BioGenesis Podcast: Tina Lopez of the Knouse Lab on the regenerative superpowers of the liver

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 Specialist at MIT Biology, and Eva Frederick, Science Communications Officer 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 4 features stories about graduate students whose fundamental research in biology is poised to have an impact on society. In our first episode, we’ll meet Tina Lopez, a graduate student in the Knouse Lab. Tina grew up in the border town of McAllen, Texas. At MIT, she’s in search of the mysterious signal that cues the liver to rebuild itself post-injury.

Edited Transcript

Tina Lopez: I want to study something that is important, that will make a difference in people's lives down the road. 

[“Something Elated” begins]    

Raleigh McElvery: Welcome to Season 4 of BioGenesis, the podcast where we get to know a biologist, where they came from, and where they’re going next. This season we have a new theme — and a new co-host!

[“Something Elated” fades out]

Eva Frederick: That’s me! I’m Eva Frederick from Whitehead Institute.

McElvery: And, as you know by now, I’m Raleigh McElvery from the MIT Department of Biology.

Frederick: This season, we’re talking about fundamental biological insights that are poised to have an impact on society. Sometimes, these discoveries emerge when a researcher is simply performing experiments to satisfy a curiosity about how the world works. 

McElvery: Consider the foundational microbiology research that revealed the CRISPR-Cas9 system, now a widely-used gene editing tool.

Frederick: Or the decades of mRNA research that laid the groundwork for the COVID-19 vaccines from Moderna and Pfizer-BioNTech.

McElvery: Here at MIT Biology and Whitehead Institute, our researchers investigate the basic cellular mechanics that underlie life itself — including organ regeneration, developmental disorders, parasitic invasions, and cancer treatment. 

Frederick: This season, we’ll introduce you four graduate students exploring these very topics.

McElvery: So, without further ado, meet Tina Lopez. She’s in search of the mysterious signal that cues the liver to rebuild itself after injury.

Frederick: By solving this puzzle, she’s hoping to find a universal indicator that could help direct other organs like the brain and heart to regenerate. 

["The Onyx” begins]

Lopez: Hi, I'm Tina Lopez and I'm a second-year graduate student in the Knouse lab. I'm from the border town of McAllen, Texas, which is found on the southern tip of Texas. I have a younger sister and then my two parents. They work at the best grocery store, H-E-B. They worked there their whole lives and they worked their way up in that chain. And they've always just instilled that education is very important for a better life. You know, they pushed. 

["The Onyx” fades out]

Me and my sister both went to public schools there. And then for high school, we went to like a special program for the students that wanted to take advanced courses, called the IB program. There weren't enough of us in the town actually to have them all at a separate high school. So we all got bused to the same one little building. 

Frederick: Tina had a long-standing interest in math and science, but she didn’t consider a career in research until the end of high school. 

Lopez: I didn't really know being a scientist was an actual thing, probably until my senior year of high school. The thrill of, you know, coming up with a question to pursue, and being able to do whatever it takes to answer that question, I thought was thrilling. And I was like, OK, maybe I'll be a chemical engineer, I like both math and chemistry. I Googled what were the best chemical engineering schools and MIT was number one. I was like, you know what? Let's see what happens.

["The Onyx” begins again]

 I'll probably end up going to a school in Texas like most of my classmates. That's where everyone usually goes. I applied early decision, I got deferred. And then I ended up getting accepted regular action. And it was actually the last school I heard from and the only school I ended up getting accepted to. So it was a very nerve-wracking time. I don't recommend. 

McElvery: So Tina arrives at MIT in the fall of 2014 for her bachelor’s degree, and — spoiler alert — she stays there for her PhD. But let’s not jump ahead.

["The Onyx” fades out]

Lopez: So I think the biggest challenge for me was the coursework. I always thought that my family was like pretty well-off, right. We don't have to put foil on our windows to keep the heat out. We had an AC unit. But then coming here to MIT, I realized that, like, so many other students had so many other opportunities that I didn't even know were possible. I didn't learn the things that my professors expected me to come in knowing. It was very hard for me to figure out how to catch up. 

