Little Lamb, Who Made Thee?

KEITH CAMPBELL WASN'T THINKING, REALLY, ABOUT ROOMS full of human clones, silently growing spare parts for the person from whom they had been copied. Nor was he thinking about giving lesbians a way to bear a biological descendant without visiting the sperm bank. And he certainly wasn't aiming to give pro-team owners a tool to copy their greatest players, hospitals their best doctors or parents their dying child. Campbell, a cell biologist at the Roslin Institute in Scotland, was thinking... sheep. Lots of sheep, hillock upon hillock of sheep, enough sheep (given enough fences) to put all the insomniacs in Scotland to sleep. And all produced from a single cell of a single ewe.

Cloned.

Campbell knew that cloning from an adult mammal was, according to every textbook, impossible. He knew that once a cell has decided what it's going to be when it grows up--part of bone, nerve, skin or any other organ-it is like a CD album that will play only a single track. Although every cell in every body, from liver cells in a person to udder cells in a sheep, contains the complete genetic blueprint for making the entire person or the entire sheep, only the genetic melody for the liver cell or the udder cell is actually played. Dr. Ian Wilmut, in his Roslin Institute lab, was just looking to build a better glass of milk--containing medicine for premature babies The other tracks--instructions for the complete organism--have been silenced. But Campbell would have none of that. He and his Roslin colleagues were going to clone a lamb from an adult cell. Even though everyone said it couldn't be done.

At Roslin they stopped saying that in February 1995, after Campbell strode down the hall to the professorially messy office of his colleague Ian Wilmut. He had figured out, he told Wilmut, how to get adult cells to sound each and every one of the genetic notes required to make a complete animal. The key was to make the cell "quiescent," or inactive. In that state, all of its genes have the potential of being played, Campbell realized. All that was needed was the player. And Campbell had just the thing: a sheep oocyte--egg cell-contains special proteins that turn on genes, playing all the tracks, one after another, like the laser beam in a CD player. "We have to be very quiet about it," Campbell told Wilmut. "We can't tell anybody." And he didn't, until last week, when the world learned of the arrival of Dolly, born last July, the first mammal cloned from an adult cell.

Cloning--manipulating a cell from an animal so that it grows into an exact duplicate of that animal--is the forbidden fruit of biotechnology. Some scientists were so sure it could not be done that, in the 1970s, they dissuaded bioethicists from pondering its moral implications. Yet at the same time other scientists, in out-of-the-way labs and under the cloak of secrecy, were getting ever closer to making clones. What cloning is not, despite all the professions of surprise in the wake of Dolly's birth announcement last week, is unexpected. For 10 years scientists have been cloning sheep and cows from embryo, though not adult, cells. And the research hasn't stopped with the beasts of the field. In 1993, embryologists at George Washington University cloned human embryos: they took cells from 17 human embryos (defective ones that an infertility clinic was going to discard), all two to eight cells in size. They teased apart the cells, grew each one in a lab dish and got a few 32-cell embryos-a size that could be implanted in a woman (though they weren't). So scientists' professed surprise over Dolly rings somewhat hollow.

The real question, of course, was, wherever the lamb went, was Mary sure to follow? In other words, how soon will scientists clone humans? Nature, the scientific journal that published the Dolly paper, editorialized, "Cloning humans from adults' tissues is likely to be achievable any time from one to ten years from now." Cornell University biologist W. Bruce Currie estimates that only 10 labs in the world (his not among them) can manipulate sheep cells the way Dolly's makers did, getting them to become quiescent and producing clones from them. But in principle "there is no difficulty at all in driving human cells I'm a lab dish] into [quiescence]," says Currie. "All that's needed is to take a culture of proliferating cells and deprive them of [nutrients]." Last week, as scientists cast about, almost desperately, for an obstacle to human cloning, embryologist Colin Stewart of the National Cancer Institute came up with one. In sheep embryos, the genes from the donor cell do not turn on until the egg has divided three or four times, he pointed out, In humans, those genes turn on after two divisions. That difference might be an insurmountable obstacle to human cloning-or it might not. But on the more profound question of what, exactly, a human clone would be, doubters and believers are unanimous. A human clone might resemble, superficially, the individual from whom it was made. But it would differ dramatically in the traits that define an individual--personality and character, intelligence and talents. "Here's the rule," says psychologist Jerome Kagan of Harvard. "You will never get 100 percent identity-never--because of chance factors and because environments are never exactly the same."

