Fine Line

With Public Wary, Cloning Scientists Watch Their Words

Dr. Schatten Wants to Copy A Monkey, but Declares He Won't Try Humans Fighting 'Charlatan' Doctors

ANTONIO REGALADO / Wall Street Journal 22dec04

In December 2002, Gerald Schatten told members of President Bush's Council on Bioethics that "primate cloning, including human cloning, will not be in our lifetimes."

Now Dr. Schatten is hoping he can clone a monkey as soon as next year. Thanks to a new technique developed in Korea and a $6.4 million grant from the U.S. government, "things are going exceptionally well," says the University of Pittsburgh School of Medicine professor.

As the technology behind cloning advances, scientists at mainstream institutions such as Dr. Schatten are walking a delicate line between promoting their work and pooh-poohing their chances of turning scary science-fiction scenarios into reality. Dr. Schatten has criticized "unethical human baby cloning" efforts and confronted rogue scientists who claim to be trying it. At the same time, he's lobbied in the United Nations to make sure scientists are free to pursue the basic science of cloning as they see fit. He says the research could bring big medical benefits for humans.

A: DNA removed from donor monkey egg B: DNA from an adult monkey is injected into the egg C: Cloned embryo D: Monkey embryonic stem cells E: Transfered to womb of surrogate mother F: Cloned monkey

Religious conservatives and some other groups want to ban all human cloning, calling it an affront to the sanctity of life. Most of the scientific establishment wants to leave the door open to "therapeutic" cloning, in which a clone is grown for a few days in the laboratory until it's an embryo of about 100 to 150 cells. At that point stem cells useful for research or treatment can be extracted. So far the two sides have fought to a draw. Many other countries have banned human cloning, but the U.S. Congress has yet to pass any law on the subject.

The issue is becoming more urgent as science advances. This year, scientists in Seoul, South Korea, reported they had created a cloned human embryo and extracted its stem cells -- the first example of therapeutic cloning of a human. Scientists argue such cloning will allow them to produce stem cells matched to any adult individual and perhaps lead someday to customized transplants of cells or organs for people suffering from nerve degeneration, liver failure and the like. But critics see a slippery slope: Every laboratory advance threatens to make cloned babies more likely.

For Dr. Schatten, the debate over high-tech reproduction is colored by personal experience. He was deeply affected by the deaths of three of his children who were stillborn because of a blood incompatibility with his first wife. Those "little souls" still haunt him, he says, and fuel his concern that human cloning attempts could create babies with no chance of survival.

Dr. Schatten's lab is one of several around the world racing to grab the scientific prize of cloning the first living primate. The Pittsburgh team is importing the Korean techniques, along with some of the Korean researchers. Many of the other contenders are in Asian countries where monkeys are easier to obtain, including Singapore, China and Vietnam.

The basic cloning technique hasn't changed greatly since 1997 when Scottish researchers announced the birth of Dolly the sheep, the first clone produced from a cell of an adult mammal. Using a thin, hollow needle, scientists draw out the DNA-containing nucleus of a fertile female's egg. They then inject DNA from a cell of the adult animal being cloned. Following an electric or chemical shock, the reconstructed egg begins to divide. Placed in a female's uterus, it can then gestate until birth.

Cloned cattle can now be purchased for about $20,000. And two cloned cats were on display recently at a national cat fanciers' show in Madison Square Garden in New York City.

The National Institutes of Health has committed several million dollars toward monkey cloning at four U.S. laboratories over the past decade in the hope of furthering research into human diseases. A supply of identical monkeys might help tease apart what role nature and nurture play in human illnesses such as autism or alcohol addiction.

But creating a living monkey clone has proved far more difficult than scientists first supposed after the Dolly success. Several teams, including Dr. Schatten's, have failed despite as many as 1,000 cloning attempts since 1997. Earlier this year, Dr. Schatten says his team transferred a total of 135 cloned monkey embryos into 25 female monkeys. They saw fleeting indications of a pregnancy once, but never detected a growing fetus. The cells inside the cloned embryos likely had misformed chromosomes or other abnormalities, defects resulting from the cloning process.

