Researchers duplicate a human embryo, provoking cries that technology has gone too far. When it finally happened - after years of ethical hand wringing and science-fiction fantasy - it was done in such a low-key way by researchers so quiet and self-effacing that the world nearly missed it. The landmark experiment was reported by Jerry Hall at a meeting of the American Fertility Society in Montreal three weeks ago. Afterward, colleagues came up to congratulate him and say "Nice job." Others voted to give his paper, written with his supervisor, Dr. Robert Stillman, the conference's first prize. But nobody seemed to want to pursue the one fact that made his little experiment - in which he started with 17 microscopic embryos and multiplied them like the Bible's loaves and fishes into 48 - different from anything that had preceded it. Hall flew back to George Washington University, where he is director of the in-vitro lab and where Stillman heads the entire in-vitro fertilization program, reassured that people would view his work as he saw it: a modest scientific advance that might someday prove useful for treating certain types of infertility.
How wrong he was. When the story broke last week - on the front page of the New York Times under the headline scientist CLONES HUMAN EMBRYOS, AND CREATES an ethical challenge - everybody focused on the one thing the scientists seemed willing to overlook: the cells Hall had manipulated came not from plants or pigs or rabbits or cows, but from human beings.
Once it was out, the news that human embryos had been cloned flew around the world with the speed of sound bites bouncing off satellites. That afternoon the switchboard at George Washington logged 250 calls from the press. By the next day more calls and faxes were flooding in from as far away as Spain, Sweden, South Africa and Australia. A spokesman for the Japan Medical Association found the experiment "unthinkable." French President Francois Mitterrand pronounced himself "horrified." The Vatican's L'Osservatore Romano warned in a front page editorial that such procedures could lead humanity down "a tunnel of madness." It was the start of the fiercest scientific debate about medical ethics since the birth of the first test-tube baby 15 years ago.
A line had been crossed. A taboo broken. A Brave New World of cookie-cutter humans, baked and bred to order, seemed, if not just around the corner, then just over the horizon. Ethicists called up nightmare visions of baby farming, of clones cannibalized for spare parts. Policymakers pointed to the vacuum in U.S. bioethical leadership. Critics decried the commercialization of fertility technology, and protesters took to the streets, calling for an immediate ban on human-embryo cloning. Scientists steeled themselves against a backlash they feared would obstruct a promising field of research - and close off options to the infertile couples the original experiment had intended to serve.
Indeed, the results of a Time/CNN poll taken last week suggest that Americans find the idea of human cloning deeply troubling: 3 out of 4 disapprove. A substantial 40% would put a temporary halt on research, and 46% would favor a law making it a crime to clone a human being.
The experiment at the center of the controversy seems, in many ways, unworthy of the hoopla. It is not the Jurassic Park-type cloning many people might think of, in which genetic material from a mature individual -or DNA from an extinct dinosaur - is nurtured and grown into a living replica of the original. This is far beyond the reach of today's science. There is a vast difference between cloning an embryo that is made up of immature, undifferentiated cells and cloning adult cells that have already committed themselves to becoming skin or bone or blood. All cells contain within their DNA the information required to reproduce the entire organism, but in adult cells access to parts of that information has somehow been switched off. Scientists do not yet know how to switch it back on.
Nor does the Hall-Stillman experiment involve genetic engineering - the cutting and splicing procedures by which DNA strands within the nuclei of cells are mixed and matched. In one kind of genetic engineering, scientists have inserted human genes into the DNA of bacteria in order to mass-produce insulin and other human proteins. They have also experimented with therapies that involve replacing genes in human patients who either lack those genes or whose genes are defective. The George Washington research required none of that. The cells were just copied with their genes intact - a far simpler process. Simple enough, in fact, that agricultural researchers have used it to clone embryos from cattle, pigs and other animals for more than a decade.
What brought the research into the human arena was the rapidly developing field of in-vitro fertilization. In clinics popping up around the world, couples who have trouble conceiving can have their sperm and eggs mixed in a Petri dish - and the resulting embryos transferred to the mother's womb. The process is distressingly hit-or-miss, though, and the odds of a successful pregnancy go up with the number of embryos used. In a typical in-vitro procedure, doctors will insert three to five embryos in hopes that, at most, one or two will implant.
