Human Genome Project

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HUMAN GENOME PROJECT

It was the Moravian monk Gregor Mendel, working in his monastery's garden in the 1860s, who cracked the secrets of heredity, but it was not until the beginning of the twentieth century that his insights were recognized and developed. Thanks particularly to the work of Thomas Hunt Morgan and his associates, working at Columbia University in New York, it was learned that the basic units of heredity, the genes, lie along thin, paired strings (chromosomes), in the centers of cells, and that these are not only the units of function—the things that carry the information used in building the finished organism—but also the units of heredity—the things passed on from one generation to the next.

In 1953, working in Cambridge, England, James Watson and Francis Crick confirmed the growing suspicion that the genes are long macromolecules of deoxyribonucleic acid (DNA), and famously they showed that the genes themselves consist of paired strings, twisted together in a double helix. The information carried by the genes comes not so much from the content of the DNA itself—a string or chain of four basic submolecules (nucleotides or bases)—but rather in the order of these submolecules along the chain. Information is read off from the DNA by another nucleic acid (RNA), and then this is used to pick up amino acids within the cell, which are then in turn strung together to make polypeptide chains, the building blocks (proteins) of new cells. Because there are twenty different amino acids used by the body, and because there are four different molecules in the DNA chain, in order take information from the DNA, there had to be (at a minimum) at least three nucleotides used in each transfer of information to catch without ambiguity a particular amino acid. Cracking this genetic code was the second great triumph of molecular biology of the 1950s.

With the basic theory now in place, biologists could turn their attentions to the discovering of the particular genes in particular organisms, a task made much easier, in the 1970s, by the discovery of powerful tools (recombinant DNA techniques) for dissecting the parts of the genome—the totality of a particular organism's genetic components. Thus was made realistically possible the idea of mapping the complete genetic content (the whole genome) of any particular animal or plant. Naturally, because people are humans, the idea of mapping human genes came to the fore, and thus the Human Genome Project (HGP) was conceived. Visionary credit is usually given to the biologist Robert Sinsheimer, who convened a crucial meeting of pertinent molecular scientists in California in 1985 to discuss and explore the feasibility of the project.

A task such as this is incredibly expensive, and governments of the world were soon asked for support and became involved both financially and organizationally. In the United States, the Department of Energy (DOE) was an early backer, a somewhat strange connection explained by the Department's involvement in the genetic effects of radiation on humans—a connection dating back to the Japanese atomic bombs and the testing of the subsequent Cold War. Less surprisingly, the National Institutes of Health (NIH) became involved and soon took the lead. By 1988, the codiscoverer of the structure of DNA, James Watson, had been appointed head of the project. (Watson resigned in 1992 and his post was then taken by the molecular biologist Francis Collins.)

The approach taken was basically one of brute force, squeezing out the information from the genome step by step, base by base. However, work in the 1990s was transformed not just by ever more powerful and rapid methods of getting results, but by the researcher J. Craig Venter. He argued for different strategies, initially aiming just to skim the genome for the really interesting results and leaving the rest until later, and then leaving governmentally supported institutions and going after private money, aiming to use even more powerful techniques to beat the NIH at its own game. In the end, both sides, public and private, announced a first draft of the human genome in 2000, and in 2003 a more detailed map was produced. The HGP was completed. Over 99 percent of the human genome has been mapped ("sequenced"), to an accuracy of 99.99 percent. Functionally speaking, there are about thirty thousand genes (a lot fewer than many would have estimated before the project began), and a huge amount of the genome seems to be nonfunctional (it is estimated that "junk" DNA may be over 90%). The cost of this enterprise, factored in at 1991 U.S. dollars (when the estimates and projections were being done), was $2.7 billion. The genome sequenced was not taken from one individual person, but was a mixture of different people for the different chromosomes.

Focusing now on philosophical questions arising from the HGP, there are those more epistemological and those more ethical and social. This entry will take them in turn.

Worthwhile Science?

The big epistemological question that has haunted the HGP is whether it should have been done in the first place. As it was being discussed, many top-notch molecular biologists argued that it was unneeded and would divert resources and attentions from far more worthwhile projects. They felt that the project was motivated mainly by biologists who, feeling insecure around physical scientists, wanted their own equivalent of the moon-landing project—and it would have about as much scientific value.

Concerns such as this keep reappearing. Simply given a list of bases seems to have little or no scientific merit. The philosopher Alex Rosenberg gives a memorable metaphor. Imagine two stacks of phone books twisted around each other in a helix and reaching a mile and a half into the sky. The covers have been removed so each book leads at once to the next; the names have been removed so there are only lists of numbers—not in columns but one after another with no punctuation; area codes are assigned here, there, and everywhere at random, and no one has any idea what code corresponds to what geographical region. The only certainty is that 90 percent or more of the codes are fictitious and have no region to which they refer.

