EP. 40: DECODING CANCER
WITH HAROLD VARMUS MD
A Nobel laureate and former Director of the National Institutes of Health and National Cancer Institute discusses his pioneering cancer research and lessons on leadership and science policy.
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Episode Summary
A pivotal development in the history of cancer was the discovery that cancers can arise from mutations in genes already present in normal, healthy cells. Joining us in this episode is Dr. Harold Varmus, who shared the Nobel Prize in Physiology or Medicine in 1989 with his colleague, J. Michael Bishop, for this discovery. Their work has enabled scientists to explore why certain cancers develop in the human body and how we can develop better cancer treatments that target these genetic mutations. In addition to his pioneering research, Dr. Varmus has served as Director of the National Institutes of Health and the National Cancer Institute, President of Memorial Sloan-Kettering Cancer Center, and Scientific Advisor to the US Government, World Health Organization, and various other foundations and academic institutions. Over the course of our conversation, Dr. Varmus describes his groundbreaking research, approach to institutional leadership, and his advocacy for the democratization of scientific knowledge through his role in the founding of PubMed Central and the Public Library of Science.
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Harold Varmus, MD, is a scientist and medical researcher who served as Director of the National Institutes of Health from 1993 to 1999. Dr. Varmus earned his undergraduate degree from Amherst College before going on to earn an MD from Columbia University in 1966.
Throughout his career, Dr. Varmus has made significant contributions to the field of cancer research, including the discovery of the first human oncogene, a piece of DNA that can transform healthy cells into cancerous ones. This discovery was instrumental in advancing the understanding of the genetic basis of cancer, and earned Dr. Varmus and his colleague J. Michael Bishop the 1989 Nobel Prize in Physiology or Medicine.
In addition to his research, Dr. Varmus has also held several high-level positions in the field of biomedical research, having served as Director of the National Institutes of Health and Director of the National Cancer Institute. He has also held positions at the Memorial Sloan Kettering Cancer Center and the University of California, San Francisco, among others. Dr. Varmus is currently a professor at Weill Cornell Medicine and a senior associate at the New York Genome Center.
Dr. Ely’s research has focused on improving the care and outcomes of critically ill patients with ICU-acquired brain disease (manifested acutely as delirium and chronically as long-term cognitive impairment). He is co-director, along with Dr. Pratik Pandharipande, of the Critical Illness, Brain Dysfunction and Survivorship (CIBS) Center, which consists of over 90 investigators from Departments of Medicine, Surgery, Neurology, Anesthesia, and Psychiatry.
The CIBS Center has amassed thousands of patients into cohort studies and randomized controlled trials, who together built the methodology for ICU acquired brain disease research and newly adopted treatment paradigms including the ABCDEF Bundle. His team developed the primary tool (CAM-ICU, translated into 35 languages) by which delirium is measured in ICU-based trials and clinically at the bedside in ICUs worldwide. He has over 500 peer-reviewed publications.
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In this episode, you will hear about:
• How Dr. Varmus’ broad educational interests led him to pursue a medical career - 2:56
• How working at the National Institutes of Health drove Dr. Varmus’s passion for research and the trailblazing path his career took - 8:48
• A summary of Dr. Varmus’s research on retroviral oncogenes, which led to major advancements in cancer diagnoses and treatments - 16:35
• How Dr. Varmus became involved in the politics of science after receiving a Nobel Prize - 27:13
• Dr. Varmus’ mission while he was Director of the National Institutes of Health and his perspectives on the elements of effective healthcare institutional leadership - 30:28
• A discussion of open access publishing, a mechanism of distributing the results of scientific research online for free - 32:37
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Henry Bair: [00:00:01] Hi, I'm Henry Bair.
Tyler Johnson: [00:00:03] And I'm Tyler Johnson.
Henry Bair: [00:00:04] And you're listening to the Doctors Art, a podcast that explores meaning in medicine. Throughout our medical training and career, we have pondered what makes medicine meaningful. Can a stronger understanding of this meaning create better doctors? How can we build health care institutions that nurture the doctor patient connection? What can we learn about the human condition from accompanying our patients in times of suffering?
Tyler Johnson: [00:00:27] In seeking answers to these questions. We meet with deep thinkers, working across health care, from doctors and nurses to patients and health care executives. Those who have collected a career's worth of hard earned wisdom probing the moral heart that beats at the core of medicine. We will hear stories that are by turns heartbreaking, amusing, inspiring, challenging and enlightening. We welcome anyone curious about why doctors do what they do. Join us as we think out loud about what illness and healing can teach us about some of life's biggest questions.
