Research as an Imperative for Clinical Excellence

Abstract

I am very grateful to our Congress of Neurological Surgeons (CNS) President, Alex Khalessi, and the CNS Executive Board for giving me the chance to share with you, a little bit about my own journey that shaped me into the neurosurgeon and neurosurgeon-scientist that I am today. CAREER FORGED BY FAMILY To understand my background, we need to go back to 1949. My parents arrived in the United States from a camp of displaced persons in Germany after surviving the Holocaust. This photograph (Figure 1A) captures a happy moment with my older brother Steven, who is now a Professor of Neurosurgery at the University of Pennsylvania, and my parents, Adele and Jacob Brem, two remarkable individuals. Just at the age of 20 years, they did not speak English, had no high school education, and had lost their entire families to the Nazi Holocaust. However, they carried with them an incredible resilience and joy for life. They rebuilt their family, and our lives were filled with joy.FIGURE 1.: A, Adele and Jacob Brem with Steven, 1949 (Author's photograph published with permission). B, Parents: Jacob and Adele Brem. Children: Steven, Henry, Shari, Harold, 1970 (Author's photograph published with permission).Despite all they had endured—the unimaginable loss of parents, siblings, and everyone close to them—they came to America with hope, ambition, and a strong desire to build a better future. Figure 1B shows my parents, with their four children—my older brother Steven; myself; my sister Shari who is a periodontist; and my younger brother Harold, who is a general surgeon. Our upbringing was grounded in the values of our parents instilled in us. These values laid the foundation for how I approach medicine today. First, there was our heritage that they imbued us with. There was a passion for learning and a respect for educators and respect for how important our teachers were, at every stage of our lives. Another principle that shaped me is the Jewish concept of TIKUN OLAM, the idea that we are all responsible for making the world a better place. This belief has been central to everything I do. We were taught to strive to leave every situation better than we found it. There was also a very deep love of mankind and fellow human beings. This is despite the horrors of what our parents had survived and the worst of humanity that they had seen with concentration camps and death camps. Instead, we were brought up with joy, compassion, and love. There is a biblical expression, “Ve-ahavta Le-reaskha kamokha” Leviticus 19:18, which means love your fellow man as yourself. We were imbued with a very deep sense of family, and this love of family also shaped me as a physician. Finally, they passed on a profound appreciation for life itself. There is a Talmudic expression that is enshrined on the entrance hall of the Johns Hopkins Hospital, “if you save one life, it's as if you've saved the whole world.” This has been a driving force behind my career in medicine. In terms of understanding who I am, the most important person in my life is my wife Rachel (Figure 2A). We started dating when she was at the age of 17 years at Brandeis. We were married in 1978, just six months before I started my internship at the Peter Bent Brigham Hospital, as Rachel was completing her premedical courses. The second photograph (Figure 2B) captures us at the same spot at the Brigham 40 years later—I do not see any significant changes! Our life together has greatly defined who I am, both personally and professionally.FIGURE 2.: A, Rachel Brem, 1977 (Author's photograph published with permission). B, Henry and Rachel Brem in front of Brigham Hospital (Author's photograph published with permission). C, Henry Brem and family (Author's photograph published with permission).Family has always been a big part of our life, and because of that wonderful 47-year journey with Rachel, we have three incredible daughters, three sons-in-law, and 10 amazing grandchildren, and we are thrilled that they all live in the Baltimore-Washington area (Figure 2C). As a physician, the deep love I experience within my family gives me a deep empathy for my patients and their families. I understand, firsthand, the profound emotional journey that families undergo when a loved one is ill, and this connection helps me care for them with greater compassion. IMPACT AND IDEAL MENTORSHIP When I chose a career in medicine, the word that resonated most with me was IMPACT. I wanted to maximize my ability to improve lives. I wanted to choose a path where I could have the greatest impact, and neurosurgery was that path. The ability to change lives so dramatically through our work as neurosurgeons is extraordinary. Along the way, I have been inspired by incredible mentors—both in medicine and in science. The beauty of medicine lies in the seamless integration of science and humanity and that has been endlessly fascinating to me. There were books that I read as a college student at New York University that were very inspirational and very important to me in building who I wanted to become. I was deeply moved by Christiaan Barnard who, in South Africa, performed the first human heart transplant taking advantage of incredible science and medicine and breaking barriers,1 the Doctors Mayo, a father and two brothers, who revolutionized American surgery,2 and then fatefully, because I am the Harvey Cushing Professor at Johns Hopkins, that in college I was so inspired by both Cushing's biography3 and by his own profound writings.4 Scientifically, I was very inspired by Pasteur and the incredible impact that his scientific discoveries had on mankind.5 René Dubos6 writes about the enthusiasm, which he calls “A God within,” that inspires science. In preparing this presentation, I revisited a lecture by Harvey Cushing from 1929. He highlighted the importance of blending science with clinical practice, suggesting that ideal practitioners engage in both fields. “There are among doctors, the scientists who may never see a patient, and the practitioners, whose work is based on the knowledge that comes from the many scientific laboratories, and who indeed, if spurred by curiosity and given the proper training, may profitably engage in scientific research and medical practice at the same time, which is the ideal combination”4 This quote from Harvey Cushing describes how important it is to have both science and medicine in the same person. Interestingly, I could not resist sharing another quote as well from the same lecture, Cushing states: “Every generation is prone to over-valuate its own accomplishments. And to feel, that it has lived through