The Stuff of Genes

In January 1953, deoxyribonucleic acid, DNA, was known to scientists numbered in the low hundreds. Its function puzzled, at most, a few score. The question of its three-dimensional molecular structure interested perhaps a dozen people. That structure was first visualized on the last day of February that year, at the Cavendish Laboratory, in Cambridge, England, by James Watson and Francis Crick. They published the first paper announcing the structure, the double helix, in the journal Nature in the issue dated April 25, 1953. They followed this up five weeks later with a second Nature paper on the structure’s "genetical implications." The discovery was transcendent—it revealed a molecule simple, parsimonious, elegant to an extreme, and of shocking explanatory power. With these first papers it was already clear to that small world of scientists that we were on the way to understanding the nature and functioning of the material substance of genes—how hereditary characters are transmitted down the generations and how they are expressed in the development and differentiation, the building, of every organism.

So now we’re marking the 50th anniversary of the publication of the structure of DNA. Is 50 years just a convenient round number, or does it have any significance, any resonance? As it turned out, the anniversary coincides with the closing of one era in molecular biology and the transition to a new one. This is, of course, the sequencing, nearly complete, of the human genome.

Of the founders of molecular biology, some have died: Max Delbrück, Rosalind Franklin, Jacques Monod, Linus Pauling, Max Perutz. Francis Crick lives: theorist and generalissimo of the golden age that followed the discovery of the structure, since the 1970s he’s been at the Salk Institute, in La Jolla, California, performing a similar role in a minor key for neuroscience. A uniquely powerful intelligence, at age 86 he is threatened by cancer but erect of carriage, clear of mind and serene of spirit. And Jim Watson? After the Nobel Prize, he turned administrator, building the Cold Spring Harbor Laboratory into a science and graduate training factory, and he remains a power and public gadfly of science, clumsy, intuitive, manic, fearless, often right, always awkward—in that fine French phrase, a monstre sacré.

DNA is a term on everyone’s lips, in every day’s newspapers and broadcast news accounts. (Recently, I saw a new line of modernistic furniture called "dna.") We are told relentlessly of the wonders that are beginning to flow from the sequencing and manipulation of DNA—from our detailed understanding of molecular genetics and from our growing skill at altering genes. The technologies of the gene have altered food crops, we are assured, radically increasing production. They have already changed organisms in stranger ways, so that goats and bacteria, for example, produce drugs. They may one day improve the diagnosis of various diseases. We are told that perhaps they will begin to offer cures for certain diseases. From the first years in the development of the technologies of the gene, in the early 1970s, the hope arose that genetic disorders—those caused by a single gene that is missing or defective—could be cured by supplying patients’ cells with the correct gene. After more than a quarter-century of fruitless efforts and the spending of hundreds of millions of dollars, gene therapy is becoming possible, though at absurd expense and with risks not yet understood. The next hope is insight, perhaps therapies, for diseases involving multiple genes, like cancers. At the least, we are told, the technologies of the gene will allow great improvements in preventive medicine, when the reading of appropriate stretches of an individual’s genome will detect genetic susceptibilities to certain ailments. Then there’s talk, still sotto voce, of making improvements in human hereditary characters by adding new genes to the germ line so that they are transmitted to offspring.

I’m not writing to advertise these wonders. The consequences of the discovery of DNA’s structure reach far deeper. The technologies of the gene will drive at least two great political changes, in my view. The first: we will not be able to deal equitably with what the human-genome project can do for the health and medical status of individuals without moving to universal single-payer medical coverage.

More startlingly, recall what the governor of Illinois, George Ryan, did on January 10 and 11 of this year, just as he was leaving office. He pardoned four men who had been convicted of murder and condemned to die, and commuted to prison terms every one of the other death-penalty sentences in that state. Ryan had been a defender of the death penalty. His was an act of conscience and courage. But the new evidence that the death penalty kills innocent people—this evidence comes mainly from the large number of cases in which DNA identifications have exonerated prisoners on death row. The practical, the political, and the ethical and moral arguments against the death penalty haven’t changed—nor have they changed public opinion much in the last half century. But now for the first time we have irrefutable scientific proof that the death penalty frequently produces irremediable injustices.

My real interest, though, is in another consequence, of a vast and entirely different order. First, a bit of history: in the summer of 1945, Vannevar Bush, an electrical engineer who was formerly vice president of MIT and director of the wartime Office of Scientific Research and Development—where he oversaw the improvement of radar, the mass production of penicillin and sulfa drugs, and the development of the atomic bomb—delivered to President Harry Truman a report titled Science: The Endless Frontier. Bush believed that basic research is technology’s feedstock and was convinced that after the war the federal government would have to continue to organize and pay for scientific research and the training of new scientists. He called for and predicted the astonishing, high-exponential growth of the enterprise of the sciences that we have all witnessed.

The uniquely compelling part of Bush’s proposal, though, was not just its assertion that basic research would produce practical payout, but that we cannot predict how long that will take, and from what particular lines. What a license for curiosity! Biologists, molecular, cell, and biomedical biologists, have been living that ideology ever since. The promise of medical advances has generated ever larger budgets.

Now, however, molecular biology is beginning to tell us things that reach beyond the practical, beyond the political, to touch and reshape our understanding of who we are and how we came to be. Since the dawn of human time, every culture has searched for stories of origins—of the universe, of the solar system, of life, of species, of humans, of language, of civilization. With gathering momentum for more than a century, science is telling better, more comprehensive, more grounded, more verifiable stories of origins.

Molecular biology has one of the greatest origin stories as yet untold—and it is now unfolding through the coming together, the fusing, of the two separate kinds of questions that have been fundamental in the century and a half since Mendel and Darwin. Biologists have always pursued questions of how, and these are about physiology—how creatures reproduce, eat, run around. Increasingly since the discovery of the structure of DNA, these questions have been approached in terms of the functioning of genes. Biologists have also been occupied with questions of why. These are about the ways we, and all other creatures, have come to have the traits and behaviors we do. "Why" questions in biology are about adaptation or extinction, the changes in species in the struggle for existence across the immense depths of geological time: in other words, they are about evolution.

Recall that not just the human genome has been sequenced, but bacteria and roundworm and fruit fly and mouse and soon chimpanzee and more, genomes over the entire range of living creatures. Now we can match these genomes up, in a new science, comparative genomics, which is just beginning to yield in full detail the fusion of genetics and evolution—of how and why. One quick example: molecular biologists in England and Germany recently discovered a DNA sequence or gene that appears essential to the human ability to use language. The sequence controls the action of a cascade of genes, affecting several functions. (Nobody said this was going to be simple.) Some members of a large family are afflicted with a single mutation in this DNA sequence that severely limits their ability to use words, to learn and employ normal syntax. Chimpanzees have that gene sequence, too—but it is slightly different from that in humans. In such discoveries lie what my friends the biologists ought to be advertising. Here are the transcendent answers we will thrill to. Darwin said it, in the poignant last paragraph of The Origin of Species: "There is grandeur in this view of life." Here is the triumph of the scientific worldview.