Cryo-Talk interviews Bret Freudenthal (University of Kansas Medical Center)

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Eva Amsen: Hi! And welcome to cryo-talk. I'm a for amson, and i'm here today. With Britt

Eva Amsen: Brett is associate professor in the department of Biochemistry at the University of Kansas Medical Center.

Eva Amsen: His Research Group studies the connection between DNA damage and Human health.

Eva Amsen: Hi, Br: how are you today

Bret Freudenthal: doing well, doing well? Thanks for having me on

Eva Amsen: looking forward to our conversation, and I know you're in Kansas now. But can you tell us a little bit about how you got there and what you've been doing so far with your career.

Bret Freudenthal: Yeah, yeah. So as you said, we're in

Bret Freudenthal: at the University of Kansas Medical Center here in Kansas City. And so it's like many, I guess, academics. We took a long journey to get here, so I was born and raised in shy in Wyoming, and then, when I turned 18, I headed to the neighboring State of Colorado, where

Bret Freudenthal: I got my undergrad degree in the Department of Biochemistry at Colorado State University. Then, after that, was weighing whether or not to do Med school or graduate school, like many of us do, and ultimately decided graduate School is a better

Bret Freudenthal: approach for me, and transition to the University of Iowa, where I got my Phd. In the lava, Dr. Todd Washington, and that was really the first place I started.

Bret Freudenthal: understand the importance of DNA damage and sort of the connection to human health. And so then, once I completed my Phd. I pushed even further east out to the National Institute of Environmental Health Sciences and Raleigh, North Carolina, and cited my postdoc there with Dr. Sam Wilson and studied basic decision repair, and really got into

Bret Freudenthal: turning out lots of different crystal structures and really focused on actually crystallography during that face of my career.

Bret Freudenthal: and then finally we pushed back to the University of Kansas. For me and my wife moved here, I guess, would be end of 2,015, which seems like a a short amount of time, but actually on the calendar. It's quite a while. So when we push back to the University of Kansas. We have 2 little boys.

We came here, and we started raising our family and open the lab, and really enjoyed it here.

Eva Amsen: Cool Sounds like you've been all over the Us.

Bret Freudenthal: Yes, yeah, we have. So yeah, it's been nice now, being in the center of the country, so we can kind of fly around and see if it's a little easier.

Eva Amsen: Yeah, that's good.

Eva Amsen: And I I find that interesting that you're working on the link between DNA damage and human health. Because I think for many of us that's something we we know is obviously there is a connection. But at what point did you realize that there were still many unanswered questions and lots of work to be done.

Yeah, I guess I guess for me, I've always

Bret Freudenthal: part of the frustration came about early in my graduate career, where

we would study

Bret Freudenthal: context of DNA damage DNA repair. But we really didn't seem to understand any of the mechanistic details about them. A lot of the work was being driven by industry and still remains driven by industry in terms of developing drugs with beneficial human health impacts. But we don't always understand how those drugs work, and how the proteins that we're targeting actually function. And so I think

Bret Freudenthal: that's been a major driver of my career is actually understanding the mechanistic details of these proteins, and how they interact with DNA to protect the genome, or how they actually can drive evolution of just a bit by promoting more and more mutations. And so that's always been fascinating to me, and and just a reductionist approach to. I feel like all things funnel back to

Bret Freudenthal: our genome. I'm a little biased in that capacity, but I really feel so. It's always been interesting to me. And then I think, as scientists, we always have to do something

Bret Freudenthal: that benefits the larger society as a whole, and so, I think, keeping human health in the background. I would say that we are a basic research or fundamental research lab at our core, and that's kind of the the goal is we're going to find out how these enzymes work, or how these proteins work, and then hopefully provide a better foundation for industry and people to develop drugs.

Eva Amsen: Hmm.

Eva Amsen: And so what what what kind of research projects have you are going on at the moment in your group

Bret Freudenthal: DNA. Repair factors can go and work within a chromatinized environment. So what does that mean? So what that means for us is that we're actually using cryoem to look at nucleus on core particles, and how DNA that's damaged and subsequently be identified and repaired in the context of a nucleus on core part.

And why this is important to this nucleus on core particle

Bret Freudenthal: is has a protein components referred to as his stones, and

Bret Freudenthal: in order for pro in order for the DNA repair factors to find the damage and actually engage the damage. They sort of go with this. What? It talented postdoc my lab terms as a tug of war.

Bret Freudenthal: And so they're kind of fighting this nucleus on core particle to get at the DNA damage and get it away from the protein, so that they can start to actually repair, and by repairing it they need to subsequently remove the damage base and put in a new new base, and subsequently mig it.

