George D. Snell

American immunologist

• Born: December 19, 1903; Bradford, Massachusetts
• Died: June 6, 1996; Bar Harbor, Maine

George Snell discovered the presence of histocompatibility antigens on the surface of cells, and provided a molecular explanation for rejection of tissue transplants. His work contributed to understanding the role played by these proteins in immune cell interactions.

Primary field: Biology

Specialties: Genetics, biochemistry, cellular biology

Early Life

George David Snell was born December 19, 1903, in Bradford, Massachusetts. He was the youngest of three children of Cullen and Kathlee Snell. In addition to his full-time job at a local YMCA, Snell’s father was also an amateur inventor. When Snell was four years old, his family moved to Brookline, where he completed his public school education. As a young student, Snell showed an early interest in mathematics and the sciences.

In 1922, Snell enrolled at Dartmouth College in New Hampshire. He became interested in genetics after enrolling in a course taught by Professor John Gerould, whose worked focused on the study of genetics and physiology of butterflies. After graduation from Dartmouth in 1926, Snell began graduate studies at Harvard University. At Harvard, he studied with biologist William Ernest Castle, who was among the first to study Mendelian inheritance in mammals. Snell spent summers working at Woods Hole, Massachusetts, where he studied the genetics of Habrobracon, the parasitic wasp.

Snell earned his PhD in 1930. His thesis work addressed gene linkage in mice. Because inbred strains of mice had yet to be developed, Snell relied on mutations for his linkage studies, which included characteristics such as hairless, short-eared, and dwarf individuals in animals brought by amateur breeders. Ultimately, he was able to describe over twenty-five such characteristics.

Life’s Work

Following his graduation, Snell spent a year as an instructor at Brown University before accepting a postdoctoral position at the University of Texas, where he worked with botanist Hermann Muller. Muller had discovered the ability of irradiation to induce mutations in fruit flies. He later earned a Nobel Prize for this work. Between 1933 and 1946, Snell built upon Muller’s work, demonstrating that irradiation could induce analogous mutations in mice.

In 1933, Snell moved to the University of Washington in Seattle. In 1935, he moved to the Jackson Laboratory in Bar Harbor, Maine, to resume his work studying mutations in mice. Geneticist Clarence Cook Little, a former student of Castle’s, had founded the Jackson Laboratory in 1929, and he appointed Snell the facility’s mammalian geneticist.

Snell was well acquainted with the challenge inherent in the study of mouse genetics. In 1935, only some twenty-five breeds of mutant mice were available, reflecting the low rate of natural mutations. Snell spent five years in Maine studying radiation-induced mutations in mice. During that time, he met and married Rhoda Carson at Bar Harbor, and the couple had three sons. In 1943, Snell edited the first book that summarized the work accomplished at Jackson Laboratory: The Biology of the Laboratory Mouse, which became a classic work in the field of genetics.

By the early 1940s, the focus of Snell’s work shifted to transplantation rejection. He began his work by studying the inability of mice to accept transplants of tumors from other mice. Little had previously demonstrated that tissue compatibility genes, which regulated incompatibility, acted in a dominant/recessive Mendelian manner. Snell’s first goal was to determine whether these genes could be better observed using visible markers. By 1945, he had a number of such markers; once Snell determined the visible marker was linked to a specific histocompatibility gene, he had a simpler means to observe mutations in those genes. By backcrossing his mice—crossing with a parent numerous times—Snell was also able to breed strains of mice differing at only a single gene locus within the region that regulated transplant rejection.

Pathologist Peter Gorer, who had been studying the immune response to tumors transplanted among mice, joined Snell in this work. Gorer had described a protein on the surface of these cells, termed “antigen II,” which was key to understanding the ability of incompatible mice to produce antibodies and reject such tissue (an antigen is any substance that triggers the production of antibodies). Snell demonstrated antigen II was a tissue antigen, which he named the histocompatibility antigen (H-2). Despite a fire in 1947 that devastated the inbred mouse colony, Snell was able to produce a number of congenic mouse strains used in identifying various loci within the histocompatibility region.

In 1952, Snell was appointed staff scientific director at the Jackson Laboratory. He continued to study the relationship between the major histocompatibility complex (MHC), as the region in the mouse chromosome encoding the histocompatibility genes came to be called, and rejection of cancer cells. Snell retired from the Jackson Laboratory in 1968, though he continued his writing on mouse genetics as well as his evolving views on the subject of ethics. He presented his ideas on ethics in the 1988 book Search for a Rational Ethic. Snell received the 1980 Nobel Prize in Physiology or Medicine in recognition of his work on histocompatibility. He died June 6, 1996.

Impact

Snell’s investigation of histocompatibility genes in the mouse was directly applicable to similar studies carried out in humans. Since the recognition of an ever-growing number of gene products within the MHC could be identified on the surface of white blood cells, the human counterparts became known as human leukocyte antigens (HLA). Snell recognized the primary function of the genes within the MHC was not in transplant rejection, but rather in regulation of the immune response itself. By the 1980s, an “alphabet soup” of gene loci were identified in the mouse H-2 region, as well as in the equivalent human HLA region. The immune genes were grouped largely into two primary classes designated class I and class II. The class I antigens define the concept of “self” for the immune system, functioning in the immune recognition of cells infected with internal parasites, such as viruses, that were also the basis for transplant rejection. Scientists have identified a large number of variations within each member of the class. Class II antigens are involved in regulating the immune response, including the cell-cell interactions, which take place in the initiation of that response.

During his later years, Snell followed the growing recognition of the enormous complexity inherent in the immune complex genes. What he had proved to be true in mice was shown to be equivalent in humans and has since been demonstrated in nearly all vertebrates.

Bibliography

Abbas, Abdul, and Andrew Lichtman. Basic Immunology: Functions and Disorders of the Immune System, 3rd ed. Philadelphia: Saunders, 2011. Print. Presents a general overview of immunology. Includes explanations and diagrams discussing the relationship of the histocompatibility complex and immune function.

Eisen, Eugene, ed. The Mouse in Animal Genetics and Breeding Research. Hackensack: Imperial College, 2005. Print. Discusses the role of the mouse in the history and application of mammalian genetics. Snell’s work in the field is reviewed.

Wilkes, David S. Immunobiology of Organ Transplantation. New York: Springer, 2004. Print. Presents detailed discussion of transplantation immunology at the cellular and molecular levels.