Berkeley Talks transcript: Ph.D. candidate Rosalie Lawrence on how our cells make decisions

Andrew Saintsing: You’re tuned in at 90.7 FM KALX Berkeley. I’m Andrew Saintsing, and this is The Graduates, the interview talk show where we speak to UC Berkeley graduate students about their work here on campus and around the world. Today I’m joined by Rosalie Lawrence from the Department of Molecular and Cell Biology. Welcome to the show, Rosalie.

Rosalie Lawrence: Thanks for having me.

Saintsing: It’s great to have you here. Do you want to tell us a little bit about what you do here on campus?

Lawrence: Yeah, I’m working in the Roberto Zoncu Lab where we’re really interested in how cells in our body make decisions. And so the process that we study is actually the decision that every cell in our body makes of whether to grow or not to grow, and different cells in our body will make different decisions depending on where they are and what the environmental conditions are. So, some tissues in our body are constantly growing and dividing, and some cells in our body are actually very long-lived, and so, it’s important to kind of understand how this process is regulated because, when it’s disrupted, this causes runaway cell growth which is a key characteristic of cancer and other diseases. So, sort of me personally, what I study is understanding how the molecules within each of our cells are actually carrying out these decisions and how these processes can be tuned appropriately so that cells in our body are dividing when they should be and not dividing when they shouldn’t be, as in the case of cancer.

Saintsing: Okay, so you talked about cells and molecules making decisions. I mean usually we think about things needing brains, right, to make decisions. So, how are — how is this happening?

Lawrence: Yeah, so this is really fascinating to me. Really thinking about how on the molecular scale or the cellular scale the way decisions happen is actually protein molecules bind to one another. So, they’re diffusing around in space, one protein molecule may recognize a specific shape of another protein molecule bind to it, and then, for example, it may make a chemical modification, for example, phosphorylation where it adds a phosphate chemical moiety to another protein. And so, really kind of bits of information, if we’re thinking about – maybe thinking about cells making decisions sort of being like an electric grid, are really encoded by protein-protein interactions. And a moiety, that’s just like a chemical group. It means a collection of atoms.

Saintsing: So what kinds of molecules are leading the cells to make decisions? Like, what kinds of molecules are you looking at?

Lawrence: Yeah, so our lab actually studies one particular protein called the mechanistic target of rapamycin complex 1 (mTORC1), which is kind of a mouthful, but this is one protein that actually interacts with a lot of different downstream proteins, so we call it a master regulator of the cell. So, when this protein becomes activated it then has the ability to turn on many different cellular programs that result in cell growth. So, this is things like amino acid synthesis, lipid synthesis. So, this one protein molecule acts as a master regulator that when activated can turn on a variety of different cell processes to ultimately result in cell growth.

Saintsing: How does it work?

Lawrence: Yeah, so the really fascinating discovery that was made in this pathway about ten years ago is actually that this protein becomes activated specifically when it gets recruited to a very particular location in the cell. So, many of us probably learned about cellular organelles when we were in high school biology. So, you may have learned about the mitochondria…

Together: The powerhouse of the cell.

Lawrence: So exactly, people remember that one, but we’re gonna — the one we’re really interested in, actually it’s called the lysosome. Do you remember anything about the lysosome?

Saintsing: They’re the stomachs of the cell, right?

Lawrence: Yeah, so we all learned about how the lysosome is maybe a stomach or maybe the trashcan. That’s right. You know, we don’t really like that terminology, but we think of the lysosome as really the place in the cell where things are broken down, where you’re digesting cellular components to bring them back to their building blocks, but the really interesting discovery is actually that the lysosome is not just a trashcan. It’s actually a signaling hub. It’s the place where it’s sort of the control center of the cell, where actually this protein that I was mentioning, the mTORC1 protein, gets recruited to the lysosome. So, it goes to the lysosome, and once it’s at the lysosome it can actually read out the status, the nutrient status of the cell. So, because all of the components of the cell are broken down in the lysosome, that means that all the building blocks that are going to be used later for new building projects are all there, and so, this protein becomes activated when it’s physically recruited to the lysosome. And understanding that process of how it’s actually recruited there is what I’ve been working on in my PhD.

Saintsing: Do you have any information on that front to tell us? How does it — how does it work?

