Cloning: Phase 2

To a geneticist, cloning is a beautufully simple process, if not completely understood. Deoxyribonucleic acid, the molecule in each cell that ries a being's (human or other) personal genetic inheritance, is combined with an egg cell stripped of its own Dna. When the process works the resulting egg grows into an exact genetic replica of the creature that supplied the DNA.

Cloning is that simple--and the source of extraordinary hopes, fears, controversy and, likely, one day, billions of dollars for people who are paying attention to the research that is quietly, going on in laboratories in various parts of the world. Inevitably, rumors ricochet around the Internet and appear as headlines. One of the most intriguing is that one of a number of international teams of researchers and investors, working in secret laboratories, will soon announce the birth of the first human clone.

Among animals, offspring have already been cloned from mice, sheep, pigs, goats, cows and gaurs (an endangered Asian ox). A handful of biotech companies offer livestock ranchers the cc chanceto clone their favorite milk cows. They also offer storage of a pet's tissue for future cloning, when, as seems certain, clones can be created for dogs, cats and other household companions. Extinct or endangered species, such as the gaur, are particularly appealing to some scientists. An Arizona geologist is defrosting the 20,000-year-old carcass of a woolly mammoth. He hopes to help clone the beast, known as the Jarkov Mammoth, if he can collect viable DNA.

But the concept of human cloning has not been calmly accepted. Squabbling persists among a witches' brew of advocates, fertility experts, rule-happy politicians, distressed religious leaders and cautious mainstream scientists. A reasonable consensus or perspective is hard to find. President George W. Bush and various congressional leaders, for example, unconditionally oppose human cloning as immoral and urge that it be banned in the U.S. Four states and at least 29 other countries already prohibit the procedure.

Meanwhile, the Food and Drug Administration, as well as most researchers with experience in cloning animals, believe we don't yet know enough to safely clone a human being. But these scientists regard a ban with considerable suspicion. As the controversy over ethical implications grows more heated, many of these scientists are lying low. Some fear losing federal or private funding if they are publicly associated with cloning research.

Nevertheless, cloning advocates push ahead. Demand for human clones is already significant, driven by an Internet underground of parents and would-be parents. Infertile couples may want to clone themselves--to keep the DNA in the family--instead of using sperm or eggs from donors. Some couples with a high risk of genetic disease want to clone a favorite relative or friend whose genetic foundation and even physical and mental characteristics they admire. A single parent could be exactly that--the sole parent. Some same-sex couples want the chance to have children who carry no outside donor's genetic blueprints. Some lesbian activists have praised human cloning as a way to be rid of that last scrap of dependence on men.

But the most emotional supporters are parents who want to clone a dead child. They don't want another child; they want the same beloved child they lost to disease or accident. Many speak 80 of giving their dead offspring's exceptional personality, intelligence or athletic promise another chance at life. Clonaid, a company founded by the Raelians, a Canadian UFO cult, claims that 200 couples or individuals have already agreed to pay as much as $200,000 to have tissue cloned. Panos Zavos, who heads two fertility centers in Kentucky, has said 700 couples are interested. Lee Silver, a molecular biologist at Princeton, predicts that worldwide demand by parents who are willing to pay for cloning will override any government attempt to control reproductive technologies.

As for cloning's future, Silver notes that "American-style marketplace economics and personal liberty seem to be on the rise around the world." And cloning, he says, will be seen by parents as another way to make a better baby. He thinks that, someday, sex will be solely recreational, and reproduction will occur in the doctor's office. After all, parents now routinely make choices about their unborn progeny with fertility doctors. The Genetics and IVF Institute, a fertility clinic in Fairfax, Virginia, has offered parents gender selection of their kids since 1996.

The drumbeat of news recalls 1978, when the first child was born from an egg and sperm that were combined outside a woman's body. Some of the loudest critics predicted these "test-tube babies,"conceived in "cold steel and glass," would be "psychological monstrosities." More than two decadeslater the forecast seems bizarre.

