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For episode 47 of 17 Minutes of Science we are joined by Dr Daniel Starr from University of California Davis. Dr. Starr and his colleague Dr. Grant Luxton were recent recipients of the coveted Allen Distinguished Investigator award. They will be studying the LINC complex and how it connects the cell's nucleus to the cytoplasm of the cell. When this connection is broken, many diseases result, ranging from cancer to neurodegenerative disorders. The goal is to better understand the normal and abnormal interactions of the proteins involved in this connection.
Tune into this episode to learn more from Dr. Starr about the circumstances of his receiving the Allen award and how it is impacting the way science is done in his lab.
Dr. Chris Hopkins (Host): [00:00:10] Hello, everyone, and thank you for attending 17 Minutes of Science today. Today, I have Dr. Dan Starr from UC Davis. He's joining us. Thank you, Dan, for joining us today. A little bit of background on Dan, together with one of his collaborators, Gant Luxton, he was recently awarded a Allen Distinguished Investigator Award. They're working on the LINC complex. They're trying to understand how the nuclear skeleton cytoskeleton interact in the cells' cytoplasmic matrix. Dysregulation of this interaction is involved in many diseases, including cancer, heart disease, muscular dystrophy and degenerative disorders. Dan will be using multiple model systems in this grant to gain a better understanding of C. elegans' transgenics. Uh, today Dan will be talking about, taking us on a journey where he was before the Allen award and where he sees the new collaboration with Gant moving towards the science forward in his lab. Hi, Dan. Nice to meet you.
Dr. Daniel Starr (Guest): [00:01:17] Good to see you.
Dr. Chris Hopkins (Host): [00:01:19] So so today in our, in this presentation, we want to ask you a few questions. One of the questions I want to ask you is, what are the attributes and capabilities, uh, does the Allen collaboration bring for you and your lab?
Dr. Daniel Starr (Guest): [00:01:31] Yeah, so the Allen collaboration is really exciting because it's it's going to allow us to go in completely new directions. When they, um, the instructions for the grant proposal were basically to write a bunch of ideas that would never be funded by the NIH because they're too, they're just not conservative. So we took that very seriously. We wrote a bunch of crazy ideas to do a bunch of interesting screens and really to take our labs, our two groups into one, combining the one group and go a new direction. So I'm trained as a classical C. elegans developmental geneticist. I've been working with C. elegans for over 20 years as a model system, and I always think about questions in cell biology in the context of a developing organism. Gant is more of a biophysicist where he thinks about individual molecules. He thinks about the mechanics of the cell and the properties inside the cell. Though we're both focusing on this complex of the nucleus envelope, the LINC complex, and how it interacts with the cytoskeleton - but since he's coming back from biochemistry, and I'm coming at it from developmental genetics, we can combine the forces into one lab and move forward to try to ask biophysical questions both in the mammalian tissue culture cell systems and induced pluripotent stem cells (IPSC) and in the C. elegans in the context of a developing organism.
Dr. Chris Hopkins (Host): [00:02:52] All right. Well, you answered sort of my one of my next questions which is what kind of model systems are you going to be using? So so that's, uh, thats, when you speak about the IPSC cell systems, you know, maybe you can mentioned a little bit more about how you can use that towards addressing perhaps defects or how the LINC system works.
Dr. Daniel Starr (Guest): [00:03:12] Yeah. So Gant has has perfected a model system where a nucleus moves in a polarizing fibroblast and presumably in any polarizing epithelial cell, the nucleus will move backwards and we can take a molecular approach to what's going on in that and how complex is then formed. The Allen Institute has developed all these of these human induced pluripotent stem cell lines so that you can then induce them to form one type of tissue or another and you can watch organelles or LINC complexes and their roles at different stages of cellular development. And so they're trying to use these, um, they're trying to develop this this induced pluripotent stem cell line really as a model. So you can watch tissue develop, intracellular developments as it changes cell types.