Lawrence: Yeah, so I guess that’s what’s been really fascinating about understanding this is that mTORC1 is recruited to the lysosome when there are nutrients present. So, if the cell is in kind of a starved state, there’s not a lot around, it’s not a good time to grow, this molecule is kind of floating around in the cell not on the lysosome. And then, when these nutrients are present, it becomes recruited to the lysosome and begins saying, “Okay, we can wake up and start growing now and turning on all of these programs.” What’s really fascinating is that actually what I have sort of studied is the fact that, rather than this protein just getting recruited to the lysosome and staying there and saying okay we have nutrients we’re just gonna grow forever now, we’ve turned the pathway on all of our growth programs are on, actually this binding to the lysosome is very short-lived. And so, the cell has sort of inbuilt this system to put a brake on this growth program. So, as soon as the molecule is recruited to the lysosome, it doesn’t stick there very well. It’s a very low affinity interaction, so it’s constantly coming on and off, and that is a mechanism that the cell has to sort of protect against the possibility of having too much growth. So, it means that the system is always having to receive a positive input to stay on rather than turning it on once and having it stay on forever.

Saintsing: So, the cell is programmed to always think that it’s hungry, it needs more?

Lawrence: Basically, yeah. So, if you had a system where if this molecule goes there once and stays there forever, then it would be like, it’s — it always thinks that it’s hungry, right? But, because it’s constantly falling off, it’s always kinda – it always needs to receive a new input to say, “Yes, we’re still hungry now. Yes, we’re still hungry now.” Instead of just turning it on once and leaving it on.

Saintsing: I see. Wait — actually, just to clarify, so the mTORC1 tells the cell that it has enough nutrients to grow, right? So, when there are nutrients in the cell, there are some other proteins that recruit mTORC1 to the lysosome where it becomes activated and turns on all of these building processes, right? And then, okay so, in a high nutrient environment the cell would recruit mTORC1 and grow.

Lawrence: Mhmmm.

Saintsing: By grow, do you mean just grow in size, or do you mean, like grow and divide, produce more cells?

Lawrence: Yeah, so mTORC1 specifically is really about causing cells to grow in size. However, there are other pathways in the cell that activate division programs once the cells have reached a certain size. It’s really mTORC1 is causing cells to grow, which then generally causes them to divide in most cases.

Saintsing: And, by grow you just mean like the area?

Lawrence: Yeah, they’re literally — like the volume is increasing.

Saintsing: Yeah, so you said that this pathway is really important to diseases like cancer. How is that?

Lawrence: Yeah, so this protein molecule in this pathway is one of the most frequently mutated pathways in cancer, and some of the work that I did was actually showing that there are specific mutations identified in cancer patients that actually cause mTORC1 to get stuck on the lysosome. So, this is one way to kind of show that this process that’s actively putting a brake on the system and kicking mTORC1 off under normal conditions, when that is disrupted and you have these mutations that cause a system to stay always on the lysosome and always on, this is often found in cancer patients. And this suggests that it’s one way that the system can get misregulated. Although it’s important to realize that cancer is a very complex set of diseases, and generally there are many different mutations that occur before cancer truly develops, but this is kind of one of the, one of the risk factors or one of the components of the disease.

Saintsing: Have you looked into some cancer treatments based around this?

Lawrence: My – the professor that I work with actually recently started a company that is interested in using small molecules to disrupt this interaction. So, you know this is – it’s still a very exploratory startup company, but it’s definitely being able to understand really physically how these decisions go down allows us to actually, with a lot of precision, design therapies to target the specific event that becomes misregulated.

Saintsing: So, in cancer there are a variety of things that are going on, but, in this particular case if this were involved in the cancer pathway, then the mTORC1 would be permanently bound to the lysosome, and the lysosome and the cell would think, “Okay, I’ll just keep growing.” But, I mean, even if there’s not enough nutrients for it to grow. So, does the cancer cell just kind of grow?

Lawrence: Right. Right. So, this is — this is kind of the place where you can see how it’s important for there to be multiple different mutations happening at the same time. So, you know in this case you would definitely need to have some other mutation happening that is providing some nutrients source for the cell, and that can happen by changing, for example, glucose metabolism, changing the way that our body stores nutrients so that there’s more of it in the blood in a way that’s circulating and available to the cancer cell rather than being say stored in a fatty tissue. So, generally you need to have multiple different mutations, so things like regulating how the — you know the growth decision is regulated, regulating how nutrients are distributed so there’s actually enough nutrients for growth. There’re often mutations in the processes that allow cells to migrate because generally we call something cancerous once it’s actually metastasized and the cell is moving to new places in the body. So, you know cancer is really sort of death by a thousand cuts. There need to be, you know, many different things going wrong to really get to the point of cancer.

