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In View: People in Transplantation

David H. Sachs, MD

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doi: 10.1097/TP.0000000000003630
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You graduated from Harvard College with a degree in Chemistry and went on to receive a Diplome d’Etudes Superieures de Sciences from the University of Paris. What motivated you to continue your studies abroad?

David H. Sachs, MD

DHS: As a premed undergraduate student at Harvard College, I took organic chemistry in my sophomore year. It was taught by Professor Louis F. Fieser, an outstanding organic chemist and an inspiring teacher. I was so inspired that I spent much of my free time for the next 2 years working as a research assistant in his laboratory and even toyed with the idea of changing my career path from medicine to organic chemistry. I also took 1 year of French at Harvard and loved it. I guess it was a combination of both of these interests that led me to apply for a Fulbright fellowship to spend a year in Paris between college and medical school, working in the laboratory of a professor who was one of Fieser’s former fellows. It was a wonderful year, during which I developed friendships and an appreciation for the French language and culture that have stayed with me ever since. Although my laboratory experience as a full-time investigator in organic chemistry was also rewarding, it became clear to me during that year (and away from the excitement of working with Fieser) that I did indeed still want a career in medicine. I returned to Boston to enter the Harvard Medical School class of 1968.

After returning from Paris, you went to Harvard Medical School. What sparked your interest in Transplantation?

DHS: When I started medical school in Boston, I still had a bench in Fieser’s labs in Cambridge and I would travel frequently between the 2 campuses on my Lambretta motor scooter. I already suspected that laboratory investigation would be part of my career, and I was waiting to see what subject would provide the stimulus to change my research from organic chemistry to something more clinically applicable. During my second year, we had a lecture by Hugh McDevitt, then an instructor at HMS, on the subject of transplantation, which was a rather new field at that time. He described the report by Ray Owen on the origin of blood groups in Freemartin cattle,1 which had led Sir Peter Medawar to his famous discovery that transplantation tolerance could be induced by exposure of an animal to foreign cells early in life. I was captivated by these findings, realizing that if ways could be found of inducing this kind of tolerance in adults, we might be able to transplant organs without the need for immunosuppressive drugs, the complications of which were already limiting the success of the new and exciting field. I had found my area of medical research!

You started a surgical residency at Massachusetts General Hospital and then went on heading a major research program at the NIH. How did you decide to become a full-time researcher? Do you regret not having finished your residency?

DHS: Most surgical residents at the MGH took 2 years out of the residency program to carry out a laboratory research project either at MGH or elsewhere. I decided to apply for a research fellowship at the NIH, since this was a way in which I could combine my obligatory military service with 2 years of medically relevant research in an outstanding research environment. At the end of those 2 years, I was offered a position as a Senior Investigator and I requested another year’s leave of absence from the surgical residency to see what it was like to have my own laboratory. The following year was incredibly productive, leading to findings that clearly required further investigation and to a request for another year’s leave of absence from the surgical residency—which was followed by another year and then another, etc. My laboratory grew to a Section and then to a Branch and eventually, I had spent 20 years at the NIH without ever resigning from the residency! I might have regretted not finishing my clinical training if I had not been offered a job at the MGH at that point, as a Professor in the Department of Surgery, with the opportunity to build a new research center (the TBRC) and to collaborate closely with outstanding surgical colleagues.

You contributed with many research milestones, one of which being the first report on the serological evidence of MHC II. Can you share insights into this research?

DHS: One of the “findings that clearly required further investigation” that I referred to in my answer to your previous question was actually that report on serological detection of class II antigens.2 I had set out to determine whether the same antigens were responsible for rejection across species as within a species and began by immunizing rats with mouse skin grafts and absorbing the resulting rat antimouse sera with cells from different strains of mice. I was surprised to find that after absorption, some of the sera showed reactivity with only a subpopulation of mouse lymphocytes. Additional studies demonstrated that these adsorbed sera were detecting a new series of antigens, also encoded in the MHC, but expressed predominantly on antigen-presenting cells and subsequently called class II MHC antigens, in contrast to class I MHC antigens, which are expressed ubiquitously. I guess the main insight was recognizing that failure of the sera to kill all of the target lymphocytes was not just an adsorption artifact.