Dr. Chris Hopkins (Host): [00:04:01] That's nice. And so when you're, when you mentioned C. elegans, and how do you see that sort of fits in the complementarity of the data that you'll be generating out of IPSC.
Dr. Daniel Starr (Guest): [00:04:11] So for me, it's really important that you that there's limitations in tissue cells. These are growing on a flat culture under extreme mechanical forces to sort of spread out in almost a 2D environment. Whereas in an organism, most cells are 3D environments and behave very differently than they do on a tissue culture plate, on a stiff stratum. In the worms, everything has got this neighboring tissues. And we find many differences in behaviors of the nuclei and stuff just because they're in a three dimensional tissue and throughout development. For instance, there's one time in development where the nucleus in the worm, where the nucleus has to migrate from the side of the worm to the stomach of the worm. In order to migrate here, it's got to squeeze through a space that's about five percent of the width of the cell, of the nucleus. So the nucleus has to squeeze the space, then come out the other side. And we like to think of that as a model of, normal part of development, but as a model for how like a metastatic cancer cell might be migrating through the extracellular matrix.
Dr. Chris Hopkins (Host): [00:05:13] Oh, wow. OK, so that's, that does make sense for why, uh, why it's good to look at multiple model systems. Uh, you know, this Allen grant, you've come from your lab - you know, tell us a little bit about how the impact that that funding did for you in your lab. What was life like before the Allen grant? And what is life like going in the future? And how are you going to commit to the grant? So what was life like before?
Dr. Daniel Starr (Guest): [00:05:38] Well, I will ignore the pandemic effects of this question. But, you know, before, you know, I've been a one a, one, our NIH lab sort of for the last 20 years, close to 20 years now, which means I'm usually running between three and six full time people, mostly graduate students, but occasionally some really good postdocs and a lot of undergraduate and graduate students. And and the NIH grants you sort of got to do what you say you're going to do in the grants, in a little bit conservative manner so you can get the next grants because you're always thinking, how am I going to renew in four years the next grant? And the Allen grant allow me to just - allows us to just go do whatever we want to do. And so we're developing forwards for genetic screens using CRISPR in these in these tissue culture cells, because I'm a geneticist and I like thinking about forward genetic screens. But this way, we now tripled the size of our group and we bring in Gant grants and we combine our two labs and we'll be by the end of the summer, up to maybe 14 or 15 people, including four new postdocs and a couple of graduate students. And now managing this group is going to be much more different because now everybody's going be going off in a different direction, which is going to be a challenge and a lot of fun.
Dr. Chris Hopkins (Host): [00:06:53] All right. It does sound like fun. And in fact, tripling the size of your lab sounds like quite a challenge. I mean, how do you attract that talent? Is it difficult to get that kind of talent in the lab?
Dr. Daniel Starr (Guest): [00:07:08] Yeah, attracting new talent in the middle of a pandemic turns out to not be easy. But we have we have one really good postdoc that I'm really excited that's that's signed to come in the summer. And we have three others that are like hopefully this close to signing. And and if we get those four, we will have a team at the end of the summer with four young postdocs that are just raring to go and with full of tons of cool ideas that are very well trained from other cell biology labs. And it would just, you know, Gant and I would be ecstatic to get that group.
Dr. Chris Hopkins (Host): [00:07:42] It sounds really, really exciting. And so when you when you imagine where you're going to go with this, you what kind of broad impact do you think you're going to see in terms of sort of disease biology here? What kind of, what kind of areas do you think you're going to have a strong impact if you if you can sort of meet your aims?
