The Compatibility Gene

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The Compatibility Gene
The Compatibility Gene cover.jpg
Author Daniel M. Davis
Subject Immunology
GenrePopularisation of science
PublisherAllen Lane/Penguin
Publication date
2013

The Compatibility Gene is a 2013 book about the discovery of the mechanism of compatibility in the human immune system by the English professor of immunology, Daniel M. Davis. It describes the history of immunology with the discovery of the principle of graft rejection by Peter Medawar in the 1950s, and the way the body distinguishes self from not-self via natural killer cells. The compatibility mechanism contributes also to the success of pregnancy by helping the placenta to form, and may play a role in mate selection.

Contents

Context

Author

Daniel M. Davis has a doctorate in physics from Strathclyde University. He was professor of molecular immunology at Imperial College London and director of research at the University of Manchester's collaborative centre for inflammation research. [1] [2] Davis is a recognised as an expert in the field by the Nature journal of immunology. [3] [4] Davis is a recognised expert for his research in the immune synapse, membrane nanotubes, and natural killer cells. [5]

Subject

The book's context is the history of immunology, from the earliest questioning about why people become ill and why some may recover, to the 19th century pioneers who demonstrated that bacteria caused many diseases. In the 20th century where, slowly at first but at an accelerating pace, biologists started to build an understanding of the genetic basis of variation and natural selection, and alongside that, the foundations of scientific medicine, including immunology. As Steven Pinker observes, few stories of scientific endeavour have never been told. "This is one of them. Ostensibly about a set of genes that we all have and need, this book is really about the men and women who discovered them and worked out what they do. It’s about brilliant insights and lucky guesses; the glory of being proved right and the paralysing fear of getting it wrong; the passion for cures and the lust for Nobels. It’s a search for the essence of scientific greatness by a scientist who is headed that way himself." [6]

Book

Contents

Diagram showing the complementary activities of cytotoxic T cells and natural killer cells Missing self.svg
Diagram showing the complementary activities of cytotoxic T cells and natural killer cells

The book is in three parts. In part 1, Davis describes the history of research into biological compatibility, starting with the story of Peter Medawar's life and discoveries in graft rejection. He tours the history of medicine from Hippocrates to the 19th century pioneers Louis Pasteur and Robert Koch, and Frank Macfarlane Burnet's concept of the immune system's ability to discriminate self from non-self. He explains how advances in understanding of immunity, from Karl Landsteiner's discovery of the ABO blood group system onwards, permit organ transplants to take place. The compatibility genes are named as three class I human leucocyte antigen (HLA) genes (A, B, and C) and three class II (DP, DQ, and DR), each with numerous versions (alleles). Lastly, Davis tells the human side of the story of the discovery of killer T-cells. Alan Townsend found that killer T-cells destroyed cells that carried an HLA protein and small fragments of viral protein. Those small peptides were all the evidence the T-cells needed to decide that a cell was diseased.

In part 2, Davis describes the nature of the genetic differences between people, like having the allele for Huntington's disease, can be small but decisive. An HLA protein variant, B*27, is associated with a serious inherited disease, ankylosing spondylitis, but also protects against AIDS. Other variants protected against other diseases. Perhaps the polymorphisms in HLA, the many forms each HLA gene can take, are maintained by natural selection for competing factors. He explains that variations in HLA genes may predict which drugs will be beneficial for individuals, implying a new era of personalised medicine. He tells the story of how Klas Kärre came up with the concept of the missing self, a sign (by the absence of an HLA protein) that a cell was diseased, and should be killed by a natural killer cell.

In part 3, Davis describes the famous experiment that called for female partners to sniff boxes containing their male partners' T-shirts, which they had worn for two days. There was a slight association between finding the smell sexy and the two partners having different compatibility genes. It could possibly indicate sexual selection for outbreeding, at least in the HLA system. He explains what is known of the role of compatibility genes in the brain. He tells the story of how the variable genes of the immune system affect the success of pregnancy. Far from the baby's HLA proteins somehow being tolerated by the mother (unlike anyone else's), the strong reaction against the baby's antigens helps to drive proper development of the placenta, in particular the growth of chorionic villi that ensure efficient transfer (for instance of oxygen) between mother and baby. Davis concludes the book by telling a story of genetic compatibility between his wife and himself. He finds himself wondering whether all women should have found him exceptionally attractive, at least when he was younger. He observes that on the contrary there is no hierarchy in HLA: some variants are good in one situation, and bad in another.

