Cloning Gets Closer

By MICHAEL D. LEMONICK

Back when it was no more than a cheesy science-fiction plot device, human cloning seemed like something that would eventually be revealed to a horrified world full-blown and fully grown--a monstrous carnival apparition ("The Amazing Cloned Boy!") out of a medical freak show.

It hasn't quite turned out that way. Cloning has been emerging gradually, over the past decade, in small increments. Each advance has been startling enough, prompting ethical debates, cautionary references to Aldous Huxley's brave new world and calls for restrictive legislation. But there have been so many milestones, starting even before the birth of Dolly the sheep in 1996, that each one seems a little less startling than the one before. Sometimes an advance is so subtle that it sounds just like the breakthrough that made headlines the year before.

That's how a report in the journal Science sounded last week--at least at first blush. Woo Suk Hwang and Dr. Shin Yong Moon, from Korea's Seoul National University, announced that they had created more than 200 embryos by cloning mature human cells and had grown 30 of them to the blastocyst stage of development, each more than 100 cells strong. This isn't the first time cloned human embryos have been produced: in 2001 the Massachusetts biotech firm Advanced Cell Technology made several. They all died quickly, but in a sense the first cloned human cells are actually old news.

Still, two things make the Korean experiment more than a little noteworthy. The first is simply that their embryos didn't die. That's a very big deal; many experts were convinced that human clones would be impossibly fragile. Second, the scientists extracted embryonic stem cells from the blastocysts and coaxed some of them into a self-perpetuating colony.

That could ultimately prove to be an even bigger deal. Embryonic stem cells are the unspecialized raw material that give rise to every cell type in the body--in fact, some of Moon and Hwang's stem cells evidently turned into bone, muscle and immature brain cells. If scientists can learn to control their development, stem cells could in theory supply replacement tissues to treat any ailment involving cell damage--and there are plenty, including heart disease, diabetes, spinal-cord injury, Parkinson's and Alzheimer's. "Our goal," said Hwang during a press conference at a meeting of the American Association for the Advancement of Science in Seattle last week, "is not to clone humans, but to understand the causes of diseases."

That disclaimer didn't satisfy critics. Indeed, the Korean breakthrough adds fuel to two different ethical debates at once. The first--whether cloning for reproduction should be allowed--is pretty well settled. Only a handful of loose-cannon scientists and members of the Raelian sect, who believe humans were created by aliens, openly favor human cloning. It is explicitly banned in many countries, including Korea.

But the debate over stem-cell research, whether those cells come from cloning or from conventional in-vitro fertilization, is far from over, at least in the U.S. Right-to-life and religious groups, including the Roman Catholic Church, believe that human life begins at conception and thus that harvesting stem cells is tantamount to murder. With views like that on one side and high-profile advocates like Christopher Reeve and Michael J. Fox touting the benefits of therapeutic cloning on the other, the Bush Administration has tried to split the difference. In August 2001 the President declared that the U.S. government would fund stem-cell research--but only using stem-cell lines that had already been isolated.

Only a dozen or so such lines have proved useful, which most American scientists consider far too few to work with. They can still tap a much more limited pool of private funding, but a bill introduced in the Senate last year would have hamstrung them further by banning human cloning even for therapeutic purposes. If that law had passed and the Koreans had done their work in the U.S., said Donald Kennedy, editor in chief of Science and a participant in last week's press conference, "they would have been jailed."

By rejecting a watered-down bill that would have banned reproductive cloning only, conservatives have ensured that the U.S is, bizarrely, one of few developed countries that doesn't forbid human cloning. Responsible scientists wouldn't try it, but an unethical researcher could read the Science paper and attempt to use the technique to bring a clone to term. "I'm afraid that some nitwit is going to try," says Larry Goldstein, a cellular and molecular biologist at the University of California at San Diego. But given the high rate of spontaneous abortions and genetic defects seen in other species, it's not likely to work. The Science paper is a recipe for cloning, said Kennedy, "only in the sense that 'catch a turtle' is the recipe for turtle soup." Said Hwang: "In my humble opinion, it's not so easy to mimic our technology."

Several factors helped the Koreans succeed where others had failed. To start with, they had a large supply of eggs. The researchers lined up 16 female volunteers who found the project through its website. To avoid any taint of coercion, the women weren't paid. They were fully informed about the research and its risks, however, and given several opportunities to change their mind. In the end, the 16 women furnished 242 eggs--many more than in any previous cloning attempt.

The scientists' basic strategy was the same as in most post-Dolly cloning experiments: remove the nucleus of the egg, with its single set of chromosomes, and replace it with the nucleus of a mature cell, containing two sets (in this case, the mature nuclei came from cumulus cells, which surround eggs during development). With a quantity of eggs that a commentary in Science calls "whopping," the scientists were able to experiment with different techniques to find which worked best--varying the time between inserting the new nucleus and zapping it with electricity to trigger cell division, for example, or testing different growth media.

The Korean team believes that two other factors may have helped them succeed. While most cloners suck out an egg's nucleus with a tiny pipette, Moon and Hwang made a pinhole in the cell wall and used a tiny glass needle to apply pressure and squeeze the nucleus out. "It's more gentle with the egg and allows you to remove only the DNA and leave some of the major components of the egg still inside," says Jose Cibelli, a professor of animal biotechnology at Michigan State University and a co-author of the Science paper. "Actually, it's pure speculation, but we can't come up with anything else, so we think that may be important." Technicians also honed their skills until they could transfer a nucleus in less than a minute, a much better time than most labs and one less likely to allow deterioration.

What makes the achievement even more significant is that it gives doctors a way to create stem cells bearing a patient's own DNA. Tissues grown from those cells could replace diseased tissue in the patient without any risk of rejection.

It could be years, however, before such replacement actually happens. "This is an important step forward," says Goldstein, "but it's just one obstacle out of the way." The Korean technique has only worked in women so far, perhaps because they alone have cumulus cells, which seem especially amenable to cloning. It should work in men too, but first, researchers will have to isolate the male equivalent of cumulus cells. Moreover, scientists are still learning how to coax stem cells into becoming particular types of tissue, and for many diseases they don't even know what kind of cells they need to end up with. "With juvenile diabetes," says Goldstein, "I think we have a sense of what cells we want to make. With ALS [Lou Gehrig's disease] we have less of a sense."

Some researchers say all the talk about replacement tissue overlooks a more immediate benefit of stem cells: if you cloned them from someone with a genetic disorder, you could perform all kinds of experiments zeroing in on the DNA that is causing the problem. "If you had that," says Dr. Irv Weissman, director of Stanford's Institute for Cancer/Stem Cell Biology and Medicine, "this would be a transforming technology as important as recombinant DNA."

The way things stand, all the benefits of stem cells will probably be developed--as this latest breakthrough was--outside the U.S. "I'm not really surprised it came from Korea," says Goldstein, citing the researchers' skill and experience. "I'm disappointed it didn't happen first in the U.S. But given the absolute stranglehold that federal policy has put on this field, that doesn't surprise me either."

Even with sensible laws, of course, there's always a chance that cloning technology will be misused. Plenty of useful technologies are abused every day, says Dr. William Gibbons, professor of obstetrics and gynecology at Eastern Virginia Medical School--including automobiles and antibiotics. "It doesn't mean that these are inherently bad," he says. The trick is to legislate against the misuse, not against the technology. --Reported by Dan Cray/Los Angeles, Donald Macintyre/Seoul, Eli Sanders/Seattle and Sora Song/New York

With reporting by Dan Cray/Los Angeles, Donald Macintyre/Seoul, Eli Sanders/Seattle and Sora Song/New York