Season 6 - Episode 616
DNA replication and repair is a constant process with implications for health challenges like cancer, infertility and more. Michael Trakselis, professor of biochemistry and director of graduate affairs in Baylor Chemistry and Biochemistry, is a leading researcher into this process. In this Baylor Connections, Trakselis helps listeners better understand DNA replication and repair and its impact on human health, and examines the impact of graduate program growth on chemistry and biochemistry research.
Derek Smith:Hello and welcome to Baylor Connections, a conversation series with the people shaping our future. Each week we go in depth with Baylor Leaders, professors, and more discuss and important topics in higher education research in student life. I'm Derek Smith, and today we are talking at DNA Cancer Research and more with Dr. Michael Trakselis. Dr. Trakselis serves as professor of biochemistry and director of graduate affairs in Baylor's department of chemistry and biochemistry. Trakselis's research focuses on DNA replication and repair a process which carries implications for cancer formation, fertility and more. His work has drawn significant funding from organizations like the National Science Foundation, National Institutes of Health, and more. In addition to his teaching and research, he serves as Director of Graduate Affairs helping grow the department to more than 110 graduate students. And he's with us today on the program. Dr. Trakselis, thanks so much for joining us. Excited to dive into your work today.
Michael Trakselis:Yeah, thanks Derek. Appreciate it.
Derek Smith:Well, looking forward to learning more about what you do. So let me ask you this. When you're talking to someone outside of higher education and have a conversation, they ask you what you do and you tell them, are there common questions you receive? Are there some are questions that you've heard a lot over the years or common responses?
Michael Trakselis:You mean before the long pause or after the long pause that happens? I think the thing that we want to get into is people are really interested in something. They're passionate about, something, they're curious naturally about things, and so just being able to connect with people on different levels about the research we do, being able to talk about it at different levels or connect with some things they're familiar with, I think that's a really important thing for professors to do and for just people in science to do in general.
Derek Smith:Well, I'm looking forward to diving in as we talk about DNA replication repair, what that means, what the implications of that are, I gave a brief description at the top of the show. How do you describe what it is that you do?
Michael Trakselis:Yeah. I think we're like a discovery team. We look at biology, we don't understand it, and we try to use tools to reverse engineer our understanding of what's going on. So everything that happens in the cell is super complicated and dynamic, but we need to break it down. We need to take it apart, peace by piece, and then we can really have a better understanding of what happens. And this is definitely true with DNA replication and repair. It's quite a complicated process. In fact, there are multiple different processes that go on there, but we'll use different tools. We'll just investigate from one direction or hit it from a different direction and we'll see what we can uncover.
Derek Smith:Visiting with Dr. Michael Trakselis, and you talked about reverse engineering a bit. Are there some specific questions that drive your work?
Michael Trakselis:Yeah. I mean really it's a basic question. It's like why and how? It's like how does it work as a really a model for our laboratory. Why is a different question. So from a reverse engineering standpoint, it's more of the how question. It's just how does it work, how can we take it apart and put it back together again, both from the bottom up and the top down perspective, and then maybe meet in the middle someday and then get a really good understanding of what's happening inside the cell.
Derek Smith:Visiting with Dr. Michael Trakselis. And as we dive in, again, you talk about this as a process that has implications for health disease, for fertility, and so many different things. Let's go back to science class. For those of us who haven't been in science class in a while, you and I are sitting here right now. There's stuff taking place in US that we're not thinking about. So could you give us a little bit of a DNA replication and repair 101? Help us see this through your eyes a little bit.
Michael Trakselis:Yeah. At the really basic level, it's just maybe a handful of reactions that are taking place over and over and over again. The genome that we have in our bodies is 3 billion base pairs long. So we need to replicate every single one of those every time before we can do cell division. So it's that process of replicating, it's connecting, it's piecing back together. It's a massive, massive puzzle that needs to be resynthesize every time you do DNA replication. So at the basic level, several enzymes do this, but they're super efficient and it just gets more complicated as you go up towards the human cell system.
Derek Smith:Why is it doing that? What is that accomplishing?
Michael Trakselis:Yeah. So it's a way to maintain our genetic information, to pass it on from generation to generation. It's involved in evolution of species on our planet and looking at different genomes from other organisms and comparing and contrasting the differences that are going on. But it's a way ultimately just for survival. It's our ability to pass down genetic information to our offspring. And that occurs really with all lifeforms on our planet. So that's a super important process.