Bret Freudenthal: So we're using to actually understand that at relatively the atomic level, I would say.

Eva Amsen: And what if you choose, cry oem for that particular project? What makes it so useful?

Bret Freudenthal: Yeah, yeah. So I think probably i'm really useful for that, because nucleus on core particles are very, very amenable to that. And so we use them almost as a

Bret Freudenthal: They're biologically relevant scaffold. But They're really also a nice scaffold. They form nice little circles. You can nicely see on the grid this the the conditions are fairly well established, and really the hard part then becomes forming complexes between an equivalent core particle and a different DNA repair proteins. And so that takes a lot of troubleshooting and a lot of hard work. But.

Bret Freudenthal: Carly, I'm really the most amenable approach to look at that. And then we complement that with x-ray crystal structures that are a much higher resolution of these repair proteins bound to

Bret Freudenthal: just naked DNA. So no nucleus home bound at all. And so we can kind of complement the 2 approaches to get a better sense of how it works as a whole.

Eva Amsen: Hmm. Yeah. So I I saw your your research website that you use, like many different techniques to approach any individual problem that you're looking at. So

Eva Amsen: So

Bret Freudenthal: yes, yeah, it seems like you have to do a little bit of everything nowadays to kind of get the full picture.

Eva Amsen: And for for cryoem, do you have a local machine or facility that you use?

Bret Freudenthal: Yeah. So actually exciting news here, which I think is kind of what brought us here is that we're gonna be installing our opening a local crime facility here at the University of Kansas Medical Center, and so that will open May ninth or sometime the month of May.

Bret Freudenthal: And so we're getting a glaciers for the selectress detector. And so we're pretty excited about this opportunity to be able to bring cryoem to the State of Kansas, because we really not had that facility at all. Here there's something there's neighboring facilities that I were sorry, but nothing really in the State of Kansas or

Bret Freudenthal: local.

Bret Freudenthal: So what if you'd be using until now.

Bret Freudenthal: barreling down the scientific pipeline, if you will. And so we had to find a way to Pivot to be able to start to utilize Korean and one of the early frustrations, I would say, from about 2,015 till about 2,017 for myself, was the lack of access. Right? It's an incredible technique, but you could never find any access. And so

Bret Freudenthal: I really give the Nih and the Federal Government a lot of credit for opening and funding national facilities, and really backing those financially. And so the ones that we've been using is Pncc.

Bret Freudenthal: And that's a Pacific Northwest, I think, Cryoem Center. It probably has a bigger acronym for that. But nevertheless, we've been using Pn. C. And they have been just an instrumental source for us for both

Bret Freudenthal: sending samples, figuring, helping troubleshoot samples. We also are able to analyze data there. And so we've been generating the samples here and then subsequently shipping them up to Pncc. And then we'll analyze the data there, and so that what that was really instrumental for us was just getting our

Bret Freudenthal: foot in the door and starting to get some momentum behind our projects and figuring out what would work. And so, once that momentum started to pick up, we were, we were able to kind of leverage those results, and also leverage the exciting time from sort of the 2,018 until now. For cry. I am to help convince people

Bret Freudenthal: that we need to have facilities here. And so I think these

Bret Freudenthal: national facilities are instrumental in sort of drumming up support, if you will.

Eva Amsen: Hmm. Yeah, that's actually my my next question. I do you think that's like shared large shared facilities like that? Make cryoem also more accessible to people who are just want to try it out, or maybe just use it occasionally.

Bret Freudenthal: Yeah, yeah, I mean, I I think it parallels what happened back when I was in graduate school synchrotron for extra crystallography. And so I think what it's. These national facilities are just, I think one of the biggest things to happen to Kirly. I'm outside of just sort of the we all talk about the resolution revolution, but I really think these national facilities are what's important, because there's lots of

Bret Freudenthal: schools and lots of people that Don't have access to priori and need that access, and they need that access without the burden of cost. Right? So you have big bills associated with Chry, I. If you go to a private facility or a local facility, whereas the national facilities, you don't have these bills, and so I think it's been important for states like Kansas for the work, which is an idea. State

Bret Freudenthal: the State that doesn't get large amounts of Nih funds. And so

Bret Freudenthal: we're a state where I think smaller schools, as well as even schools like ourselves can use these national facilities, and my my ultimate hope would be to start to see

Bret Freudenthal: these national facilities continue, and P. And C. Is a big advocate of this, that to continue to push into trying to support other States that have really no access to Chry, and whether it be a States like my home state like Wyoming, I'll use it as an example where it feels like. Oh, this is an awesome technique, but I don't even know where to go to do this. And so I think these national facilities.