"We know what they turned out to be--children," says Gregory Stock, director of UCLA's Program on Medicine, Technology and Society. Cloning, says Stock, is just another step in the quest to improve on the "genetic lottery" of conventional reproduction. He and others believe the issue isn't whether humans should or should not be cloned. "To me," he says, "it's not whether it's going to happen. It's whether people are going to be able to use it. And what access they will have to it."

"Genetic enhancement is just an extension of what we do already," says Silver. "Once societies get over the notion that genetic enhancement is playing God, some--like the European countries--may offer it to all their citizens. They would consider this the fair thing to do." Otherwise, he fears, only the wealthy will have access to improved genes for their children. Over time, different classes of people would develop. He has dubbed them GenRich and Natural. Over hundreds of years, the two could become so different that they would essentially be separate species.

In Remaking Eden: Cloning and Beyond in a Brave New World, Silver sketches out just what genetic enhancement could mean. Parents could give their kids the genes to fight off all known diseases, to be outstanding athletes, to excel in mathematics or business or to have the night vision of cats or the olfactory sensitivity of dogs. As overpopulation turns earthlings' gaze toward other worlds parents could give their babies the specialized physiques--"lung-modified, thick-skinned, dark-green" bodies, for instance--that could allow them to survive as colonists on Mars.

How Cloning Works

With good old-fashioned sexual intercourse, a man's sperm wriggles into a woman's womb and penetrates the egg, and the genes from both are combined. But not all couples can carry out the full maneuver. One in 10 in their prime child-bearing years has trouble conceiving children.

More than 200 years ago, a Scottish physician made the first true procreative advance--human artificial insemination--by successfully depositing sperm from a man with a deformed penis into his wife's reproductive system. The technique is now so easy that a woman can impregnate herself with a turkey baster.

The next big breakthrough was the birth of Louise Joy Brown, the first "test-tube" baby. The egg and sperm that created her were combined in a glass petri dish. Then the embryo was implanted in her mother's uterus. The joyous conception was dubbed in vitro fertilization, or IVF. In vitro fertilization not only permits couples to conceive when their reproductive plumbing doesn't work, it also allows them to use the sperm or eggs of a donor if their own are defective. IVF has become commonplace--and a thriving business for fertility specialists. By one estimate, at least a million otherwise infertile couples worldwide have used IVF to produce happy, healthy, if fairly expensive, children.

IVF also makes cloning possible, because cloned fertilization must occur in a lab. In February 1997, Dolly, a sixmonth-old white-faced Scottish lamb, was introduced to the public. Other animals had been cloned; even other sheep had been cloned. But these had been done as identical twins are formed in nature, at the very first stages of the embryo's growth.

Dolly was the first mammal cloned from the cell of an adult animal--the popular conception of a clone. This meant that the distinct DNA of an adult human being could be intentionally duplicated in a new individual. You would know, more or less, what you were getting. The cells used to produce (continued on page 144)Cloning(continued from page 80) Dolly came from the mammary tissue of an adult ewe, which prompted one of the scientists to name the lamb after Dolly Parton.

Cloning is a labor-intensive, though not particularly exotic, procedure. After eggs are gathered from female donors, their nuclei are sucked out through a fine glass pipette. Other cells are taken from the individual being cloned--from a tiny snip of tissue from inside the mouth, for instance. If the individual is dead, properly preserved tissue sometimes can be used. If the individual has long been dead, as with the Jarkov Mammoth, DNA from marrow or other repositories could work, at least in theory. But no one has managed to produce a Jurassic Park--yet.

In the lab, each egg is fused with the nucleus of a cloner's cell and activated with a tiny electrical or chemical charge. If all goes well, the egg begins to multiply--becoming an embryo with only the genetic traits of the creature being cloned. The most promising embryos are implanted in surrogate mothers to be brought to birth.

Genetically, this makes the clone and the cloner identical twins, though born years, not moments, apart. To date a clone of the girl next door, you would have to wait for the clone to grow up. And, even then, she still wouldn't be exactly the same.

