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BOOKS: ‘The Compatibility Gene,’ by Daniel M. Davis

Young, Robert C. MD

doi: 10.1097/01.COT.0000476204.28026.c0
Books
REVIEWED BY ROBERT C

REVIEWED BY ROBERT C

With such a vast array of elegant science discussed in The Compatibility Gene, it's nice to see that the story starts with a serious clinical problem. In 1940 near London, Peter Medawar and his family watched as a British plane crashed and burned near his home. The pilot survived but was severely burned. This tragedy apparently crystallized Medawar's interest in burns and skin transplantation. A zoologist by training, Medawar went to work in a burn hospital, studying why some patients rejected skin grafts and others didn't.

He studied graft rejection in patients, as well as supplementing the clinical work with laboratory experiments. These were the war years and he did a monumental series of surgical experiments while doing all of the care and feeding of the animals himself. Out of this work came our initial understanding of immune rejection and acquired tolerance, which culminated in his sharing the Nobel Prize in 1960 with Macfarlane Burnet.

Dr. Daniel Davis, the book's author, is a professor of immunology at the University of Manchester and the winner of the Oxford University Press/Times Higher Education Supplement Science Writing Prize in 2000. He takes us through the complex intricacies of the immune system with a remarkably readable and understandable style. He does not confine himself to just the scientific story but also provides us with tantalizing tidbits about some of the more colorful characters in this saga.

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And what a strange group of brilliant scientists they were: Just amongst the Nobel Laureates, we meet a sadomasochist (Niels Jerne), an introverted humorless dry old stick who wrote letters to his dead wife (Burnet), a loner who lived with his mother and kept a cast of her face on his bedroom wall (Karl Landsteiner), and a workaholic who said that his wife had a “claim on his love but not on his time” (Medawar).

After the transformational work of Burnet and Medawar, scientists had a reasonable idea of the basics of rejection and tolerance, but it was not known how the immune system learned to recognize self and non-self. Burnet's next discovery proved more important than the work for which he received the Nobel Prize. He recognized that it was cells not antibodies that were responsible, and then built on the work of others to evolve the clonal selection theory.

But Burnet didn't know how each cell could make a different antibody. This problem was ultimately solved by Susumu Tonegawa (who won the Nobel Prize for Physiology or Medicine in 1987).

Davis points out that these brilliant minds also made their share of mistakes. For example, when the central role of the thymus in the production of non-self T-cells and elimination of self-directed lymphocytes was described, Medawar called it “an evolutionary accident of no very great significance.”

Not all of these remarkable scientists even recognized the significance of their work. Landsteiner, for example, said, “I hope this work will be of some use,” and even after receiving the Nobel Prize, said, “the discovery of the blood groups would not interest a layperson.”

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Organized Naming System

The 1960s brought out an organized naming system for the compatibility genes. Three Class I HLA genes—HLA-A, -B, and -C were described, as well as three Class II genes—HLA-DR, -DP, and –DQ. Work into the 1970s showed that the success of kidney transplantation was dependent upon successful HLA matching.

Nevertheless, scientists recognized a paradox. The complexity of the immune system couldn't exist only to make transplantation difficult. What in fact was the normal purpose of these HLA compatibility genes?

Subsequent work done by Zinkernagel and Doherty in Australia revealed the real biological importance of the HLA proteins, for which they were awarded the Nobel Prize in Physiology or Medicine in 1996). Their work on the lymphocytic choriomeningitis virus (LCMV) showed that genes for transplant compatibility also control immune responses against the virus. They demonstrated that the immune system acts through recognition of “altered self.”

It remained for others to define by x-ray crystallography the three-dimensional structure of the HLA protein, which established how the 10 percent of the molecule at the top functioned by clasping and presenting peptides for T cells to recognize as self or non-self.

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The Edges of What is Known about the Compatibility Gene System

In the second half of the book, Davis begins to explore the edges of what is known about the compatibility gene system. He examines the relationship of HLA type to certain diseases such as ankylosing spondylitis, type 1 diabetes, multiple sclerosis, and others. He illustrates how the strength of antigen presentation often accounts for the variability in susceptibility to disease. Interestingly, people predisposed to ankylosing spondylitis have resistance to infection by HIV because their particular HLA-B*57 is good at binding and presenting a particular conserved part of the virus.

Davis also delves into the possible uses of the HLA system to search for new drugs, noting that HLA types correlate with the toxicity of some drugs.

One of the most provocative but unresolved segments of the HLA story is the relationship of HLA types to smell. Claus Wedekind, a Swiss zoologist working in Bern, did a series of experiments asking women to rank different men's T-shirts according to how sexy or pleasant they smelled. Women consistently ranked those with different HLA types than their own as “smelling best.” Women on the pill had no such pattern of recognition.

Wedekind and others have suggested that this may be a possible mechanism that humans use to select an optimal mate, avoid interbreeding, and produce hybrid vigor. The initial publication was rejected by Nature (as “not rigorous”) and Science (as “not worthy of full review”). Substantial laboratory study has established that mice can detect each other's compatibility genes by smell, but there is no consensus as to how they do it.

It is not a surprise that this avenue of research has evoked tremendous controversy and has been like catnip for the press. The issue remains unresolved.

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Interspersed with Humor

One of the delightful qualities of The Compatibility Gene is that its author has the skill to intersperse the details of the science with its humorous aspects. For example, in the epilogue of the book, Davis decides that he and his wife should have HLA typing to determine what diseases they might be susceptible to and, as an alternative to the smelly T-shirts, see how compatible they are. He concludes: “I am very rare, but my wife is rather common.” His HLA type is only four in 18 million, whereas his wife's is one in 100,000. That said, though, it also means that she is much more likely to find a compatible transplant donor and he might be out of luck.

The book is skillfully written and easy to read. Dr. Davis has used his immunology expertise to produce a fine informative book that does not shortchange the elegant and complicated science, but illustrates it with clarity and insight.

OXFORD UNIVERSITY PRESS, ISBN 0199316414, AVAILABLE IN HARDCOVER, PAPERBACK, KINDLE, AND AUDIO EDITIONS

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