You have published as early as in 1971 on immune responses to xenotransplants. This field has made tremendous progress and is now with the development of gene editing even closer to clinical application. What do you foresee as next critical steps?

DHS: From the time I started working in the field of transplantation, I recognized 2 major problems facing this field: (1) the side effects and complications caused by immunosuppressive drugs; and (2) the insufficient supply of human organs to save the lives of all the patients dying because of the loss of one organ. As mentioned above, I decided that the first of these problems might be solved by finding a means for inducing tolerance in adults. For the second problem, I was struck by the similarity of organs in other mammals to those of humans and wondered whether xenotransplantation might provide a solution. When I learned about another experiment of nature, the nude mouse, which lacks a thymus and a thymic-derived immune system and could accept skin grafts from other species,3 I realized that induction of tolerance for transplants across species might be the answer to solving the second problem as well. Indeed, the field of xenotransplantation has made enormous progress recently in pig-to-primate large animal models. Taking this procedure to the clinic will now require demonstration that xenografts will be safe and effective. Considerable effort has already been directed toward the safety issues and guidelines have been established.4 Demonstration of efficacy will require finding circumstances, which justify the use of a xenograft. In my opinion, we will first need to find clinical situations in which no other solution is currently available. Then, if the outcomes are successful, wider use of xenotransplantation will depend on demonstration that results using a xenograft are at least as good as those achievable for an unrelated, non–HLA-matched donor-recipient combination. I believe that tolerance will play a major role in achieving that result.

You have developed the miniature swine as a source for xenotransplants. If we were to overcome immunologic challenges, will pig organs respond to the human physiological and metabolic demands?

DHS: There are remarkable similarities in the structure and function of most of the vital organs of humans and of pigs. Indeed, recent reports demonstrating survivals measured in weeks and months, for nonhuman primates with life-supporting swine organs, confirm the ability of these organs to meet all of the most important physiological and metabolic requirements across this species barrier. Clearly, there will be differences that will have effects that are not immediately life-threatening but nevertheless important enough that they will require further attention. However, assuming that the number of such differences is not enormous, gene editing of the donor pigs may be able to correct any resulting deficiencies.

Safety and the potential of disease transmission have been concerns in the past. Most recent studies have also shown a genome-wide impact of gene editing in addition to potentially reduced defense mechanisms to malignancies. How will those challenges be tackled on the way to a clinical application of xenotransplantation?

DHS: Much of the gene editing now being carried out on donor pigs has been directed toward decreasing the immune response to organs from these pigs by modifying genes encoding cell surface antigens to make them more like their human counterparts. While the modification of very important xeno antigens, such as Gal, will undoubtedly be required to avoid hyperacute rejection, I believe that the number of genetic modifications introduced for this purpose should be kept to a minimum. Indeed, every genetic modification carries with it the potential to induce another unintended antigenic difference.5 Our own approach to overcoming the immune response to the myriad of potential antigenic differences between humans and pigs is the same as that which we have taken toward mismatched allotransplantation (ie, induction of tolerance).

You have also been a pioneer in clinical tolerance and are looking back to a 20+ year experience in combined kidney and bone marrow transplants for patients with multiple myeloma and end-stage renal disease. How did this series impact your subsequent tolerance trials for patients without malignancies?

DHS: When attempting something new clinically, it is always important to start with a population of patients for whom other therapeutic options are limited. For us, multiple myeloma patients with end-stage renal disease, who had exhausted all available treatments for their malignancy, were just such a population. They could not receive additional chemotherapy for their myeloma due to renal failure and were ineligible for renal transplants due to their malignancy. We started with transplants in which the patient had an HLA-identical sibling, willing to provide both a kidney and bone marrow. We developed a protocol for tolerance induction through mixed hematopoietic chimerism, based on our previous successful studies in mice, swine, and nonhuman primates. While not all 6 initial patients were cured of their myeloma, all accepted their renal allografts long-term.6 We were sufficiently encouraged by these results to move on to our next study, treating patients in end-stage renal failure, who had neither a malignancy nor an HLA-identical sibling donor, with a protocol similarly directed toward tolerance.