Derek Smith:So what happens, Dr. Trakselis, when things go to right, maybe no news is good news, but what also on the other side of the coin can happen when things go wrong?
Michael Trakselis:When things go right, it's what you see in the textbook. It's what we teach in biochemistry. Everything is super efficient and well orchestrated type machine. In reality, it's never the case that happens. Every process goes wrong. So if you just take those five basic enzyme activities, they have to work in concert to one another, they have to be playing off one another, one can't be more active than the other. There has to be a really good balance of all the different activities. So if things go wrong, we get a lot of DNA damage, we get mutations that occur, we get breaks to our genome. All of those things create what we call genomic instability. And that genomic instability is what leads to various types of cancer. And I think probably all of us have some experience with in our family and friends. So it's those processes we are studying and trying to figure out.
Derek Smith:We've talked about over 3 billion pairs. We've talked about the replication. I want to make sure I don't go past asking you specifically we talk about replication. What's the repair part of that?
Michael Trakselis:So replication makes a perfect copy and it's a 3 billion base, perfect copy. But you can imagine over 3 billion bases, there are times or situations where maybe things don't go perfect. So it's a mistake to one of the bases. It's a insertion maybe or of one base over the other. It's a change of a base. So all those things can create mutations either or damage events, and those things just need to be repaired. So it's okay to make a damaged event or a mistake during DNA replication, but you have to have a process to fix it. And I'll just give you one example that I like to use in class is every day in our cells, every single one of our cells has 100,000 DNA damage events per cell per day. So we make mistakes during replication, but we have many different mechanisms to fix them.
Derek Smith:So you think 100,000 sounds like a lot, I suppose out of 3 billion, that's a pretty good percentage. And most of this, the body naturally takes care of?
Michael Trakselis:100,000 is not a lot in the context of 3 billion, but just keep in mind, one mistake can give rise to us cancer cell or so the beginning of cancer. So yes, you have to balance those numbers for sure.
Derek Smith:Okay. You talk about it can have an impact on a cancer event or other health problems. What are some of the human health implications we see when it comes to replication and repair?
Michael Trakselis:First of all, a lot of people have genetic predispositions to cancer. You've probably heard about some of them, including the breast cancer genes, BRCA1, BRCA2 in particular. It's a routine screen for several different genetic causes to cancer now. Those are mutations that have occurred in those genes that allow cells to either over replicate or have uncontrolled replication. And you can just think about cancer as there replication gone wrong. It's over replication of a cell. It's creating a mass of cells that build into a tumor. So those basic processes can go wrong if they're not controlled. And that's what a lot of the cell is meant to do is control the basic process of replication. It's got to be efficient, fast, controlled, and also fixable.
Derek Smith:Visiting with Dr. Michael Trakselis. So this pretty enormous puzzle to study that you and your students and other colleagues in this areas are taking a look at. You mentioned tools at the beginning of the show. What are some of the tools that you have at your disposal to try to reverse engineer this?
Michael Trakselis:I was trained as a biochemist. So we think about originally or early in my career, thinking about basic reactions inside test tubes. But as a professor, I maybe I get easily bored with some of those techniques. So we build in other tools, things that I'm not experts at, but we can bring in collaborations or other people or just really a willingness to learn new techniques. So we've applied genetic tools, which is something I was never really trained in. We've utilized mass spectrometry. We use single molecule techniques to look at individual molecules of DNA on a surface or a slide, all kinds of different tools. In fact, just thinking about the work we do, we're not really an expert in any one particular technique. It's the biological understanding of replication and repair that drives us and we'll approach it from a lot of different directions.
Derek Smith:Are there some common directions, some common inroads that are really the foundation of what you do?
Michael Trakselis:Going back to what you asked me before about the question, it's really the question of how, and so we want to have a mechanistic understanding of what's going on. So from the atomic level, from the molecular level, from the protein level, from the DNA level, what are the interactions that are occurring? What are the dynamics or the comings and goings of different enzymes as they do their processes? It's very, very dynamic and super fast and efficient and we're probing all of those things.
Derek Smith:How much has increased computing power? Has that impacted your work a great deal?
Michael Trakselis:It's starting to for sure. Just having access to the human genome project, which was now over 20 years ago or 25 years ago actually where it came out. I mean, just looking at cancer genomes, for example, from people, it really starts to help us understand what mutations give rise to certain diseases and where those diseases come from. What is the genotype of a particular person and how does it contribute to a disease progression that they might have? So really computing power at the level of genomics I think is becoming a more and more important for our work.
