Season 2, Ep. 4

José Orozco: I love the idea of tackling new problems. And not just learning about things that other people had solved, but actually thinking about my own questions and trying to design experiments to address those questions.

[“Something Elated” begins]

Conor Gearin: 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: And I’m Raleigh McElvery from the MIT Department of Biology—

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

McElvery: And just a quick note about today’s episode — we made it while working from home as part of the effort to maintain social distance and flatten the curve of the coronavirus pandemic.

Gearin: That means the audio might sound a little different than usual. But we hope to be back in our normal studio soon.

McElvery: Anyway, on with the podcast. Today we meet José Orozco. He’s a student in the Harvard/MIT MD-PhD Program, which means he’s pursuing both an MD and a PhD.

Gearin: This allows him to make a difference in patients’ lives by tackling big mysteries about how our cells work, and how their dysfunction leads to disease.

[“Greyleaf Willow” begins]

Orozco: My name’s José Orozco. I am a fifth year PhD student and I work in David Sabatini’s lab at the Whitehead Institute. I was born in Colombia, I lived there until I was 10 years old in a city called Cartagena. So I had a typical childhood there. Around that period of time right before 2000, the economy was doing really poorly. Economic prospects were not great. So my family decided to move to the United States. My dad at that time had a job opportunity in south Florida. So we settled there and I lived there until I was 18. I went to middle school and high school there.

[“Greyleaf Willow” ends]

McElvery: José didn’t grow up planning to be a scientist, partly because he didn’t know any. 

Orozco: No one in my family was a scientist. I had never met a scientist. I had never considered a career in pure science. I have an older brother and a younger sister. They’re both lawyers. My dad, he’s an entrepreneur, so he’s always been in business from a young age. The closest one to the science field is my mom. She’s a family therapist. She did her undergrad in psychology and then she did a master’s in family therapy. And she did therapy for many years. She wanted to go to medical school when she was young, but decided against it for various reasons. But she was always very interested in science. And, you know, when I was first starting in biology, actually, I remember getting some of her old textbooks from college. 

Gearin: José’s mom helped plant the idea of med school in his mind. But becoming a doctor wasn’t foremost in his thoughts during high school. Soccer was.

[“Game Hens” begins] 

Orozco: I took that pretty seriously. So I played midfield for the most part. I always liked being the one controlling the pace of the game. So I liked the ball to always go through me.

McElvery: Late in high school, though, José had an epiphany that showed him how exciting molecular biology could be.

Orozco: So I had already applied to colleges and I was really unsure what I wanted to major in. But at the time, I was taking chemistry and at that time actually a psychology course. But the part of the psychology course I like the most was the chapter where you learn about neurons and how action potentials work. I thought understanding something so complex, like the psychology of an organism down to the level of molecules and ions traveling through an axon was fascinating. And I think the other reason I thought it was a viable path forward was because studying biology would allow me to then pursue medical school.

[“Game Hens” ends]

McElvery: José was hoping for a change of scenery for his college experience. He visited Northeastern University in Boston.

Orozco: I had a sense that it was a place where I could make a fresh start. And I really liked the city. I really liked the vibe of the school. And I just kind of knew that I wanted to try something new. It almost seemed like an adventure.

[“Sage the Hunter” begins]

Gearin: Once José got into Northeastern, his feelings about academics began to change. His interest in biology took on a new force.

Orozco: And I think it was in part being away from my family, away from the world that I knew and into a new world where I was defining what that world was. I started thinking about working in a lab and I reached out to a professor in the biology department, and she allowed me to come in and work in her lab.

[“Sage the Hunter” ends]

McElvery: That professor, Erin Cram, studies the roundworm C. elegans, a model organism in biology research. The Cram lab investigates how cells in C. elegans sense mechanical forces, like body tissues getting stretched, and trigger changes in cell migration in response.

Orozco: It was one of those things where right away I sort of got bit by the research bug.

Gearin: José was on the pre-med track, but he also developed a taste for basic biology and the puzzle-solving challenges it posed.

Orozco: So I took a seminar that they have for juniors and seniors. It was a professor called Wendy Smith, she organized a seminar on aging. It was during this course that I really became interested in the idea of metabolism and aging. And specifically, it was about how the body seemed to be sensing what nutrients we were getting from our diet and how that was influencing the aging process.

[“Calisson” begins]

Gearin: In everyday speech, metabolism often just means burning calories. But in biology, it refers to how cells take in nutrients and use chemical reactions to make new compounds that keep the cells alive.

McElvery: There are still many open questions about metabolism — thanks to the sheer abundance of metabolic processes in the body. José thought it could be an exciting area to study next.

Gearin: And thanks to his time in the Cram lab, he had a much better idea about what it took to take on a research question and answer it.

Orozco: So when I first started working in the lab, I got very interested in doing something like that. And then I learned that you can do PhDs in research and you can dedicate yourself completely to the lab. 

McElvery: José’s vision for his future was taking on a new shape. Just following the standard route to med school didn’t seem like enough.