Identical twins have the same genetic information because they come from embryo that split and became separated in the womb after it was fertilized. But identical twins are never exact duplicates. Their fingerprints are different, for instance. Cloned calves and goats often don't have the same color patterns in their coats. In some cases twins can be strikingly different in temperament as well as in physical appearance. Chang and Eng Bunker, the original Siamese twins, were joined at the abdomen. But they were remarkably dissimilar. Eng was outgoing, while Chang was moody and alcoholic.

"The idea that a clone will be exactly like the person who donated the nucleus is completely ridiculous," says Jay Tisch-field, chairman of the genetics department at Rutgers University. Each twin or clone is formed in its own way, beginning with each embryo's position in the womb and the exact composition of the amniotic fluid around it. In fact, because a clone would almost certainly be developed in the womb of a surrogate mother--not the womb the cloner was nurtured in--clones would be even more dissimilar than true identical twins. Finally, after birth, each clone or twin will have individual life experiences that make them even more distinct beings. This is why Ira Levin's book The Boys From Brazil was an entertaining yarn but a highly unscientific vision of a pack of identical boys cloned from Adolf Hitler.

First, do no Harm

Deformities showed up in the early work on cloning--tadpoles with no heads or no bodies; two-headed salamanders. But in the mid-Eighties, more troubling abnormalities appeared--particularly in Texas, where a now-defunct biotech company, Grenada Genetics, had hoped to build a business cloning prize-cattle embryos. To improve their herds, beef ranchers routinely paid as much as $1500 for the single embryo of a valuable cow. If expensive embryos could be cloned--the first goal was to produce 16 embryos from one--a lot of money could be made. W.R. Grace and Co., which then had a big cattle operation, backed the Grenada project.

But many of the cloned embryos were abnormal. Spontaneous abortions were common at all stages of the pregnancies but particularly near birth. Many calves that lived were oversize, even in the womb--a phenomenon that came to be known as large-offspring syndrome. Typical calves weigh 75 pounds at birth. Some cloned calves weighed 180 pounds. Also, the placenta connecting the fetus to the mother was abnormally large, leaving clones with distinctively big belly buttons. The calves often had enlarged, poorly working hearts and lungs. Many had diabetes. As many as 20 percent of those that made it to birth died soon after. Ranchers quickly shied away from spending big bucks on "freak" cattle, and the business died.

Other clones have had different problems, many of which appear randomly and unpredictably--as if genes are being injured haphazardly during cloning. A lot of cloned mice have trouble developing properly. Some get mysteriously fat at the human equivalent of 30 years old. Dolly the sheep had to be put on a diet when her weight ballooned, though most researchers say Dolly seems physically sound. But MIT biologist Rudolf Jaenisch in March 2001 told members of the House Energy and Commerce Subcommittee on Oversight and Investigations, "There's probably not a normal clone around.... Dolly, I believe, is not normal."

All this is what scientists call the safety problem. Efficiency is another obstacle. Animal cloning is expensive because it is so laborious. Dolly started out with the cloning of 277 eggs. Twenty-nine continued to develop and were transferred to the wombs of 13 surrogate-mother ewes. Only Dolly's surrogate got pregnant. With mice, animal cloning has had about a three percent success rate. And phenomenal numbers of embryos and fetuses have died along the way to each successful clone.

"We're making progress," reports Robert Lanza, vice president of Advanced Cell Technology, a Massachusetts biotech company working on human-health products that could be produced on a commercial scale from cloned animals. ACT produced Noah, the baby bull gaur, in January. Lanza notes that each cloned species has presented unique scientific puzzles, some more easily solved than others. While cloning cows and mice is still inefficient, Lanza says goats have been a big success. A cloned goat embryo becomes a healthy new kid more than 85 percent of the time.

Lanza agrees that large-offspring syndrome is still a problem with cows. But he says ACT is working around it. "At this point, we've cloned 40-plus cows, and except for placenta abnormalities, we don't see defects," Lanza says. "Out on the farm, no one would be able to distinguish them from normal, healthy animals."