Bret Freudenthal: our key component to that outreach, and also, I think we'll facilitate bringing the cost down, training the next generation of scientists and making it more accessible to everyone to where it becomes a tool instead of only the

Bret Freudenthal: wealthy labs could do it. And so I think that's been a huge push.

Bret Freudenthal: My credit to Federal Government and the National Institute centers for that.

Eva Amsen: Yeah, definitely. A good way for people to to just get to know it, even if it not. Everyone has a big facility.

Bret Freudenthal: Yes, yeah.

Eva Amsen: Hmm. But you are very exciting to to get your local facility set up. Do you have any plans for it? Do you know what you're going to do first.

Bret Freudenthal: Yeah. Well, you know, hopefully everything goes smooth. So right now, you know, the first thing we want to do is get the equipment here. I think it's. I don't know if it's formally shift, but it's in the process. So you know, as as you know, with these things it's what you don't know. So we're always worried about the things that we don't know, but so far

Bret Freudenthal: it's going really well, and I think some of the first things we're gonna do is have a little symposium where some trainees can give some talks here and try to. Right. Now we're doing a seminar series and have had different speakers come through, and so

Bret Freudenthal: I think probably the first thing we'll do is open it up to local users as well as anyone that wants to use it.

Bret Freudenthal: But some of the first projects will probably be scouting out with a handful of labs at working such things as Nucleosome Trust, or there's a proteasome and kind of start to get the work flow up and going, and we anticipate, hopefully starting to get, or I personally anticipate, hopefully starting to do a little bit more outreach to the smaller schools.

Bret Freudenthal: and maybe try to funnel in some of the undergrads as well. But that is something that's going to be sort of down the line if you will. So I think the first goal for us is to get it up and going and work out any kinks that there may be, even though Thermal says it'll be none. But you always very little bit about the unknown.

Eva Amsen: Yeah, get it all working. Yes, yes, it's seminar series. Sounds interesting as well. And yeah, yeah, it's been. It's been nice. We had a recent talk by Greg, by Dr. Lander out here, and so it's been exciting to have the seminar series where a medical center. And so there's not a lot of

Bret Freudenthal: There's not a lot of awareness around structural biology here, and so I think the the seminar series has really had about 100 people at each seminar, and we've had different folks come out and really starting to show enthusiasm for the approach and trying to implement it into their program. Because one of the big things is as well. What do I do with this? And how do I make it work? They all know it's exciting with how they actually implement it. So

Bret Freudenthal: we've been working a lot on that.

Eva Amsen: And and what's next for your research?

Bret Freudenthal: Anything you're worried about. Yeah, I would say so next for our research, you know, at this point we've

published a paper. So we work on the basic Decision Repair Pathway, which is a a DNA, one of the subsets of the DNA repair pathway. And so we've solved one of the enzymes. I think there's I would say. There's about 6 or 7 enzymes in the pathway depending on how you define it. When we solved one of the enzymes, bound to its cognitive form of DNA damage it's preferred form of DNA damage. And so now what we're trying to do is look at how the other enzymes within that pathway, all function. And so that's been a big push for us, Kyram related. You know we

you kind of you get the system up and going. And now you're like, Well, what about this inside? You know very

Bret Freudenthal: classic scientists. Right? Let's start working down the pathway. And so I think we're going to start looking at that as well as starting to look at larger complexes. And so I think that's been the big push for us.

Bret Freudenthal: as always. I think it's programs wonderful, but you know it's it's a slow process in terms of data analysis and working through that. So it will have plenty of years of work left on this topics. That's good. You won't get bored. No, no!

Eva Amsen: And and what do you do when you're not working. Do you have any hobbies?

Bret Freudenthal: Yeah. Yeah. So I mean, I think the

Bret Freudenthal: the big thing that I do when i'm not working is to to spend time with the family, and I've got 2 boys that are 7 twin boys that are 7 years old, so I spent a lot of time with them one of their soccer games and things. We actually are headed out next week for the spring break on a ski trip. So, being from Wyoming ice, hunt and fish, and

Bret Freudenthal: I guess I technically snowboard. But we refer to it as a ski trip, and so we're taking. We're teaching the kids how to ski. So we're headed out to do that for the next week, which should be fun. They're sort of still adjusting to the fear of the lyft, which is always scary at that age, but they be enjoying it. So that's

Bret Freudenthal: that's probably kind of the things that I like to do. Try to get outside.

