Cloning captured public attention when Scottish scientists startled the world by announcing the birth of a sheep named

Dolly that had been cloned by combining the nucleus of an adult mammary cell and an enucleated sheep egg. Interest intensified when Richard Seed, a physicist with no expertise in cloning, no institutional affiliation, and no funding, announced that he would clone humans for a fee. Fear that human-cloning factories might soon appear before anyone had a chance to digest the implications of this new technology sent Congress into action. Legislation was introduced in both the Senate and House of Representatives that would ban human cloning indefinitely or impose a long moratorium on it. Such a moratorium was more or less uncontroversial, given the preliminary nature of the technology required to clone animals and the unknown risks of cloning humans. Unfortunately, the impetuously drafted bills in both the Senate (the BondFrist bill) and the House (the Ehlers bill) would go far beyond restricting the cloning of humans. These bills would put a stop to all cloning experiments that use human cells, in particular research into what is known as somatic-cell nuclear-transfer technology. Never before has Congress passed legislation to halt a single kind of scientific or medical research. Like many others, we believe that any plan to ban research on cloning human cells is seriously misguided. To make our position clear, it is important to explain the biology of somatic-cell nuclear transfer and then point out how this approach if it ever becomes feasible may have unique therapeutic applications. The experiments under discussion involve transferring a human diploid nucleus into a human ovum from which its native nucleus has been removed. In principle, the donor nucleus could be taken from a fetal stem cell or an adult somatic cell. If the nucleus comes from an adult somatic cell, many complex and as yet unproved transformations would have to occur. First, the adult cell nucleus would have to fuse with an enucleated ovum and then dedifferentiate in its new environment. Second, the new cell would have to be capable of dividing into daughter cells, which would have to be pluripotent stem cells with the capacity to differentiate into specific tissues (such as muscle or skin). Finally, the genetic makeup of these stem cells or the newly differentiated cells might have to be altered so that the tissues could then be used to treat human diseases. Some of these transformations have already been achieved in laboratory animals. For example, scientists have developed models of human disease by adding, subtracting, or altering genes in embryonic stem cells derived from early mouse embryos and then reincorporating these cells into recipient embryos. The resulting progeny, generally known as "knockout" animals, are invaluable tools for studying the roles of genes in normal development and in disease. Advances in hypertrophic cardiomyopathy and various cancers are examples of such work.1,2 Research on somatic-cell nuclear transfer might yield numerous benefits. Studies of stem-cell differentiation could provide valuable information about the mechanism of aging or the causes of cancer. Stem cells derived from this technology might also be a rich source of material for transplantation if specific genes or sets of genes in these pluripotent stem cells could be activated and if, as has been described before, the cells could then be coaxed to differentiate. Such a possibility is not strictly theoretical, because differentiated cell types (vascular endothelium, myocardial and skeletal muscle, hematopoietic precursors, and even neurons) have been obtained by culturing embryonic stem cells from mice.3 If this technology could be applied to human stem cells, the resulting products might revolutionize medical therapeutics. The treatment of such diseases as diabetes mellitus, leukemia, and genetic disorders might change dramatically with the availability of genetically altered cell lines that would be immunologically compatible with a given patient and therefore not seen by the immune system as foreign. These are heady goals. Nonetheless, enthusiasm for these therapeutic possibilities must be tempered with a strong dose of reality. Proposed therapeutic applications of somatic-cell nuclear transfer remain largely conjectural, and considerable research will be needed to validate the underlying technology. For example, the evidence that nuclei from fully differentiated adult cells can be reprogrammed is far from conclusive; it may be impossible to activate certain dormant genes in an adult nucleus. In fact, there is still uncertainty about whether the donor nucleus used in the Dolly experiment was derived from a differentiated adult cell or a stem cell.4 Moreover, the rapidity with which the nucleus of a fertilized egg must divide may be too much to ask of a nucleus that has long ceased to divide at all. (These technical obstacles would hinder the production of stem-cell lines customized for individual patients, but adult stem cells might be suitable substitutes for differentiated cells as a source of nuclei.) We also do not know whether differentiation of human pluripotent cells can be controlled in vitro, or whether in this altered state they would be viable once transplanted into a patient. These fundamental questions and many others must be resolved before we can distinguish fact from speculation. Notwithstanding enormous hurdles, future