But some couples cannot produce more than one embryo, perhaps because the man's semen is in short supply or the woman's ovaries are running out of eggs or do not respond well to hormone treatments designed to stimulate them into superovulating (producing large numbers of eggs on demand). A woman with only one embryo has about a 10% to 20% chance of getting pregnant through in-vitro fertilization. If that embryo could be cloned and turned into three or four, the chances of a successful pregnancy would increase significantly.
This is the reason Hall and Stillman began experimenting with cloning. But they weren't trying, in their initial effort, to produce clones that would actually be implanted in their mothers and later born. The scientists said they just wanted to take the first step toward determining if cloning is as feasible in humans as it is in cattle. Working in George Washington's in-vitro fertilization clinic, they selected embryos that were abnormal because they came from eggs that had been fertilized by more than one sperm; these flawed embryos were destined for an early death whether or not they were implanted. Thus Hall and Stillman saw nothing unethical about experimenting with them, and they got permission to do so from the university.
When one of those single-celled embryos divided into two cells, the first step in development, the scientists quickly separated the cells, creating two different embryos with the same genetic information. (This sometimes happens naturally inside a mother, and the result is identical twins.) In the process, though, the researchers had to strip away an outer coating, called the zona pellucida, that is essential to development. Then came the trickiest part of the procedure. Over the years, Hall had been working with a gel derived from seaweed that could serve as a substitute for the zona pellucida. When Hall put the artificial coating around the cloned embryos, they began to grow and develop. The experiment was a success.
The scientists replicated their procedure many times, producing 48 clones in all. That was the entire experiment. None of the clones grew for more than six days. The scientists had no intention of starting an embriyo factory, selling babies or doing anything else that ethicists worry about.
In fact, Hall and Stillman were totally taken aback by the furor they created. Time correspondent Ann Blackman asked Hall if he feared that his work would create a backlash against this kind of research. "I revere human life," said Hall, his voice choking with emotion. "I respect people's concerns and feelings. But we have not created human life or destroyed human life in this experiment." To Hall and Stillman, human cloning is simply the next step in the logical progression that started with in-vi-tro fertilization and is driven by a desire to relieve human suffering—in this case, the suffering of infertile couples.
That is certainly the least controversial of the technology's potential applications. In the Time/CNN poll, Americans were evenly split on whether they approved or disapproved of cloning for this purpose. If it works - and that is still a big if - it could probably find a market among infertility patients who have tried everything else. "It's pretty scary," said Barbara Tilden, a 39-year-old Illinois woman who has gone through eight different infertility treatments in the past 10 years. "But I'd probably consider it as a desperate last attempt."
Arthur Caplan, director of the Center for Bioethics at the University of Minnesota, could conjure up several equally defensible ways in which cloning human embryos might be medically appropriate. Suppose, for example, a woman knew she was about to become sterile, either because of chemotherapy or through exposure to toxic substances. She might consider having an embryo cloned for future use. Or suppose a couple knew that their children had a chance of inheriting hemophilia or cystic fibrosis. Researchers have developed DNA-analysis techniques to screen embryos for such disorders, but the procedures require snipping cells off embryos, a process that sometimes kills them. In such situations, having a couple of extra clones around could mean the difference between passing on a defective gene or giving birth to a perfectly healthy child.
Even these uses of cloning are fraught with ethical difficulties - not the least of which is the assumption that a defective embryo will be discarded, an action that most right-to-life advocates equate with murder. Medical ethicists have worried for some time that advances in reproductive technology in the U.S. are proceeding in an ethical vacuum, one created not by the technology but by the politics of abortion. "Congress and our state legislatures are fearful of anything that gets them near the abortion debate," complained Caplan. "As a result, we have had no systematic discussion of surrogacy, of what to do with frozen embryos when parents die, of who can operate a fertility clinic. And we have had no systematic discussion of cloning."
As soon as Caplan heard the news from the American Fertility Society meeting, he phoned Gina Kolata, the reporter at the New York Times who broke the story. As a result, Caplan helped shape the discussion that followed. For example, although Hall's technique cannot produce more than two or three clones of any embryo, several stories written about his experiment included the scenario, put forward by Caplan and other ethicists, in which an infertility clinic offers prospective parents a catalog filled with children's photographs. Below each picture is a report on the child's academic and social achievement. Couples could choose from among the pictures, receive a frozen embryo, and then raise that child - not a sibling or near relative—but an exact genetic duplicate.
