Dr. Cynthia Dunbar — Stem Cell Therapies for Blood and Immune System Diseases

Monday, October 7, 2019

Our blood is made up of a diverse array of different cells, all of which originate from the same source: the ‘hematopoietic’ stem cells in our bone marrow. Dr. Cynthia Dunbar is a clinician working to understand how these stem cells grow, divide, and ultimately produce the cells that carry oxygen around the body and fight disease. Learning to safely transplant and manipulate hematopoietic stem cells could lead to treatments for a wide variety of diseases caused by a lack of properly functioning blood cells, including leukemia and aplastic anemia.

Cynthia Dunbar, M.D., is a Principal Investigator in the Molecular Hematopoiesis Section at the NIH's National Heart, Lung, and Blood Institute (NHLBI). Learn more about Dr. Dunbar and her research at https://irp.nih.gov/pi/cynthia-dunbar

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Transcript

>> Is it true that you function on only four hours of sleep a night?

>> [Laughter] Not anymore. When I was, up until about five years ago, that was probably true, when I still had my children at home, and my elderly parents that I was caring for. And besides my NIH laboratory work, I was also involved with editing a scientific journal called Blood. When I was doing all four of those things, I didn't get a whole lot of sleep. But I'm actually enjoying the luxury of sleeping six or seven hours a night now, so hopefully, I'm a little more coherent than I was on almost no sleep.

>> Were you, like optimally functioning on four hours' sleep, or is that more of a necessity?

>> Well it was a necessity. I think you'd have to ask my family and my lab members whether, how grumpy I was on only four hours of sleep. But no, I didn't. I think that maybe that's  something for people who are, you know, under 50, or under 40, but not anymore.

>> I'm just barely under 40, and I would not be alive on four hours of sleep.

>> Yeah, but no, it was kind of a necessity.

>> And I also read that you, you used to manage your daughters' soccer teams. I believe they're grown now, so you probably don't manage their soccer teams anymore.

>> Well, I'm a very organized person, and I like things to run, run appropriately and efficiently, so I tend to take on things like managing teams or managing groups or trying to fix processes. So yeah, I kind of get over involved with soccer in that way, because I wanted to, you know, when I showed up with my daughter for practice for it to be the right day. So yeah, I started--and I also love soccer, so it was, it was fun. And yeah, I did that for a while, including a team where a couple of the kids are now on the national team, so that was fun.

>> Oh, very cool!

>> Not my daughter, but some of the others, so that's great.

>> So for the non-scientists out there, what is it that you do?

>> Well, I work on trying to understand how the bone marrow makes blood cells. And I work on mostly stem cells, which are the most primitive type of cells in the bone marrow that are the mother cells of both platelets, which clot the blood, and red cells, which carry oxygen to your tissues. And white blood cells that fight infections and viruses, and even tumors. So if we understand what the signals are and the processes are that control and drive hematopoiesis, or this process of making new blood cells, it's very useful to try to design therapies when you want to make more blood cells for a specific reason. Or you want to do a transplant to bring you know normal stem cells to a person that is having their own stem cells wiped out by leukemia or by you know they need a bone marrow transplant to treat a genetic disease. Or to understand stem cells better so we know how to genetically correct them, if you have an inherited disease like, say, sickle cell anemia. And also to understand when things go wrong. We have to understand normal blood cell production to understand perhaps what goes wrong in leukemia or bone marrow failure or other abnormal bone marrow diseases. So you have to understand normal to try to be able to treat and prevent the abnormal things that go wrong in human disease.

>> Yeah, I mean this is such an interesting field of research. I'm constantly, I'm soaking up everything I can in the news and other podcasts about people going out and getting stem cells injected all over their body, pulling it out of their own bone marrow, and stuff like this. Do you feel like this is too early in our knowledge to be doing that?

