Harvard Scientists Try Cloning to Create Stem Cells

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Harvard University researchers have entered the race to do what Korean scientist Hwang Woo Suk falsely claimed to have accomplished last year: clone a human embryo in the lab to create stem cells genetically matched to a living person.

The Harvard researchers said today they have begun an effort to combine egg cells donated by women with the genetic material of mature cells from adults to create human embryos in a dish.

If they succeed, the scientists will grow the embryos for several days so they can extract stem cells from them. The cells, which can develop into a variety of tissues, may then be transplanted to treat diseases such as sickle cell anemia or diabetes. The cells would be ``patient-specific,'' matched to a person's own genes, avoiding the risk of rejection.

"Researchers must glean what is usable from Hwang's research -- like taking apart a crime scene and putting it back together to figure out the lies from the truth,'' said Christopher Thomas Scott, a medical ethicist at Stanford University, in an e-mail today. ``The group that does it best, and applies the best `art' from other laboratories, will take the turf claimed by the South Koreans.''

At least one other research team in the U.S. is now attempting the same controversial work. Scientists at the University of California-San Francisco, have received the needed approvals from university ethics committees and are ready to try this type of cloning, resuming an effort they abandoned in 2001.

Promising Technology
"It is a promising technology and no one has really succeeded in it,'' said Renee Reijo-Pera, co-director of the university's Human Embryonic Stem Cell Center.

Xiangzhong Yang, a researcher at the University of Connecticut's Center for Regenerative Biology in Storrs who was the first to clone a cow from a skin cell, is also working on this technique. Yang believes that once he has all the needed approvals from ethics boards he will be able to create stem cells using the cloning technique within 1 to 2 years, he said in an interview yesterday.

President George W. Bush has restricted funding for human embryonic stem cell research. The Harvard studies will be entirely privately funded, said Steven Hyman, Harvard provost, on the conference call.

The work is controversial because to accomplish it, human embryos must be created and then destroyed. Many people, including President Bush, object to that on moral grounds.

Moral Objections
Supporters of the research argue that the embryos are destroyed at a stage when they are far from ``personhood'' -- less than 2 weeks old and scarcely bigger than a period at the end of a sentence.

The cloning procedure being attempted at both universities is known as somatic cell nuclear transfer and has been accomplished in numerous animals but not so far in humans. Scientists take a piece of skin from a patient, isolate a cell and remove its nucleus. They then insert that nucleus into an egg cell whose original nucleus has been removed. The resulting embryo is an exact genetic match of the patient.

The cloning technique gained prominence last year when Hwang claimed to have created new stem cells using donor eggs and DNA from patients, a feat that drew headlines and accolades from scientists around the world. Hwang was disgraced when none of the lines he claimed to have created could be found.

The Harvard group decided to announce the beginning of its studies only because of the controversial nature of the work, Hyman said.
'Highly Charged Debate'

"Normally scientists don't discuss their work publicly until it's been peer-reviewed and published,'' he said. ``We're making an exception to our usual policy because of the intense public interest in stem cell science and the highly charged ethical debate over the work.''

Both sets of researchers will be making use of human eggs from different sources. They are now using eggs provided by women who are trying to become pregnant through in vitro fertilization. Some of the eggs, when mated with sperm in a dish, will fail to fertilize. Though they won't lead to pregnancy, they may be suitable for cloning.

Harvard and the University of California-San Francisco also say they will begin soon to seek donations of eggs specifically for use in stem cell research. Ethics rules prevent women who provide eggs from being paid.
Seeking Eggs Donors

"We might guess that women who have families that are afflicted with diseases that we study might step forward,'' said Kevin Eggan, a Harvard stem cell scientist, on the call. ``We'll have to wait and see because it's an entirely new situation.''

Hyman, the Harvard provost, said eight human research committees at the following institutions have reviewed and approved the proposed experiments: Harvard; its affiliates Children's Hospital and Brigham and Women's Hospital; Partners Health Care, the non-profit owner of some Harvard-affiliated hospitals; Boston IVF, a Harvard-affiliated fertility clinic; and Columbia University in New York.

"We're very excited that this research has finally reached the point where we can actually begin experiments,'' said Leonard Zon, a researcher at Children's Hospital in Boston, Harvard's main pediatric teaching hospital, on a conference call. "It has taken just over two years to get to the point where the experiments can proceed.''

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Two American research teams, one on each coast, said yesterday they were trying to clone human embryos to harvest stem cells genetically matched to patients.

