The legacy is not just with you: an interview with Stephen Baylin
2023; Future Medicine; Volume: 15; Issue: 4 Linguagem: Inglês
10.2217/epi-2023-0097
ISSN1750-1911
Autores Tópico(s)Cancer-related gene regulation
ResumoEpigenomicsAhead of Print InterviewFree AccessThe legacy is not just with you: an interview with Stephen BaylinStephen BaylinStephen Baylin *Author for correspondence: E-mail Address: sbaylin@jhmi.eduhttps://orcid.org/0000-0003-3697-3798Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USAPublished Online:26 Apr 2023https://doi.org/10.2217/epi-2023-0097AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: cancercollaborationepigeneticsepigenome •immunelegacytranslationworkInterviewerHello, Stephen, thank you for agreeing to do the interview for Epigenomics. I have prepared a few questions that I would like to ask you for the journal's audience.Stephen BaylinSure.InterviewerCould you please introduce yourself and briefly describe your research focus?Stephen BaylinI am Stephen Baylin, and I am a professor of oncology and medicine, and I am in the Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins Medical Institutions and a professor at The Van Andel Institute. And my current work is as a cancer biologist, trying to understand abnormal epigenetic changes in cancer, from their origins to how we can use them translationally to improve health, particularly for cancer.InterviewerAlongside fellow Epigenomics Editorial Board member, Peter Laird, you were both the original investigators of the epigenomic portion of The Cancer Genome Atlas (TCGA). How did you get into the field of cancer and epigenetics?Stephen BaylinOriginally, we came into the TCGA project as a pilot project because there was a lot of skepticism as to whether you could build epigenetic abnormality assays and measurements and learn anything from this in a project such as this. And so we came up with a way of using epigenetic drugs to screen cancer cells for such epigenetic abnormalities, and we took an earlier iteration of that with Peter Laird's wonderful refinement and were finally successful in receiving a pilot project for the first 3 years of TCGA. I was the principal investigator (PI) and Peter was the co-PI and our project played a prominent role for defining abnormally DNA hypermethylated genes in the first TCGA papers that ensued. When we recompeted for the subsequent first competitive renewal for the next years of TCGA, we received acceptance for a full project and we actually got one of the best scores. We switched to Peter being the principal PI, and I remained as a co-PI for many years, and Peter was magnificent in being a force within TCGA, not only for the specific DNA methylation work but for the whole performance of TCGA and he still is. I did it for many years, but my job description got so complex, so I watch from afar now. Well, not totally from afar but that, in a bulleted way, I hope tells the story.InterviewerYes, it definitely does. What was the field like in its early inception?Stephen BaylinWell, all along epigenetics has not been an easy thing to perpetuate and get into, although its traction has increased mightily over the past several decades, as it really involves so many different aspects of basic biology, normal development and tissue functions, aging and pathophysiology. Now people recognize how important epigenetics and the epigenome, are to biology, no question about that. I guess our interest in cancer starting in the '80s and through TCGA was a help to that because as we started to drill down on DNA methylation, I think you can watch the publications in epigenetics evolve a steep upward vector since that time. Work in cancer gave basic and clinical investigators an important arena to consider as a potential driving force for cancer progression, which has expanded along with understanding and defining the epigenome. The intersection of DNA methylation and chromatin for regulating not only coding but noncoding regions of the genome has gotten very complex, in a good way, to foster research.InterviewerYou have a very well-tenured and well-decorated research journey, working with, among others, the National Institutes of Health, the National Cancer Institute, the National Institute of Environmental Health Sciences, the American Cancer Society, the American Association of Cancer Research, the Adelson Medical Research Foundation and for so many years at the Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center. Looking back at your career, please could you share what has been your favorite highlight or perhaps a defining moment in your work?Stephen BaylinWell, there are a series of things for me at least that are defining moments. First, I have been very fortunate to work with those above institutions and foundations allowing me and my colleagues to receive research funding at pivotal points in our work. Second, being fortunate to have worked for far more years than most people are old, there have been, at least for me, multiple eureka moments, some of which may actually have had durable value! One for sure joined the two major research areas of my career. In the 1970s and '80s, in my initial career stage, my group was trying to understand and define why tumors that did not come from organs that were not considered to be endocrine as their defining state often could manifest endocrine activity, like inappropriate production of hormones that could even cause very damaging symptoms for patients and worsen disease. In the mid-'80s, we focused on a gene for a hormone and how an unusual but important thyroid cancer that came from normal cells making the hormone produced it, but why other tumors could do so as well. We got the idea that maybe DNA methylation, which I knew nothing about at the time, but was coming to the fore as a feature regulating gene expression, might be playing a role. So we started to study it and, boom, we observed that an abnormal change in DNA methylation at the start side of that gene actually seemed specific for cancer, being different in the thyroid cancer from other cancers we were studying. And so all of this morphed into identifying that lots of important 'tumor suppressor' genes were being abnormally blocked from being activated to protect