Of Clones and Clowns

Biologists have been rather silent on the subject of human cloning. Some others would accuse us, as they have with predictable regularity in the recent past, of insensitivity to the societal consequences of our research. If not insensitivity, then moral obtuseness, and if not that, then arrogance—an accusation that can never be disproved.

The truth is that most of us have remained quiet for quite another reason. Most of us regard reproductive cloning—a procedure used to produce an entire new organism from one cell of an adult—as a technology riddled with problems. Why should we waste time agonizing about something that is far removed from practical utility, and may forever remain so?

The nature and magnitude of the problems were suggested by the Scottish scientist Ian Wilmut's initial report, five years ago, on the cloning of Dolly the sheep. Dolly represented one success among 277 attempts to produce a viable, healthy newborn. Most attempts at cloning other animal species—to date cloning has succeeded with sheep, mice, cattle, goats, cats, and pigs—have not fared much better.

Even the successes come with problems. The placentas of cloned fetuses are routinely two or three times larger than normal. The offspring are usually larger than normal as well. Several months after birth one group of cloned mice weighed 72 percent more than mice created through normal reproduction. In many species cloned fetuses must be delivered by cesarean section because of their size. This abnormality, the reasons for which no one understands, is so common that it now has its own name—Large Offspring Syndrome. Dolly (who was of normal size at birth) was briefly overweight in her young years and suffers from early-onset arthritis of unknown cause. Two recent reports indicate that cloned mice suffer early-onset obesity and early death.

Arguably the most successful reproductive-cloning experiment was reported last year by Advanced Cell Technology, a small biotech company in Worcester, Massachusetts. Working with cows, ACT produced 496 embryos by injecting nuclei from adult cells into eggs that had been stripped of their own nuclei. Implanting the embryos into the uteruses of cows led to 110 established pregnancies, thirty of which went to term. Five of the newborns died shortly after birth, and a sixth died several months later. The twenty-four surviving calves developed into cows that were healthy by all criteria examined. But most, if not all, had enlarged placentas, and as newborns some of them suffered from the respiratory distress typical of Large Offspring Syndrome.

The success rate of the procedure, roughly five percent, was much higher than the rates achieved with other mammalian species, and the experiment was considered a great success. Some of the cows have grown up, been artificially inseminated, and given birth to normal offspring. Whether they are affected by any of the symptoms associated with Large Offspring Syndrome later in life is not apparent from the published data. No matter: for $20,000 ACT will clone your favorite cow.

Imagine the application of this technology to human beings. Suppose that 100 adult nuclei are obtained, each of which is injected into a human egg whose own nucleus has been removed. Imagine then that only five of the 100 embryos thus created result in well-formed, viable newborns; the other ninety-five spontaneously abort at various stages of development or, if cloning experiments with mammals other than cows are any guide, yield grossly malformed babies. The five viable babies have a reasonable likelihood of suffering from Large Offspring Syndrome. How they will develop, physically and cognitively, is anyone's guess. It seems unlikely that even the richest and most egomaniacal among us, intent on recreating themselves exactly, will swarm to this technology.

Biological systems are extraordinarily complex, and there are myriad ways in which experiments can go awry or their results can be misinterpreted. Still, perhaps 95 percent of what biologists read in this year's research journals will be considered valid (if perhaps not very interesting) a century from now. Much of scientists' trust in the existing knowledge base derives from the system constructed over the past century to validate new research findings and the conclusions derived from them. Research journals impose quality controls to ensure that scientific observations and conclusions are solid and credible. They sift the scientific wheat from the chaff.

The system works like this: A biologist sends a manuscript describing his experiment to a journal. The editor of the journal recruits several experts, who remain anonymous to the researcher, to vet the manuscript. A month or two later the researcher receives a thumbs-up, a thumbs-down, or a request for revisions and more data. The system works reasonably well, which is why many of us invest large amounts of time in serving as the anonymous reviewers of one another's work. Without such rigorously imposed quality control, our subfields of research would rapidly descend into chaos, because no publicly announced result would carry the imprimatur of having been critiqued by experts.

