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It’s Even Less in Your Genes

In real life there will be some difference between the varieties when averaged over locations and some variation between locations when averaged over varieties; but there will also be some interaction variation accounting for the failure of the separately identified main effects to add up to the total variation. In an extreme case, as for example our jungle drummers with a common consciousness of what drums should sound like, it may turn out to be all interaction.

The Mirage of a Space Between Nature and Nurture appears in an era when biological—and specifically, genetic—causation is taken as the preferred explanation for all human physical differences. Although the early and mid-twentieth century was a period of immense popularity of genetic explanations for class and race differences in mental ability and temperament, especially among social scientists, such theories have now virtually disappeared from public view, largely as a result of a considerable effort of biologists to explain the errors of those claims.

The genes for IQ have never been found. Ironically, at the same time that genetics has ceased to be a popular explanation for human intellectual and temperamental differences, genetic theories for the causation of virtually every physical disorder have become the mode. “DNA” has replaced “IQ” as the abbreviation of social import. The announcement in February 2001 that two groups of investigators had sequenced the entire human genome was taken as the beginning of a new era in medicine, an era in which all diseases would be treated and cured by the replacement of faulty DNA. William Haseltine, the chairman of the board of the private company Human Genome Sciences, which participated in the genome project, assured us that “death is a series of preventable diseases.” Immortality, it appeared, was around the corner. For nearly ten years announcements of yet more genetic differences between diseased and healthy individuals were a regular occurrence in the pages of The New York Times and in leading general scientific publications like Science and Nature.

Then, on April 15, 2009, there appeared in The New York Times an article by the influential science reporter and fan of DNA research Nicholas Wade, under the headline “Study of Genes and Diseases at an Impasse.” In the same week the journal Science reported that DNA studies of disease causation had a “relatively low impact.” Both of these articles were instigated by several articles in The New England Journal of Medicine, which had come to the conclusion that the search for genes underlying common causes of mortality had so far yielded virtually nothing useful. The failure to find such genes continues and it seems likely that the search for the genes causing most common diseases will go the way of the search for the genes for IQ.

A major problem in understanding what geneticists have found out about the relation between genes and manifest characteristics of organisms is an overly flexible use of language that creates ambiguities of meaning. In particular, their use of the terms “heritable” and “heritability” is so confusing that an attempt at its clarification occupies the last two chapters of The Mirage of a Space Between Nature and Nurture. When a biological characteristic is said to be “heritable,” it means that it is capable of being transmitted from parents to offspring, just as money may be inherited, although neither is inevitable. In contrast, “heritability” is a statistical concept, the proportion of variation of a characteristic in a population that is attributable to genetic variation among individuals. The implication of “heritability” is that some proportion of the next generation will possess it.

The move from “heritable” to “heritability” is a switch from a qualitative property at the level of an individual to a statistical characterization of a population. Of course, to have a nonzero heritability in a population, a trait must be heritable at the individual level. But it is important to note that even a trait that is perfectly heritable at the individual level might have essentially zero heritability at the population level. If I possess a unique genetic variant that enables me with no effort at all to perform a task that many other people have learned to do only after great effort, then that ability is heritable in me and may possibly be passed on to my children, but it may also be of zero heritability in the population.

One of the problems of exploring an intellectual discipline from the outside is that the importance of certain basic methodological considerations is not always apparent to the observer, considerations that mold the entire intellectual structure that characterizes the field. So, in her first chapter, “Nature and Nurture as Alternatives,” Fox Keller writes that “my concern is with the tendency to think of nature and nurture as separable and hence as comparable, as forces to which relative strength can be assigned.” That concern is entirely appropriate for an external critic, and especially one who, like Fox Keller, comes from theoretical physics rather than experimental biology. Experimental geneticists, however, find environmental effects a serious distraction from the study of genetic and molecular mechanisms that are at the center of their interest, so they do their best to work with cases in which environmental effects are at a minimum or in which those effects can be manipulated at will. If the machine model of organisms that underlies our entire approach to the study of biology is to work for us, we must restrict our objects of study to those in which we can observe and manipulate all the gears and levers.

For much of the history of experimental genetics the chief organism of study was the fruit fly, Drosophila melanogaster, in which very large numbers of different gene mutations with visible effects on the form and behavior of the flies had been discovered. The catalog of these mutations described, in addition to genetic information, a description of the way in which mutant flies differed from normal (“wild type”) and assigned each mutation a “Rank” between 1 and 4. Rank 1 mutations were the most reliable for genetic study because every individual with the mutant genetic type could be easily and reliably recognized by the observer, whereas some proportion of individuals carrying mutations of other ranks could be indistinguishable from normal, depending on the environmental conditions in which they developed. Geneticists, if they could, avoided depending on poorer-rank mutations for their experiments. Only about 20 percent of known mutations were of Rank 1.

With the recent shift from the study of classical genes in controlled breeding experiments to the sequencing of DNA as the standard method of genetic study, the situation has gotten much worse. On the one hand, about 99 percent of the DNA in a cell is of completely unknown functional significance and any two unrelated individuals will differ from each other at large numbers of DNA positions. On the other hand, the attempt to assign the causes of particular diseases and metabolic malfunctions in humans to specific mutations has been a failure, with the exception of a few classical cases like sickle-cell anemia. The study of genes for specific diseases has indeed been of limited value. The reason for that limited value is in the very nature of genetics as a way of studying organisms.

Genetics, from its very beginning, has been a “subtractive” science. That is, it is based on the analysis of the difference between natural or “wild-type” organisms and those with some genetic defect that may interfere in some observable way with regular function. But to carry out such comparison it is necessary that the organisms being studied are, to the extent possible, identical in all other respects, and that the comparison is carried out in an environment that does not, itself, generate atypical responses yet allows the possible effect of the genetic perturbation to be observed. We must face the possibility that such a subtractive approach will never be able to reveal the way in which nature and nurture interact in normal circumstances.

An alternative to the standard subtractive method of genetic perturbations would be a synthetic approach in which living systems would be constructed ab initio from their molecular elements. It is now clear that most of the DNA in an organism is not contained in genes in the usual sense. That is, 98–99 percent of the DNA is not a code for a sequence of amino acids that will be assembled into long chains that will fold up to become the proteins that are essential to the formation of organisms; yet that nongenic DNA is transmitted faithfully from generation to generation just like the genic DNA.

It appears that the sequence of this nongenic DNA, which used to be called “junk-DNA,” is concerned with regulating how often, when, and in which cells the DNA of genes is read in order to produce the long strings of amino acids that will be folded into proteins and which of the many alternative possible foldings will occur. As the understanding and possibility of control of the synthesis of the bits and pieces of living cells become more complete, the temptation to create living systems from elementary bits and pieces will become greater and greater. Molecular biologists, already intoxicated with their ability to manipulate life at its molecular roots, are driven by the ambition to create it. The enterprise of “Synthetic Biology” is already in existence.

In May 2010 the consortium originally created by J. Craig Venter to sequence the human genome gave birth to a new organization, Synthetic Genomics, which announced that it had created an organism by implanting a synthetic genome in a bacterial cell whose own original genome had been removed. The cell then proceeded to carry out the functions of a living organism, including reproduction. One may argue that the hardest work, putting together all the rest of the cell from bits and pieces, is still to be done before it can be said that life has been manufactured, but even Victor Frankenstein started with a dead body. We all know what the consequences of that may be.

Letters

What Genes Can’t Tell Us: An Exchange October 13, 2011

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