The full-page advertisement in the Harvard Crimson a year ago came as no surprise. The text was straightforward: Intelligent, Athletic Egg Donor Needed For Loving Family. You must be at least 5´ 10´´ / Have a 1400+ SAT score / Possess no major family medical issues. It was only the latest in a steady stream of smaller ads with similar messages--"healthy Caucasian," "dark hair," "intelligent, kind," "drug free," "age between 20 and 30." But the new ad did cause surprise because the fee offered--$50,000--far exceeded the $3,000 to $8,000 previously promised for egg donations. Clearly, the acquisition of eggs for artificial fertilization had become an expensive proposition for anyone seeking donors with special pedigrees in the belief that intelligence, athletic ability, good looks, and good health would be carried in their genes.

The desire to produce better human beings by manipulating heredity and reproduction is not new. What is new is that the techniques for reproductive and genetic manipulation are outstripping earlier programs that relied primarily on voluntary, slow efforts at selective breeding--and on occasional involuntary programs for sterilizing or otherwise forbidding the reproduction of those deemed genetically unfit. Louise Brown, the first "test-tube" baby, was born in the United Kingdom more than 20 years ago; Dolly, the sheep cloned in Scotland three years ago from mammary-gland cells, crossed another important barrier in reproductive science; and the intense (if not yet successful) effort of the last 15 years to develop gene therapies for human genetic diseases further indicates that science and technique have stepped out in front of social policy and ethical judgments. In a very recent experiment in which jellyfish genes were inserted into monkey embryos, the potential for similar insertion into human embryos was mentioned--not only to block diseases, but to enhance memory. "What if it worked," Dr. Ruder Verma of the Salk Institute was asked, "and humans wanted that gene?" "If something can be done," he replied, "people will do it"--before hastening to note that few could afford the expensive procedure.

The historical record proves that Verma was right about the eugenic drive. Harvard biologist William E. Castle, A.B. 1893, Ph.D. '95, professor of zoology and then of the new science of genetics, published a text and taught courses linking genetics and eugenics (as the application of genetics to humans was termed) in the second decade of the twentieth century. Although his tone was cautious, Castle, like many of his colleagues, wanted to root out such negative human characteristics as alcoholism, feeblemindedness, criminality, and other traits then considered heritable. He noted, however, that the "biologically poorest elements" were reproducing more rapidly than the "intellectual and cultural elements." Castle lamented this situation and acknowledged that the understanding of human heredity lagged behind that for plants and other animals because geneticists were "debarred from experimentation in the human field." Eventually, broad programs of research, counseling, education, and propaganda were established, supplemented by efforts at restrictive immigration (adopted in the United States in the 1920s), by laws governing marriage, and--in some 30 states--by programs of involuntary sterilization. Well into the late 1930s, many eugenic projects had support across the political spectrum, from communist to conservative, and were widely accepted in the medical and scientific communities.

The Nazi eugenic program and the institutionalization of race laws, enforced sterilization, and selective euthanasia shocked even the staunchest eugenic advocates. But as early postwar textbooks of human genetics published in this country demonstrate, eugenics was not abandoned but merely cast in a more restrained and cautious tone. The "fit" were to be encouraged to propagate --through financial incentives, child allowances, and preferential housing arrangements. Persuasion was to be used to convince the "unfit" to voluntarily limit reproduction through birth control, induced abortion, and voluntary sterilization. While the immediate focus was on eliminating those diseases identified as hereditary, many of the texts could not resist the temptation to deal with the genetics of behavioral traits, including intelligence.

Early in the 1960s the American geneticist Hermann Muller, a Nobel laureate, proposed collecting sperm from men with outstanding qualities such as high intelligence and altruism, and then seeking out women of intelligence and good health as recipients. Although he died before it opened, the Hermann J. Muller Reposi tory for Germinal Choice was established in 1971 and initially accepted sperm exclusively from Nobel Prize-winning scientists, only a few of whom publicly acknowledged their donations. The "sperm bank" went out of existence last year, leaving no public indication of how many artificial fertilizations actually took place.

For the first two-thirds of the twentieth century, introducing new genetic materials into the genomes of animals and plants relied completely on the traditional modes of breeding and hybrid-crossing techniques--practices of very limited value for human experimentation. Since then, the situation has been shifting rapidly: we have an increasing ability to target gene changes, and the full expectation that these techniques will be used in human cells. Once DNA was conclusively identified as the "stuff" of heredity and its remarkably simple code was deciphered, genetics entered the scientific fast lane.