>> Well, I think there's, you know, I think the, unfortunately the term "stem cell" is a very imprecise term, and you know hematopoietic stem cells are the stem cells that have been studied and used therapeutically for, you know, 40 or 50 years. The first hematopoietic stem cell transplants to treat leukemia or bone marrow failure or certain genetic diseases, you know, began you know to be successful in the, in the mid- to late 1970s. And so, you know, we've come a long way since then, but we know a lot about the cells because they're easy to, you know, look at and study in the laboratory. And it turns out you can just give them back in a vein and they know how to go back to the bone marrow and set up production again. So that's, you know, for that hematopoietic stem cell therapies are, you know, well established, cure a lot of diseases, and the more we understand hematopoietic stem cells, the better we're getting at genetically modifying them and having gene therapies that work. And in the future, hopefully, actually editing abnormal genes and bone marrow stem cells to permanently correct things like sickle cell disease. But then there's pluripotent stem cells, and those are the stem cells that are similar to cells in the embryo that are responsible for making an entire new, you know, organism or human being. And there's embryonic stem cells which you know have a long history of being useful in research, especially studying mouse stem cells, and more recently human embryonic stem cells. But there's lots of issues with obtaining those cells, and there's a lot of ethical concerns. And different cultures' concerns over using these cells. But there's also ways to make embryonic-like stem cells from any cell in your body using a technology called induced pluripotent stem cells for you, basically fool a skin cell or a blood cell or a liver into becoming sort of de-differentiating, and going back to its youth as an embryonic, primitive stem cell. So those are two very well-studied stem cell populations. And I've worked on both at the NIH. I've worked on induced pluripotent stem cells, and I've worked on, obviously, hematopoietic stem cells. But there's a whole other field of quote/unquote "stem cell treatments," that have been developed over the past ten to 15 years. And there are other adult stem cell populations and stem cells just are defined as a cell that can basically replicate itself for indefinite periods of time, and so you can find cells that have characteristics of stem cells in other tissues in the body, in amniotic fluid, in cord blood, the blood that's present, you know, in the placenta and the umbilicus at birth that can be collected. You can find them in the bone marrow that are not hematopoietic stem cells, but other cells in the bone marrow. And these cells have many interesting properties and have been very useful to study in the laboratory. And have some clear applications in the clinic that do seem real and have been studied in clinical trials at major, you know, academic medical centers around the world. But the problem is, is that there are a lot of clinics that have been set up around the world, as well as in the United States, where they are saying that they're doing stem cell therapies, and they're taking cells out of the fat, which sounds great. You know, find stem cells in the fat, and you know do something good with fat! [Laughter] Or from the blood or from bone marrow, and basically injecting them into the same person or in some cases, into another person in ways that have had no scientific evidence that it'll work. And outside of clinical trials, because in many areas of the world, there's no regulation for this kind of thing. And even in the US, if you use somebody's own cells, and you take those cells out of the bone marrow or the blood or the fat in the clinic, and inject it back in the same day into that same person, the FDA hasn't had the clear mandate that they have regulatory oversight of that kind of process. So there's a lot of stem cell clinics that you've heard about for football players getting, you know, quote/unquote, "stem cells" in their joints, or getting, you know, people getting stem cells to get their face look younger. Or you know if they're stem cells from another person, they're almost certainly being rejected immediately. So it makes no--they're not regenerating. They're not fixing any tissue. If they're getting your own stem cells, you know, they're getting their own stem cells. If the stem cells were meant to do something, they would do it in their own body. So injecting them from one place to another, you know, doesn't always make a whole lot of sense, and there's not a lot of evidence for a lot of these applications as being, being medically, you know, beneficial. You know, hopefully it at least is not dangerous, but, you know, there's been some really bad instances of clinics outside the United States, primarily, of injecting, you know, ten different people's stem cells into somebody with spinal cord injury. And you know that patient, in Russia, developing, you know, tumors along the spine years later. So anyway, there's a lot of--I think of it in many ways as the snake oil salesmen of the 21st century. And it's really concerning, and International Societies of Stem Cell Research, and American Society of Hematology are, you know, trying to provide educational materials to physicians and to patients, so they don't get, you know, sucked into using therapies that are no chance of helping. And you know possibly are going to hurt them, and are not, you know they have to pay out of pocket for. And you know it's really concerning. You just search "stem cell therapies" on the web, and you'll find hundreds and hundreds of these clinics. And you hear these just heart-rending stories of people that would do anything to help their child or their loved one, you know, who's had a spinal cord injury or brain injury. Or has, you know, Parkinson's disease. And there are certainly cell therapies that are being developed that may have promise in all those areas, but a lot of these unregulated clinics are really scary. Because there's just no evidence for a lot of the things that are being done. So when I say I'm a stem cell biologist, I get worried that people are going to think that I'm, you know, one of the doctors that's out there, you know, putting unregulated, poorly-characterized stem cells into all sorts of different parts of the body trying to cure people when, you know, you really need to do very careful research on most of those applications first.

>> Yeah, yep. That makes a lot of sense. Are there, what's the most challenging part about getting any potential evidence for the efficacy of those treatments?

>> Well, I mean, I think that first you sort of have to think about what you're trying to do. And in a way, the blood system is pretty easy, because, I mean, not easy, but you know the cells normally circulate, and even during development, when you're in, when you're developing as a baby or a fetus before birth. You know, where you make blood cells actually moves from you know three or four different locations in the fetus at different times. So hematopoietic stem cells are very good at migrating and moving to a new, a new house. You know, so they move from the liver earlier in development, to the bone marrow at the last stage of fetal development. So they're already, you know, cells that are, that are you know very good at migrating and setting up shop, and being able to function. And they don't have a lot of three-dimensional structure, you know? It's a tissue; it's not a complicated organ. You know, so it's not nearly as difficult to figure out how to transfer stem cells to somebody, and get them to set up shop and work well as it is to say try to regrow a whole heart or a whole kidney or a whole organ that has hundreds of different kinds of cells, making up that organ to make it, to make it work. And it involves a lot of, you know, kind of engineering of sort of steel beams, or, you know, dividers between different floors. It's like you're really building a complicated building, you know for a kidney. You know, you have to figure out how things are coming in and how things are going out, and how everything is being connected up correctly and to the bladder and to, you know, your blood supply. So that's just so much more challenging to imagine how you're going to grow a whole new organ that has all this complicated, three-dimensional structure, and all this complicated different, you know, types of tissues that make up that organ. And, you know, then be able to put that into a patient, and get those cells to, to function. So it's just way, way, way more challenging. So I think the applications of various regenerative therapies that involve, you know, organs, whole organs that have failed is really a lot more challenging. Whereas things like, you know, the bone marrow, maybe pancreatic islets, eventually, which are, you know, kind of a group of cells that can be making insulin anywhere in the body, in many ways. You know, maybe the liver which is already pretty good at regeneration, and you can actually, you know, bridge people to a full liver transplant by giving, you know, basically allogeneic, meaning a donor's cells, even if not the whole organ. They can engraft sort of short-term and provide some liver function. So there's a couple of tissues like that where I think, you know, it's, there, it's sort of, the liver is full of, you know, a whole lot of cells doing the same thing. So that's easier to imagine how you regrow that than a kidney or a brain or a heart, where there's, you know, very specialized, geographically complicated structures to regenerate. So you know, you don't just need biologists like me. You need engineers. You need people working on, you know, various types of, okay, mesh and you know plastics or other structures that you can grow new cells on.

>> Yeah, scaffolding.

>> Scaffolding! And, you know, and when things have gone into patients too quickly, as happened in Sweden with people that were trying to regrow tracheas for patients that had, you know, been born without a functional trachea, windpipe, or who had had damage in an accident, or a cancer. You know there were a number of tracheal transplants done with tracheas regenerated from different types of progenitor, not stem cell, but sort of early cell populations. There were lots of problems, and that's been in the news a lot lately. So that, those structural things are really challenging, and I think that's where a lot more research has to kind of catch up to the biology.

>> I guess you're in, you're in kind of a unique place here at the IRP. You're in the clinical center. You do basic research, but you also meet with patients. I'm sure that keeps you very busy, going back and forth from the lab to the clinic. I believe you're, you're looking at certain diseases, such as bone marrow failure. I think there's a few different types of that, so you're looking at problems, but you're also, I imagine learning it, and trying to learn how healthy hematopoiesis functions. Maybe you could talk a little bit about that.

