by Bill Bryson
Clearly something has gone wrong with our maths here. The answer, it may interest you to learn, is that your line is not pure. You couldn’t be here without a little incest—actually quite a lot of incest—albeit at a genetically discreet remove. With so many millions of ancestors in your background, there will have been many occasions when a relative from your mother’s side of the family procreated with some distant cousin from your father’s side of the ledger. In fact, if you are in a partnership now with someone from your own race and country, the chances are excellent that you are at some level related. Indeed, if you look around you on a bus or in a park or café or any crowded place, most of the people you see are very probably relatives. When someone boasts to you that he is descended from Shakespeare or William the Conqueror, you should answer at once: “Me, too!” In the most literal and fundamental sense we are all family.
We are also uncannily alike. Compare your genes with any other human being’s and on average they will be about 99.9 per cent the same. That is what makes us a species. The tiny differences in that remaining 0.1 per cent—“roughly one nucleotide base in every thousand,” to quote the British geneticist and recent Nobel laureate John Sulston—are what endow us with our individuality. Much has been made in recent years of the piecing together of the human genome. In fact, there is no such thing as “the” human genome. Every human genome is different. Otherwise we would all be identical. It is the endless recombinations of our genomes—each nearly identical to all the others, but not quite—that make us what we are, both as individuals and as a species.
Sir John Sulston at work at the Sanger Centre in Cambridgeshire, where much of the decoding of the human genome took place. (Credit 26.2)
But what exactly is this thing we call the genome? And what, come to that, are genes? Well, start with a cell again. Inside the cell is a nucleus and inside each nucleus are the chromosomes—forty-six little bundles of complexity, of which twenty-three come from your mother and twenty-three from your father. With a very few exceptions, every cell in your body—99.999 per cent of them, say—carries the same complement of chromosomes. (The exceptions are red blood cells, some immune system cells and egg and sperm cells, which for various organizational reasons don’t carry the full genetic package.) Chromosomes constitute the complete set of instructions necessary to make and maintain you and are made of long strands of the little wonder chemical called deoxyribonucleic acid or DNA—“the most extraordinary molecule on Earth,” as it has been called.
A full set of human chromosomes, arranged in twenty-three pairs. One half of each pair comes from the father and one half from the mother. The last pair denotes the sex of the owner. Here it is XX, or female. XY would indicate a male. (Credit 26.3)
DNA exists for just one reason—to create more DNA—and you have a lot of it inside you: nearly 2 metres of it squeezed into almost every cell. Each length of DNA comprises some 3.2 billion letters of coding, enough to provide 103,480,000,000 possible combinations, “guaranteed to be unique against all conceivable odds,” in the words of Christian de Duve. That’s a lot of possibility—a one followed by more than three billion zeros. “It would take more than five thousand average-size books just to print that figure,” notes de Duve. Look at yourself in the mirror and reflect upon the fact that you are beholding ten thousand trillion cells, and that almost every one of them holds two yards of densely compacted DNA, and you begin to appreciate just how much of this stuff you carry around with you. If all your DNA were woven into a single fine strand, there would be enough of it to stretch from the Earth to the Moon and back, not once or twice but again and again. Altogether, according to one calculation, you may have as much as 20 million kilometres of DNA bundled up inside you.
Your body, in short, loves to make DNA, and without it you couldn’t live. Yet DNA is not itself alive. No molecule is, but DNA is, as it were, especially unalive. It is “among the most nonreactive, chemically inert molecules in the living world,” in the words of the geneticist Richard Lewontin. That is why it can be recovered from patches of long-dried blood or semen in murder investigations and coaxed from the bones of ancient Neandertals. It also explains why it took scientists so long to work out how a substance so mystifyingly low-key—so, in a word, lifeless—could be at the very heart of life itself.
As a known entity, DNA has been around longer than you might think. It was discovered as far back as 1869 by Johann Friedrich Miescher, a Swiss scientist working at the University of Tübingen in Germany. While delving microscopically through the pus in surgical bandages, Miescher found a substance he didn’t recognize and called it nuclein (because it resided in the nuclei of cells). At the time, Miescher did little more than note its existence, but nuclein clearly remained on his mind, for twenty-three years later, in a letter to his uncle, he raised the possibility that such molecules could be the agents behind heredity. This was an extraordinary insight, but one so far in advance of the day’s scientific requirements that it attracted no attention at all.
Johann Friedrich Miescher, who discovered DNA in 1869 and, even more extraordinarily, saw that it might have a role in heredity. (Credit 26.4)
For most of the next half-century the common assumption was that the material—now called deoxyribonucleic acid, or DNA—had at most a subsidiary role in matters of heredity. It was too simple. It had just four basic components, called nucleotides, which was like having an alphabet of just four letters. How could you possibly write the story of life with such a rudimentary alphabet? (The answer is that you do it in much the way that you create complex messages with the simple dots and dashes of Morse code—by combining them.) DNA didn’t do anything at all, as far as anyone could tell. It just sat there in the nucleus, possibly binding the chromosome in some way or adding a splash of acidity on command or fulfilling some other trivial task that no one had yet thought of. The necessary complexity, it was thought, had to exist in proteins in the nucleus.