Henry Bair: [00:01:03] One of the pivotal developments in the history of cancer is the discovery that cancers can arise from mutations in genes that are present in normal, healthy cells. Joining us in this episode is Dr. Harold Varmus, who in 1989 received the Nobel Prize in Physiology or Medicine with his colleague, Dr. J. Michael Bishop, for this discovery. It is hard to overemphasize the significance of their work. It opened doors for scientists to explore why cancers develop in various organs and tissues throughout the human body, how certain carcinogens such as cigaret, smoke cause cancers, and how we can develop better cancer treatments that target these genetic mutations. In addition to his pioneering research, Dr. Varmus has served as Director of the National Institutes of Health, Director of the National Cancer Institute, President of Memorial Sloan-Kettering Cancer Center, and Scientific Advisor to the US Government, World Health Organization, and various other foundations and academic institutions. Finally, he's a vocal advocate of the democratization of scientific knowledge. Dr. Varmus, it's an honor to have you with us here today. Thank you so much for being here and welcome to the show.
Harold Varmus: [00:02:15] Thank you.
Henry Bair: [00:02:16] So there is so much for us to explore. Throughout your career you have been a researcher, educator, science communicator, policymaker, and more. But first, I'm hoping you can take us back to the start of your career. In particular, I know that you dedicated a lot of your higher education to the study of English literature. That's fascinating for me since I studied medieval Celtic and Anglo-Saxon literature during college. So tell us about your path to medicine. What was the beginning of that path? Did you know, even as you were reading Beowulf, that you wanted to embark on a medical career?
Harold Varmus: [00:02:56] Well, college wasn't exactly the beginning. Of course, we're not going to go back to conception, but we might go back to childhood. I grew up as the child of suburban New York parents who exhibited a trait that's pretty extraordinary in America. They were the children of immigrants. All four of my grandparents were immigrants, and yet they got to go to Ivy League colleges and did work in health professions. And I grew up with a default position, which was to become a doctor because my father was a doctor, my mother was a psychiatric social worker. They exhibited those great traits of generosity and public service, and that was sort of in our bloodstream as we grow up. But along the way, especially through a summer, as something called the Putney School summer work camp, and later in my experience as an undergraduate at Amherst College, I got exposed to a lot of other things. You describe my career as being very broad. There were different kinds of activities, but all of it turned out eventually to be in the biomedical sciences. But but when I was growing up, I suddenly got exposed, especially in college, to a lot of other fields of interest. And one of those, not the first, but one of the first, was English literature. And as you say, I majored in it. I went to graduate school in literature for a while. That's where I read Beowulf and in Anglo-Saxon.
Harold Varmus: [00:04:21] And those were all important experiences. But then the story gets more complicated because I wasn't a totally happy graduate student, and I decided that other college classmates were having more fun and were more inspired doing medical school studies. And and I decided to give medical school a try, after all, with a very different kind of ambition than than I ultimately developed, and that I thought I would go to medical school, in part because it seemed to open the doors to lots of directions. And I was interested in psychiatry, partly because of my extensive readings of Sigmund Freud, and in part because I thought at that time I wouldn't agree with this. Now that psychiatry could open up important windows into the understanding of literature, I don't credit that approach too much anymore. But but at the time it seemed like an attractive way to go. A lot of doctors became writers later in life, Somerset Maugham and many others. I like being a student and I was interested in spending more time as a student and not joining the armed forces, which was on the horizon then. This was the early days of the Vietnam War, going to medical school and seeing if it took and if it allowed me to go through a door that I did or didn't appreciate was open to me at that time, that seemed like a reasonable thing to do.
Henry Bair: [00:05:50] So at what point after you made the transition, did you realize or think to yourself that, yes, this is indeed the most meaningful work that I can do, this is right for me?