Or what about the couple that sets aside, as a matter of course, a clone of each of their children? If one of them died, the child could be replaced with a genetic equivalent. If another required a bone marrow or kidney transplant, a donor could be thawed and raised with tissues that are guaranteed to be 100% compatible. Or what if the couple just feels like having a third child that is more like their daughter than their son? By thawing out the corresponding embryo they could have a second daughter who would be a twin of the first, only several years younger. A couple for whom money was no object could give birth to the same child every few years. A woman could even give birth to her own twin, provided her parents had the foresight to preserve a clone of the embryo that produced her.
One does not have to be an ethicist to see the difficulties these situations could create. All parents know how hard it is to separate what they think a child ought to be from what he or she actually is. That difficulty would be compounded - for both the parent and the child - if an exact template for what that child could become in 10 or 20 years were before them in the form of an older sibling. "I think we have a right to our own individual genetic identity," said Daniel Callahan, director of the Hastings Center, an ethics-research organization in Briarcliff Manor, New York. "I think this could well violate that right."
Many of the uses envisioned for cloning are not particularly farfetched compared with things that are already happening. A few years ago, a California couple made a remarkable decision when faced with the news that their daughter was dying of leukemia. The father braved a vasectomy reversal and the mother a pregnancy at 43 to have a new child born for the express purpose of providing the bone-marrow transplant that saved the older child's life.
Husband and wives who have been through in-vitro fertilization with some embryos left over have had to wrestle with the fact that they have a potential human being stored on ice. There are already 10,000 frozen embryos floating around in liquid-nitrogen baths in the U.S., stuck in a kind of icy limbo as their would-be parents sort out the options. Do they let the embryos thaw out and die? Do they give them away? Do they have the right to sell embryos to the highest bidder? And who gets custody - or the cash - in a divorce?
When the profit motive enters into the equation, ethical considerations tend to be forgotten. And private profit drives the infertility business in the U.S. "We are one of the few countries in the world where you can sell sperm and eggs," said George Annas, a medical ethicist at Boston University. There are already catalogs that list the characteristics of sperm donors-including one made up of Nobel prizewinners. Without regulation, it will only be a matter of time, said Annas, before some entrepreneur tries to market embryos derived from athlete Michael Jordan or model Cindy Crawford.
"This is the dawn of the eugenics era," declared Jeremy Rifkin, founder of the Foundation on Economic Trends, a biotechnology-watchdog group in Washington. Painting a dark picture of "standardized human beings produced in whatever quantity you want, in an assembly-line procedure," Rifkin organized protests last week outside George Washington University and other U. S. reproductive -research institutions.
Rifkin, however, was the exception. Few people seemed to be thinking of the Brave New World visions in which a totalitarian government creates whole subclasses of clones designed expressly for particular tasks. As Annas pointed out, there are better ways to create a crack U. S. Navy seal team or an astronaut corps than to clone the appropriate mix of sperm and egg and wait 20 years. "Maybe if this were Nazi Germany, we would worry more about the government," said Annas. "But we're in America, where
we have the private market. We don't need government to make the nightmare scenario come true."
Most people seemed to respond to the idea of human cloning at a more fundamental level. In the Time/CNN poll, 58% said they thought cloning was morally wrong, while 63% said they believed it was against God's will. "It's not that anyone thinks there is a commandment 'Thou shalt not clone,' " said Margaret O'Brien Steinfels of Catholic Commonweal magazine. "But there are limits to what humans ought to be thinking about doing." For many, the basic sanctity of human life seemed to be under attack, and it made them angry. "The people doing this ought to contemplate splitting themselves in half and see how they like it," said Germain Grisez, a professor of Christian ethics at Mount Saint Mary's College in Em-mitsburg, Maryland.
The reaction from around the world was, in may ways, even more heated. "This is not research," snapped Dr. Jean-Francois Mattei of Timone Hospital in Marseilles, France. "It's aberrant, showing a lack of a sense of reality and respect for people." In Germany, Professor Hans-Bernhard Wuermeling, a medical ethicist at the University of Erlangen, was equally repelled by the notion of producing clones for spare parts, calling it "a modern form of slavery."
German officials were quick to point out that the experiment Hall and Still-man conducted - cloning a human embryo - would be considered a federal offense in Germany, punishable by up to five years in prison. "The Americans do not even have our scruples," complained Rudolf Dressier, deputy whip of the Social Democratic opposition in the Bundestag. "They simply go ahead with research, cost what it may." More than 25 countries have commissions that set policy on reproductive technology. In Britain, cloning human cells requires a license the governing body refuses to grant. Violators face up to 10 years in prison. In Japan all research on human cloning is prohibited by guidelines that in the country's highly conformist society have the. force of law.