We participate in the peer-review process not only to create a sound edifice of ideas and results for ourselves; we do it for the outside world as well—for all those who are unfamiliar with the arcane details of our field. Without the trial-by-fire of peer review, how can journalists and the public possibly know which discoveries are credible, which are nothing more than acts of self-promotion by ambitious researchers, and which smack of the delusional?

The hype about cloning has made a shambles of this system, creating something of a circus. Many of us have the queasy feeling that our carefully constructed world of science is under siege. The clowns—those who think that making money, lots of it, is more important than doing serious science—have invaded our sanctuary.

The cloning circus opened soon after Wilmut, a careful and well-respected scientist, reported his success with Dolly. First in the ring was Richard Seed, an elderly Chicago physicist, who in late 1997 announced his intention of cloning a human being within two years. Soon members of an international religious cult, the Raëlians (followers of Claude Vorilhon, a French-born mystic who says that he was given the name Raël by four-foot-high extraterrestrials, and who preaches that human beings were originally created by these aliens), revealed an even more grandiose vision of human cloning. To the Raëlians, biomedical science is a sacrament to be used for achieving immortality: their ultimate goal is to use cloning to create empty shells into which people's souls can be transferred. As a sideline, the Raëlian-affiliated company Clonaid hopes to offer its services to couples who would like to create a child through reproductive cloning, for $200,000 per child.

Neither Seed nor the Raëlians made any pretense of subjecting their plans to review by knowledgeable scientists; they went straight to the popular press. Still, this wasn't so bad. Few science journalists took them seriously (although they did oblige them with extensive coverage). Biologists were also unmoved. Wasn't it obvious that Seed and the Raëlians were unqualified to undertake even the beginnings of the series of technical steps required for reproductive cloning? Why dignify them with a response?

The next wave of would-be cloners likewise went straight to the mainstream press—but they were not so easily dismissed. In March of last year, at a widely covered press conference in Rome, an Italian and a U.S. physician announced plans to undertake human reproductive cloning outside the United States. The Italian member of the team was Severino Antinori, a gynecologist notorious for having used donor eggs and in vitro fertilization to make a sixty-two-year-old woman pregnant in 1994. Now he was moving on. Why, he asked, did the desires of infertile couples (he claimed to have 600 on a waiting list) not outweigh the concerns about human cloning? He repeatedly shouted down reporters and visiting researchers who had the temerity to voice questions about the biological and ethical problems associated with reproductive cloning.

The American member of the team was Panayiotis Zavos, a reproductive physiologist and an in vitro fertilization expert at the Andrology Institute of America, in Lexington, Kentucky. "The genie is out of the bottle," he told reporters. "Dolly is here, and we are next." Antinori and Zavos announced their intention of starting a human cloning project in an undisclosed Mediterranean country. Next up was Avi Ben-Abraham, an Israeli-American biotechnologist with thwarted political ambitions (he ran unsuccessfully for the Knesset) and no reputable scientific credentials, who attempted to attach himself to the project. Ben-Abraham hinted that the work would be done either in Israel or in an Arab country, because "the climate is more [receptive to human cloning research] within Judaism and Islam." He told the German magazine Der Spiegel, "We were all created by the Almighty, but now we will become the creators."

Both Antinori and Zavos glossed over the large gap between expertise with established infertility procedures and the technical skills required for reproductive cloning. Confronted with the prospect of high rates of aborted or malformed cloned embryos, they claimed to be able to weed out any defective embryos at an early stage of gestation. "We have a great deal of knowledge," Zavos announced to the press. "We can grade embryos. We can do genetic screening. We can do [genetic] quality control." This was possible, he said, because of highly sensitive diagnostic tests that can determine whether or not development is proceeding normally.

The fact is that no such tests exist; they have eluded even the most expert biologists in the field, and there is no hope that they will be devised anytime soon—if ever. No one knows how to determine with precision whether the repertoire of genes expressed at various stages of embryonic development is being "read" properly in each cell type within an embryo. Without such information, no one can know whether the developmental program is proceeding normally in the womb. (The prenatal tests currently done for Down syndrome and several other genetic disorders can detect only a few of the thousands of things that can go wrong during embryonic development.)