Harold Varmus: [00:06:03] Well, I have to say, I never really thought about whether something was going to be the most meaningful. I just don't know what that means. But I thought it would be enjoyable. But, you know, my notion of what it was changed pretty dramatically when I was a third or fourth year medical student. The most pleasurable thing for me at the time was trying to take care of a patient with complex disease and see whether they were. Existing therapies, coming therapies that might be useful have look for help to help someone survive the assault that nature was performing on them. But my view of what was most enjoyable did change over the next few years. I enjoyed being a house officer, but in those days some form of public service was required because we were in the middle of this combat in Southeast Asia. We had to deal with something called the Berry Plan, which required male medical school graduates either serve the country through the army or the public health service or leave the country or go to jail. And of all those options, the thing that seemed most attractive to me was the idea of going to the National Institutes of Health as a public health service officer. And happily, despite my incredibly meager research credentials, I was taken in by a new member of the staff of the NIH, someone about eight years, my senior, who had done some very nice work in endocrinology, a field of medicine that interested me anyway.
Harold Varmus: [00:07:41] As for reasons that probably too complicated to go into here, he was just getting interested in molecular biology, in part because he had perceived that cyclic AMP, a compound that was first discovered by studying signaling and hormonal control in mammals, might be important in controlling gene regulation and bacteria. That seemed very, very far from anything that I had learned about, certainly as an undergraduate and even as a medical student. And yet once I got into a lab and started doing things that were not simply efforts to reproduce classical observations of the past, but instead do my own original work, I got extremely excited about discovery and about the task of trying to understand the unknown about how cells work, even if there are bacterial cells didn't matter. And that was the way in because that's where molecular biology began and was easy to do in a time before the kinds of cloning methodology that you and your colleagues are all familiar with from birth.
Henry Bair: [00:08:48] So you talk about how during medical school you really enjoyed the interactions you had with patients, you know, being by the bedside, caring for someone with a complex and chronic condition. But you also enjoyed being in the lab setting, working on cutting edge technologies and pushing the frontiers of scientific knowledge. Now, lab research doesn't entail a whole lot of patient interactions. So I'm wondering what was that transition like?
Harold Varmus: [00:09:17] At the NIH, I did have some clinical responsibilities because I was probably too inexperienced as a research scientist who have been brought into the public health service as what we call a research fellow. Instead, I was a clinical fellow in principle, which meant doing a little bit of clinical work and working on the wards at the Clinical Center at the NIH until those first two years. But I really at that point saw that as simply a kind of obligation that had to be fulfilled. Interesting. But part of someone else's clinical research project and I was basically the hands on person to be sure the patient got their medications, but I was very quickly transformed into somebody who was a lab rat who really enjoyed just doing experiments day and night.
Henry Bair: [00:10:07] So now you've discovered the joy of doing research just to frame the rest of our conversation. Can you walk us through your research career after that? What institutions did you work in and what kinds of scientific questions were you trying to answer?
Harold Varmus: [00:10:24] I had a very abrupt introduction to research at the NIH when I was there as a public health service officer. I learned the basic moves in molecular biology as they existed then while working on gene regulation and bacteria working on the control of of the lac operon, something that many of your listeners will know about and not the classical form of regulation of the lac operon through the lac repressor, but instead the form that was discovered by my mentor then, Ira Pastan, and who's still an active investigator at the NIH.
Henry Bair: [00:10:59] Just as a quick aside for our listeners, the lac operon is a famous mechanism by which bacteria can switch on and off a specific gene in response to an environmental stimulus. In this case, the sugar lactose. Studying the lac operon was important in helping us understand gene regulation and how we could harness bacteria to produce antibiotics and other proteins for medical and industrial purposes. Anyway, back to you, Dr. Varmus. You were telling us what you learned there at the NIH.
Harold Varmus: [00:11:31] What I learned there was how to do molecular hybridization, how to how to work with bacteria and bacteriophage, to to prepare molecular reagents, to do things that only then in the late sixties becoming accessible, even in the lead up to the discovery of recombinant DNA technologies, was, of course simplified everything. So it was hard work, but we were able to learn fundamental things about how cyclic AMP regulated gene control. At the same time, especially for people like me who were pretty much the great unwashed in the research arena, we didn't know very much about research at all, but great courses were being offered to us because there were hundreds of smart medical school graduates doing laboratory work at the NIH to fulfill their obligations under the Barry plan that govern the behavior of the the the the worth of work ethic of people who had graduated from medical school were pretty violently opposed to the Vietnam War and had wanted to do something other than than go to jail or Canada. So I learned a lot about the potential for using the molecular biological techniques I was using in Pastan's laboratory to study other things that were a little closer to my medical experience. For example, cancer, heart disease, diabetes, a lot of other diseases were appearing to be susceptible to to a deeper level of understanding through molecular technology, through understanding of genetics. Cancer was the thing that drew me most intensively infectious disease as well, but cancer mainly, and for a variety of reasons, having to do with cancers in my own family and the availability of one incredibly important approach to to understanding disease, and that is the existence of viruses in animals that cause cancer.