What, asks Rosenberg, is the point of having information on something such as this? Why bother to go to the effort of feeding all of these numbers into a computer? No one in their right mind would think it worth the effort. And yet this is equivalent to just what the HGP set out to do. And now that there is a string of numbers, so what? It is not that sequencing as such is worthless, but that unless there is some idea of what is being sequencing and why, it is misconceived effort. Far better to concentrate on specific problems—finding particular genes of interest and tracing their effects—than simply scooping up everything in one massive project.

Not surprisingly, from the beginning many biologists have disagreed. The junk DNA is a particularly sore issue because it does seem as if huge effort is being given over to mapping something—the vast portion of the genome—that is without function or purpose. The biologist and ethicist Frederick Grinnell argues that an attitude such as Rosenberg's is intellectual ludditism. It is precisely because scientists do not now see any function behind junk DNA that it should be explored and uncovered. Only then can its true nature be seen, and perhaps in fact they will find that far from being without purpose, perhaps junk DNA plays a crucial role in the living being.

Above the level of detail however—and more importantly—is that the project has never been simply one of listing bases on a line. From the start, biologists have been using the data to locate and to identify particular genes of interest, and to explore their functioning. As a tool, the results of the HGP have been made far more powerful because, from the beginning, the human genome was not the only genome being sequenced. Many others—bacteria such as E. coli, insects such as the fruit fly Drosophila, and mammals such as the mouse, as well as yeasts and plants—have been studied and mapped. The comparative results to which these have led have given rise to some of the most exciting and forward-looking branches of pure science active today. Particularly noteworthy is the field of so-called evolutionary development ("evo-devo"), where comparisons between gene sequences are a vital component of understanding and have led to insights as surprisingly unexpected as they are of far-reaching consequence. It is now known, for instance, that almost identical sequences of genes are to be found in organisms as separate as fruit flies and humans, pointing not only to shared ancestry but also to the fact that even today the ways in which these different organisms develop are identical, and for the same reasons. Results such as these are calling for significant rethinking of the workings of evolution. As Charles Darwin himself always suspected, so much change is a matter of making do with what one has rather than regrouping and starting again to go for an ideal solution.

No doubt more results will come in future years. While one may probably legitimately question the motives of all of the early backers of the HGP—the DOE certainly seemed to be looking for a project to justify its existence—it would be incorrect to say that no good science has emerged and churlish to say that the project has set molecular biology entirely down a misguided path.

Eugenics

Even more than its potential scientific worth, the HGP was promoted as something that would have major social and ethical virtues, particularly in areas of medical care. As one moves toward these topics, what is first encountered is a cluster of issues around the topic of eugenics—however it may be called and described. Traditionally, "eugenics" referred to programs designed to improve the human race by interfering with or modifying its genetic constitutions. This could be thought of in two ways—positively, trying actively to perfect human genomes; and negatively, trying simply to eliminate the worst effects of the genes. The whole program fell into great disrepute because of the horrific activities of the Nazis, and today eugenics tends to be one of the topics from which people of all persuasions flee. Naturally, any suggestion that the HGP may in some way be an excuse for a new eugenical program is something that fills people with horror. It is something from which the promoters of the program have been at pains to divorce themselves.

Prima facie, one can see why there are worries. If the aim is simply to list the human genes, then the next move could well be trying to produce designer babies of some kind. But before one rushes to this as an inevitable conclusion, it is worth stopping and asking whether eugenics is necessarily always a bad thing. In particular, one may well reject positive eugenics—one may deplore the attempt to produce a race of superhumans—and yet endorse negative eugenics—attempting to eliminate horrendous genetic diseases. In fact, by another name, namely "genetic counseling," negative eugenics has never stopped. Paradoxically, although it was Jews who were the focus of the Nazi race laws, it is Jews who have been at the fore of genetic counseling as they try to discover carriers of the gene for Tay-Sachs disease, and through selective abortion prevent children being born with the affliction.

In this sense, therefore, one can see the completion of the HGP as a powerful tool in this direction, but at the same time argue that it is of positive moral and social worth rather than the other. Of course, one can see how this could be the thin end of the wedge to more draconian—perhaps even state-enforced—policies designed to eliminate even minor or idiosyncratic traits, or to eliminate those who may carry traits that could in certain circumstances prove wrong or disliked by some others in society. Perhaps Tay-Sachs disease yesterday, alcoholism (if it proves to have a genetic link) today, and homosexuality (again, if there is a link) tomorrow. This is clearly a danger, although whether the HGP as such should be faulted or whether any kind of genetic approach to humankind is more truly to blame is another matter.