NEW FRONTIERS
A brief history of cloning:

YEAR	ANIMAL	COMMENT
1960s	Frog	Tadpoles cloned in Britain
1996	Sheep	Dolly the sheep is first cloned
		mammal
1998	Mouse	Mice cloned in Hawaii
2000	Pig	Pig cloned, organ harvesting 
		is goal
2003	Horse	Italian researchers make Prometea, 
		1st cloned horse
2004	Human	Korean researchers clone
	embryo	human embryo, extract stem cells

In most species, just 1% to 2% of cloning attempts result in a healthy clone. In domesticated species, such as cattle, a large number of eggs is cheaply available from females killed in slaughterhouses. No such source exists for monkey eggs. Like humans, monkeys ovulate monthly and typically can carry only one fetus. Scientists say the limited supply of monkey eggs is a major factor behind their lack of success so far.

Dr. Schatten, 55 years old, is among those who have tried the hardest to clone a monkey. The son of a butcher, he grew up near Flushing, Queens, and was fascinated by the reproduction of jellyfish and other creatures he fished out of the East River. He started his career studying sea urchin eggs but eventually shifted to fertilization in primates.

Then came the Dolly bombshell. Dr. Schatten, then working at Oregon National Primate Research Center, jumped at the opportunity to replicate the feat in monkeys.

The Oregon center was already home to another cloning researcher, Don Wolf. In 1997 Dr. Wolf created two monkeys, Neti and Ditto, by taking DNA from eight-celled monkey embryos and injecting it into monkey eggs. Technically this process was cloning, but it was easier than Dolly-style cloning from an adult animal because the embryo DNA is considered more likely to generate a properly developing organism than DNA from a mature animal. Drs. Schatten and Wolf both hoped to be the first to create a monkey equivalent of Dolly. They clashed over access to scarce monkey eggs, and neither succeeded.

Another First

In 2001, Dr. Schatten and Oregon colleague Anthony Chan did achieve another first when they created the first primate born with a gene added from another organism -- a monkey called ANDi engineered to carry a jellyfish gene. The result led to a windfall of publicity and soon after Dr. Schatten accepted an offer from the University of Pittsburgh to create a multimillion-dollar research center focusing on monkey cloning.

Studying their past failures, Dr. Schatten and an associate, Calvin Simerly, hit on what they thought was the problem. In sucking the nucleus from the monkey eggs, they believed that a crucial protein needed for cloning was also being removed. Dr. Schatten began saying publicly that cloning a monkey might be impossible, including in his appearance before the president's Council on Bioethics. This was a politically useful stance, since the council was debating whether major curbs on research were needed.

Dr. Schatten's theory, later published in the journal Science, became influential in the debate surrounding cloned human embryos. If monkey clones aren't viable, advocates of aggressive research began arguing, then cloned human embryos can't develop either. In that case it would be ethical to experiment freely with human embryo clones, which could in theory produce stem cells for treating diseases such as Parkinson's disease and diabetes.

But many specialists in cloning believe Dr. Schatten's pessimism was overstated, and even he seemed to think the technical problems could be fixed. A month before his Washington testimony, he had submitted a grant application promising his lab would try to create "at least ten cloned NHPs," or nonhuman primates, within five years. A partially redacted copy of the grant application was provided by the NIH following a Freedom of Information Act request. The five-year grant, approved in August 2003, gave the team $6.4 million to clone monkeys, including $175,000 a year to purchase additional animals.

Dr. Schatten now says he should have qualified his comments to the bioethics council by leaving open the possibility that new technology could pave the way for primate clones in our lifetimes. He says he wasn't deliberately lowballing his chances to defuse opposition but admits that his views could appear "erratic."

