Issue #30: Of mice, men and women in the deep history of H-2 genetics

Setting it Straight - Issue #30

Written by Nobel Laureate Professor Peter Doherty

Last week, I introduced the subject of graft rejection and the major histocompatibility complex (MHC), called H-2 in the mouse and HLA in humans. The dissection of what the MHC is about in the biological sense reflects the interplay between observational studies of humans and experiments in mice. Both were important but, when it came to illuminating how the HLA and the H-2 genes are involved in viral immunity, the science that led to that breakthrough was based in classical mouse genetics. Telling this tale from more than 45 years back, I need to take those of you who have some biological understanding back to a time that predates recombinant DNA technology, gene sequencing, the polymerase chain reaction, gene-knockouts and gene-insertions, and monoclonal antibodies. These were the days before the molecular science revolution that has so transformed biological research and aspects of health care.

This was the situation when Rolf Zinkernagel and I started, in 1973, the mouse experiments that led to the elucidation of the biological role of the MHC that began the modern analysis of T cell-mediated immunity in infectious diseases and cancer. I’ll tell you about that next but, for now, we’ll concentrate on what went before in ‘mouse world’. There are heroines and heroes in this tale. The first is the ‘mother of mouse genetics’, Miss Abbie Lathrop, who (conveniently side-lined by the academic culture) was ‘rediscovered’ by Czech geneticist Jan Klein. A big man in every sense, Klein, who was then at Washington University, St Louis (Wash U) published (1975) a seminal book, Biology of the Mouse Histocompatibility-2 Complex, that reviewed this field until the time that Rolf and I made our discovery.

Lathrop was an Illinois schoolteacher who relocated to Granby, Massachusetts where, with friends Edith Chapin and Asa Gray, she took wild mice and line bred them to produce various ‘fancy’, or ‘ornamental’ strains. This was a big operation with up to 1100 mice on hand at any one time. Ornamental mice? Sometimes, in antique shops, you may find what look like tiny birdcages. But these housed pet mice, which, like dogs in Crufts dog show, had been bred to ‘fix’ particular characteristics, especially coat colour. That took a more scientific direction in 1908 when, noticing that some of her black mice were developing tumours, she began working with pathologist Leo Loeb (University of Pennsylvania, then Wash U) in 1908, then Harvard geneticist, William Castle. Derived by brother/sister mating and backcrossing, her stocks are considered to be the ‘founders’ of five of the ‘classical’ inbred mouse lines we use today.

When Harvard geneticist CC Little founded (1929) the Jackson Laboratory (JAX) on the island of Bar Harbor, Maine, one of the inbred mouse strains he took with him was Lathrop’s black line. Most of us know these as C57BL6/J, with the ‘J’ indicating that they are from JAX. Named for philanthropic donor Roscoe B Jackson, an executive of the Hudson Motor Company (defunct in 1975), JAX is both a leading genetics research centre and a major commercial supplier of inbred mice for medical research. Little’s essential insight was to have animal handlers watch for abnormal babies, which were nurtured to adulthood and bred to produce mouse lines with genetically-defined diseases, such as diabetes, obesity, bone abnormalities, neurodegeneration and so forth. These have been invaluable investigative tools.

Graduated from Dartmouth College in 1922, New Englander George Snell, completed his PhD in mouse genetics with Castle at Harvard, taught at Brown for a while, then worked in Texas with HJ Muller, the pioneer of radiation biology, on the mutational effects of X-rays. Recruited to JAX in 1935, Snell spent the next 35 years defining the mouse H-2 system in studies that led to his 1980 Nobel Prize. At first, Snell expanded on CC Little’s interest in cancer by looking for evidence of immune control. Taking cells from tumours induced by exposing mice to the carcinogenic chemical methylcholanthrene, he injected these into different inbred strains and found that, while the tumours grew for a few days, they were rapidly rejected. Though we now understand that this undoubtedly happens with (especially) naturally emerging skin cancers as part of our normal ‘immune surveillance of self’, fast and complete elimination did not fit with anything known at the time about cancer immunity.

As a consequence, Snell reasoned that his experiments were not ‘interrogating’ tumour immunity, but the genetic differences between inbred mouse strains. Using classical breeding techniques, augmented by gene linkages for other traits that sped up the process, he and those who worked with him (or came later) went on to define the H-2 system. The tumour transplant model was both cumbersome and nasty, so they soon moved to using tail skin grafts (developed by Don Bailey) instead. By the time Rolf Zinkernagel and I came on the scene in the 1970’s, the H-2 geneticists had established a range of inbred mouse lines that isolated particular alleles (genes) at the main H-2K and H-2D loci. There were even mutant mice where the only difference was a point mutation (one amino acid change) in a single H-2 allele. All science builds on what went before, and we were extraordinarily fortunate in the living technology that we inherited.