clinical applications of research into human-cell cloning should not be dismissed as science fiction. Because this new direction of investigation is in its infancy, it is impossible to predict where it will lead. Research on somatic-cell nuclear transfer needs nurturing before it can be branded a success or failure. How the public reacts to this line of research will be critically important. Some opponents argue that it is immoral to carry out experiments on human embryonic cells. The arguments against this technology are analogous in many respects to those against abortion. People of good will line up on both sides of the issue. Is there a way to prevent potential abuses of somatic-cell nuclear-transfer technology without legislating against all of it? Discussions about restricting research were held in the 1970s, when recombinant DNA technology was introduced. Rather than legislate against such work, coalitions of scientists in conjunction with representatives of the government and the public drew up stringent self-imposed guidelines and standards to regulate it. Needless to say, this technology has yielded enormous benefits in medicine. Many scientific organizations have announced a voluntary five-year moratorium on the cloning of human beings, but they have argued that research involving the use of somatic-cell nuclear transfer should continue. The BondFrist bill in the Senate and the Ehlers bill in the House, which would ban all cloning in human-embryo research,5,6 are opposed by dozens of medical organizations, biotechnology companies, and distinguished scientists. We join them in opposing this

restrictive legislation. Perhaps voluntary guidelines with oversight by the Food and Drug Administration7 would be an acceptable solution. We believe that a bill modeled after the one introduced recently by Senators Feinstein and Kennedy is a reasonable compromise. That bill would ban the implantation of an embryo developed by the technology into a human uterus for the purpose of creating a child, but it would protect research on somatic-cell nuclear transfer to clone molecules, cells, and tissues. It would also preempt all state laws, and it contains a "sunset" clause that would end the prohibition in 10 years.8 Research on the cloning of human cells holds the promise of medical benefits, but cloning humans is a far more complex and ethically disturbing issue. Some have argued strenuously that human cloning should be barred permanently. They have called it immoral, repugnant, and abhorrent. Most European countries have already banned it; one U.S. state has done so, and others are considering a proscription. While allowing fundamental research in the field to progress, we need a wide debate on human cloning. We need to think about what, if any, circumstances might warrant cloning, as well as the circumstances under which it should never be allowed. At one extreme, cloning of human cells conjures up images of wasted embryos and deformed babies, of infinite life, master races, and duplicates of famous scientists, athletes, and the rich. At the other extreme, cloning is touted in grandiose fashion as a technology with boundless implications for the treatment of infertility and disease. The truth probably lies somewhere in between. The difficult ethical judgments about how to apply this new technology can be made only with full knowledge of the scientific facts. The burden of educating the public about these facts falls squarely on the shoulders of the scientists themselves, whose commitment to full disclosure may never be more stringently tested.

In February the U.S. Senate voted 54 to 42 against bringing an anticloning bill directly to the floor for a vote.1 During the debate, more than 16 scientific and medical organizations, including the American Society of Reproductive Medicine and the Federation of American Societies for Experimental Biology, and 27 Nobel prizewinning scientists, agreed that there should be a moratorium on the creation of a human being by somatic nuclear transplants. What the groups objected to was legislation that went beyond this prohibition to include cloning human cells, genes, and tissues. An alternative proposal was introduced by Senator Edward M. Kennedy (D-Mass.) and Senator Dianne Feinstein (D-Calif.) and modeled on a 1997 proposal by President Bill Clinton and his National Bioethics Advisory Commission. It would, in line with the views of all of these scientific groups, outlaw attempts to produce a child but permit all other forms of cloning research.2,3 Because the issue is intimately involved with research with embryos and abortion politics, in many ways the congressional debates over human cloning are a replay of past debates on fetal-tissue transplants4 and research using human embryos.5 Nonetheless, the virtually unanimous scientific consensus on the advisability of a legislative ban or voluntary moratorium on the attempt to create a human child by cloning justifies deeper discussion of the issue than it has received so far. It has been more than a year since embryologist Ian Wilmut and his colleagues announced to the world that they had cloned a sheep.6 No one has yet duplicated their work, raising serious questions about whether Dolly the sheep was cloned from a stem cell or a fetal cell, rather than a fully differentiated cell.7 For my purposes, the success or failure of Wilmut's experiment is not the issue. Public attention to somatic-cell nuclear cloning presents an opportunity