The Compatibility Gene, page 1
The Compatibility Gene
DANIEL M. DAVIS
The Compatibility Gene
How Our Bodies Fight Disease,
Attract Others, and Define Our Selves
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© Daniel M. Davis 2014
The illustration on p. 77 is adapted by permission of Macmillan Publishers Ltd from
Nature, 329, pp. 506–12, copyright © 1987
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Library of Congress Cataloging-in-Publication Data
Davis, Daniel M. (Daniel Michael), 1970–
The compatibility gene : how our bodies fight disease, attract others, and define our selves / Daniel M. Davis.
pages cm
Includes bibliographical references and index.
ISBN 978-0-19-931641-0 (hardback)
1. Medical genetics. 2. Infection—Immunological aspects. 3. Immunogenetics. 4. Human molecular genetics. I. Title.
RB155.D36 2014
616’.042—dc23 2013020914
1 3 5 7 9 8 6 4 2
Printed in the United States of America on acid-free paper
For Katie, Briony and Jack
Contents
Acknowledgements
A Brief Note to Professional Scientists
Introduction
PART ONE
The Scientific Revolution in Compatibility
1 Frankenstein’s Holy Trinity
2 Self / Non-self
3 Dead but Alive in Parts
4 A Crystal-clear Answer at Last
PART TWO
The Frontier of Compatibility Gene Research
5 Differences between Us that Matter
6 A Path to New Medicine
7 Missing Self
PART THREE
The Overarching System
8 Sex and Smelly T-shirts
9 Connections with the Mind
10 Compatibility for Successful Pregnancy
Epilogue: What Makes You So Special?
Notes
Index
Acknowledgements
I am especially grateful to those I had the privilege of interviewing for this book: Brigitte Askonas, Gary Beauchamp, Pamela Bjorkman, Walter Bodmer, Leslie Brent, Derrick Brewerton, Mary Carrington, Margaret Dallman, Mark Davis, Elizabeth Dexter, Peter Doherty, Ron Germain, Klas Kärre, Jim Kaufman, Rolf Kiessling, Steve Marsh, Polly Matzinger, Hugh McDevitt, Andrew McMichael, Charles Medawar, Avrion Mitchison, Ashley Moffett, Jon van Rood, Eric Schadt, Carla Shatz, Elizabeth Simpson, Andrew Strominger, Jack Strominger, Alain Townsend, Bruce Walker, Claus Wedekind, Wayne Yokoyama and Rolf Zinkernagel. Several discussions with Peter Parham were particularly influential.
I also thank Steve Marsh and the team at Anthony Nolan, who performed the HLA typing for my wife and me. Others who helped me to address specific issues while writing this book include Danny Altmann, Jorge Carneiro, Andrew Giddy, Salim Khakoo, Ofer Mandelboim, Jim McCluskey, Maryam Mehrabi, Sophie Pageon, Marco Purbhoo and Anton van der Merwe. I’m also indebted to those who commented on early versions of some or all of the text: Brigitte Askonas, Mary Carrington, George Cohen, Richard Dawkins, Peter Doherty, Steve Marsh, Peter Parham, Elizabeth Simpson, Jack Strominger and Claus Wedekind. Of course, any remaining errors are my responsibility alone.
Many others supported me while writing this book, including members of my research team, the senior faculty at Imperial College London, who allowed me to take a year’s sabbatical leave, and faculty at the University of Manchester, where I completed the project. Armand Leroi, author of Mutants, was exceptionally helpful throughout, pushing me to develop my ideas more carefully at the outset and showing me where to rework the text at the end. Caroline Hardman, my agent initially at the Christopher Little Literary Agency and now at Hardman and Swainson, has been fantastic throughout and gave useful feedback at every stage. Sarah Levitt at the Zoë Pagnamenta Agency also had an important input in improving my text. Alice Brown, Lucy Hairsine, Clive Gerner and Joel Rickett all helped my proposal get noticed early on.
I’m indebted to Stefan McGrath and William Goodlad at Penguin Press, who supported this project at the outset. My editor at Penguin Press, Thomas Penn, author of The Winter King, had a wonderful influence on my writing and the structure of this book. My editor at OUP, Joan Bossert, also made many very helpful, formative suggestions. I’m also grateful to David Watson, who carefully copy-edited my text. Finally, my wife, Katie, edited the book first and suggested many important changes; I thank her, and our kids, Briony and Jack, for encouraging me throughout and sharing the journey.
