Nathan Chen explores a day in the life of physician-scientists

comfortable and where I feel confident and then we will be going around to different locations across Yale's campus to see different professionals, mostly MD, PhD professionals who have a very amazing career that they've developed and seeing where the research is taking them. So given that I've spent my whole entire life as a skater, I think my exposure to fields outside of skating has been quite limited. So I'm really excited today to get to explore new fields, get to explore new ideas and thoughts and hopefully just get some inspiration to understand what it is exactly that I want to do in the future. We are excited to show Nathan some ongoing biomedical research, show why it is important, how it may one day treat disease and save lives. How did you develop that discipline? Like did you just kind of learn it? Did your parents mentor you, family, your coaches? Like what village helped you become Nathan Chen, you know, world famous ice skater? Yeah, I mean as you said it's a village, right? And I think it started with definitely my parents and I think they just like had the intent that, you know, no matter what, doesn't matter how far we take our hobbies or our careers, as long as we try our very best to do as best as we can every day and try to improve every single day. And that was sort of the mentality that I had with the ice. Physician scientists make up about 1.5 percent of all doctors in the U.S. and they help push forward understanding, prevention and treatment of disease by doing both research and clinical work. Yeah, I've been, I've had the pleasure to be able to work with physician scientists over the past couple months and it's just, it's been really eye-opening and very inspiring to be able to see the work that's being done and realize that while clinicians are doing amazing things and helping patients, there's a whole world out there of possibility that physician scientists are trying to encapsulate on and help continue to progress medicine in a way that it currently isn't. So I think that's really inspiring and, you know, it's definitely a career path that I think I have opened my eyes to. Here are some scientists and physician scientists working to tackle these conditions. And yeah, I'm just going to show you a little bit about engineered heart tissue and talk a bit about what we use it for. Okay, so I don't know if you can see that, but there's that little web that goes across there. That is a little engineered heart tissue with human heart cells growing on it. We are using it to evaluate different drugs that are targeted towards specifically treating genetic forms of heart disease. So that's a big application that we want to see. Maybe even more exciting is the fact that we can create tissues from specific patients and try to unravel the origins of their particular cardiac disorders. So basically what I want to do is try to study that in a dish using engineered heart tissue so we can try to come up with new therapies and treatments. My project this year is working using our engineered heart tissues as a model for human hearts to investigate how a certain heart failure drug can be optimized to have different combinations of dosages and timings to produce the best results. And so today what we'll do is I'll show you how to process some blood samples. For many of our experiments we collect blood from patients into these tubes. And so what this machine does is that it spins the blood or the tubes and it'll help us separate the different components of the blood. So once you've accumulated all this data what are the next steps with this data? We can use this data for diagnosing patients condition. We can look at the different markers and see what treatments may be able to help you know either lower some of the markers or improve the function of these cells. Each dot represents an individual cell and so we can categorize these cells based on you know the markers that are expressed into these different populations. For example many of these are cytokines and cytokines are involved in inflammatory processes. So if you have an infection or if there's an autoimmune disease these can be elevated so it could be a good indicator of these conditions. Dr. Jennifer Kwon is a physician scientist at Yale School of Medicine specializing in cardio-oncology which is a specialty that helps to manage and prevent cardiotoxicity associated with cancer therapy. She also studies the biology of single cells and genomics and leverages cardiac imaging to understand how they can affect and predict health and disease states. We've been working with each other now for a couple months and I just wanted to give you a little bit more background in terms of one of the bigger areas of the lab which is looking at this condition called clonal hematopoiesis of indeterminate potential or the short name for it or acronym is CHIP and so this condition is a disease of aging so as people get older they're more likely to develop it. Why is it important? So CHIP has been shown to double the risk of heart disease. It also has been shown to increase the risk of heart failure both due to heart disease as well as non-heart disease. It also has been shown to increase the risk of developing blockages in the blood vessels that supply your legs and your arms. So we're trying to understand what could be those potential mechanisms. We see in our own patients here at Yale in a heart failure group that the patients without CHIP survive better compared to the patients with CHIP and this has been shown in other studies as well. In