Eva Dale 0:00 From the heart of the Ohio State University on the Oval, this is Voices of Excellence from the College of Arts and Sciences, with your host, David Staley. Voices focuses on the innovative work being done by faculty and staff in the College of Arts and Sciences at The Ohio State University. From departments as wide ranging as art, astronomy, chemistry and biochemistry, physics, emergent materials, mathematics and languages, among many others, the college always has something great happening. Join us to find out what's new now. David Staley 0:32 Susan Cole joins me today. She is Professor of Molecular Genetics at The Ohio State University College of the Arts and Sciences. Her research interests include vertebrate development, cell signaling, and post transcriptional regulation. In 2017, she received the Ohio State Alumni Award for Distinguished Teaching. Welcome to Voices, Dr. Cole. Susan Cole 0:53 Thank you very much. I'm glad to be here. David Staley 0:54 So let's start first with a definition. What is molecular genetics? What is it that molecular geneticists study? Susan Cole 1:01 This is one of those things that we get a lot, because it's a combination of two words that everybody knows the meaning of, molecules, and genes, right. But when genes were originally identified, nobody knew what they were, they were kind of an imaginary thing that influenced inheritance, and it wasn't until we identified DNA in the structure of DNA that we understood what molecule was involved in genetics. So, molecular geneticists are interested in how genes are encoded in the DNA, and how their genetic products which we call RNA and proteins actually influenced the traits that genes control. David Staley 1:36 Remind me what RNA is. Susan Cole 1:38 RNA is an intermediate between the DNA which stores the genetic information, and it kind of takes that information and allows the cells to make proteins that are what actually does the work. David Staley 1:49 And what methods, how do molecular geneticists do what they do? Susan Cole 1:54 Some of what we're interested in is what happens in normal cells all the time. So, we're looking at sequences in DNA that are genes, and seeing what proteins those genes encode and figuring out what work those proteins do in the cell. We also do a lot of things where we will manipulate genetic sequences, either in cells growing in a dish or in an organism that we work with in the lab, and seeing what the effects are on the traits of that organism to help us understand what the genes are doing as their job in underlying traits. David Staley 2:29 You work specifically with notch signaling, tell us what notch signaling is. Susan Cole 2:36 Notch signaling is a way for two cells that are very close together in an organism to essentially talk to one another. It actually... David Staley 2:43 They talk to each other? Susan Cole 2:44 Yeah, they do. They talk to each other. One cell puts proteins up onto the surface, and it touches proteins that are on the surface of the neighboring cell, and that sends a signal where one cell is helping tell another cell what to do next, during development or in the organism. It actually got its name because it was identified originally in fruit flies, and there are mutations in genes in this pathway that cause a little divot in the wing that looks like a notch, and so they called the pathway the notch pathway. David Staley 3:15 So what's the mechanism? How do cells communicate with each other? Susan Cole 3:20 This is actually one of the most straightforward cell signaling pathways that's out there. Basically, we have one cell that sending a signal, and it puts a protein out on its surface, and that touches a receptor molecule on the surface of a neighboring cell that's receiving the signal. When that interaction happens, a small protein goes into the nucleus of the receiving cell and turns on a bunch of genes. David Staley 3:45 Turns them on? Susan Cole 3:46 Turns them on, sits down on the DNA and actually promotes transcription or production of RNA from certain genes. And those RNAs make proteins that allow that cell to do things in response to the signal. David Staley 4:01 But I'm trying to go back to high school biology. I don't know if I ever learned anything like this before. Is this sort of a recent understanding or...? Susan Cole 4:08 This is something that's probably developed over the last 20 or 25 years that we've started to understand this, so... David Staley 4:15 High school biology. Susan Cole 4:16 Yeah, so but it's definitely something that most people don't encounter until their college coursework, is this idea that we learned in high school what genes are and that they can be on or off and that they make proteins or they don't, but the idea that how a cell decides what gene should be on or off is really important, and is not something most people think about till college. David Staley 4:43 So do you work with notch signaling in any particular area, any particular cells, any particular applications? Susan Cole 4:49 We're really interested in two specific areas. One is cancer because it turns out that notch signaling becomes dysregulated in a large number of human cancers dysregulated, meaning that it's on when it's supposed to be off, or it's off when it's supposed to be on, and that that change