by Frank Ryan
ALSO BY FRANK RYAN
Virolution
Tuberculosis: The Greatest Story Never Told
Virus X
Darwin's Blind Spot
Metamorphosis: Unmasking the Mystery of How Life Transforms
Published 2016 by Prometheus Books
The Mysterious World of the Human Genome. Copyright © 2015 by Frank Ryan. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, digital, electronic, mechanical, photocopying, recording, or otherwise, or conveyed via the Internet or a website without prior written permission of the publisher, except in the case of brief quotations embodied in critical articles and reviews.
Design by Jo Walker
Cover design © HarperCollinsPublishers Ltd 2015
Figures by Mark Salwowski, © Frank Ryan
Inquiries should be addressed to
Prometheus Books
59 John Glenn Drive
Amherst, New York 14228
VOICE: 716–691–0133
FAX: 716–691–0137
WWW.PROMETHEUSBOOKS.COM
20 19 18 17 16 5 4 3 2 1
Originally published in the English language by HarperCollins Publishers Ltd. under the title The Mysterious World of the Human Genome © Frank Ryan 2015
The Library of Congress has cataloged the printed edition as follows:
Names: Ryan, Frank, 1944- , author.
Title: The mysterious world of the human genome / by Frank Ryan.
Description: Amherst, New York : Prometheus Books, 2016. | Includes bibliographical references and index.
Identifiers: LCCN 2015037539| ISBN 9781633881525 (hardcover) | ISBN 9781633881532 (ebook)
Subjects: | MESH: Genome, Human.
Classification: LCC QH447 | NLM QU 460 | DDC 611/.0181663—dc23 LC record available at http://lccn.loc.gov/2015037539
Printed in the United States of America
Possibly I am a scientist because I was curious when I was young. I can remember being ten, eleven, twelve years old and asking, “Now why is that? Why do I see such a peculiar phenomenon? I would like to understand that.”
LINUS PAULING
Introduction
1. Who Could Have Guessed It?
2. DNA Is Confirmed as the Code
3. The Story in the Picture
4. A Couple of Misfits
5. The Secret of Life
6. The Sister Molecule
7. The Logical Next Step
8. First Draft of the Human Genome
9. How Heredity Changes
10. The Advantage of Living Together
11. The Viruses That Are Part of Us
12. Genomic Level Evolution
13. The Master Controllers
14. Our History Preserved in Our DNA
15. Our More Distant Ancestors
16. The Great Wilderness of Prehistory
17. Our Human Relatives
18. The Fate of the Neanderthals
19. What Makes You Unique
20. The Fifth Element
Bibliography
Notes
Index
Acknowledgments
No special act of creation, no spark of life was needed to turn dead matter into living things. The same atoms compose them both, arranged only in a different architecture.
JACOB BRONOWSKI, THE IDENTITY OF MAN
Bronowski begins his more famous book, The Ascent of Man, with the words, “Man is a singular creature. He has a set of gifts which make him unique among the animals: so that, unlike them, he is not a figure in the landscape—he is a shaper of the landscape.” But why should we humans have become shapers of the landscape rather than mere figures inhabiting it? We differ from, say, a sea horse or a cheetah because our genetic inheritance, the sum of the DNA that codes for us, is different in humans when compared to the horse or the cheetah. We call this the genome, or, to be more specific in our case, the human genome.
Our genome defines us at the most profound level. That same genome is present in every one of the approximately 100,000 billion cells that make us who we are as individual members of the human species. But it runs deeper than that. In more personal terms, in myriad tiny variations that we each possess and are individual to us only, it is the very essence of us, all that, in genetic and hereditary terms, we have to contribute to our offspring, and through them to the sum total evolutionary inheritance of our species. To understand it is to know, in the most intimate sense, what it means to be human. No two people in the world today have exactly the same genome. Even identical twins, who will have been conceived with exactly the same genome, will have developed tiny differences between their genomes by the time of their births: differences that may have arisen in parts of their genomes that don't actually code for what we normally mean by genes.
How strange to realize that there is actually more to our individual genome than genes alone. But let us put aside such details for the moment to focus on the more general theme. How could a relatively simple chemical code give rise to the complexity of a human being? How could our human genome have evolved? How does it actually work? Immediately we are confronted by mysteries.
To answer these questions we need to explore the genome's basic structure, its operating systems, and its mechanisms of expression and control. Some readers might react with incredulity. Surely any such exploration promises a journey into extraordinary complexity, one that is far too obscure and scientific for a non-scientist reader? In fact this book is aimed at exactly such a reader. As we shall see, the basic facts are easy enough to grasp, and the way to grasp them is to break the exploration into a series of simple, and eminently logical, stages. This journey will lead us through a sequence of remarkable revelations about our human history—even into the very distant past of our ancestors’ lives and their prehistoric exploration of our beautiful life-giving planet.