Harold Varmus: [00:13:31] And it just seemed like the potential for trying to understand cancer was greatly enhanced in those days before genome projects and molecular cloning to lie in the existence of viruses that had small numbers of genes but had the capacity to change the behavior of a normal cell into a cancer cell that just seemed like an avenue to discovery. And that was right. It was an avenue to discovery, and a lot of us discovered. So I looked around after two years at the NIH for a place where I thought I'd be happy to live, especially it was especially interested in trying out California. I was looking for people in California who were trying to use these new technologies to understand cancer. There were several. Some had no interest in someone like me who had only done a couple of years of science and was already 30 years old. But there were others. Most obviously a guy I discovered in my travels around the major centers of scientific life in California, in San Francisco, named Mike Bishop, who had had very similar training to my own, was interested in a broad range of subjects from history to to science, and had gone to a small college, had gone to a good medical school, had spent time at the NIH. He was using molecular techniques to understand polio virus was interested in trying to study cancer viruses.
Harold Varmus: [00:15:01] And I joined him as a postdoctoral fellow, along with a number of other faculty and postdocs who were working in a in a lab consortium. That taught me quite a lot right in the beginning about how teams work effectively in the right environment to get work done. We were fortunate in that regard because I think a lot of people grew up in single labs with single mentors and he and I quickly developed a partnership and we started working on various aspects of a virus that you would now call a retrovirus. At that time, we simply called it an RNA tumor virus, a virus that that grows effectively in chicken cells and makes cancers in chickens, sometimes in other animals as well. And we had two big questions driving us. One is how do these viruses grow, how they multiply? And secondly, how do they cause cancers? And both proved to be very fruitful avenues of investigation and very dependent on the new methods in molecular biology for learning how these how these viruses can converted their rna genomes into DNA. How that DNA was read out, what were the controls? How were the RNA molecules massaged by the cell to produce viral proteins? What were the viral proteins that were responsible for the ability of this virus to cause cancer? Where did those genes come from? And a variety of other questions that maybe we'll have time to talk about.
Henry Bair: [00:16:35] I think now would be a good time to discuss your landmark work with retroviral oncogenes. Your findings fundamentally transformed our understanding of cancers and what caused them and opened new avenues of research for generations of scientists. For listeners who may not be familiar with oncogenes, can you share with us what your research entailed and what its implications are?
Harold Varmus: [00:17:02] Yeah, well, it's of course, hard to do that terribly briefly because it's a pretty broad topic. But if you want to pare this down to its essential features, I would list the following the following developments first. Others, not us, had people who were trained as geneticists and thought deeply about the genetic approach to viruses, had said to themselves, Well, can we identify a gene in these viruses of animals that cause cancer that's responsible for causing the cancer? And in the case of the virus, we chose to work with the Rouse Sarcoma Virus, a virus that had been discovered as early as 1910 and had certain advantages in that it was fully capable of carrying out all the steps in virus replication and also had the ability to change the behavior of cells and cause a cancer. The geneticists working on this problem had identified mutants that told us that there was at least one gene, possibly more, but at least one that was required for the ability of the virus to transform the behavior of cells. And then work done on the genome of the virus, the RNA that carries all the genetic information of the virus, showed that there was a region of the viral genome that contained the one or more genes required for transformation. It was possible for us using molecular techniques, but they were very similar to what I had used to study the lac operon and E coli allowed us to ask the following question: Can we make a molecular probe -a kind of tool- that would allow us to say whether the gene that the virus uses is related to any gene that exists in a normal cell? It turns out to be a single gene in mouse sarcoma virus called the Sarc gene. The name is chosen because this virus causes the kind of cancer referred to as a sarcoma in chickens. And the Sarc gene is incredibly closely related to a normal gene that exists in all chickens. In fact, when you look carefully, you can find that the gene is also conserved throughout the Metazoan Kingdom and everything from fruit flies to human beings. The gene is varied a bit during evolution, but you can recognize that the same gene has been highly conserved during evolution. It must be important in some way for development and function of the organism. Both the cellular gene and the viral gene encode a protein of about 450 or 500 amino acids in length, and the cellular version and the viral version of the gene are not identical. They differ in important ways. There was obviously a great deal of interest in that gene created by these observations, and it became apparent that both the normal cellular gene and the viral gene were able to produce proteins of very similar sizes with a specific enzymatic activity that was shown by others, not by us, to be specific for the amino acid tyrosine.
