: The Vander Heiden lab studies the metabolic traits of cancer cells, and how these characteristics contribute to their uncontrolled growth.

Abbott: Metabolism is the sum of all the reactions in a cell that allow it to grow. A cancer cell differs from a normal cell whenever the cancer cell undergoes uncontrolled proliferation. A cancer cell doesn’t have the brakes that are put in place to prevent normal cells from proliferating too much. So the goal of a lot of cancer biology labs is to develop therapeutics that can target cancer cells specifically over non-cancer cells. And so you want to take advantage of differences between cancer and non-cancer cells. There are a lot of drugs that target metabolic pathways.

Frederick: Many of these drugs kill cancer cells or stop them from growing in vitro, meaning in a test tube or culture dish — anywhere outside of a living organism.

Abbott: But a lot of them, when we try to treat tumors in a mouse, for example, they don’t work anymore. And so a big question is why do these compounds not work anymore?

[“Talltell” fades out]

McElvery: This question led to Keene’s primary project: studying how drugs work differently in traditional lab conditions versus a more physiologically relevant medium.

Abbott: There are many things that are different in terms of how cancer cells are growing in vitro on a dish versus how they grow in an animal.

Frederick: These might include oxygen or other chemical levels, the structure of the tissue, or the other cell types that may or may not be present nearby. Because of the Vander Heiden Lab’s focus on metabolism, Keene’s research zeroed in on the levels of nutrients available to the cells.

Abbott: Back in the 1960s, scientists figured out how to grow cells in media that was basically just formulated with the sole purpose of growing cells. It wasn’t meant to reflect what cancer cells actually see, what the nutrient levels are in vivo. So this is all well and great, and we can grow cells in this culture medium. But the problem is levels of nutrients, and the types of nutrients that a cancer cell sees, can affect its metabolic pathways.

[“Borough” begins]

Frederick: Alex Muir, a postdoc in the Vander Heiden lab, had previously discovered that nutrient levels in media affected the efficacy of a cancer drug called CB839. The drug worked to kill cancer cells in standard lab conditions, but when he tried it in a more physiologically relevant medium—

Abbott: Called adult bovine serum, so basically serum from a cow—

Frederick: The cancer cells were unfazed.

Abbott: One of my projects was basically, can we find other drugs that show differences in efficacy, depending on what culture medium we grow the cells in? So one goal is, can we find drugs that either kill cells in standard media, but they’re protected in physiological culture media, or the opposite? Can we find drugs that kill cancer cells more effectively in the more physiological medium? And maybe that don’t work as well in the standard media? And maybe if those compounds that work better in the medium with physiological nutrient levels, they might be predicted to work better in vivo as well.

McElvery: Keene has also worked on creating his own media that is tailored to a specific cancer: leukemia.

Abbott: Leukemia cells will circulate throughout the blood. They mainly proliferate in the bone marrow. We basically determined the levels of metabolites and plasma from mice and made media that reflected these metabolite levels. And we were able to grow our leukemia cells in this media. And since then we’ve been able to basically test a bunch of genes to see if you knock out certain genes, does it affect cells’ ability to grow in standard versus this plasma like media?

Frederick: Like many grad students, though, Keene doesn’t just have one project.

[“Borough” fades out]

Abbott: I think it’s very common to have two projects concurrently because with research, you never know if something is really going to work out. We have our best guess that maybe a project will succeed, but you really don’t know.

[“Tapoco Critter” begins]

Another project that I’m working on also has to do with how nutrient levels affect cancer cell metabolism and our cells’ ability to grow in different tissues.

McElvery: The project focuses specifically on breast cancer, which can easily spread to other parts of the body.

Abbott: Breast cancer commonly metastasizes to the brain. And when in the brain, it’s very hard to treat this disease. You can take human breast cancer cells and you can implant them into either the mammary fat pad—

Frederick: That’s the soft fatty tissue in the breast—

Abbott: Or the brain of mice, which reflect the primary and the metastatic site of these cancer cells. And we wanted to understand, what are some differences in terms of how these cells grow in these different tissues? And how can we find metabolic vulnerabilities of these cells when they grow in the brain? What we found is that when these cancer cells are growing in the brain, they seem to turn up a lot of lipid synthesis genes.

Frederick: Lipids — also known as fats — are one of the key macromolecules that all cells need to grow. They are essential for generating energy, and important in signaling and creating cellular features like the cell membrane.

McElvery: Although the brain is a fatty tissue, Vander Heiden lab researchers had previously observed that there are fewer lipids floating around in the brain where they are accessible to cancer cells than there are in the mammary fat pad where breast cancer originates. When the cells metastasize, they need to find a way to make their own fats, hence the cranking up of lipid production.

Frederick: Keene and his collaborators wondered whether they could use breast cancer cells’ dependence on lipids against them.

Abbott: And so we hypothesized that, if you delete the key gene that’s involved in making lipids from scratch — this gene is called fatty acid synthase — we hypothesize that if you delete fatty acid synthase and you reimplant cancer cells back into the brain, that they might not grow as well. And this is indeed what we saw.

Drugs that target fatty acid synthase are currently in Phase 2 clinical trials, but they’re only currently being used to treat primary disease in the breast. So they’re not being used to treat brain metastases. But our work suggests that this is a good avenue to explore.

[“Tapoco Critter” fades out]

One of the problems, though, with using the particular inhibitor that’s in the clinical trials is that it doesn’t actually cross the blood brain barrier. So this is a key problem that occurs when you try to treat tumors in the brain because you have this barrier that prevents diffusion of a lot of compounds from just entering into the brain. However, we found an inhibitor of fatty acid synthase—

McElvery: A different one than is being used in the clinical trials—

Abbott: that was able to penetrate the blood brain barrier. And it did have some effect in reducing and inhibiting tumor growth.

Frederick: In the future, they hope to find other enzymes that, like fatty acid synthase, are essential to cancer cells and could be targeted through therapies.

Abbott: My follow-up experiment is to see if we can nominate additional enzymes that could be targeted, specifically enzymes that are involved in making amino acids. One of our ideas is to improve delivery of drugs that could target these proteins, including fatty acids.

[“Lamplist” begins]

And we are planning on collaborating with a lab here at MIT that uses nanoparticles that we can encapsulate our drugs. And then these nanoparticles are much more able to be delivered to the brain.

McElvery: Pretty much all of Keene’s work is done in close collaboration with other members of the Vander Heiden lab.

Abbott: I really think that you can get a lot more done if you work together with someone. It’s also just a lot more fun and exciting to have someone that you’re closely collaborating with. Finding other people to work together on projects really keeps you motivated and keeps you going.

[“Lamplist” fades out]

Frederick: That’s a wrap on season four. Thanks for joining us. Next semester, we’ll be talking to MIT Biology grad students about how they’ve found — or created — community spaces in grad school.

[“Something Elated” begins]

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

Frederick: Thanks for listening.

[“Something Elated” fades out]

Produced by Eva Frederick and Raleigh McElvery.

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

• “Hardsider” — Blue Dot Sessions
• “Vegimaine” — Blue Dot Sessions
• “Talltell” — Blue Dot Sessions
• “Borough” — Blue Dot Sessions
• “Tapoco Critter” — Blue Dot Sessions
• “Lamplist” — Blue Dot Sessions