Friday, October 01, 2004

Seeking More Goodly Creatures

By: Henry T. Greely J.D.

If you’d like to engineer your unborn child into an Albert Einstein, Placido Domingo, or Sandra Day O’Connor courtesy of molecular biology, be prepared for a long wait before sufficient knowledge is available, if ever. Meanwhile, a minefield of problems and societal obstacles lie ahead. Ironically, child“enhancing” genetic technologies would only be the latest variation among practices that have been employed, even cherished, throughout history.

In principle, genetic and reproductive technologies might allow “enhanced” children— with mental aptitudes and personal qualities improved beyond their expected abilities or even beyond humanity’s normal range. Worry about a “brave new world” has already begun, but is that world imminent? And assuming that parents could choose traits for their children, would this be a bad thing? Many people think so for many different reasons, Henry Greely writes, but before we decide to regulate genetic enhancement, we need to decide how it differs from other forms of enhancement, traditional and new, and if those differences are important enough to justify regulation.

O, wonder! How many goodly creatures are

there here?

How beauteous mankind is.

O brave new world,

That has such creatures in’t.

The Tempest, Act 5, Scene 1

In The Tempest, Shakespeare coined the phrase “brave new world” as an expression of delight pulled from Miranda the first time she sees more than two people. Aldous Huxley’s 1932 novel, Brave New World, used the phrase ironically, implying that the alphas and the epsilons, the freemartins and the controllers, of his dystopia are not “goodly creatures.” Today, “brave new world” has become a cliché to be attached to any new genetic or reproductive technology. But is the cliché fair? Are these advances leading us to Miranda’s brave new world or to Huxley’s frightening and contemptible new world? Or is this new world new at all? 

We have been fascinated by speculation about how genetic and reproductive technologies might allow parents (or others) to “enhance” children before they are born—to improve them beyond their expected abilities or, perhaps, beyond humanity’s normal range. But where does science fiction end and plausibility begin? What are the real possibilities for such prenatal genetic enhancements, what are its limits, what are its problems? And just how worried should we be? This article will not answer these questions, but it does try to clarify the issues they raise. 

METHODS

We could try to enhance our children’s genes in two different ways. The first approach would be to select children to be born based on which variants of genes, called “alleles,” they carry. The second would be keep the children we randomly beget but then to select new alleles for them. The first method is currently available through a range of methods of prenatal genetic selection; the second might be possible in the future through gene therapy. 

In one sense, genetic enhancement through selecting children based on their alleles, or their likely alleles, is very old news. The characteristics of your mate affect the characteristics of your offspring. But, as all parents learn, predicting these effects is far from perfect. Although in their alleles our children are exact 50/50 mixes of their parents, in their traits they are a far more complicated product, combining their parents’ old genes in new and unique ways. Picking an excellent mate may give you genetically “enhanced” children—or it may not. 

Prenatal genetic testing can give you more knowledge by doing direct genetic tests on the particular combination of parental alleles found in the egg and sperm that combined, implanted, and developed into a fetus. This process has been available clinically for more than 30 years; with each passing year it can be used to test for more genetic traits. It relies on obtaining a sample of cells from the fetus. Currently, these cells are obtained either through amniocentesis, which draws off some fluid from the amniotic sac, or through chorionic villi sampling (CVS), which snips off a bit of the developing placenta. Both CVS and amniocentesis involve invasive procedures, and each has risks and costs. The biggest risk is miscarriage; both procedures roughly double the odds of a miscarriage from about 1 percent to around 2 percent. And both procedures are expensive, costing more than $1,000. 

The fetal cells, however they are obtained, can then be tested, both for chromosomal abnormalities such as the three copies of chromosome 21 in Down syndrome and for alleles associated with genetic diseases such as cystic fibrosis, Tay Sachs disease, sickle cell anemia, beta thalassemia, Huntington’s disease, and several hundred others. The same cells can also be tested for genetic variations associated with non-disease traits, such as sex.