That was small comfort to politicians, ethicists and pundits. President Clinton, citing "serious ethical questions," ordered a federal bioethics panel to report in 90 days on whether the United States should regulate human cloning or ban it. (Britain, Denmark, Germany, Belgium, the Netherlands and Spain already do.) Ethicists dusted off arguments they had mothballed in the 1970s, and thousands of trees gave their lives so dueling scholars could publish articles arguing that cloning was a humane way for infertile couples to have a child, joking that cloning made males superfluous or conjuring hideous images of cloned humans raised for spare parts.

That prospect seems awfully remote from the Roslin Institute's mundane goal: building a better glass of milk. The scientists, backed by PPL Therapeutics P.L.C. of Edinburgh, wanted to genetically engineer sheep and cows so that their milk contains human proteins. Not just any proteins, but those with pharmacological uses--medicines. Earlier this year PPL threw a coming-out party for Rosie, a cow whose milk contains human alpha-lactalbumin. This protein contains just about all the amino acids a newborn needs; the idea is to purify the protein from Rosie's milk and sell it, in powdered form, for premature babies who cannot nurse. Other companies are also banking on animals with human traits, for everything from blood to hearts.

ROSIE MAKES A HUMAN protein because, when she was a mere embryo in a dish, scientists slipped the gene for the protein into her cells. (The human gene is rigged so that the protein is made only in milk glands and not in, say, the retina.) When Rosie was born she carried the human gene; this makes her a "transgenic" animal. But putting a human gene into each and every Rosie-to-be is not only tedious but inefficient. It fails more often than it succeeds. Wilmut figured that cloning offered a better way. His recipe: first make transgenie sheep, which he preferred to cows. When the lamb grows up, take one of its cells, slip it into an egg cell from a different sheep, put the whole package into a surrogate mother sheep and wait 150 days. Do this a few times and pretty soon there is a flock of sheep making medicine-laced milk. After he built up a flock of maybe 10 cloned sheep, Wilmut figured, he would breed the animals the old-fashioned way. That way the flock would be more genetically diverse and thus less vulnerable to viruses and disease.

The stumbling block to cloning had been that cells in an adult animal have already chosen what they want to be when they grow up. They are liver cells, or skin cells, or neurons, for instance. Any gene not needed in a cell is switched off, though still present. As a result, skin cells do not make estrogen; brain cells do not make insulin. Proteins, acting like a medieval chastity belt, seem to block a cell's access to those genes. For this reason scientists had never cloned an adult cell: like a frustrated knight, they couldn't get at all the genes needed to make a complete animal.

The Scottish scientists' key discovery was making adult cells live up to their full potential. First the researchers removed udder cells from a 6-year-old pregnant sheep. They grew the cells in lab dishes, immersing them in nutrients. Then, in the eureka step that sent Campbell down the haft to Wilmut two years ago, they dialed back the nutrients to one twentieth of what cells need to grow. After five days the cells had become quiescent, stilled at exactly that stage in their life cycle when their genes are open to what the Roslin scientists call "reprogramming of gene expression." In other words, the genes could receive signals from the ovum that they should start making a lamb embryo. It is hardly a foolproof method-of 277 adult cells fused with ova, only 13 pregnancies resulted and only Dolly was born alive-- but it is better than anyone else has ever done.

The Roslin scientists had no sooner trotted out Dolly than they assured everyone who asked that no one would ever, ever, apply the technology that made Dolly to humans. Pressed to answer whether human cloning was next, scientists prattled on about how immoral, illegal and pointless such a step would be. But as The Guardian of London pointed out, "Pointless, unethical and illegal things happen every day." If society decided that it wanted to stuff the cloning genie back into the bottle, could it? In the case of nuclear bombs, the five nuclear powers have controlled proliferation, more or less, in part because the United States showed, at Hiroshima and Nagasaki, what horrors the bomb can wreak. The taboo on biological weapons has also held. And with the exceptions of the Iran-Iraq War of the 1980s and the Tokyo subway attack by the Aum Shinrikyo cult in 1995, chemical weapons, too, have remained on the shelf, at least since the horrific mustard-gas attacks of World War I. Will it take a few human-clone disasters to bring a ban?

