Pat Brown on DNA Mutations and Cancer, Leukemia and Targeted Cancer Therapyz

Transcript:

What happens is one of the cells in the blood just by chance in the normal process of DNA replication a mistake is made and the wrong The wrong base pair ends up in the wrong place and that's what's that's a genetic mutation If that mutation if that change in base pairs happens in the flip 3 gene In a blood cell and specifically in that kinase domain and it affects the way the cells functioning so all four of those things have to be true Then suddenly that cells starts to behave abnormally and it's light switches on all the time and it is creating new cells over and over and over and over again and does not turn off What happens then is that's happening in your bone marrow now your bone marrow gets crowded with all these unnecessary blood precursors and that is looking at that's the definition of leukemia Hi, welcome to the science fair podcast. I'm your host Susan Keatley. I'm a PhD chemist writer and I love talking to scientists On the science fair podcast I aim to bring you conversations with scientists doing fascinating, cutting edge work on all kinds of interesting phenomena Ranging physics, to chemistry, to biology and even the nature of science itself In this second season of the podcast we'll start by asking each scientist a little bit about their journey to becoming a scientist And then we'll talk about their research and how it relates to one or two of the high school science standards from that scientist state So come along and tune in for some science fair Our guest today is Pat Brown. Pat Brown is a senior clinical trial physician in hematology clinical development at the pharmaceutical company Bristol Myers-Swip And for listeners who are not familiar with the word hematology it means the study of blood and blood disorders Pat earned a bachelor's degree in engineering from the United States Military Academy in West Point, New York and a master's degree in philosophy and politics from Oxford University in England He then went on to get his medical degree from Medical University of South Carolina College of Medicine and then completed his internship and residency training in pediatrics at Johns Hopkins Hospital Followed by completion of fellowship training in pediatrics, hematology and oncology in the joint Johns Hopkins National Cancer Institute program He joined the Johns Hopkins faculty as an instructor and then was promoted to assistant associate and full professor of oncology and pediatrics And the director of the pediatric leukemia program at the Sydney Kimmel Comprehensive Cancer Center With a focus on childhood leukemia, which is a cancer of the blood and bone marrow During his time at Hopkins, Pat mentored many students who went on to have impactful careers in academia and industry And he was honored for his teaching by several awards and being selected to teach for the premier national board review course for pediatric hematology in oncology His lab found that a gene called flip three, which was initially discovered by Pat's mentor, Don Small He found that this gene is especially important in certain kinds of childhood leukemia that are especially hard to cure His lab also identified and helped develop promising combinations of standard chemotherapy drugs and flip three inhibitors that can work together to more effectively kill leukemia cells So in the conversation today, Pat's going to talk to us about leukemia and how it helps us understand the molecular foundation of cancer He's going to talk to us about the work he did as a scientist and honing in on what was challenging about treating a specific kind of leukemia And how he's used his training as a scientist and also a physician and his recent move from academia to industry, fueled by his wish to translate lab discoveries into clinical realities for patients So Pat, welcome to the show Thanks Susan, it's great to be here. I really appreciate the invitation. I would love to start today's episode by asking you about your path as a scientist I'm sure listeners would love to hear some behind the scenes parts of your story that we didn't hear about in the introduction So how did you get to where you are today and please include any unexpected twists and turns that happened on your journey? Sure, there are certainly several of those. So, you know, early on in school, I found that I was interested in math and science courses primarily And, you know, really, that was from a very early age. And so in high school, you know, when you meet with guidance counselors, I was, you know, based on my aptitude and interest was kind of one thing that was suggested to me was engineering, you know, as a career since I was really kind of kind of interested in math and science. And so, you know, when I went looking for colleges, I ended up going to West Point, which was a really good engineering school and it was free And it had great uniform. So all those things factored in. And I decided, you know, within the first year or so to major in computer engineering, you know, this was the kind of late 80s when, you know, computers, personal computers are really just kind of taking off And so it was really kind of a hot field. And I found during college that I loved studying engineering, but when I had a chance to actually kind of go to an engineering work environment, I found that I really didn't enjoy doing it very much. And, you know, I just found it kind of lacked some of the interpersonal interactions that I enjoyed and maybe some creativity. And so I decided at that point to pursue medicine. And I got into the pre-med program at West Point and, you know, but I eventually ended up having to put that off until after I had completed my military commitment. Because of, you know, the opportunity for a scholarship to go to Oxford came up and I just took that. So that's where my interest in medicine came from was kind of when I figured out that engineering wasn't exactly right. So I got to medical school and in my early medical school classes, I really became fascinated with cancer as a topic. And specifically what fascinated me was how changes in our chromosomes and genes cause cancer. And then I got to my clinical rotations in med school and I met and was able to take care of some children with cancer. And I kind of had a gut feeling. I knew immediately that's what I wanted to do. I wanted to be a pediatric oncologist. And of all the cancers that I studied and that I took care of patients with the one that fascinated me the most was blood cancer, which is called leukemia, which you referred to in your introduction. My interest in scientific research and, you know, laboratory based scientific research really began during my specialty training after medical school in pediatric oncology since that was kind of a requirement to do or at least an expectation to do a laboratory based research project. Well, it's a really interesting journey from engineering to medicine to research. And I think your point about thinking about the work environment and the other things we need beyond the topic of study is critical. I often think, at least when I was growing up, it may be less so today that children and adolescents