Harold Varmus: [00:20:18] So we're really made it a very dramatic change that everybody began to point to as evidence that cancer was becoming an understandable disease was the fact that first of all, there were other viruses of the same class, which we'd now call retroviruses, that caused cancer in the same way. That is, they had acquired a gene, the normal version of which was was found in normal cells of normal animals, but that the gene underwent genetic changes along the way and made it a gene capable of encoding a very similar protein but with different biochemical characteristics so that now the protein was able to to launch a cancer. And that introduced us well before there was any human genome project to a range of genes that became known as cellular oncogenes. So that was important and interesting and drew a lot of people into the study of these genes. The set of discoveries that really blew this field open was the discovery that many human cancers that have no relationship to infection by cancer viruses, but just so called spontaneous human cancers had mutations that affected that class of genes that we knew gave rise to retroviral oncogenes. Sarc was not a major example among those. In fact, mutations of Sarc are really quite rare.
Harold Varmus: [00:21:45] But the Sarc gene belongs to a large family of genes. That code for a very similar enzyme. And many of those genes had mutations that are drivers of cancer development and quite a few other genes known as the rasp gene, the Mick gene, The epidermal growth factor receptor gene, and quite a few others that were identified because of the relationship they have as precursors of retroviral oncogenes also were found to be mutated in human cancers. And the obvious next step was to try to make drugs that interfered with the function of the proteins made by those genes. And that did come to pass over the course of several years. And it's still happening on almost monthly basis. So this is not the whole story of cancer. Cancer involves a lot of changes to our genome, some of which are mutational, some of which are changes in gene expression. And we don't have drugs that interfere with all of those activities. So we've introduced one important approach to the treatment of cancer and importantly to the diagnosis of cancer, because these mutations, they don't simply represent the way a cellular gene becomes a cancer gene. They also represent a kind of diagnostic marker for how a cell might be classified as a cancer and the kinds of approaches that might be taken to treat it.
Henry Bair: [00:23:14] The understanding that cancers are caused by mutations in normal functioning genes that are already present throughout our cells really altered our conception of what cancers are. The applications of this understanding have been endless. For example, scientists have since been able to uncover why certain environmental triggers cause cancer, which then led to cancer prevention efforts that have safeguarded the health of millions of people worldwide. What does it mean to you for your work to have had such wide ranging impact?
Harold Varmus: [00:23:48] You know, I've never really felt that I had to sit back and think about my emotional reaction to transformation of of cancer therapy. And I think that's in part because I think while we have to, we all recognize that targeted therapy has had a lot of utility and I think has a lot of potential. It's not the only game in town that traditional forms of therapy are still incredibly important. And there's no one less important, of course, than early diagnosis by screening, finding polyps in the colon before they become carcinomas of the colon. Nothing less important than taking out a cancer that hasn't yet spread and preventing death from cancer by performing surgery. Chemotherapy still is a very effective way to control and sometimes cure cancer. And despite the fact that it's a very imperfect therapy because of the side effects, we all know people. Indeed, my medical school roommate was cured of advanced cancer with chemotherapy. And then today, one of the most dramatic changes in therapy is the use of immunotherapy. And that comes out of a completely different kind of approach to cancer, which is based on research that was largely a failed area for many, many years until Jim Allison came along and recognized that the immune system was complex. And until we learn to interfere with the suppressive effects on the immune system and allow the positive immune protectors to do their work against cancer cells, suddenly we have therapies against a wide variety of cancers that are far from perfect.
