By IRVING WEISSMAN, MDThirty seven years ago I sat where you now sit, having just finished a 5 year medical education in lock-step with my classmates. A few months before I had decided to take a less-traveled road I was the only one in my class) and finish my formal clinical training to enter a career of biomedical research. I could not have made that informed choice had I not decided to apply to the new, unique 5 year MD program that Stanford instituted upon it’s move from San Francisco to join the rest of Stanford University. Stanford was the only medical school to which I applied, because Stanford was unique in offering a curriculum that allowed students the time and the opportunity to explore all that a great university and medical school have to offer, and therefore to find their special talent. The lessons I picked up on the way, only a few from the formal classes, have stuck with me, as have my associations and collaborations with my Stanford fellow travelers. I loved the clinical years in med school, both for the patient contact, and more importantly, how the desire to treat patients well and rationally forced me to read more deeply, and to try to understand the diseases we were treating largely empirically. But I knew that empiricism would not keep away my growing frustration that we didn’t know enough to advance treatments from knowledge of disease mechanisms. So I chose a career in biomedical research, and learned many lessons on the way. I hope today to pass on the lessons I’ve learned, and how the lessons learned might help you to find or use your talents as well.
I have spent 46 years directly engaged in biomedical research, starting in a small transplantation genetics lab in Great Falls Montana. I have been an immunologist, and cancer biologist, and for the past 15-20 years a stem cell biologist deeply involved in biomedical science and medical translation. As time has gone by I am increasingly in awe of the complexity and efficiency of nature and of organisms like us. Let me be clear—this is no mystical or religious view, but one grounded in the context of the view that the human body is a result of hundreds of millions of years of evolution. While I have heard repeatedly many distinguished scientists, usually near the end of their career, say that we know so much (in 1962, or 1976, or 1990, etc) that all the rest will be only dotting i’s or crossing t’s. I couldn’t disagree more. I am firmly of the view that we are just now at the beginning of exploring how the body develops, functions, and what happens when it malfunctions. It is you, not my generation, that will have the greatest opportunity to unlock the great secrets of health, the mind, and disease, and how the body regulates itself, regenerates its components, and simply endures. Imagine, I am a 62 year old man driving a 4 year old car that will be gone before it is 10. And I was one of the first occupants of the Fairchild science building, entering at mid-career, and now I’m told it has reached the end of its useful life and must be torn down and rebuilt; hopefully the leaders who make such decisions won’t look too close at me. I am still amazed that while I go through my 24/7 my body repairs itself continuously (from stem cells!), and while I sleep, my heart keeps beating and I breathe. These phenomena may seem ordinary to you, but they are extraordinary to me. And think of this: I am talking to you, you are listening to me, and all of us understand what was said. No neuroscientist has even the beginnings of an understanding of the complexity of this almost instantaneous set of perceptions, assembly of information, synthesis of assembled information, resultant learning, and the properties of mind that go into these events, much less the memories that will follow. Or to take the example further, one of my first patients in psychiatry as a medical student was to diagnose a patient that was silent and withdrawn. Over a week of meeting it came out he had been hearing voices, and these voices knew him well and tried to direct him. He had finally concluded that the voices came from alien powers, and in that observation departed from the path of understanding the world as most of us do; he became estranged from reality. About 10 years ago I read that perfectly rational patients hearing voices were studied by PET scan technology, and when the voices came on, deep brain centers fired. So incipient schizophrenics hear organized voices from self-firing foci without input from the ear, and then must deal with the fact that no one else is hearing them. I know a few well who have been made aware that these are like epileptic foci, and live with the voices with a little help from therapies; they live essentially normal lives, although the voices annoy them. These examples might seem far-fetched, especially from a stem cell biologist, but of this I am sure:These phenomena are rational, involving nothing more mystical than cells and molecules and their organization. These mysteries will be susceptible to understanding by biomedical science, and will certainly be useful eventually in medical practice.