[“Calisson” ends] 

Orozco: I started thinking about things in a way not like, “What can I do for a living?” And I actually started thinking about, “Well what do I think is interesting?” But I think then I had two possibilities. I was either going to go on the research track and spend all my time in the lab or I was going to become a doctor and spend all my time in a hospital treating patients. And I actually remember one particular instance where a more senior student said to me, I must have… I can’t remember what I told her, something like, “Now I don’t know what to do.” And I remember her saying, “Well, why don’t you do an MD- PhD?” And I had never heard of that. And she said, “Well, you known, you do your MD and then you do your PhD, you do both of them. And then you can but a doctor but you could also do research.” And I thought, well, it’s perfect. I don’t have to choose.

[“Secret-Pocketbook” begins]

Gearin: José was excited to have found a type of training that brought together all his interests. But the MD-PhD application process was daunting.

Orozco: They’re hard to get in. And I didn’t know much about it, I didn’t really know anyone that many people who had done it. I applied broadly. There was a few programs that really stood out. 

McElvery: The Harvard-MIT program ultimately seemed like the best fit for José, largely because he was so comfortable in Boston and really liked the area. In 2013, he applied, got in, and accepted their offer. He would spend the first 2 years at Harvard Medical School, studying human anatomy, physiology, and pharmacology, followed by several years earning his PhD as an MIT Biology graduate student. Finally, he’d finish his MD with two years of clinical rotations.

[“Secret-Pocketbook” ends]

Gearin: The first two years studying medicine were jam-packed with new information and new experiences.

Orozco: It was very intense from an academic point of view. I really enjoyed the whole experience. I think the medical school class is a very unique population where there are people who are more into the social sciences, down to people who are extremely interested in basic science. But all ultimately trying to deal with the same subject matter, which is how to improve people’s lives, improve people’s health.

Gearin: José found med school complemented his approach to research, too.

Orozco: A geneticist who works on a model organism will tell you that the first thing you need to do is learn the organism. And if you want to study human biology, you need to learn the organism. And medical school provides that, more so than the PhD programs.

McElvery: But José began to look forward to shifting to the PhD portion of the program at MIT, partly because med school is full of exams. The second year featured a big one, called Step 1, the first in a series of medical board exams.

Orozco: And that entailed basically a three- or four-month period where I was just sitting in the library memorizing stuff so that I could get a good score on that test, which seemed like the most important thing in the world at the time. And when I came to MIT, it was the complete opposite. I remember being extremely happy.

[“The Summit” begins]

Gearin: As a new MIT Biology PhD student, José loved how the scope of his learning became wider and wider.

Orozco: The philosophy here is to understand how to ask questions. So how do you approach a problem using genetics, or how do you approach a problem using biochemistry? And then we take this paper reading course called Methods and Logic that really dissects both classical and modern scientific papers to really exercise the idea of how do you approach problems? How do you go about that? So there are papers that we read that, today, would take an afternoon to solve, you know. But back then, the technologies that we have now didn’t exist. And so they had to take an alternative approach. So the challenges that we face are actually more similar than we think.

[“The Summit” ends]

McElvery: The next step, though, was taking that passion for asking questions and choosing a specific lab and PhD project for his next few years.

Orozco: For me, I knew coming in that I wanted to work on something, you know, basic science, fundamental. And of course, having that background of having gone to medical school, I wanted my work to be relevant to disease and relevant to public health.

Gearin: There was one lab in particular he had in mind — David Sabatini’s lab at Whitehead Institute. José had already read some of David’s papers in that college seminar on metabolism and aging.

[“Scallat” begins]

McElvery: The Sabatini lab studies mTOR, a protein that’s essential for regulating cell growth. It helps cells sense nutrient levels in their environment, and then adjust their growth rate to adapt.

Gearin: Controlling growth is essential to keeping our bodies healthy. Unregulated growth can lead to cancer. mTOR also plays roles in metabolic diseases, such as diabetes and neurodegenerative conditions.

Orozco: So David discovered mTOR as a graduate student in the 90s. At that time, it was known to be important in cell proliferation. And eventually it was very clear that was very important for cell growth in organismal metabolism and physiology.

Gearin: mTOR forms part of a protein complex called mTOR complex 1, or mTORC1 for short. This complex is a protein kinase, meaning that it activates other proteins that go on to help build new structures in the cell.

McElvery: If you think of the cell as a soccer team, you could think of mTORC1 as center midfielder. It’s always at the center of the action, setting up plays. It takes signals from outside of the cell and converts them into cellular decisions.

[“Scallat” ends]

Gearin: That makes studying mTORC1 take on special importance in devising new therapies for diseases that currently lack treatments.

Orozco: The core of the lab is meant to study the signaling pathway that regulates the mTORC1 kinase, discovering the parts to it. And we have a pretty exhaustive parts list. We have a pretty good idea of how the signaling pathway is wired, in what order things happen. Though, I think there are parts we haven’t discovered, and I think that there are some mechanisms that that we don’t know about yet that we still don’t understand.

