Stepping Back from the Germ Line

By Marc Lappé

What would you do if you were told the only way to treat a genetic disease in your family and prevent its likelihood in your children was to participate in a trial of a radical new therapy called "germ line engineering"? You are told this new technology promises to correct untreatable, dominantly inherited or X-linked conditions and possibly rescue genetically handicapped families from perpetuating their suffering simply by altering a single gene in your or your spouse's reproductive cells. Sound too good to be true? According to a recently completed statement from the American Association for the Advancement of Science, the only significant obstacles to germ line engineering are present uncertainties of its risk and long-term safety.

So what is germ line engineering? It is the use of genetically altered eggs or sperm to correct or improve the genetic makeup of a resulting baby. Proponents of this new technology often assume it will receive widespread acceptance because a "cure" of an otherwise intractable disease will always trump intrinsic questions of morality. Keep in mind, the historical antecedents to germ line therapy, notably in vitro fertilization and other assisted fertility techniques, also raised ethical issues in their time. Many of these issues, notably the failure to consider the ethics of experimentation on the unborn or intergenerational risks produced by fertility interventions were ignored or overturned once someone in the private sector succeeded in showing in vitro fertilization was feasible. In 1978, the birth of a beaming baby named Louise Brown put an end to otherwise valid concerns of long-term safety and future harms of tissue-culture based technologies. The fact that a higher population of In Vitro Fertilization (IVF) babies have since been found to express more birth defects than expected is a disturbing reminder of the ability of science to proceed without meeting or countering ethical concerns.

A similar dilemma faces the present spate of proposals for germ line manipulations. As with in vitro fertilization, as long as the only objections to the technology are risk-based, a surreptitious, private sector "success" could open the way for the public sector's quiet acquiescence. Unfortunately, much more is at stake in altering the germ line than its immediate safety.

One issue is that the resulting technologies of cloning and germ line "therapy" can be misused, e.g., for the selection of "enhanced" human beings. Unfortunately, the line separating therapy and enhancement is currently blurred. For instance, where once acceleration of growth rate in short-stature youngsters was considered "out of bounds" for pediatricians considering human growth hormone therapy to correct pituitary-based dwarfism, such use is now commonplace.

Potential Applications of Germ Line Therapy
Given that germ line engineering, like in vitro fertilization before it, can demonstrate likely bona fide therapeutic benefits, why would anyone oppose them? Even some theologians are likely to be thrown by arguments in favor of germ line intervention. Take this natural law argument: if God or Nature did not want germ line engineering to be done, (S)He would have provided a failsafe system which would have short circuited gene exchanges, ensuring that mixing cells or genes could not be done. In fact, the genes from many diverse organisms already "contaminate" each other and viral genomes have become stably (and not so stably) integrated into human and mammalian cells generally. Why then should we be troubled by the potpourri of genetic alterations being proposed by human genetic engineers?

Fundamental Objections
While many persons have expressed an intuitive revulsion against moving genes across species lines, or tampering with our own germ line, until now no one has identified just what fundamental principles are violated by these actions. Ethicists remain vague on the right to self-experimentation or giving "proxy" consent for the unborn. And once we admit a disease like sickle cell anemia is serious enough to warrant gene therapy why not cure it altogether by eliminating the genetic error in the egg or sperm, which causes the disease if a child inherits one copy from each parent?

But this argument overlooks some fundamental objections to germ line engineering. First and foremost, germ line alterations would of necessity thwart the ability of the treated individual to perpetuate her own, "natural" germ plasm. In the case of hereditary disease, carriers will not of necessity pass on "defective" genes. Only half of their gametes will carry any defect whether recessive, dominant, or X-linked. Second, the manipulation itself would condemn the biological program carried by someone who already exists as sufficiently defective to warrant correction, thus condemning a family or whole group who happen to carry similarly flawed genomes. Such thinking potentially reopens the door to eugenics. Third, in all but a few circumstances, the germinal changes would have been selected by someone other than the affected individual herself and hence violate fundamental rules of experimentation.

Recall that a principle objective of correcting a hereditary defect in its reproductive cells is to ensure that a defective gene is not passed to a new generation, not merely that a potentially affected carrier is cured. However, such an objective requires that an informed consent be given both by the potentially affected individual and, by proxy, by her progeny. For germ line therapies which require embryonic manipulations for their application, this means that proxy consent be given both for the potentially affected individual and that person's descendants in a future generation, all of whom would be liable to get any altered gene. I question whether such a consensual process could be done ethically, or if consent can be leap-frogged, even in the case of disease conditions which are "universally recognized" as undesirable. I note that no adequate model of intergenerational responsibility is available to make such an analysis. Do these counterpoints constitute irrefutable objections to germ line engineering? Not necessarily. Some would point out they are simply an extension of the natural law arguments which declare that any deviation from the "natural" is ipso facto wrong. But, I find one ultimate natural law argument persuasive.