to consider the broader issues of public regulation of human research and the meaning of human reproduction. Cloning and Imagination In the 1970s, human cloning was a centerpiece issue in bioethical debates in the United States.8,9 In 1978, a House committee held a hearing on human cloning in response to the publication of David Rorvik's In His Image: The Cloning of a Man.10 All the scientists who testified assured the committee that the supposed account of the cloning of a human being was fictional and that the techniques described in the book could not work. The chief point the scientists wanted to make, however, was that they did not want any laws enacted that might affect their research. In the words of one, "There is no need for any form of regulation, and it could only in the long run have a harmful effect."11 The book was an elaborate fable, but it presented a valuable opportunity to discuss the ethical implications of cloning. The failure to see it as a fable was a failure of imagination. We normally do not look to novels for scientific knowledge, but they provide more: insights into life itself.12 This failure of imagination has been witnessed repeatedly, most recently in 1997, when President Clinton asked the National Bioethics Advisory Commission to make recommendations about human cloning. Although acknowledging in their report that human cloning has always seemed the stuff of science fiction rather than science, the group did not commission any background papers on how fiction informs the debate. Even a cursory reading of books like Aldous Huxley's Brave New World, Ira Levin's The Boys from Brazil, and Fay Weldon's The Cloning of Joanna May, for example, would have saved much time and needless debate. Literary treatments of cloning inform us that cloning is an evolutionary dead end that can only replicate what already exists but cannot improve it; that exact

replication of a human is not possible; that cloning is not inherently about infertile couples or twins, but about a technique that can produce an indefinite number of genetic duplicates; that clones must be accorded the same human rights as persons that we grant any other human; and that personal identity, human dignity, and parental responsibility are at the core of the debate about human cloning. We might also have gained a better appreciation of our responsibilities to our children had we examined fiction more closely. The reporter who described Wilmut as "Dolly's laboratory father,"13 for example, probably could not have done a better job of conjuring up images of Mary Shelley's Frankenstein if he had tried. Frankenstein was also his creature's father and god; the creature told him, "I ought to be thy Adam." As in the case of Dolly, the "spark of life" was infused into the creature by an electric current. Shelley's great novel explores virtually all the noncommercial elements of today's debate. The naming of the world's first cloned mammal also has great significance. The sole survivor of 277 cloned embryos (or "fused couplets"), the clone could have been named after its sequence in this group (for example, C-137), but this would only have emphasized its character as a laboratory product. In stark contrast, the name Dolly (provided for the public and not used in the scientific report in Nature, in which she is identified as 6LL3) suggests a unique individual. Victor Frankenstein, of course, never named his creature, thereby repudiating any parental responsibility. The creature himself evolved into a monster when he was rejected not only by Frankenstein, but by society as well. Naming the world's first mammal clone Dolly was meant to distance her from the Frankenstein myth both by making her something she is not (a doll) and by accepting "parental" responsibility for her. Unlike Shelley's world, the future envisioned in Huxley's Brave New World, in which all humans are created by cloning through embryo splitting and conditioned to join a specified worker group, was always unlikely. There are much more efficient ways of creating killers or terrorists (or even soldiers and workers) than through cloning. Physical and psychological conditioning can turn teenagers into terrorists in a matter of months, so there is no need to wait 18 to 20 years for the clones to grow up and be trained themselves. Cloning has no real military or paramilitary uses. Even clones of Adolf Hitler would have been very different people because they would have grown up in a radically altered world environment. Cloning and Reproduction Even though virtually all scientists oppose it, a minority of free-marketers and bioethicists have suggested that there might nonetheless be some good reasons to clone a human. But virtually all these suggestions themselves expose the central problem of cloning: the devaluing of persons by depriving them of their uniqueness. One common example suggested is cloning a dying or recently deceased child if this is what the grieving parents want. A fictional cover story in the March 1998 issue of Wired, for example, tells the story of the world's first clone.14 She is cloned from the DNA of a dead two-week-old infant, who died from a mitochondrial defect that is later "cured" by cloning with an enucleated donor egg. The closer one gets to the embryo stage, the more cloning a child looks like the much less problematic method of cloning by "twinning" or embryo splitting. And proponents of cloning tend to want to "naturalize" and "normalize" asexual