in notch signaling helps cancer cells grow. David Staley 5:14 Wow. Okay, this is, this is... Susan Cole 5:17 Tt's really very exciting. The other thing that we're interested in as a lab is an early stage of embryonic development, where embryos are creating the structures that are going to be the vertebrae and ribs of what we call your axial skeleton. And during that process, it turns out that the levels of notch signaling, oscillate the cycle very rapidly between an on state and an off state, and how fast that oscillation occurs helps the developing embryo decide how many vertebrae it's going to have. So this is something that's very tightly controlled within a species. All humans have essentially the same number of vertebrae and the same number of ribs, but it's very variable across evolution. So we have a very different number of ribs from a snake or a mouse, and so we're interested in how you can have something that's very tightly regulated within a species, but very different across evolution. David Staley 6:13 So let's talk about this work with cancer. Do you work with a particular type of cancer and with what sorts of implications? Susan Cole 6:19 We work mostly with solid tumors, which are tumors that are not of blood origin, and mostly what we do is collaborate with colleagues in the James and the Cancer Center. David Staley 6:30 That was my next question. Susan Cole 6:31 Providing mostly information about what notch is supposed to be doing, and they're providing the cancer input. So, a lot of people think about cancer is almost development in reverse, so cells that become cancerous are turning on signaling pathways and proteins that they're supposed to have turned off, in order to be differentiated cells have saved the liver. And so we provide information about how not just supposed to be working normally, and that helps cancer biologists understand what's going wrong in the cancer. David Staley 7:06 And well, I hesitate to ask this, but are there any indications that work toward what a causal mechanism? In other words, are we... how does this work helping us understand and, what, prevent. cancer? Susan Cole 7:19 Prevent or cure or... David Staley 7:20 I say this very, very hesitatingly. Susan Cole 7:21 Cancer is a variety of different diseases, and I think the idea that we're going to find a cure for all cancers is probably not something we're going to achieve. David Staley 7:31 Too optimistic. Susan Cole 7:31 Too optimistic. But on a cancer by cancer basis, there are definitely circumstances in which people are using specific drugs that target notch signaling to help treat cancers and give people a better quality of life or cure the cancer, that specific cancer in that specific individual. David Staley 7:49 And the cancers you're working with, these are... you work on human subjects, or...? Susan Cole 7:53 We don't do any work specifically on human subjects, but definitely our collaborators are doing trials in the James to working with human cancer. David Staley 8:02 Sorry, tell me about the nature of that collaboration. I'm very interested to know more about what that looks like working with the James. Susan Cole 8:08 So the most common ways that these collaborations have arisen for me is that somebody's doing cancer research. They're interested usually in a type of cancer, so they might be interested in brain cancer, and they're studying a specific subset of brain cancers. And they find that in that specific subset of brain cancers, they see dysregulated notch signaling, what those people frequently do is then reach out and see if they can find somebody on campus or off campus, who's an expert in that type of signaling pathway. So usually what happens to me is that I get a call or an email from a colleague in the James or at Nationwide Children's, saying, I've determined that notch signaling is dysregulated and my cancer, and I don't know where to go from here. So let's sit down and talk about ways to understand mechanistically how that signaling is going wrong and how that incorrect signaling might affect cancer development. David Staley 9:01 How did you end up this area notch signaling as a problem? What was the path to get to this problem? Susan Cole 9:07 I was really interested in how cells communicate during embryonic development. So if you think about it, everybody started as a single cell, and what's in that cell is one copy of your genome, and some RNAs and proteins that were in the egg. And all that happens during development is cells divide, and genes get turned on and off in the right places at the right times. And in order for this to happen, cells have to be able to communicate to each other. So cells communicate to their neighbors and signal things like we're going to be a liver cell, you should be a liver cell too, because we're in the same part of the embryo and we should all be part of the same organ, or they might signal to their neighbors, I'm going to be a neuron, you should be at neural support cell so that I have support cells. And I was really interested in that process, but I wanted a very simple pathway to try and understand and the notch pathways clearly, at the time, the most straightforward signaling pathway that was out there. And so, I sometimes joke that my entire career has been trying to make the notch pathway