Dr. Daniel Starr (Guest): [00:08:02] So I think that at the interface of two fields, biophysics and development genetics is - whenever you're working on an interface, you can find new things real fast. And what we're really looking at is what are the mechanical properties inside the cell? How is, how are all the organelles sort of interacting with each other inside the cell and then sort of staying in place? So it's not just a bowl of soup, right. So you can either have a cell that's got a matrix of some sort, and it's sort of like jello where everything's sort of in the right place, things are moving around in direction. Or you could get rid of that whole matrix and you can come liquified, which is the term the biophysicist don't like to use but I find the developmental geneticists can understand. And now all of a sudden everything is soup, and the organelles are all flopping around. And how does that affect the development of the tissue? Because without a doubt, this is going to affect the behavior of cells in disease. And the mechanical properties are important for regulating all sorts of things, including, you know, even setting up spindles and setting up ribosomes. Setting up organelles really require on the chemical properties between other organelles and the rest of the cell.
Dr. Chris Hopkins (Host): [00:09:14] Ah, right on. And so it sounds, you know, from the biophysical aspect that you're working on - and you know, you're geneticist, so anyway, what does that sort of merger of the tools, the instrumentation or the genetics or the instruments that you'll be needing and what what do you wish was possible or plan to bring in what kind of instrumentation are you are you going to bring in with this?
Dr. Daniel Starr (Guest): [00:09:36] That's a great question. So we would like to use transgenic approaches, such as things that InVivo Biosystems does. In fact, we've been working very closely with you for the last couple of years to move some of our products forward during this pandemic. And when we don't when we can't hire fast enough - it's been great working with you. And we can then take, you know, disease associated mutants, make the transgenics in our worm system. But then we can also go make it in the tissue culture system and see how that affects the mechanical properties of the cell. And so we want to take it from the tissue, from the system, the whole organism to the individual cell, and then the common theme in both these places besides transgenics is microscopy. So we're doing a lot of cutting edge microscopy, working very closely with our our world leading microscope core facility here at UC Davis, where we we have a brand new area scan microscope that we're doing a lot of live imaging. High resolution, um, hopefully we'll be - hopefully we'll be trying to get the new ZEISS laser scanner. That's kind of our dream right now. And so to do a lot of live imaging at super resolution on transgenic organisms would be the approach of this.
Dr. Chris Hopkins (Host): [00:10:53] All right on. Well, we have about about another five more minutes left in our entire 17 Minutes of Science here. Time does go by pretty quick. So perhaps the, you know, we've talked a little bit about the Allen award and just maybe, a little bit of advice to others, perhaps on on this kind of a funding. How, where else can some other people kind of approach this? How did you actually get on the Allen award or did you apply for this? I mean, how does someone get one?
Dr. Daniel Starr (Guest): [00:11:26] Yeah, so the Allen Institute decided consciously to move into a field of how the nucleus interacts with the rest of the cell, which was - they then asked about 30 or 40 people if they were interested in applying, including both Gant and I. And I think if I'd written my own grants or if Gant Luxton had written his own grant, I don't think either one of us would have gotten funded because we would have just sort of done one off of what we're doing now. But the fact that we we came together and we wrote a grant at the interface of two fields and I think what made this grant so exciting to the Institute and that they wanted to give us all this money to move forward in the next few years. So my advice is to is to find a collaborator that pushes you outside of your comfort zone and that the clarity will be outside the comfort zone, the two of you can meet at an interface that's that's novel, whether here in this case it's biophysics and developmental genetics. But we're both interested in cell biology questions. If you can find that interface, that's where the newest technologies and where the crosstalk between the two fields can really occur and we can hopefully make great progress.
Dr. Chris Hopkins (Host): [00:12:38] All right on. That is, it does make sense, you know, we do see a lot of that push with NIH standard funding that we all sort of chase. You know, they love seeing a collaborative, highly integrative approach. And so that does sound like that, that is, you know, the standard recipe for -
Dr. Daniel Starr (Guest): [00:12:58] Yeah, students and faculty, students and labs, they shouldn't be afraid of this. And so if you want to move into a place where you're using C. elegans as a transgenic model, you find a collaborator. And if you have a collaborator down the hall, great. But if you don't, there's companies like yours that - you know, you can collaborate really well with you. And we've done a couple of collaborations with you guys now where we're where we're designing mutations into this into Lamins, which are involved in tons of different diseases. And it's been a really fruitful collaboration because you guys can crank the transgenics out faster than we can. And now we can use our skills to analyze it in our assays of nuclear movements and things like that. And it's just, you know, there's there's no excuse to stay in your silo in today's science. There's no such thing as a cell biologist or geneticist. These these categories are all merging now, maybe under some greater molecular biology or something. But you have to be flexible and be able to move between things, move to the system that's easiest to study your question.