Should America adopt similar restrictions? That may be difficult at this point. Such research is usually controlled indirectly through the federal purse strings: the government simply cuts off funding to projects the U.S. Congress finds offensive. But that wouldn't work in this case since there
is no federal funding for embryo research; experiments are financed largely by private money, much of it derived from the booming business of in-vitro fertilization.
Making matters even more complicated, there is no federal body charged with setting artificial-fertilization policy in the U.S. The last congressional commission empowered to debate the new technology was disbanded in 1990. Instead, policy is set by a patchwork of state laws, professional societies and local review boards, like the one at George Washington that gave the go-ahead to Hall and Stillman.
Two weeks ago, a report by the congressional Office of Technology Assessment presciently recommended that the government step in. In the past, bioethical policy could have been addressed by any one of a series of federal boards. Perhaps the best was a presidential commission established under President Carter that developed broad policy guidelines on some of the most controversial issues in medicine, such as deciding when brain death has occurred or when it is ethically correct for a doctor to withhold treatment. The commission was disbanded in 1983. Last week's debate made it likely that some kind of national board will be established during President Clinton's watch. It had better be done quickly. Hall told Time that his technique could produce human clones within "a minimum of a couple of years."
Sensing a shift in the regulatory wind, many reproductive scientists wished aloud that the cloning issue had never been raised - or at least not in this way. "[Hall and Stillman] haven't done science or medicine any favors," said Dr. Marilyn Monk, a researcher at London's Institute of Child Health. Dr. Leeanda Wilton, director of embryology at Australia's Monash IVF Center, where much of the in-vitro fertilization technology was developed, said there were hundreds of scientists who could have split an embryo in half, just the way Hall and Stillman did. "They haven't done so because it opens a can of worms," she said.
Hall and Stillman discovered this, to their dismay, in the glare of publicity. At an impromptu press conference the evening the story broke, and in subsequent appearances on Nightline, Good Morning America and Larry King Live, the bewildered scientists tried to keep the discussion focused on the facts of their experiment: that the embryos were defective, that they were never implanted, and that they could never have grown into living humans. Instead they had to field questions from callers like the one who wondered if their technique could be used to put a lion's head on a horse's body.
Having set the terms of the debate - which focused not on what had actually happened but on the frightening scenarios that could arise sometime in the future—the ethicists clearly carried the day. Hall and Stillman retreated to the last refuge of the research scientist. "We have set out to provide some basic information," said an exasperated Hall on Larry King. "It's up to the ethicists and the medical community, with input from the general public, to decide what kind of guidelines will lead us in the future."
But that stance may not be adequate in the years to come, as genetic engineering and cloning begin to converge. It is becoming increasingly apparent to the researchers exploring these frontiers that they have to become ethicists as well as scientists. Technology tends to develop a momentum of its own. The time to discuss whether it is right or wrong is before it has been put to use, not after.
How the Embryos Were Cloned
1. As part of a fertility treatment, eggs were removed from a woman and fertilized in a Petri dish. Some of these eggs were fertilized by more than one sperm-an abnormal condition.
2. One such abnormal cell divided in two as the first step in development.
3. The coating was removed with an enzyme, and the two cells were separated.
4. Using a novel technique, artificial zona coatings were added, allowing development to proceed.
5. The cells continued to divide, forming genetically identical embryos. Development stopped after six days, partly because the embryo was abnormal.
Clone Cattle
Want to peek into a crystal ball and glimpse at the future of cloning? One way might be to look at the livestock industry, the proving ground for reproductive technology. More than a decade has passed since the first calves, lambs and piglets were cloned, and yet there are no dairy herds composed of carbon copy cows, no pigpens filled with identical sows. While copying particular strains of valuable plants such as corn and canola has become an indispensable tool of modern agriculture, cloning farm animals, feasible as it may be, has never become widespread. Even simple embryo splitting, the technique used by the George Washington University researchers on human cells, is too expensive and complicated to take off commercially. "Cloning," says George Seidel, an animal physiologist at Colorado State University, "remains very much a niche technology."