more complicated than it was when I started. David Staley 10:10 Is that happening? Susan Cole 10:11 It's very much happening, because we turns out that the pathway itself kind of acts like a switch. So, you turn it on, and you activate genes in the nucleus of the signal receiving cell, and it's used in a lot of situations where we have to have really, really tight control. So, we're interested in how you tightly control something that from the outside looks like flipping a switch, and so we found a lot of different ways that subtle changes to the proteins, or how they go up to the cell surface, change the strength of the signal, for example. And so we're interested in understanding how you modulate a pathway that looks like it's really a switch. Eva Dale 10:56 Did you know that 23 programs in the Ohio State University College of Arts and Sciences are nationally ranked as top 25 programs with more than 10 of them in the top 10? That's why we say the College of Arts and Sciences is the intellectual and academic core of the Ohio State University. Learn more about the college at artsandsciences.osu.edu. David Staley 11:18 So you say "we" and you mentioned your lab, I'm interested to know more about your lab, the structure and organization and the work of your lab. Susan Cole 11:32 So my lab largely consists of graduate students who are candidates for PhDs, and they're doing a thesis in order to graduate with a PhD, and then I also have undergraduates in the lab, essentially all the time. What we basically try to do is kind of roll people on as people leave my lab size at any given time is between six and nine people. And as people graduate, we try to bring in new people to replace them and have some overlap, so that there's some training, I have different people working on different subsets of the pathway. So, I have a group of people who are interested in how this oscillation of notch activity acts as a clock, and I have people interested in how we can modify proteins to change the strength of signals. So it turns out that many of the proteins were interested in get decorated by sugars. David Staley 12:31 Decorated? Susan Cole 12:32 Yes, decorated, there are specific enzymes that add sugars that kind of hang off of the proteins, and those sugars affect how strongly they interact and can be used to modulate signaling, and so we're interested in that aspect as well. David Staley 12:44 Tell me what undergraduates do in your lab. Susan Cole 12:48 They actually, the best ones do everything that the early grad students do. So most of them start in the lab learning techniques, we have a large mouse colony of mice with different genetic backgrounds. So the first thing they all learn is how to genotype the mice genotype genotype, so we have mice that carry genetic mutations, and when we breed them, we have to see which of the baby mice got the mutation and which didn't. And so that's called genotyping, and so all the students learn how to do that. And as they learn how to do that and learn other techniques, usually they find one of the projects in the lab more exciting and they start working on that. And I have had undergraduates work with tissue culture cells, which are cells growing in dishes to try and fundamentally understand how proteins interact. And I've also had undergraduates work with mouse development, where they're actually looking at genetically manipulated mice and seeing what traits we see in the genetically manipulated offspring. David Staley 13:48 How does an undergraduate get the privilege of working in your lab? Susan Cole 13:53 Most of them contact me by email saying that they've seen something about my lab on the internet, and that my lab looks interesting to them, and that they would like to come and talk to me about opportunities in my lab. The other common way is molecular genetics has a class that is designed to introduce our undergraduates to faculty in our department that are taking undergraduates. And so, I frequently lecture in that class and I almost always get a student from that when I lecture in that class. David Staley 14:24 So students in your lab, are they getting credit, are they...? Susan Cole 14:27 Most of them are getting credit, and then frequently, undergraduates will decide that they want to stay for a summer between either their sophomore in junior year or junior and senior year, especially if they're planning to do a senior thesis. And in those cases, we usually find a way to pay them. Either they get a fellowship from Arts and Sciences or from the university or I pay them off of my grants. David Staley 14:49 I don't know if you know this or track this. What do your undergraduates do after they graduate, really do they go to graduate school? Are they working in industry? Do you have a sense of that? Susan Cole 14:57 I do have a sense of that. The vast majority of them either go to medical school or go on to graduate school, and then a subset of them will go on to be technicians in a research lab or will change, you know things all together and do science sales or a variety of other things. David Staley 15:14 That's fascinating. That's the connection between our research mission and our teaching. Susan Cole 15:19 Absolutely. David Staley 15:20 You had said that notch activity sometimes acts as a clock. Susan Cole 15:24 