the most eventful era in history. So, it's music to our ears to be told that the recent half century [1920s], has seen the greatest progress of all!!” and Cushing goes on to say, “Not everyone is entirely happy about it…” I think nothing's changed on that front! Mentorship is so critically valuable, it is how we pass on our experience, knowledge, and our approaches, but it is not unidirectional. I think that the mentee and the mentor both invest major efforts, but the outcome is phenomenal and transformative! My most influential mentor has been Dr Judah Folkman (Figure 3A and 3B), an incredible surgeon scientist, teacher, and humanist, to whom I am incredibly indebted.7 Years later, when he was a visiting professor at Hopkins, I tried to express how grateful I was to him for what he had imparted to me, and I said I wish I could somehow do something for him. He was the kindest, gentlest person in the world, so I was surprised that he said:“No, there's nothing you can do for me… whatever you think it is that I've done for you, give it to your students, do the same.” That's always been my ideal, I don't think that I’ve come close to what he did for me, but that has been my aspiration. FIGURE 3.: A, Judah Folkman B, Judah Folkman and Henry Brem as a medical student C, Steven Brem (Author's photograph published with permission).My brother Steven Brem (Figure 3C) has been a lifelong influence on me—inspiring me to pursue medicine as a career and to choose neurosurgery as a passion. His love of science and medicine was inspirational, and indeed, it was Steven who introduced me to Judah Folkman. Other major mentors for me who have INSPIRED my development as a surgeon scientist and had a substantial impact on me are as follows: Arnall Patz8 who revolutionized ophthalmology and won the Lasker Award for curing the principal cause of neonatal blindness at the time, retrolental fibroplasia. Donlin M. Long who revolutionized the understanding of brain tumors in his PhD work and nurtured an environment at Hopkins, where a surgeon truly could devote himself to the laboratory and to being a master surgeon in the operating room,9 and Michael Colvin who mentored me in oncology and pharmacology, so I could answer the questions that I was trying to address for brain tumors.10 Solomon (Sol) Snyder, a great neuroscientist, has been a major influence, friend, and mentor in so many ways and in helping build up some of the work that I am going to briefly discuss. Finally, my closest friend Robert (Bob) Langer (Figure 4), with whom I have worked as students in Judah Folkman's laboratory and shared Dr Folkman as a mentor. Bob has performed extraordinary work and changed the world through his research. Bob Langer's work is not only critical to my research in brain tumors, but he is also a founder of Moderna, who developed the COVID-19 vaccine that has saved millions of lives!11FIGURE 4.: Dr Judah Folkman's laboratory. 1974 (Author's photograph published with permission).RESEARCH Reflecting on my journey, I think about the various phases that shaped my focus in medicine. At the age of 18 years, I had the incredible opportunity to work in the Columbia microbiology laboratory with Herbert Rosenkrantz, where I investigated the mutagenicity of alkylating agents, while also gaining hands-on experience in the operating rooms at Columbia. During that summer, I published two articles on 1,2 di-bromoethane as a carcinogenic agent and its mechanisms of action.12,13 This experience taught me a valuable lesson: even with limited scientific background, if you narrow your research question down deeply enough, you can become an expert in that specific area and make meaningful contributions. This principle has guided many of my scientific endeavors. When I had the fortune of working with Judah Folkman, I read his work and his hypothesis that angiogenesis was a critical control point in tumor growth. While I was taking embryology in college, I came across the observation that cartilage is vascularized in the fetus and then it loses its vascularity. Having read so much about the theory of antiangiogenesis and talking to Dr Folkman about it, I suggested, based on that observation in nature, that we will investigate if cartilage has an active inhibitor for angiogenesis at the point that it loses its vascularity (Figure 5).14FIGURE 5.: Inhibition of tumor angiogenesis in rabbit cornea.14We spent a year working with Judah Folkman on this, and this was the key finding that cartilage in fact had an inhibitor for angiogenesis.14,15 Antiangiogenesis has had a profound impact in treating ocular disease, dermatological conditions, and, of course, cancer. I am proud of my role in initiating this process and, even more importantly, the surgeons who were responsible for initiating these profound scientific and clinical advances. Stemming out of this work, Bob Langer and Judah Folkman wrote the first article on polymers for the sustained release of proteins and macromolecules effectively creating the field of drug delivery,16 and later together with David Tapper, who eventually became the chairman of pediatric surgery at the University of Washington, we explored how to make these polymers safe for human applications.17 I was very excited by science, but I was really thrilled to be in medical school! As I look back at medical school, in addition to the incredible thrill of working with Judah Folkman and others, it was really about learning and improving medicine and devoting tremendous amount of effort and time to mastering the scientific and clinical sciences, enabling me to provide the best care for my Judah Folkman about the and general to something that is but you do not it because you can a when it was is general the scientific questions we need to answer through as how to As a I have always a profound from my patients because they me to care for them and their in me, a to them through some of their most and they me to me to do my given the best knowledge, to We were taught that you the that you to be However, what I have time is that this is not an high The really was to understand how the to be and to make that you are that My neurosurgery at Columbia was really six years of just incredible to learning and of course, the incredible that are These my entire focus that When I started on the at Hopkins in I that I had this incredible scientific background, I was by science, and that scientific was very I the impact it could However, I also that I had spent years learning and for and I that clinical neurosurgery was and I about taking care of patients I care of patients and do brain surgery and me to care of their I be a not as a not but on my