Season 4, Ep. 3

Alex Chan: The reason why basic research is so important is that it’s like casting a wide net across biology, touching on various different types of cellular processes and molecular biology.

[“Something Elated” begins]

Raleigh McElvery: Welcome to BioGenesis, the podcast 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” fades out]

Eva Frederick: And I’m Eva Frederick from Whitehead Institute. In this season of BioGenesis, we are talking to MIT Biology graduate students who are conducting fundamental research that could have big impacts on society down the road.

McElvery: Today we’ll hear from graduate student Alex Chan, who works in the lab of Whitehead Institute Member and MIT Biology professor Sebastian Lourido.

Eva: Alex is studying how Toxoplasma gondii — a parasite best known for its presence in cat poop — can infect cells in the human body, sometimes leading to a condition called toxoplasmosis.

McElvery: His basic research has revealed new roles for one specific protein called a kinase that helps the parasite latch onto and enter its host’s cells.

Frederick: And he’s taken it a step further to investigate whether scientists could use any existing drugs to target this kinase and treat or prevent toxoplasmosis.

[“Grimmail” begins]

Chan: My name is Alex Chan, and I am finishing up my fourth year in the Biology Department and I’m currently a student in Dr. Sebastian Lourido’s lab at the Whitehead Institute. I was born and raised near San Francisco in this neighboring city called Daly City. I am ethnically Chinese, but my parents had a more interesting path to coming here to the U.S. They were originally Chinese, but they were born and raised in Myanmar (that was previously known as Burma). And they grew up there into their teens and then eventually moved to Macao in China, where they met. And then they got married and then moved to California, where they had my two older brothers and then me.

For most of growing up, my dad worked in delivering meats to restaurants so he would take orders and he had a truck so he would load meat onto it and fulfill orders for different restaurants. He had a truck, so he would load meat onto it and fill orders for different restaurants. And my mom mostly worked in fast food growing up. And when I was getting older, they were actually able to start their own restaurant, like a Hawaiian barbecue restaurant, near a beach in the Bay Area.

Food is, in my opinion, the most beautiful type of art form there is. And I think part of that reason is that it engages all your senses. So taste, your sight, the textures, the smell and like the sound — certain sounds when you eat food or presented with food. And foods that mean a lot to you, I feel like eating it can kind of transport you back in time in your mind to certain moments throughout your life. That is really special.

[“Grimmail” fades out]

McElvery: After five years in grad school, Alex often finds himself missing his mom’s cooking.

Chan: Over the pandemic, she was so nice. She, like, actually cooked a lot of my favorite things and shipped them on dry ice from California here. And then I was able to enjoy some of her cooking that way.

Frederick: Beyond instilling Alex with a love of cooking, his parents also emphasized the importance of education.

Chan: It was very important for them as they were raising us to ensure that we had the choice to learn what we want and have the options to be able to choose what we wanted to do in our future careers — instead of having to be restricted in terms of choosing something that would just help us get by.

McElvery: But growing up, he didn’t know much about his options in scientific research.

Chan: I had a clear image of like what a doctor was and how a doctor could help people, because I had, like, direct interaction with doctors growing up. But never really with scientists that would do the type of research that I’m doing now. I think the closest thing to getting exposed to that was mostly from seeing things on TV, like watching cartoons like Jimmy Neutron where he could build different technological devices and do cool things with them.

Frederick: In a high school biology course, Alex was drawn to the intricate workings of cellular processes.

Chan: And at that time, like, I thought I wanted to become a doctor. Things aligned that I should go into and study STEM.

[“Caverna” begins]

McElvery: Alex started school at the University of California, Los Angeles as a neuroscience major with the intention of following the premed track. His freshman year, he started doing research in the lab of Alvaro Sagasti, who studies sensory neurons in zebrafish.

Chan: So sensory neurons are a type of neurons that innervate your skin and allow you to feel things like temperature, touch, pain, and these different sensations. And his lab uses zebrafish as a model because they’re very much like us in that they also have a complex sensory nervous system. But it’s very interesting because the zebrafish, as they develop as embryos, develop transparently. And what that means is that you can genetically encode labels for these sensory neurons to visualize them in live time as they develop in an organism and watch them branch out from the spinal cord and into the skin. And I remember when deciding labs, seeing these images, I was like completely sold and just really just fascinated in trying to understand how the body is able to ensure that you can cover its entire surface to ensure that you can sense different stimuli in your environment, since that is required for survival.

