Life's Greatest Secret

by Matthew Cobb

  ‘Matthew Cobb is a respected scientist and historian, and he has combined both disciplines to spectacular effect in this compelling, authoritative and insightful account of how life works at the deepest level. It’s a bloody brilliant book.’ Professor Brian Cox

  ‘Life’s Greatest Secret is the logical sequel to Jim Watson’s The Double Helix. While Watson and Crick deserve their plaudits for discovering the structure of DNA, that was only part of the story. Beginning to understand how that helix works – how its DNA code is turned into bodies and behaviours – took another fifteen years of amazing work by an army of dedicated men and women. These are the unknown heroes of modern genetics, and their tale is the subject of Cobb’s fascinating book.’ Jerry Coyne, University of Chicago and author of Why Evolution is True

  ‘Most people think the race to sequence the human genome culminated at the 2000 White House “Mission Accomplished” announcement. In Life’s Greatest Secret, we learn that it was just one chapter of a far more interesting and continuing story.’ Eric Topol, Professor of Genomics and Director, Scripps Translational Science Institute and author of The Patient Will See You Now

  ‘Gripping, insightful history, often from the mouths of the participants themselves.’ Kirkus Reviews

  ‘Rich, thrilling and thorough, this is the definitive history of arguably the greatest of all scientific revolutions.’ Adam Rutherford, science writer, broadbcaster and author of Creation

  ‘Writing with flair, charisma and authority, this is Cobb’s magnum opus. But more important than that, this is humankind’s magnum opus. This is the story of a great human endeavour – a global adventure spanning decades – which unravelled how life really works. No area of science is more fundamental or more important; read about it and be filled with wonder.’ Daniel M. Davis, author of The Compatibility Gene

  ‘Cobb reveals the astonishing drama of the moment genetics and information technology collided, shaping the modern world and modern thought.’ Paul Mason, Channel 4 News

  ALSO BY MATTHEW COBB

  The Egg and Sperm Race: The Seventeenth Century

  Scientists who Unravelled the Secrets of Sex, Life and Growth (published in the US as Generation)

  The Resistance: The French Fight Against the Nazis

  Eleven Days in August: The Liberation of Paris 1944

  Copyright © 2015 by Matthew Cobb

  First published in Great Briain in 2015 by

  Profile Books Ltd

  3 Holford Yard

  Bevin Way

  London wc1x 9hd

  www.profilebooks.com

  Published by Basic Books, A Member of the Perseus Books Group

  All rights reserved. Printed in the United States of America. No part of this book may be reproduced in any manner whatsoever without written permission except in the case of brief quotations embodied in critical articles and reviews. For information, address Basic Books, 250 West 57th Street, 15th Floor, New York, NY 10107.

  Books published by Basic Books are available at special discounts for bulk purchases in the United States by corporations, institutions, and other organizations. For more information, please contact the Special Markets Department at the Perseus Books Group, 2300 Chestnut Street, Suite 200, Philadelphia, PA 19103, or call (800) 810-4145, ext. 5000, or e-mail special.markets@perseusbooks.com.

  Typeset in Palatino by MacGuru Ltd

  info@macguru.org.uk

  Library of Congress Control Number: 2015937254

  ISBN: 978-0-465-06266-9 (e-book)

  10987654321

  In memory of John Pickstone (1944–2014)

  – historian, colleague, friend.

  CONTENTS

  Foreword

  1Genes before DNA

  2Information is everywhere

  3The transformation of genes

  4A slow revolution

  5The age of control

  6The double helix

  7Genetic information

  8The central dogma

  9Enzyme cybernetics

  10Enter the outsiders

  11The race

  Update

  12Surprises and sequences

  13The central dogma revisited

  14Brave new world

  15Origins and meanings

  Conclusion

  Glossary and acronyms

  Further reading

  Acknowledgements

  References

  Photo insert

  Notes

  List of illustrations

  Index

  The RNA genetic code, as finally established in 1967. U, C, A and G are the RNA bases. The 20 naturally occurring amino acids are given in the table, as three-letter abbreviations (e.g. Phe = phenylalanine). In RNA, Uracil (U) replaces the Thymine (T) base found in DNA. AUG codes for both methionine (Met) and for the start of the message. Slight variants of this code are found in some species, and in the mitochondria that are found in our cells – see Chapter 12.

