movies | publications
Robert Sackstein, M.D., Ph.D.
Professor, Harvard Medical School; Director of the Program of Excellence in Glycosciences

EDUCATION:
Harvard College
A.B., Summa Cum Laude, 1973-1977
Harvard Medical School
M.D., Ph.D., 1977-1985

POST-DOCTORAL TRAINING:
University of Miami/Jackson Memorial Hospital
Internship, Internal Medicine, 1985-1986
University of Miami/Jackson Memorial Hospital
Residency, Internal Medicine, 1986-1988
University of Miami
Postdoctoral Fellowship, Immunology, 1987-1989
University of Miami/Jackson Memorial Hospital
Hematology Training, 1989-1991

For more information on Biosynthesis & Function of Lactosaminyl Glycans in Hematopoiesis please visit
http://harvardpeg.bwh.harvard.edu/

Dr. Sackstein’s efforts as a basic scientist and clinician are intimately intermeshed. He is a basic science immunologist/biochemist/molecular biologist with clinical expertise in internal medicine/hematology/immunology and, in particular, in hematopoietic stem cell transplantation (HSCT).  Accordingly, his bench research efforts aim to elucidate biologic processes critical to improving outcomes for patients undergoing HSCT, such as: (1) hematopoiesis (and other cell/tissue regeneration from stem cell-based therapies), (2) tissue-specific lymphocyte migration (including the immunobiology of lymphocyte migration in host defense and in pathologic reactions such as graft-versus-host disease), and (3) pathobiology of tumor cell proliferation and tumor metastasis.  The common thread for all these efforts is to manipulate the biology of cellular trafficking, as it pertains to stem cell transplantation and tissue regeneration, to host defense/inflammation, and to cancer growth and metastasis.

At the outset of Dr. Sackstein’s career as an HSCT physician (1980s), there were two principal obstacles to successful application of this life-saving technology: (1) Graft failure, and (2) Graft-versus-host disease (GVHD).  In that era, the problem of graft failure was profound, as >20% of recipients died from lack of blood cell formation within certain transplant groups (e.g., aplastic anemia, T-cell depletion, unrelated donors, etc.).  Though many factors contributed to graft failure, a fundamental piece of information related to solving this mystery was missing: there was essentially nothing known about the molecular basis of hematopoietic stem cell migration to the marrow.  Just as the development of GVHD was clearly related to the capability of infused donor lymphocytes to preferentially migrate to certain target tissues (i.e., the skin, the gut and the liver), there was also no knowledge of the molecular effectors of such trafficking.    Dr. Sackstein sought to define the specialized adhesion molecules on the surface of blood-borne cells called  “homing receptors” that bind to endothelial cells at target tissues, thus directing cellular migration patterns.

In early work, the Sackstein lab found that the molecule known to direct lymphocyte migration to lymph nodes, the “lymph node homing receptor” (now known as “L-selectin”), was expressed not only on lymphocytes but also on early hematopoietic progenitor cells, and this observation led Dr. Sackstein to examine the expression of selectin ligands among human bone marrow cells.  These studies led to the identification of a novel selectin ligand present on early hematopoietic progenitor cells.  Subsequent biochemical studies by the Sackstein group revealed that this selectin ligand, now known as Hematopoietic Cell E-/L-selectin Ligand (HCELL), is the most potent naturally-expressed E- and L-selectin ligand in the body.  The HCELL molecule is a unique glycoform of CD44, and it is natively expressed on human hematopoietic stem cells.  By mediating binding to marrow sinusoidal endothelium that constitutively expresses E-selectin, HCELL functions as the “bone marrow homing receptor”, directing stem cell migration into bone.  Current studies are aimed at elucidating HCELL’s role in hematopoiesis and in the regulation of stem cell homing to bone marrow and to sites of tissue injury.  In addition, HCELL is characteristically expressed on blasts of human acute leukemia and also among certain human cancer cells, and the lab is thus also investigating how HCELL expression is related to leukemogenesis/carcinogenesis and to cancer metastasis.  In further studies of cellular “homing”, the Sackstein team is investigating the physiology of lymphocyte migration following stem cell transplantation, in particular, how pathologic tissue-specific migration patterns develop post-transplant, such as in acute GVHD. Current studies are examining the structural biology and expression of adhesion molecules that regulate skin-specific migration of lymphocytes in cutaneous GVHD reactions, in order to elucidate the molecular basis of this process and develop therapeutic agents to treat or prevent this condition.  The overall aim in these studies is to devise novel therapies to eliminate the detrimental GVHD reaction of allogeneic transplantation without disturbing beneficial immune reactions such as the graft-versus-malignancy effect.  Toward this goal, Dr. Sackstein is also developing technologies to enforce HCELL expression to improve the delivery of regulatory lymphocytes to blunt GVHD and also to promote migration of systemically-administered adult stem cells to affected site(s) for tissue regeneration.  In other studies, the Sackstein lab is investigating the structural biology of key molecules that mediate adhesive interactions that create microenvironmental “niches” for tumor cell proliferation, the adhesion molecules that allow for tumor cell dissemination, and the adhesion molecules that regulate lymphocyte trafficking to sites of tumor.  The goal in these studies is to utilize structural information for the rational design of drugs that disrupt key adhesion molecules in tumor cell growth and metastasis, and of agents/technologies that may improve immune effector cell infiltration of tumor tissue.