What I am saying is that the study of humans in the context of nature is just at the beginning, and that those who will commit to this adventure are coming in at just the right time. But I want to re-frame what I’m saying in the context of a biomedical education, and where you are at the end of one stage of training, on edge of going from competency to mastery of your subject. I want to step back and say that collectively our job, our responsibility, is to end the tragedies of premature incapacity, premature morbidity, and premature death of our current and future patients. Some of you will do so by gaining mastery in some field of biomedical science, others by translating discoveries and principles (medical, scientific, economic, etc) to advancing medical practice, and still others by incorporating these translations into what you have learned and will continue to learn into direct medical practice, hopefully as a lifelong exercise. But you need to know what you are up against. In my view nature and disease are relentless forces that operate independent of what we think or hope. In order to be effective in understanding nature and overcoming diseases we must go forward with the knowledge and principles you are now adopting and will amplify. There is no room in this venture for self-deception or self-interest; neither can influence what is true. Our observations must become increasingly more accurate, and we have to temper our enthusiasm over our nascent discoveries and insights with an acquired habit of self-criticism. Although money, fame, and/or patient adulation can be motivators, they are not helpful, as they have historically, and will in the future simply serve to divert you from what you are best at doing. Finding your talent and practicing it will keep you engaged, and usually other desired rewards follow anyway.
At least since Stanford moved from San Francisco to Palo Alto it has committed itself to provide a unique graduate medical education and opportunity. We have sought to be a leader in advancing medical sciences, in providing a scholarly approach to all we do, in providing for our patients the highest standard of medical care, and in attempting to be leaders in the translation of medical discoveries. With your class, as with others, we intended to admit those who by their actions before medical school had demonstrated concretely that thy possessed the capabilities and motivation to take advantage of these goals. After you came here, we intended to provide for you the education, and independently the opportunities to do all of these. If jointly we have been successful, you will have taken advantage of your opportunities, and you will also recognize the equivalent values of 1)the role of science and scholarly inquiry in advancing medical knowledge and practice, 2)the role of medicine in revealing the reality of human disease as well as treating it, and 3) the role of translational medicine in moving discoveries from the bench to the patient. Hopefully you will have chosen role models that exemplify these values and practices. I certainly did. I think you will find that these role models got where they did by a combination of traits we all should recognize—commitment, responsibility, integrity, and idealism.
You who are about to be MD’s are about to take an oath that has it’s roots in the Hippocratic Oath, taken by physicians for centuries. Like you, I took a similar oath. I am constantly reminded of the wisdom of that oath, and how it has guided much of my own career. It is important that you realize that this is a commitment, a commitment of physicians that the care of their patients is their first consideration. For those of us who are physician-scientists, I would say that this is a commitment to the health of the patients who could benefit from the translation of our findings. When I think of this commitment, I don’t have to go far. Today you are honoring Stan Schrier, who is my role model for commitment; nothing else ever comes first for Stan. He was a legend when I entered medical school, and he is a legend today. And Harry Oberhelman, who in his late 70’s (I think) outperforms and outlasts faculty and residents a fraction of his age. And of course there are many others on our faculty.
This year I reread the oath (The Stanford Affirmation) when I needed guidance on a difficult issue. I was chairman of the panel of the National Academies on Human Reproductive Cloning, and the related subject of Nuclear Transplantation to produce human embryonic stem cells for research and therapy. My panel had determined that reproductive cloning was dangerous medically, poorly feasible scientifically, and in terms of the human participants in the exercise—the cloned fetus and the mother that carries it—carried the almost certain probability of fetal death and maternal morbidity. In fact any such research violates several specified recommendations of the Nuremberg Code, articulated in 1947 by the US Military Tribunal Number 1 at the Doctor’s Trial, which, by the way, I believe should be required reading for all medical graduates. The Panel considered also the production of embryonic stem cells by nuclear transplantation, a procedure wherein the nucleus of a somatic cell is transplanted into the enucleated egg from a pre-defined donor, the diploid cell is then electrically stimulated, and allowed to progress to the preimplantation blastocyst, a stage of development of about 150 cells. The inner cells can then be cultured to produce pluripotent stem cell lines, cells which at the single cell level can either self-renew and expand their numbers, or be caused to differentiate to