are told to think about the topics that they love with not enough consideration on the environment that will help them thrive. And that is maybe more important sometimes. So I think that's absolutely 100% agree. And I think, you know, the lesson that I drew from that is, you know, you really got to try to put yourself in the real world with people that are doing what you're potentially interested in to understand whether it's a good fit for you. Yeah, it's great advice. So let's talk about leukemia in general. What is leukemia? What's going on molecularly in leukemia? And how does it help us understand other cancers? Absolutely. So the really the definition of leukemia, as I mentioned, is it's a blood cancer. And specifically leukemia is a cancer that arises from the cells in our bone marrow that produce normal blood. And so those are what we refer to as blood precursors. So there are, you know, blood is produced in the bone marrow by cells that have stem cell like qualities that produce our normal blood. And those are the normal blood cells are red blood cells platelets and white blood cells. And leukemia can arise from any of those precursors from any of those three blood cell precursors. There's different subtypes of leukemia. And in general, there's four major types. And there's two that are called chronic leukemias and two that are called acute leukemias. So that's the first distinction is acute versus chronic leukemia. Acute leukemias tend to be very aggressive, need treatment right away and can really be life threatening. in the immediate period after patients are diagnosed, whereas chronic leukemias can actually be really slow growing and can sometimes be monitored and not even treated for years before they require treatment. And then, so the second major categorization of leukemia is myeloid or lymphoid. And so that refers to the two major classes of blood cells we have. The lymphoid blood cells are lymphocytes, B cells and T cells, and those are components of the immune system. And leukemias that arise from those cells are called lymphoid. And then, all the other blood cells, red blood cells, platelets, and non-limphosite white blood cells, those are myeloid. And so that gives you your four major types of leukemia. Acute myeloid, acute lymphoid, chronic myeloid, chronic lymphoid. And those are typically used, we use acronyms, ALL, AML, CML, CLL, those are the four major types of leukemia. In terms of the epidemiology, so it's important to understand that acute leukemias are by far the most common leukemias occurring in children. And it's, in fact, acute lymphoid leukemia, ALL, is the most common cancer in children. In adults, it's very different. So chronic leukemias are more common than acute leukemias in adults. And CLL, chronic lymphocytes leukemias, the most common leukemia in adults. Now that's not the most common cancer in adults. Those are mostly solid tumors, things like colon cancer, breast cancer, and so forth. So leukemia is actually a pretty rare cancer in adults in the grand scheme of cancer, whereas leukemia is really the most common cancer occurring in children. Great. So that just gives you an overview of leukemia. Yeah. And before we started recording, we were chatting about this amazing book, The Emperor of Almalades, of Iorah, He of Cancer, by Siddhartha Mukherjee. I thought it was so interesting. Before people had access to imaging tumors, leukemia really made it possible to study the efficacy of treatments, because you could literally count the cells after administering a treatment to see if something was working. Leukemia, for a lot of reasons, has been at the forefront of the understanding of cancer, cancer treatments, et cetera. And really that's for a very simple reason and you referred to it, is that the cancer cells are so accessible. When someone has leukemia, you can get a sample of the tumor simply by drawing their blood, because the leukemia cells are circulating in the blood. For all other cancers, you really need a biopsy, which is a surgical procedure. It's complicated. So it's really simply a matter that leukemia cells are extremely accessible. Not only that, when you draw somebody's blood, the leukemia cells are there and they're already in a form that's very easy to study in the lab. When you biopsy a cell tumor, you've got to figure out how to separate the cells. And that's extremely difficult, technically challenging. Whereas leukemia, the cells are already separated and it's very easy to study them in the laboratory. I think that's a big part of why discoveries about cancer in general have often-- and actually the vast majority of the time have occurred in leukemia first and then been applied potentially to other cancers. It's fascinating. And so how did you come to work on and then really decide to focus on leukemia? Yeah, so after I had my hospital-based training in pediatric oncology, I got to the research portion of my training. And I selected Don Small's lab. You mentioned Don's name at Hopkins. And that was specifically because that his lab was discovering new, molecularly targeted therapies for leukemia. And that really resonated with me. I think it was that intersection between the lab and the patient that was very immediately clear. Some of the other laboratories that were available were much more at the basic side of the spectrum of research. That was not immediately clear how we would apply what we were doing in the laboratory to the patients. And so we refer to this as bench to bedside, that discoveries that we made at the laboratory bench were-- it was immediately apparent how we would apply that to the patients at the bedside right across the street in our case. And so this lab was exclusively focused on leukemia, which was what my clinical interest was in. So it really resonated. And the final attraction of this lab to me was that up until that time, they had really focused on adult leukemia. And so I had an opportunity as a pediatric oncologist to come into this established laboratory with established procedures and just apply what they had been learning about adult leukemia to a new area. And that could potentially impact children with leukemia. So for all those reasons, that was really a great choice for me at the time. And I would love to ask you when you joined this lab, because-- and that sort of relates to the idea of molecularly targeted cancer therapy. And so my understanding is always that it was really-- in the early 2000s, when cancer therapy changed dramatically, and you're going from kind of like this one-size-fits-all approach to let's look at the patient, let's get some genetic information about their cancer, and let's try to tailor something to them. So I'd love to hear about what the state of the science was at that time when you joined the lab and what it was like to be in the forefront of that. Absolutely. So I joined the lab in 2000-- let's see, in '98, 2001, 2002. So really, it was really right at that time. And so just to take a step back, cancer therapies historically, from the very first time that it was even attempted to treat cancer, there's really been three major modalities. There's been surgery, radiation, and systemic therapy or chemotherapy. And