Derek Smith:This is Baylor Connections. We are visiting with Dr. Michael Trakselis, professor of biochemistry and director of graduate affairs in Baylor's department of chemistry and biochemistry. And you've had a lot of research projects that have gone some interesting directions that whether it's with the NSF, NIH and others. Could you take us inside a couple of those? What are some projects that have been particularly meaningful or interesting to you?
Michael Trakselis:Yeah. I'm really fortunate to have a really diverse group of scientists working for me in my lab. And it just allows us to have a couple of different projects going on where we can focus on different areas. So maybe I'll just highlight two. One, I talked about efficiency of DNA replication, the textbook model of DNA replication. A subgroup in my lab is really interested in what happens when that doesn't occur when we get what we call decoupling or thinking about all of those enzymes working together, but now they're decoupled, they work independently or one has more effect than the other. And what implications does that have in genomic stability? So what we see when we decouple replication is more breaks, more DNA breaks, more mutations, more prone to cancer type phenotypes. So coupling is becoming a super important thing. It's just coupling of enzyme diverse enzyme activities. So that one is really exciting and that's funded by the NSF. The other project that is really interesting at the moment is our links to infertility and cancer. So we've helped discover a couple genes called MCM8 and MCM9, where mutations in those genes gave rise to infertility or ovarian insufficiency in women. So that's the phenotype, that's the what happens when you have mutations in these genes. And then it was really our job afterwards to go out and figure out, well, why is that? What is the molecular reason for this infertility or single mutation in a gene is now giving rise to infertility and then coming up later and seeing that it's also implicated in various types of cancer. So it's connecting cancer and infertility in a way we didn't understand before and only are just starting to understand now.
Derek Smith:Visiting with Dr. Michael Trakselis. So obviously you're breaking down some huge human challenges like disease, like infertility into bite size, at the smallest possible level in a lot of ways. How much do those big questions, how much do they impact your day-to-day work as you think about them, how much is it that focus on at the molecular level that can eventually give rise to those bigger problems?
Michael Trakselis:Yeah. We're always thinking at the molecular level, but we try not to lose sight of the bigger picture. So that really just allows us to bring in, like I said before, different techniques to study the problem. As far as these two genes, MCM8 and MCM9, maybe they become a target for cancer therapy in the future, but before that happens, we have to understand them at the molecular level and understand are they a viable target for chemotherapy or a combined chemo chemotherapy? So those are things we're trying to identify first. So yeah, we're focused on the molecular level, but we're thinking about the disease level and how we can help them.
Derek Smith:Visiting with Dr. Michael Trakselis and as we talk about your division, there's a lot of professors in chemistry and biochemistry doing great research that has implications for cancer and health in other ways. And you know mentioned we work with faculty who have tools or expertise that are different than yours. One of those is Alyssa Gallagher we've had on the program before mass spectrometry. Tell us about that a little bit. And then also if you would elaborate more on what it's like working in a division where you've got a lot of great people doing a lot of great work in different areas.
Michael Trakselis:Yeah. Such an important point. So I really knew nothing about mass spectrometry. That's the best part of being a professor. We get to learn new things too. But Dr. Gallagher does, I mean, she's an expert in that direction. So living at the interface of science, in between biology and mass spectrometry is an area not a lot of people work in. So we had a conversation in could we do this in the mass spec? Can we understand a particular question? So we're really one of very few people that look at protein DNA complexes in the mass spectrometer, trying to understand how they bind, what their affinities are, how they assemble on DNA. And just having Dr. Gallagher in our department is really important for us to build new areas of science.
Derek Smith:How much better of a picture does do mass spectrometry tools give you than what you would find without?
Michael Trakselis:The high resolution is great. We're applying mass spectrometry in a slightly different way than most people do, so we're using it to look at a stability. You can just think about something interacting with something else. We're looking at the strength of that interaction. How strongly do the one things interact with something else, but in the gas phase, in the mass spectrometer, and so that's the novel part of it. These are also DNA replication proteins. So it leads back to our DNA replication work of how strong a complex are we talking about? What's the assembly mechanism for these proteins, but can we look at it in a novel way? And that just provides another angle to study this problem.
Derek Smith:As we talk about your work, as we shift to your work with graduate students, I'm curious, could you give us an insight into how big of a role students play in this research that we're talking about graduate or undergraduate?
Michael Trakselis:Yeah. I mean all of it. They are so essential and having great PhD students and undergraduate students contribute to these projects are essential to what we do. It's not often I get into the lab anymore. I definitely want to, and I definitely try to, but my students are doing 99% of the work in the lab. So having strong, smart, engaging, dynamic students to help tackle these problems from different directions is really very, very important too.
