David H Sachs, MD
David H. Sachs was born on January 10, 1942 in New York City. He graduated from Harvard College in 1963, Summa Cum Laude, with an A.B. in Chemistry. In 1964 he received a Diplome d'Etudes Superieures de Sciences in organic chemistry from the University of Paris, where he studied as a Fulbright fellow. In 1968 he received an M.D., Magna Cum Laude, from Harvard Medical School.
From 1968 to 1970, Dr. Sachs trained as a surgical intern and research fellow in transplantation at the Massachusetts General Hospital. He then moved to the National Institutes of Health in Bethesda, Maryland, where he developed a major program in transplantation research. He became Chief of the Transplantation Biology Section, Immunology Branch, National Cancer Institute in 1974, and Chief of the Immunology Branch, National Cancer Institute in 1982. During a sabbatical year in 1984-1985 Dr. Sachs was Visiting Professor, Department of Cell Research, Wallenberg Laboratory at the University of Uppsala, Sweden, where he initiated studies of the molecular biology of transplantation antigens in the miniature swine model. In 1991, he returned to the Massachusetts General Hospital as Director of the Transplantation Biology Research Center (TBRC) and the first Paul S. Russell/Warner-Lambert Professor of Surgery (Immunology), Harvard Medical School. He is currently Director of the TBRC Laboratories in the MGH Center for Transplantation Sciences and the Paul S. Russell/Warner-Lambert Emeritus Professor at Harvard Medical School. In July, 2015, he became Professor of Surgery at Columbia University Medical Center’s Center for Translational Immunology (CCTI).
Dr. Sachs has published over 700 articles in scientific journals. His research achievements include: 1) discovery of Ia (Class II) antigens in 1973; 2) development of monoclonal anti-bodies to MHC antigens; 3) development of a unique large animal model for transplantation using miniature swine; 4) use of mixed marrow reconstitution as a means of inducing specific transplantation tolerance; and 5) studies of specific transplantation tolerance to allografts and xenografts in murine, swine and primate models. Dr. Sachs is a member of the Editorial Board of several journals in his field, including: Clinical Transplantation, Transplantation and Xenotransplantation. He was one of the three North American Editors of Transplantation and was the founding Editor of Xenotransplantation.
Dr. Sachs was the recipient of the Public Health Service Commendation Medal in 1979 and the Meritorious Service Award in 1984. He was a Councilor of the Transplantation Society from 1988-1994 and Vice-President from 1996-1998. From 1992-1996, Dr. Sachs was a member of the Immunobiology Study Section at the National Institutes of Health, and has served on the Immunology Executive Committee at Harvard Medical School since 1991. Dr. Sachs was elected to the Institute of Medicine of the National Academy of Sciences in 1996. In 1998 Dr. Sachs received the Jean Borel Award in Transplantation and the ASTP/Novartis Established Investigator Award. In 2001 Dr. Sachs was presented the Award for Distinguished Contributions to Health Research by The Medical Foundation and the Mary Jane Kugel Award by the Juvenile Diabetes Research Foundation. In 2005, he received the Roche Ernest Hodge Memorial Award (formerly called the Roche AST Distinguished Achievement Award), the highest award bestowed by the AST. In 2006, Dr. Sachs was awarded an Honorary Degree (Docteur Honoris Causa) from University of Nantes, France. In 2009, Dr. Sachs received the Martin Prize for Excellence in Clinical Research. In 2010, he was Samuel Jason Mixter Lecturer of the New England Surgical Society. In 2011, he was Claude Amiel Lecturer at the World Congress of Nephrology and also received the Thomas E. Starzl Prize in Surgery and Immunology. In 2014, Dr. Sachs received The Federation of Dutch Medical Scientific Societies Lifetime Achievement Award and was honored with the Medawar Prize, awarded by the Transplantation Society.
Dr. Sachs married Kristina Olsson in 1969 and they have 4 children and 9 grandchildren. He enjoys sailing, fishing, skiing, photography, woodworking, squash and gardening. He is fluent in English, French, Swedish and German.