so surgery and radiation are really localized therapy. Surgery, you cut out a tumor. Radiation is-- you direct actual radiation energy at a specific area to treat a cancer in a tumor. Chemotherapy referred kind of classically to drugs that were taken either by mouth or injected, that would get everywhere in the body. Those were so-called systemic therapies, because they kind of went throughout the entire body. And the mechanism for the initial chemotherapy drugs was extremely non-specific. They were developed because they inhibited growth of any cell. And it just turns out that the reason they had any specificity for cancer is because the cancer cells were the most rapidly growing cells in the body for the person that was taking these drugs. But that didn't mean the drugs weren't also affecting other rapidly growing cells in the body, namely, hair follicles. And that's why your hair falls out. The lining of your gastrointestinal tract, and that's why chemotherapy joist calls nausea and vomiting. And also the normal blood cells, which are constantly regenerating, and that's why chemotherapy suppresses blood production and suppresses the immune system and makes patients susceptible to infections and stuff like that. So targeted cancer therapy was really the advent of it was in the late '90s, early 2000. And to understand that kind of revolution in cancer therapy, it's important that to understand that that really arose specifically from the 30 years or so prior when the initial discovery of chromosome abnormalities driving cancer, this was Janet Rowley, an incredible woman in the 1970s who discovered the Philadelphia chromosome, which was this chromosomal change that drove leukemia, CML. And from that discovery that chromosomal change actually was driving the cancer. The next 30 years was a refinement of the understanding of genetic changes driving cancer. There were many attempts to take advantage of that understanding to develop targeted therapies. And that was finally successful in the late '90s. And it was indeed that Philadelphia chromosome. So what that chromosomal translocation that drive CML does is it takes one gene that's normally on chromosome 9 and a gene that's normally on chromosome 22 and it abnormally fuses them together. That turns on a growth signal to the cell. That growth signal is coming from a specific gene called Able 1 and a laboratory in Oregon, a guy named Brian Drucher, figured out that a small molecule, a chemical, could inhibit that Able 1 signal in CML. It turned into a pill that you'd take once a day and that completely revolutionized the treatment of that disease. That was previously incurable except for the bone marrow transplant and became manageable and even curable with a pill that you could take once a day that had very minimal side effects because it's specifically targeted that stuff. That's just amazing. And that was the advent of it. And so now, fast forward to 2024, the proportion of cancers that are treatable with these targeted types of drugs and there's now many different types of targeted drugs has expanded exponentially. And so I would guess that more than half of cancers now can be treated with at least one of the components of their treatment or one of these targeted drugs. It's really humbling to think that scientists have been able to figure this out and especially thinking that everything felt so mysterious for so long. What do we do to treat the cancer and why is it even here and to know that molecularly? It's amazing. So let's get into some of the specifics of your work with Flip 3. Please tell us what is Flip 3? How did your research lead to it? I knew you knew something about it before joining the lab or your advisor did. But why is it important in leukemia? Sure. So Flip 3, it's really not that important but it stands for FIMS-like tyrosine kinase 3. What's important about that is the tyrosine kinase. So I'll get to that. But Flip 3 is, that's the kind of class of protein. It's a tyrosine kinase. So it was discovered as one of the genes that was expressed in these early blood precursors that I mentioned are the source of leukemia. And so what was discovered was that the Flip 3 gene and the protein that comes from that promotes growth of these stem cells, these blood precursors in early blood development. And so that made the Flip 3 gene and protein a very logical place to look for mutations that might cause leukemia, right? Because the normal gene was involved in the process of cellular growth in these cells. And so it made sense that one of the ways that leukemia might develop was mutating the Flip 3 gene. And in fact, when the technologies were developed to screen, easily screen cancer cells for, to look at specific genes for mutations, it was actually discovered that Flip 3 was mutated in a very high proportion of adults with AML, which is the most deadly form of leukemia. It was about a third of adults with AML, their AML is driven by a mutation in the Flip 3 gene. So it overnight became an extremely hot topic and an extremely important area to try to develop targeted therapies just as had been done for the able one kinase that I mentioned for. And this is where the fact that Flip 3 is attirusing kinase is really important because of all of the, all of all the cancer causing genes and proteins, those that are the easiest to define chemicals to target are the kinases. And that's just because that protein has a specific area of the protein that is responsible for the functional part of the protein that promotes growth. There's a little pocket that these chemicals can fit into and interrupt the way those proteins work. And so that's why the Flip 3 discovery was so immediately important and immediately actionable is because it was a kinase and we already had a track record of developing chemicals that could inhibit kinases. So, and so once that was discovered, our Don's lab started to work to find those chemicals that could inhibit Flip 3. When I joined the lab, they had just found the first kind of lead chemicals that could inhibit Flip 3. And when I joined the lab, I began working with those drugs and with pediatric leukemias to try to apply it to that disease area. And, oh, well, I think we were going there. But just, yeah, so tell us, you know, give us some examples of what you worked on. Right. So, the first step was, okay, we knew that adult AML Flip 3 mutations were happening in a high proportion of cases and were very important. But no one had looked yet at pediatric leukemias. And so, what I did with, you know, with help in the lab was to look at all the different types of childhood leukemias. There were two subsets of childhood leukemias where Flip 3 was mutated and important as well. One was in childhood AML, which is less common than adult AML, but was still important and very deadly. The second, and this was the more kind of novel discovery was, so leukemia can develop as early as at the age of birth and in the first year of life. And that's called infant and kinase. And that's, again, one of the most deadly forms of childhood leukemia. And we discovered that Flip 3 was actually mutated and activated and driving leukemia in a high proportion of infant leukemia. And so, we