So, when I started as an I was very on building a practice and building with I up before an and I the and I was very and that very I a that I up a that and patients come to me, for brain tumor that and that I that and did the best that was in medicine at that time, after a little it was a that I could do these that I was taught and could the best of our this was However, I to that it really was not I that there was a from it because I that patients were from great for with brain tumors, and I became very close with and they me. I worked with them and their and we these incredible and then they I that even with all the work that I was and all the that they in me, the outcome was I that we just did not how to do When I was close with the and I them if they I them the answer that I we that there was no for this, but we that you are working on making it you are at Hopkins, you are a scientist and a neurosurgeon and that is We to be part of that process of making the I that I had a with patients and a to patients not only to do my best with the but also to ways to do better than what was of me. I that I had the opportunity and to do an of practice, there was an understanding that it just was not I I could I could do what I was to do and what the but it really was not enough, and we just to do the is then we is in so much of medicine, so when it comes to the patients with that we care but really in so much of medicine. However, if the is to improve the then we do We both by our clinical and care of the patients and their families and their In with my I that even the that do in a year and do have this they are grateful that me and the whole were there with them in the process and that we were always there for we and they were not They that we do not the but we can truly with as they go through the but the the change that I had to was to change I that had to We had to even in Another that I came to was to some as much as I care about and I do deeply we also to some from the and the because it is how much some of our patients go We of think are the at and that we are we are the and care I think that is what us through and that is how we can go and be with our families go to a laboratory and do research. We can from the and that we also are with when we are with our We at However, despite that of that we some patients that and they make us their very and we to and that is it is to do some of the we have to do. that is a very strong and it us of how the patients are when they come to to our There is a to give back for the patients and their families in us. us to do research and improve the of medicine and When it comes to which one go in their I have also come to in many research as a career is a much than brain The is brain surgery is a of knowledge that you you you work and you master its and if you the and do what could be there is very little to the person. the in a research you could your whole life working on a scientific and work and and it could out to be could out to be an it could out to be So, in the is in a sense much greater in your is to be you could really a in a laboratory and not be the of neurosurgery and what I do are and very great to my However, I think the impact is much greater in and I even that as I look back at my own I have of patients by operating on them and taking care of and the of surgery is I have many more patients in an through the research I have our to this has even the impact through their work, which Harvey Cushing's ideal of the of the and more patients have from our discoveries and our than I have seen as an person. So, it is how the two of our have very and to them for the who practice of the in brain tumors is the work we have done in of and the of clinical of every at the the was the big (Figure We had that these just were not to where they to so we the polymers that had been developed at the of for drug which had never been in New to brain tumor with a at Hopkins with an of at that time, to work with a based on to the with (Figure for the Professor of Neurosurgery at Johns Hopkins and of our worked with us as a fellow and the brain tumor (Figure We brain tumors into these and with polymers with for We in we a much better for the same drug as with it being (Figure A, of B, for the of is a photograph of a surgery where we have out the brain tumor and we the with (Figure The release of the and we that this approach was with a significant in (Figure in the than the with Bob Langer and I and many at Hopkins were this work and it at what we found is that it was very well the work, that it was science, but they never work you was is that the years were as to it not Figure some of the to that were with of to they said the polymers could not be they with the they said that the polymers were they be and the drug could not into the So, we and published the to answer these We did not and we did not the We just said we will these and and We back to the and we did all these and we and we just these then said do not clinical can in is not what is going to with So, we did the clinical We the same that we in the laboratory. was very to do However, by we the and that we really had something that was We did a in medical a significant in for the was to be At the time, the had not for brain tumors for I was also to out that even after our was by the not for it. So, we had to go and and from the Congress to to make it for we eventually both for and after these were was limited by clinical its This is because even recent performed in in with patients at have significant and that be a of The journey to a change in clinical practice is with We have many approaches, and the 40 years, and I am that many of them will and improve In research progress is not the same as In when I out a brain that goes it is and the from our in the laboratory is but the progress only if you and with The of Harvey Cushing and (Figure lives on at Hopkins and is our extraordinary of We have an incredible of at Hopkins (Figure this by the and it is not a man it was in Harvey Cushing's and This is an incredible of all with the same that of helping in the through clinical work and through research. me, the greatest has been in the to both master our field and to it for the from Harvey Cushing and of by published with the I started my own journey in I am grateful for the I have had in working with great both as a student and then my career with incredible students, and And of course, the tremendous from our patients who have me to care of them in the best that we is but never There is so much more work to be it is the patients who give us the and to the

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