- Professor of Surgical Sciences (in Surgery) and Professor of Medical Sciences (in Medicine)
Credentials & Experience
Education & Training
- AB, 1963 Harvard College
- DES, 1964 University of Paris
- MD, 1968 Harvard Med Sch (Boston MA)
- Internship: 1969 Mass General Hospital, Boston, MA
- Residency: 1970 Mass General Hospital, Boston, MA
- Fellowship: 1970 Mass General Hospital, Boston, MA
Honors & Awards
- 1962 Phi Beta Kappa, Harvard College
- 1963 Paul Revere Frothingham Award, Harvard College
- 1964 Fulbright Fellowship
- 1964-1968 John Harvard Scholarship, Harvard Medical School
- 1967 Alpha Omega Alpha, Harvard Medical School
- 1968 Dean's Prize, Harvard Medical School
- 1979 Public Health Service Commendation Medal
- 1984 Public Health Service Meritorious Service Award
- 1984-1985 Office of International Health Foreign Work/Study Fellowship, Uppsala, Sweden
- 1985 Commissioned Officer, PHS, Foreign Duty Award
- 1995 Swedish Society of Medicine Medal (Huddinge Hospital)
- 1996 Elected to Institute of Medicine of the National Academy of Sciences
- 1998 Jean Borel Award in Transplantation
- 1998 ASTP/Novartis Established Investigator Award
- 1998 The Nelson Lectureship and Clemens Von Pirquet Award, UC Davis School of Medicine
- 2001 The 2001 Medical Foundation Award, for Distinguished Contributions to Health Research
- 2001 The Mary Jane Kugel Award, Juvenile Diabetes Research Foundation
- 2005 Roche Ernest Hodge Memorial Award (AST Distinguished Achievement Award)
- 2006 Honorary Degree (Docteur Honoris Causa) from University of Nantes, France
- 2006-2011 Merit Award, National Institute of Allergy and Infectious Disease
- 2008 The 3rd Annual Oscar Salvatierra, Jr., M.D. Lectureship in Transplantation, Stanford University School of Medicine
- 2009 Martin Prize for Excellence in Clinical Research
- 2009 The Annual Kredel-Springs Visiting Professorship, Department of Surgery, Medical University of South Carolina
- 2009 Pioneer Lecturer in Transplantation at The Transplantation Society New Key Opinion Leader Meeting, Jackson Hole, WY
- 2009 Invited Speaker, The Transplantation Society New Key Opinion Leader (nKOL) Meeting, Gothenburg, Sweden
- 2010 Invited Speaker: 26th Annual Samuel Jason Mixter Lecture, 91st Meeting of the New England Surgical Society, “Transplantation Tolerance: Bench to Bedside”, Saratoga Springs, NY
- 2011 Invited Speaker: Methodist Hospital Research Institute (TMHRI) Inaugural Scientific Symposium, “Transplantation Tolerance: Bench to Bedside”, Houston, TX
- 2011 Claude Amiel Lecturer, World Congress of Nephrology, “The Future of Renal Transplantation: Tolerance & Xenografts?”, Vancouver, B.C.
- 2011 2012 Thomas E. Starzl Prize in Surgery and Immunology
- 2011 Pillars Article: A Mouse B-Cell Alloantigen Determined by Gene(s) Linked to The Major Histocompatibility Complex. The Journal of Experimental Medicine. 1973. 138: 1289-1304. Sachs DH, Cone JL. J Immunol. 2011 1; 187 (5):2045-60.
- 2011 Susan G. Lee Memorial Lecture “Transplantation Tolerance- Bench to Bedside”, Georgetown University
- 2013 International Xenotransplantation Association Honorary Membership Award
- 2014 Medawar Prize (awarded by The Transplantation Society)
- 2014 The Federation of Dutch Medical Scientific Societies Lifetime Achievement Award
Over the course of my research career, I have worked predominantly at the interface between basic science and clinical applications in the field of transplantation, with the goals of understanding the immune mechanisms involved and developing new therapies to improve the quality of life of transplant patients.
Dr. Sachs’ major areas of research are the following:
A. Induction of transplantation tolerance:
A major thrust of transplantation research in this laboratory has been directed toward induction of tolerance as a means of permitting transplantation of organs to be achieved without a requirement for immunosuppressive drugs. Two major models for tolerance induction are studied:
1) Regulatory tolerance: Using miniature swine with defined MHC haplotypes (see below), Dr. Sachs and colleagues demonstrated that a short course of immunosuppression with a high-dose of calcineurin inhibitors is capable of inducing long-term tolerance in juvenile animals. This phenomenon has become and remains an important basic model for the study of tolerance induction across MHC barriers in a large animal model. Among active studies being carried out in this model are: a) the role of the thymus in permitting regulatory tolerance to develop; b) the dependence of tolerance on T regulatory cells; c) the adoptive transfer of tolerance; and d) the mechanism of tolerance induction and maintenance at cellular and molecular levels.
2) Deletional tolerance: It has been known for many years that when a bone marrow transplant is successful, it carries with it tolerance to any other tissue or organ from the bone marrow donor. Dr. Sachs’ research demonstrated that this kind of tolerance does not require a complete bone marrow transplant, but rather only requires that a small number of bone marrow-derived cells persist in the recipient at the time of the organ transplant. This state, involving a mixture of bone marrow from recipient and donor, has been called “mixed chimerism” and is the method which investigators in this laboratory have developed to induce tolerance to transplanted organs without the requirement for a full bone marrow transplant or for lifelong immunosuppressive drugs. Since their original description of this phenomenon in mice, Dr. Sachs and colleagues have pioneered a series of studies, extending the work first to large animals and most recently to clinical applications. Because of these studies, there are now patients who have normal, functioning kidneys without the need to remain on chronic immunosuppressive drugs.