discovered that those two subsets in childhood leukemia was where Flip 3 inhibitors may have their greatest impact. And so, what did you, what did you do from there? Well, so the first step was to take samples from patients with these forms of leukemia into the laboratory. We set up laboratory experiments that would expose these leukemia cells to these medicines. We'd also have controls and these were leukemias that were not driven by Flip 3. And so, we would try to demonstrate that the drugs were selectively effective in the cells that had the Flip 3 mutations and were less effective in those that did not. So that was our hypothesis and it was important to have negative controls. It was also important to have positive controls. So we knew that it worked in adults with Flip 3 mutations. We included those in the experiments. And so, that was one set of experiments. These were kind of in the laboratory what we call X-Vivo outside of the organism, outside of the human being, studying whether the cells responded to these inhibitors by inducing cell death. We also set up animal experiments. We worked with mice. So there were mice that we could ingraft with human tumors. These are called xenographs. And we could treat the mice with these drugs and again with all the controls and figure it out if they were effective. So that was step one. Those are called preclinical experiments. And so we took the data from those preclinical experiments which were extremely promising. And we proposed the first clinical trials in CHOA. And that was an important and exciting step in my career was that because I had, because I was a physician scientist and because I had the ability to not only do laboratory research but also take care of patients, I was in a great position to take on leadership of developing those clinical trials for the first time in CHOA. And that became a big part of my career and my research from that point forward was clinical research. And again, I just want to point out this bench to bedside. So what I did from that point forward was I was both a clinical researcher developing and leading the clinical trials, but I kept my laboratory so that we could take samples from the patients that were actually receiving the drug and study. Was it working if not why and look for mechanisms of resistance and all these other incredible, incredibly important questions that arose from this development from the laboratory. How long did that first trial take? Oh, boy. From beginning, from the planning stages to the, to when we actually had results and reported them and published them was about 10 years. And so talk about humbling, you know, that's one thing to understand. You know, I want to think a step back about humility, right? So I talked about how from the 1970s, from that first observation that a specific genetic mutation can drive a cancer to the development of targeted therapeutics was over 30. Right. And then once you, once you, you know, can kind of link a specific genetic mutation to a treatment, it's not a fast process from that point forward, you know, no matter how promising it is, it is a painstaking and time consuming process to get from that point to where a treatment is either proven to be effective or proven to not be effective. Right. And there's just as many failures as there are successes along that. So, but you had some successes in terms of treatments that were made into, I don't remember if they were pills or an injection, but so tell us about that. Absolutely. So the small molecule of inhibitor for flip three that I mentioned, the one that we worked with was called the store tenet. And these names don't really matter. And they're always hard to say. But they all they exactly they and that's for inhibitor believe it or not. That's like short for inhibitor. You know, there's like these conventions for naming them. But anyway, the store tenet was really the first generation of flip three inhibitor. It was an oral medication. Now that's a challenge when you're treating babies with leukemia. So we had to we had to turn the pills into a liquid formulation. We had to figure out, you know, how to how to give it. That's a huge challenge. It's part of part of why it takes ten years is all these logistical challenges that come up when you look look to treat. So, you know, and we also the other form of flip three targeted therapy that I want to mention was a monoclonal antibody. So, you know, the flip three kinase is, you know, it signals through that binding pocket that I mentioned. And that's what the small molecules like the store to do. Impact. But the other opportunity for flip three was it's expressed on the surface of the leukemia. So it's available to the immune system to see and to target. And so we so we partnered with a different company to produce a monoclonal antibody that could attack that these monoclonal antibodies are are proteins that are B cells normally make an R immune system. And this is when you get, for example, when you receive a vaccine say the free vaccine. What it's doing is it's stimulating your normal B cells to make monoclonal antibodies against the flu virus so that when you get infected those monoclonal monoclonal antibodies bind cells that are infected by the flu and get rid of them. So this is what we are doing with cancer directed monoclonal antibodies is we create these monoclonal antibodies. We inject them into the patient. They go and they bind to the leukemia cells because they express that flip three and then the immune system can eradicate that you know that cell just as if it's an infected cell it eradicates it in this case it's getting rid of the loop right. So so anyway those were the two major types of flip three target of therapies that we worked with. The main challenge with both of these therapies was and this is the challenge with cancer therapies targeted cancer therapies in general is the maddening ability of the cancer cells to become resistant. Yeah, you know and there's lots of different mechanisms from that. So for the small molecules what the cancer cells often do is they just mutate that little pocket where the chemical binds and now the chemical can't bind there. The drug can't bind any right and that allows the cells the leukemia cells to continue to to grow even if the patient's taking the drug. For the monoclonal antibodies what these leukemia cells were able to do is they mutated themselves they changed themselves so that the flip three was no longer expressed on the surface it just sat inside the cell where the monoclonal antibody could see it is it is so this it's infuriating and it gives you the idea of why cancer why are we not curing every right now well we're curing a lot more cancers but the reason why these medicines are we have difficulty with any one individual medicine curing a cancer is because the cells the cancer cells just like our own normal cells want to survive they are driven by the laws of nature of natural selection that they want to survive they want to undergo adaptations that will allow them to survive just as our normal cells that's what's driven evolution from the very beginning and it's what's driving cancer as well and so we what we have to do is is figure