They do require special care, he admits. Because of their size, the calves are delivered early by cesarean section. Then, like all preemies, they get special handling until they can fend for themselves. "An animal that's a little large isn't really so bad," says Lanza. "These are valuable animals."

Infigen Inc., a Wisconsin biotech company, is cloning Lauduc Broker Mandy EX-95 2E, a champion Holstein. "This is one hell of a cow," says Infigen spokesman Peter Steinerman. "The sheer quantity of milk this cow puts out is extraordinary." A clone of Mandy, due in September, was sold in advance at auction for $82,000 last fall at the World Dairy Expo in Madison, Wisconsin. The price is believed to be the highest ever paid, worldwide, for an unborn calf. Normal daughters of Mandy have typically sold for about $20,000. At the Expo, where the world's cows compete for the "Oscars" of the dairy industry, Mandy made her appearance onstage ambling through an artificial fog bank to the music from 2001: A Space Odyssey.

Into the Looking Glass

Human cloning seemed to take an especially serious first turn in 1978, the year of the test-tube baby and two years after The Boys From Brazil became a bestseller. Public debate was exploding over the implications of genetic manipulation. J.B. Lippincott published In His Image: The Cloning of a Man, by medical writer David Rorvik. The book purported to be the true story of how Rorvik had helped a millionaire--pseudonym Max--secretly clone himself. While ethicists lined up to denounce the abominable procedure, researchers flatly said the deed could not have been done. Four years later, to settle a lawsuit from an Oxford University embryologist mentioned in the book, Lippincott conceded it "now believes the story to be untrue." Rorvik, who has always maintained the book was bona fide, today no longer answers questions about the story. And scientists are even more convinced that human cloning was then technically impossible.

Optimism is now the watchword in the flourishing human-fertility business. New techniques relentlessly emerge. Clients of the more than 370 U.S. fertility clinics are willing to go to great lengths to have a baby. The American Society for Reproductive Medicine, the industry's professional trade group, opposes human cloning until it's safe. But at least one longtime member is forging ahead.

The potential of human cloning "can't be negated by a few dead cattle in Texas," Zavos, the Kentucky fertility specialist, told the House subcommittee this past March. "There is a big difference between a cow and a woman." Zavos retired earlier this year as a professor of reproductive physiology at the University of Kentucky.

Zavos is part of an international consortium led by Italian fertility specialist Severino Antinori. The team has announced that it will clone a human within the next two years at one of several secret labs around the world. Antinori, president of the Italian Society of Reproductive Medicine, is considered by many scientists to be the most experienced of the group. He is skilled in in vitro fertilization and is widely known for inducing pregnancy--using donated egg cells--in postmenopausal women. In 1994 he orchestrated the successful birth of a boy to a 63-year-old woman.

The consortium has been criticized by scientists who ask how it will prevent the abnormal offspring seen in other species. Zavos says the team has developed screening methods to catch defective embryos before they are inserted into surrogate mothers. The effort will be comparable to putting a man on the moov, Zavos proclaims, but "this consortium has no intention to step over dead bodies and deformed babies to develop this technology."

The other leading effort, at least publicly, is Clonaid, set up by the Raëlians, the Canadian techno-religious cult. As a practical matter, the Raëlians at least claim to have the needed funding for a first attempt, from a U.S. couple whose child died last year from a medical mistake. The anonymous couple is described by Clonaid's scientific director, Brigitte Boisselier, as Christian churchgoers "who want to give that genetic code a chance to live." The Raëlians also have another advantage in place--50 young women willing to bear embryos as surrogate mothers. They are also apparently willing to abort their fetuses if tests show abnormal development.

The Raëlians believe that all life-forms were created as a scientific experiment by the small, olive-skinned inhabitants of another planet. These beings, misunderstood here as gods, have dropped by in their UFOs over the past few thousand years to keep track of our progress. A French journalist, Claude Vorilhon, says he was confronted by one of these aliens in France in1973. The visitor invited Vorilhon into his flying saucer, making him a prophet and renaming him Raël. Now the group, which bills itself as the world's largest nonprofit, UFO-related organization, with 55,000 members in 84 countries, is raising money to build an embassy to welcome the experimenters back to earth. The Raëlians would prefer to build their embassy in Israel, where, they say, much of the progeny of past sexual encounters between earthlings and the aliens now live. But Israel has so far declined. The Raëlians' request for unrestricted airspace over the embassy could be an issue.