The exploration will raise other, equally important, questions, too. How, for example, does this extraordinary entity that we call the human genome enable our human reproduction—the fertilization of our maternal egg with the paternal sperm? How does it control the quasi-miracle of the developing embryo within the mother's womb? Returning to generalities for the moment, though, we can be sure that an important ingredient of the genome, and its essential nature, is memory—the memory, for example, of the totality of every individual human's genetic inheritance. But how exactly does it perform this remarkable feat of memory? We know already that this wonder chemical we call DNA works like a code, but how could any code recall the complex instructions that go into the making of cells and tissues and organs, and then once made, bring them into function in the single coordinated whole that comprises the human being? Even then we have hardly begun to confront the mysteries of the human genome. How does this same extraordinary structure acquire the programming that gifts the growing child with the wonder of speech, that bestows the related capacity for learning, writing, and education, and which makes possible the maturing of the newborn to the future adult, who then repeats the cycle all over again when he or she becomes a parent in turn?
The wonder is that all of this might be encompassed in a minuscule cluster of chemicals including, but not exclusive to, the master molecule we call deoxyribonucleic acid—or DNA. This chemical code somehow records the genetic instructions for making us. Built into that code must be the potential for individual liberty of thought and inventiveness, enabling every human artistic, mathematical, and scientific creativity. It gives rise to what each of us thinks innately as our private inviolate “self.” Somehow that same construction of “self” made possible the gen
ius of Mozart, Picasso, Newton, and Einstein. It is little wonder that we look at the repository of such potential with awe. No more is it surprising that we should want to understand this mystery that lies at the very core of our being.
Only recently have we come to understand the human genome in sufficient depth and subtlety to be able to put together its marvelous story—to discover, for example, that there is rather more to it than DNA alone. This is the story I shall attempt to convey in this book.
A few years ago I gave a lecture on a related theme at King's College London. The chairman asked me if I planned to write a book about it. When I said yes, he asked me to please write it in words that a lay reader, like himself, could readily understand.
“Just how simple do you want me to make it?”
“I want you to assume that I—your reader—know nothing at all to begin with.”
This, then, I promise to do. There will be no complicated scientific language, no mathematical or chemical formulas or unexplained jargon, and I shall introduce no more than a handful of simple illustrations. Instead I shall begin from first principles and assume that the readers of this book know little about biology or genetics. Even non-biologists might recall the many surprises when the first rough draft of the human genome was announced to the world in 2001. The discoveries since then have confirmed that a good deal of the human genome—in its evolution, structure, and workings—is far from what we had earlier imagined. Those surprises do not diminish the importance of the wealth of knowledge that had gone before, but rather, like all great scientific discoveries, they enhance it. Thanks to this new understanding, humanity has entered what I believe to be a golden age of genetic and genomic enlightenment, which is already being extrapolated to many important fields, from medicine to our human prehistory. I think society at large deserves to understand this and what it promises for the future.
The large and important and very much discussed question is: How can the events in space and time which take place within the spatial boundary of a living organism be accounted for by physics and chemistry?
ERWIN SCHRÖDINGER
In April 1927, a young Frenchman, René Jules Dubos, arrived at the Rockefeller Institute for Medical Research in New York on what would appear to have been a hopeless mission. Tall, bespectacled, and a recent graduate of Rutgers University, New Jersey, with a PhD in soil microbiology, Dubos had an unusually philosophical attitude to science. He had become convinced, through the work of eminent Russian soil microbiologist Sergei Winogradsky, that it was a waste of time studying bacteria in test tubes and laboratory cultures. Dubos believed that if we really wanted to understand bacteria we should go out and study them where they actually lived and interacted with one another and with life in general, in the fields and the woods—in nature.
On graduation from Rutgers, Dubos had found himself unemployed. He had applied to the National Research Council Fellowship for a research grant but had been turned down because he wasn't American, but somebody had scribbled a handwritten message on the margin of the rejection letter. Dubos would later reflect upon the fact that it was written in a female hand, almost certainly added as a kindly afterthought by the official's secretary. “Why don't you go and ask advice and help from your famous fellow countryman, Dr. Alexis Carrel, at the Rockefeller Institute?” Dubos duly wrote to Carrel, which brought him, in April 1927, to the building on York Avenue, on the bank of the East River.
Dubos knew nothing about Carrel, or indeed about the Rockefeller Institute for Medical Research, and was surprised on his arrival to discover that Carrel was a vascular surgeon. Dubos had no academic knowledge of medicine and Carrel knew nothing about the microbes that lived in soil. The outcome of their conversation was all too predictable; Carrel was unable to help the youthful microbiologist. Their conversation closed about lunchtime and Carrel did Dubos the courtesy of inviting him to have lunch with him in the Institute's dining room, which had the attraction for a hungry Frenchman that they served freshly baked bread.
It seemed entirely by accident that Dubos found himself sitting at a table next to a small, slightly built gentleman with a domed bald head who addressed him politely in a Canadian accent. The gentleman's name was Oswald Theodore Avery. Although Dubos later confessed that he knew as little about Avery as he did of Carrel, Professor Avery (his close associates referred to him as “Fess”) was eminent in his field, which was medical microbiology. It would prove to be a meeting of historic importance both to biology and to medicine.