Bret Freudenthal: you know, or hang out with frowns. Great it! I love watching little kids ski because it's like they have no fear at all. They just don't think about falling, they just go. Yeah, yeah, it is fun watching them, you know. Kind of learn the pie and the fry and everything. So it's they they're they're just budding skiers.

Bret Freudenthal: I guess you don't have very far to fall when you're on the middle.

Bret Freudenthal: but it's also the fun part. Yeah. Absolutely

Bret Freudenthal: kind of a round of quickfire questions.

Eva Amsen: So do you enjoy traveling?

Eva Amsen: I know you've been all over the country.

Bret Freudenthal: Yeah, yeah, yeah, absolutely. I mean, that's by by far. Probably one of my favorite things to do is go on different trips, or we we're hoping to try to get back overseas with the pandemic. It's kind of limited our, but we need to travel overseas, but a spot me and my wife are Iing is trying to get back out to Italy. We went out there.

Bret Freudenthal: I guess it'd be 4 years ago now, so like to get back out there, but otherwise

Bret Freudenthal: travel a lot within sort of the North America area. Lots of ski resorts, or my wife is much more of a beach person. So we recently we're in Florida, spend some time out on the beach with the kids.

Eva Amsen: and they like to read. So you have any book recommendations for us.

Bret Freudenthal: Oh, man! Oh, unfortunately, I must admit that I am the person that doesn't like to read as much for fun anymore. So which is a bad and embarrassing thing. And i'm i'm hoping I was talking to my wife about it, trying to get

Bret Freudenthal: back end to reading. So it's something I should try to enjoy more. But lately the free time that I've had. I've been doing more kind of house project for renovating our basement. So i'm spending time doing that, and

Bret Freudenthal: and i'm convincing myself, so I unfortunately don't have good book recommendation. I should be a better scientist on that front. But I think the writing and reading of the the job makes it where, when I go home I like to do stuff with my hands

Eva Amsen: things on screen films or TV.

Bret Freudenthal: Oh, yeah. So yes, yeah, we yeah, we do like to

Bret Freudenthal: do. You like to watch shows. So it's actually been watching, I guess. Relevant right now. We've been watching the last of us, which is a show on Hbo Max. Right now that we're watching. And so I really enjoy that style of

Bret Freudenthal: that sort of style of show. And so that's been something that we watched actually last night Me and my wife did, and so it's been interesting. I I sort of like these

Bret Freudenthal: sort of end of the world things in sort of how humanity would deal with that. So I've always found the social dynamics interesting within those films.

Eva Amsen: Yeah. And there's there's so many in the genre, and it's it's it's it's it's scaryly close to home that can really happen. And

Eva Amsen: and what about do you like cooking? Do you? Do you do that at all?

Bret Freudenthal: Get more and more, I think. Actually, this yesterday was nice. Here I was sort of had a nice break in the weather, and so it's got up into the seventies. And so I ended up smoking

Bret Freudenthal: what's called a it's called a copa, which is basically it's like a pork shoulder. And so we smoked that and do sort of pulled pork, and had some friends over, and so I I really like to grill. I definitely like cooking in the kitchen as well, but I much more prefer to be outside on the grill, or making habiters or steaks, or kind of doing the whole barbecue thing, which is a big Kansas City.

Bret Freudenthal: Yeah, and it's it's it's almost spring and summer. So we're milling ahead. Yeah, we're in that time of year. Here where it swings, temperature kind of swings from about 30 degrees. So you know, I think today it'll hit 60, and tomorrow the high, maybe 40. That's kind of the spring in the midwest, where

Bret Freudenthal: just we have these big temperature swings.

Eva Amsen: It's hard to prepare for. But

Eva Amsen: and what about music? Do you listen to music at all?

Bret Freudenthal: Yeah. Yeah. So I guess there's kind of 2 styles that I would listen to generally. So if i'm working or writing, it tends to be sort of more classical or jazz music to try to keep me focused on what i'm working on. So that's what I would listen to with that.

Bret Freudenthal: Otherwise i'm very much a a nineties kid, and grew up listening to nineties hip, hop, and rap, and so I tend to listen to that style. And now I've kind of transitioned a little bit more probably with the kids more into kind of the

Bret Freudenthal: the pop genre that we'll listen to with our kind of electronic music. So it's kind of a spectrum. We listen to a little bit of country, but not a lot. I grew up listening to a lot of country being in my opening, and so kind of shifted away. But the 90 s sort of wrapper I had a big influence on my style of music.