against cancers arising. Thus, this research 'collision' underpinned the theme of the rest of my career perhaps, helped to stimulate explorations from my colleagues and others in the field, which was a brand-new field.InterviewerI am surprised you did not say it was being featured in GQ's 'Rockstars of Science'.Stephen BaylinWell, there are some unusual benefits which arise in scientific research and one of them for me arose via my invaluable collaboration with a preeminent researcher in epigenetics, P Jones at the Van Andel Institute in Grand Rapids, where I also have an appointment. I have had the pleasure of being co-leader with Peter in a Stand Up to Cancer (SU2C) project, which is aimed at taking basic findings in cancer epigenetics and translating them into clinical trials for therapies that might work. SU2C emanated in Hollywood. It was the brainchild of nine women linked to the film industry who wanted foster team collaboration to bring new concepts for cancer therapies to patients. They had the good wisdom to have the process be competitive for team applications and have stellar peer review from the American Association of Cancer research. SU2C has proved to be a wonderful success including for me and many other investigators. So, how did all this lead to my being in GQ and some great fun moments for me? A key SU2C leader, L Ziskin, had the idea that if movie stars, athletes and other celebrities could be rock stars, why not cancer researchers. I posed with a star rapper known as B.O.B, and admittedly I had no idea who he was. Not only did he turn out to be one smart young guy but my grandchildren knew him – and when they found who I was posing with, I got verified as a real grandpa and other fun stories have rolled out about the picture in GQ ever since!InterviewerThat is a very cool anecdote! Your research has described how DNA demethylating agents enhance immune checkpoint therapy. And this concept is now used in multiple clinical trials aimed at the use of epigenetic therapies to improve the efficacy of immune checkpoint for multiple cancer cell types. For a nonspecialist, could you please explain briefly, if you can, how this topic involves epigenetics in the development of cancer and why it is important.Stephen BaylinI think the topic joins now at least two areas. Since we started working on the above 'eureka moment', the fact that abnormal DNA methylation can be imposed on the start site of genes, we and the research community have continued to learn many things, kept evaluating its importance and place the findings continually into context within the rapidly expanding knowledge about normal and cancer epigenomes. We learned that the inappropriate dysfunction or silencing of genes in cancer tumor suppressor genes is imposed on these genes that are otherwise normally controlled without the abnormal DNA methylation during normal development and the renewal of normal tissues. So that is the one big area we and others have worked on going forward to understand the association of the abnormal DNA methylation change in cancer with its interactions with proteins that help establish the change and that mediate the abnormal gene silencing.The second joined area concerns how we came to focus upon how our epigenetic therapy triggers key aspects of immune responses to viruses. For some years, other investigators have recognized that the drugs to use to block DNA methylation can cause cancer cells to re-express proteins that are silenced in mature cells after embryo development. These proteins called 'fetal antigens' can potentially activate immune responses against cancer. Our group and P Jones' group independently, through work from young investigators who are now faculty members, including K Chiappinelli at George Washington University and D deCarvalho at the Princess Margaret in Toronto, allowed us to recognize a more systematic, widespread pattern for immune responses induced by our DNA demethylating drugs that we termed 'viral mimicry' because treated cancer cells acted as if they were recognizing a viral infection. But they were not infected with viruses but were actually expressing RNA from our DNA that has been incorporated into our genomes through years of evolution.And we recognized that the above dynamics were driving this process of the immune changes that we were studying. And this morphs into linking these dynamics to what our therapies might be doing and how we could use them to take advantage of all the above dynamics to potentially sensitize cancer cells to the effects of what has changed cancer treatment forever, immune checkpoint therapy. Multiple clinical trials are now ongoing to test epigenetic therapy for this purpose, including in our SU2C team efforts.So, this explanation is a little long-winded but that is how we came to join two components, abnormal silencing of tumor suppressor genes and trying to reactivate them with an anticancer strategy linked to immune activation.InterviewerWith over 475 authored and coauthored publications surrounding the topics of epigenetics and cancer biology, what advice would you have for early-career scientists in the field?Stephen BaylinWell, I think there are several points that are pertinent for people going into science from the time that they start training right up to their early professional careers. First, I believe they must recognize what does that science mean to them. And what I mean by that is those people who stay in have recognized, as a basic core of their careers, doing science is a passion. It is almost like it drives you despite yourself to want to do it, and I think this drive is a fundamental element in any really successful scientist. Second, they may go to use what they do in science in many different constructive ways. They can stay fully laboratory focused, become leaders for big laboratory programs or use their derived insight and talents to enter scientific administration, to benefit science in academic institutions, pharmaceutical companies, journal leadership etc. But it is that passion to do the science, learn from the science and benefit humanity from the science as well as just your sheer joy of discovery, because the latter has to be there, too, at least for me – that love of basic