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weinberg.ch19.the-dark-side-of-the-genome.lib-iss

weinberg.ch19.the-dark-side-of-the-genome.lib-iss - 19 The...

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Unformatted text preview: 19. The Dark Side of the Genome ROBERT A. WEINBERG Among the most rapid and important scientific advances of the past two decades have been developments in molecular biology. The breaking of the genetic code and the development of new techniques to analyze genetic materials have given scien— tists the ability to understand the relationship between the biochemical building blocks of cells and the traits and characteristics of living organisms, including humans, During the past several years, life scientists in several countries have begun a coordinated, systematic effort to create a complete biochemical description of the human genome (i.e., the DNA contained in the chromosomes in human cells) and to develop a map or atlas indicating which components of this genetic material determine which human traits, from susceptibility to particular disorders to eye color to mathematical or artistic ability. Already, geneticists have identified the location of genes associated with dozens of disorders, including cystic fibrosis, fragilevX synr drome (a form of mental retardation), and Huntington’s disease. These new capabilities offer the prospect of eliminating a great deal of human suffering, but they also present some serious ethical dilemmas and risks to society. Use of genetic information by insurance companies, by employers, and by govern» ment agencies could infringe on individual rights to privacy and could even make it difificult for some people to get health insurance, find employment, or find a mar— riage partner. Robert A. Weinberg, one of the leading figures in molecular genetics, discusses some of these perplexing issues in his essay, “The Dark Side of the Genome.” \Weina berg is a professor of biology at the Massachusetts Institute of Technology and a member of the Whitehead Institute for Biomedical Research. His laboratory was among the first to recognize the existence of human oncogenes, which are responsi— ble for converting normal cells into cancer cells. Weinberg holds a PhD. in biology from MIT. He is a member of the National Academy of Sciences and the recipient of a long list of honors, scientific prizes, and honorary degrees, including, in 1997, the National Medal of Science. In the past 10 years biology has undergone a revolution that has repeatedly attracted wide attention. At first, controversy swirled over whether the genetic cloning technology that powers this revolution could create new and possibly dangerous forms of life. These fears have dissipated as thousands of investigators have found that the organisms created by gene splicing pose no threat to human health or the ecosystem around us. 216 Technology and the Future A m ' mg to gigiarger stream of headlines next touted the power of genetic engineer uce great quantities of valuable med' ' ‘ . ical and a ric It 1 d cheaply. Without doubt g u ”I3 pro UCtS , over the next decades these frui ' ts of biotech ' enErmOilisly benefit health and economic productivity ~ HOIOEY W111 ar ' ' ‘ mate] 5: : V160: fanilidst these stories, however, are developments that will ulti— ar arger socia impact Recentl ' d b' ' ' [ex . ‘ . . . . y game a ilities to anal ze com— Zaitsgfergfrtic infprrgation, including our own, will soon allow us to predict human pOSitions t Slglp e NA tests. [In Just a few years], routine tests will detect predis— traits W E ozerrids o; diseases as well as indicate a wide range of normal human . e ave o y egun to confront the r 1 - O geneuc dlagnosis. p blems engendered by the power of Con ' ' recent :Siglergfor egafrlnple, the societal problems that will likely develop from the cou S 1 a ion 0 t e gene that in a defective form causes cystic fibrosis. Genetic th 11 e ors can now trace that version of the gene in families . ) expse cguplels who could have children with cystic fibrosis r O o . n v . a r inari y useful information for cystic fibrosis carriers, this technique raises . l . .1. . . . . and the ter ' . . . insurance, ms under Wthh the“ Offspring W111 be able to obtain health and life thereby revealing While providing ovirrisdlgadualcifcesses like the isolation of the cystic fibrosis gene will soon be labs Theoewe . y fihe avalanche of genetic information flowing out of research . ngine t at Will drive these advances in gene analysis is the biologists’ m0 ‘ intsriighgllgfgfigfiatn Gegome 1PirOJect. (See box.) The ambitious goal of this 0 rea out t e sequence of the 3 billion b strung end to end, carry the information of all t 3585 OfDNA that, . he bod ’ ' 63511 t . y s genes. Given a clear the :ateCadtatlefi'of, our genetic endowment, researchers will be able to accelerate year b :1 1 svfglcd thgy discovielr important genes — now several dozen each —— — an eventua y maybe even 100 f ld S ' ' ‘ able to study how the ‘ — o . Cientists Will then be normal verSions of these ’ rant versions cause disease. genes work, and hOW the” abet! Some ' we will rgfgacruthat by readirélg through the entire library of human gene sequences y come to un erstand the ultimate s ‘ . ecrets of life and th our humanity For my part 5 e essence Of . . , uch fears are far astra of th k O ' tion as complex networks of ' ' Y e mar I ur bOdleS funC’ interacting com on t h ' by our variabl ' p en 5 t at are often influenced e enVironment. By enumeratin ' ' ' ' . g and studying indiVid l orients — ' ' U3 C0m‘ pomplexfiy $322111: lthis case — we Will only begin to scratch the surface of our . ess, certain genes can be especiall ' ' ' . influential in d t ' ing one or another aspect of hum ' Y e ermm‘ an form and function Herei l' . ’ . . 