daughter cells that represent all cell types in the body, albeit arranged in a disorganized fashion. These daughter cells can be transferred to newborn immunodeficient mice, and there they undergo normal differentiation specified by their own genes and stage of commitment, and the adequacy of the environment into which they are placed. Thus for the first time, if this were allowed with human tissue sources, one could prepare pluripotent cell lines representing each genetically determined human disease, which is most diseases, and even from each cancer, which has undergone it’s own life history of somatic mutations that specified cancer development., While such a procedure is abhorrent to some for moral, ethical, or religious reasons, it had to be recognized that it could lead to breadthoughs that will change biomedical science and medicine itself, much like the recombinant DNA revolution in the 70"s (begun at Stanford by Paul Berg and Stan Cohen) led to technology and therapies that save tens of thousands of lives today. This was recognized by my panel, and we voted unanimously that the promise of such research was so great, and the risk to human participants (egg donors) so minimal, that such research should go forward. But when I testified before the Senate, and before the President’s Council on Bioethics I realized that several MD’s were the advocates of a complete ban on such research. Further, the Brownback and Weldon bills that ban such research also propose penalties including up to 10 years in jail and a 1 million dollar fine for any physician who would prescribe for a patient a remedy coming from anywhere in the world that is derived from nuclear transplantation embryonic sem cell lines. In today’s Stanford Affirmation you will take the oath that you "will treat any who need my ministrations, without regard to religion, nationality, race, politics, sexual orientation, or social standing;" When I sought guidance from that oath I interpreted that to mean that as an MD biomedical researcher I must leave at the door my own personal politics, religion, ethics, etc, so that meaningful research and therapies can be generated. In my view, therefore, either as a physician or a physician-scientist, the passage of these bills would require us to fail to honor our oaths, as there will be a time when you will have to deny current and future patients therapies that could have been in our grasp.
After commitment comes responsibility. When you develop a new finding or insight, you can let others know and act on it or not, or you can take the view that you are responsible for taking it as far as it can go. Here we have several role models. One of mine was my mentor, Henry Kaplan, who not only showed experimentally that radiation had the possibility to treat cancers, but took the responsibility with Stanford physicists like Ed Ginzton to help develop high energy linear accelerators that could deliver their ionizing radiation in the tumor, and not the skin. With colleagues that included Saul Rosenberg, Henry developed the therapy model which in their clinical trials changed Hodgkin’s Disease from an universally lethal to a readily curable disease. It took amazing insight and courage to carry this all the way from discovery research to clinical therapies, and established radiation oncology as a mode for therapies with curative intent that is now world-wide, and for several kinds of cancers. I could have cited Norman Shumway for developing through research the practice of heart transplantation, or Paul Berg and Stan Cohen who not only pioneered the recombinant DNA revolution, but helped to establish biotechnology companies that translated these discoveries. And they and other molecular biologists had the integrity to question the safety of what they were doing in the lab to call for a moratorium on doing their research until it could be shown to be safe for those who made recombinant microorganisms. In all of these cases the insights, courage, and responsible action of these investigators led to medical practices, not previously possible, that now saves tens of thousands of patients each year.
It is important to re-state the issue of integrity. In addition to finding your talent, you have to develop core values of honesty and integrity, so that you have a center that will hold when all else seem to be flying away. Make no mistake that when you have assumed responsibility (with little or no oversight) your integrity will be tested, and usually when you are unprepared. This happens in the science that goes on in your own labs, with the patients you treat, in the companies you advise or establish to translate your discoveries, and in the quest for fame and prizes. There is no doubt that there will be times when you make mistakes, or discover them. It is then that you should remember your oaths and your standards.
Finally, I want to preach idealism. It is too easy to give way to cynicism, or to pursue objectives that promise rewards for you at the cost of your commitment to patients. We are now in a crisis in medical care in both academia and the private sector, where managers, administrators, legislators, and clerks who have not taken the oaths you have taken look to medicine as something other than a right of all citizens. It will take courage, commitment, integrity, and idealism if we are to carry the lessons learned here into careers in medicine and the biomedical sciences. There is one way to counter cynicism, or boredom, or acquiescence to the will of the managers. Find your talent, and practice it for life. You will be happier, and society will benefit.
Stanford Report, January 22, 2003