Publication

The book was first published in the UK by Allen Lane (hardback) in 2013. Paperback editions were brought out by Penguin Books in Britain, and by Oxford University Press in America, both in 2014. An Italian translation was published by Bollati Boringhieri in Turin in 2016. [7]

Reception

The Compatibility Gene has been well received by critics and scientists. [8] Mark Viney, reviewing the book in the New Scientist , comments that Davis covers human compatibility genes well, but that he should have gone into more detail on the different systems in other organisms. [9]

The science writer Peter Forbes, writing in The Guardian , notes that when Watson and Crick cracked the genetic code in 1953, it seemed that medicine would instantly profit: but half a century went by before the genome was decoded, and 98% of it seemed at first glance to be junk DNA. Now its complexity is starting to be understood, one function at a time. One specialised area is the immune system, with its own ultra-variable set of proteins. They are not only complicated, but have many functions, in immunity, sexual attraction (perhaps), pregnancy, and brain function. Unsurprisingly, Forbes observes, this makes immunology, and its popularisation, "extremely difficult". Davis "sugars the pill" by choosing to go into the researchers' lives and struggles in great detail. Forbes notes that Davis does not mention that most of the genetic differences between humans and chimpanzees are to do with the immune system and brain development: perhaps (he suggests) these are connected. [10]

Nicola Davis, reviewing the book in The Times , writes that Davis "weaves a warm biographical thread through his tale of scientific discovery, revealing the drive and passion of those in the vanguard of research." The tale of the pioneers such as Medawar is "fairly familiar but Davis's readable narrative allows them to be seen afresh". She finds the account more challenging as it approaches more recent discoveries, but with "plenty of rewarding moments". [11] Emily Banham, reviewing the book for Nature , notes that compatibility genes lie at the heart of our immune systems, playing a part in the success of skin grafts, pregnancy, and more. [12]

The biologist Rebecca Nesbit, reviewing The Compatibility Gene for The Biologist, writes that Davis shares many stories of dedicated scientists, brought together by "a small cluster of 'compatibility genes' which play a large role in how we react to disease, and are central to how our immune systems work." She notes that the book is as much about the people as the discoveries, but these are made worthwhile by the medical advances they keep producing, for example with possibilities for personalised medicine, as when people with one particular compatibility gene react adversely to an AIDS drug. She observes that all the same, he ends with the scientist's favourite refrain: "more research needed". [13]

Related Research Articles

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.

Histocompatibility, or tissue compatibility, is the property of having the same, or sufficiently similar, alleles of a set of genes called human leukocyte antigens (HLA), or major histocompatibility complex (MHC). Each individual expresses many unique HLA proteins on the surface of their cells, which signal to the immune system whether a cell is part of the self or an invading organism. T cells recognize foreign HLA molecules and trigger an immune response to destroy the foreign cells. Histocompatibility testing is most relevant for topics related to whole organ, tissue, or stem cell transplants, where the similarity or difference between the donor's HLA alleles and the recipient's triggers the immune system to reject the transplant. The wide variety of potential HLA alleles lead to unique combinations in individuals and make matching difficult.

<span class="mw-page-title-main">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

<span class="mw-page-title-main">Human leukocyte antigen</span> Genes on human chromosome 6

The human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 in humans that encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histocompatibility complex (MHC) found in many animals.

<span class="mw-page-title-main">Cytotoxic T-lymphocyte associated protein 4</span> Mammalian protein found in humans

Cytotoxic T-lymphocyte associated protein 4, (CTLA-4) also known as CD152, is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells. It is encoded by the gene CTLA4 in humans.

<span class="mw-page-title-main">X-linked severe combined immunodeficiency</span> Medical condition

X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.

<span class="mw-page-title-main">HLA-A</span> Protein-coding gene in the species Homo sapiens

HLA-A is a group of human leukocyte antigens (HLA) that are encoded by the HLA-A locus, which is located at human chromosome 6p21.3. HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of human MHC class I transmembrane proteins. The others are HLA-B and HLA-C. The protein is a heterodimer, and is composed of a heavy α chain and smaller β chain. The α chain is encoded by a variant HLA-A gene, and the β chain (β2-microglobulin) is an invariant β2 microglobulin molecule. The β2 microglobulin protein is encoded by the B2M gene, which is located at chromosome 15q21.1 in humans.

<span class="mw-page-title-main">KLRD1</span> Mammalian protein found in Homo sapiens

CD94, also known as killer cell lectin-like receptor subfamily D, member 1 (KLRD1) is a human gene.

Immunogenetics or immungenetics is the branch of Medical Immunology and Medical Genetics that explores the relationship between the immune system and genetics.

<span class="mw-page-title-main">HLA-G</span>

HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene.