science, the love of questions. So, again for a fulfilling career to emerge, you have to determine early on, do you have that drive? I think that is the key thing.The third thing involves probing how you embrace, almost inherently, the exercise of recognizing the juxtaposition of things that may initially appear incongruous but yet come together to give you those eureka moments – and say, okay, I am going to pursue investigating this juxtaposition or encourage colleagues to do so. Now some of the juxtapositions may fall off a cliff, but for me, at least, and I hope to the benefit of at least some scientific arenas as investigations of the juxtaposed ideas are perpetuated and can define key moments in a scientific career. So be open to ideas that are out-of-the-box, see things come together that others might not, and I guess this defines an absolutely seminal element in a productive scientific career – creativity in one way or another. It has been said by some prominent scientists that "if a new idea is not crazy, it is probably not worth pursuing".Finally, I would stress the need to learn very early in training, and early during faculty careers, of the value of knowing how and when and wisely to constructively collaborate strength to strength within one's group and with outside partners. I have alluded to this above in my own career. It goes without saying that so much of today's science is 'big' with a myriad of avant-garde technology in the spheres of genomics, proteomics, imaging, bioinformatics etc. No one lab can do it all but reaching out as great projects and science so often dictate can benefit and extend the impact and scope of an individual investigator's presence in his or her field. I have seen how young investigators starting their labs and innately sense this collaborative need early, exercise it and rise quickly to national and international recognition.InterviewerAnd you can definitely see that drive and excitement in the way you talk about the topics from yourself.Stephen BaylinWell, passion for doing science can grab you to a fault. Then you have to balance life with encompassing those passions because doing science well subjects you to the demands of a jealous master. There's no other way but to immerse yourself in the science and never be a dilettante. My family can attest to the fact that I have achieved that balance often in a far imperfect way – but they have been incredibly supportive at so many junctures and I still keep trying to learn that balancing art and life is a precious thing!InterviewerDo you currently have any interesting research that you are working on and that you would like to share with the journal's audience?Stephen BaylinWell, I guess I would return to those two broad areas joining cancer and epigenetics that I introduced earlier. In my microcosm, you have to recognize how the broad context of the epigenome and the genome, both in normal and in pathophysiology, drive the work and any potential to translate findings to therapies and human benefit. You obviously cannot work on it all; you have to place your work in the context of the time in science you are in and I think this is really critical. I think it's important to learn but you think you know as substrate to quickly quest for what more you need to know.Given this above preamble, I would say the excitement comes from having immersed myself and with so many colleagues in our latest work to pursue defining what causes and establishes cell signaling programs for how epigenetic silencing and prevention of normal gene activation of tumor suppressor genes arises as the whole process of tumorigenesis evolves. I am excited by the growing appreciation of the role of chronic inflammation, and its ties to aging and DNA damage play a seminal role in initiating the above programs well before, and probably even years before, frank cancers arise. The studies, in our group led by faculty members M Vaz and H Easwaran suggest that normal cells use abnormal epigenetic changes to learn how to survive the damaging environment of chronic inflammation. But by doing so they also evolve a road toward cancer and being sensitized to how driver genetic mutations allow the cancers to be initiated. At least, this is my bias as fostered by the work of trainees and above collaborating scientists who I am so fortunate to work with.I am also very excited about the work I introduced above concerning inflammation and understanding how our drugs that manipulate viral mimicry are integrated within a much larger signaling pathway known as the inflammasome. For this work, I am fortunate to be a collaborator with my wife, F Rassool, a professor in the Cancer Center at the University of Maryland. She is an expert in studies of DNA damage in cancer and is leading studies which are revealing how our viral mimicry is actually encompassed in a process known as the inflammasome which in the end is a critical step for how activating tumor cells with epigenetic therapy has the potential to collide with immune cell attraction, bring these immune cells to tumor sites and thus improve treatments such as immune checkpoint therapy. revealing how a key cell component, mitochondria house a fundamental gateway to the inflammasome signaling stimulated by epigenetic therapy. This is a field that immunology research will likely become enmeshed in and produce a deep understand of the critical biochemistry and molecular biology of mitochondria, which underlies long observations that mitochondrial energy metabolism is so important to cancer development and outcomes for therapeutic intervention. Finally, all of these immediately above studies came about in a scenario that illustrates how the study of one disease can provide critical insights for another. I began during the COVID pandemic, a virtual sabbatical in residence where I became the student, with my above former student M Topper, and others active as my mentors. We are participating in a big international consortium called COVIRT, led by A Beheshti who works at NASA to study how specific steps in inflammation cause lethal disease from the viral infection. It is here that mentors and especially, a pioneer in basic studies of mitochondria D Wallace at the University of Pennsylvania began to educate