Born That Way

by William Wright

  Among the ramifications they illuminate is the simple fact of human variation and how essential tiny changes are to the evolution of different species. To assure this variation, of all the billions of sperm and egg cells that become humans, as well as the zillions that are produced but never develop, no two are the same. Identical twins, who are genetically the same, are not exceptions to this fact, as they come from the same egg and sperm cell. As chromosomes divide in the reproductive process (meiosis) and half the mother’s DNA binds with half the father’s—the genes shuffle their millions of elements to produce endless variations on the human theme. This process assures the species infinite opportunities for change, yet always sticking within genetic boundaries that guarantee a degree of species stability.

  This roiling sea of variation is occasionally given a jolt with an outright mutation, a tidal-wave variation like six toes or smaller ears—anomalies that will probably go nowhere but into the evolutionary ash can. Of all mutations that occur, many of them, estimates run as high as 50 percent, abort before birth. If, on the other hand, a mutation appears in a living organism and gives it a procreational advantage, the change, through natural selection, will all but inevitably spread slowly throughout the species. If it is a highly advantageous mutation, in a brief million years or so it will probably become a permanent part of the species’ basic equipment and lead to the extinction of all members of the species lacking it.

  According to the fossil evidence, it generally takes vast periods of time for mutations to achieve specieswide success, but a 1994 book, The Beak of the Finch by Jonathan Weiner, provides strong evidence that the evolutionary process can occur much faster—with the Galapagos finches, in a scant fifty years, even less. This has interesting ramifications for humans, in particular for the pessimistic idea that we evolved to our present form in an environment totally different from the one in which we now find ourselves. We are stuck, the thinking goes, with outdated evolutionary equipment and cannot hope to evolve fast enough to catch up. Weiner’s book offers hope. I can’t predict which human traits will be detrimental and which advantageous, but just on a wild hunch, I would bet on computer whizzes for winning the genetic sweepstakes. And I wouldn’t rule out seven-foot basketball stars.

  Another feature of many DNA primers is a reluctance to announce parts of the picture not yet known. I found all the books quick to reveal that each of the 100 trillion cells in the human body has a complete complement of that body’s DNA. Each cell’s DNA is broken down into twenty-three pairs of chromosomes. The DNA from just one set of these chromosomes contains all the information needed to make and operate a human and, if laid out in one continuous strand, would be six feet long. That’s just the DNA from one of our body’s trillions of cells. (British geneticist Steve Jones makes this incredible fact even more indigestible by pointing out that if the DNA from one human were stretched out in a line, it would go to the moon and back eight thousand times.)

  Except for identical twins, the DNA in each cell is identical and particular to one individual, to the dismay of many criminals. Each cell’s DNA, all twenty-three chromosomes, is made up of some three billion nucleic bases. Most of this appears to be nonfunctioning, “junk” DNA as it is called, but about 3 percent are operating genes. The total number of working genes is thought to be somewhere between 50,000 and 150,000. The wide spread in the estimate reveals a glimpse of the lingering uncertainties among scientists about fundamental divisions. On the other hand, considering that the DNA molecule’s structure was only discovered forty years ago, it is amazing how much of the overall arrangement is understood.

  As I waded through the textbooks, I was struck by the absence of any talk about the relationship of DNA molecules to chromosomes. The books all say that the double helix is a long, to-the-moon molecule and it is, at times in its life, wound yarnlike in the sausage-shaped spindle of the chromosome. No mention is made, however, of the number of these molecules in a chromosome. If the number of chromosomes in a cell is important enough for constant reiteration, why not the number of DNA molecules in a chromosome?

  Sure I had nailed them for leaving out this elementary point, I popped my question to a prominent molecular biologist at the N.I.H. Slowly, he replied, “We think it is one molecule per chromosome, but we don’t know.”

  Don’t know? How are they going to find the one-billionth bit that causes depression or optimism if they don’t even know the number of molecules in a chromosome? Adding to my confusion, when the scientists talk about cutting snippets of the DNA molecule, they also call the resulting fragment “a molecule.” Like worms, a DNA molecule cut in half becomes two DNA molecules. Such sliding terminology does not inspire confidence in the nonscientist who prefers words to stay within definitions, especially one who is struggling to learn the rudiments of molecular biology.

  A gene is defined as a sequence of nucleic bases that is self-replicating and from which a protein can be synthesized. Proteins are what make everything happen, what is more, they are everything. They have many forms and functions—messenger proteins, instructive proteins, timing proteins, and building-block proteins. The gene creates them and tells them their mission. They then spread the word to all relevant departments.