Recall that nature works in part by assuring that organisms are free to evolve towards genetic independence. Every species incorporates some type of extraneous-DNA-denying technique, such as enzymes which degrade foreign DNA, prevention of cross-fertilization, reproductive isolating mechanisms, etc. Violation of these "rules" of genetic conduct is both possible and necessary for ensuring the success of biotechnology interventions. Since we readily allow plant species to be contaminated by extraneous DNA–right down to their pollen–why should we balk at doing the same for people? The answer in part is that we probably should think twice about doing it in plants.

An argument based on these observations might go something like this: because living systems have evolved towards isolation and purity of their species-specific genetic heritage, any intercession into the germ line is inherently wrong. By this reasoning, the technologies of genetic engineering are wrong because they radically disturb the natural harmony that underlies the integrity of species. Because nature does not allow genes to move between species, we should not do so either. Similarly, while recognizing that genetic variability is constantly reintroduced into our lineage by mutation and recombination, no one yet knows how to insert a single gene stably into the human genome without risk.

Questions of Imminent Harm or Irreversible Harm
A key counter argument against limiting technology is that no technology is wrong per se in its invention, but only in one or more of its potential applications. Opponents of a basic technology most show why and how its development offends some fundamental human good, and why in its invention it will inevitably and irrevocably lead to an outcome that is universally repugnant. I believe germ line engineering is such an instance because it is a gateway to a new eugenics. We have a sorry history of misuse of genetic knowledge to underscore the intrinsic danger of that eventuality. No sooner were the basic facts of human heredity known than were handicapped persons here and abroad sterilized and mass campaigns of annihilation undertaken. While no one expects germ line engineering to be used on a truly "eugenic" scale, it is reasonable to conclude it would be used preferentially by the rich and powerful to improve their bloodlines at the expense of the poor.

The most insidious process of acceptance of germ line engineering centers on the belief that germ line alterations would be acceptable if they were achieved by accident, say secondarily to a present, identified "good use" of genetics. For instance, if a germ line "cure" occurred as an indirect consequence of an otherwise justified therapeutic intervention to correct a genetically based somatic or body cell defect, it would be acceptable to some religious scholars.

At its core, the acceptability of this consequentialist argument turns on the validity that any secondary germ line alteration is genuinely accidental. However, researchers currently proposing in utero gene therapies, such as the one put forward by C. French Anderson, know germ line changes are possible and actually contemplate the likelihood of germ line alterations as a predictable and acceptable consequence of therapy.

The second limiting case I identified is science based: can germ line therapy reasonably proceed without intimate knowledge of how a displaced or otherwise replaced gene will function, particularly if the originally defective gene is also left in the genome? Since most early forms of germ line therapy will do just that, e.g., by superimposing a new gene on an old one, the downstream problems of pleiotropy where a single gene produces multiple phenotypic effects, and co-dominance may produce insurmountable obstacles to doing the first experiments on human embryos ethically. The penultimate question is why somatic gene therapy alone (in which only body cells are altered) is insufficient to correct a given "defect" such that germ line therapy becomes necessary? The knowledge used to treat the body cells of an individual for somatic gene engineering almost always come before germ line therapy. Why not stop at treating disease in an extant individual and not worry about future generations (for whom you would have treatments)?

These questions would appear to make human germ line engineering highly questionable from a moral standpoint and possibly legally unacceptable based on existing rules for human and embryo experimentation. Further issues of identity, social acceptance or stigmatization, and individual rights of self-identity are inherent in the downstream consequences of permitting eugenic choice and selection by the so-called "gene rich" through preferential access to germ line manipulation. This possibility alone raises serious societal and moral questions of justice and discrimination.

At a minimum, these and the related questions posed above would need to be resolved prior to embarking on any experimental interventions towards germ line interventions, whether in the private or public sectors. To do otherwise, would be to court societal dissonance and evoke the specter of eugenics in a new, sanitized and scientifically vouchsafed form developed in the name of therapeutics. For now, I see no compelling reasons for even starting the irrevocable course of interventions which would likely stem from an excursion into the human germ line.