Medicine can now offer an earlier way of selecting children based on their alleles— preimplantation genetic diagnosis (PGD), an offshoot of in vitro fertilization. PGD starts the same as any in vitro fertilization attempt: the mother is given drugs to hyperstimulate her ovaries, thus ripening far more than the usual one egg per cycle. The ripened eggs are then harvested and each one is fertilized by the father’s sperm. The resulting embryos—usually 10 to 15 in number—are nourished for three to five days, after which some of them will be implanted in the mother’s womb to try to start a pregnancy. But between the fertilization and the implantation comes PGD. During the third day of development, the embryo is a little ball of about eight loosely connected cells, enclosed in a clear jelly called the zona pellucida. Embryologists manipulate these embryos under microscopes and pluck out one cell from each embryo. Those cells are then tested for chromosomal abnormalities and genetic characteristics. This “amputation” of one cell of an early embryo sounds as if it could lead to babies missing large parts of their bodies, but the experience of more than a thousand PGD births covering 15 years shows that the remaining seven-celled embryo, if implanted, has roughly the same chance of becoming a healthy baby as it would have with all eight of its cells. 

Preimplantation genetic diagnosis is valuable because it gives parents more information for choosing which embryos to implant. In most attempts at in vitro fertilization, only two or three embryos will be implanted, based on how good they look under the microscope, a test that predicts, weakly, which embryos will implant successfully, thrive, and become healthy babies. With PGD, the clinic and the parents can decide which embryos to implant based on more information—information about both the chromosomes and the genetic variations. PGD can be and has been used negatively, to avoid implanting embryos with chromosomal abnormalities or genetic variations that would lead to serious diseases or death. But, like prenatal genetic diagnosis, it could also be used affirmatively, to choose to implant embryos with particular genetic traits. 

Selecting babies based on their alleles is thus already a possibility. 

Selecting babies based on their alleles is thus already a possibility. What about selecting alleles for existing babies? This approach requires some form of what is called gene therapy, adding a different allele to an existing genome. So, parents with a child—or a fetus, embryo, or egg and sperm—with alleles that produce dark hair might replace them with alleles for light hair. One could replace the alleles later in childhood or even in adulthood, but many traits of interest develop very early; one could not, for example, switch an adult’s alleles from those that produce tall people to those that produce short people and expect much change. The new alleles would usually be inserted into an early embryo, a fertilized egg, or even into the eggs and sperm that will be combined to try to make a child. This kind of early stage gene replacement could use other alleles of standard human genes, but it need not be so limited. One could imagine adding non-human genes or even artificial genes to give the resulting child traits that are beyond the human norm. 

LIMITS

These methods make genetic enhancement either possible or at the edge of possible today, but each method has problems. Prenatal testing can reveal a fetus’s alleles and hence its genetic traits but offers parents few choices. They can prepare for the birth of a child with those genetic traits, or they can abort the pregnancy. Few parents will approach an abortion lightly. Aborting a fetus that would inevitably have a severe genetic disease is a difficult decision for many people; aborting a fetus because it does not carry “above-average genes,” in the hope that there will be another pregnancy with a fetus with better genes, is likely to be rare. And it is only a hope; the random combination of egg and sperm in the next pregnancy could easily produce a fetus with the same or worse genetic variations. PGD avoids the drastic step of abortion. The “average” or “below-average” embryos are not aborted; they are never implanted. On the other hand, unlike pregnancies initiated the old-fashioned way, PGD requires the use of in vitro fertilization. This assisted form of reproduction requires uncomfortable and somewhat risky egg donation procedures, has a relatively low success rate, and costs a lot of money—and comes with none of the compensating advantages of sex. 

PGD does give the parents more control over a fetus’s genetic makeup than does the random combination of sexual intercourse, but it is still only some control. Getting a child with the combination of “enhanced” genetic variations the parents want will not be easy. First, the parents themselves will have to carry those variations; parents with only dark-hair genes will not give birth to a blond child. Second, the parents will have to be lucky. Of the, let’s say, 15 embryos created by one cycle of in vitro fertilization, at least one will have to carry all the right variations. 

If the parents only care about one trait, and it is controlled by only one gene, that may not be difficult. Few traits, though, are so straightforward.

If the parents only care about one trait, and it is controlled by only one gene, that may not be difficult. Few traits, though, are so straightforward. Let’s say their perfect baby needs a set of eight specific alleles, four from each parent, and the chance is about 50 percent that any of the embryos will get the “right” allele from a parent. The chance that all eight alleles will be “right” is one in 256—steep odds when only 15 embryos would be a good result from even a very productive in vitro fertilization cycle. And, of course, some of the embryos with those eight perfect alleles may have other chromosomal or genetic problems. How many IVF cycles would the parents be willing go through to get their perfect baby? 