>> Well, and I think that's what's really unique about working in the IRP and having the clinical center as a resource that you can use. I mean, for physician scientists, at most places in the United States, even at academic medical centers that you think of as, you know, incredibly wonderful in terms of bringing new therapies forward. Physicians who are primarily seeing patients, or who are seeing patients at all, are usually not doing any, you know, basic laboratory work, and vice versa. It's gotten more and more separated in the last ten to 15 years, as funding has gotten more and more difficult to get for research grants, you know, in the basic laboratory. So that's gotten more competitive, and as healthcare has gotten so much more expensive, and also clinical research has gotten so much more regulated, that it's very hard in academia to be able to do both. Because you're usually, you know, you have to fund your research by getting grants, preferably from the NIH, and your department is really going to push you to do only that and not to what they would consider kind of distract yourself with patient care. And then the people who are hospital administrators don't really want you to see patients because, you know, you're not doing it full time, so you're not as good at filling out all the insurance forms, and making sure the institution gets paid. And you might not be as efficient and quick at seeing patients, because you're actually a researcher and interested in the disease, and interested in the science, and you know maybe not seeing patients as quickly as they would want you to see. So in everywhere else except the NIH clinical center, you know, it's very hard to be a real clinician scientist. I mean, you can be a physician scientist because you have your MD degree, and you're a scientist. But you're probably doing completely one or the other. But here you can still really do both. And so that's really a gift to be able to do that, and it's also really a gift that, you know, my salary and my worth to the institution is not based on how many patients I'm billing, you know? And so I only do clinical work when I have an idea based on my science that is worth taking in to patients. Because it has evidence that it, you know, based on my laboratory work, that it has a chance of working, and also, you know, based on laboratory and animal work, that it's safe. And yes, I do do a little bit of other clinical work because we all take turns. You know, kind of supervising and teaching, you know, the clinical fellows and medical students that are at the clinical center. And we all take turns, you know, with weekend call and evening call, just so, you know, we spread out kind of the workload so you're not taking care of your own patients 100% of the time. Because then you can never take vacation, but compared to what you were doing anywhere else, where, you know, you have to see whoever comes in the door to make money for the department. It's really, it's really a wonderful situation to be in, to do clinical work because you're actually moving treatment forward, not because you know, you have to, to kind of, you know, make your salary. I mean, it's great. I mean, people who really want to be, you know, the primary doctors or the primary sub-specialists taking care of patients, you know, either in private practice or in the community hospitals, or in academia, that's great if that's what they like to do. But it's very hard if you're doing that anywhere else to also be working in the laboratory.

>> Yeah, and you can really sort of, I guess, follow your nose and look at exploratory investigational treatments whereas a lot of other doctors aren't able to do that. They just have to treat the patient. The nice thing here, too, is the patients, you don't have to bill them at all because I believe everything's covered for them.

>> Yeah, I don't know which of me — I mean, you learn which of your patients have, you know, good insurance, and which or your patients are struggling with, you know, getting coverage. You know, you learn that because, you know, you're discussing, you know, what they're doing at home when they're not here. But in terms of getting them into the clinical center, all that matters is that they want to come here, and that they qualify, you know, for a clinical research protocol. And you know clinical research here is also really focused on first-in-human, or very early phase to prove, you know, safety and efficacy. This is not a place where we're doing, you know, huge trials that are going to lead generally to, you know drug approval for a common disease. Because that's the kind of thing that drug companies want to do, you know, at ten different centers across the country, and accrue thousands of patients, and that's not obviously what we do here. But instead, we study a few patients really closely to try to understand why treatments are working or not working. And how to move forward. So you know and when you're doing clinical research, you know, at big hospitals and medical schools around the country, a lot of the time those protocols are being, you know, written and administered by a drug company. Which is appropriate because they are the ones that, you know, know the most about the drug usually. And they are the ones that are going to have to put all the paperwork together to the FDA to get approval. And so they control every aspect of the process, because you know, they're spending millions and millions of dollars, and they want to make sure that the forms are filled out right, and that, you know, to design the trial, you know, in a way that fulfills their need, which is to move the treatment, you know, forward to approval to make it available to everybody as soon as possible. But it means that creativity is kind of difficult if you're a clinical researcher sometimes because, you know, you're handed a trial. This is a protocol, you know? Take it or leave it?

>> You know what you're looking for already.

>> Take it or leave it, you know? And until you get to be very senior, where then the companies are asking you to participate maybe in writing the trial or giving them ideas. But any time, unless you're kind of a one or two world's experts, you're not going to be involved in trial design. So here, you know, we're doing the early phase stuff, where it really is coming out of a, you know, your laboratory's idea, you know, or animal studies that suggests something will work. And you write the protocol. You have help and mentoring in all kinds of programs on campus to make sure the trials are being written appropriately. And there's lots of people around who have done this before, so that's great, but you don't have anyone else from the outside telling you, you know, which way you have to go, because it's more likely that it'll become a product that will, you know, make money quicker.

>> Yeah, so do you, do you have any open clinical trials now? Or and what's most exciting right now in your research?

>> You know, I mean, I, you know, my work with eltrombopag is, you know, we've, we've gotten is actually approved, just with an NIH trial for patients with aplastic anemia. So that was, you know, I said that doesn't happen very often, but when it does happen, it's great. It's a rare disease, so drug companies were, you know, maybe not that interested in it to start with. But now they're taken it, and there are multicenter trials going on.

>> So that's eltrombopag?

>> Eltrombopag, yeah.

>> That's the generic sort of molecular name?

>> That's the molecular name for a drug called Promacta, yeah.

>> Okay.