out how to take stay a step ahead to combine different therapies to prevent resistance and just like you know it's it's very analogous to antibiotic resistance right we know that that's a big problem in the and the HIV is a great example when HIV first came on the scene any individual drug was really limited by the fact that the HIV virus would mutate and change right what is revolutionized HIV treatment is multimodal therapy right where several different drugs are given at the same time to prevent that resistance right that's the kind of approach we need to take in right did you or would you would would people give a patient a small molecule oral medicine and also a monoclonal anybody at the same time. Sure that's actually been that's been done successfully and in other in other settings as well and that's a great example of how you would try to prevent resistance by attacking multiple different mechanisms at the same time. You know it's it sometimes it's most effective that that is that would be potentially less effective than even targeting more than one mechanism within a cancer. Oh sure so the flip three mutation is one of several different cancer driving mechanisms in any individual leukemia cells so it might even be more effective to target flip three through either a small molecule and modically about your both but then also target another mechanism that that leukemia cell is using and this really highlights the concept of personalized therapy. Yeah because even even if you look at flip three mutated infant leukemias for example they're not all the same right because some of them almost all of them will have at least one other pathway that's also helping to drive their luteus and that can differ from patient to patient and so you know the idea moving forward is that we can sample any individual patients cancer whatever cancer type it is understand what are the what are all the things driving that that patients cancer and try to come up with you know a so called cocktail of targeted therapies that address as many of those as we can possibly address at the same time to prevent resistance from developing right and that I understand that's kind of being used more and more I was recently writing a piece on colon cancer but like even after the surgery doing liquid biopsies to see you know is it coming back do we have evidence of tumor cells and what's their makeup and you know really getting like you said it's like personalized it's like almost like that patient's fingerprint of their cancer. Absolutely and then also I love the fact you brought liquid biopsies so that remember I talked about how leukemia has been at the forefront because the cancer cells are so accessible so what we figured out is that now that our tech technological techniques technological techniques now that our technological savvy has gotten to the point where we can find very small numbers of cancer cells in a blood sample we can now apply now solid tumors are becoming accessible through the blood as well right and that's really been so helpful not only for early diagnosis right so you can imagine now if you could take a blood sample from a patient and survey their blood for the potential circulating cancer cells that and even before these tumors are able to be detected either from symptoms or even from imaging you know that would that would revolutionize cancer treatment right because so many so many so many cancer patients were unsuccessful treating them not because we don't have the tools to treat them but because we find their cancer to right so you know the improvement of cancer curates is really has many different facets one is earlier in earlier detection before things spread to the point where they can't be treated by simple modalities like surgery and but the second is better and better treatments systemic treatments like target therapy but the first is just as important as yeah well I think the next decades will be will be very exciting on that front 100 percent and you know it's you know it's sometimes you if if if I ever find myself wearing that oh boy we've gotten past the point where we can learn anything new it it never happens because you know just as we you know as we developed these new target initial new target therapies it was a really exciting time and then resistance mechanisms you know became a parent was like oh no you know we're going to run out of we're going to this is going to run its course where they're not going to be effective but no we just keep we just keep in a vein keep following the science keep hypothesizing testing the hypotheses and you know the next the next advance is out there and you just have to keep working towards it so I would love to hear your reflections about being able to work in translational medicine like this you know bench to bedside you know you've worked as a physician and as a scientist what what are your thoughts on that? Absolutely you know and I can say that when I look back by far the most exciting and rewarding part of my research experience from when I first started in the laboratory to now was when we got the first you know when we got the first approval and green light. to take this first-generation flythrin inhibitor, the stored to node, and design and conduct the first clinical trials in children with leukemia. To me, that was the ultimate translation of what we were doing in the laboratory to a potentially new treatment for human being, in some cases a baby that had a disease that was very deadly. And so that bench-to-bedside translation was just extremely exciting and rewarding. The other part of translational research that I mentioned before, but I really want to focus on, is the opposite direction. So we do these experiments in the laboratory to try to identify promising treatments. We then translate those into clinical trials for patients. A lot of times that's where unfortunately, it's a one-way street. And it really shouldn't be so many of the important discoveries have been made in the opposite direction, where we take samples from the first patients receiving these drugs in these clinical trials back to the laboratory. And we ask the hard questions, is it working? First of all, is the drug getting to the levels in the patient's blood that are sufficient to kill the cells? So that ultimately-- and that's a matter of optimal dosing. Like, are we giving the patient a much enough drug? So that's one very important component. A lot of therapies fail, not because the drug wouldn't work, but because the work in the lab wasn't done to optimize the dosing, which is extremely frustrating. Yes. So we built into the clinical trial the laboratory studies to confirm that the dosing was right. And we made sure that we were adaptable to that. And we ended up amending the study to change the dosing. We actually figured out that you could individualize dosing. We created a test to say, is this individual patient getting enough? Because you could have the same dose for two patients, and because of just interpatient variability, they might not get the same levels of drug, so we could personalize. That's amazing. So-- and then the second thing was, OK, so let's say a patient was getting enough levels that