In my intro bio course actually, the first day, they're telling us the things that we should know that they're not going to bore teaching us with, right. And they talk about prokaryotes and eukaryotes. And I'm sitting there like, what are those? And so that was pretty hard. But the thing that I do love was that everyone was willing to help me get there. All my classmates were definitely willing to help me get there. It just took a lot of time and effort on both of our parts 

Eva: One of Tina’s biology professors and a source of support throughout her MIT experience was the late Angelika Amon, who passed away in 2020.

[“Trex VX” begins]

McElvery: Angelika ran her lab out of the Koch Institute, where she investigated chromosome segregation: the point in cell division when the chromosomes move to opposite poles of the nucleus as the cell prepares to split into two identical daughter cells.

Frederick: She was interested in knowing how errors in that segregation process can lead to diseases like cancer.

Lopez: She was a yeast geneticist. So she was interested in the pure science of it, and took a very, very fundamental approach, which was very inspiring for me. Her enthusiasm was infectious, and she told us how she worked at the Koch and I was kind of interested in cancer research. And after that first time hearing her talk, I knew I had to work for her. I immediately emailed her and she put me with Kristin Knouse, who at the time was an MD-PhD student in her lab. And I worked for her for the rest of my undergraduate career. 

McElvery: Tina worked in the Amon lab under Kristin’s supervision for four years, studying how cells behave when they’re taken out of an organism and plopped into a dish to grow.

Lopez: We noticed that when you take cells from an organ, take them out of their natural context and put them in a dish, they can't divide properly. And so we wanted to know why that was. We discovered that the architecture, so the shape the cells take in the organ, they can't take that shape in a dish. And that 3D shape is very important for their ability to properly divide their chromosomes. 

I ended up changing my major from what I thought would be chemical engineering to biology, because I just fell in love. I remember like the moment I fell in love was I was staining slides at the bench with Kristin. We're going to get a big, you know, exciting result for our project. And I was like, this is what I want to do for the rest of my life. This is so exciting to be like the first person, you know, kind of in the world to know something. 

[“Trex VX” ends]

Frederick: Tina and Kristin finished their respective degrees in the same year, but neither of them strayed from campus. Kristin headed across the street to the Whitehead Institute to start her own lab as a Whitehead Fellow. And Tina —

Lopez: I had initially chosen a different PhD program. Kristin had actually just opened her lab. And so I helped her start up that summer. And the research she was doing was exactly what I was interested in. It made a perfect fit. And that's when I came back to MIT to join her lab officially as a PhD student, which was super exciting. 

McElvery: Tina’s undergrad research — Kristin’s graduate work — had involved studying division in cells from several different organs, including the liver. Every time they removed cells from the liver for their cancer experiments, it would regenerate.

[“Trex VX” begins again]

Lopez: The act of regeneration, I think both captivated both of us. And so she decided that she really wanted to pursue the liver going into her own lab. If we think of the body in general, we can usually classify organs into two categories: those that continuously divide, such as the intestine and the skin, when they're injured, or organs that cannot divide once they're injured. You can think of a heart attack. We don't have a cure for that one. Those heart cells, cardiomyocytes, die. You can't replace them. And same with neurons in neurodegenerative diseases. 

The body also provides a unique difference between these two groups, which is the liver, which is a conditionally renewing tissue. And so the liver, upon injury, has the ability to completely regenerate itself and regrow the organ to the same functional ability and the same mass. And in mice, this takes place in a week and in humans it's about a month. And so Kristin and the lab were interested in understanding how the liver has this unique ability, and can we confer it to other tissues such as the heart and the heart attack and the brain and neurodegenerative diseases?

[“Trex VS” fades out]

Frederick: There’s no disputing that liver regeneration is a magnificent feat of cellular resilience. But the mechanisms behind this special ability remain unclear.