Cloning is a central technology in Radian belief. In fact, the cult claims that the resurrection of Jesus Christ was accomplished by cloning. One Christ died and was buried and it was, according to the Raëlians, his clone who began to appear to disciples a short time later. Clonaid, based in the Bahamas, focuses its international marketing on infertile and homosexual couples. "Come and return to your country pregnant with the child of your dreams!" promises the website Clonaid.com. For $50,000, Insuraclone, another Clonaid service, will store cells from your living child or "beloved person," in case that person dies unexpectedly and you want to bring their DNA back for another life cycle.

As to how Clonaid will prevent abnormal fetuses, Boisselier claims, "We know how to screen." She says that three unnamed scientists in a U.S. lab are working on the first clone. If legal restrictions force the project out of the country, Boisselier will press on. "If I have to finish on a boat in international waters, I will," she says.

No one really knows what's going on underground. An article in Wired magazine earlier this year recounted a reporter's experience with an anonymous scientist--the Creator--whose effort is supported by a European businessman. The businessman kept tissue from his son's body after the boy died of disease.

Whether accomplished openly or in hiding, cloning a human is a formidable undertaking. "With the technology in its current primitive state," says Silver at Princeton, "it could take a lot of eggs and a lot of women."

Silver raps out the most optimistic scenario. Several hundred eggs would be needed merely for a first attempt. Treated with hormones, a donor can yield 20 eggs. They are typically paid $5000 to provide these--or roughly $100,000 in all. Cells from the cloner are easy to come by, and are free.

After the eggs and donor's nuclei are prepared and fused, perhaps 10 percent would begin to divide, becoming embryos, says Silver. The yield is about 40 embryos. At this early stage, these 40 embryos would be observed as they divide and grow. Obvious abnormalities would be eliminated. This would likely winnow out half the candidates, leaving 20 promising embryos. With current technology, each surrogate mother can be implanted with three embryos--so at least seven women would have to be willing to accept the task.

One to three of those women would actually become pregnant "if they're lucky," says Silver. At the end of the second trimester, the pregnant surrogates would be carefully tested by amniocentesis and high-resolution ultrasound, again to detect abnormalities. At this point, at least 20 percent of the fetuses would likely be abnormal, says Silver, and would be aborted. The project might end up with a single baby who "could very well" be healthy.

Silver is highly skeptical of claims by the Raëlians that they have better ways to effectively screen abnormal embryos. Others are equally skeptical of these claims by the Zavos--Antinori consortium. Jonathan Hill dissected many of the abnormal Texas calves in his years as a Texas A&M veterinarian. He and virtually all other mainstream researchers argue that since the first road map to the human genome--listing 30,000 genes--has only recently been completed, "we don't know which genes have the problems yet. People who are involved in the animal work think cloning humans is premature, because we don't know what to expect."

Late-second-trimester tests could detect "most, but probably not all, abnormalities," says Silver. Some researchers ask how many women would care to bring a 15-pound baby to term; others joke that clones will be obvious at the beach--from their jumbo-sized navels.

The Unsung Promise OF Cloning

Many of the researchers are irritated at rushed efforts to clone a human because they could provoke badly crafted legal restrictions that could hobble research in stem cells and other areas. Gregory Stock, at UCLA, calls human cloning "kind of a sideshow."

Pet cloning is another matter. It may not change the world, but it could make a fortune for Genetic Savings and Clone of College Station, Texas. The company was founded by a good-humored bunch of biologists at Texas A&M after they agreed to clone a 14-year-old Border collie mix named Missy. Missy's unnamed owners put up $3.7 million to fund the Missyplicity Project. The biologists found themselves besieged with inquiries from other pet owners and set up a company.