A Brief Note to Professional Scientists
Immunology is a vast and complex science. In this book, I have sought to present some of the big ideas alongside the stories of individuals who have played a central role in gaining this knowledge. But I am acutely aware that there are a huge number of people who contributed to our understanding of the immune system and the relevant genetics, who are not explicitly named in this book or have been mentioned only superficially. I have made many ruthless omissions in my attempt to keep the narrative and the scientific ideas as clear as possible for the general reader. Quite simply, this is an extraordinarily rich story in which there have been many players, and it’s impossible to catalogue everyone’s contribution. Immunologists will notice that some details are covered more thoroughly than others; I have discussed class I genes far more than class II genes, for example. Rather than present a complete textbook-level description of the immune system, I wanted to focus on broad issues, such as the variation in human immune-system genes which can, for example, be illustrated equally well with class I or class II genes. I can only apologize to anyone whose discoveries I have not included or have mentioned all too briefly; any one book can only tell part of a story.
Introduction
There’s a man, happy and minding his own business, who sees an open gate in the corner of the room where he is. He approaches the gate, wondering where it leads. But as he does so, he sees that it’s being guarded. The guard – who looks powerful from a distance but appears unkempt close up – warns the man that nobody has ever been through this gate. He also mentions that beyond this gate there’s another, with a guard who’s even more powerful. So the man just backs away and spends his days – which turn into decades – in the room, occasionally wondering about the gate and where it leads to. Eventually, when the man is weak and knows his own death must be near, he realizes what he should ask the guard. He shuffles back and asks, ‘In all the time I’ve been in this room, why has nobody ever been through the gate?’ ‘Because,’ the guard replies, ‘this gate was only meant for you . . . but it’s too late now.’
Written in 1914, Franz Kafka’s parable ‘Before the Law’ has inspired me often. The version that I carry in my head now is slightly different from what Kafka actually wrote, or the way Anthony Hopkins tells it in the 1993 movie of The Trial. There are many interpretations of any great allegory; this one works for me on two levels. First, as a scientist, I want to open doors to where nobody has been before. Second, there is the simple, but all-too-easy-to-forget, truth that each of us really is unique, right down to the molecular detail of what our bodies are made of. My aim is for this book to work on these two levels. I want to tell some inspiring stories of men and women who have fought their way to new rooms of knowledge and describe how, from the vantage point they reached, we see a fundamental importance for our own personal uniqueness.
Essentially, this is the story of a few human genes and how we discovered what these genes do. The knowledge we now possess of these genes reveals a great beauty in how we work at a microscopic – and macroscopic – level. We are not merely a more-or-less average blend of our parents; rather we gain specific traits and characteristics through the individual genes we inherit. As human beings we each have around 25,000 genes. To a large extent, we each have a very similar set of these genes but there are variations that provide us with individual characteristics such as hair and eye colour. Genetic variation also gives us more subtle – and superficially undetectable – differences. Crucially, the genes in this story are t
It is this feature that led to their discovery. These genes – we’ll call them our compatibility genes (though their unwieldy formal name is the major histocompatibility complex or MHC genes) – are not uniquely human and they were first discovered in mice. During the 1930s, scientists were trying to understand what determines the acceptance or rejection of skin cells transplanted from one mouse to another. They observed that transplanted cells were rejected when they had different compatibility genes; transplantation worked well when these genes were matched. In the 1950s and ’60s, this was also found to be true for humans, and today, these are the genes that, when matched between donors and recipients, help provide the best chance of success in many types of organ transplantation. But the normal job for these genes can’t be to make life difficult for transplant surgeons. What do these genes really do?
Decades of patient scientific inquiry and the occasional stroke of genius have unravelled the workings of our compatibility genes. This book charts this human endeavour – a global adventure spanning sixty years – tracing the history of transplants and immunology, leading to our eventual understanding of how and why compatibility genes are crucial to our health. This amounts to a scientific revolution, but not one that came from a single eureka moment; rather a revolution in our understanding of the human body that emerged from a swell of ground-breaking ideas and experiments happening in different places across the globe over decades.
We will see that a great many people made vital contributions – and that their characters do not fit any particular mould of scientist. Some collected data while others contributed more theoretically. Many classified and ordered the information, while others explored more like artists. Often one didn’t appreciate another’s approach. A picture of science emerges in which hundreds of researchers – each digging away in their own experiments and thoughts – individually uncover a fragment of the big picture.
The view we now have of what these few genes do reveals much about how your immune system works; how your body can detect what is not part of you, such as germs or transplanted organs from someone else. That is to say that these few genes help your body distinguish self from non-self. Practically – as a consequence of the way this system has evolved – we each have a different set of these genes. And it can really matter which versions you have inherited.