  An outline of how the genetic code works during protein synthesis. A DNA double helix in the cell nucleus is partially unravelled and one strand is transcribed into RNA (mRNA). In organisms with a cell nucleus, this mRNA often contains irrelevant sequences (introns) that are spliced out to form mature mRNA which then leaves the nucleus. In the cell’s cytoplasm, RNA-based ribosomes read the message, beginning at AUG. Transfer RNA (tRNA) molecules, synthesised by the cell from its DNA, carry on one side an anti-codon that binds with a particular mRNA codon and, on the other side, a binding site that links to a specific amino acid. In a process known as translation, tRNA molecules attached to an amino acid shuttle through the ribosome, bind with the mRNA codon and release their amino acid, thereby creating a protein chain.

  AUG

  FOREWORD

  In April 1953, Jim Watson and Francis Crick published a scientific paper in the journal Nature in which they described the double helix structure of DNA, the stuff that genes are made of. In a second article that appeared six weeks later, Watson and Crick put forward a hypothesis with regard to the function of the ‘bases’ – the four kinds of molecule that are spaced along each strand of the double helix and which bind the two strands together. They wrote: ‘it therefore seems likely that the precise sequence of the bases is the code which carries the genetical information.’

  This phrase, which was almost certainly the work of Crick, must have seemed both utterly strange and completely familiar to those who read the article. It was strange because nothing so precise had ever been said before – no one had previously referred to ‘genetical information’. This was a category that Watson and Crick had just invented. And yet it was familiar because it fitted so well with the ideas that were in the air at the time. It was adopted without debate; this new way of looking at life seemed so obvious that it was immediately accepted by scientists around the world. Today, these words, or something like them, are said every day in classrooms all over the planet as teachers explain the nature of genes and what they contain.

  This book explores the surprising origin of these ideas, which can be traced back to physics and mathematics, and to wartime work on anti-aircraft guns and signals communication. It describes the way in which these concepts entered biology through the then-fashionable field of cybernetics, and how they were transformed as biologists sought to understand life’s greatest secret – the nature of the genetic code. It is a story of ideas and experimentation, of ingenuity, insight and dead-ends, and of the race to make the greatest discovery of twentieth-century biology, a discovery that has opened up a brave new world for the twenty-first century.

  Manchester, April 2015

  –ONE–

  GENES BEFORE DNA

  In the early decades of the nineteenth century, the l
eaders of the wool industry in the central European state of Moravia were keen to improve the fleeces produced by their sheep. Half a century earlier, a British businessman farmer called Robert Bakewell had used selective breeding to increase the meat yield of his flocks; now the Moravian wool merchants wanted to emulate his success. In 1837 the Sheep Breeders’ Society organised a meeting to discuss how they could produce more wool. One of the speakers was the new Abbot of the monastery at Brnö, a city that was at the heart of the country’s wool production. Abbot Napp was intensely interested in the question of heredity and how it could be used to improve animal breeds, fruit crops and vines; this was not simply a hobby – the monastery was also a major landowner. At the meeting, Napp argued that the best way to increase wool production through breeding would be to address the fundamental underlying issue. As he put it impatiently: ‘What we should have been dealing with is not the theory and process of breeding. But the question should be: what is inherited and how?’1