addition to looking at the known CHIP genes, we've also expanded that search to other genes as well that have been more shown to be more prevalent in heart failure patients. So HF stands for heart failure, non-HF is non-heart failure patients using the top med cohort. The heart failure patients actually have a much higher burden of these somatic variants meaning that the gene sequence gets changed in not the not the DNA sequence that they were born with but over time our cells can acquire these mutations and usually it goes up with as we age. So that's kind of some of the research that you've been getting involved with is understanding what kind of effect do these gene variants that are not the gene sequence that we were born with but have acquired that we have acquired over time that's circulating in our blood, how can that impact heart disease? How can that impact heart failure? And so that's what we're trying to understand. One very useful tool that physician scientists have is big data sets. So when they looked at that patient population they actually found that the patients who preferentially benefited from suppressing the inflammatory cytokine called IO1 beta with with one of their antibody drugs that significantly reduced future heart attacks, future death, heart death, compared to the patients who did not get that drug. And interestingly in that study the patients who had CHIP preferentially benefited from that drug even more. So there is evidence that you could potentially reduce the risk of heart disease, heart failure in CHIP patients. So it seems that like being being able to be a physician and a scientist allows you to do really cutting edge and like brand new novel research and information gathering. Yep so yeah that's the beauty of being in that straddling those two worlds, being able to see the clinical problems that affect your patients or even see the problems where you know they're they're affecting the patients and where we currently don't have any therapies for. For CHIP even though it doubles the risk of heart disease we currently do not have any established guidelines to monitor them and there are no approved therapies to treat these patients. So we are using cardiac magnetic resonance imaging and we are basically integrating over space and time to produce to to be able to understand the spatial and temporal patterns that characterize the conditions such as CHIP in the human heart. Dr. David Braun is a physician scientist in oncology at Yale School of Medicine who studies what makes immunotherapy work in cancer, preventing its toxicities and is working to improve its cancer fighting effects. We actually you know through their generosity get their tumor material, get blood, get other material so we can actually study how their cancer develops, how it actually grows, if it does respond to treatment why that is and unfortunately if it doesn't respond to treatment why that is. So can you explain a little bit more about what exactly is immunotherapy? It's not new it's the idea of using your own immune system to try to fight cancer. The cancers figure out ways to actively escape or evade from the immune system. While there's been little inroads here and there really the past 10 years has been a transformative experience where it went from a theory a concept to something that is actually helping you know thousands if not tens of thousands of patients worldwide and for patients with advanced cancer really providing hope. Even for some patients with very advanced cancers, cancers that have spread throughout the body or metastatic cancers, some of those patients are cured with immunotherapy. Something that would have been unheard of 10 or 15 years ago but still the minority of patients and so how can we understand when things go right what's going on but also in the majority of patients where it ultimately doesn't work can we figure out what are those ways that the drugs just aren't getting there and how can we come up with version two and version three to improve upon it? And currently immunotherapy seems to be a very good approach to treating cancer but what sort of side effects might come about with immunotherapies and what are things that you're trying to do to reduce those side effects? We think of this generation as really releasing the brakes but you can imagine when you're just releasing the brakes without a steering wheel you hope that the immune system steers towards and targets cancer and it doesn't target other normal parts of the body but we know that's not always the case. We know that sometimes it doesn't attack the cancer and we don't have the effect we want to have or sometimes it's overactive and it attacks other organs in the body and when it does that that's where we get the immune related side effects and some are more common some are less common but can be anywhere from head to toe really anywhere from you know severe inflammation of the brain to the heart to the lungs to the bowels and anywhere in between so if we move from just that general releasing the brakes can we figure out when things go right and the immune system really works and targets and clears cancer what is it recognizing on the tumor specifically what is it recognizing on those cancer cells and can we use that to actually design more custom or personalized therapies that will be that steering wheel to help really direct the immune system to attack the cancer and hopefully only the cancer. So in 1990s congress US congress decided to sequent the human genome and the idea was that all the secrets will be known as well as then we will be able to know what