  Richard Dawkins, in his book The Selfish Gene, offers the controversial view that the gene is the end product, the point of it all. Organisms like humans are mere vehicles for serving, generation after generation, the gene’s mindless drive toward immortality. According to Dawkins, the relentless, exploitive gene uses our bodies to replicate itself and reproduce for future use as many similarly hospitable bodies as possible. The gene aims only to propagate itself and assure “its” survival in ever more numerous generations of descendants. As with most theories that reduce our cosmic status and render us less adorable (us? selfish?), this theory is hotly contested. Presumably for scientific reasons and not wounded pride, Stephen Jay Gould feels such a view of genes mistakes the messenger of change with its cause. The argument, however, seems more about the precision of Dawkins’s metaphor rather than the genetic principle it seeks to describe.

  The Dawkins picture of gene single-mindedness gets murky when you consider some 100,000 genes, all with different functions, using for their selfish ambitions the same “vehicle.” And these vehicles that are merely serving the genes’ ambitions would include every human—from Mother Teresa to Saddam Hussein—plus every other earthly creature, from microspira protozoa to sperm whales. Anarchical as this sounds, there is more than a little evidence that it is true, at least the part about genes having different purposes from one another and certainly from us vehicles. There they all are, pushing us this way and that, each doggedly determined to carry out its mission of self-perpetuation, sometimes in concert with their neighbors, sometimes in opposition—but all oblivious to everything but their own survival.

  In the past year or two, the lid has been lifted a bit from the black box; and the peek has revealed a lot about the mechanics of genes and the way they function. When a gene goes into action, which happens in different cells at different times, it transcribes its information onto a molecule that it assembles from the free-floating sugars and phosphates in the surrounding nucleus. This is messenger RNA that carries the genetic news into the surrounding cytoplasm, where it hooks up to a molecule of transfer RNA, to which it delivers its information. The transfer RNA assembles itself according to this information and, depending on its form, proceeds to attract one of twenty amino acids to form polypeptide chains that constitute the proteins and enzymes that make up humans. (The word protein is chemically descriptive, whereas enzyme refers to function. Enzymes are proteins that act as organic catalysts.) When activated, RNA carries out the DNA’s instructions to form a particular protein very quickly, at a staggering rate of 100 molecules a second. The same complicated process, using the same genetic code, occurs in every living organism.

  Some of the genes in each human cell carry instructions for building arms, legs, and livers. The g
enes for creating the complex hemoglobin molecules are well understood, as are many of those creating various enzymes. But as an indication of how complex it all is, and as an indication of why it takes three billion base pairs to make an operative human, there are sixty different proteins in a human tear, two hundred in a drop of blood. To locate the specific genes for creating arms, legs, and tears is a complicated business. It is undoubtedly far more complicated to pinpoint genes that influence behavior.

  IN SETTING OUT on the grueling task of locating behavioral genes, the current procedure is to find families that have a high incidence of a recognizable and unusual trait or disorder, enough instances within one family to suggest genetic involvement. Then from as many family members as possible, the DNA is examined in the hope of finding a variation that is common to the afflicted members but absent in the nonafflicted. Because any one of the three billion DNA base pairs could be involved, the search is daunting.

  In describing a hunt for a behavioral gene, a frequent analogy is searching for a leaky faucet known only to be somewhere on Earth. If a gene search can be narrowed to a specific chromosome, that is comparable to learning the leak is somewhere in Texas. There are techniques for narrowing the search somewhat—to tell you, for instance, that the problem faucet is in Dallas; but here the shortcuts end. Having arrived at the correct city, you must walk up and down its streets knocking on doors until the leak is found. Given the length and the thinness of the DNA molecule, a better analogy might be seeking a defective spike on the trans-Siberian railroad. In a sense, that is what Arlen Price and Dani Reed and hundreds of others do each day, walking the track, or the streets of Dallas, looking for an infinitesimal snippet of DNA that causes a behavior.

  At the present time the most successful means of narrowing the search is the linkage study. This technique rests on the principle that if traits lie close together on a chromosome, the chances are extremely low they will separate during the DNA shuffling that occurs when offspring are conceived. The search is aided by the existence of markers, locations on the DNA chain that appear at the same spot on every chromosome and are sufficiently similar in all humans to serve as guideposts and sufficiently different to be identifiable as coming from one family. If the guide post and the trait appear together consistently in subsequent generations—freckles and diabetes, as a hypothetical example—the suspicion runs high that the marker and the target gene are too close to separate during the gene shuffling at inception. The two genes are said to be linked. The principle is that if two knots are a quarter inch apart on a ball of twine and the twine is cut every twenty-five feet, the chances are almost nonexistent that a cut will separate the knots. It’s not impossible, just extremely unlikely. If the two traits repeatedly turn up together in generation after generation, the searched-for trait is said to be linked to that particular marker. Since the location of the marker is known, the rough location of the searched-for gene is now known as well.

  But when linkage is discovered, that brings the gene-tracker only to Dallas. There are still all those streets and buildings to search. Still, closing in even to the degree of finding the right chromosome, or better, the gene’s general location on the chromosome, is considered an important advance, as when the Huntington’s chorea gene was linked in 1983 by Nancy Wexler and James Gusella. But as discouraging evidence of the gulf between linking and finding the actual gene, it took six research teams working at ten different institutions another ten years before they found the Huntington’s gene itself in 1993.