Derek Smith:So they're rather important. You play a role in helping bring graduate students here, whether it's to your own lab or others within your division, the director of graduate affairs. What all does that entail in chemistry and biochemistry?
Michael Trakselis:Yeah. So I've been the director of graduate affairs for six years now in our department. And really our goal or my goal at the time was to grow the graduate program. We started with around 55 students or so, and we've just about doubled it in our department to over 110 over those six years. And a couple of the things I'm proud of in that growth period is we balanced out the male to female ratios. So we've increased the number of female graduate students in our program to be pretty much 50/50 with the male students and also bringing in international students creating more diversity and interests and from elsewhere across the globe and building our program at the same time. So super excited and happy about the growth of our program. It comes with having strong faculty in our department as well.
Derek Smith:You mentioned strong faculty of answers, at least in part what I was going to ask you. What are some of the factors that you've seen that have lead to that growth besides your great recruiting skills, of course?
Michael Trakselis:Yeah. I mean the commitment by the graduate school has been very important for the growth of our department and our students, but providing support for teaching assistance for our students. But really the strength in hiring of faculty in our department has also led to the growth of our department because we have so many more faculty are doing great science and getting external funding. So we have more than half of our students supported by external funds throughout the department. So if we can grow externally and internally both, then we can really grow the total population.
Derek Smith:We need to talk about faculty. We had Sara Dolan from the graduate school on a few weeks ago, and it sounds like maybe for people who don't know, I think when you're thinking about undergraduate, in a lot of cases students are like, "Well, I want to go to Baylor, or I want to go to this school, or I want to go to a school that has this." But how important are the faculty when you think about graduate students, many of whom are like, "Well, I want to work with a faculty doing this and this faculty at Baylor's doing that?"
Michael Trakselis:Yeah, I work closely with Sara Dolan. She's great in the graduate school, but I think that's happening more and more in our department. We're hiring really excellent faculty members, and so students are now coming to Baylor to work with certain faculty in all areas of chemistry in our department. So yeah, I mean, that's a big attraction, having a smaller research group, and we advertise it as a way to get really good hands-on training with high level instrumentation for students. So being able to work really closely with faculty is a big benefit for those students that come here.
Derek Smith:Your division has done a lot of research over the years. R1 is a metric that the university reaches as a whole, so maybe saying that you've been doing R1 level research isn't quite the right way to put it, but I think that idea that chemistry and biochemistry have been doing great research for a long time. How much have you seen that impact growth within the school and what opportunities does that provide?
Michael Trakselis:Yeah. I came to Baylor in 2014, and really I saw potential there for that growth, and I saw the chemistry and biochemistry department leading the way for the research output and research funding area, and I was really excited to be a part of that direction and growth for the department and super excited to reach R1 just a year ago or so. But yeah, I think we've been a leader in our department. We have a lot of great external funding. We're developing relations across the university and across the world, and all of that goes into being R1. And yeah, we do feel like we were there several years before, but now, so pleased that the university is as a whole.
Derek Smith:Visiting with Dr. Michael Trakselis. And Dr. Trakselis, as we head into the final moments here, I just want to ask you, what's on the horizon that you're really excited about? What do you see that you're really anticipating in the months or years ahead?
Michael Trakselis:Yeah. Well, it changes all the time. I mean, today we're submitting a paper on some of this MCM8 to 9 work, and I'm super excited about it that at the moment, but tomorrow we turn the page and we're going to work on our next paper to submit it, so it changes. But the coupling aspect of replication, how we maintain an efficient cellular system to replicate the genome is still a fascination to me and so many different directions we can take. So it's really going to be a focus over the next year for us.
Derek Smith:Well, we'll look forward to seeing that and more good news from your research group in the years ahead. Dr. Trakselis, really appreciate you taking the time to join us today.
Michael Trakselis:Yeah. Thanks, Derek. I really enjoyed it. I'm a big fan of Baylor Connections and happy to do it.
Derek Smith:I appreciate that. Glad we can have you to talk about this topic that we haven't been able to share before. So this'll be great as we share this. Dr. Michael Trakselis, professor of biochemistry and director of graduate affairs in Baylor's department of chemistry and biochemistry, our guest today on Baylor Connections. I'm Derek Smith. A reminder you can hear this and other programs online at baylor.edu/connections and you can subscribe on iTunes. Thanks for joining us here on Baylor Connections.