Dr. Chris Hopkins (Host): [00:14:02] Yeah, I've heard that said before that the standard animal models may not be the best and there might be alternative animal models to use that can answer - that are best for answering a very particular specific question. You mentioned, again, this one about the C. elegans being a system for looking at cell migration. If perhaps you could describe that one a little bit more. We have probably about a minute left and would love to hear about how how you think that that is a great model for, uh.
Dr. Daniel Starr (Guest): [00:14:35] Yeah, so because C. elegans has this clear skin you can actually watch nuclei moving around throughout different stages of development. And there's this one - we watch nuclear migration events and we, in one event in the embryo, it's using a plus and directed motor to move this way. And then another event in the larva is moving a minus and directed motor to move in the opposite direction of the microtubules. And we're trying to get the interface right now, one of my students is trying to figure out how there's a nucleus biased towards one way or the other way. And we're also finding out there's other pathways, including an acting, a branch acting pathway, that's pushing on the nucleus to help it squeeze through those narrow spaces. And we're also finding out that something about the heterochromatin and the stiffness or softness of the nucleus can help it migrate or not migrate. We're trying to work out the combinations, all three of those mechanisms to how the nucleus moves around.
Dr. Chris Hopkins (Host): [00:15:29] All right on. So that then you can imagine for for a metastasizing cancer, it allows you to look, I mean, how do you look at a metastasized cancer in a human and be able to see a transparency that that's not there. So that's the unique advantage I guess.
Dr. Daniel Starr (Guest): [00:15:45] Yeah, we have a genetic system, we can four genetic screens, to look at a normal process of development as a nucleus and squeezing through, whereas our imaging is not as good as a nucleus migrating through a micro channel or something. But we've got the genetic approaches that we can do.
Dr. Chris Hopkins (Host): [00:16:01] All right. Well, it looks like we have about about another another two more minutes here. And perhaps the um, some of the other stuff we could talk about is after the Allen Grant, what do you imagine you're going to be doing then? Let's look way down the road.
Dr. Daniel Starr (Guest): [00:16:20] I would love to figure out a way to keep Gant here so we can keep this collaboration going and keep the keep the momentum going. And then we can just ask them to start - to learn more about these mechanical properties of the cell. Then we can start to apply them to disease tissues or disease models to see how the mechanics of inside the cell affect the pathogenesis of these diseases ultimately would be the long term goal.
Dr. Chris Hopkins (Host): [00:16:50] All right. Well, it looks like we're coming up on the end of our time. It's been a great conversation with you, Dan, and I appreciate you taking the time to speak with us.
Dr. Daniel Starr (Guest): [00:17:00] Thank you. A lot of fun and it's been a lot of fun working with you guys the last couple of years. And I highly recommend that.
Dr. Chris Hopkins (Host): [00:17:06] Well I appreciate the plug. And it has been very, very fruitful. We have had some rare disease work with the UDN (Undiagnosed Diseases Network). You're talking about the LMNA work, we've got collaborations there. So like you say, the collaborative landscape and developing the collaborations, you know, we pride ourselves at InVivo for that. And it sounds like, you know, you've been chasing that and having great success has allowed you to get the Allen grant. And that's a really amazing opportunity that you were able to land. And it sounds very exciting where you're going to be going. So thank you for speaking with us today.
Dr. Daniel Starr (Guest): [00:17:43] Thanks for this opportunity to let me to tell all the listeners out there what we're up to.
Dr. Chris Hopkins (Host): [00:17:47] All right. All right. Thanks, Dan.