  Even having at last achieved the miracle of pinpointing the actual gene—Huntington’s turned out to be, as suspected, a single, dominant gene—Wexler and her colleagues have no idea how it causes the disease, nor have they devised a strategy for disabling it. Still, few would argue that finding the specific gene put them no closer to a remedy.

  OF THE VARIOUS LINKAGE STUDIES in recent years aimed at pinpointing genes for behavioral traits, the biggest breakthrough appeared to come in 1987, when a group headed by Janice Egeland from the University of Miami School of Medicine studied thirty-two Older Order Amish families in which a high incidence of manic depression was found. The Pennsylvania Amish were an ideal group for genetic study in that they were descended from the same forty families, they kept detailed health records, and there was little marriage with outsiders. The group had come to the melting pot in the nineteenth century and had not melted. They were also free of the alcohol and drug-abuse problems that can wreak havoc on diagnoses of amorphous conditions like depression and anxiety disorders.

  When the Egeland group announced linking the depression-causing gene to a marker on chromosome 11, it was heralded on the front pages of the New York Times as a landmark genetic development. It was the first claim of hard evidence that an intricate behavioral disorder was inherited in a straightforward Mendelian pattern. The finding caused considerable excitement and looked as though it would bring back to life psychiatric genetics, a field all but comatose since the advent of Freudianism. The Amish study, however, enjoyed a far briefer period of triumph than did Freud. When another team from the National Institutes of Health tried to replicate the study, at the same time increasing the number of family members examined, they could not substantiate the earlier findings.

  The same year, similar hopes were raised for locating a genetic basis for manic depression by a group at Columbia University headed by Miron Baron. Three Israeli families were found with an unusually high incidence of clinical depression. After scanning their DNA, the Columbia team announced they had located the genes responsible. This group, too, later had to retract their claim because of insufficient evidence. With the Amish study, the biggest blow came when two of the individuals considered well—no signs of the disease and lacking the incriminating stretch of DNA—later came down with depression. This seriously reduced the statistical weight of the earlier finding. The Barron study apparently had different methodological problems. With or without design flaws, both studies provided discouraging evidence of the complexity of the gene-behavior relationship and the elusiveness of pinning down direct biochemical causes. They also proved yet again a difference between studying humans and white mice.

  In 1990 excitement again ran high when Ernest Noble, a psychiatrist at the University of California, and Kenneth Blum, a pharmacologist at the University of Texas, announced they had found a gene on chromosome 11 for alcoholism, or more precisely, “a reward gene” that heightens susceptibility to alcoholism and many other compulsive behaviors. Of a large group of alcoholics tested, an impressive 69 percent had a variant in this gene that was not present in 80 percent of the control group. When the discovery was made public, again on the front pages, the finding was taken as the long-awaited hard proof of a gene-behavior connection.

  As with the Amish study, the victory unraveled quickly when other institutions could not replicate the findings. Convinced they were right, Noble and Blum argued against their detractors’ methods—alcoholics in the control groups, for instance, or eliminating for medical reasons the alcoholics most likely to carry the gene variant—and they may yet be vindicated; but for the moment the study has been judged another behavioral genetics failure.

  PREDICTABLY, THE OPPONENTS of behavioral genetics were delighted by these misfires, touting them as proof of zero connection between genes and behavior. Such a conclusion was unjustified. With the Amish study, the most casual glance at the high incidence of depression in certain families and not others, and among skipped generations unknown to each other (a depressed child’s grandfather was also depressed, for example), should dispel anyone’s doubt that genes and heredity were somehow involved in the phenomenon. The Amish study’s collapse meant only that searching along the three billion base pairs in the human genome, these scientists were unable to pinpoint exactly which chromosomal area or areas were responsible for the extraordinarily high number of afflicted people in one bloodline over a number of generations. But in the shortened press versions of the setback, the im
pression was left that a genetic connection to depression had yet to be established. This was untrue; science had merely failed to locate the specific gene.

  Many were beginning to feel the misfire problem lay in leaning too heavily on the assumption that only one gene was causing the problem under investigation. Understandably, behavioral researchers were envious of the genetic triumphs relating to physical afflictions like Huntington’s and cystic fibrosis. Like Mendel with his peas, the scientists involved had been lucky to have targeted disorders for which only one gene turned out to be responsible. There was no guarantee such genetic simplicity would be true of all conditions; with behavior, the likelihood was high it would not. The elusiveness of behavioral genes was bringing more and more scientists to the view that behavioral traits invariably have more than one genetic cause—either different genes working in concert to bring on depression, for example, or totally unrelated genes causing the same disorder in different people. Your depression might have one genetic cause, mine another. A third person’s might not be related to genes at all.