11 ie the seeds of substantial problems we Will begin to encounter over the next decade the MAPPING THE GENETIC TERRAIN Ten t ’ fists sdflllftfie: yedars from now — barring unforeseen technical obstacles —— scien’ before th‘ a e .escribed every bump in our complex genetic terrain. Yet long is prolect is finished, information yielded by “mapping” this land Weinberg / The Dark Side of the Genome 217 DNA and Babylonian Tablets To find every human gene, scientists will have to determine the sequence of the 3 billion characters in our DNA that together form the genetic blueprint known as the human genome. One can convey how daunting the effort will be by comparing the genome to a Babylonian library uncovered in some nineteenth‘century archeological dig. Imagine tens of thousands of clay tablets —— individual genes —- scattered about, each inscribed with thousands of cuneiform characters in a language with few known cognates. The library’s chaos mirrors that encountered when the precisely ordered array of DNA molecules that is present in a living cell is extracted and introduced into a test tube. Imagine, too, that the library’s full meaning will be understood only when most of its tablets have been deciphered. Geneticists today have ways of laboriously sifting through heaps of “tablets” to find certain genes of special interest. Once a gene is located and retrieved, or “cloned,” the sequence of its 5,000 or more bases of DNA — our cuneiform characters — can be determined. While biologists are proud of having sequenced more than one percent of the “tablets” so far, these achievements represent only a piecemeal solution to a very large problem. Gene cloning and sequencing techniques developed in the 19705 are so time—consuming and painstaking that systematic searches for many genes have been impossible. A better answer, in the form of the human genome project, will begin by mapping the genome — cataloguing all the Babylonian tablets. In effect, geneticists will gather and systematically shelve the scattered tablets, reconstructing their original order. Initially, groups of tablets (DNA fragments) thought to derive from a common 5er tion (chromosomal region) of the library will be placed together on a shelf. Then genetiv cists will order the tablets within a group and give each a label. They will do so without any understanding of the tablets’ contents. How is this possible? Imagine that our Babylonian scribes have used the final phrases at the end of one tablet as the opening phrases of the next one. Short, redundant strings of characters would enable tablets to be shelved in the right order without any knowl- edge of the bulk of the text. Long, carefully ordered lists of the labels identifying individ— ual tablets, in effect a complete library catalogue, will compose the human genome map. Only after this work is completed can the reading of all the characters in eachtablet proceed — the sequencing of the DNA bases. Great technical progress will be required before the work becomes economically viable. Sequencing a 1,000rbase stretch of DNA now c0sts $5,000 to $10,000. And some genes are giants; the one involVed in muscular dystrophy was recently found to encompass 2 million bases. The cost will have to drop by a factor of 10 through automation before sequencing can begin in earnest. Think of the technology required to develop automated readers that could photo— graph 3,000—year—old tablets, analyze and read the characters with greater than 99 per— cent accuracy, flag ambiguous ones, and introduce everything into a computerized database. The details of the automated DNA—sequencing equipment under develop— ment differ, but the technical problems are no less challenging. ——R0bert A. Weinberg 218 Technology and the Future scape — breaking it into sectors of manageable size and placing them in a logical array —— will make possible powerful genetic analysis techniques. These, in turn, will engender a host of ethical issues. To understand why, it is important to know a little about the underlying biol— ogy. The human genetic landscape — our genome — consists of all the DNA information carried on the 22 pairs of chromosomes in our cells plus the X and Y chromosomes involved in determining sex. Each chromosome carries a linear molecule of DNA ranging in size from 50 