Saintsing: I see. So, how do you actually study this? What kind of organism first of all do you use?

Lawrence: Yeah, I work with human tissue culture cells. So, these are cells that were at one point isolated from a living person and can then essentially grow indefinitely in test tubes. So, these have, actually we call them, have been transformed so they are different from cells in our body, and that some of these breaks on the system that prevent cell growth have been bypassed. And so, they’ll sort of grow indefinitely in culture. It’s very useful to us to be able to grow them in the lab.

Saintsing: So, is everybody in the lab working on cells from the same person?

Lawrence: We have actually several different cell lines that we work on in the lab, but there are examples. For example, the HeLa cell line many people have heard of is a cell line derived from one person, Henrietta Lacks, which is used in probably thousands — hundreds of thousands of labs around the world. I don’t typically work with that cell line, but we have maybe five to ten different cell lines in the lab, and in theory they were all derived from a single person.

Saintsing: Cool. Do you — what do you do like actually do?

Lawrence: So, I really originally fell in love with microscopes and imaging, so what I can do is actually add a fluorescent tag to mTORC1, to this molecule and actually look with a microscope within the cell and watch the molecule move around in time. So, I really enjoy – I really enjoy that stuff, like getting to look at cells and watch these processes happen. And then, I also do a lot of biochemistry, which means that I purify the individual protein molecules and I can really understand how the pathway works by purifying the individual components and then putting them back together and seeing if I can recapitulate the behavior that I saw in a living cell. So, the way that we think about it is: what you cannot build you do not understand. So, if you really want to understand how a complex signaling network is built, if you can reconstitute it from its pieces, that’s a good sign. So, I’m not gonna say we’re all the way there yet, but I’ve — we’ve learned a lot of things by purifying the proteins and working with them in test tubes as well.

Saintsing: So, you get all the proteins and then like throw them together in a test tube?

Lawrence: Yeah it depends. I often use methods like fluorimetry. So, I actually put my proteins in a fancy quartz cuvette and then I can measure actually spectroscopic properties of the protein that tell me something about what state it’s in. So, actually proteins in our body have an intrinsic fluorescence and so we can take advantage of that to learn to learn things about their conformation or what state they’re in.

Saintsing: Okay, so every protein is unique because of its — the way it shines?

Lawrence: Uh, not so much. So, this is part of why it’s important to purify a protein so you have only one. So, I would say, okay all proteins in our body for example absorb at 280 nanometers. This is just you know kind of a property of proteins. So, I could monitor this protein signal at 280, and I can know that it’s due to a particular protein if I only have one protein in the tube. Then there are other things we can do, like add specific tags to proteins of interest so that we then are maybe reading at different wavelengths and know that it’s specific to that one tag.

Saintsing: Okay, I see. This is just a reminder that you’re tuned into The Graduates. I’m Andrew Saintsing, and I’m speaking with Rosalie Lawrence. So, Rosalie, you actually don’t spend all your time in the lab, right?

Lawrence: Yes.

Saintsing: You’re a scientist, but you like to get out and do some stuff, right? You were actually telling me that you like to run in triathlons.

Lawrence: Yeah, so I’ve actually always been a pretty athletic person. I swam competitively growing up. I swam in college for you know D3 at Swarthmore College, and something that has really been fun at Berkeley and has been, I think, a really great way to stay balanced and stay happy during, you know, what can sometimes be a long process of grad school, has been taking up triathlons. So, I actually like learned to ride a bike with clips pedals and went all the way from doing my first triathlon to competing with the Cal triathlon team, which is a club team on campus. So, that’s been super fun.

Saintsing: Cool, have you won anything?

Lawrence: Last year, actually, the Cal women’s triathlon team won the national title, so –

Saintsing: Nice

Lawrence: – I got to contribute to that. That was super fun.

Saintsing: That sounds really cool.

Lawrence: Definitely an experience that I didn’t anticipate having in grad school. Um, but it’s really kind of added to the experience.

Saintsing: Cool. Wow. Do you just try to do this every day? Like try to exercise, just to get out of the lab, like to clear your mind?