Bret Freudenthal: Yeah, that's a that was a big era for rapture. So yeah, growing up in the nineties. Yeah, it's can't played around the kids, and it's always. But we're still. Listen to it

Eva Amsen: sounds like you have a lot of different things to listen to. That's fun. Yeah, absolutely. And this is a question that I always love asking scientists if you are not a scientist, what would you be?

Bret Freudenthal: Oh, that is a good question. So

Bret Freudenthal: if I wasn't a scientist, I would probably.

Bret Freudenthal: you know, let not withstanding the financial aspects, but I actually would. I always thought it would be interesting to open kind of a speak easy, like a cocktail bar, so I've always enjoyed the settings of cocktail bars and sort of restaurants like that to where you can get together with sort of

Bret Freudenthal: other friends and adults and kind of a camaraderie associated with that. So I actually think that probably would be something that I would actually really enjoy doing. I mean, I recognized as the challenges of that industry to do it. But that's something that I have always

Bret Freudenthal: always kind of wanted to go and be able to do is go open a nice adult cocktail bar with some sort of food component to it.

Eva Amsen: and it's still kind of sciencey. It's. It's making cocktails always feels like doing a science experiment to me with the careful measurements. And absolutely yeah, and it's always nice to get together, you know, with friends and chat about things and catch up. So it's always been something I thought would be a fun thing to do, being part of the community as well.

Eva Amsen: Hmm.

Eva Amsen: But leaving the cocktail bar going back to the lab. Do you? Do you enjoy mentoring students? Yeah, yeah. I I would say that it's by far the part of the job that I enjoy the most. It's a part of the job. That, I think, is

Bret Freudenthal: probably the we all think that the experiments we do in the science that we do is the most important part of the job, but I actually think it's the people. And so

Bret Freudenthal: hi bye, far it it, there's just something about

Bret Freudenthal: the the the trainees, and the excitement that they have, and helping them kind of launch their career. I mean, I think it's. It has its own challenges in terms of you know they're only here for a small amount of time. We sort of are like oh, and then they sort of launch their own career. And so, you know, the turnover can always be a challenge

Bret Freudenthal: a bit in terms of finding the next generation. But I, the the mentoring, I think is really where

Bret Freudenthal: the long term impact of my career will be. Not another paper. It will be the people that I interact with, and that's part. I enjoy the most.

Bret Freudenthal: It's just it's just fine. They have such a joy for science, and are always, you know, so excited about it. And so I I've just always enjoyed that aspect

Eva Amsen: and and in your own career have you had any useful advice from people who mentored you?

Bret Freudenthal: Yeah, I would say, you put me on a spot here, so

Bret Freudenthal: I would say, you know a handful of advice. So one of the ones that I had from both of my graduate mentor, and then my post Doctor Long term was to, you know. Just keep it simple and remind it for people, and you know, Think about the reader instead of the writer. You know it's a lot more about the reader and keeping it simple, as I say, simple, stupid, you know. Just try to keep it very

Bret Freudenthal: understandable. And then one of my postdoctoral mentors always said that you know it's very hard to float a battleship and shallow water, and so it's important that you

Bret Freudenthal: address a topic at a level of depth. Then you don't do it very shallowly, and because you need to be able to really get at those topics. And so I think, understanding something in great detail as opposed to serving lots of different things with some really good advice, and it's probably reflective of my inherent nature of wanting to jump around and survey lots of different things. And so I think that was something I always try to keep in mind.

Eva Amsen: Yeah, that sounds like useful advice, especially for a feel like biochemistry where there's just there's there is so much to look at, and there's so many pathways that you can go down. And yeah, it can become overwhelming

Bret Freudenthal: with this nucleus on core particle that we're trying to study. It sort of even becomes. Where do we put the damage within 147 possible locations? And you know how do you pick the right spot? So it can become very daunting.

Eva Amsen: Hmm.

Eva Amsen: Well, I think we have reached the end of our episode for today.

Eva Amsen: I hope you, you, your installation of the new equipment goes well and start up problems. And it sounds really exciting. Yeah, it should go smoothly. I think the institution is excited, and you know it's just it's an exciting time right now. I think it institution are really investing in basic research. And so

Bret Freudenthal: it's it's a fun. Time to be here.

Eva Amsen: Yeah, that's great. That's gonna be amazing. Yeah. Yeah, thanks for having me as well. Yeah, thank you so much. And that brings us to the end of today's episode. And thanks everyone for listening to or watching cryo talk.

Bret Freudenthal: Thank you.

Creators and Guests

Bret Freudenthal
Bret Freudenthal
Associate Professor of Biochemistry at University of Kansas Medical Center
Cryo-Talk interviews Bret Freudenthal (University of Kansas Medical Center)