it theoretically should kill the arrachemia cells, but wasn't. Well, why? And so we set up experiments in the lab to try to figure out what were the mechanisms of resistance. And that's where we discovered that there were additional mutations that could happen in the flip region that could change the affinity of the drug for the pocket that it was targeting. And there were other discoveries as well of alternative mechanisms that would be upregulated so that the leukemia no longer was dependent on flip-3 signaling for its survival. So anyway, the translational medicine is at two-way street. It is translating from the lab to the clinic, from the bench to the bedside, but also from the patient back to the bench. It's a double-headed arrow between those two. That's a great perspective. So you've been officially working in industry for a few years. And this kind of maybe gets at what we started talking about in the beginning. How would you characterize working in academia versus industry? And do you think there are certain skill sets, personality types, work styles, where that would make one environment better than another for a scientist? Absolutely. I think it's a great topic and very timely from me, as you mentioned, with my recent transition. So first, I want to say I'll talk about it first from the perspective of what I do as a physician scientist. So when you're a physician scientist working in academia, which basically just means you're working in a university environment, you really have three different jobs in one. You're a clinician. You take care of patients. So I saw patients in the clinic, and I saw patients in the hospital. So you're a doctor for patients. You're a research scientist, which is what I was doing in the laboratory and also through clinical trials. And thirdly, you're a teacher. So you have responsibility for passing on the knowledge that we as a field have gained and you as a gain to trainees, medical students, residents. And so it's really-- you really have three jobs in one. One of the reasons that one of the drivers for me to go into industry was it allowed me the ability to really focus more on one aspect, specifically the research component of that. After 25 years as a clinician and researcher and an educator, I got to the point where I was really ready just to focus on one thing. And going into industry really facilitated that focus on research. And so that's one thing to understand. And then let's talk now more in general about doing science writ more large in academia versus industry. So the first difference is in academia, the key metrics of success, the key kind of-- the critical things that your job is looking to produce are research grants and publications. So there's the saying of publisher parish in academics. So that's important because in academics, your main goal is scholarship. You are trying to create new knowledge that can be disseminated to the scientific community. And the way you do that is you have to, first of all, you have to get funding for your research. And that's the grant part. So you apply to-- in the US, we're very fortunate to have the NIH. Our government has a very large source of funding for research. So we apply to the NIH. We also are very fortunate to have many philanthropic research organizations, specifically in cancer. There's the V Foundation, there's the leukemia in lymphoma society. Those are very active in leukemia. There's also breast cancer research foundations. There's stand up to cancer. You've heard of these. So our job as academicians is to apply to those organizations, describe our hypotheses, show them our preliminary data, and lay out our plans for research to get funding to do our work. And then when we do that work, to publish it for the general community. So grants and publications are really the key product of what we're doing in those jobs in academia and the key metric of success for any individual scientists. Now, so in industry, there's less of a focus on grants and publications and more on contributing to what is going to lead any individual drug to progress along the company's pipeline. So you can work as a scientist anywhere along that drug development pipeline. You can be in the very early stages, which is laboratory-based preclinical research, or you can be a scientist working on the later stages where you're actually working on clinical trials. But that's really the pipeline of the asset that the company is developing is-- that's the key metric is you are helping to move that drug along that pipeline. Ultimately, the goal is for regulatory approval in the US, that would be the FDA, and then availability of that drug to patients. And establishing that drug is standard of care. So we're doing the same things in the laboratory. We're doing the same things in the clinical trial. It's the same language you're speaking. It's just that the metrics of success and the primary byproduct of that work have a slightly different purpose. Right. I think that's a great perspective. And it made me think of my undergraduate science advisor who had gone from Bell Labs to academia. And so you kind of went in the other direction. But I think as a scientist, it's just probably fascinating to see the world of science in these two environments and the different-- 100%. Yeah. Yeah. And one thing I'll say is one of the things that attracted me to moving to industry, at this point in my career, was because of the complexity of developing cancer therapies, the early in my career, when I first started, it was the academic institutions that were doing so much of this work. Wow. Because it was very early days. And you had the resources to kind of develop those first jobs, the first data. Now it's a much more-- because of the success of this approach, it's a much more competitive environment. It requires many more resources. And so the nexus of control and the nexus of innovation has moved from academia to industry. That's the first thing. And so really, to be at the cutting edge of cancer research now, you're almost better positioned in industry than you are in academia. I think academia is extremely important to go through those phases, to get the training you need. But I do think that's an important component of this. realize as well. That's important. So can you tell us what you're specifically working on now and what are your hopes thinking ahead 20 years out? 100 percent sure. So you know first of all so as a physician in industry there's a number of different roles that that I could have taken on. You know and so primarily there's three major areas that physicians in industry can work. One is in research and development which is what I do and that's very much you know kind of an extension of what I did in academia but there's also an area called medical affairs and that's those are physicians that are really engaged in kind of forward facing to the potential prescribers of drugs to educate them on the clinical trial results and you know to kind of promote in a way the use of the company's drug versus other competitors in the environment for example. And that there are physicians that do that work as well and then finally there's pharmacovigilants so there are physicians that