Harold Varmus: [00:25:33] They don't work for everybody, but they have been dramatically saving lives and apparently curing cancers for about 15 years or more. So I don't look back on the situation and say we've conquered cancer and that this is something that we have done. Our work and the work of many of our colleagues in this field has introduced a whole new sector of therapies that you and I would call targeted therapies. Pleased by that, obviously. But we also recognize that these things happen because of a community of scholars who've worked on the problem. We were fortunate to identify the first so called proto oncogene cellular oncogene in normal cells and set a standard for how this might all develop by having viruses bring a gene to our attention, by capturing and mutating a gene that turns out to cause cancers in experimental animals, and then to find similar mutations in human cancers and others, to find drugs that kill the cells that express those mutant proteins. So it's a lot more complicated than to say that we made a discovery that led to the end of cancer mortality, because that's where far from that. And we don't sit back and spend too much time thinking about the lives that you've saved. I think about the good work we've done, the way in which cancer research has progressed and recognize there's still a hell of a lot of hurdles left to jump.
Henry Bair: [00:27:13] I'd love to turn our attention now to your governmental and policy oriented work. For our listeners. Can you trace the development of your career in the politics of science?
Harold Varmus: [00:27:28] Like many scientists, I had strong views about how science was governed and supported before I got engaged. Like most scientists, I felt I was already pretty busy working in the lab, teaching. Raising a family and doing other things that I enjoy to have much role in, in the governance of science. But something fairly dramatic happened in 1989 when Mike and I received a Nobel Prize, and suddenly our opinions seemed to matter more than they had before. I was being asked by the NIH to help them think through some problems that were occurring in the agency having to do with scientific misconduct and poor success rates for grant applicants. And as a result of that activity, engagement with people who were worrying about the future of the National Institutes of Health. I just became more prominent in this area of the politics of science. And when the NIH directorship became available in 1993, I was considered for the job, and I was fortunate to be selected by the secretary of HHS, who was then Donna Shalala, and by the president, who at that point didn't know me but was willing to take the word of Secretary Shalala and became the director of NIH, which of course put you in the center of at least medical science politics.
Harold Varmus: [00:29:04] And I enjoyed it. It was a good time to prosper in that kind of field because we weren't at war. The Congress and the executive branch were more or less on the same page. We weren't as divided a country as we appear to be today. I had plenty of friends in Congress on both the Republican and Democratic sides, and there was a lot of enthusiasm for trying to promote the growth of biomedical sciences with a view to just making America stronger in the sciences, to do the right thing in a way that would promote the health and well-being of American citizens. So it was a good time to do that kind of work. The budgets, the economy was in good shape. After a year or two of difficulty, so the NIH grew dramatically and its budget got bigger and gave out more grants. And all all things were prospering. And we built new buildings and improve the intramural program at the NIH and had more resources for the extramural program. Good science was getting done, and it made me feel that there was a lot of satisfaction to be had by by being a political as well as a scientific leader in this area.
Henry Bair: [00:30:28] What was your mission as you took on this leadership role? What were some of the concrete objectives you hope to accomplish?
Harold Varmus: [00:30:38] It's an important question because when I see people taking on the responsibilities of running an organization, especially one as big as the NIH, I always think that the only reason you should be doing that job is because you have an idea of what you want to accomplish. Just to run an institution is obviously a good source of income and gives you a certain amount of pleasure. But the thing that I find really exciting is saying here are a list of things that I would like to accomplish. And indeed, I've had three leadership positions the NIH, Memorial Sloan-Kettering Cancer Center and the National Cancer Institute. And in each case, I always tried to begin by saying, here are five objectives and it helps you when you try to decide how long you should do the job, because when those objectives are laid out with some clarity, it gives you an indication of when you either need a new set of objectives or you should step aside and let someone else take on the job. And I can't recite in detail exactly what I told the Senate confirmation Committee that I was going to do. But one of them is certainly to improve the budget of the NIH. One was to improve the intramural scientific program. Another was to pay attention to clinical research, try to reduce disparities in research. And I can't say I got to the ultimate level of success in any area, but I felt motivated by having articulated some specific goals. Those goals have to be phrased correctly, so they're not ridiculously ambitious or too narrowly defined. But I do think that that general principle of having things you would like to achieve is a very important one. If you're going to succeed as a leader, it keeps your eye on the ball.
Henry Bair: [00:32:37] I'd like to turn next to your work in advocating for open access publishing. For those who are unfamiliar with the term, open access refers to the process by which research outputs such as manuscripts, are disseminated online and free of charge to the public. This is in contrast to traditional academic, peer reviewed journals, which are often accessible through subscriptions, institutional licenses or pay per view charges. Dr. Varmus Can you tell us how you first got involved with championing open access, this free flow of research knowledge?