Yes. David Staley 15:24 What does that mean? Susan Cole 15:25 So, during the process of developing the structures that are going to be your vertebrae, those structures are formed one at a time in the embryo. So they first form a structure, that's going to be your first vertebrae up close to your head, and then the next one, and then the next one. And the timing of that process is controlled by notch cycling between on and off, it's kind of like a pendulum on a clock. So knots turns on, and then it turns off, and then it turns on, and then one of these structures, which is called a soulmate forms, and that's one swing of the pendulum and how fast that pendulum ticks, determines how many of these soulmate structures you can form. And that reads out as how many vertebrae you have. David Staley 16:10 And that regulation is consistent across all individuals? Susan Cole 16:14 All individuals, all humans do exactly the same thing, and all animals with bony spines do this as well, vertebrates. David Staley 16:22 So you've talked a little bit about this, but I'm interested in learning more about the consequences of your research, so the practical applications. So, armed with the knowledge, can we manipulate, I'm gonna say this very carefully, can we manipulate embryonic processes for like desired outcomes or genetic processes? Susan Cole 16:42 So in mice and other lab model organisms, we can definitely do that, and we do it all the time. Ethically, in humans, this becomes a little more difficult. So we can do things on the cancer end, where we're treating adult or pediatric patients with drugs that control notch signaling. And there are definitely movements afoot to use things like CRISPR, and other kinds of genetic manipulation, as cancer treatments, when we pull back and think about the embryonic defects that we see. So, there are mutations in notch signaling that cause abnormalities of the vertebrae and ribs. So things like scoliosis, or a much more severe disease called unfortunately Spatola, costal decisis. And those things, it's much harder to think about manipulating because those arises a combination of genetic issues and environmental issues. And there's no real way to know ahead of time which embryos are going to be affected. And so going in and doing those kinds of manipulations is both unethical, and not particularly pragmatic. David Staley 17:55 So you can understand my hesitation. Susan Cole 17:57 Absolutely. David Staley 17:59 Well, you mentioned CRISPR, and I know CRISPR has been much in the news: first of all, give us a definition, a sense of what CRISPR is. Susan Cole 18:05 CRISPR is an acronym, and it's a set of tools that allow us to make targeted changes to the DNA sequence of any cell or organism that we want. It's a combination of an RNA sequence that can find a sequence in the DNA, and that RNA pulls a protein called caste nine to that site in the DNA. And what caste nine is, is a molecular pair of scissors, and what it does is it cuts the DNA, cells really dislike having their DNA cut, and so they repair it. And when they repair it, you can give them a template to use, and they'll repair it using that template and change the DNA sequence. So, you know, at the baseline, what CRISPR allows us to do is make single nucleotide changes affecting one base pair of the DNA changing one base pair to a different base pair, or much bigger changes if we want, at any site in the genome of a cell of as far as we can tell any organism. David Staley 19:07 Including humans. Susan Cole 19:08 Including humans. David Staley 19:09 I've heard it sometimes called a find and replace function like a Word doc. Susan Cole 19:13 Right, it basically is. So the RNA is doing the finding, and the protein and the template are doing the replacing. David Staley 19:13 Well, this technology must have implications in your field. Are there changes already afoot in the field of molecular genetics, because of CRISPR? Susan Cole 19:27 Absolutely. This has allowed us to make genetic manipulations and organisms that we've never been able to manipulate before, and it's allowed us to make manipulations very rapidly and very accurately. So, since the 90s, we've been able to manipulate the genome sequence of mice, but it's something that takes three years and 10s of 1000s of dollars, and it's not always very accurate. With CRISPR, we can do it in a year, and it's much cheaper. In some organisms like zebrafish it's gotten to the point where undergraduate projects can be designed around doing a CRISPR mutation in a zebrafish. David Staley 20:05 And then you sort of gestured this way, sort of the implications and future of gene editing and CRISPR, especially as we talk about using this technology on humans. Susan Cole 20:20 And I think as far as treating existing diseases in living adult human beings in their somatic cells, where those genetic changes are not going to be passed to their offspring, that's coming, that's happening. Now, there are dozens of genetic trials using CRISPR to treat diseases such as sickle cell anemia, other blood problems and cancers. The idea of doing genetic manipulation in an embryo where that manipulation is going to be passed on to future offspring is ethically very problematic, but apparently has been done in China. So, there was a researcher there who used CRISPR