>> And but that work is kind of coming, we've kind of shown it works, and we're doing some kind of biology of trying to figure out why it works so well, and we're trying to look at long-term safety and whether normal versus mutated cells that might be lurking are being stimulated by, by the drug. So we have, we have I'd say another couple years of work to finish up. And we don't, we finished entering new patients into the studies, but we're following them, you know, we follow them for a couple years. So there's a bunch of patients still on follow up. And in terms of new clinical trials? Right now I have a lot of stuff going on in the laboratory, and like I said, you know, things go in and out of cycle as to whether you're doing a lot of clinical work. So right now, I don't have any plans for really new clinical trials. But I'm working on a lot of stuff in the laboratory that might have applications maybe with clinicians in other areas, even. So I doubt I'll be running the clinical trials, but I'm doing a lot of work on natural killer cells, which is a, a type of cell that's being pursued by a lot of people as an anticancer treatment. And I'm not working per se on how they might fight cancer, but if you're going to basically make these cells as a cell therapy that you're going to give to patients, understanding how the cells are produced by the bone marrow, and how the cells are expanded or maintained in the body. And what they're reacting with in the body is really important. So that's a lot of work is going on in my laboratory now on natural killer cells.

>> Trying to figure out how natural killer cells work? And if you can manipulate or improve their function?

>> It's, yeah, mostly trying to understand if they have to be--what their life history is. They were thought to be very short-lived cells for various reasons. And we actually made a kind of serendipitous discovery when we were looking at other, something else. And we basically came up with a lot of interesting findings that can really only be explained by natural killer cells being able to self-renew and persist very long-term in the blood. And also that they're thought of as innate immune cells, meaning cells that are sort of naturally killing either virus-infected cells or tumors. And they don't actually have this huge array of receptors that T cells and B cells have that result from recombination of genes that give T cells and B cells a whole bunch of different specificities to fight different viruses and bacteria. Natural killer cells don't have this receptor, you know, recombination going on, so it's not, so they were thought to be innate and have no ability to react specifically to things in the environment. And no ability to have memory, but our work along with some other work that's complementary kind of going on around the world has really suggested that NK cells do have memory. And my work in the laboratory and in my non-human primate monkey models really suggest that these cells, you know, have a very long lifespan. They don't have to be continuously produced by the bone marrow, and have a lot of analogies with T cells. And we're getting some clues about, you know, how this could be happening. But just to show, for the first time, that NK cells can persist and expand, and have specific receptors on their surface that seem to be reacting to things in the environment, you know has been my most recent kind of major finding that I'm chasing down in a lot of different ways.

>> Cool! And so are there any technologies or any, what allows you to sort of look at that? Are other people looking at that?

>> Well we have, I mean, what we have is an ability to basically genetically label hematopoietic stem cells from mouse or monkey, and give those cells back, and we basically barcode the cells. Kind of like, you know, when you go to the supermarket, and you have a scan, and you have a barcode that tells you just from looking at a series of black and white lines what that, what that package actually contains and how much it costs. We put in genetic barcodes into hematopoietic stem cells using gene transfer, vectors that have been designed to deliver new genes into cells. And we basically barcode these cells with these, you know, sort of unequivocal labels that are passed on to every daughter cell. So that allows us to basically study the life histories of thousands and thousands of individual hematopoietic stem cells and progenitor cells and all the daughter cells they make. So those, that technology is pretty unique, and we've used you to ask a lot of questions about hematopoietic stem cells and their, you know, their progeny. And we've studied hematopoietic stem cell aging using this approach. We've studied kind of the geography of hematopoiesis in the bone marrow. We've studied, you know, production of different types of cell lineages, and this natural killer finding was one of the most interesting ones that, you know, I knew nothing about natural killer cells before. But I've learned a lot, and spent some time in Sweden at the Karolinska Institute, which is, you know kind of where 90% of the major natural killer cell work seems to have been done for the last 50 years. So I've learned a lot, so and then Rick Childs, who's the National Heart, Lung, and Blood Institute's clinical director, has been working on natural killer cell therapies for 15 years. And so it's been great to work together with him. I can help him by hypothesizing how it might be better to try to, you know, expand these cells or keep them alive in the patient. And he can help me about like what do we need to know about NK cells to make them better therapy. So that's been, that's been great.

>> So and, are you looking mostly at like the healthy--?

>> Right now I'm looking at mostly healthy, yeah. But he works in cancer patients, so you know, so if we figure out better ways to get these cells to expand and to stick around in the patient, then, or in the normal monkey or a normal individual, then it would apply to maybe using them to treat cancer. And there's a lot of, you know, exciting work going on out there. You've heard about CAR-T cells?

>> Yes.

>> CAR NK cells may have some major advantages over CAR-T cells because they don't seem to cause cytokine release syndrome, so they may be a lot less toxic.

>> Interesting.

>> And they may, you know, be kind of more hit and run. I mean, sometimes you want them to stick around, but if you don't want them to stick around, there may be a way for it to work that out as well. So you know, it's an exciting time in you know kind of cancer cell therapies right now.

>> Yeah, and so, so you're learning about how these things work, and how these NK cells work in, in healthy, healthy lives. And then so to move that into some sort of a therapy, is that where gene therapy might come in?

>> Yeah, I mean, the way you make CAR-T cells or CAR NK cells is definitely, you know, various approaches to gene therapy. And gene therapy would, you know, basically just be transferring or changing genetic material in a way that you hope would benefit the patient. And you know, I've been working, I mean, probably I'm best known for having worked on, you know, various kinds of gene therapies targeted at hematopoietic stem cells, and most of that work has been using viruses and basically using viruses as kind of Trojan horses, taking out all the bad stuff from viruses, and using them instead as kind of delivery devices to get new genes into cells. And those approaches have been great, and the first, you know, viral gene therapies have been approved by the FDA, and by the European Regulatory Agencies in the last four or five years. But they, they add genes to cells. They, they add genes kind of randomly to cells. The don't actually correct mutations. And now the sort of explosion of research in ways to specifically correct a target, a mutation in a cell, or target a gene that you want to get rid of or fix using nucleases or proteins that cut DNA and correct DNA has been a huge research focus for many people working in gene therapies, and also in stem cells. And so CRISPR-Cas, which probably most people have heard about, is one of these nuclease systems, and the reason it's kind of gotten so much more press than the other systems is it's easy, and it's simple. And it's very easy to design new, you know, design--. When you want to target a new gene or a new mutation, you can just do it, you know, at your bench using a laptop. You don't have to spend a year trying to figure out how to target a new gene. So it's really made a huge difference in the pace of research in correcting genes, and so the first clinical trials with CRISPR-Cas are already going on in China, and will probably start in the US pretty soon. But there's been other gene editing or gene correction trials going on with these more complicated, you know, ways to correct DNA. You know for the last ten years, so there's been some progress, but I think this CRISPR-Cas is definitely a revolution. And we're doing a lot of work in the laboratory to apply those methodologies to creating models of human diseases, and also to you know target different diseases by correcting genes.