really focus specifically on the safety of drugs and reporting different safety parameters to for example the FDA. So those are the three major areas that one can work as a physician in industry. I've chosen to work in research and development and then for non-physician scientists in industry they're almost all in research and development and as I mentioned they're working somewhere along that pipeline from early laboratory research to to to clinical science work. So as I mentioned I'm in research and development and I'm specifically in clinical development meaning clinical trials and specifically I'm in late clinical development so when you when you have clinical trials in industry most companies will separate early development and those are kind of the you know first in human phase one kind of the first approaches to the drug to kind of establish a proof of concept and then they often transition to late development which is now we're going to go for FDA approval and we're going to do the large phase two phase three randomized you know placebo controlled trials that really establish the level of evidence needed for a drug to become standard of care and so I I've chosen to work at this point in late development I'm actually thinking about moving into early development because of my laboratory you know experience as well but anyway it gives you an idea of what different potential you know areas of focus there are so and then you know there's a within each of these areas there's different disease areas so for example in in my company Bristol Myra Squibb we have you know cancer is one big area but we also have immune disorders we have heart diseases we have neurologic disorders and I'm specifically focused within cancer and specifically in leukemia so the drug that I'm working with right now is a monoclonal antibody so just like that we talked about before so this is a you know a protein that targets a specific protein that's that might be important in cancer and the one I'm working on is actually targeting a a the monoclonal antibody monoclonal antibody targets a protein that's important in red blood cell development so one of the big problems in leukemia is that it prevents the production of normal blood right so patients with leukemia very often are also and me right meaning their red blood cell cancer low so the drug I'm working with targets a protein that prevents red blood cells from fully developing and so what we're working on is a drug that will reverse anemia that occurs in patients with leukemia and this this can substantially improve their quality of life and prevent complications that come from red blood cell transfusions so that's what I'm working on now so what about the vision for the future so I think that what we're hoping for is that drugs like the one I'm working on will can be combined with other drugs that target the leukemia cells specifically like flit3 inhibitors for example or other you know molecularly targeted drugs and that together these can you know not only eradicate the leukemia but also improve the quality of life of the leukemia patient that's going through treatment you know the idea here is that leukemia which continues to be very scary word for patients that could the diagnosis the hope is that with better and better drugs to target the leukemia specifically with fewer side effects but also to target the side effects of the cancer itself so that the patient feels better more quickly that leukemia can become something that's you know a difficult diagnosis but one that becomes manageable rather than life threatening that's really exciting and I I uh I'll be interested to learn more you know on my own about the idea of drugs that are fighting cancer but also improving the patient's health at the same time um yeah and it's a relatively new area of study so it's that's another thing that's pretty exciting about it so we are going to pivot to the high school science portion of the episode and um great we're going to consider the first statement in the life science section of the next generation high school science standards and this states that students should be able to construct an explanation based on evidence for how the structure of DNA determines the structure of proteins which carry out the essential functions of life throughout systems of specialized cells so um I thought we could probably think about this in the context of flip three and how mutations are affecting flip three and it's and it's the role that it plays in the cells absolutely great so first let's talk about flip three so every cell in your body has the flip three gene at the DNA level okay and that DNA sequence is very similar in in all of our cells and in all people um not identical we all have different polymorphisms slight changes in the DNA code but the flip three sequence and the protein that comes from that sequence is it is you know the you know in the normal situation is identical from from uh person to person um so the and the protein the flip three protein is dictated by that genetic sequence right you know you have three three of the letters together make a codon that makes an amino acid those are put together to make a protein now so why is flip three important really exclusively in early blood cells well that's because when our cells go from the you know we had one original cell right the sperm and egg came together and that was an individual cell one cell and then over nine months that one cell divided and and became every cell in your body in that process of specialization which is what occurs when the cells you know kind of you know where that first cell became an i cell another cell became a skin cell another cell became a liver cell the what what drives that is certain proteins get turned on and other ones get turned off so for in the example of you know the liver well liver proteins are on and liver cells and non liver proteins are off so flip three is not on and liver cells flip three is on in blood precursor cells um flip and you know liver liver proteins are off in blood cells so you know we have somewhere around 30,000 genes every cell has its own it's got the same genetic code but only certain proteins are on in the cell and that's what gives the cell its specificity so flip three is on in these early blood precursor cells that are that are making our normal blood that are that are basically differentiating into our normal blood okay so what is flip three doing right so we've established that flip three is turned on in the early blood cells well what's it doing it's job in the early blood cells is to promote growth and what that means is so when the body needs a new red blood cell or a new white blood cell or a new platelet flip three gets activated temporarily to to cause that stem cell to divide to kick off a daughter cell and that daughter cell goes on to become a mature blood cell either a red blood cell platelet or white blood cell okay and that say the flip three is one of the proteins that gets turned on to tell the cell okay time to divide and kick off a new cell and then it gets turned off it's a light switch turn the light switch on the the cell divides and creates daughter cells and those go on and then