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Megan Sykes, MD: Michael J. Friedlander Professor of Medicine and Professor of Microbiology & Immunology and Surgical Sciences (in Surgery) and Director of Columbia Center for Translational Immunology Columbia University, New York City, NY

Sykes, Megan MD

doi: 10.1097/TP.0000000000001864
In View: People in Transplantation
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Transplantation: You started your career with a medical residency in Toronto and then moved into a research position at the NIH. When did you decide to concentrate on a career in research?

MS: As a first-year student and throughout medical school, I had the opportunity to carry out research on the effect of hypothyroidism on receptor-mediated LDL clearance. I chose an endocrinology laboratory because I had become intrigued by receptor-ligand biology through my basic science coursework and had not yet discovered immunology. In the ensuing years of medical school, when we were introduced to clinical topics, I realized that so many diseases seemed to be autoimmune in origin. I became fascinated by the sophistication of a receptor-ligand system (only antibody receptors and not T cell receptors had been discovered at that time) that so effectively distinguished self and nonself under normal conditions. The pathologic consequences of this self-nonself distinction in transplantation, causing both graft-versus-host disease and graft rejection, and the failure of self-nonself recognition in autoimmune diseases captivated me. By the end of medical school I was certain that immunology research would be a major part of my career.

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During my medical residency, I thought about hematology, nephrology, and rheumatology as subspecialities that could incorporate my research interests. During this time, however, I witnessed first-hand the difficulties that young physician/scientists finishing their subspecialty training encountered in getting the protected time needed to establish research programs while simultaneously establishing themselves as clinicians. Upon finishing my residency, therefore, I decided to defer the decision on subspecialty training and instead to carry out a pure research fellowship in the laboratory of David Sachs at NIH. I met David during a memorable day of Medical Staff Fellowship interviews, when I had 16 interviews all over the NIH campus in the space of 8 hours. David immediately inspired me with his infectious enthusiasm, and I decided that transplantation was the main area of self-nonself recognition that I would pursue in my research career. During that time in the laboratory, I began projects that absorbed me completely, including an effort to induce tolerance to allografts by resetting the immune system with lethal TBI and T cell-depleted syngeneic bone marrow transplantation, as well as an analysis of the role of suppressor cells in protecting against GVHD in mixed allogeneic chimeras. I discovered during that time that donor lymphocyte infusions (DLI) could convert mixed chimeras to full allogeneic chimeras without causing GVHD, which I later pursued as a platform for achieving GVL without GVHD. This approach ultimately became the foundation for our clinical trials to treat hematologic malignancies with intentional mixed chimerism induction followed by DLI at MGH, and later (without the DLI) permitting clinical mixed chimerism for kidney tolerance. I realized by the end of that first year at NIH that there was so much I wanted to accomplish in my research that it would be frustrating to try to carry out clinical work as well, so I decided on a full-time research career.

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Transplantation: Xenotransplantation has been an early research interest. Most recently, xenotransplantation has regained attention and interest with novel techniques that have become available. What potential do you see for xenotransplantation both, short and long term?

MS: Technologies modifying the porcine genome have opened up exciting new potential in xenotransplantation. We are already seeing the benefits of genetic modifications in a number of large animal xenotransplant programs achieving survivals of months to years. While I think clinical xenotransplantation is still a few years away, I believe it is a more imminent solution to the allograft shortage than other organ regeneration/replacement technologies. It is possible that xenografts will eventually incorporate human cells in chimeric organs constructed via blastocyst complementation.

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Transplantation: Clinical xenotransplantation trials have been performed in geographic areas that have not been recognized of having a track-record for an integrated, high-level clinical and research approach. Are there too many barriers for the implementation of novel clinical applications in North America or in the western world?

MS: Actually, there have been some well-regulated xenotransplantation trials carried out in the western world using porcine islets and human skin epithelium grown on murine feeder cell layers. I do not think the regulatory barriers are currently preventing clinical xenotransplantation trials. While it has become apparent that the infectious risks of xenotransplantation are manageable with appropriate oversight and surveillance, this regulatory oversight will be essential to avoid unsafe and unproven xenotransplantation procedures. Some forms of unproven, unsafe stem cell transplantation have been carried out even in the United States, and such practices are damaging not only to the patients but to the field. For any novel therapy, it is essential to proceed cautiously to clinical trials only when there is a high, data-driven expectation of success. In view of the progress and potential of xenotransplantation, engaging regulatory agencies in preparation for future trials, as exemplified by the International Xenotransplantation Association, is very appropriate at this time.