Rudolf Jaenisch, a colleague of mine with extensive experience in mouse reproductive cloning, was sufficiently exercised to say to a reporter at the Chicago Tribune, "[Zavos and Antinori] will produce clones, and most of these will die in utero ... Those will be the lucky ones. Many of those that survive will have [obvious or more subtle] abnormalities." The rest of us biologists remained quiet. To us, Antinori, Zavos, and Ben-Abraham were so clearly inept that comment seemed gratuitous. In this instance we have, as on other occasions, misjudged the situation: many people seem to take these three and their plans very seriously indeed. And, in fact, this past April, Antinori claimed, somewhat dubiously, that a woman under his care was eight weeks pregnant with a cloned embryo.

In the meantime, the biotechnology industry, led by ACT, has been moving ahead aggressively with human cloning, but of a different sort. The young companies in this sector have sensed, probably correctly, the enormous potential of therapeutic (rather than reproductive) cloning as a strategy for treating a host of common human degenerative diseases.

The initial steps of therapeutic cloning are identical to those of reproductive cloning: cells are prepared from an adult tissue, their nuclei are extracted, and each nucleus is introduced into a human egg, which is allowed to develop. However, in therapeutic cloning embryonic development is halted at a very early stage—when the embryo is a blastocyst, consisting of perhaps 150 cells—and the inner cells are harvested and cultured. These cells, often termed embryonic stem cells, are still very primitive and thus have retained the ability to develop into any type of cell in the body (except those of the placenta).

Mouse and human embryonic stem cells can be propagated in a petri dish and induced to form precursors of blood-forming cells, or of the insulin-producing cells of the pancreas, or of cardiac muscle or nerve tissue. These precursor cells (tissue-specific stem cells) might then be introduced into a tissue that has grown weak from the loss of too many of its differentiated worker cells. When the ranks of the workers are replenished, the course of disease may be dramatically reversed. At least, that is the current theory. In recent months one version of the technique has been successfully applied to mice.

Therapeutic cloning has the potential to revolutionize the treatment of a number of currently untreatable degenerative diseases, but it is only a potential. Considerable research will be required to determine the technology's possibilities and limitations for treating human patients.

Some worry that therapeutic-cloning research will never get off the ground in this country. Its proponents—and there are many among the community of biomedical researchers—fear that the two very different kinds of cloning, therapeutic and reproductive, have merged in the public's mind. Three leaders of the community wrote a broadside early this year in Science, titled "Please Don't Call It Cloning!" Call therapeutic cloning anything else—call it "nuclear transplantation," or "stem cell research." The scientific community has finally awakened to the damage that the clowns have done.

This is where the newest acts of the circus begin. President George Bush and many pro-life activists are in one ring. A number of disease-specific advocacy groups that view therapeutic cloning as the only real prospect for treating long-resistant maladies are in another. In a third ring are several biotech companies that are flogging their wares, often in ways that make many biologists shudder.

Yielding to pressure from religious conservatives, Bush announced last August that no new human embryonic stem cells could be produced from early human embryos that had been created during the course of research sponsored by the federal government; any research on the potential applications of human embryonic stem cells, he said, would have to be conducted with the existing repertoire of sixty-odd lines. The number of available, usable cell lines actually appears to be closer to a dozen or two. And like all biological reagents, these cells tend to deteriorate with time in culture; new ones will have to be derived if research is to continue. What if experiments with the existing embryonic-stem-cell lines show enormous promise? Such an outcome would produce an almost irresistible pressure to move ahead with the derivation of new embryonic stem cells and to rapidly expand this avenue of research.

How will we learn whether human embryonic stem cells are truly useful for new types of therapy? This question brings us directly to another pitfall: much of the research on human embryonic stem cells is already being conducted by biotech companies, rather than in universities. Bush's edict will only exacerbate this situation. (In the 1970s a federal decision effectively banning government funding of in vitro fertilization had a similar effect, driving such research into private clinics.)