  This question, which looks so straightforward to us, was at the cutting edge of human knowledge, as the words ‘heredity’ and ‘inheritance’ had only recently taken on biological meanings.2 Despite the centuries-old practical knowledge of animal breeders, and the popular conviction that ‘like breeds like’, all attempts to work out the reasons behind the various resemblances between parents and offspring had foundered when faced with the range of effects that could be seen in human families: skin colour, eye colour and sex all show different patterns of similarity across the generations. A child’s skin colour tends to be a blend of the parental shades, their eye colour can sometimes be different from both parents, and in all except a handful of cases the sex of the child is the same as only one parent. These mysterious and mutually contradictory patterns – all of which were considered by the seventeenth-century physician William Harvey, one of the first people to think hard about the question – made it impossible to come up with any overall explanation using the tools of the time.3 Because of these problems it took humanity centuries to realise that something involved in determining the characteristics of an organism was passed from parents to offspring. In the eighteenth and early nineteenth centuries, the tracing of human characteristics such as polydactyly (extra fingers) and Bakewell’s selective breeding had finally convinced thinkers that there was a force at work, which was termed ‘heredity’.4 The problem was now to discover the answer to Napp’s question – what is inherited and how?

  Napp had not made this conceptual breakthrough alone: other thinkers such as Christian André and Count Emmerich Festetics had been exploring what Festetics called ‘the genetic laws of nature’. But unlike them, Napp was able to organise and encourage a cohort of bright intellectuals in his monastery to explore the question, a bit like a modern university department focuses on a particular topic. This research programme reached its conclusion in 1865, when Napp’s protégé, a monk named Gregor Mendel, gave two lectures in which he showed that, in pea plants, inheritance was based on factors that were passed down the generations. Mendel’s discovery, which was published in the following year, had little impact and Mendel did no further work on the subject; Napp died shortly afterwards, and Mendel devoted all his time to running the monastery until his death in 1884. The significance of his discovery was not appreciated, and for nearly two decades his work was forgotten.5 But in 1900 three European scientists – Carl Correns, Hugo de Vries and Erich von Tschermak – either repeated Mendel’s experiments or read his paper and publicised his findings.6

  The century of genetics had begun.

  *

  The rediscovery of Mendel’s work led to great excitement, because it complemented and explained some recent observations. In the 1880s, August Weismann and Hugo de Vries had suggested that, in animals, heredity was carried by what Weismann called the germ line – the sex cells, or egg and sperm. Microscopists had used newly discovered stains to reveal the presence of structures inside cells called chromosomes (the word means ‘coloured body’) – Theodor Boveri and Oscar Hertwig had shown that these structures copied themselves before cell division. In 1902, Walter Sutton, a PhD student at Columbia University in New York, published a paper on the grasshopper in which he used his own data and Boveri’s observations to audaciously suggest that the chromosomes ‘may constitute the physical basis of the Mendelian law of heredity’.7 As he put it in a second paper, four months later: ‘we should be able to find an exact correspondence between the behaviour in inheritance of any chromosome and that of the characters associated with it in the organism’.8

  Sutton’s insight – which Boveri soon claimed he had at the same time – was not immediately accepted.9 First there was a long tussle over whether Mendel’s theory applied to all patterns of heredity, and then people argued over whether there truly was a link with the behaviour of chromosomes.10 In 1909, Wilhelm Johannsen coined the term ‘gene’ to refer to a factor that determines hereditary characters, but he explicitly rejected the idea that the gene was some kind of physical structure or particle. Instead he argued that some characters were determined by an organised predisposition (writing in German, he used the nearly untranslatable word Anlagen) contained in the egg and sperm, and that these Anlagen were what he called genes.11

  One scientist who was initially hostile to the new science of what was soon known as ‘genetics’ was Thomas Hunt Morgan, who also worked at Columbia (by this time Sutton had returned to medical school; he never completed his PhD).12 Morgan had obtained his PhD in marine biology, investigating the development of pycnogonids or sea spiders, but he had recently begun studying evolution, using the tiny red-eyed vinegar fly, Drosophila.13 Morgan subjected his hapless insects to various environmental stresses – extreme temperatures, centrifugal force, altered lighting conditions – in the vain hope of causing a change that could be the basis of future evolution. Some minor mutations did appear in his fly stocks, but they were all difficult to observe. In 1910, Morgan was on the point of giving up when he found a white-eyed fly in his laboratory stocks. Within weeks, new mutants followed and by the summer there were six clearly defined mutations to study, a number of which, like the white-eyed mutant, seemed to be expressed more often in males than in females. Morgan’s early doubts about genetics were swept away by the excitement of discovery.