Amid the exciting progress being made in molecular genetics, conflicting voices were heard among the scientists involved. Nobel laureate Linus Pauling, the scientist responsible for one of the earliest identifications of the molecular basis of a genetic disease (sickle cell anemia), in 1968 urged compulsory screening for defective genes before marriage. He suggested some form of visible display--such as forehead tattoos--to prevent the mating of two carriers of a defective gene.

But during the same years, the geneticist Marshall Nirenberg, in a 1967 guest editorial in Science, asked the critical question about human genetic engineering: "Will Society Be Prepared?" It was becoming increasingly clear in the genetics community that humans were gaining the capacity to program their own cells before examining the long-term consequences and resolving the ethical, moral, and social issues raised. Nirenberg warned that man should "refrain from [genetic engineering] until he has sufficient wisdom to use this knowledge for the benefit of mankind." Joshua Lederberg (another Nobel geneticist) replied at once, fearing that Nirenberg's words might lead to restrictions that could "undercut the very research needed to reach sufficient wisdom."

Others joined to downplay the possibilities of genetic manipulation. On the eve of achieving the technical ability to transfer genes from one organism or species to another, some scientists doubted that a DNA sequence could ever be taken from a normal human cell, inserted into a diseased cell, and then transferred throughout the body. Unfortunately, these doubts had the effect only of postponing the multiple ethical and social considerations that should have accompanied the development of this very form of genetic engineering--the focus of intense experimentation today.

The technical achievements that led to the ability to transfer genes came rapidly in the early and mid 1970s; a whole new biotechnology business was created. Genetically engineered microorganisms became minifactories for producing useful molecules for industry, pharmaceuticals, and agriculture. Genetically manipulated plants with properties for resisting frost, pests, and other hazards; animals with higher protein ratios; and other economically valuable properties were produced and introduced into agriculture. But further discussion of the emerging practice of genetic engineering, though called for by some critics, was deferred.

Not surprisingly, as the technology progressed, there was immediate interest in inserting genes into human cells identified as carrying genetic diseases. But the techniques were not nearly refined enough for accurate gene insertions in the 1970s, and National Institutes of Health rules precluded experiments on humans. In 1980, however, a medical researcher from UCLA took his gene-transfer therapy experiments to Israel and Italy and attempted to administer recombinant DNA to two patients suffering from thalassemia. Although the experiments failed and the experimenter was disciplined, it became clear that the temptation to engage in human gene therapy was great and the guidelines and review procedures were inadequate. The means for solving the technical issues were understood; those for resolving the social problems were neither visible nor articulated.

In 1982, then Congressman Albert Gore held hearings on the future of genetic engineering. At his request, the Congressional Office of Technology Assessment examined the emerging field and reported on two forms of gene therapy: somatic-cell and germ-line. Somatic-cell therapy would target only nonreproductive cells, attempting to repair genetic mistakes in the inpidual patient, but not to introduce changes that could be inherited by offspring. Germ-line therapy, in contrast, would introduce genetic alterations that could be passed on to the inpidual's progeny. There was strong support at the time for somatic therapy, but no agreement existed concerning the technical and ethical issues involved in germ-line experimentation. The focus then was on developing therapeutic responses to illnesses caused by inherited gene deficiencies: Lesch-Nyhan Syndrome, ADA deficiency, cystic fibrosis, sickle cell anemia, familial hypercholesterolemia, and others.

But as a review in Science noted in 1985, critics concerned about where the technologies might lead were asking, "If we can cure lethal diseases by altering an inpidual's genes, what's to stop us from using the technology to 'enhance' human characteristics such as strength or eye color, or even, one day, intelligence?" Today, 15 years later, after very active research, success has not yet been achieved and more than one highly visible death has been attributed directly to gene-therapy experimentation. As Ruth Macklin, the bioethicist, put it: "Gene therapy is not yet therapy."

Still, the scientific frontier is being extended. James D. Watson, who together with Francis Crick determined the physical structure of DNA in 1953, took over as head of the newly established Human Genome Project in 1990. He announced a timetable for mapping and sequencing the entire human genome (all 23 pairs of chromosomes)--through which the full molecular order of all human genes would be identified--by September 30, 2005. The current director of the project, medical geneticist Francis Collins, describes the program as "the most important organized scientific effort that humankind has ever attempted....It dwarfs going to the moon." Hyperbole aside, the Human Genome Project has added intensity and visibility to the already very active efforts to unravel the human genetic code. New machines and techniques developed in the late 1980s and early 1990s have made possible the rapid sequencing of DNA bases.

Watson added what he identified as an ethical imperative to the political-economic one of keeping Congress happily funding the research--finding the gene for something. Noting that the gene linked to Alzheimer's disease is located on chromosome 21, he claimed that it would be "unethical not to [identify it] as fast as possible." That argument has resurfaced on many occasions, and mirrors the claims of ethical efficacy made in other areas of medical research. (It is worth noting that human genome projects here and in Europe have set aside small sums--circa 3 percent--of all government grants for ethical, social, and legal examinations of this fast-moving area of research.)