replication by arguing that it is just like having "natural" twins. Embryo splitting might be justified if only a few embryos could be produced by an infertile couple and all were implanted at the same time (since this does not involve replicating an existing and known genome). But scenarios of cloning by nuclear transfer have involved older children, and the only reason to clone an existing human is to create a genetic replica. Using the bodies of children to replicate them encourages all of us to devalue children and treat them as interchangeable commodities. For example, thanks to cloning, the death of a child need no longer be a singular human tragedy but, rather, can be an opportunity to try to replicate the no longer priceless (or irreplaceable) dead child. No one should have such dominion over a child (even a dead or dying child) as to use his or her genes to create the child's child. Cloning would also radically alter what it means to be human by replicating a living or dead human being asexually to produce a person with a single genetic parent. The danger is that through human cloning we will lose something vital to our humanity, the uniqueness (and therefore the value and dignity) of every human. Cloning represents the height of genetic reductionism and genetic determinism. Population geneticist R.C. Lewontin has challenged my position that the first human clone would also be the first human with a single genetic parent by arguing that, instead, "a child by cloning has a full set of chromosomes like anyone else, half of which were derived from a mother and half from a father. It happens that these chromosomes were passed through another individual, the cloning donor, on the way to the child. That donor is certainly not the child's `parent' in any biological sense, but simply an earlier offspring of the original parents."15 Lewontin takes genetic reductionism to perhaps its logical extreme. People become no more than containers of their parents' genes, and their parents have the right to treat them not as individual human beings, but rather as human embryos entities that can be split and replicated at their whim without any consideration of the child's choice or welfare. Children (even adult children), according to Lewontin's view, have no say in whether they are replicated or not, because it is their parents, not they, who are reproducing. This radical redefinition of reproduction and parenthood, and the denial of the choice to procreate or not, turns out to be an even stronger argument against cloning children than its biologic novelty. Of course, we could require the consent of adults to be cloned but why should we, if they are not becoming parents? Related human rights and human dignity would also prohibit using cloned children as organ sources for their father or mother original. Nor is there any constitutional right to be cloned in the United States that is triggered by marriage to someone with whom an adult cannot reproduce sexually, because there is no tradition of asexual replication and because permitting asexual replication is not

necessary to safeguard any existing concept of ordered liberty (rights fundamental to ordered liberty are the rights the Supreme Court sees as essential to individual liberty in our society). Although it is possible to imagine some scenarios in which cloning could be used for the treatment of infertility, the use of cloning simply provides parents another choice for choice's sake, not out of necessity. Moreover, in a fundamental sense, cloning cannot be a treatment for infertility. This replication technique changes the very concept of infertility itself, since all humans have somatic cells that could be used for asexual replication and therefore no one would be unable to replicate himself or herself asexually. In vitro fertilization, on the other hand, simply provides a technological way for otherwise infertile humans to reproduce sexually. John Robertson argues that adults have a right to procreate in any way they can, and that the interests of the children cannot be taken into account because the resulting children cannot be harmed (since without cloning the children would not exist at all).16 But this argument amounts to a tautology. It applies equally to everyone alive; none of us would exist had it not been for the precise and unpredictable time when the father's sperm and the mother's egg met. This biologic fact, however, does not justify a conclusion that our parents had no obligations to us as their future children. If it did, it would be equally acceptable, from the child's perspective, to be gestated in a great ape, or even a cow, or to be composed of a mixture of ape genes and human genes. The primary reason for banning the cloning of living or dead humans was articulated by the philosopher Hans Jonas in the early 1970s. He correctly noted that it does not matter that creating an exact duplicate of an existing person is impossible. What matters is that the person is chosen to be cloned because of some characteristic or characteristics he or she possesses (which, it is hoped, would also be possessed by the genetic copy or clone). Jonas argued that cloning is always a crime against the clone, the crime of depriving the clone of his or her "existential right to certain subjective terms of being" particularly, the "right to ignorance" of facts about his or her origin that are likely to be "paralyzing for the spontaneity of becoming himself" or herself.17 This advance