Technologies that require big capital investments and infrastructure, like weapons, are easier to control than those that can be carried out by a couple of graduate students in abasement lab. The United States, for instance, bans the use of government money for research on human embryos. But in January a biologist at George Washington University resigned after he was discovered doing research on human embryos in an attempt to find a way to diagnose those with genetic abnormalities. It is easy to imagine another researcher, also with altruistic motives, attempting to clone humans despite a ban. It is equally easy to imagine creepier reasons for cloning. The journal Nature reported that, just before its Dolly issue went to press, it received an e-mail from a Harvard University scholar, pleading that the paper be dropped because "abuse [of the cloning technique] by extralegal or foreign groups is almost inevitable." Alarmism? British futurologist and author Patrick Dixon claimed last week that he had been contacted by a woman who wanted to clone her deceased father-- and possibly carry the baby to term herself.

But who, exactly, would that baby be? Both the dreams and the nightmares of cloning--the thousands of Mother Teresas and the thousands of Pol Pots--are no closer to reality after Dolly than they were before. As far as anyone can tell, Dolly is an exact copy of the ewe whose DNA she carries. But with sheep it's kind of hard to spot differences anyway. When it comes to people, genes are only the start, as even Hollywood recognized 19 years ago. In "The Boys From Brazil," the 94 boys made from one of Hitler's cells were exposed to the same traumatic and other formative experiences as Hitler, for the fictional plotters knew that genes alone would not guarantee Fuhrers II through VC.

If Dolly had been born 10 years ago, the explanations would have ended there, with comforting boilerplate about how people are more than their genes, how they are complex products of their interactions with their parents, their friends, their teachers, their culture and their times. But Dolly happened along just when behavioral geneticists and psychologists have begun to figure out exactly how genes--nature--are either turned up or turned down by their environment--nurture. "Environmental influences can alter the physical structure of the brain, determining in part how genes express themselves in both biology and behavior," notes psychiatrist Stanley Greenspan of George Washington University in his new book "The Growth of the Mind."

Take shyness, considered the most heritable personality trait. Harvard's Kagan has found that fetuses with fast heartbeats tend to become shy babies. In other words, these children are biologically predisposed to be supercautious and anxious. (The genes seem to have something to do with making the brain recoil from stimulation and new experiences.) But if parents nudge their shy children into situations that they would otherwise cringe from, like playing with other kids, the biochemical systems that induced shyness in the first place may somehow get dialed back. Which leads to lesson one for would-be cloners: if you clone a sociable person but then protect the precious creation with the zeal of Juliet's nurse, you may produce a quaking wallflower.

Achievement is under even weaker genetic control. "A Mozart born into a primitive tribe in Papua New Guinea would never have written a symphony," says neurologist Harold Klawans of Rush Medical College in Chicago. But because Mozart's father was a composer and his older sister took piano lessons, whatever innate talent little Wolfgang possessed could be realized. Intellectual revolutionaries are also made and not born, let alone cloned. Frank Sulloway of MIT, who has made his reputation with studies showing how birth order influences everything from political views to personality, argues that "if Darwin had been his mother's firstborn, he would not have been an evolutionist." Based on data from 600 of Darwin's contemporaries, Sulloway calculates that only 5 percent of (conformist) firstborns were evolutionists, but 50 percent of (establishment-challenging) later-borns were. Moreover, Darwin came from a politically and religiously liberal family. "He's loaded to the gills with everything that could have made someone a revolutionary," says Sulloway. Lesson two: to clone aniconoclast, make him your second child.