Each of our 25,000 genes can be ranked according to which are most important for our susceptibility or resistance to any given disease. The outcome is that compatibility genes come out top in influencing our susceptibility or resistance to an enormous array of illnesses: multiple sclerosis, rheumatoid arthritis, type I diabetes, psoriasis, leprosy, ankylosing spondylitis and many others.1
Take one example: In 2003, Doug Robinson, forty-six, from Truro, Massachusetts, was infected with HIV. Yet, ten years on, his immune system has managed to keep it in check: the virus is almost undetectable in Doug’s blood.2 About 1 in 300 people infected with HIV do not progress to full-blown AIDS for seven years or more, because, like Doug, their immune system is able to fight the virus effectively. But what is so special about Doug’s immune system that allows him to do this? Why is Doug so, so lucky? Doug’s super-power turns out to be a version of compatibility gene that he inherited – one that appears to be particularly beneficial in fighting HIV.
For people infected with HIV, their rate of progression to AIDS depends on, amongst other things, which variants of compatibility genes they have inherited. Doug has a version designated as B*57 (said as B-fifty-seven), which happens to be one that protects most effectively against the progression of HIV to AIDS. Protection against disease is surely enough to warrant a book about how these genes work, but in fact, their importance stretches further. There is evidence that these very same genes are linked to whole other areas of human biology.
Radical and provocative research has suggested that finding a lover might be made simpler: as a ‘scientific’ process in which there’s no need to waste time looking in bars or at parties. Just take a swab and run it along your inside cheek. Put it in an envelope and fill out the brief form – not forgetting to include your customer number. Send it off, wait a few days, then log in to your online account. Having analysed your DNA, your ideal partner will be selected from a company’s database. Just go ahead and arrange a date. Marriage, happiness and wonderful kids are all assured, with minimal risk of either one of you ever cheating.
This highly controversial view of what’s possible is based on experiments that suggest that you find others more or less sexy according to which type of compatibility genes they have. There have even been claims that women experience higher rates of orgasm if they choose partners with the right set of compatibility genes. The experiment that started this line of thinking used a very unusual protocol for scientific work.
Women were to refrain from sex for two days, use a nasal spray to keep their nostrils clear, read Patrick Süskind’s novel Perfume – a book about a man with olfactory hypersensitivity who is obsessed with people’s smells – and then come into the lab to smell a collection of T-shirts worn by men who hadn’t showered for two days. The experiment yielded an astonishing result: T-shirts worn by people with different compatibility genes smelt the sexiest. The big idea that follows from this research is that we subconsciously favour sexual partners who have different compatibility genes from ourselves. Profoundly personal, life-forming and life-changing decisions can, it appears, be reduced to the actions of a few inherited genes.
Is this true? How and why could it possibly work? We each spend a great deal of effort defining our personalities by choosing the things we like or dislike, and form friendships with people who have similar tastes. Many of us spend a great deal of our lives in the quest for a soul-mate. The idea of genes pervades our culture, and we have no problem accepting that our physical characteristics – hair and eye colour, for example – are dictated by our genetic make-up. But can something that feels as intimate as choosing a partner be similarly influenced by our genetic inheritance? There’s no short answer to this question; the subject is contentious.
Controversy surrounding compatibility genes doesn’t stop there. Other research suggests these genes might also influence parts of our brain. Specifically, the wiring between some neurons may be kept or broken according to the activity of compatibility genes. Most recently, evidence has emerged to suggest that compatibility genes are also able to influence the chance that two people have a successful pregnancy.
Quite simply, it seems that these few genes can affect who’s born and who dies – at many levels. This multi-functionality of compatibility genes suggests that all of these different aspects of us could be fundamentally connected. And if so, then a shocking amount of who we are and what we do is directly influenced by the way we have evolved to survive disease.
Understanding this in depth – resolving the controversies – is not simply a matter of academic interest. Given, for example, that we each respond slightly differently to any particular disease, it can be expected that we also respond slightly differently to any given medicine. In the not-too-distant future, we can anticipate that vaccines or a choice of therapeutic drugs might be tailored to match our compatibility genes. Unlocking the secrets of our compatibility genes is undoubtedly important for medical practice in the twenty-first century.
Other sorts of issues also arise from these discoveries. The possibility is already available to seek a partner according to compatibility genes,3 and disease treatments tailored to our gene types are just around the corner. But how much of this is where we want to go? Governments and the pharmaceutical industry must move forward mindfully, so that we don’t end up in a Brave New World. We must each make our own personal decisions, fully informed about how this wondrous system works within each of us and across us all.
As I mentioned, there are many interpretations of any great allegory. In Kafka’s ‘Before the Law’, the man and guard might be one and the same; there’s an internal struggle in anyone stepping forward somewhere new. More importantly, it is surely impossible that a gate will be opened and closed to fit the term of one person’s life. More likely, once a new room has been seen, its guard will not actually be able to shut the gate.