[“Caverna” fades out]

Frederick: Alex also balanced his research with science outreach programs.

Chan: I came across this program called City Lab that is a student-run organization that gets funding to essentially bring middle school and high school kids from the local greater Los Angeles area that wouldn’t necessarily have opportunities to be exposed to the molecular biology tools, and to be able to bring them into UCLA labs on Saturdays to perform theme-based labs throughout the day to not only get them exposed to science, but also to empower them to know that if they wanted to pursue a major and career in STEM that it’s possible and that it’s rewarding and is a viable career choice.

McElvery: As he progressed through his undergraduate degree, he began to see a world of possibilities for research careers beyond the medical field.

[“Begrudge” begins]

Chan: Over time, as I started taking my classes and started doing research, I realized that I was much more fascinated by the fundamental cell biology and molecular biology — just in general, not necessarily focused on neuroscience. And I realized by switching my major, I could be exposed to a wider breadth of biological processes.

Frederick: Alex changed his major to molecular cell and developmental biology, but still wasn’t sure whether he wanted to go to med school. His final research experience during undergrad was what finally convinced him to apply to grad school instead.

McElvery: He worked in the lab of Sue Biggins at the Fred Hutch Cancer Research Center in Seattle.

Chan: In that lab, they’re focused on studying how chromosomes are able to segregate into daughter cells. So this is very much involved in cell division and needing to copy your DNA and ensure that it ends up going from one cell into two cells. And the lab was particularly interested in studying a molecular machine that controls this process called the kinetochore, that actually helps pull the chromosomes into the daughter cells.

In that summer of doing research in a completely different subject around different people and a new environment, I think really convinced me that I really found research aspects more fascinating than the prospect of going to medical school and seeing patients. So I made the decision to just go down the PhD route and apply to grad schools.

Frederick: Alex ended up choosing MIT’s biology program — he liked the broad scope of the program and the location on the East Coast. And he arrived on campus in 2017.

[“Begrudge” fades out]

Chan: When I came to MIT, I was just going in with a very open mind. But I found myself getting drawn more towards pathogen research, just seeing how there are these bacterial or eukaryotic pathogens that are very opportunistic and can infect their hosts, and how the interplay between these two organisms in terms of how they can influence each other’s behaviors and how they have to adapt and evolve to thrive within these environments and persist, I thought was very fascinating.

McElvery: When he rotated in Sebastian Lourido’s lab, which focuses on the parasite Toxoplasma gondii, he knew he’d found the perfect place to study these interactions.

Chan: So Toxoplasma is an obligate intracellular parasite, and people have most commonly heard about it when we think of cat poop.

[“Big River Run” begins]

Frederick: In fact, the parasite can infect nearly any kind of warm-blooded mammal, but it does have a special relationship with cats. Cats are the only host in which the parasite can undergo sexual reproduction, which is critical for genetic diversity.

McElvery: In other hosts, such as humans, the parasite can replicate slowly, or even lie dormant for years.

Chan: So it’s only within cats that they’ll differentiate into male Toxo and female Toxo and be able to cross and mate and produce these things called oocysts that get shed in cat poop.

Frederick: To most healthy humans, a Toxoplasma infection is nothing to worry about.

Chan: Actually, about 40 percent of the world’s population has been infected with Toxo. And because most people have a good immune system, they can clear Toxo just fine. It’s only in patients that are immune compromised where it becomes an issue — like patients with HIV or AIDS or other patients that are undergoing treatments that might render them immune-compromised.

McElvery: The parasite can also cause problems for pregnant women.

Chan: If you get infected with Toxo, it could pass on to your fetus, where it’s able to then switch to the fast-replicating stage and cause rapid tissue destruction, which can lead to a miscarriage or birth defects.

[“Big River Run” fades out]

Frederick: Across the Lourido Lab, researchers are studying many different aspects of the parasite’s biology — including how it infects its hosts, and where its biology overlaps with that of its relative, the Plasmodium parasite, which causes malaria. Alex’s research focuses on two kinds of organelles that are essential for a successful Toxoplasma infection.

Chan: So the parasite is kind of like banana-shaped and at the very tip, which they call like the apical end, there are these two sets of organelles called the micronemes. So these are tiny circular — or they’re like missile-shaped — organelles that are packed with proteins that, once these organelles fuse with the plasma membrane, they’ll release these proteins.