B. Development of miniature swine as a large animal transplantation model:
More than 40 years ago, Dr. Sachs and colleagues recognized the need for a large animal model for studies of transplantation, and chose miniature swine because of their appropriate size, physiologic and immunologic similarity to man, and their breeding characteristics. When full grown, these animals reach sizes approximately the same as human beings, with maximal weights of approximately 200-300 pounds -- in contrast to domestic swine, which can attain weights over 1,000 pounds, and would therefore be a difficult laboratory animal model. Like domestic swine, miniature swine have outstanding reproductive parameters, making it possible to establish lines of miniature swine homozygous for different alleles at the MHC of pigs, known as SLA. These MHC defined animals have become an invaluable resource for preclinical research in the field of organ transplantation, providing numerous insights for understanding tolerance and histocompatibility (see above). In addition, the capacity for genetic engineering of miniature swine has enabled production of both transgenic and knockout animals, making one subline of these inbred miniature swine likely to be the ideal organ xenograft donor (see below).
C. Xenogeneic transplantation
Even if the induction of tolerance is able to eliminate treatment-related complications and chronic rejection as limitations to allogeneic transplantation, it will not solve the third problem in this field, the shortage of available donor organs. It is for this reason that xenotransplantation, the transplantation of organs from animals to humans, has also been the subject of major investigations in Dr. Sachs’ laboratory. For a variety of reasons, most investigators in this field have settled on the pig as the most appropriate potential donor for xenotransplantation of organs to human recipients. Pigs are readily available, have very favorable reproductive characteristics, can be bred in controlled, clean environments to avoid pathogens and are less likely to raise ethical concerns about their use for this purpose than non-human primates, since they are accepted as a food source in most modern societies. Dr. Sachs and colleagues have developed a special strain of miniature pigs through selective breeding over more than 30 years. Unlike domestic swine, which attain adult weights of greater than 1000 pounds, the maximum size of these “miniature swine” is 200 to 300 pounds. They can therefore be used as organ donors at sizes appropriate for any potential human recipient, from a baby to a large adult. In addition, through selective breeding, it has been possible to control the genetics of these animals and achieve a very high coefficient of inbreeding, so that all animals of one strain are essentially identical. This property could be very important for the induction of tolerance, since one could use the cells from one animal to induce tolerance for an organ from another animal of the same strain.
Over the past twenty years, extensive research in this laboratory has been performed using pig to non-human primate transplants as a model for potential clinical xenotransplants. The major stumbling block to these studies originally was the presence of a large amount of natural (i.e. present without intentional induction) antibody in non-human primates and humans directed toward the cells of pigs. The reason for the presence of these antibodies is that during evolution, at the level of Old World primates, a gene was lost for an enzyme that puts the Gal sugar epitope onto cell surface glycoproteins in all species except for Old World primates and humans. Since the Gal antigen is found on bacteria and other environmental antigens, humans and Old World primates make a large amount of antibody against Gal. It is these anti-Gal antibodies that then reacted with pig tissues after xenotransplantation, causing vigorous rejection.
Dr. Sachs’ group was among the first to eliminate this enzyme from their special inbred strains of miniature swine through an intentional “knock-out” mutation. These new pigs, like humans and Old World primates, do not put Gal on to the surface of their cells. As a result, xenotransplants can now be performed without the powerful rejection previously caused by natural anti-Gal antibodies. The results have been remarkable, with increased survivals of both heart and kidney transplants from pigs-to-baboons. Using immunosuppressive drugs, organ survivals were prolonged using these new Gal knock-out (GalT-KO) pigs, but new antibodies soon appeared, causing rejection. However, using a regimen directed toward induction of tolerance, organ survivals were prolonged markedly, and no rejection was seen. Studies of tolerance induction in the pig-to-primate models are a major area of ongoing research in Dr. Sachs’ laboratory.
- Immune tolerance
- Transplantation tolerance
5 SEMINAL PUBLICATIONS
1. Sachs DH and Cone JL, A mouse B-cell alloantigen determined by gene(s) linked to the major histocompatibility complex. J.Exp.Med. 138:1289-1304, 1973.
2. Ildstad ST and Sachs DH, Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 307(5947): 168-170, 1984.
3. Sharabi Y and Sachs DH, Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen. J.Exp.Med. 169: 493-502, 1989.
4. Marked prolongation of porcine renal xenograft survival in baboons through the use of alpha1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Yamada K, Yazawa K, Shimizu A, Iwanaga T, Hisashi Y, Nuhn M, O'Malley P, Nobori S, Vagefi PA, Patience C, Fishman J, Cooper DK, Hawley RJ, Greenstein J, Schuurman HJ, Awwad M, Sykes M, Sachs DH. Nat Med. 2005 Jan;11(1):32-4. Epub 2004 Dec 26.
5. Kawai T, Cosimi AB, Spitzer TR, Sykes M, and Sachs DH, HLA-mismatched renal transplantation without maintenance immunosuppression. N.Engl.J.Med. 358: 353-361, 2008.