In 2008, you reported on a clinical series of patients undergoing transplantation without maintenance immunosuppression. What lessons have been learnt from this series and what are next steps for clinical tolerance protocols?

DHS: The paper you are referring to,7 reported the first intentional induction of transplantation tolerance in a series of HLA-mismatched human kidney recipients and represented the culmination of over 20 years of work, extending our original mouse studies to large animals and eventually to man. That report demonstrated that tolerance of HLA-disparate organ transplants was indeed possible in humans and both we and others are now pursuing the extension of these results to additional mismatches and to other organs. However, this field is still at an early stage of development. Perhaps the main lesson I have learned from the endeavor is that even when one discovers an exciting new therapy in an animal model, it takes much longer than one would anticipate to bring it to the clinic. Some of the delay might have been predicted, being due to differences between the immune systems of different species and requiring changes and optimization of protocols at each step. However, much of the delay would have been hard to predict, being due to regulatory and commercial considerations that complicate translation of research findings to clinical applications.

You are looking back to 50+ years of academic excellence. What is your recommendation for young clinician/scientists entering the field of transplantation today? What has been your focus in mentoring generations of successful researchers and clinicians?

DHS: One of the most attractive aspects of the field of transplantation is that it links challenging basic research with exciting clinical applications. Over the years, I tried to maintain a balance between PhD and MD research fellows in my laboratory, recognizing that many of the most important advances in transplantation have involved such collaborations. However, I have also mentored numerous young clinician/scientists who have endeavored to do both. Those who have been successful have been able develop the discipline needed to divide their time effectively. Regardless of which path they wish to take, I counsel them to choose the most important problem that they believe they can solve and to first do the experiments that will prove their ideas wrong, which can often be carried out more quickly than the experiments needed to prove them right.

You have not only spent extensive time in Paris but also spent a Visiting Professorship from 1984 to 1985 in Uppsala/Sweden. As a multilingual polymath, how do you enjoy spending your time when you are not thinking about research and transplantation?

DHS: While having English as a native language has many advantages, I think most Americans miss a lot in life by not having to learn other languages too, like our foreign colleagues. I think one gets to know people and their culture better when one can speak their language and it certainly makes travel more fun. I am fluent in French and Swedish, do pretty well in German and I am now learning Spanish. When I read for enjoyment, I frequently choose books written in these languages, which may be why I have retained my fluency, despite having relatively few occasions to speak anything but English in my everyday life. I have a lot of other hobbies too, including gardening, woodworking, and fishing, and I enjoy biking, swimming, and sailing. I used to do a lot of skiing in the winter and windsurfing in the summer, but with caution appropriate to my age, those sports are now behind me and I have resumed my interest in golf. Last but certainly not least, my wife and I are blessed with 4 children and 11 grandchildren, all of whom live nearby and who get first priority when any free time becomes available.

REFERENCES

1. Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twins. Science. 1945;102:400–401.
2. Sachs DH, Cone JL. A mouse B-cell alloantigen determined by gene(s) linked to the major histocompatibility complex. J Exp Med. 1973;138:1289–1304.
3. Kindred B. Functional activity of T cells which differentiate from nude mouse precursors in a congenic or allogeneic thymus graft. Immunol Rev. 1978;42:60–75.
4. The U.S. Public Health Service. PHS Guideline on Infectious Disease Issues in Xenotransplantation. 2001. Available at https://www.fda.gov/media/73803/download
5. Ariyoshi Y, Takeuchi K, Pomposelli T, et al. Antibody reactivity with new antigens revealed in multi-transgenic triple knockout pigs may cause early loss of pig kidneys in baboons. Xenotransplantation. 2021;;28:e12642.
6. Spitzer TR, Delmonico F, Tolkoff-Rubin N, et al. Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism. Transplantation. 1999;68:480–484.
7. Kawai T, Cosimi AB, Spitzer TR, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2008;358:353–361.
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