Scientists at the Harvard Stem Cell Institute and the University of California at San Francisco said their goal was to use embryonic stem-cell colonies to model certain diseases. That could lead to developing stem-cell therapies, although probably not for a decade or more.

"We are convinced that working with embryonic stem cells holds tremendous promise for the treatment of a host of currently intractable and incurable diseases," Harvard University provost Steven Hyman said yesterday.

Pursuing this promise is controversial. The field remains under a cloud cast by Hwang Woo Suk, the South Korean researcher who a year ago published a fraudulent paper that claimed to have achieved what the Americans are now attempting. Some conservative groups oppose the research - and government rules block federal funding of it - because it involves destroying human embryos.

What is more, the technology needed to tap the potential of genetically tailored stem cells is hit-or-miss, if not nonexistent.

The process starts with a patient's cell, such as a skin cell, and a woman's donated egg. The nuclear DNA from the patient's cell is inserted into the egg, which has been emptied of its own nucleus. An electrical or chemical signal fuses this "cloned" organism, which begins dividing into an embryo that, at about 100 cells, briefly contains the wondrous stem cells that give rise to all specialized tissues and organs in the body.

Only one team, at the University of Newcastle in the United Kingdom, has published credible evidence of cloning a human embryo to the 100-cell stage - and it took 36 eggs donated by 11 women. The British group did not try to harvest embryonic stem cells, much less coax them to differentiate into specialized cells.

Despite the obstacles, the American researchers said they were optimistic and determined.

Douglas Melton, codirector of Harvard's stem-cell institute, and his colleague Kevin Eggan, a molecular biologist, have spent more than two years going through scientific and ethical reviews to get approval for their work, which will be funded entirely with private and university money.

Federal funding is available only for research using about 20 embryonic stem-cell lines created before federal restrictions took effect in 2002. Those colonies are considered old and difficult to use.

Initially, the pair will focus on diabetes, a disease that afflicts Melton's son and daughter. Eggan also plans to study amyotrophic lateral sclerosis, or Lou Gehrig's disease.

"Diabetes is a complex disease that involves many genes interacting with the environment," Melton said. "It's hard to get at the root cause. In essence, we want to use embryonic stem cells to move the study of the disease from the patient to the petri dish."

George Daly, a Harvard Medical School professor and associate director of Boston Children's Hospital stem-cell program, hopes to use patient-tailored stem cells to decipher and treat blood diseases such as sickle-cell anemia and leukemia.

In 2002, Daly and colleagues used mice to successfully test the concept of therapeutic cloning. They cloned an embryo using an immune-deficient adult mouse cell, extracted stem cells from the embryo, repaired the genetic defect in some stem cells, then used those stem cells to restore immune function in the mutant mice.

"Since then, we have improved our methods considerably," Daly said.

At the University of California at San Francisco, researchers hope to create cell models of neurodegenerative diseases, including Parkinson's and Huntington's. Arnold Kriegstein, director of UCSF's Institute for Regeneration Medicine, said such models could be used to develop conventional drug therapies as well as stem-cell therapies.

By cloning embryos using nuclear DNA from sick people, the scientists aim to produce stem cells that are genetically matched to the patients, thus avoiding the problem of rejection.

Using human eggs poses problems. Egg donors - especially college women - are paid up to $10,000 to undergo unpleasant hormone shots and the invasive extraction procedure.

To avoid the appearance of coercing donors - a problem in the South Korean research - the Harvard researchers will pay only the women's medical expenses. Whether this will deter donations remains to be seen, Eggan said.

Daly and the UCSF team initially will use eggs donated only after they fail to fertilize at in-vitro fertilization clinics. Such eggs are normally treated as waste.

"The availability of top-quality eggs and embryos is extremely limited and this can slow the research," Daly said.

Opponents of the research were quick to condemn it.

"You can't do evil even if good comes out of it," said Judie Brown, president of the American Life League, an antiabortion group.

David Christensen, director of congressional affairs at the Family Research Council, raised the prospect that successful human-embryo cloning would "lead to baby cloning."

Stem-cell experts say reproductive cloning - an idea denounced by those on both sides of embryonic-stem-cell research - is impossible with current technology because scientists don't know how to artificially give the embryo certain genetic programming that is crucial to fetal development.

"The major power of [cloning] comes in studying the development of human disease in human cells," said Debra Mathews, a bioethicist at Johns Hopkins University. "It will be many years, at best, before patients benefit."