Evaluating the science coming from the labs of the biotech industry is often tricky. Those who run these companies are generally motivated more by a need to please stock analysts and venture capitalists than to convince scientific peers. For many biotech companies the peer-review process conducted by scientific journals is simply an inconvenient, time-wasting impediment. So some of the companies routinely bypass peer review and go straight to the mainstream press. Science journalists, always eager for scoops, don't necessarily feel compelled to consult experts about the credibility of industry press releases. And when experts are consulted about the contents of a press release, they are often hampered by spotty descriptions of the claimed breakthrough and thus limited to mumbling platitudes.

ACT, the company that conducted the successful cow-cloning experiment and has now taken the lead in researching human therapeutic cloning, has danced back and forth between publishing in respectable peer-reviewed journals and going directly to the popular press—and recently tried to find a middle ground. (For a fuller discussion of ACT's efforts, see "Cloning Trevor," by Kyla Dunn, beginning on page 31.) Last fall, with vast ambitions, ACT reported that it had conducted the first successful human-cloning experiment. In truth, however, embryonic development went only as far as six cells—far short of the 150-cell blastocyst that represents the first essential step of therapeutic cloning. Wishing to cloak its work in scientific respectability, ACT reported these results in a fledgling electronic research journal named e-biomed: The Journal of Regenerative Medicine. Perhaps ACT felt especially welcome in a journal that, according to its editor in chief, William A. Haseltine, a widely known biotech tycoon, "is prepared to publish work of a more preliminary nature." It may also have been encouraged by Haseltine's stance toward cloning, as revealed in his remarks when the journal was founded. "As we understand the body's repair process at the genetic level, we will be able to advance the goal of maintaining our bodies in normal function, perhaps perpetually," he said.

Electronic publishing is still in its infancy, and the publication of ACT's research report will do little to enhance its reputation. By the usual standards of scientific achievement, the experiments ACT published would be considered abject failures. Knowledgeable readers of the report were unable to tell whether the clump of six cells represented the beginning of a human embryo or simply an unformed aggregate of dying cells.

One prominent member of the e-biomed editorial board, a specialist in the type of embryology used in cloning, asked Haseltine how the ACT manuscript had been vetted before its publication. Haseltine assured his board member that the paper had been seen by two competent reviewers, but he refused to provide more details. The board member promptly resigned. Two others on the editorial board, also respected embryologists, soon followed suit. (Among the scientists left on the board are two representatives of ACT—indeed, both were authors of the paper.) Mary Ann Liebert, the publisher of the journal, interpreted this exodus as a sign that "clearly some noses were out of joint." The entire publication process subverted the potentially adversarial but necessary dynamic between journal-based peer review and the research scientist.

No one yet knows precisely how to make therapeutic cloning work, or which of its many claimed potential applications will pan out and which will not. And an obstacle other than experimental problems confronts those pushing therapeutic cloning. In the wake of the cloning revolution a second revolution has taken place—quieter but no less consequential. It, too, concerns tissue-specific stem cells—but ones found in the tissues of adults. These adult stem cells may one day prove to be at least as useful as those generated by therapeutic cloning.

Many of our tissues are continually jettisoning old, worn-out cells and replacing them with freshly minted ones. The process depends on a cadre of stem cells residing in each type of tissue and specific to that type of tissue. When an adult stem cell divides, one of its two daughters becomes a precursor of a specialized worker cell, able to help replenish the pool of worker cells that may have been damaged through injury or long-term use. The other remains a stem cell like its mother, thus ensuring that the population of stem cells in the tissue is never depleted.

Until two years ago the dogma among biologists was that stem cells in the bone marrow spawned only blood, those in the liver spawned only hepatocytes, and those in the brain spawned only neurons—in other words, each of our tissues had only its own cadre of stem cells for upkeep. Once again we appear to have been wrong. There is mounting evidence that the body contains some rather unspecialized stem cells, which wander around ready to help many sorts of tissue regenerate their worker cells.