McElvery: The proteins, called virulence factors, help the parasites break free from the original host cell, and then bind to and infect other potential host cells.

Chan: Once the parasite is able to bind to and attach to a host cell, it’s actually able to create its own molecular handle into invading that cell, which is why it’s able to invade a wide array of cell types. And that’s primarily mediated by a second set of organelles called rhoptries.

Frederick: That’s R-H-O-P-T-R-I-E-S. It is not spelled how it sounds.

Chan: And these are larger than the micronemes but also at the apical end. And they look more like clubs, like troll clubs. And they contain a separate set of virulence factors that are able to integrate into the host cell in the parasite membranes that allow it to create this handle and enter that cell to begin initiating replication in a new vaculoe.

McElvery: So, the lab knows that these two types of organelles — micronemes and rhoptries — work together to help the virus infiltrate a host. But the molecular players that allow them to do that are not well understood.

[“Dany PKL” begins]

Chan: My project is interested in studying what controls these organelles to be mobilized and fuse to the plasma membrane and to be released. And I am particularly interested in this one protein. It’s a kinase. So kinases are enzymes that will bind to a protein of interest and ATP, and transfer a phosphate onto this protein of interest. And kinases tend to have multiple protein targets. By attaching this phosphate, which is a strong, negatively-charged molecule, you can influence a wide variety of processes within the cell. You can affect how one protein binds to another protein. You can affect the conformation of a protein to turn it on or off. You can affect a protein’s localization, so moving something from, I don’t know, like the basal end of the parasite to the apical end of the parasite. A wide variety of consequences can be influenced just by phosphorylating a protein.

Frederick: The particular kinase Alex studies is called calcium dependent protein kinase 1 — or CDPK1 for short. It’s necessary for the parasite to successfully release the virulence factor proteins and break free from the host cell to spread.

McElvery: Alex hopes to find out exactly which proteins that kinase is targeting and phosphorylating in order to have these effects on the parasite.

Chan: Humans and animals won’t have this kinase, which means it’s very unique. What that means is that it’s attractive in terms of a druggable target. So typically when you want to drug something, you want to ensure that it’s specific and you’re targeting this one thing and not other things that can have other deleterious consequences. So the fact that this was a divergent kinase from humans made it an attractive target. And the fact that it was so critical for pathogenesis also added to that. If we can target the kinase and we can inhibit the kinase, then we can know how to basically block it and basically prevent parasites from establishing infection within its hosts.

[“Dany PKL” fades out]

Frederick: Alex has already undertaken a project on this himself, partnering in the past with the pharmaceutical company Novartis to conduct an enormous drug screen that could, eventually, inform some possible treatments for a Toxoplasma infection.

Chan: It was an exciting opportunity because I got to not only meet people at Novartis that we collaborated with, but I also got to go into Novartis and use their lab space and not only see their high-throughput instrumentation device — so all these robotic arms and automated devices that can actually screen through thousands and thousands and thousands of compounds — but actually to be able to use these devices to perform our screen as well. Through that, we were able to screen like over 50,000 compounds to see if it could inhibit the kinase. And we identified a few interesting candidate molecules.

[“Campfire Interlude” begins]

McElvery: But just identifying a drug that works against the kinase is not enough — and that’s where more translational work will be necessary.

Chan: You have to be able to develop the drug as well, right. And in order to develop the drug, you either want to make it more specific or enhance its potency within the organism to basically inhibit the kinase. And a lot of the time, in order to do that, you need to understand more about how the kinase is acting on a structural level and on a physiological level as well. And a lot of that can come from industry research, but a lot of it can be built on a lot of the basic science research where we’re asking these questions and learning about this parasite, simply for the curiosity of knowing how it’s able to establish infection.

[“Campfire Interlude” fades out]

Frederick: That’s all for today. Tune in next time to hear about a grad student who is working on ways to make cancer cells feel more at home in a dish, by identifying growth conditions that mimic a tumor’s natural microenvironment, so researchers can develop better therapies.

[“Something Elated” begins]

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

Frederick: Thanks for listening.

[“Something Elated” fades out]

Produced by Raleigh McElvery and Eva Frederick.

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
• “Grimmail” — Blue Dot Sessions
• “Begrudge” — Blue Dot Sessions
• “Big River Run” — Blue Dot Sessions
• “Dany PKL” — Blue Dot Sessions
• “Campfire Interlude” — Blue Dot Sessions