Instead of relying on chance to bring together the right combination of alleles, parents might try to use gene therapy to put the proper “enhancing” alleles into their offspring. But a problem exists: Gene therapy has been tried for the treatment of serious genetic diseases for more than 15 years with very little success. A handful of people have been helped or even cured by the insertion of new copies of functioning alleles into their cells. Unhappily, the single greatest success in gene therapy—the curing of 11 children with severe immune deficiency— has been linked to the development of leukemia in at least two of them. And the efforts at gene therapy thus far have only tried to replace nonfunctioning alleles with new, working copies. No one has yet tried to take out one version of genes, such as those for light hair, and replace them with others. Nor does anyone know what damage might be inadvertently done to children by inserting or deleting alleles into sperm, eggs, or embryos. Great advances will be necessary before gene therapy could responsibly be used to try to enhance a future child’s abilities. 

The impediments discussed so far have been problems of the methods used to select or create genetically enhanced offspring, but there is another, more fundamental difficulty: We know almost nothing about the genetics of “enhanced” traits. Understandably, human genetics has focused on genetic disease. We know little or nothing about the genetics of such clearly inherited traits as skin color, hair color and type, eye color and shape, or height. We know the gene associated with red hair and freckled skin only because it is also associated with a heightened risk of melanoma, a dangerous skin cancer. Science can today help you select your child’s blood type, if you care, but not her eye color. And what we do know even about these cosmetic traits is not encouraging. We know they are not simple; children do not inherit skin color from their parents in the way Mendel’s peas had either white or yellow flowers. The only thing clear about the inheritance of these traits is that it is affected by more than one gene. 

Although parents may care somewhat about body shape, gray hair, or male-pattern baldness, they are likely to care much more about other traits: intelligence, personality, and musical or athletic ability, among others.

Still, it seems likely that within a few years, the genetic determinants of many cosmetic traits will be understood, traits that are easily defined, relatively unaffected by environment, and fairly common. But, although parents may care somewhat about body shape, gray hair, or male-pattern baldness, they are likely to care much more about other traits: intelligence, personality, and musical or athletic ability, among others. These traits are hard to define, dramatically affected by environment, and, in their most valuable forms, often rare. We know that some of these traits have some connections to genes; how many genes, how strong a connection, and how strongly determined by the interaction of genes with environment are all unknown. We know, for example, something about the genetics of some kinds of subnormal intelligence; we know almost nothing about alleles involved in normal or above-normal intelligence. And, at this point, it is not clear how much we ever will know. The genetic links that may exist may be so obscured by pervasive environmental interactions or depend on so many dozens or hundreds of genes as to be forever beyond our grasp. Humans, after all, do not make good laboratory animals, and those human traits we care about most we probably cannot usefully model in mice. 

Some degree of prenatal genetic enhancement will undoubtedly be possible. How safely, effectively, and significantly babies will prove to be genetically enhance-able very much remains to be seen. 

PROBLEMS

Now forget, for the moment, everything you just read about the serious limits of genetic enhancement. Assume that parents could choose enhanced traits for their children: high intelligence, beauty, coordination, perfect pitch, or whatever else their hearts desired. Would this be a bad thing? Many people think so, but for a wide range of reasons. Consider seven possible objections. 

First, such enhancement might not be safe. Parents, drawn by the prospect of perfect children, could use techniques that caused unforeseen—perhaps unforeseeable—damage to their children and their children’s children. More insidiously, genetic combinations that produced a desired goal, such as excellent mathematical ability, might also be tied in unexpected ways to disease or disability. Preliminary work with nonhuman animals can only go so far in assuring us of the safety of these methods in humans. 

Second, such enhancement could be coercive. One could fear outright coercion— a government requiring, for example, that all children be blond, blue-eyed, and tall. But coercion can be more subtle. Parents could feel coerced by competition; if all the other parents are choosing to give their children genetic advantages, they may feel they have no choice, even though the end result of parents “enhancing” their children would give no child a comparative advantage. And, from the child’s perspective, all such choices are, in a sense, coercive. Decisions are being made about the traits of these not-yet-existent children without seeking their consent. 

If all parents used enhancement techniques and they all made similar choices, we could become a human monoculture, as vulnerable as the potatoes in the Irish potato famine. 

Third, enhancement could reduce human genetic diversity. If all parents used enhancement techniques and they all made similar choices, we could become a human monoculture, as vulnerable as the potatoes in the Irish potato famine. Or, if not dangerous, boring—too many people who looked, talked, and thought the same could take all the spice from the world. Of course, this worry assumes both that most of the world’s 6.3 billion people will be able to use, and will want to use, genetic enhancement and that they will all make similar choices. Both seem unlikely. 