goes wrong when there is a disease and then we can find the cure. So this center as I mentioned has identified so many genes for cardiovascular disease cancers skin disorders kidney diseases you can name it and one of the reason is that we collaborate the combination of the genome facility and the top scientists at Yale that makes us so successful. Nathan meets with the new dean of data scientists at Yale physician scientist Dr. Lucille Anomachar. As I'm in data science what do you think will be sort of what are the most exciting aspects of data science and what are things that you think will how do you think the field of data science is going to continue evolving in the next many years? I think in medicine in particular medicine has always tried to be evidence-based but with more data and new data modalities such as genome whole genomes and other kinds of new data we will be able to more and more personalize medicine to a level that we weren't able before. How are you going about ensuring that there is diversity in data and diversity in the in the field of data science in itself? Which is that we want to have more data from more diverse populations and that's the crux of the problem. So in various projects such as one named all of us research program funded by the NIH the whole purpose is to ensure that we have wide representation. Physician scientists have given us insulin, vaccines, new cancer and heart disease therapies. What else will they bring us in the future? It's really cool to be actually to be able to be working with you and seeing the data science application to healthcare and in genomics as well as you know being able to experience a lot of these the different avenues of medicine it's been really enlightening and I've really enjoyed a lot of the oncology sort of lectures or presentations that I've been able to see and I think that's something that still has continued or that has sort of continued inspiring me. Where do you foresee yourself going with some of your research endeavors? I think right now definitely just to get more experience and get more knowledge get some of the hard skills needed to accomplish whatever goals might be there for me in the future but I'm really lucky to be able to have the opportunity to work on the research that you're currently doing and excited to you know continue learning continue learning more about the project as well as figuring out how to again develop the hard skills to be able to accomplish a project like this. You see insights from seeing patients you see the challenges that they face and the problems that they have and so you're able to go back to the lab and say like can I help address this question you know you have clinically relevant questions that you can take back to the lab and try to do some experiments or you take it back to your database and say is that you know is that gene variance associated with this heart disease or heart failure that we see in this patient that I saw in clinic so you're able to go back and try to ask those questions and try to do research to try to answer that question for your patient and if you lose them you may never come up with that you know with the new therapies or prevention strategy for heart disease and heart failure or cancer. This career has challenges but also potentially very rewarding and absolutely necessary for society and humanity if we are to continue to make progress in addressing human disease and allowing us to live happier and healthier and longer lives. Nathan Chen is very popular amongst everyone we met everyone wanted a photo with him and also some of the hospital staff was very excited to meet him many of them said that that made his made their day so it's like he he has a lot of influence already even you know before he becomes a medical student before he becomes a physician he's already had a lot of positive influence so I'm sure we'll continue to be able to do that as a doctor and beyond. How can we support the research they do? Go to the link below to support. Make a tax deductible donation and type in Dr. Jennifer Kwan's research. So I think basically we started the genomic era and then also we started the precision medicine era so you know what is precision medicine I should definitely tell you this is very exciting. So at that time it was very well known only 10 percent of the melanoma patients responded to chemotherapy 90 percent gain nobody knew the reason so when we sequenced this 300 melanoma patients we realized that oh my god the melanoma is not caused by just one defect in one gene but there are other genes and fair enough that the drug was acting only in one of those genes not the other so that explained that the drug was effective because it was specifically targeted that particular and the others didn't respond. So this is the basic idea about precision medicine so the current medicine is like one shoe fits all see we are all different people we are individual people we're wearing different sizes of shoes but the current medicine assumes that we are all wearing the same but you are different I am different Jennifer is different because we are all different color different body different way of thinking liking everything is different. Genetically we are all human beings identical 99.9 percent but there is something beyond that now so you might have heard the new technique called CRISPR have you? Yeah well I'm well familiar my sister works my sister worked for Jennifer Doudna in her lab actually yeah so she was part of she was part of her team. We work with trying to prevent blood clots related to central venous catheters.