But people have certainly tried to turn livestock cloning into a booming branch of agribusiness in the U.S., and they're still trying. Wisconsin-based American Breeders Service, a subsidiary of WR. Grace & Co., now owns the rights to cattle-cloning technology developed by Granada Biosciences, a once high-flying biotech firm that went out of business in 1992. The process calls for single cells to be separated from a growing calf embryo. Each cell is then injected into an unfertilized egg and implanted in the womb of a surrogate cow. Because the nucleus of the unfertilized egg is removed beforehand, it contains no genetic material that might interfere with the development of the embryo. In theory, then, it ought to be possible to extract a 32-cell embryo from a prize dairy cow and use it to produce 32 identical calves, each brought to term by a less valuable member of the herd. In practice, however, only 20% of the cloned embryos survive, meaning that instead of 32 calves, researchers end up with only five or six.
While the success rate may improve, at present this method of cloning does not seem much better than embryo splitting, which typically produces twins and sometimes triplets. There have been other problems as well. Some of the calves produced have weighed so much at birth that they have had to be delivered through caesarean section. Scientists aren't sure what causes this phenomenon, but they know that ranchers wouldn't appreciate the expense of having to deliver some calves with surgery. Says Carol Keefer, an embryologist at American Breeders Service: "There is so much to learn about cattle yet."
When cattle cloning is perfected, it may not be welcomed down on the farm. Idaho dairyman Kurt Alberti, for instance, isn't so sure he wants to clone the offspring of prizewinning cows like his Twinkie, even though she was the American Jersey Cattle Club's top milk producer last year and her calves fetch handsome prices on the auction block. Using cloning to create large numbers of identical calves runs counter to what breeders strive to do. Alberti wants to create cows even better than Twinkie, and the only way to do that is by constantly reshuffling the genetic deck with a fresh supply of genes. Indeed, rather than a major advance in livestock breeding, cloning taken to extremes could prove to be the exact opposite a big step, all right, but in the wrong direction.
Cloning Classics
When it comes to dealing with cloning, ethicists and science-fiction writers have almost indistinguishable job descriptions. Both groups propose hypothetical situations in which cloning might happen, then examine the likely implications. The only real difference is that ethicists respect the laws of plausibility and don't waste much time on scenarios that probably won't ever come to pass. Science-fiction writers trash those same laws with creative gusto.
The result has been a relentless stream of outrageous books, movies and television shows, beginning with Aldous Huxley's Brave New World, published 61 years ago, and continuing through the box-office behemoth Jurassic Park. There are mysteries, thrillers, love stories-even a sci-fi parody of an old pop song ("Weird Al" Yankovic's I Think I'm a Clone Now, sung to the tune of Tommy James and the Shondells' I Think We're Alone Now). Cloning in fact, has been a fertile enough subject to earn its own ' lengthy entry in the Encyclopedia of Science Fiction.
Freed from the anchor of realism, fiction writers have drifted off in all sorts of strange directions. Huxley's idea was that cloning based on embryo splitting (he called it "bokanovskification") would be used to mass-produce drones for performing menial labor. Huxley's Gammas, Deltas and Epsilons were separated from the higher-class Alphas and Betas not just by economic status but also by biologically engineered physical and intellectual traits.
A different vision of cloning, involving not just the splitting of embryos but the generation of an entire human from a bit of tissue, leads down another fanciful path: re-creating a specific person. In Ben Bova's novel Multiple Man (1976), several exact copies of the U.S. President are found dead and no one is certain whether a clone or the real McCoy sits in the Oval Office. In Nancy Freedman's 1973 book Joshua, Son of None, the clone is a real President, John F. Kennedy. And Ira Levin's 1976 novel (later a movie), The Boys from Brazil, imagines neo-Nazis cloning a batch of Hitlers; luckily the conspirators' failure to duplicate precisely the real Hitler's upbringing leaves the ersatz Fuhrers imperfectly evil.
If cloning became common, then sex - along with male and female genders - would be unnecessary. That's the conceit of books such as Charles Eric Maine's World Without Men (1958) and Poul Anderson's Virgin Planet (1959). Conversely, cloning might be a device for preserving love. The 1991 British TV miniseries The Cloning of Joanna May, based on a Fay Weldon novel, is about a man who dumps his unfaithful wife - but only after cloning her so he can replace her with her twin a few years down the line.
There is one aspect of cloning, though, that writers have largely overlooked: its potential for laughs. The most obvious exception to that rule is Woody Allen in Sleeper. The high point of the film comes when Allen's character kidnaps the severed nose of a Big Brother-like dictator before it can be cloned to oppress the world once more, and holds it hostage at gunpoint. It's hard, though intriguing, to imagine what ethicists would do with that one.
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