Additional pressures on scientific and ethical choice have come from relationships between public and private interests in genomic research. Although initial efforts to sequence the genome were government-funded both here and in Europe, in 1998 the entrepreneurial scientist J. Craig Venter began a private-sector effort, promising to complete the sequencing by 2001 and hold the data for profit, rather than releasing it to the international scientific community. The consensus date for completion is now 2003.

Successful genomic sequencing, new techniques for inserting modified genes into cells, and new reproductive technologies (cloning, embryo modification) pose significant questions for ethical and social policy in four fields of scientific and applied research: diagnosis and screening; somatic and germ-line therapy; modification of human behavior; and reproductive engineering.

One area of signal success in the genome project will be the ability to diagnose and identify many important genetic diseases at a molecular level. Charles Cantor, one of the leading molecular geneticists, points to a future "single multiplex test to fetuses in utero, babies at birth, or in many cases, parental carriers" that will be able "to detect somewhere between 100 and 1,000 of the most common genetic risk factors for environmental insults, drug-dose responsiveness," et cetera. But, he adds, the protective benefits from identifying genes linked to diseases "could lag 20 to 50 years behind diagnosis." This, he says, "exposes one of the serious social issues raised by the Genome Project."

Thomas Caskey, an active participant in medical genetic research, identified another key problem of diagnostic success: "Once we can predict disease at birth, how should we use the information to improve the care provided to the inpidual?" Caskey and others have expressed concern about the data available from prenatal and other broad-scale screening encouraged by genome research. What are the implications for privacy, for later discriminatory use in employment, health insurance, and law enforcement? Caskey was candid: "I lack sufficient confidence in the security of data banks...and I think a good deal more public discussion of the subject is required." One geneticist has advocated a strong program for the use of such genetic information: "the law must control the spread of genes causing severe deleterious effects, just as disabling pathogenic bacteria and viruses are controlled." This was the logic that guided the programs for sterilization of the genetically unfit 80 years ago, albeit the deleterious forms are now more narrowly defined as diseases caused by gene deficiencies and damaged genes, rather than such earlier social categories as alcoholism and criminality.

Germ-line gene therapy cuts to the core of basic moral and social concerns. The aim is not only to affect the health of the inpidual under treatment, but to prevent passage of the genetic disease to future generations. The arguments in favor of such therapies follow a public-health model--that is, reduce the incidence of inherited diseases in the human gene pool. But this method would work only if there were large-scale germ-cell intervention, since most diseases are carried in heterozygous form and not expressed in the inpidual. Broad-scale genetic screening will add impetus to this vision. Joshua Lederberg foresaw this in 1962 and argued that the advances already made in molecular biology militated against "somatic elections" and instead called for new efforts to learn "how to manipulate chromosome ploidy [number of sets of chromosomes], homozygosis [the union of gametes that are identical for one or more pairs of genes], genetic selection, and full diagnosis of heterozygotes, to accomplish in one or two generations of eugenic practice what would now take 10 or 100."

Although Lederberg's goals are not yet achievable, clearly it is time to address directly the implications of the likely eventual success of such a technique. Thoughtful analysts have already proposed "a voluntary program to reduce the incidence of genetic disease through germ-line intervention." Harris polls in 1986 and 1992 recorded majority public support for limited forms of germ-line intervention, especially to prevent "children inheriting usually fatal genetic disease"--stronger support, in fact, than that expressed among experts in the field.

The perfecting of techniques for human genetic intervention has been driven largely by the desire to confront genetic diseases. But gene insertion and correction are not limited to medicine. They have regularly been explored, at least speculatively, with the aim of affecting such physical characteristics as weight, strength, height, and longevity--in short, genetic enhancement. Genetically influenced behavioral modification has also been of persistent interest. The Institute of Medicine of the National Academy of Sciences attempted in 1986 to set in place important distinctions between disease elimination or modification, on the one hand, and the genetics of behavior on the other. Somatic therapy raised no issues beyond those encountered in any new therapy, its report noted, while "in contrast, germ-line therapy, enhancement genetic engineering, and eugenic genetic engineering raise scientific and ethical issues beyond those associated with other medical technologies." The experts noted that many groups felt it would be "unethical to withhold somatic gene therapy from gravely ill patients solely because other forms of genetic engineering might be misused in the future," a view that was firmly supported by gene-therapy enthusiasts, who argued that the focus must be on genuine medical problems.