Harold Varmus: [00:33:15] Sure. I mean, I've written about this in some detail, and it's interesting you raise this question because one of the most influential person in developing my own attitude toward this was at that time a Stanford faculty member named Pat Brown, who's now the founding director of Impossible Foods. Pat had been a postdoc with me and Mike Bishop at UCSF. We were meeting for coffee one morning near the end of my time as the NIH director, and Pat told me that he had recently read about the work of a physicist named Paul Ginsburg who had developed what we now call a preprint server, Internet based mechanism for placing work that had not yet been reviewed and accepted for publication into the public domain just by placing it on a single website as a part of a collection of preprints. And he said, This is something we ought to think about in biomedicine, where traditionally there's always been some sharing of work before publication, but not that much, and began thinking about how the science that we do is biomedical scientists could be more quickly and more widely shared. The Internet changes everything. If you think about how publication proceeded, once the printing press was developed, there really wasn't much change until the internet came along. If a paper was accepted for publication, some publisher had to put it onto paper and and send it around in exchange for a subscription fee. And that meant that distribution of work was essentially limited. There was no way to make a work completely available to anybody at any time. You can put it into a university library or some other library so people could have access in that way.
Harold Varmus: [00:35:11] But that still was not nearly as efficient or as appealing as making all work accessible to anybody who had an Internet connection and a computer. So we began thinking about how that might happen, and I wrote a somewhat of a political tract at the time called E Biomed, a description of how the NIH could help to organize a world in which all work became available either before review or after review, appropriately labeled, of course, to indicate what had and hadn't been reviewed. These were the seeds for the development of a public digital library of full text papers. Up until then, there was a very important development, but it wasn't a development that allowed full access to scientific work called PubMed. Everybody uses PubMed. They know what it is. It's title authors and abstracts for almost any paper that's published in the world. But it didn't provide the full text, which is what anybody would want if they wanted to understand the work fully or build on it. So we ended up after a lot of fighting, proposing the creation of a full text digital library called PubMed Central. But at that stage we're only proposing that journals turn over this work which which they held the copyright. And the journals were very reluctant to do that because they foresaw a slippery slope in which they suddenly would lose all their very considerable profits. Because if all this work became available and nobody was paying subscription fees, then they would collapse as journals financially and we would lose a very important apparatus for making work available. So we then had to think through the next important component, which is a business plan and what business plan in which and which the authors or more explicitly, the people who fund authors of scientific work, the NIH, private funders, societies, others would pay a fee to ensure that the that the work of publishing, the formatting, the reviewing the other events that have to occur to make publishing an attractive.
Harold Varmus: [00:37:37] Position and efficient and efficient proposition and one that that judges work and tries to exclude work that's erroneous would require resources that are significant. But many pushers became interested in working in that way so that the work was instantaneously available to anybody who had an Internet connection. And that's basically how. Open access publication and the biological sciences got started, but it's taken a long time for it to become even a substantial part of the publishing industry. And even now it's still a minority effort. But we do have a requirement that NIH supported work appear in PubMed, central within within a year or so. Public access is improved, but it's not nearly as good as it as it could be and needs to be. And that's where the new proclamations from the Office of Science and Technology Policy become important because they're. They're requiring that the embargo be removed and that work become available immediately. And that's. Seems to me only the appropriate it's a it's an effort that I think people understand now because they've gone through the COVID pandemic. It's one of the few benefits of the pandemic we've all suffered through that People now understand that they have a right, and it's a virtue to see work as it gets approved by journals or even before through preprint servers.
Henry Bair: [00:39:05] Well, I have to say, whenever I do any kind of research, clinical, translational or basic, I as well as anyone else who does medical research rely on PubMed on a daily basis. Even when we are treating patients, we often use PubMed to check the latest research guidelines and findings. So on behalf of all of us, I must express my gratitude to you for making that happen. And with that, our time has also come to a close. So thank you again, Dr. Varmus, for all the incredible work you have done in oncology, science policy and medical education, It was a privilege speaking with you.
Harold Varmus: [00:39:47] A pleasure. Good luck today. Thank you. Bye.
Henry Bair: [00:39:52] Thank you for joining our conversation on this week's episode of The Doctor's Art. You can find program, notes and transcripts of all episodes at the Doctors art. Com. If you enjoyed the episode, please subscribe rate and review our show available for free on Spotify, Apple Podcasts, or wherever you get your podcasts.
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Henry Bair: [00:40:25] I'm Henry Bair.
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