Like other biotech firms, they already do cows. Chief executive Lou Hawthorne says his researchers have a 50-50 chance of a cloned puppy by November. They are also hard at work on cats, horses and endangered species. Exceptionally talented guide and rescue dogs will be cloned at subsidized rates, as a public service. Hawthorne plans a horse race of clones in five years. Until a species can be cloned, the company will preserve the necessary cells for ranchers and pet owners. Cell harvesting and storage for a healthy dog costs $895.

Hawthorne is a businessman, and he paid particularly close attention when marketing studies predicted that 1.5 percent of the owners of the 60 million "loved" dogs in the U.S. would be interested in cloning their pals. He was even more surprised at the stats on the nation's 40 million cats. "We thought cat owners lacked that certain obsessive je ne sais quoi that dog owners have. We were flat-out wrong."

At Advanced Cell Technology, scientists are also deep into cloning high-priced cows and other livestock. And in an agreement with the Spanish government, ACT is attempting to clone the extinct bucardo mountain goat, using tissue preserved before the last goat was killed by a falling tree in 2000.But cloning human cells and tissues--a field known as therapeutic cloning--and producing animal-created pharmaceuticals to be used in the human body, are their true focuses. The Holy Grail is a whole human replacement heart, cloned from the patient to avoid rejection.

"A lot of people think that you have a little baby with arms and legs and you're pulling it apart," says Lanza, who is in charge of medical and scientific development. "That's not the case. We are talking about a microscopic ball of cells."

That ball of cells in a petri dish can be engineered to produce tissue to patch a diseased heart, liver or kidney much as skin is now grown commercially for use on burn victims. "We have a whole dish of beating heart cells," says Lanza. ACT is also developing insulin-producing cells for diabetics and other cloned cells to treat victims of Parkinson's and Alzheimer's diseases, multiple sclerosis, rheumatoid arthritis, juvenile diabetes, lupus and inflammatory bowel disease. The idea is not new: More than 10 years ago a man who had lost his pancreas was cured of the resulting diabetes with an infusion of engineered cells. But the tools are much improved. "We're now having success growing every part of the body," says Lanza.

The next goal is to clone whole replacement organs. Not only does this eliminate immune system rejection but it also solves the enormous problem of the health system's chronic shortage of donor organs for transplants. A researcher at Children's Hospital in Boston has already grown and transplanted an entire bladder into a dog. A liver could be relatively easy, a kidney would be more difficult and a heart is the toughest of all, says Lanza. A lesser application of ACT's work would be to clone hair follicles. "It's not one of the life-threatening diseases," Lanza admits, "but it would be of interest to a lot of people, including myself."

Infigen, home of Mandy's clone, is doing similar work. In 1997, the company created Gene, a Holstein bull, the first calf cloned from adult cells--as Doll) was the first such sheep. The company has cloned a prize Limousin bull, Cole First Down 46D, once one of the most "influential" bulls--as breeders describe it--in the business. Supplies of his expensive semen had dwindled since he was injured in 1996. But Infigen, too, has its eye on the human therapeutic market.

The company is breeding cows engineered to produce human proteins in their milk, key ingredients in pharmaceuticals that are often difficult to obtain. The American Red Cross, through a Dutch partner, hopes to use Infigen's research to produce proteins to help hemophiliacs control bleeding. Also if clotting factor were more readily available, bandages could be infused with it, to help manage traumatic injuries.

"You can see a farm of the future," says Steinerman of Infigen, "a pig stall with engineered pigs whose organs, tissues and cells would be used for human therapy. On the other side of the farm, you might have five or 100 dairy cows, each providing a therapeutic protein. One cow might ultimately provide $300 million worth of a particular protein every year."

The pig-cloning research at Infigen is aimed at the human-organ replacement market. The idea is to create pigs whose organs are genetically compatible with humans. Is your liver giving out? Order a new one from the medical pig farm. Bad for the pig but good for you.

For $50,000 Clonaid will store a beloved's cells if you want to bring their DNA back for another life cycle.