>> So you mentioned that CRISPR-Cas is kind of a simple thing to do. So what kind of tools would maybe a high school student need to sort of tinker around, if they're like really just intellectually curious? Is that feasible?

>> Well, I mean, you know, I know this becomes an issue when people are talking about bioterrorism. Like how easy is it? Well, I mean, you know, to basically edit, you know, an immortalized cell line like HeLA cells? Yeah, I mean you could actually go, and you can buy CAS-9 protein, which is the actual editor, the actual scissors. You could buy that from, you know, a lot of biotech supply houses. And then you could buy and you could design using OpenSource software, you could design what's called a guide RNA which actually is the, what brings the scissors in the right place in the genome. And that guide RNA you can design, you know, quite easily to any site that you want to target. And then you can actually have that synthesized by, you know, biotech companies. They'll send it to you, and then you  just mix the protein and the RNA together, and you actually take the cells and mix it with this protein and RNA, and you shock them with electricity, and they take it up.

>> Oh, cool!

>> And then, you know, you look and you see if it worked. But you know I think you could do this in high school or a college lab. You know, I mean you'd have to, you know, get someone to pay for all of this guide RNAs and protein. But no, it is pretty simpler, you know. And you know it, it varies. I mean HeLa cells and some of the cells we work with in the laboratory cell lines or you know you can't, it's very hard to kill them. So you know, [laughter]. It doesn't, but, you know, targeting hematopoietic stem cells and other primary cells that are not, you know cell lines that grow in the lab for years. Targeting hematopoietic stem cells is, is harder. I mean, you know, you have to work out exactly how much electricity you can shock them with, and exactly the concentrations and et cetera. And it's more challenging, but you know, it's doable.

>> Maybe in five years they'll have a little set-up I can give to my nephew and he can--.

>> Yeah! [Laughter]

>> Maybe not?

>> Maybe not quite, but compared to what, you know, some of the other approaches required. I mean, besides the therapeutic implications, what CRISPR-Cas has done is really just accelerated discovery and experiments in the laboratory. Because to make transgenic mice, to make mice that have genetic modification, you know, is a very complicated, cumbersome. You know, when I, when this all started, probably a two-year process. And now, you know, with CRISPR-Cas editing, you can inject these into the, you know, mouse embryo and, you know, you have a new mouse, you know? With the right, right gene defect that you created or corrected, you know, two months later. So anyway, it's really accelerated science overall, so that's great.

>> Yeah! And so you're, you're clearly working on a lot of different things, and I just wanted to go back a little bit to eltrombopag. And so, what led you to figuring that out? How did you go down the path of working on that?

>> I mean, I worked on ways to make hematopoietic stem cells basically divide and self-renew in culture outside the body. Because to genetically modify them, you generally have to keep them growing. And for some ways that we modify stem cells was certain viruses that we worked with, especially, you know, ten or 15 years ago, cells actually have to be actively dividing. So trying to keep cells alive, self-renewing and not dying or not going down the differentiation pathway so far that they were no longer stem cells has been a big focus. And thrombopoietin which is a natural hormone that our body makes, seems to be very important for keeping stem cells alive and cycling. And it's called thrombopoietin because thrombocytes or platelets are where it's role was thought to originally, you know be. And it does, it is important in making platelets, the last stage of making platelets, but it also seems to be important for stem cells, and basically 20 years ago, I was just trying to understand what regulated stem cell and platelet production in patients, and we looked at the levels of thrombopoietin in patients with a bunch of different bone marrow diseases, and that's how I first got interested in this and was trying to understand how it's regulated. And it was originally being developed as a drug itself, thrombopoietin, but there were some allergic side effects, basically the preparation being used. So it stopped development, and then 15 years later, this company, you know, derived a small molecule that, that kind of was a mimic of thrombopoietin, and that's eltrombopag. That's what we started working with. And it actually binds to the same receptor on cells as thrombopoietin, but it binds in a different place in a different way, but then it turns on the cell the same way that thrombopoietin does. And you know this really is, its application in aplastic anemia was based on, you know, Neil Young who's my colleague and boss here, who'd been working on aplastic anemia for his entire career, and had developed lots of new therapies, immunosuppression therapies that many patients responded to, but the ones that didn't respond to the therapies and couldn't be transplanted had nothing. And so when eltrombopag was developed, we decided, well it works on stem cells, and you know, you know, we're not sure it'll work because they already have high levels of thrombopoietin, so we kind of thought well, they already are trying to stimulate their stem cells, but there's nothing there to be stimulated. So giving this drug is just like giving more of something they already have, so frankly, I wasn't very optimistic it would work, but the drug seemed really safe. And these patients had no other options, so we tried it, and it worked really well. And then it became through this whole thing to trying to figure out why, and a guy that I trained in my lab who's now independent, Dr. Underlaw Raschel, has now figured out that thrombopoietin in patients with aplastic anemia isn't working very well because these patients have a lot of inflammation going on in their body, and they make a lot of this hormone called interferon, and interferon interferes with the ability of thrombopoietin to work. But eltrombopag can get around that, so that's probably why it works in these patients, even though they already are making plenty of their own thrombopoietin. So anyway, so it's been fun. But it's a pill that patients take once a day with almost no side effects.