million to 250 million pairs of four kinds of chemical bases. They are commonly referred to by the letters A, C, G, and T. In all, 3 billion base pairs of DNA lie on the chromosomes. Some 50,000 to 100,000 discrete segments of DNA —— each several thousand or more base pairs long — constitute the genes that store our genetic information. The trick is to figure out where these genes lie, and what information each encodes. As a first step in understanding this enormous information base, investigators have started mapping each chromosome by labeling small segments along its length. The labels used are actually built—in features of the genome. They consist of minor genetic variations called polymorphisms that occur frequently through— out human DNA sequences and distinguish one person’s DNA from another’s. For example, at a certain chromosomal site, one person’s DNA bases may read AAGCTT while a second person’s may read AAGTTT. Such polymorphisms, widely scattered throughout the genome, are readily detected using existing tech niques, even without any knowledge of the genome’s detailed structure. Polymorphisms are not only important for their usefulness in marking the genome at specific places. The location of a particular gene in the human genome is usually obscure. Geneticists can track down such a gene by localizing it near one or another polymorphic marker. To do this, they ascertain the presence of markers in DNA samples collected from members of large families and even large, unrelated populations. Researchers have already used a polymorphic marker to determine the rough location of the gene that in one variant form, or “allele," leads to Huntington’s disease. This illness appears as a severe neurological deterioration in midlife. Within a large kin group studied in Venezuela, all the relatives showing the dis— ease were found to carry a distinct polymorphic marker on a particular chromo— some, while their middle—aged, diseaseafree relatives did not. This concordance means that the still unknown gene lies close to the polymorphic marker on that chromosome, and therefore that detection of the marker signals the presence of the gene that causes the disease. The marker will prove invaluable in helping researchers to directly identify the Huntington’s gene, isolation of which offers the only real hope for understanding and treating the disease. Genes linked to terrible diseases are not the only ones geneticists study. During the next 10 years, researchers may well make associations between polymorphic markers and normal, highly variable traits such as height, eye color, hair shape, and even foot width Without knowledge of the genes that serve as blueprints for these traits. Not much further down the road, scientists may uncover links between certain markers and more complex, subtle traits, such as aspects of phys— Weinberg / The Dark Side of the Genome 219 ical coordination, mood, and maybe even musical ability. At that point, we will confront social prOblems that will bedevil us for decades to come. Imagine that investigators could predict with some accuracy certain aspects of intelligence through simple analysis of an individual’s DNA. Consider the power this would give some people and the vulnerable position in which it would put others. The magnitude of the problems of genetic diagnosis depends on one’s view of how many complex human traits will be successfully associated with polymorphic markers. Some observers, such as geneticists Richard Lewontin and Jonathan Beckwith of Harvard University, believe that few such associations will be made correctly. Some people argue that traits such as perfect pitch and mathematical ability depend on the workings of dozens of genes. Yet others think that the con— tributions of nature and nurture can never be teased apart. Most likely, the doubters will be correct in many cases but wrong in others. Mathematical analysis has led some geneticists to conclude that the expression of many complex traits is strongly influenced by the workings of a few genes operat‘ ing amid a large number of more silent collaborators. Moreover, scientists can most easily explain rapid organismic evolution, such as humans have experienced over the last several million years, by attributing important roles to a small num— ber of especially influential genes. According to this hypothesis, each such gene has undergone alterations over the course of evolution that have in turn resulted in profound changes in our embryological development and adult functioning. For these reasons, I believe that a number of genetic markers will be strongly linked to certain discrete aspects of human behavior and mental functioning. Yet other traits will, as some argue, prove to be influenced by many interacting genes and the environment, and will not lend themselves to the genetic analysis soon to be at our fingertips. What type of higher functions will be understood and predictable by genetic methods? One can only speculate. The list of possibilities — say, shyness, aggres— siveness, foreign—language