<span class="mw-page-title-main">HLA-F</span> Protein-coding gene in the species Homo sapiens

HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene. It is an empty intracellular molecule that encodes a non-classical heavy chain anchored to the membrane and forming a heterodimer with a β-2 microglobulin light chain. It belongs to the HLA class I heavy chain paralogues that separate from most of the HLA heavy chains. HLA-F is localized in the endoplasmic reticulum and Golgi apparatus, and is also unique in the sense that it exhibits few polymorphisms in the human population relative to the other HLA genes; however, there have been found different isoforms from numerous transcript variants found for the HLA-F gene. Its pathways include IFN-gamma signaling and CDK-mediated phosphorylation and removal of the Saccharomycescerevisiae Cdc6 protein, which is crucial for functional DNA replication.

<span class="mw-page-title-main">KLRC2</span> Protein-coding gene in humans

NKG2-C type II integral membrane protein or NKG2C is a protein that in humans is encoded by the KLRC2 gene. It is also known as or cluster of differentiation 159c (CD159c).

The following outline is provided as an overview of and topical guide to immunology:

Human leukocyte antigens (HLA) began as a list of antigens identified as a result of transplant rejection. The antigens were initially identified by categorizing and performing massive statistical analyses on interactions between blood types. This process is based upon the principle of serotypes. HLA are not typical antigens, like those found on surface of infectious agents. HLAs are alloantigens, they vary from individual to individual as a result of genetic differences. An organ called the thymus is responsible for ensuring that any T-cells that attack self proteins are not allowed to live. In essence, every individual's immune system is tuned to the specific set of HLA and self proteins produced by that individual; where this goes awry is when tissues are transferred to another person. Since individuals almost always have different "banks" of HLAs, the immune system of the recipient recognizes the transplanted tissue as non-self and destroys the foreign tissue, leading to transplant rejection. It was through the realization of this that HLAs were discovered.

Reproductive immunology refers to a field of medicine that studies interactions between the immune system and components related to the reproductive system, such as maternal immune tolerance towards the fetus, or immunological interactions across the blood-testis barrier. The concept has been used by fertility clinics to explain fertility problems, recurrent miscarriages and pregnancy complications observed when this state of immunological tolerance is not successfully achieved. Immunological therapy is a method for treating many cases of previously "unexplained infertility" or recurrent miscarriage.

Immune tolerance in pregnancy or maternal immune tolerance is the immune tolerance shown towards the fetus and placenta during pregnancy. This tolerance counters the immune response that would normally result in the rejection of something foreign in the body, as can happen in cases of spontaneous abortion. It is studied within the field of reproductive immunology.

Daniel Michael Davis is Head of Life Sciences and Professor of Immunology at Imperial College London. Davis was previously Professor of Immunology at the University of Manchester. He is the author of The Secret Body, The Beautiful Cure and The Compatibility Gene. His research, using microscopy to study immune cell biology has helped understand how immune cells interact with each other.

References

  1. ↑ "Daniel M. Davis" (PDF). University of Manchester. Archived from the original (PDF) on 6 March 2017. Retrieved 5 March 2017.
  2. ↑ "Professor Daniel Davis". Imperial College. Retrieved 5 March 2017.
  3. ↑ "Focus on Natural Killer Cells: Classics". Nature Immunology . 9 (5). 2008.
  4. ↑ "Fellow Professor Daniel Davis". The Academy of Medical Sciences. Archived from the original on 21 April 2019. Retrieved 5 March 2017.
  5. ↑ "Focus on Natural Killer Cells: Classics". Nature Immunology . 9 (5). 2008.
  6. ↑ "Book: The Compatibility Gene". University of Manchester. Retrieved 6 March 2017.
  7. ↑ "Compatibility Gene". WorldCat. Retrieved 1 October 2021.
  8. ↑ "Reviews of The Compatibility Gene". University of Manchester. Retrieved 5 March 2017.
  9. ↑ Viney, Mark (11 September 2013). "The genes that make you a true individual". New Scientist. Retrieved 5 March 2017.
  10. ↑ Forbes, Peter (8 August 2013). "The Compatibility Gene by Daniel M Davis – review". The Guardian. Retrieved 5 March 2017.
  11. ↑ Davis, Nicola (17 August 2013). "From war wounds to the mysteries of pre-eclampsia, Davis examines the discovery and significance of compatibility genes". The Times. Retrieved 5 March 2017.
  12. ↑ Banham, Emily (18 September 2014). "New in paperback". Nature. 513 (7518): 308–314. Bibcode:2014Natur.513R.308B. doi: 10.1038/513308b .
  13. ↑ "Book Reviews: The Compatibility Gene". The Royal Society of Biology. Retrieved 5 March 2017.[ permanent dead link ]
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