>> Very cool.

>> It's been great. And some of the patients that we treated had been, you know, being transfused with red blood cells and platelets you know every week for 15 years, and have had, you know, bleeds in their brain and had had multiple infections, and you know, were really, you know, were really not having a good lifestyle and were really, you know, at risk of dying from infections and bleeding. So to take a pill once a day and have this all get better was really kind of miraculous. It doesn't work in everyone, and we don't know long-term how long the effect will last, but we have patients that are almost ten years out, and they're still doing well. Anyway, but it really was based on Neil Young having, you know, followed these patients and had this huge, you know, population of aplastic anemia patients come into the clinical center. I mean, it's not, it's a rare disease. It's not a super-rare disease, but people in the community are scared to treat it just because these patients are so sick, and you know, they don't see a lot of these patients. And so we get a lot of them referred here. So you know we really have our department has really, mostly Neil, you know, has really changed the treatment of these patients, you know, enormously over the last, you know 40 years. So anyway, it's been great to add to that.

>> And so what exactly is aplastic anemia.

>> It's a, it's a situation where your immune system or something happens, so your body basically wipes out its own stem cells.

>> All over? Or just in the bone marrow?

>> In the bone marrow, just in the bone marrow, just the hematopoietic stem cells. And it seems to be kind of an autoimmune disease much of the time, but even if you treat, and you treat it with immunosuppression, with really high doses of, you know, tamping down the immune system, and 60, 70% of the time that works. But sometimes the patients relapse. Sometimes they don't get a complete improvement, and it seems like maybe this inflammation that I've talked about is really hurting their stem cells and making them not able to respond to normal thrombopoietin and normal signals. So we found that by really sort of hyper stimulating the stem cells with eltrombopag, and bypassing this problem with inflammation, that they recover their counts. And then, you know, they're doing okay. You know, figuring out all the mechanisms has been hard, as I told you, because we can't study this very easily in mice or other animals. Yeah, and I guess probably not a lot of entities in the private sector would even spend time exploring it because well, they have the drug already, so who cares how it works.

>> Right. You know, but I mean the drug was actually initially approved for another, another hematologic problem where you destroy your platelets too fast. You have immune destruction of just your platelets called ITP or Idiopathic thrombocytopenic purpura, which is a more common disease. And the reason to use eltrombopag in that disease was actually based in part on my original work 20 years ago when I was looking at levels of thrombopoietin. In ITP, then there'll be super low platelets. Their thrombopoietin levels are low, so they're not kind of compensating the way you want them to. So by giving more thrombopoietin, you drive up their platelet count, and they do better. So that's what the drug was originally approved for, and it's a more common disease, and you know, the company took it forward, GSK, Glaxo-Smith Kline, but then we decided to, you know, apply it to aplastic anemia and got a new FDA approval for application in that disease. So anyway, it was sort of repurposing a drug that was already out. It wasn't approved when we started the protocol, but it was almost approved, and it was approved a year later in ITP, so we could then, you know, use it in our patients.

>> And so, so how big is your team here?

>> About anywhere between 12 and 15 people in my lab, including me. And then I have a number of people that are, you know, working with me who are nurses and protocol managers who are part of sort of NHLBI's clinical research infrastructure which is very good. And then we have people that work on our animal facility that are five or six people that are part of my group.

>> Thinking back to your days as a postdoc, here at the NIH, I believe--so when did you come to the NIH?

>> 1987.

>> Okay, and that was as a postdoc?

>> Yeah, I finished my medical school and internal medicine training in Boston, and had actually planned to stay on at the Dana-Farber Cancer Center there as a fellow, but I really didn't have a lot of basic research experience. I had been a history and science and history of science and philosophy of science major in college. I worked in some labs during the summer, but I really had not had any sustained lab experience, and I was really interested in hematology, and I realized that hematology, to really contribute, especially in academic hematology, you had to, you know, have a pretty good grasp of science, and hopefully have experimental training. So I came to the NIH to interview for a clinical fellowship at the NCI, and literally checked a box on a, some kind of application form that asked about hematology, and I said, "Oh, yeah, I'm interested in hematology," and ended up in an interview with NHLBI leadership who used to run a program to have people come here as clinicians to help take care of the patients, kind of at the end of their residency, before doing sub-specialty training because there were no internal medicine residents at the clinical center. So it was a way to cover the patients and it was a way to have physician scientists come to NIH to get kind of excited about science. And so they, I ended up in this interview, but I was already kind of finishing my residency. I didn't need to do another year of residency, and so you know I sort of thought that was the end of having checked the wrong box. But Art Neanhise, who was the head of the hematology research program at the NIH at that point, after the interview came up to me and said, "Well, you know you shouldn't do this program because you don't need, you know, another year of residency. You don't need to improve your CV which is why a lot of people did it before they applied for cardiology fellowships. But do you want to come work in my lap? You seem really interested in, you know, hematopoiesis, and then sickle cell anemia, the two things that he worked one. And so I went back to Boston, and you know, I really hadn't, you know, meant to come to a lab postdoc, but I went back to Boston and thought about gee, maybe if I really want to be involved in hematology, I should spend two or three years really immersing myself in research and learn something, instead of having just been a summer students and decided to come and do it and defer my fellowship at Dana-Farber. And I never went back, so anyway, but it was, literally, you know, one of these things that you do in your life that, you know, has all these downstream repercussions because I checked the wrong box on a form. So yeah, anyway, I'm glad I did!

>> Yeah, just followed where life took you.

>> So I came here as a postdoc, and for three years, and then left for one year to go complete my clinical training for hematology so I could you know be, take some specialty boards in hematology. At that time point there wasn't actually a hematology fellowship training program based at the NIH. There was just oncology, which is often paired with hematology, but I really didn't want to do oncology. So I left for one year to go to UCSF, University of California, San Francisco, to do hematology training, and then came back. I knew I had a tenure track position to come back to at that point.

>> So you've been here about 30 years? Is that right?

>> Almost, exactly, yeah.

>> Minus a year break.