Lopez: It's such a fundamental question in liver biology, how this happens. And when I was talking with Kristin, I assumed I just like couldn't find the right paper or something. How can we appreciate that this organ has this remarkable ability to regenerate, but we don't know how it does it, and no one's been able to answer this question for decades? It was kind of like, oh, I want to give it a shot. 

[“Gra Hovedvei” begins]

McElvery: What researchers like Tina and Kristin do know so far is that the regeneration process depends on a protein called hepatocyte growth factor, or HGF. HGF is found in humans and pretty much all animals with livers, including mice, which Tina and Kristin use as model organisms. HGF serves as a cue to induce the cells in a damaged liver to divide and fix the injury. 

Lopez: When those cells see that signal, then they know what to do next. But we weren't entirely sure where it's coming from and how the body can sense liver insufficiency in order to induce HGF synthesis. We kind of took an unbiased organism-wide approach to answer this question, like what organs in the body are sensing liver insufficiency? So we would induce liver injury, and then I checked the major organs and looked for which ones are inducing HGF synthesis shortly after liver injury. And the liver actually was one of the higher HGF-producing organs, which we thought was pretty interesting. And so then the question became, what cell type or cell types in the liver are inducing HGF synthesis? And then we found these stellate cells.

Frederick: Stellate cells, named for their star-shaped appearance, help form scar tissue in the liver in response to injury.

Lopez: Their fun fact is they store 80 percent of the body's vitamin A.

Frederick: But other than that —

Lopez: We don't really know much about them.

Frederick: Tina thinks they could be the source of the enigmatic HGF signal that directs regeneration.

Lopez: So now what I'm working on is figuring out is the signal of liver insufficiency systemic? Is it found in the blood? Is it something that all the organs see or is it something that's localized within the liver? And then once I answer that question, I will be able to answer what exactly that signal is. 

[“Gra Hovedvei” fades out]

McElvery: She’s been working to isolate stellate cells from mouse livers, placing them in a dish with nutrients from the blood to see if she can coax them to make HGF outside the body.  This information, combined with some experiments she has planned, will help her determine what exactly cues these cells to make HGF — and if that signal is found within the circulatory system.

Lopez: It would set an understanding for how the body can sense the injury of an organ. And once we figure out how the liver is able to tell the body, “Hey, I need growth factor so that we don't die,” can we figure out whether other organs are able to do this or other organs do this? Does this also apply to other organs that are injured? And where is the roadblock in that? For example, a heart attack — is it just that there is no signal that the cardiomyocytes, the heart cells, are dead? Or is it that there isn't someone sensing the signal? And can we modulate at those ends? 

[“These Times” begins]

Frederick: Kristin recently moved her lab from Whitehead Institute back to the Koch Institute, where she and Tina first met under Angelika Amon. This time, though, Kristin is running the lab, and Tina has accompanied her as the group’s first graduate student.

Lopez: I want to be a PI in the future at an academic institution, and so it's been very useful for me to see how to start up a lab, which I think is not something I think everyone gets to experience. So it's nice to see, like, OK, what worked for Kristin, what didn't work, what should I keep for my own experience? And kind of shaping the culture of the lab has been nice. You know, how we do things, what traditions do we want to instill? Things like that. 

McElvery: When she becomes a PI, Tina wants to head a lab that uncovers fundamental biological insights with clinical relevance. 

Lopez: To me, conducting fundamental research is so important because I think we need to understand at the very basic level how things work in order to modulate or fix them. And if we don't have that understanding, we don't know what to fix, where the problem is. And so for me, that's why basic science is so important. 

[“These Times” fades out]

Frederick: That’s it for today. Next time, tune in to meet a grad student who’s investigating how errors in genetic code can confuse the cells that mold facial structures.

[“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 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:
•    “Something Elated” — Broke for Free
•    "The Onyx” — Blue Dot Sessions
•    “Trex VX” — Blue Dot Sessions
•    “Gra Hovedvei” — Blue Dot Sessions
•    “These Times” — Blue Dot Sessions