by Bill Bryson
Still facing the possibility of being trumped at any moment, Watson and Crick applied themselves feverishly to the problem. It was known that DNA had four chemical components--called adenine, guanine, cytosine, and thiamine--and that these paired up in particular ways. By playing with pieces of cardboard cut into the shapes of molecules, Watson and Crick were able to work out how the pieces fit together. From this they made a Meccano-like model--perhaps the most famous in modern science--consisting of metal plates bolted together in a spiral, and invited Wilkins, Franklin, and the rest of the world to have a look. Any informed person could see at once that they had solved the problem. It was without question a brilliant piece of detective work, with or without the boost of Franklin's picture.
The April 25, 1953, edition of Nature carried a 900-word article by Watson and Crick titled "A Structure for Deoxyribose Nucleic Acid." Accompanying it were separate articles by Wilkins and Franklin. It was an eventful time in the world--Edmund Hillary was just about to clamber to the top of Everest while Elizabeth II was imminently to be crowned queen of England--so the discovery of the secret of life was mostly overlooked. It received a small mention in the News Chronicle and was ignored elsewhere.
Rosalind Franklin did not share in the Nobel Prize. She died of ovarian cancer at the age of just thirty-seven in 1958, four years before the award was granted. Nobel Prizes are not awarded posthumously. The cancer almost certainly arose as a result of chronic overexposure to X-rays through her work and needn't have happened. In her much-praised 2002 biography of Franklin, Brenda Maddox noted that Franklin rarely wore a lead apron and often stepped carelessly in front of a beam. Oswald Avery never won a Nobel Prize either and was also largely overlooked by posterity, though he did at least have the satisfaction of living just long enough to see his findings vindicated. He died in 1955.
Watson and Crick's discovery wasn't actually confirmed until the 1980s. As Crick said in one of his books: "It took over twenty-five years for our model of DNA to go from being only rather plausible, to being very plausible . . . and from there to being virtually certainly correct."
Even so, with the structure of DNA understood progress in genetics was swift, and by 1968 the journal Science could run an article titled "That Was the Molecular Biology That Was," suggesting--it hardly seems possible, but it is so--that the work of genetics was nearly at an end.
In fact, of course, it was only just beginning. Even now there is a great deal about DNA that we scarcely understand, not least why so much of it doesn't actually seem to do anything. Ninety-seven percent of your DNA consists of nothing but long stretches of meaningless garble--"junk," or "non-coding DNA," as biochemists prefer to put it. Only here and there along each strand do you find sections that control and organize vital functions. These are the curious and long-elusive genes.
Genes are nothing more (nor less) than instructions to make proteins. This they do with a certain dull fidelity. In this sense, they are rather like the keys of a piano, each playing a single note and nothing else, which is obviously a trifle monotonous. But combine the genes, as you would combine piano keys, and you can create chords and melodies of infinite variety. Put all these genes together, and you have (to continue the metaphor) the great symphony of existence known as the human genome.
An alternative and more common way to regard the genome is as a kind of instruction manual for the body. Viewed this way, the chromosomes can be imagined as the book's chapters and the genes as individual instructions for making proteins. The words in which the instructions are written are called codons, and the letters are known as bases. The bases--the letters of the genetic alphabet--consist of the four nucleotides mentioned a page or two back: adenine, thiamine, guanine, and cytosine. Despite the importance of what they do, these substances are not made of anything exotic. Guanine, for instance, is the same stuff that abounds in, and gives its name to, guano.
The shape of a DNA molecule, as everyone knows, is rather like a spiral staircase or twisted rope ladder: the famous double helix. The uprights of this structure are made of a type of sugar called deoxyribose, and the whole of the helix is a nucleic acid--hence the name "deoxyribonucleic acid." The rungs (or steps) are formed by two bases joining across the space between, and they can combine in only two ways: guanine is always paired with cytosine and thiamine always with adenine. The order in which these letters appear as you move up or down the ladder constitutes the DNA code; logging it has been the job of the Human Genome Project.
Now the particular brilliance of DNA lies in its manner of replication. When it is time to produce a new DNA molecule, the two strands part down the middle, like the zipper on a jacket, and each half goes off to form a new partnership. Because each nucleotide along a strand pairs up with a specific other nucleotide, each strand serves as a template for the creation of a new matching strand. If you possessed just one strand of your own DNA, you could easily enough reconstruct the matching side by working out the necessary partnerships: if the topmost rung on one strand was made of guanine, then you would know that the topmost rung on the matching strand must be cytosine. Work your way down the ladder through all the nucleotide pairings, and eventually you would have the code for a new molecule. That is just what happens in nature, except that nature does it really quickly--in only a matter of seconds, which is quite a feat.