knowledge of what another has or has not accomplished with the clone's genome destroys the clone's "condition for authentic growth" in seeking to answer the fundamental question of all beings, "Who am I?" Jonas continues: "The ethical command here entering the enlarged stage of our powers is: never to violate the right to that ignorance which is a condition of authentic action; or: to respect the right of each human life to find its own way and be a surprise to itself."17 Jonas is correct. His rationale, of course, applies only to a "delayed genetic twin" or "serial twin" created from an existing human, not to genetically identical twins born at the same time, including those created by cloning with use of embryo splitting. Even if one does not agree with him, however, it is hypocritical to argue that a cloning technique that limits the liberty and choices of the resulting child or children can be justified on the grounds that cloning expands the liberty and choices of would-be cloners.18 Moratoriums and Bans on Human Cloning Members of the National Bioethics Advisory Commission could not agree on much, but they did conclude that any current attempt to clone a human being should be prohibited by basic ethical principles that ban putting human subjects at substantial risk without their informed consent. But danger itself will not prevent scientists and physicians from performing first-of-their-kind experiments from implanting a baboon's heart in a human baby to using a permanent artificial heart in an adult and cloning techniques may be both safer and more efficient in the future. We must identify a mechanism that can both prevent premature experimentation and permit reasonable experimentation when the facts change. The mechanism I favor is a broad-based regulatory agency to oversee human experimentation in the areas of genetic engineering, research with human embryos, xenografts, artificial organs, and other potentially dangerous boundary-crossing experiments.19 Any such national regulatory agency must be composed almost exclusively of nonresearchers and nonphysicians so it can reflect public values, not parochial concerns. Currently, the operative American ethic seems to be that if any possible case can be imagined in which a new technology might be useful, it should not be prohibited, no matter what harm might result. One of the most important procedural steps Congress should take in setting up a federal agency to regulate human experimentation would be to put the burden of proof on those who propose to undertake novel experiments (including cloning) that risk harm and call deeply held social values into question. This shift in the burden of proof is critical if society is to have an influence over science.20 Without it, social control is not possible. This model applies the precautionary principle of international environmental law to cloning and other potentially harmful biomedical experiments involving humans. The principle requires governments to protect the public health and the environment from realistic threats of irreversible harm or catastrophic consequences even in the absence of clear evidence of harm.21 Under this principle, proponents of human cloning would have the burden of proving that there was some compelling contravailing need to benefit either current or future generations before such an experiment was permitted (for example, if the entire species were to become sterile). Thus, regulators would not have the burden of proving that there was some compelling reason not to approve it. This regulatory scheme would depend on at least a de facto, if not a de jure, ban or moratorium on such experiments and a mechanism such as my proposed regulatory agency that could lift the ban. The suggestion that the Food and Drug Administration (FDA) can substitute for such an agency is fanciful. The FDA has no jurisdiction over either the practice of medicine or human replication and is far too narrowly constituted to represent the public in this area. Some see human cloning as inevitable and uncontrollable.22,23 Control will be difficult, and it will ultimately require close international cooperation. But this is no reason not to try any more than a recognition that controlling terrorism or biologic weapons is difficult and uncertain justifies making no attempt at control. On the recommendation of the National Bioethics Advisory Commission, the White House sent proposed anticloning legislation to Congress in June 1997. The Clinton proposal receded into obscurity until early 1998, when a Chicago physicist, Richard Seed, made

national news by announcing that he intended to raise funds to clone a human. Because Seed acted like a prototypical "mad scientist," his proposal was greeted with almost universal condemnation.24 Like the 1978 Rorvik hoax, however, it provided another opportunity for public discussion of cloning and prompted a more refined version of the Clinton proposal: the FeinsteinKennedy bill. We can (and should) take advantage of this opportunity to distinguish the cloning of cells and tissues from the cloning of human beings by somatic nuclear transplantation25 and to permit the former while prohibiting the latter. We should also take the opportunity to fill in the regulatory lacuna that permits any individual scientist to act first and consider the human consequences later, and we should use the controversy over cloning as an opportunity to begin an international dialogue on human experimentation.