Which is not to say that genes do not matter. They do. Genes gently nudge a baby into certain behaviors, which then shape her world by, among other things, eliciting from those around her certain kinds of reactions. But the reactions, and the baby's experiences, are hardly predestined and outside human control. Yes, a squalling baby can make his parents angry, even abusive; but parents can recognize the destructive cycle that's beckoning and make a herculean effort to hug, kiss, hold, talk to and coo at him. And the baby "genetically predestined" to be emotionally cold may become a loving preschooler. Conversely, parents who give in to the oversensitive baby, letting her play alone, only exacerbate innate tendencies; parents who withdraw from the difficult baby exaggerate his worst traits. Parents, says Greenspan, can "change the way their [children's] nervous systems work and thus their personalities." Lesson three: genetic seldom means immutable.

EVEN PHYSICAL TRAITS, such as risk for a disease, can be pumped up, damped down or even snuffed out by life's experiences. About 15 percent of women who inherit BRCA1, known as the breast-cancer gene, do not get the disease. Something in their environment, perhaps dumb luck, protected them. Another gene, related to skin cancer, is turned on by exposure to radiation; if the person carrying the gene takes precautions against ultraviolet rays, he may never get skin cancer, explains Mark Feinberg of Johns Hopkins University. More complex diseases, such as heart disease and mental illness, are even less subject to genetic control. One might clone what seems to be a well-adjusted, healthy person only to find that the clone undergoes experiences that make him hypertensive or schizophrenic. For example, the incidence of schizophrenia doubled among Dutch children born in the Netherlands' "winter of famine" during World War II. Maternal malnutrition can trigger the disease. But a clone of one of these children, a genetic duplicate, might evade schizophrenia if borne by a woman who ate normally during pregnancy. Lesson four: don't count on avoiding a genetic disease just because you clone what seems to be a disease-free person.

What you clone may not be what you get for an even more basic reason: the cell being cloned has undergone years of mutations. These changes in its genes-caused by radiation, chemicals or just chance-might not have caused any apparent problem. If a gene for a brain chemical is mutated in a skin cell, it's not even detectable. But what if a lab happened to be unlucky enough to choose that cell to clone? The baby would be born with horrible or even fatal defects. "[Mutations are] a problem with every cell, and you don't even know where to check for them," says reproductive biologist Ralph Brinster of the University of Pennsylvania. Aging also affects the cloned cell, and perhaps the animal grown from it. Although Dolly looks like an 8-month-old lamb (albeit a pudgy one, bemuse her handlers have to keep feeding her to make her stand still for photographers), is she, biochemically, really 6 years old, the age of the ewe from whose cell she came?

If Dolly's creation offers any lessons, it is these. First, that which is not absolutely prohibited by the laws of nature is possible. Second, science, for better or worse, almost always wins; ethical qualms may throw some roadblocks in its path, or affect how widespread a technique becomes, but rarely is moral queasiness a match for the onslaught of science. Society, then, would do well to face the fact that no known law of nature prohibits the cloning of humans. If it wants a voice in whether adults clone themselves, either to raise as children or to grow spare parts, the time to speak up is now.

Or maybe we shouldn't worry about it. After all, they say it won't be done.

Technologies for reproduction started small, on the farm, but embryology and genetics moved them from animals to humans to clones. The progress has been steady--both in science and science fiction.

Scientists once thought that cloning an animal from an adult cell was impossible. Although every cell contains the complete genetic blueprint for making a new animal, those instructions cannot be read in adult cells; they've become specialists, producing cells only for a single body part. The Scottish team figured out how to turn on all the genes needed to make a lamb from a single adult sheep cell.

1. A Finn Dorset ewe provides the mammary cell for cloning.

2. A mammary cell contains copies of every gene needed to make a sheep, but only genes for proteins required by mammary cells are active.

3. Cells grow and divide, making carbon copies of themselves. But if the cells are starved of nutrient, they enter a quiescent state. At this point all of their genes can be activated.

4. A Scottish Blackface ewe provides the egg.

5. The egg, or oocyte, is kept alive in a laboratory dish.

6. The nucleus is removed from the egg.

7. The mammary cell and the egg fuse with a spark of electricity. Molecules in the egg then program genes in the mammary cell to produce the lamb embryo.

8. Clusters of embryonic cells are grown.

9. Embryos are implanted into a surrogate mother.

10. The lamb that results is a clone of the donor ewe.

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