Most of the time our DNA replicates with dutiful accuracy, but just occasionally--about one time in a million--a letter gets into the wrong place. This is known as a single nucleotide polymorphism, or SNP, familiarly known to biochemists as a "Snip." Generally these Snips are buried in stretches of noncoding DNA and have no detectable consequence for the body. But occasionally they make a difference. They might leave you predisposed to some disease, but equally they might confer some slight advantage--more protective pigmentation, for instance, or increased production of red blood cells for someone living at altitude. Over time, these slight modifications accumulate in both individuals and in populations, contributing to the distinctiveness of both.
The balance between accuracy and errors in replication is a fine one. Too many errors and the organism can't function, but too few and it sacrifices adaptability. A similar balance must exist between stability in an organism and innovation. An increase in red blood cells can help a person or group living at high elevations to move and breathe more easily because more red cells can carry more oxygen. But additional red cells also thicken the blood. Add too many, and "it's like pumping oil," in the words of Temple University anthropologist Charles Weitz. That's hard on the heart. Thus those designed to live at high altitude get increased breathing efficiency, but pay for it with higher-risk hearts. By such means does Darwinian natural selection look after us. It also helps to explain why we are all so similar. Evolution simply won't let you become too different--not without becoming a new species anyway.
The 0.1 percent difference between your genes and mine is accounted for by our Snips. Now if you compared your DNA with a third person's, there would also be 99.9 percent correspondence, but the Snips would, for the most part, be in different places. Add more people to the comparison and you will get yet more Snips in yet more places. For every one of your 3.2 billion bases, somewhere on the planet there will be a person, or group of persons, with different coding in that position. So not only is it wrong to refer to "the" human genome, but in a sense we don't even have "a" human genome. We have six billion of them. We are all 99.9 percent the same, but equally, in the words of the biochemist David Cox, "you could say all humans share nothing, and that would be correct, too."
But we have still to explain why so little of that DNA has any discernible purpose. It starts to get a little unnerving, but it does really seem that the purpose of life is to perpetuate DNA. The 97 percent of our DNA commonly called junk is largely made up of clumps of letters that, in Ridley's words, "exist for the pure and simple reason that they are good at getting themselves duplicated." * 45 Most of your DNA, in other words, is not devoted to you b
ut to itself: you are a machine for reproducing it, not it for you. Life, you will recall, just wants to be, and DNA is what makes it so.
Even when DNA includes instructions for making genes--when it codes for them, as scientists put it--it is not necessarily with the smooth functioning of the organism in mind. One of the commonest genes we have is for a protein called reverse transcriptase, which has no known beneficial function in human beings at all. The one thing it does do is make it possible for retroviruses, such as the AIDS virus, to slip unnoticed into the human system.
In other words, our bodies devote considerable energies to producing a protein that does nothing that is beneficial and sometimes clobbers us. Our bodies have no choice but to do so because the genes order it. We are vessels for their whims. Altogether, almost half of human genes--the largest proportion yet found in any organism--don't do anything at all, as far as we can tell, except reproduce themselves.
All organisms are in some sense slaves to their genes. That's why salmon and spiders and other types of creatures more or less beyond counting are prepared to die in the process of mating. The desire to breed, to disperse one's genes, is the most powerful impulse in nature. As Sherwin B. Nuland has put it: "Empires fall, ids explode, great symphonies are written, and behind all of it is a single instinct that demands satisfaction." From an evolutionary point of view, sex is really just a reward mechanism to encourage us to pass on our genetic material.
Scientists had only barely absorbed the surprising news that most of our DNA doesn't do anything when even more unexpected findings began to turn up. First in Germany and then in Switzerland researchers performed some rather bizarre experiments that produced curiously unbizarre outcomes. In one they took the gene that controlled the development of a mouse's eye and inserted it into the larva of a fruit fly. The thought was that it might produce something interestingly grotesque. In fact, the mouse-eye gene not only made a viable eye in the fruit fly, it made a fly's eye. Here were two creatures that hadn't shared a common ancestor for 500 million years, yet could swap genetic material as if they were sisters.
The story was the same wherever researchers looked. They found that they could insert human DNA into certain cells of flies, and the flies would accept it as if it were their own. Over 60 percent of human genes, it turns out, are fundamentally the same as those found in fruit flies. At least 90 percent correlate at some level to those found in mice. (We even have the same genes for making a tail, if only they would switch on.) In field after field, researchers found that whatever organism they were working on--whether nematode worms or human beings--they were often studying essentially the same genes. Life, it appeared, was drawn up from a single set of blueprints.
Further probings revealed the existence of a clutch of master control genes, each directing the development of a section of the body, which were dubbed homeotic (from a Greek word meaning "similar") or hox genes. Hox genes answered the long-bewildering question of how billions of embryonic cells, all arising from a single fertilized egg and carrying identical DNA, know where to go and what to do--that this one should become a liver cell, this one a stretchy neuron, this one a bubble of blood, this one part of the shimmer on a beating wing. It is the hox genes that instruct them, and they do it for all organisms in much the same way.
Interestingly, the amount of genetic material and how it is organized doesn't necessarily, or even generally, reflect the level of sophistication of the creature that contains it. We have forty-six chromosomes, but some ferns have more than six hundred. The lungfish, one of the least evolved of all complex animals, has forty times as much DNA as we have. Even the common newt is more genetically splendorous than we are, by a factor of five.