>> Minus a year break. But I mean, I came here in '87, and now it's, yeah, 2008, so yeah.

>> What's your number-one most memorable experience? Doesn't have to be your number one. But are there any things that come to mind, like this was a big aha moment, or something really cool happened with one of your trainees, or anything like that?

>> Well, I mean I do, you know, I definitely have been very interested in  mentoring, and I probably get more enjoyment out of my, people that I've trained, succeeding you know, almost of myself. And so the fact that, that you know, John Tisdale who was, who came here as a clinical fellow in the clinical fellowship program that I started once I came back from my own clinical training. We decided, okay, we need our own clinical training program here. People like me shouldn't have to leave to finish their clinical training. So we set up a clinical fellowship program, and John was one of the early fellows that came in the program, and then he decided to work in my lab, and he had no prior lab experience to speak of. He was actually playing in what became Hootie and the Blowfish, so that's another--you should interview him because he has a really interesting background.

>> Sounds fun!

>> But anyway, he was in my lab, and he's great, and he's smart, and he learned fast. And you know we accomplished a lot together, and then he went on and got his own lab, and, you know is really, you know very successful working primarily on doing stem cell transplant and gene therapy for sickle cell disease. So it's a definite outgrowth of what we, you know, were working on together, and he's taken it to sickle cell. And then he's trained Courtney Fitzhugh who came here a medical student, and now she's a PI, has her own group. So it's like a scientific granddaughter, you know? For me, and then Andre Labershell, who I mentioned earlier came here, having wonderful training during his PhD and then went back to medical school because he wanted to apply stem cell biology to patients. And he was in my lab, and now he has his own research program, and he just got the PESC award, which is the Presidential Early Scientific Career Award for 100 people in the country in all areas of science that are most promising. So we got that, I guess two years ago, and met, or year and a half ago and met Obama at the White House, and so for me, and then I saw him, you know, his, his student get up and present at the plenary session at the American Society of Hematology, this work about figuring out why the eltrombopag might be working. He took that part of it. And so seeing him up there doing that made me more happy than almost anything.

>> Yeah, I can only imagine. It's kind of like your scientific children are spreading out into the world.

>> Yeah! And my mentor, Art Nienhuis, I think was really like that as well. I mean, if you, he got a huge mentoring award from the Hematology Society, because if you look at sort of who is, you know, are really leaders in hematology today, a huge number of them, you know, trained with Art you know? I mean, he was editor of Blood, then I became editor of Blood. Then Dave Bodine who's here trained with him, and Neil Young and Ed Benz who's the head of Dana-Farber, and you know he really had an amazing impact on hematology. You know, his own work was really good, but his impact, much more I think is who he trained.

>> What do you think made him such a great mentor?

>> I mean, you know, he had very high expectations, very high. But he also, you know, he just always had his eye on the prize, which was to discover something new and apply it to patients. And he just didn't get distracted by, you know, I mean, he had a collection of people in the lab, you know. Some of the personalities were really unique or challenging, but you know, Art's just like, he just related to everybody kind of the same, you know? Just had high expectations, you know, he didn't, you know, you could never hurt Art's feelings. His ego just seemed to be, I don't know. I just found, you know, he really could deal with sort of everybody, a talent I wish I had. I'm not like him quite that way, but you know, he just sort of, you know, he was very fair, and he just kind of pushed everybody forward. And if you were good, if you were a success, if you were working hard and, you know, he trusted you. He sent me to speak for him. I mean he really furthered my career. I mean he had me speaking at national, international meetings, you know, as an invited speaker when I'd been in the lab for a year.

>> Oh, cool!

>> You know, so he was very, at least to me, and I think to many people, incredibly generous about you know like sending you out there and letting you talk about what you'd done. And get credit for it, and getting networking, and you know so that was, you know, that was really--I realized in retrospect pretty unusual. You know, so that, so I try to do that as well.

>> Yeah, and you've, I believe you've won some awards for teaching and mentoring?

>> Yeah, no. I mean I, yeah.

>> So if I asked some of your mentors or students the same question, what do you think they would say about your style of mentoring that's made you successful.

>> [Laughter] Oh, you know. I mean, I think people that don't work directly with me find me scary, I hear. But the people that are in my group, you know, I don't think find me as scary. I mean, I'm very available, and I, you know, I do want to help them succeed. And hopefully we figure out something that will help, you know, my, get me to my goals and make sure that I, you know, produce something so we can get, you know, funding for the next four-year period through the Board of Scientific Counselors. But you know coming up with a way that they, if they work hard and, and really, you know, want to do well, that they can succeed. And succeed both by accomplishing something important, but also publishing a paper, and being able to get onto their next, you know, kind of step. I mean, I'm never, you know, there's been some failures, and there's been some people I think I could have been much better mentors to, but overall, you know, I've trained a lot of people who've done very well. And I also have actually been very pleased in the last, especially six or seven years with post-bacs, post-baccalaureate fellows between college and medical school, or college and graduate school who've been in my group. And I've just had a set of just incredibly productive and stimulating, you know, really young, you know students in my group who've gone onto MD, PhD programs, or bioinformatics programs. And you know they were a huge help when they were here because they're really, really computer literate which I'm not and could do a lot of programming and analytics and our statistical you know software, and creating big data graphics in a way that, you know, me and most of my older postdocs can't. So they bring that, and we, you know, bring them the biology. And they get together, and they've been, you know, really productive. So that's been great.

>> And so I imagine you probably get quite a few applications to join your lab as a trainee on--what do, how do you select? What do you look for?