Whether these newly discovered, multi-talented adult stem cells present a viable alternative to therapeutic cloning remains to be proved. Many of the claims about their capabilities have yet to be subjected to rigorous testing. Perhaps not surprisingly, some of these claims have also reached the public without careful vetting by peers. Senator Sam Brownback, of Kansas, an ardent foe of all kinds of cloning, has based much of his case in favor of adult stem cells (and against therapeutic cloning) on these essentially unsubstantiated scientific claims. Adult stem cells provide a convenient escape hatch for Brownback. Their use placates religious conservatives, who are against all cloning, while throwing a bone to groups lobbying for new stem-cell-based therapies to treat degenerative diseases.

Brownback would have biologists shut down therapeutic-cloning research and focus their energies exclusively on adult stem-cell research. But no one can know at present which of those two strategies is more likely to work. It will take a decade or more to find out. Many biologists are understandably reluctant to set aside therapeutic-cloning research in the meantime; they argue that the two technologies should be explored simultaneously.

Precisely this issue was debated recently by advisory committees in the United States and Germany. The U.S. committee was convened by Bruce Alberts, the president of the National Academy of Sciences and a highly accomplished cell biologist and scientific educator. Quite naturally, it included a number of experts who are actively involved in exploring the advantages and disadvantages of stem-cell therapies. The committee, which announced its findings in January, concluded that therapeutic cloning should be explored in parallel with alternative strategies.

For their trouble, the scientists were accused of financial self-interest by Steven Milloy of Fox News, who said, "Enron and Arthur Andersen have nothing over the National Academy of Sciences when it comes to deceiving the public ... Enter Bruce Alberts, the Wizard of Oz-like president of the NAS ... On his own initiative, Alberts put together a special panel, stacked with embryonic-stem-cell research proponents and researchers already on the taxpayer dole ... Breast-feeding off taxpayers is as natural to the NAS panel members as breathing."

The German committee, which reached a similar conclusion, was assembled by Ernst-Ludwig Winnacker, the head of his country's national science foundation. Winnacker and his colleagues were labeled "cannibals" by the Cardinal of Cologne. Remarks like the ones from Steven Milloy and the cardinal seem calculated to make public service at the interface between science and society as unappealing as possible.

President Bush, apparently anticipating the NAS panel's conclusion, has appointed an advisory committee all but guaranteed to produce a report much more to his liking. Its chairman, Leon Kass, has gone on record as being against all forms of cloning. (Earlier in his career Kass helped to launch an attack on in vitro fertilization.)

Meanwhile, a coalition of a hundred people and organizations recently sent a letter to Congress expressing their opposition to therapeutic cloning—among them Friends of the Earth, Greenpeace, the Sierra Club, the head of the National Latina Health Organization, and the perennial naysayer Jeremy Rifkin. "The problem with therapeutic cloning," Rifkin has said, "is that it introduces commercial eugenics from the get-go." Powerful words indeed. Few of those galvanized by Rifkin would know that therapeutic cloning has nothing whatsoever to do with eugenics.

Usually progress in biology is held back by experimental difficulties, inadequate instruments, poorly planned research protocols, inadequate funding, or plain sloppiness. But in this case the future of research may have little connection with these factors or with the scientific pros and cons being debated earnestly by members of the research community. The other, more public debates will surely be the decisive ones.

The clashes about human therapeutic cloning that have taken place in the media and in Congress are invariably built around weighty moral and ethical principles. But none of us needs a degree in bioethics to find the bottom line in the arguments. They all ultimately converge on a single question: When does human life begin? Some say it is when sperm and egg meet, others when the embryo implants in the womb, others when the fetus quickens, and yet others when the fetus can survive outside the womb. This is a question that we scientists are neither more nor less equipped to decide than the average man or woman in the street, than a senator from Kansas or a cardinal in Cologne. (Because Dolly and the other cloned animals show that a complete embryo can be produced from a single adult cell, some biologists have proposed, tongue in cheek, that a human life exists in each one of our cells.) Take your pick of the possible answers and erect your own moral scaffolding above your choice.

In the end, politics will settle the debate in this country about whether human therapeutic cloning is allowed to proceed. If the decision is yes, then we will continue to lead the world in a crucial, cutting-edge area of biomedical research. If it is no, U.S. biologists will need to undertake hegiras to laboratories in Australia, Japan, Israel, and certain countries in Europe—an outcome that would leave American science greatly diminished.