Gearin: The part that José is focused on is how mTORC1 senses glucose in the cell. Glucose is a form of sugar that is the go-to energy source for our cells.

Orozco: So we know that the mTORC1 pathway is sensing the availability of glucose, which is most organisms’ favorite carbon source from bacteria to yeast to human cells.

McElvery: If a cell can’t sense glucose, then it can’t adjust its growth rate accordingly. But right now, there’s no consensus on the sensing mechanism.

[“Astrisx” starts]

Gearin: The way nutrient sensing pathways work is that glucose is broken down — metabolized — into many different molecules, called metabolites, and mTORC1 probably senses one of those metabolites rather than glucose itself. José’s list of possible suspects is long. Glucose metabolism is so complex it has its own name: glycolysis. The process makes many different metabolites.

Orozco: Hundreds of molecules in the cell are actually derived from glucose. And that may be an understatement.

[“Astrisx” fades out]

Orozco: What we would love to be able to do is to remove all those molecules and to add one at a time, and ask which one activates mTORC1. But that, from a technical point of view, is very difficult.

McElvery: Cells need to metabolize glucose to stay alive, so experimenting with the steps in glycolysis can often disrupt function and kill the cells.

Orozco: And it’s very hard to study things when cells are very sick. We had to really innovate.

[“Astrisx” fades in]

McElvery: José and his colleagues had to see past the limitations of current techniques and come up with new ones — just the kind of trailblazing research that inspired José to pursue a PhD in the first place.

Gearin: They figured out how to get cells to survive on alternate energy sources—

Orozco: And to also block specific steps in the glucose metabolism pathway to figure out which metabolite was the one that mattered. The metabolite we found is called Dihydroxy Acetone Phosphate, or DHAP. It is, I think, four steps removed from glucose itself.

[“Astrisx” ends]

McElvery: What José’s results showed is that mTORC1 doesn’t know there’s glucose in the cell until DHAP is produced. Then, the signal reaches mTORC1 that the cell has nutrients and it’s time to activate growth pathways.

Gearin: mTORC1 becomes activated, and in turn it activates other proteins that cause the cell to build more structures and grow.

Orozco: At the core it was a very simple question, but technically very challenging.

[“The Bus at Dawn” begins]

McElvery: The hunt for the metabolite that mTORC1 senses has helped convince José that he wants to devote all his time to probing biological mysteries.

Orozco: So I made the decision not to pursue residency. So I will complete the MD, but I will not be doing any further clinical training. What really does it for me is to be in the lab. What really does it for me is to come up with new questions, and designing experiments. It is freeing in a way. I can pour all of my energy into that one thing.

Gearin: But José’s medical training plays a big part in how he thinks about research.

Orozco: I think that a focus on human physiology is very important. And that influences a lot how you approach questions in the lab.

[“The Bus at Dawn” ends]

McElvery: There are gaps — big ones — in what the medical field understands about disease, and how a healthy person becomes sick. And that makes it important to go back to the root cause in order to figure out a good treatment.

Orozco: And I think something like diabetes is an example of this. How does someone become insulin resistant? OK, well, let’s go back to the first thing that went wrong to lead you to this disease state.

Gearin: It has helped that José’s advisor, David Sabatini, made a similar choice about not practicing medicine and instead pursuing research full-time.

Orozco: I mean, I’m kind of trying to follow the same path David did. So he did an MD-PhD and then didn’t do residency. He had discovered mTOR, and he really wanted to focus on it and work on it. And so he started his own lab right out of his MD-PhD. You know, there’s no correct path, and David never really pushed me one way or another. I told him what I want to do and he’s very supportive.

[“Vela Vela” begins]

McElvery: Spending time with his fellow Sabatini lab members has been a big part of José’s grad school experience, and he hopes to stay connected with the lab after he graduates.

Orozco: We’re definitely a highly motivated lab that recruits very motivated students who work extremely hard. But we also have a very good sort of attitude towards, you know, going out and having fun. It definitely is sort of like a work-hard play-hard attitude. David hosts a Sabatini lab retreat every two years. We’ve been doing it for the last two times in New Orleans, which is incredibly fun. We did it once in Savannah, Georgia. Everyone who’s in the lab now gets to meet the alumni. And from a current member’s point of view, it’s really fun thinking that in the future I’ll be able to come back as an alum and share what I’ve been working on.

[“Vela Vela” ends]

McElvery: Thanks for listening to our season on “Converging Paths.” We hope to bring you more stories soon, so stay tuned.

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

[“Broke for Free” begins]

McElvery: 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
• “Greyleaf Willow” — Blue Dot Sessions
• “Game Hens” — Blue Dot Sessions
• “Sage the Hunter” — Blue Dot Sessions
• “Calisson” — Blue Dot Sessions
• “Secret-Pocketbook” — Blue Dot Sessions
• “The Summit” — Blue Dot Sessions
• “Scallat” — Blue Dot Sessions
• “Astrisx” — Blue Dot Sessions
• “The Bus at Dawn” — Blue Dot Sessions
• “Vela Vela” — Blue Dot Sessions