to do genetic manipulation of embryos, and two of those embryos gave rise to young girls who are alive and out there. David Staley 21:16 So what does that portend then for the future? I mean, aside from ethics dumping, which is what I assume you're... you're sort of mentioning here. Susan Cole 21:24 So, I think it's going to be one of those things where researchers have a long history of coming together and self regulating. So, when we first started manipulating DNA at all, there were a series of meetings where scientists from across the world came together, and we decided how ethically and safely to do genetic manipulation and molecular biology. And pretty much all scientists across the planet have really followed those guidelines. and I think we're trying to do that again, but it's very hard at this point. CRISPRs come so easy, that it's very hard to say we're absolutely going to be able to control this. So the reality is that genetic manipulation using CRISPR of human beings is coming, and the questions are going to be how we deal with it and how we can control it. David Staley 22:19 Well, we should probably say that scientist in China has been reprimanded both internationally and in China as well. Susan Cole 22:24 Yes, he's been reprimanded internationally, he's been reprimanded in China, he apparently disappeared for several weeks in China. So, there are definitely repercussions to going off the beaten path and trying this in humans. But we need to be on top of this and thinking about it. David Staley 22:43 Are you teaching CRISPR today to students? Susan Cole 22:46 In all the different contexts that I teach, actually, so I teach a freshman seminar called Exploring Biology Through Fiction, and in a module on genetic manipulation, we talk about CRISPR. There, I teach a molecular genetics course and we talk about CRISPR. There I teach human genetics course, and we talk about it when we talk about gene therapy. And this spring, for the first time, I'm going to be teaching a course called genes and development, that I'm co teaching with a faculty member in the philosophy department Justin D'Arms. David Staley 23:15 Oh, yes, interesting. Susan Cole 23:16 And we'll be talking about CRISPR. They're in the context, much more of the ethics of genetic manipulation. David Staley 23:21 Tell us more about that class, that sounds fascinating. Susan Cole 23:23 I'm really looking forward to this class. So this is an interdisciplinary class that we developed together, so we're teaching it in modules, where we'll learn both the science and genetics of something, and then philosophical implications of that. It's crosslisted between molecular genetics and philosophy, it has no prerequisites. So, the idea is that we can take students from both the science side who want to get an idea of philosophy, and students from the humanities side who want to get an idea of science. So we'll start with genetics boot camp and philosophy boot camp, and then we'll move on to thinking about questions like, what are the ethical implications of genetic manipulation? What are some of the privacy issues that arise with the ability to do rapid genome sequencing? How does altruism evolve if it's genetically based, and it's helping other people instead of helping your own offspring? And I'm really, really excited about it. David Staley 24:24 Is this Autumn 19? Susan Cole 24:25 This will be Spring 20. David Staley 24:26 Spring 20. Okay. What's next for your research? Susan Cole 24:30 So, we have several different mouse models that we've made very recently trying to understand how this speed of the genetic clock is controlled how quickly the pendulum ticks. And so, we're following up on understanding what traits we see in those mutant mice. We also have these ongoing collaborations, so we're working with a colleague in Wright Meier who works on zebrafish trying to understand how many of the mechanisms that regulate the clock are conserved from species to species, and which ones are different. So in mice, the clock ticks once every two hours, and in zebrafish, it ticks once every 30 minutes, and then human beings it ticks once every six hours. And we're interested to see are there mechanisms that all of these organisms share that make an oscillation work, and then which mechanisms are different that make it tick really fast in zebrafish, and much slower in a human being? And then we have ongoing collaborations with colleagues in chemistry and biochemistry, where we're starting to look specifically at what the proteins themselves are doing, thinking more of the proteins as machines. David Staley 25:42 Machines. Susan Cole 25:42 So yes, how do we control how tightly one protein can bind to a different protein? And so, these colleagues have mechanisms of measuring things like how tightly do two proteins attached to one another, and so we're using those collaborations to try and really understand essentially, the cogs in the clock and how they're functioning. David Staley 26:06 Susan Cole, thank you. Susan Cole 26:08 Thank you very much. Eva Dale 26:09 Voices from the Arts and Sciences is produced and recorded at The Ohio State University College of Arts and Sciences Technology Services Studio. Sound engineering by Paul Kotheimer, produced by Doug Dangler. I'm Eva Dale. Transcribed by https://otter.ai