Biologists have been rather silent on the subject of human cloning. Some people accuse us of insensitivity to the consequences of our research. If not insensitivity, then moral obtuseness, and if not that, arrogance-an accusation that is never disprovable.
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 agonising about something that is far removed from practical utility and may forever remain so?
The nature and magnitude of the problems were suggested by Ian Wilmut's initial report, six years ago, on his cloning of Dolly the sheep. Dolly represented one success amongst 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 foetuses are often two or three times larger than normal. The offspring are usually larger than normal too. Several months after birth, one group of cloned mice weighed 72 per cent more than mice created by normal reproduction. In many species, cloned foetuses must be delivered by caesarean section because of their size. This abnormality, the reasons for which no one understands, is so common that it now has a name-large offspring syndrome. Dolly (who was normal at birth) was briefly overweight when young and suffers from early-onset arthritis of unknown cause. Two recent reports say that cloned mice suffer obesity and early death.
Arguably the most successful reproductive-cloning experiment was reported in November 2001 by Advanced Cell Technology (ACT), a small biotech company in 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, 30 of which went to term. Five of the newborns died shortly after birth and a sixth died several months later. The 24 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 5 per cent, 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 favourite 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 95 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 amongst 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 the results of research and experiment can be misinterpreted. Still, perhaps 95 per cent 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 built over the past century to validate new research findings and the conclusions derived from them. Research journals impose quality controls to ensure that 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.
We participate in the peer-review process not only to create a sound edifice of ideas and results for ourselves; we also do it for the outside world. Without the trial-by-fire of peer review, how can journalists and the public know which discoveries are credible and which are no more than acts of self-promotion by ambitious researchers?
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 serious scientific work-have invaded our sanctuary.
The cloning circus opened soon after Wilmut, a 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 a religious cult, the Ra?lians (followers of Claude Vorilhon, a French-born mystic who says that he was given the name Ra?l 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 Ra?lians, 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. On 26th December last year, the Ra?lian-affiliated company Clonaid claimed that it had produced the world's first cloned baby, but produced no evidence.
Neither Seed nor the Ra?lians made any pretence of subjecting their plans to review by knowledgeable scientists; they went straight to the press. Still, this wasn't so bad. Few journalists took them seriously, although they did oblige them with extensive coverage. Biologists were also unmoved. Wasn't it obvious that Seed and the Ra?lians were unqualified to undertake even the beginnings of the series of technical steps required for reproductive cloning? Why dignify them with a response?
Another set of would-be cloners also went direct to the press-but they were not so easily dismissed. In March 2001, at a press conference in Rome, an Italian and an American physician announced plans to undertake human reproductive cloning outside the US. The Italian member of the team was Severino Antinori, a gynaecologist notorious for having used donor eggs and in vitro fertilisation to make a 62-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 shouted down reporters and researchers who asked questions about the biological and ethical problems associated with cloning.
The American member of the team was Panayiotis Zavos, a reproductive physiologist and an in vitro fertilisation 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 Antinori-Zavos 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."
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. This was possible, Zavos 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 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 programme is proceeding normally in the womb. (Prenatal tests currently done for Down's 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 about Antinori and Zavos to tell a Chicago Tribune reporter, "they 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. 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, in April 2002 Antinori claimed that a woman under his care was eight weeks pregnant with a cloned embryo. In December he said the baby would be born in January; at the time of writing, no further announcement has been made.
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 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 tissue-specific stem cells might then be introduced into a tissue that has grown weak from the loss of too many 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 revolutionise 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.
Stem cell research in Britain is flourishing. In September, the Medical Research Council announced, with government approval, plans to create Europe's first stem cell bank. But in the US, some worry that therapeutic-cloning research will never get off the ground. Its proponents among biomedical researchers fear that the two very different kinds of cloning, therapeutic and reproductive, have merged in the public's mind. Three leaders in the field wrote a broadside early last 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, at least in America. 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 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 in August 2001 that no new 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 federally funded research on the potential applications of human embryonic stem cells, he said, would have to be conducted with the existing repertoire of 60-odd lines. The number of available, usable cell lines actually appears to be closer to a dozen or two. And like all biological re-agents, these cells tend to deteriorate with time in culture; new ones will have to be derived if federal research is to continue.
Much of the research on human embryonic stem cells is already being conducted by private biotech companies rather than in universities. Bush's edict will only exacerbate this situation in America. (In the 1970s, a federal decision effectively banning government funding of in vitro fertilisation had a similar effect, driving such research into private clinics.)
But 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 science journals is a time-wasting impediment. So some of the companies bypass peer review and go straight to the mainstream press. Science journalists, 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 so limited to mumbling platitudes.
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. Moreover, 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 specialised 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 unspecialised 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.
US lawmakers are gearing up to debate legislation that would ban reproductive cloning and possibly therapeutic cloning too. In his recent State of the Union address, President Bush made it clear he wants all cloning off-limits. Some politicians want biologists to 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. Most researchers support another approach, closer to the legal position in Britain, that would ban reproductive cloning but permit therapeutic cloning under licence.
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 researchers. 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 the US Congress are invariably built around weighty moral and ethical principles. But 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 foetus quickens, and yet others when the foetus can survive outside the womb. (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.) This is a question that we scientists are neither more nor less equipped to decide than the average man or woman in the street. In the end, politics, not science, will settle the debate in America, and elsewhere, about whether human therapeutic cloning is allowed to proceed.