Lawrence: Yeah I think it, you know, kind of ebbs and flows with what’s going on in lab, but I would say I’m generally more happy and productive in the lab on the days when I get a swim in or a bike ride in to the extent that my lab mates will comment on it. They’re like, “Oh you haven’t, you haven’t swam in a while.” Like, so yeah, I think it’s something that I, you know, I think it’s — it’s great I’m in grad school to have some outlet outside of the lab. Because doing science is one of those things that sometimes everything is working and life is awesome and sometimes you go through three months at a time when none of your experiments work and it may or may not — it’s often not any fault of your own, it’s just the process of doing science is very arduous and unpredictable sometimes. So, it’s really nice to have kind of some other outlet to keep you motivated and happy.

Saintsing: So, you actually went to school, is that what you were saying, for swimming?

Lawrence: Um, well I swam like competitively there you know NCAA, but it was — it’s Division III, which means that it’s not scholarship level. So, okay yeah but I got in there. Yeah, it was awesome.

Saintsing: Nice. Did you know when you went there that you were gonna be a scientist?

Lawrence: I always really loved biology. I loved hiking, or I would say loved camping as a kid. Actually, didn’t love hiking. I loved like camping outside with my family and like wandering around and looking at flowers and just always was super fascinated by looking at the world around me. I wouldn’t say that I necessarily expected to be a scientist. I think I had a bit of a picture of what being a scientist was like that was very you know wearing a lab coat and working in the lab all the time, and being like I don’t know. I had sort of a picture of maybe a sort of isolated person before I really kind of got to college and met people who were scientists and started realizing that the life of a scientist is actually pretty awesome.

Saintsing: Was there like one class or one experience where you’re just like, “Yeah I’m gonna be a scientist.”

Lawrence: “I took actually a plant biology class in college. I was actually working in plant biology at the time, but I had this one class where my professor designed all the labs in the class to have us essentially take one type of plant or flower and do a ton of different experiments to understand how for example the reproductive system of that plant worked. Just to sort of like design our own experiments rather than many other kinds of lab courses that I had taught had been very sort of cookie-cutter, like follow the directions. And so, I think really getting to kind of jump in and follow my own curiosity and work with a really amazing professor got me interested in actually like trying to work in a lab. And then, once I had my first experience working in a real research lab, I realized, “Oh, this is like totally different from doing labs in a class.” And, I really liked it.

Saintsing: Right, so your first lab experience was in plant biology, or…

Lawrence: Actually, it wasn’t. I did my first lab experience the summer after my sophomore year of college, and I remember the summer after my freshman year of college I had gone home for the summer and worked as a lifeguard, like that was my summer job. And, I came back and realized like a bunch of my friends had gone and done all this really interesting academic research stuff, and I had no idea that this is you know even a thing that people were doing. And I realized like, oh, you know, I know I like biology. If I maybe want to do this someday, I should figure out what people do in a lab. And so, I ended up applying to a ton of different labs. I wasn’t really in a position that I could volunteer in a lab, so I wanted to get paid. So, I ended up actually working in a lab at Carnegie Mellon studying motor proteins and cells and how cargos are moved around. Um, so that was actually a different experience that was awesome, and then I came back and actually started working for that plant biology professor back at Swarthmore where I was for college. And, I worked with him for the rest of my time in college.

Saintsing: Nice. How did you end up at Berkeley?

Lawrence: I actually took a year off after undergrad and was abroad, and that project was actually also working in plants. And, through those experiences I realized that I’ve always been pretty excited about understanding basically this question of how do cells in our body make decisions. Like I would, you know, would read textbooks in undergrad, and there would be all these pictures of like blobs coming together and saying okay you know the process of cell division is governed by these molecules. And, it was always a little bit unclear to me like how do they — how do they actually know, you know, when to turn on, when to do these things. There were, I always felt like, there were these kind of deeper questions about how these decisions were made that I didn’t really understand just by reading some of the larger summaries, and I realized after actually working in plants for a while that a lot of the kind of cutting-edge work on those kinds of questions were really more in mammalian cells, which is really actually an unfortunate like consequence just of the funding situation. But a lot of really like awesome cutting-edge microscopy that I was pretty excited about was happening in more like molecular and cell biology departments. So, I applied to a bunch of a – bunch of different schools and interviewed at Berkeley and really thought it looked it seemed like a really amazing place to be both scientifically and as a place to live. So, I found myself here.

Saintsing: You’re thinking about what you’re gonna do after graduate school, right? Are you potentially interested in getting back into plants?