aptitude, chess—playing ability, heat tolerance, or sex drive — is limited only by one’s imagination. Likewise, the consequences of one or another identification — and therefyvill surely be some successes — can barely begin to be foreseen. .1 THE LONG REACH OF GENETIC SCREENING From cradle to grave —even from conception to grave — the coming genetic diagnostic technology will have profound effects on our descendants’ lives. Parents— to’be in the latter part of the 19905 will confront an ever—lengthening menu of prenatal genetic tests that will affect a variety of reproductive decisions. Termi— nating a pregnancy may come relatively easily to some whose offspring carry genes dooming them to crippling diseases that appear early in life, such as Tay— Sachs and cystic fibrosis. But the mutant gene leading to Huntington’s disease usually permits normal life until one’s 405 or 505, typically after the trait has 220 Technology and the Future been passed on to half of the next generation. Will its detection in a fetus justify abortion? As the years pass, this gray area of decision making will widen inexorably. Sooner or later, an enterprising graduate student will uncover a close association between a polymorphic marker and some benign aspect of human variability like eye color or body shape. And then genetic decision making will hinge on far more than avoiding dread disease. Such knowledge and the tests it makes possible could lead to eugenics through elective abortion. In India, thousands of abortions are said to be performed solely on the basis of fetal sex. It would seem to be but a small step for many to use the genetic profile of a fetus to justify abortion for a myriad of other real or perceived genetic insufficiencies. This prospect may appear remote, seemingly encumbered by complicated labo— ratory procedures that will limit these analyses to a privileged elite. And the revulsion built up against eugenics would seem to present a significant obstacle. But the onward march of technology will change all this. Current programs for developing new diagnostic instruments should, by the end of this decade, yield machines able to automatically detect dozens of markers in a single, small DNA sample. As genetic diagnosis becomes more automated, it will become cheap and widely available. And the responsibility for children’s genetic fitness will shift from the uncontrollable hand of fate into the hands of parents. [Within a few years], the birth of a cystic fibrosis child will, in the minds of many, reflect more the negligence of parents than God’s will or the whims of nature. Still other specters loom as the coming generation matures. Twenty'five years hence, educators and guidance counselors intent on optimizing educational “effi ciency” could find children’s genetic profiles irresistible tools. Once correlations are developed between performance and the frequency of certain genetic sequences — and once computers can forecast the interactions of multiple genes — such analyses could be used in attempts to predict various aspects of cognitive function and general educability. The dangers here are legion. Some will use tests that will at best provide only probabilistic predictors of performance as precise gauges of competence. And fac— tors strongly affecting education, including personality and environment, will likely be overlooked, leading to gross misreadings of individual ability. Only slightly less insidious could be the effects of genetic analysis on future marriages. Will courtships be determined by perceptions of the genetic fitness of prospective partners? Over the past decade, how many Jewish couples who have dis— covered that their children could be born with Tay—Sachs disease, and black couples with similar concerns about sickle—cell anemia, have opted to forgo marriage altogether? As we uncover genes affecting traits that fall well within the range of normal variability, will these too become the object of prenuptial examination? Once again, such an Orwellian vision would seem to reach far beyond current realities. Yet nightmares have already occurred. Two decades ago, genetic screen— ing among the population in central Greece for the blood disease sickle—cell ane— mia revealed a number of normal individuals carrying genes that predispose their offspring to the disease. Because the test results were inappropriately disclosed, Weinberg / The Dark Side of the Genome 221 these individuals became publicly identified and stigmatized, and formed an unmarriageable genetic underclass. Along with facing new issues around marriage, young adults with unfavorable constellations of genes may be limited in their employment possibilities. Employ— ers want to hire productive, intelligent people. Will they exploit genetic screen— ing to decide how rapidly a prospective employee will adapt to a new job or contribute to a company’s productivity? Even more likely will be attempts to use genetic markers to predict susceptibil— ity to dangers in the workplace...
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