  By 1912, Morgan had shown that the white-eyed character was controlled by a genetic factor on the ‘X’ sex chromosome, thereby providing an experimental proof of the chromosomal theory of heredity. Equally importantly, he had shown that the shifting patterns of inheritance of groups of genes was related to the frequency with which pairs of chromosomes exchanged their parts (‘crossing over’) during the formation of egg and sperm.14 Characters that tended to be inherited together were interpreted as being produced by genes that were physically close together on the chromosome – they were less likely to be separated during crossing over. Conversely, characters that could easily be separated when they were crossed were interpreted as being produced by genes that were further apart on the chromosome. This method enabled Morgan and his students – principally Alfred Sturtevant, Calvin Bridges and Hermann Muller – to create maps of the locations of genes on the fly’s four pairs of chromosomes. These maps showed that genes are arranged linearly in a one-dimensional structure along the length of the chromosome.15 By the 1930s, Morgan’s maps had become extremely detailed, as new staining techniques revealed the presence of hundreds of bands on each chromosome. As Sutton had predicted, the patterns of these bands could be linked to the patterns with which mutations were inherited, so particular genes could be localised to minute fragments of the chromosome.

  As to what genes were made of, that remained a complete mystery. In 1919, Morgan discussed two alternatives, neither of which satisfied him. A gene might be a ‘chemical molecule’, he wrote, in which case ‘it is not evident how it could change except by altering its chemical constitution’. The other possibility was that a gene was ‘a fluctuating amount of something’ that differed between
individuals and could change over time. Although this second model provided an explanation of both individual differences and the way in which organisms develop, the few results that were available suggested that it was not correct. Morgan’s conclusion was to shrug his shoulders: ‘I see at present no way of deciding’, he told his readers.16

  Even fourteen years later, in 1933, when Morgan was celebrating receiving the Nobel Prize for his work, there had been little progress. As he put it starkly in his Nobel Prize lecture: ‘There is no consensus of opinion amongst geneticists as to what the genes are – whether they are real or purely fictitious.’ The reason for this lack of agreement, he argued, was because ‘at the level at which the genetic experiments lie, it does not make the slightest difference whether the gene is a hypothetical unit, or whether the gene is a material particle. In either case the unit is associated with a specific chromosome, and can be localized there by purely genetic analysis.’17 It may seem strange, but for many geneticists in the 1930s, what genes were made of – if, indeed, they were made of anything at all – did not matter.

  In 1926, Hermann Muller made a step towards proving that genes were indeed physical objects when he showed that X-rays could induce mutations. Although not many people believed his discovery – among the doubters was his one-time PhD supervisor Morgan, with whom he had a very prickly relationship – within a year his finding was confirmed. In 1932, Muller moved briefly to Berlin, where he worked with a Russian geneticist, Nikolai Timoféef-Ressovsky, pursuing his study of the effects of X-rays. Shortly afterwards, Timoféef-Ressovsky began a project with the radiation physicist Karl Zimmer and Max Delbrück, a young German quantum physicist who had been working with the Danish physicist Nils Bohr. The trio decided to apply ‘target theory’ – a central concept in the study of the effects of radiation – to genes.18 By bombarding a cell with X-rays and seeing how often different mutations appeared as a function of the frequency and intensity of the radiation, they thought that it should be possible to deduce the physical size of the gene (the ‘target’), and that measuring its sensitivity to radiation might reveal something of its composition.