This answer to the third problem raises a fourth. If genetic enhancement were, in practice, limited to the rich, or to those in rich countries, it could be profoundly unfair. Limited access to the benefits of enhancement could make a mockery of the ideal of equal opportunity, particularly as these genetic advantages might be passed on from one generation to the next, creating what one writer has called a “genobility” and locking humanity permanently into a bitter struggle between the genetic “haves” and “have nots.” This justice-based concern is particularly associated with the political left. 

The fifth argument is one made about the use of performance-enhancing drugs in sports. Genetic enhancement, in sports and more broadly, might be “cheating.” Its use could undermine the integrity of the game of life, harming those who were not enhanced, devaluing the accomplishments of those who were enhanced, and diminishing the entire effort. Of course, this depends on viewing life as a game, one with rules that enhancement would violate. 

The sixth argument focuses on the parents and particularly on the relationship between the parents and their children. This view holds that, because parents will be able to choose some of the genetic traits of their children, they will see their children as products, not as gifts and not as fully independent persons. This concern is generally, but not exclusively, associated with the political right. It was voiced perhaps more powerfully by Michael Sandel, a member of the President’s Council on Bioethics, in a 2004 article in Atlantic Monthly

The final argument against genetic enhancement comes in two “alleles,” one religious and one secular. This is the claim that genetic enhancement is against God’s will or is unnatural. It is particularly associated with fears not just of selecting the “best” alleles of human genes but of adding nonhuman or even artificial genes to humans. Some on both left and right, who agree on little else, unite in this argument. But although the argument has great visceral power, it also has a serious weakness. Almost everything man has done, at least since the invention of agriculture, can be viewed either as against God’s will or as unnatural. A principled line between permissible human actions and impermissible ones is hard to draw. 

Different people find different arguments more or less convincing. And each argument could gain or lose strength based on the setting. The safety argument is less powerful if the Food and Drug Administration plays a strong role in approving enhancements; the justice argument is lessened if, for example, genetic enhancements are provided in equal amounts to all parents who desire them. But all seven of the objections to prenatal genetic enhancement require answering another question: what makes this form of enhancement different from those we currently use and approve? 

JUST HOW NEW IS THIS WORLD?

It is rarely remembered today that Huxley’s brave new world relied very little on genes. Its alphas were given extra oxygen in their artificial wombs; its deltas and epsilons received less oxygen but were given brain-deadening alcohol. The mandatory child care taught each classification of children according to their assigned place in the world—and taught them to love their place. Instruction was relentless; taped voices in their pillows continued their “enhancement” through their nightly sleep. 

Is prenatal genetic enhancement meaningfully different from other, accepted forms of enhancement? One can argue that it is more permanent, but other enhancing interventions may have permanent effects, too. 

Today, we humans already work hard to enhance our children. Before their birth, we eat well, down prenatal vitamins, avoid alcohol and tobacco, and get regular prenatal medical care. But our enhancing efforts really kick in after birth. We childproof our homes; we read Green Eggs and Ham until we have memorized it for life; and we generally encourage our children to grow into responsible, loving, and moral adults. Some of us make children who can barely talk attend fancy private schools, take golf lessons, or play the violin. All these actions are efforts to enhance them beyond what they would otherwise be. And our actions are not limited to our children. As adults, we “enhance” ourselves with cosmetic surgery, caffeine, and fancy gyms. In the near future, drugs and implants may further increase our normal abilities in many ways. Is prenatal genetic enhancement meaningfully different from other, accepted forms of enhancement? One can argue that it is more permanent, but other enhancing interventions may have permanent effects, too. Prenatal care can have permanent consequences; teaching a foreign language to a child may have consequences that can neither be reversed nor duplicated by teaching her as an adult. And, if gene therapy ever becomes possible, at least some genetic effects might be reversed by replacing alleles. One can also argue that prenatal genetic enhancement will have longer-lasting effects because it will be passed down from generation to generation. But humans long ago carefully constructed a mechanism to pass down advantages from generation to generation; we call it a family. Some families have few advantages to pass on; others pass on, with greater or lesser success, personalities, education, money, and even high political office. 

Prenatal genetic enhancement is different from other forms of enhancement, but then each form of enhancement is different from all the others. Before we decide whether and how to regulate prenatal genetic enhancement, we need to decide not just how it differs from other forms of enhancement, traditional and new, but how, and if, those differences are important enough to justify regulation. Miranda’s excited outburst to her father about the brave new world is well known. Less well remembered is Prospero’s response: “ ’Tis new to thee.”



About Cerebrum

Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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