>> You know, it's difficult. I mean, especially for post-bacs who probably get you know like during the post-bac application season, I probably get 20 inquiries a week coming to me. And so you know I, I actually try to just go to the database and search, like I'll search for math majors, or search for computer science majors because right now I do need a lot of big data, you know, facility. And you know and I, I search for that, and then I read their personal statements and look at their, you know, grades and everything. And then I set up a Skype call and try to see, you know, how they'll fit. And sometimes it is pretty subjective, just like okay, I like what they're, how they present themselves. They seem interested, and they have a spark, you know? And other times, you know, if I know somebody else that either a graduate student who's applying for a postdoc, or an, you know, an undergrad applying to be a post-bac. If I know someone they've worked with, it is actually super useful to be able to find out directly from someone who's worked with them that they are, you know, like hard-working, and not, you know, don't have a personality disorder that will make it, you know, difficult to be in the lab. Because I have found, I mean, you know, a laboratory is a, you know a very, in some ways an unusual work environment because you know people are coming and going, and setting up experiments at weird times, and it's, you know, it's not a nine to five job. And you know you're working in a big room, usually all together, so if you have one person who's really impossible to be around, and who is really divisive, it makes everybody not want to come to work. And the whole group is less productive. So I've had that happen, you know, luckily not very many times.

>> Was there something that you think, looking back that you saw that you missed in the screening process?

>> In the cases, you know, sometimes people are too good to be true, and that's because they are too good to be true, you know?

>> Ah, something hidden there that--?

>> Yeah, and sometimes, you know I really, it hasn't happened a lot, but in the sort of couple of instances where, you know, there really was a person that was really making the whole group not look forward to coming to work. I can actually in those instances say that I couldn't have avoided it, you know? They were people that presented very well, and had seemingly the right background.

>> In a couple of meetings, it's hard to tell.

>> And you know maybe I should have talked more carefully to their prior mentors, you know? And I, I try to do that now. But you don't want to, you know don't want to exclude people that, you don't want to take only people who have worked here for your friends. You know, because then you're going to, you know, it's hard to get diversity in your laboratory that way. It's hard to, you know, take people from, you know, colleges or medical schools or university programs that aren't, you know, Harvard and Hopkins, and you know, UCSF. So you know, you try to balance it, and I have been pretty involved with, you know some of the kind of increasing diversity post-bac and student programs. And you know sometimes those are, they're funded in other ways, so it's taking an extra person in your lab. You're not, you're not necessarily having to cover their salaries. So even if they're not trained as well, or maybe you're not as impatient because, you know, you're not paying them, you know. So they have time to prove themselves, and time to learn and not, not taking up your, you know, two postdoc slots. So that's a good, I think that's a good way to try to increase diversity and bring people from different backgrounds to have these programs that, you know, try to help people that don't have a strong educational background, necessarily.

>> I'm sure, and they all can, they all can learn from you. And one way that people learn is by making mistakes. So are there any big mistakes that you've made in your career that you learned a really great lesson from that you could share?

>> That's a really good question. I don't know if I've thought about that, you know? I'm very forward-thinking. I'm sure I've made loads of mistakes.

>> You probably learn from them and move on.

>> You know, I mean. Gosh, you know, that's probably one I should have thought about first, and you're going to think I'm really conceited to not come up with 15 mistakes I've made, but you know, I mean, have I pursued certain things for longer than I should because I was trying to prove something that was wrong? Yeah, here and there. But you know I'm pretty, pretty lucky in terms of not having any, you know, of my papers turn out to be either, you know, luckily I've had nobody that's been accused of, you know, scientific misconduct who's worked with me. Or you know as far as I know, that hasn't happened, and, you know, I haven't had things that, that turned out to have been scientifically wrong, you know, based on later work. So no.

>> You're very involved in scientific integrity like groups of committees or something like that, I believe?

>> Well, because of my role editing a journal, I unfortunately got to see when things go really wrong, when people have published stuff or submitted stuff, and then it turns out that it was, you know, fabricated or misinterpreted, or people fighting with each other about credit. So I saw a lot of that, you know, the underside of science in a way. And I got interested in, you know, thinking about how to, how to prevent it. How to detect it, and so I got very involved in that arena, and I got very involved in investigating these cases. So then NIH figured it out, so they put me on a lot of committees to, and investigative committees, you know, for specific instances. And it's, it's really difficult work, but it's really important, and I think you learn, you know, you learn by seeing when things go really wrong to think about ways to try to fix that in the future. And I do think that, you know, I am, I think I put pressure on people just by my personality, but I don't, I try really hard not to put pressure on people to get one result that I want. Because that's, I see again and again, that's how people end up--maybe nine out of ten people will never, will not, you know, fudge numbers because their boss is pushing them to get a result. But one in ten will, and you know whose fault is that? Is that the boss or the person? You know? Usually it's the person that gets, you know, who did it, whose career is totally trashed. But you know, the lab chief bears some responsibility for sure, and I think, you know, you can't--you have to have an open mind, and you have to be willing to have data that, you know, doesn't support your own theory. And you can't just throw that data out, and you can't just keep pushing a person to do an experiment again and again and again until they get the answer you want. Because then they're eventually going to get an answer you want in ways that are not good. Whether it' actually fraud or they're just, you know, throwing out things. "Oh, that, that was an outlier," or you know, "Oh that didn't, you know, that, that mouse, you know, I don't know--that mouse fell in the cage and wasn't acting normally, so I'll throw that one out." You know, just, I don't know, things that, that aren't outright fraud but that are data manipulation. And you have to not put pressure on people to only get an answer that you decided you want in advance.

>> Yeah, so I definitely don't want to take too much of your time, so I'm just checking here. We've probably gone a little bit over what I asked for. So maybe just another question or two? So what do you think is probably one of the biggest misconceptions that people, either the general public or very early-career students or researchers have about what, what life is like being a scientist, or a scientist at the NIH?

>> Well one thing about being a scientist, you know, it is, I'm very involved with trying to improve gender representation, especially in you know principle investigator level and leadership levels of the NIH. And you know I think it's a great time to be a scientist, working on human disease because the genome project, and really what we've learned from that has come into fruition. That crossed with sort of really powerful computers allows you to do, you know, sort of unimaginable things in terms of trying to figure out disease and design treatments. And you know we're seeing huge progress in my area, in cancer biology, and then you know designing drugs that actually are, you know, not just poisons to kill all your cells and hope cancer cells die, you know, more than your normal cells, but actually targeting just cancer cells. So it's just a great time to be doing this.