Researcher | Research Overview
The Alper lab studies the genetics of complex (polygenic) disease in humans, with a focus on autoimmunity, particularly within the genes of the major histocompatibility complex (MHC) of chromosome 6. Many human diseases of unknown origin, but mostly involving immune reactions against the patients’ own tissues, show associations with the MHC. Autoimmune diseases affect over 5% of the U.S. population, represent a major medical and public health challenge and many are rising in incidence at an alarming rate.
Specifically, Alper and colleagues investigate the relationship between genetic differences in the human MHC with differences in the immune function of a variety of "white blood cells," or leukocytes. Gene products of the human MHC are also sometimes called human leukocyte antigens (HLA), and are major proteins expressed on and within leukocytes. Many of these proteins are used by the body to differentiate "self" from foreign cells, and HLA proteins play a critical role in organ and tissue recognition and rejection after transplantation as well as in detecting foreign pathogens.
Over 100 expressed genes are located within the human MHC. As would be expected for a region that contains genes encoding proteins that help define "self," this region is among the most diverse of the human genome. The Alper lab often studies the blood of donors bearing conserved extended MHC haplotypes (CEHs) to explore control by these genes. Alper and colleagues established the concept of CEHs as a means of understanding the high degree of structural genetic fixity within relatively large stretches (e.g., the MHC) of the human genome. Although the lab has studied the MHC genetics of a number of immune functions and diseases, they are currently focused on four specific areas. These are the genetic mechanisms of autoimmunity—with a particular focus on type 1 diabetes (T1D), immunoglobulin deficiency (particularly IgA deficiency), the role of population admixture in the rising incidence of polygenic disease, and complement.
Researcher | Research Background
Dr. Chester Alper received his MD from Harvard Medical School in 1956. In addition to practicing medicine in the late 1950s, both in the US Navy and while completing his Harvard Medical Services internship and residency at the Boston City Hospital, Dr. Alper trained in basic protein techniques in Albert Coons’ Laboratory at Harvard. In the early 1960s, he studied human serum proteins with a USPHS postdoctoral fellowship in Sweden under the guidance of Jan Waldenström and Carl-Bertil Laurell at the Malmö allmänna sjukhus. In the 1960s, as a Research Associate in Medicine, Dr. Alper conducted medical research both at the Peter Bent Brigham Hospital and the Children's Hospital--collaborating in some cases with the then Children's Hospital Physician-in-Chief, Dr. Charles A. Janeway, and Dr. Fred Rosen. In 1965, Dr. Alper joined the Children's Hospital Blood Grouping Lab (BGL), then under Dr. Louis K. Diamond, where Dr. Alper added serum protein analysis to clinical testing. This helped support other research activities and provided patient material for research. As a result, Dr. Alper detected the first described genetic polymorphism in a complement protein, C3, that led to his pioneering the field of complement genetics. In 1969, he was appointed an Associate Professor of Pediatrics and, in 1970, as an Associate in Hematology at the Children’s Hospital/Harvard Medical School. Dr. Alper was promoted in 1975 to Professor of Pediatrics, Harvard Medical School.
In 1971, Dr. Alper became the Scientific Director of the BGL. In 1972, in a re-organization by Dr. Janeway, the BGL merged with the Blood Research Institute (formerly, the Protein Foundation) to become the new Center for Blood Research (CBR)--to which Dr. Alper was named Scientific Director (until 1993). While at BGL and in the early years at CBR, Dr. Alper devised immunofixation, a precursor of Western blotting, for clinical detection of serum proteins, and he, in collaboration with Dr. Robert Ritchie, automated immunonephelometry to replace manual gel methods for serum protein measurement in clinical laboratories worldwide.
From the 1970s into the 21st century, as CBR transformed, eventually, into what is now PCMM at Boston Children's Hospital, Dr. Alper's research focus switched from hematology to immunology focused on protein products to immunogenetics. Propelled by the fact that some complement proteins are encoded by genes (C2, C4A, C4B and CFB) in the human major histocompatibility complex (MHC), Dr. Alper began an intense study of this genomic region in relation to autoimmune disease and other immune phenomena. In the 1980s, Dr. Alper found that these complement genes formed a haplotypic unit (the complotype) and this in turn led to his group's recognition of long fixed segments of MHC DNA, conserved extended haplotypes (CEHs). He published the first family study of the MHC in type 1 diabetes (T1D; to provide intrafamily control haplotypes as ethnically matched to the patients’ as possible). That study showed that all of the MHC susceptibility and protective markers for T1D were parts of a few CEHs. In 1989-90, he obtained a Guggenheim Fellowship to study molecular biology on sabbatical leave in a laboratory at the Rockefeller University. Dr. Alper also won a 10-year NIH MERIT Award from NIAID in 1990, and, in 1998, he was named the Honorary Congress President of the VIIth Complement Genetics Workshop and Conference in Mainz, Germany.
Currently, Dr. Alper's laboratory focuses on two areas. The first is devising new techniques to analyze the structure of common population-level CEHs using pedigree-phased haplotypes, with a focus on the MHC. The other is analyzing MHC polymorphisms to identify the genetic and epigenetic mechanisms underlying susceptibility to and the causal trigger(s) of T1D. Recently, the latter has focused on a large international consortium biorepository and database to which we contributed, the Type 1 Diabetes Genetics Consortium.