Lawrence: I wouldn’t rule it out. I’m not particularly unfortunately. I guess I’ll make a plug for public funding of science, you know, I – one thing that people who are in science are always thinking about are, you know, what are the areas of science where we can get funding to do our work. And, the reality is there are certain areas that are more recognized by sort of government funding than others. So, most labs for example at UC Berkeley are receiving grant money from the National Science Foundation or the National Institute of Health, which are government funding agencies funds through which are distributed actually by Congress or the budgets are partially decided by Congress, and these grants are paid by tax dollars. So, one thing to realize is that you know these basic processes underlying cancer people are studying are often really studied in labs that are doing basic science. However often the sort of decisions about what types of research are getting funded are going to be very kind of biased towards fields that have clear disease relevance. So, unfortunately plants aren’t often thought of as having a lot of disease relevance even though there’s a lot of really awesome and interesting stuff that you can do in plants. So yeah, so I’m still interested in studying something else relating to cellular decision making. I’m thinking a little bit about maybe going in a neuroscience direction but at this point I’m actually very open-minded and still thinking about it.

Saintsing: I see. Well you know plants — agriculture.

Lawrence: Yeah. Yeah. I know. When I was an undergrad actually I worked on heat stress response in plants and how plants can – some certain plants can actually adapt and grow in warm climates, which is super important as by thinking ahead to global warming for example. So, yeah, I think – I think that stuff is all really important.

Saintsing: As a graduate student, you’ve worked with undergrads that come to you much like you went to your plant lab. How is that experience from the other side?

Lawrence: Oh yeah, it’s awesome. I actually think one of the most fun things is to work with people as they’re learning how to do the scientific process and mentor them. I feel like I was extremely fortunate to have amazing mentors. I actually went to like a primarily undergraduate institution so got a lot of attention from the professor, but actually at Berkeley I’ve both kind of been involved in teaching, you know, teaching undergraduate classes as well as working with undergrads. I had one undergrad student who actually worked with me for three years, so almost her whole time in undergrad, and she actually just recently graduated and is now a grad student herself which is very exciting. But, yeah, I think getting to really kind of share the joy of the scientific process and work with someone over a long period of time so they can really develop their own — yeah, their own confidence and their own ability to design experiments and actually have original ideas that are better than your own ideas is super fun. So, I really, really enjoyed that.

Saintsing: Cool. Do you try to do mentorship with people that you don’t have in your lab?

Lawrence: So, I have actually been involved in a program called the Prison University Project, which is actually teaching in San Quentin prison. So, that’s not exactly, it’s not exactly research, but it is actually a chemistry class that I was involved in teaching where we actually do have an active lab component. So, that’s an example of definitely kind of – really kind of getting to share the love of science with people outside of the lab that I would recommend to anyone if they’re interested in doing that. It’s a really amazing program, and some of our graduates from that program actually when they left prison got jobs in labs which is amazing.

Saintsing: Yeah that’s really cool.

Lawrence: Yeah.

Saintsing: Yeah, that’s so cool. I actually had another guest who taught Spanish.

Lawrence: It’s a really excellent program, and a lot of grad students at Berkeley are involved in it. Yeah, so there’s that. I also am involved in some like inter-grad student mentorship stuff. So we have this program in MCB called “MCB Grad Network” that’s really about providing venues for older grad students to kind of have a reason to talk with younger grad students and kind of talk to them about the process of going through challenging aspects of grad school like choosing a lab or taking their quals. So, being involved in that has also been fun to try to hope that some of the hard-won knowledge that you have gained could help someone else, and that’s been fun as well.

Saintsing: We’re coming up towards our time limit. Is there anything that you would like to say? You kind of talked about science funding, but are there any other things you’d like to share with the public or make a plug for?

Lawrence: I guess maybe my only other weird or interesting perspective is having the perspective of having worked abroad. So, I actually did research for a year in Southern Africa and Botswana after undergrad, and a really eye-opening experience for me there was realizing the extent to which really amazing science can be done all over the place. And, there are awesome scientists all over the place. However, the opportunities to do science really vary depending on where you are, and I think something that’s really valuable is ensuring that there are opportunities for people to do good science all over the place. And, part of that actually in practice can actually mean making it easier for scientists to cross borders. So, many of the people that I actually worked with in Botswana are now you know in labs in the UK or in the US, and so, I think making sure that we continue to have programs to allow scientists to collaborate internationally and make the visa process not too hard, that’s something that I think is also very important.

Saintsing: Very true, very true. Thank you so much for being on the show, Rosalie.

Lawrence: Thanks for having me. This was really fun.

Saintsing: Yeah, tune in in two weeks for the next episode of The Graduates.