There were, however, two problems with dismissing DNA. First, there was so much of it—nearly 2 metres in nearly every nucleus—so clearly the cells esteemed it in some important way. On top of this, it kept turning up, like the suspect in a murder mystery, in experiments. In two studies in particular, one involving the Pneumonococcus bacterium and another involving bacteriophages (viruses that infect bacteria), DNA betrayed an importance that could be explained only if its role were more central than prevailing thought allowed. The evidence suggested that DNA was somehow involved in the making of proteins, a process vital to life, yet it was also clear that proteins were being made outside the nucleus, well away from the DNA that was supposedly directing their assembly.
No-one could understand how DNA could possibly be getting messages to the proteins. The answer, we now know, was RNA, or ribonucleic acid, which acts as an interpreter between the two. It is a notable oddity of biology that DNA and proteins don’t speak the same language. For almost four billion years they have been the living world’s great double act, and yet they answer to mutually incompatible codes, as if one spoke Spanish and the other Hindi. To communicate they need a mediator in the form of RNA. Working with a kind of chemical clerk called a ribosome, RNA translates information from a cell’s DNA into terms proteins can understand and act upon.
A section of ribonucleic acid taken from the salivary gland of a midge. The RNA acts as a translator—a kind of chemical interpreter—between the cell’s DNA and the protein it makes. (Credit 26.5)
However, by the early 1900s, where we resume our story, we were still a very long way from understanding that, or indeed almost anything else to do with the confused business of heredity.
Clearly there was a need for some inspired and clever experimentation, and happily the age produced a young person with the diligence and aptitude to undertake it. His name was Thomas Hunt Morgan and in 1904, just four years after the timely rediscovery of Mendel’s experiments with pea plants and still almost a decade before gene would even become a word, he began to do remarkabl
y dedicated things with chromosomes.
Chromosomes had been discovered by chance in 1888 and were so called because they readily absorbed dye and thus were easy to see under the microscope. By the turn of the century it was strongly suspected that they were involved in the passing on of traits, but no-one knew how, or even really whether, they did this.
Morgan chose as his subject of study a tiny, delicate fly formally called Drosophila melanogaster, but more commonly known as the fruit fly (or vinegar fly, banana fly or garbage fly). Drosophila is familiar to most of us as that frail, colourless insect that seems to have a compulsive urge to drown in our drinks. As laboratory specimens fruit flies had certain very attractive advantages: they cost almost nothing to house and feed, could be bred by the millions in milk bottles, went from egg to productive parenthood in ten days or less and had just four chromosomes, which kept things conveniently simple.
Thomas Hunt Morgan at work in the Fly Room at Columbia University in New York in the early 1900s. (Credit 26.6)
Working out of a small lab (which became known, inevitably, as the Fly Room) in Schermerhorn Hall at Columbia University in New York, Morgan and his team embarked on a programme of meticulous breeding and cross-breeding involving millions of flies (one biographer says billions, though that is probably an exaggeration), each of which had to be captured with tweezers and examined under a jeweller’s glass for any tiny variations in inheritance. For six years they tried to produce mutations by any means they could think of—zapping the flies with radiation and X-rays, rearing them in bright light and darkness, baking them gently in ovens, spinning them crazily in centrifuges—but nothing worked. Morgan was on the brink of giving up when there occurred a sudden and repeatable mutation—a fly that had white eyes rather than the usual red ones. With this breakthrough, Morgan and his assistants were able to generate useful deformities, allowing them to track a trait through successive generations. By such means they could work out the correlations between particular characteristics and individual chromosomes, eventually proving to more or less everyone’s satisfaction that chromosomes were at the heart of inheritance.
The problem, however, remained the next level of biological intricacy: the enigmatic genes and the DNA that composed them. These were much trickier to isolate and understand. As late as 1933, when Morgan was awarded a Nobel Prize for his work, many researchers still weren’t convinced that genes even existed. As Morgan noted at the time, there was no consensus “as to what the genes are—whether they are real or purely fictitious.” It may seem surprising that scientists could struggle to accept the physical reality of something so fundamental to cellular activity, but, as Wallace, King and Sanders point out in Biology: The Science of Life (that rarest thing: a readable textbook), we are in much the same position today in respect of mental processes such as thought and memory. We know that we have them, of course, but we don’t know what, if any, physical form they take. So it was for a very long time with genes. The idea that you could pluck one from your body and take it away for study was as absurd to many of Morgan’s peers as the idea that scientists today might capture a stray thought and examine it under a microscope.
A normal fruit fly with two wings and a mutant version with four. Such anomalous forms allowed Morgan to determine the genetic role of chromosomes. (Credit 26.7)
What was certainly true was that something associated with chromosomes was directing cell replication. Finally, in 1944, after fifteen years of effort, a team at the Rockefeller Institute in Manhattan, led by a brilliant but diffident Canadian named Oswald Avery, succeeded with an exceedingly tricky experiment in which an innocuous strain of bacteria was made permanently infectious by crossing it with alien DNA, proving that DNA was far more than a passive molecule and almost certainly was the active agent in heredity. The Austrian-born biochemist Erwin Chargaff later quite seriously suggested that Avery’s discovery was worth two Nobel Prizes.