that goes off and it goes back to sleep so that's what flip three does I mentioned that it's a kinase okay so kinase genes there's a specific way chemically that indicates the cell the gene is on the protein is on and then turns off and it's that that kinase portion of the gene of the protein is what drives that okay so that's the normal situation well well how does it become abnormal and cause leukemia well what happens is the genetic sequence the DNA sequence that's being used as the blueprint to create the protein changes and so What happens is one of the cells in the blood just by chance in the normal process of DNA replication a mistake is me and the wrong The wrong base pair ends up in the wrong place and that's what's that's a genetic mutation If that mutation if that change in base pairs happens in the flip 3 gene in a blood cell and specifically in that kinase domain and it affects the way the cells functioning so all four of those things have to be true Then suddenly that cells starts to behave abnormally and it's light switches on all the time and it is creating new cells over and over and over and over and over again And does not turn off What happens then is that's happening in your bone marrow now your bone marrow gets crowded with all these Unnecessary blood precursors and that is looking that's the definition of leukemia Wow uncontrolled growth of blood precursors. Yeah That was Fascinating and vivid and such a clear connection from just that that simple as you put it DNA replication mistake And then we have this cascade of real facts And one thing to understand is that these mistakes are happening all the time in our bodies Yeah, right, no, but the vast majority of them happen either in DNA that isn't encoding a protein so they don't matter Yeah, non-coding region. Yeah, or they happen in a coding region, but they're not have they're not happening in a gene that's turned on in that cell So a flip three was mutated in a liver cell. It's a matter because the protein is not on it's not being made, right? Or it's happening in a part of the flip three gene that's not important not in the kinase Right wouldn't matter because it wouldn't turn on growth, right? So it's like the perfect storm cancer the reason why cancer is not happening in everybody all the time Is because it's really kind of a rare event for these mutations to happen with just the right circumstances Yes, or just the wrong circumstances actually, right? So that's just important to understand and you know why why does our DNA replication machinery making us make mistakes? Well the flip side of that is evolution, right? If the DNA replication machinery never made a mistake, we'd never have genetic diversity, right? So you can't have life Without life the way we know it without cancer. Yeah, because the mutations are are the mutations have to happen, right? In order to drive The diversity of life at least the way life is designed, right? So So much to think about so now I'm gonna ask Two two questions I ask every guest so the first one is can you share a memory from high school science something that impacted you and stays with you today? Yeah, absolutely so I'll never forget so I remember the first time I had a science teacher that brought in some pond water from like a stagnant pond and we put a drop of the pond water on a microscopic slide and put it under the microscope and looked at it and you know this one drop of water was just Teaming with all these single-celled organisms that we could see with the microscope you know in Miba, Paramicia, Euglina like all these and it just blew my mind that there was whole tiny universe that I you know underlying everything that I couldn't see you know and then and then to learn further that inside each of these single cells Was this you know incredible universe of membranes and cytoplasm and nuclei and chromosomes and DNA RNA protein it just was mind-blowing and I remember thinking you know wow you know like I want to know more yeah, so that was really the moment in high school that kind of Talk about light switches kind of flip the light switch on to me. It's wonderful. I love that. I love that description and What advice do you have for high school students today interested in studying science? Well, you know, I'm a little You know has a tend to give too much you know advice, but one thing I will say is you know when I look back All I can say is take it one step at a time you know I I Could never have pictured in high school, you know my Interit you know my kind of interest in math and science courses to end up where I am today, you know it just You know it just wasn't It just wasn't at all what I was thinking at the time right so and What happened was you know as tough with each step? Opportunities will will open up that will ignite your passion and your interest and You know and then the only vice is just as that happens to follow them and you know Science is such a huge fast varied world of opportunity and It's only you've got to become science is only becoming more important and more fascinating as time goes by and the more we discover right so You know at this point. I would just say you know take the classes that interest you to the best you can in those classes and You know if there are additional opportunities outside the classroom that interest you also take those opportunities I mentioned that I thought I was going to be an engineer until I actually did engineer right so gives you an idea get out in the real world if you can and If those opportunities are there, you know try to take advantage of those and then over time as you go you know potentially to college and beyond Be open to the idea your interests and passions are going to change and that's okay, you know it There's no one right path, you know, you just follow your interests and opportunities as they present themselves be ready to take advantage of them You know and most of all have fun along the process, you know when you follow your interests and passions It doesn't feel like work as much There are times of course where it feels like work, but you can minimize that by just really trying to follow as much as you can your interests and passions Wonderful advice Thank you. Thank you so much Pat for Coming on today and for this just completely fascinating description of leukemia and your work and how it all fits into bigger issues and medicine and research just really fascinating Well, thanks Susan. I appreciate you saying that. I certainly enjoyed it and I hope it's helpful. Thank you so much That was Pat Brown talking with us about leukemia cancer therapy medicine and the experience of science in an academic versus pharmaceutical company setting This was also the end of season two right now high school students and teachers are highlighting some of these episodes in their classrooms if you're interested in trying this podcast out in your classroom Please send me a note through my website Susan Keely dot com or send me a DM on Instagram the account is Science Fair podcast. I'll send you a feedback survey form. Thank you for tuning in to today's episode of science fair Please rate and review the episode on the podcast app of your choice. See you next time