In fact, one may argue that the HGP is a good thing in this respect, precisely because it takes the focus from individual genes and shows that the human being is a conglomeration of genetic factors. That (as the late Stephen Jay Gould pointed out) blunt "reductionistic" approaches to human nature—where each feature is supposedly controlled by one gene—are highly simplistic. Thirty thousand genes are not many to produce a complex entity such as a human being. It is clear that much about us is a product not just of one gene working in splendid isolation, but rather of many genes interacting to give rise to many complex traits. Hence, one starts to realize that, even with the best of intentions, thoughts of eliminating all genetic diseases are probably unrealistic. As one eliminates one gene, one affects the workings of others, which may in itself have negative effects. There is no simple route to perfection, and the HGP underlines this fact.

In any case, as has also been hinted at by the reference to evo-devo, the HGP is part of an ever-increasing awareness brought on by molecular biology. Simply thinking of genes leading to completed features is as naive as unqualified reductionism. There is no such thing as unadulterated genetic determinism, where people are the product of and only of their genes. It is always the genes in interaction with the environment, whether this be the physical environment or culture or whatever. Rather than argue that the HGP will at once lead to programs for genetic elimination, one could argue that the HGP will lead to programs to manipulate environments so that deleterious genes will not have full effect. Suppose that alcoholism is a function of the genes in some way. Rather than eliminating the genes and their carriers, one may rather try for programs that help people to learn to live adequately and happily with their biologically informed natures.

The point is that, as always in dealing with moral and social issues, scientific findings are never definitive or the last word. How one deals with these findings—including the findings of the HGP—is going to be a function of many things. While new knowledge can be dangerous, it is unfair to think that it will always be disastrous.

Pariahs?

This leads at once to what is already an immediate and pressing concern. Now that there is the information from the HGP in the public domain, what is to stop institutions—public and private—from using this information for their own ends, ends that may not necessarily be the ends of individuals? Take most obviously the question of insurance. The idea behind insurance is that people bet on ignorance, with a group of other people, to protect themselves if things go wrong. People buy health insurance knowing that 10 percent of the population will need a procedure; each individual in the group hopes he or she will not need the procedure, but knows that if so it will have cost (approximately) 10 percent of what it would have cost without the insurance. If people know they do not need the procedure, they will not buy the insurance—no man is going to buy insurance for gynecological problems. But, if a person is known to need the procedure, no one will sell that person the insurance—no one will sell cancer protection to someone with leukemia.

The worry is that the HGP is going to render some people pariahs and ineligible for insurance. Even worse, these will not necessarily be people who are or ever become physically sick. Thanks to the HGP, scientists are increasingly discovering genes that lead to various ailments or the predispositions to such ailments. This means that individuals can be tested against such standards to see if they are or are not possessors of the pertinent genes. Suppose that the knowledge obtained from the project enables a test for the disposition to a certain ailment or habit, alcoholism for instance. Normally, one may think that alcoholics should be discriminated against because of their habits; people with drunk driving convictions should pay more in car insurance. But is it fair to discriminate against the person who has a gene that simply sets up a predisposition? Does the state have the right to demand of a private insurance company that it not test for such a gene? Is this not unfair to others who buy insurance from that company? Do they not have the right to demand that their company obtain all pertinent information? The company surely has the right—the obligation—to discover if their would-be clients have drunk driving convictions.

The general problem has led some, notably the philosopher Philip Kitcher, to argue that the only viable solution to the new knowledge pouring forth from the HGP is some kind of state-supported, universal health care. Private insurers are simply going to be unwilling and unable to carry on with such plans unless there are massive, state-enforced rules preventing the obtaining of pertinent knowledge—which in itself is not necessarily a good thing (because, apart from anything else, one may need such knowledge), and probably not enforceable anyway. Society generally frowns upon fetal sex-determination, but that is little barrier for those determined to find and act on such information.

Even if Kitcher's proposal is followed through—after all, virtually every sophisticated society other than the United States already has such health care—this does not solve other related problems, such as life insurance. The moral ambiguity of such issues and the difficulties of working toward satisfactory solutions presents two notions of prejudice. On the one hand is the social prejudice that will be shown against those unable to buy such insurance. On the other hand is the potential for the prejudice abhorred by insurers, namely that society should not discriminate unfairly against the fortunate for the benefit of the unfortunate. A business deal is a business deal, not a policy of social welfare.

Assessment

One point is clear. The HGP is not some isolated phenomenon; it is part of a general move toward the understanding of organisms at the genetic level, and of technological applications that stem from such understanding. It is hardly a philosophical argument to point out that no amount of bemoaning the fact is going to stop this process. But philosophical argument does show that although there are great dangers and problems, there are also exciting opportunities and prospects, theoretical and practical. The philosopher's aim must be to guide in the right direction the bounties that stem from this new knowledge and its powers.

See also Philosophy of Biology; Science Policy.