me and my colleagues about how mitochondria get damaged to initiate the inflammasome signaling and how our group passed down information which led F Rassool's lab to embrace the concepts and creatively bring them to bear in the arena of epigenetic therapy.InterviewerAlthough you may have answered this already, where do you think the field of cancer epigenetics is heading and what are some of the new developments that excite you?Stephen BaylinI think one big area where epigenetics, for both normal processes such as development, comes to intersect with dynamics that can go wrong in diseases, not just cancer but also autoimmune diseases, neurodegenerative diseases, diabetes and others. Epigenetic control is at the heart of the events involved. The field is headed toward ever better understanding of the epigenome as it intersects all of the above, bringing so many sophisticated tools available today to make key discoveries.Coming back to the specific area I work in, cancer and benefiting patients, I think we need to use all of the above to understand how the drugs we have been using to target abnormal DNA methylation and the proteins involved in mediating this can be ever better utilized. This will help us better employ the old drugs we now use and understand how to combine them with new ones and utilize other drugs to target the epigenetic abnormalities being identified. If you balance the basic work with trying to develop cancer therapies, it all has to go in these directions. Ultimately, these above types of investigations may perhaps take forward the promissory notes that have evolved to successes in clinical trials and US FDA approvals for drugs, that bring epigenetic therapy to the forefront of cancer therapy. Right now, there is FDA approval for drugs in liquid tumors that can block abnormal DNA methylation, as brought forward by my colleague in SU2C, Jean-Pierre Issa, who is the scientific director at the Coriell Institute for Medical Research in New Jersey and L Silverman at Mt. Sinai School of Medicine in New York City, but such approval has not been achieved in solid tumors. What we are learning in our clinical trials to date relates to a much discussed quest for many cancer therapies which is to utilized personalized medicine to identify which patient are likely to benefit. In this manner, we can be far more successful in taking new therapy approaches forward. A key to this personalization is to perform molecular analyses in pre- and post-therapy tumor biopsy and blood samples. We are seeing emerging evidence that subgroups of patients in our ongoing clinical trials respond to our epigenetic therapy with exceptional outcomes. These patients can even have formal radiologic evidence of tumor shrinkage and/or very durable disease stability and increased survival times while on therapy or beyond. And then, we must derive molecular signatures for such patients that better categorize them and provide biomarkers, so we know which patients to whom we should direct the therapy. We hypothesize that then, of course, if you give the therapy to the right people, your overall percentage of success should theoretically go way up. We need to get wiser and wiser about how to capture all this.InterviewerFinally, is there anything else you would like to add for the readers of the journal that wasn't covered from the questions?Stephen BaylinWell, I think we have covered a myriad of things trying to address the great questions you have put to me. I hope that my responses allow the readers to capture a bit of what I have experienced and am experiencing and what has kept me excited throughout my scientific career. I feel exceptionally fortunate to have been and still be engaged in the science we have been discussing. To young trainees and scientists, I hope as you go on in your careers, you reach my stage and age and recognize that you are still passionate about what you are doing and still want to do. I recognize that when you do get to my stage you increasingly start pointing much of your efforts more and more towards trying to help young scientists develop their careers and feel as excited about science as I do. This means not only those you directly work with but also others entering the field. And you increasingly recognize that any legacy you achieve is not about you but rather the work that might be valuable enough to attract young scientists, often much smarter than you, to engage in it and take it forward in their careers in ways you may have never imagined. So legacies, I think in general, are most often about the work, seldom about the person. Legacies for people certainly can emerge, sometimes for the best of reasons and then sometimes for infamy. Look for a good legacy for the work you do and how it serves the people you have been fortunate to engage with and as I wish in my pursuits, patients.Edboard disclosureS Baylin is a member of the Epigenomics Editorial Board. They were not involved in any editorial decisions related to the publication of this article, and all author details were blinded to the article's peer reviewers as per the journal's double-blind peer review policy.Interview disclosureThe opinions expressed in this interview are those of S Baylin and do not necessarily reflect the views of Future Medicine Ltd/Future Science Ltd/Newlands Press Ltd.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.FiguresReferencesRelatedDetails Ahead of Print Follow us on social media for the latest updates Metrics History Received 21 February 2023 Accepted 16 March 2023 Published online 26 April 2023 Information© 2023 Future Medicine LtdKeywordscancercollaborationepigeneticsepigenome •immunelegacytranslationworkEdboard disclosureS Baylin is a member of the Epigenomics Editorial Board. They were not involved in any editorial decisions related to the publication of this article, and all author details were blinded to the article's peer reviewers as per the journal's double-blind peer review policy.Interview disclosureThe opinions expressed in this interview are those of S Baylin and do not necessarily reflect the views of Future Medicine Ltd/Future Science Ltd/Newlands Press Ltd.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
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