Oswald Avery, whose meticulous investigations over fifteen years demonstrated the importance of DNA in inheritance. (Credit 26.7a)
Unfortunately, Avery was opposed by one of his own colleagues at the institute, a strong-willed and disagreeable protein enthusiast named Alfred Mirsky, who did everything in his power to discredit Avery’s work—including, it has been said, lobbying the authorities at the Karolinska Institute in Stockholm not to give Avery a Nobel Prize. Avery by this time was sixty-six years old and tired. Unable to deal with the stress and controversy, he resigned his position and never went near a lab again. But other experiments elsewhere overwhelmingly supported his conclusions, and soon the race was on to find the structure of DNA.
Had you been a betting person in the early 1950s, your money would almost certainly have been on Linus Pauling of Caltech, America’s leading chemist to crack the structure of DNA. Pauling was unrivalled in determining the architecture of molecules and had been a pioneer in the field of X-ray crystallography, a technique that would prove crucial to peering into the heart of DNA. In an exceedingly distinguished career he would win two Nobel Prizes (for chemistry in 1954 and peace in 1962), but with DNA he became convinced that the structure was a triple helix, not a double one, and never quite got on the right track. Instead, victory fell to an unlikely quartet of scientists in England who didn’t work as a team, often weren’t on speaking terms and were for the most part novices in the field.
The British molecular biologist Rosalind Franklin, who played a central part in discovering the structure of DNA but suffered from the heavy chauvinism of her male colleagues. (Credit 26.8)
Of the four, the nearest to a conventional boffin was Maurice Wilkins, who had spent much of the Second World War helping to design the atomic bomb. Two of the others, Rosalind Franklin and Francis Crick, had passed their war years working for the British government on mines—Crick on the type that blow up, Franklin on the type that produce coal.
The most unconventional of the foursome was James Watson, an American prodigy who as a boy had distinguished himself as a member of a highly popular radio programme called The Quiz Kids (and thus could claim to be at least part of the inspiration for some of the members of the Glass family in Frannie and Zooey and other works by J. D. Salinger) and who had entered the University of Chicago aged just fifteen. He had earned his PhD by the age of twenty-two and was now attached to the famous Cavendish Laboratory in Cambridge. In 1951, he was a gawky 23-year-old with a strikingly lively head of hair that appears in photographs to be straining to attach itself to some powerful magnet just out of frame.
Crick, twelve years older and still without a doctorate, was less memorably hirsute and slightly more tweedy. In Watson’s account he is presented as blustery, nosy, cheerfully argumentative, impatient with anyone slow to share a notion, and constantly in danger of being asked to go elsewhere. Neither was formally trained in biochemistry.
An X-ray diffraction image of DNA taken by Franklin in 1953. (Credit 26.9)
They assumed—correctly, as it turned out—that if you could determine the shape of a DNA molecule you would be able to see how it did what it did. They hoped to achieve this, it would appear, by doing as little work as possible beyond thinking, and no more of that than was absolutely necessary. As Watson cheerfully (if a touch disingenuously) remarked in his autobiographical book The Double Helix, “it was my hope that the gene might be solved without my learning any chemistry.” They weren’t actually assigned to work on DNA, and at one point were ordered to stop doing it. Watson was ostensibly mastering the art of crystallography; Crick was supposed to be completing a thesis on the X-ray diffraction of large molecules.
Although Crick and Watson enjoy nearly all the credit in popular accounts for solving the mystery of DNA, their breakthrough was crucially dependent on experimental work done by their competitors, the results of which were obtained “fortuitously,” in the tactful words of the historian Lisa Jardine. Far ahead of them, at least at the beginning, were two academics at King’s College in London, Wilkins and Franklin.
The New Zealand-born Wilkins was a retiring figure, almost to the point of invisibility. A 1998 PBS documentary on the discovery of the structure of DNA—a feat for which he shared the 1962 Nobel Prize with Crick and Watson—managed to overlook him entirely.
Franklin was the most enigmatic character of them all. In a severely unflattering portrait, Watson in The Double Helix depicted Franklin as a woman who was unreasonable, secretive, chronically uncooperative and—this seemed especially to irritate him—almost wilfully unsexy. He allowed that she “was not unattractive and might have been quite stunning had she taken even a mild interest in clothes,” but in this she disappointed all expectations. She didn’t even use lipstick, he noted in wonder, while her dress sense “showed all the imagination of English blue-stocking adolescents.”1
However, she did have the best images in existence of the possible structure of DNA, achieved by means of X-ray crystallography, the technique perfected by Linus Pauling. Crystallography had been used successfully to map atoms in crystals (hence “crystallography”), but DNA molecules were a much more finicky proposition. Only Franklin was managing to get good results from the process, but to Wilkins’s perennial exasperation she refused to share her findings.