Clearly it is not the number of genes you have, but what you do with them. This is a very good thing because the number of genes in humans has taken a big hit lately. Until recently it was thought that humans had at least 100,000 genes, possibly a good many more, but that number was drastically reduced by the first results of the Human Genome Project, which suggested a figure more like 35,000 or 40,000 genes--about the same number as are found in grass. That came as both a surprise and a disappointment.
It won't have escaped your attention that genes have been commonly implicated in any number of human frailties. Exultant scientists have at various times declared themselves to have found the genes responsible for obesity, schizophrenia, homosexuality, criminality, violence, alcoholism, even shoplifting and homelessness. Perhaps the apogee (or nadir) of this faith in biodeterminism was a study published in the journal Science in 1980 contending that women are genetically inferior at mathematics. In fact, we now know, almost nothing about you is so accommodatingly simple.
This is clearly a pity in one important sense, for if you had individual genes that determined height or propensity to diabetes or to baldness or any other distinguishing trait, then it would be easy--comparatively easy anyway--to isolate and tinker with them. Unfortunately, thirty-five thousand genes functioning independently is not nearly enough to produce the kind of physical complexity that makes a satisfactory human being. Genes clearly therefore must cooperate. A few disorders--hemophilia, Parkinson's disease, Huntington's disease, and cystic fibrosis, for example--are caused by lone dysfunctional genes, but as a rule disruptive genes are weeded out by natural selection long before they can become permanently troublesome to a species or population. For the most part our fate and comfort--and even our eye color--are determined not by individual genes but by complexes of genes working in alliance. That's why it is so hard to work out how it all fits together and why we won't be producing designer babies anytime soon.
In fact, the more we have learned in recent years the more complicated matters have tended to become. Even thinking, it turns out, affects the ways genes work. How fast a man's beard grows, for instance, is partly a function of how much he thinks about sex (because thinking about sex produces a testosterone surge). In the early 1990s, scientists made an even more profound discovery when they found they could knock out supposedly vital genes from embryonic mice, and the mice were not only often born healthy, but sometimes were actually fitter than their brothers and sisters who had not been tampered with. When certain important genes were destroyed, it turned out, others were stepping in to fill the breach. This was excellent news for us as organisms, but not so good for our understanding of how cells work since it introduced an extra layer of complexity to something that we had barely begun to understand anyway.
It is largely because of these complicating factors that cracking the human genome became seen almost at once as only a beginning. The genome, as Eric Lander of MIT has put it, is like a parts list for the human body: it tells us what we are made of, but says nothing about how we work. What's needed now is the operating manual--instructions for how to make it go. We are not close to that point yet.
So now the quest is to crack the human proteome--a concept so novel that the term proteome didn't even exist a decade ago. The proteome is the library of information that creates proteins. "Unfortunately," observed Scientific American in the spring of 2002, "the proteome is much more complicated than the genome."
That's putting it mildly. Proteins, you will remember, are the workhorses of all living systems; as many as a hundred million of them may be busy in any cell at any moment. That's a lot of activity to try to figure out. Worse, proteins' behavior and functions are based not simply on their chemistry, as with genes, but also on their shapes. To function, a protein must not only have the necessary chemical components, properly assembled, but then must also be folded into an extremely specific shape. "Folding" is the term that's used, but it's a misleading one as it suggests a geometrical tidiness that doesn't in fact apply. Proteins loop and coil and crinkle into shapes that are at once extravagant and complex. They are more like furiously mangled coat hangers than folded towels.
Moreover, proteins are (if I may be permitted to use a handy archaism) the swingers of the biological world. Depending on mood
and metabolic circumstance, they will allow themselves to be phosphorylated, glycosylated, acetylated, ubiquitinated, farneysylated, sulfated, and linked to glycophosphatidylinositol anchors, among rather a lot else. Often it takes relatively little to get them going, it appears. Drink a glass of wine, as Scientific American notes, and you materially alter the number and types of proteins at large in your system. This is a pleasant feature for drinkers, but not nearly so helpful for geneticists who are trying to understand what is going on.
It can all begin to seem impossibly complicated, and in some ways it is impossibly complicated. But there is an underlying simplicity in all this, too, owing to an equally elemental underlying unity in the way life works. All the tiny, deft chemical processes that animate cells--the cooperative efforts of nucleotides, the transcription of DNA into RNA--evolved just once and have stayed pretty well fixed ever since across the whole of nature. As the late French geneticist Jacques Monod put it, only half in jest: "Anything that is true of E. coli must be true of elephants, except more so."
Every living thing is an elaboration on a single original plan. As humans we are mere increments--each of us a musty archive of adjustments, adaptations, modifications, and providential tinkerings stretching back 3.8 billion years. Remarkably, we are even quite closely related to fruit and vegetables. About half the chemical functions that take place in a banana are fundamentally the same as the chemical functions that take place in you.