But is the distinction that clear? By 1994, Sir Walter Bodmer, former president of the Europe-based Human Genome Organization, seemed willing to cross the line. "Would it really be so bad," he queried, "if we added genes for height to small people, or for hair to the bald, or good eyesight to the myopic? Probably not," he claimed. But to add genes for intelligence, athleticism? "Just where we get off the slippery slope is therefore a matter for society to choose...," Bodmer added, noting that technically there was still a long distance to go and, therefore, "We have plenty of time to debate the issues and resolve them." But the argument was joined. In 1995, for example, then archbishop of York John Habgood accepted that in principle it may be good to cure diseases, but he urged his readers to be extremely "suspicious about improving human nature; and be even more suspicious of those who think they know what improvements ought to be made."

"Nature does not know best," argues bioethicist Tristam Engelhardt, who identifies a number of human attributes that he would recommend for germ-line genetic engineering: nearsightedness; female menopause and the concomitant osteoporosis; and the shortened life expectancy of men as compared to women--linked, he believes, to genetically increased risk of certain diseases, including heart attack and cancer of the prostate.

A Boston Globe headline last September made the point nicely: "Manipulated Genes Produce Smart Mice, Tough Questions." The report in Nature on the underlying research done by Joseph Z. Tsien and colleagues from Princeton, MIT, and Washington University in fact did not even mention humans. But by producing transgenic mice they had introduced changes that created mice with enhanced memory and better learning scores. The authors modestly conclude their paper: "This study also reveals a promising strategy for the creation of other genetically modified mammals with enhanced intelligence and memory." The New York Times described Tsien as believing that his work opens the way to do the same for humans: helping those "with memory loss in counteracting the fading memory in the elderly, or even in making healthy inpiduals smarter." But he immediately went on to say that none of these possibilities should be explored without public discussion and the establishment of guidelines.

One of the fullest and most enthusiastic cases made for genetic modification of human behavior can be found in a recent book by Dean Hamer of the National Cancer Institute. In his popular volume Living with Our Genes, Hamer identifies a series of "behaviors determined largely by heredity:" an obese gene, genetics of gender, "addictions to alcohol, tobacco, and dangerous drugs." He asserts that violence and aggression "also have genetic roots" and, not surprisingly, that "the evidence that IQ is largely inherited is overwhelming." He also claims that his researchers have identified genes for other personality traits: novelty-seeking and worry. Hamer confidently claims that "the emerging science of molecular biology has made startling discoveries that show beyond a doubt that genes are the single most important factor that distinguishes one person from another." In fact, he indicates, "we come in large part ready-made from the factory."

Hamer sees the successes of genome research raising the ultimate issues: "We soon will have the ability to change and manipulate human behavior through genetics." He labels this new field "functional genomics" and predicts, "Dolly the sheep [is] the first well-known example, but humans are just a few steps away.... Lives are at stake....Money is at stake.... That's a powerful combination anywhere, and in America it's invincible." Inverting the suggestion of others that technique is slow and plenty of time exists for discussion, Hamer says, "It's too late to wonder whether we are going to genetically tinker with human behavior. What we need to decide very quickly is how we are going to do it." Which are the good genes and which are the bad? Which traits should be sought and which shunned? And, perhaps, most important, who gets to choose?

Less rhetorical voices have expressed somewhat similar ideas, noting that in time the technical ability to enhance some intellectual, moral, and physical human characteristics will be achieved. Ethical acceptance for some modifications will develop, especially for disease and disability. These authors urge judicious use of the new genetic techniques.

But sharp lines are being drawn. A Canadian advisory committee stated "no research involving the alteration of DNA for enhancement purposes will be permitted or funded" there. Britain and European countries are eyeing similar restrictions.

We have lived through two turbulent decades in which advances in the science and techniques of genetics have seen many applications to humans, most notably in genetic screening and the development of somatic-gene therapy. New germ-line attempts at genetic engineering and behavioral enhancement are clearly being examined. Old boundaries are being challenged and previous norms are under pressure. Technical advance has been driving social and moral judgment--largely by default.

The challenge faced today by scientists and the lay public is how to sharpen the discussion of ethical and social policy, to bring focus and clarity to sensible decision-making. The institutions of genetic scientific and technical research, and the industries of genetic application, are relatively well organized and generously funded. Their imperatives are clear: push toward new knowledge and its applications. By contrast, our ethical, social discussion is unfocused, episodic, and scattered. We need to harness moral thinking to genetic technique. The need for organized, intelligent debate involving an active public and committed scientists has never been clearer. Solving the "technically sweet" problems first (the phrase is from atomic scientists) and only then turning to deal with the moral and social consequences has in the past prov ed much too costly, and will again.

Everett Mendelsohn, Jf '60, Ph.D. '60, is professor of the history of science.