A year after his comments to the council, Dr. Schatten stumbled onto a potential technical breakthrough. He was touring a Korean pig and cattle cloning laboratory in December 2003 when its director, Hwang Woo Suk, pulled him aside with an urgent whisper. Dr. Hwang revealed that his workers had cloned a human embryo and extracted its stem cells, a historic first. After Dr. Schatten helped the Korean team get the result published in Science, a leading U.S. journal, it made headlines around the globe.

Dr. Schatten quickly tried out the Koreans' new approach in the critical first step of the cloning process -- the removal of DNA from a female's egg to make room for the DNA of the animal being cloned. Instead of sucking the DNA out, the Korean "squish" technique involves puncturing the egg's thin shell and then gently squeezing out its nucleus, explains Chris Navara, one of the Pittsburgh scientists. Since each egg is less than one-hundredth of an inch across, success depends on a researcher's skill in using specialized microscopes. Pittsburgh recently brought in a young student, Park Eul Soon, trained by the Korean group. "We are suddenly going past roadblocks," Dr. Schatten says.

Breeding Season

On a Saturday early in October this year, the fall breeding season arrived for the rhesus monkeys housed near Dr. Schatten's lab. Veterinarians removed 14 eggs from one female. Dr. Schatten's team then removed their DNA and replaced it with DNA taken from skin and other adult cells of a living adult monkey. Five days later, Dr. Schatten was peering at 14 healthy monkey embryos through a microscope -- all clones of the adult.

The purpose of that experiment was to confirm the Korean results by extracting a viable supply of stem cells from the monkey embryos. The team hasn't succeeded in doing so yet, but Dr. Schatten intends to keep trying. If his group can create cloned stem cells regularly, it would then try to transplant the cells back into the adult monkey to test for signs of immune rejection. A successful transplant would point to a possible benefit of cloning human embryos: the ability someday to transplant cells -- or even organs -- created from a patient's own body.

The even bigger prize would be to create the monkey equivalent of Dolly the sheep, and Dr. Schatten's team is working on that too. In February or March 2005, he plans to implant clone embryos again in surrogate monkey mothers, hoping they will gestate successfully until a live birth.

Scribbling estimates on a sheet of paper, Dr. Schatten sees two possibilities for monkey cloning and, by extension, human cloning. One is utter failure or a live birth in only one out of several hundred implanted embryos. In that case "not even the charlatans" could argue that an attempt at human cloning is remotely safe to try, he says. The other possibility, reflected in Dr. Schatten's grant application to the NIH, is that his work will be a step toward making cloned monkeys "reliably and routinely."

If so, it would likely encourage doctors who want to clone a human. Preparing for that day, Dr. Schatten has sought to draw a line between the scientific establishment, which generally sees major ethical problems with attempts to create a human Dolly, and the activities of a small minority of scientists who advocate the idea.

At the American Society for Reproductive Medicine's annual meeting of fertility doctors last year in San Antonio, Dr. Schatten attended a lecture by the human cloning advocate Panayiotis Zavos of Kentucky, which drew TV cameras and a heavy press presence. During the question period, Dr. Schatten confronted Dr. Zavos, calling his preliminary laboratory results an "abject failure."

Sean Tipton, a spokesman for the society, says that following protests by Dr. Schatten and others the organization is no longer allowing papers on human cloning to be presented at its meetings. Dr. Zavos says human cloning could help people, for example by making it possible for infertile parents to have biologically related children. He says of Dr. Schatten, "He uses the media like I do."

On at least two occasions, proponents of human cloning have approached Dr. Schatten seeking assistance, he says. He turned them away, but recognizes that he may one day publish a recipe they could use. Dr. Schatten sees parallels to "T2", the second in the Terminator series of movies. In the film a scientist is confronted with evidence his computer research threatens humanity, and must then decide whether to end his own life. "One of the reasons I get involved in the ethical discussions is so I don't end up on my deathbed as the poor schmuck who destroyed civilization," Dr. Schatten says.

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