Avery subsequently hired Dubos as a research assistant, in which role Dubos discovered the first soil-derived antibiotics. Meanwhile Avery led his small team—who were working on what he called his “little kitchen chemistry”—on another quite different quest, one that would help unravel the key to heredity. Why then does society know little to nothing about this visionary scientist? To understand how this anomaly came about we need to go back in time to the man himself and the problems he faced three-quarters of a century ago.
In 1927, when Dubos first met Avery, the principles of heredity were poorly understood. The term “gene” had been introduced into the nomenclature two decades earlier by a Danish geneticist, Wilhelm Johannsen. Curiously, Johannsen had adopted a vague concept of heredity, known as “pangene,” that was first proposed by Charles Darwin himself. Johannsen modified it to take on board the belated discovery of the pioneering work of Gregor Mendel, which dated back to the nineteenth century.
Readers may be familiar with the story of Mendel—the cigar-smoking, Friar Tuck–like abbot of an Augustinian monastery in Brünn, Moravia (now the Czech Republic)—who undertook some brilliantly original studies of the peas he cross-bred in the monastery vegetable garden. From these studies, Mendel discovered the basis of what we now know as the laws of heredity. He found that certain characteristics of the peas were transmitted to the offspring in a predictable manner. These characteristics included tallness or dwarfishness, presence or absence of the colors yellow or green in the blossoms or axils of the leaves, and the wrinkled or smooth skin in the peas. Mendel's breakthrough was to realize that heredity was stored within the germ cells of plants—and this would subsequently be extrapolated to all living organisms—in the form of discrete packets of information that somehow coded for specific physical characters or “traits.” Johannsen coined the term “gene” for Mendel's packet of hereditary information. At much the same time, a combative British researcher, William Bateson, extrapolated the term “gene” to the discipline he now called “genetics” to cover the study of the nature and workings of heredity.
Today, if we visit the Free Dictionary online, we get the following definition of a gene: “The basic physical unit of heredity; a linear sequence of nucleotides along a segment of DNA that provides the coded instructions for the synthesis of RNA, which, when translated into protein, leads to the expression of hereditary character.” But Mendel had no notion of genes as such, and he certainly knew nothing about DNA. His discoveries languished in some little-read papers for forty years before they were rediscovered and their importance was more fully understood. But in time his idea about the discrete packets of heredity we now call genes helped to answer a very important medical mystery: how certain diseases come about through an aberration of heredity.
We now know that genes are the basic building blocks of heredity in much the same way that atoms are the physical units that make up the physical world. But during the early decades of the twentieth century, nobody had any real notion of what genes were made from or how they worked. But here and there, people began to study genes in more depth by examining their physical expression during the formation of embryos or in the causation of hereditary diseases. Fruit flies became the experimental model for pioneering research in the laboratory of Chicago-based geneticist Thomas Hunt Morgan, where researchers located genes, one by one, onto structures called chromosomes, which were themselves located within the nuclei of the insect's germ cells. The botanical geneticist Barbara McCl
intock confirmed that this was also the case for plants. McClintock developed techniques that allowed biologists to visualize the actual chromosomes in maize, leading to the groundbreaking discovery that, during the formation of the male and female germ cells, the matching, or “homologous,” chromosomes from the two parents lined up opposite each other and then the chromosomes swapped similar bits so that the offspring inherited a jumbled-up mixture of the inheritance from the two parents. This curious genetic behavior (which is known as “homologous sexual recombination”) is the explanation of why siblings are different from one another.
By the early 1930s, biologists and medical researchers knew that genes were actual physical entities—chemical blocks of information that were lined up like beads in a necklace along the lengths of chromosomes. In other words, the genome could be loosely compared to a library of chemical information in which the books were the chromosomes. The discrete entities known as genes could then be compared to discrete words in the books. The libraries were housed in the nuclei of the germ cells—in human terms, the ova and sperm. Humans had a total stack of 46 books, which were the summed complement of ova and sperm, in every living cell. This came about because the germ cells—the ovum and the sperm—contained 23 chromosomes, so that when a human baby was conceived, the two sets of the parental chromosomes united within the fertilized ovum, passing on the full complement of 46 chromosomes to the offspring. But this initial unraveling of the “heredity mystery” merely opened up a Pandora's box of new mysteries when it came to applying genetics to the huge diversity of life on our fecund planet.
For example, did every life-form, from worms to eagles, from the protozoa that crawled about in the scum of ponds to humanity itself, carry the same kinds of genes in their nuclei-bound chromosomes?
The microscopic cellular life-forms, including bacteria and archaea, do not store their heredity in a nucleus. These are called the “prokaryotes,” which means pre-nucleates. All other life-forms store their heredity in nuclei and are known collectively as eukaryotes, which means “true nucleates.” From the growing discoveries in fruit flies, plants, and medical sciences, it was becoming rather likely—excitingly so—that some profound commonalities might be found in all nucleated life-forms. But did the same genetic concepts, such as genes, apply to the prokaryotes, which reproduced asexually by budding, without the need for germ cells? At this time within the world of early bacteriology there was even a debate as to whether bacteria should be seen as life-forms at all. And viruses, which were for the most part several orders of magnitude smaller than bacteria, were little understood.