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Transplantation: Envisioning next steps on clinical trials in xenotransplantation, what patient population may benefit the most and what organ/tissue may be best to use?

MS: Porcine kidney transplantation could benefit highly presensitized patients who cannot find a suitable donor and have a short life expectancy on dialysis. Likewise, patients with end-stage heart failure, many of whom are also PRA-positive, and who are likely to die waiting for a transplant, could receive pig hearts in the not-too-distant future. However, more work is needed in large animals before this can be done, as long-term orthotopic heart transplant survival has not yet been achieved in primates. There is also a potential role for xenogeneic liver transplantation as a bridge to liver regeneration in patients with acute fulminant hepatic failure. Finally, while islet xenografts are less invasive than organ transplants, I think these will be most appropriate in conjunction with tolerance induction.

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Transplantation: You have spearheaded the successful implementation of clinical tolerance protocols. What do you see as the main challenges moving forward?

MS: While hematopoietic cell transplantation is currently the most promising and reliable method of achieving clinical tolerance, I feel that GVHD is a completely unacceptable complication. Thus, the challenge is to reliably induce a state of mixed chimerism with no risk of GVHD. While transient chimerism works in concert with a kidney graft to achieve tolerance, I believe that durable chimerism is needed to assure tolerance to all types of organ grafts. The ideal tolerance protocol would be carried out after the organ transplant so that it could be applied to deceased donor allografts. We are getting closer to meeting these challenges.

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Transplantation: Conditioning regimens are critical for the success of tolerance trials. Are there novel approaches on the horizon?

MS: There are several promising antibody/immunotoxin-based approaches on the horizon for making “space” for donor hematopoietic cells to engraft in the marrow niche. These reagents may prove to be less toxic than other forms of myelosuppression. However, immunouppressive agents will still be needed in the short term to either deplete or tolerize preexisting recipient T cells so they will not reject the graft.

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Transplantation: An additional essential component for the success of tolerance is a reliable prediction of the best candidates. Are there novel tests available that could help to guide treatment and tolerance protocols?

MS: The field has not yet validated biomarkers identifying patients who have “spontaneously” achieved tolerance and can be weaned from immunosuppression on the basis of those markers. I am excited about the potential of alloreactive T cell repertoire tracking as a highly specific biomarker, but more studies are needed to test this potential. For rapid tolerance induction/immunosuppression withdrawal trials, I think nonhuman primate studies showing safety and efficacy are a prerequisite.

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Transplantation: You serve currently as the director of a translational immunology center. What are the advantages to be working in an environment with a multidisciplinary input? How do you use this input to advance tolerance?

MS: The synergy among basic and applied immunology disciplines cannot be overstated- we are all trying to monitor and manipulate the human immune system, though in different directions for different disease areas. New technologies have been applied in some disease areas before being implemented in others, and integrated programs allow more rapid transitions between them. The greatest synergies, though, are intellectual. As an example, in autoimmune diseases we are dealing with established immune responses and a role for inflammatory cytokines. As we appreciate the role of memory responses and cytokines in transplant rejection and in blocking tolerance induction, it becomes easier to think about which immunotherapies can be applied from the autoimmunity field to transplantation.

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Transplantation: Transplantation continues to offer unique opportunities to combine clinical work with translational and basic research. What is your advice for young (female) investigators or clinician/scientists?

MS: If I have to give a short answer, I always tell people that you have to love your work to sustain a research career. There are so many challenges and the rewards are usually not as immediate as those obtained from caring for patients. Thus, passion is the only sustainable motivation for a research career. I think it is easiest, both on a practical level and on the level of maintaining that motivation, to conduct research and clinical work in the same area if one is trying to do both. Until our society changes in a way that better equalizes domestic and child-care responsibilities between men and women, the challenges will continue to be greater for women in trying to juggle science, medicine and life.

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Transplantation: You are an enthusiastic runner, and I know many who are not able to keep up with you! How do you enjoy your time off work?

MS: I am not as fast as I used to be, so most people can keep up with me on a run these days! I do run, bike and swim on a regular basis, not only to keep fit but also to maintain my sanity. These activities allow me to relax and process my thoughts and often provide opportunities to be outdoors, which I very much enjoy. I keep a second home on Cape Cod that provides a valuable escape to a world where birds rule instead of cars. Otherwise, spending time with friends and family, reading, playing flute in small ensembles and watching theater and movies are among my favorite pastimes.

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