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Biomedicine

Lack of Human Eggs Could Hamper US Cloning Efforts

Researchers want to make patient-matched stem cells, but success could depend on gaining a reliable source of human eggs.

Last week marked the end of a two-year waiting period for several scientists at Harvard University who are planning to start human cloning experiments, a crucial first step in generating stem cell lines matched to specific patients. While the announcement came amid much fanfare, the researchers will now start a new waiting game. They need fresh human eggs to begin their experiments – and they have no idea how many women will step forward to undergo the lengthy and potentially risky donation procedure.

In the last step of the nuclear transfer process (here demonstrated with a sheep embryo), a cell is inserted into an egg that has had its nucleus removed. (Courtesy of Photo Researchers, Inc.)

Much of the attention on human cloning has centered around ethical issues associated with destroying embryos. In fact, getting access to an adequate number of eggs may end up being the biggest hurdle in the thorny field of human therapeutic cloning, also known as somatic cell nuclear transfer. Scientists have no idea how many eggs it will take to clone a human embryo, and therefore don’t know how big a pool of egg donors they’ll need for success.

To clone an embryo, scientists first strip an egg of its genetic material. Then they insert DNA from an adult cell, such as a skin cell from a diabetic patient, into the egg. Through an unknown process, the egg turns back the clock on the adult DNA and begins to develop as a normally fertilized egg would. Researchers can then collect from the embryo a specialized ball of cells, which can be coaxed into stem cells. So far, though, no one has successfully performed this feat.

Since these stem cells are genetically matched to the DNA donor, they could be used to generate new, more accurate models of complex genetic diseases, such as diabetes. Eventually, scientists also hope to use the cells as the basis for cell transplant therapies (see “Stem Cells Reborn”).

Multiple U.S. institutions have started or will start human cloning research. Last week Harvard announced it had approved research proposals from three scientists to do human nuclear transfer, after lengthy ethical and scientific reviews. Under the new Harvard project, Kevin Eggan and Doug Melton, of the Harvard Stem Cell Institute, aim to create models for diabetes and neurological diseases. George Daley of Children’s Hospital Boston plans to develop cell transplants for children with blood diseases.

Last month, with much less pomp, scientists at the University of California, San Francisco started human nuclear transfer experiments. Like Harvard, they aim to create patient-specific stem cells, as well as to study the reprogramming process that takes place when an egg is fertilized. In addition to the two universities, Advanced Cell Technologies (ACT), an embryonic stem cell company with offices in Worcester, MA, plans to restart its human cloning program, which was shut down in 2004 due to a lack of funds and an inadequate supply of eggs.

But all these groups face an potentially insurmountable problem. Unlike other embryonic stem cell research, these experiments require unfertilized human eggs. The egg donation procedure is uncomfortable, potentially painful, and carries some medical risk. Women must undergo hormone treatments to stimulate ovulation, counseling sessions to understand the risks involved, and a medical procedure in which a needle is inserted into the vagina to remove eggs from the ovary. A small percentage of donors develop ovarian hyperstimulation syndrome, which in rare cases can cause kidney damage.

Harvard scientists say they have taken steps to ensure the safety of egg donors. “We are limiting the number of oocytes we will retrieve from one women to a small number in order to decrease or eliminate any risk of ovarian hyperstimulation,” says Eggan. He estimates that they will be able to harvest 8 to 10 eggs from each woman who undergoes the procedure. Women will be monitored throughout the process to make sure they are not having an adverse hormonal reaction.

Robert Lanza, vice president of research at ACT, says the company has already had problems securing egg donors. “We ran an exhaustive recruitment program over the last six months, with disappointing results,” he says. While more than 100 women replied to advertisements for egg donors, according to Lanza, almost all of them dropped out of the process when they learned about the time and medical procedures involved. Lanza says they now have one donor who has signed consent forms for egg donation.

Worries over egg donation are not new – concerns have cropped up repeatedly as a handful of groups have attempted human nuclear transfer research in the last few years. Most notable is South Korean researcher Hwang Woo, who in 2005 claimed to have developed a remarkably efficient cloning technique, but who was later discovered to have fabricated almost all his human cloning research.

Investigation committees found that Hwang not only faked his results, but also used a much larger number of eggs than he originally reported. According to some news reports, Hwang obtained some eggs unethically, coercing junior scientists to donate. And some women donated eggs multiple times, despite adverse reactions and medical risk.

Unlike other types of human research, there are no U.S. federal guidelines governing how these experiments should be carried out. President Bush severely limited federal funding for embryonic stem cell research in 2001, including all research involving the creation of new stem cell lines. This has meant that the National Institutes of Health, the nation’s largest source of biomedical funding, has not played its normal regulatory role, and individual states and research institutions have had to pick up the slack. “If there were agreed-upon national standards, it would probably speed up much of this protocol approval process,” says Arnold Kriegstein, director of UCSF’s stem cell program.

Both Massachusetts and California, the latter via the California Institute of Regenerative Medicine, have recently enacted rules governing embryonic stem cell research. Both sets of guidelines prohibit paying egg donors, but do allow compensation for direct expenses, such as childcare and transportation. California takes it one step further, allowing women to be paid for time off work. It’s unclear if Massachusetts law permits this practice.

David Magnus, a bioethicist at Stanford University, says these regulatory systems lack adequate monitoring mechanisms, though. “I think it would be an advantage to think about ways to make sure researchers are doing what they say they are going to do,” says Magnus. “I would guess that we won’t see problem with the first few institutions, which have been very careful. Problems would more likely occur down the road, when [nuclear transfer research] starts to become routine.”

While some research suggests that the tricky cloning procedure will require fresh eggs, two teams of scientists are trying another alternative. Rather than using freshly donated eggs, researchers at the University of California, San Francisco and Daley at Children’s Hospital are using so-called fail-to-fertilize oocytes, eggs that failed the in vitro fertilization process and were donated to medical research. Fail-to-fertilize oocytes are likely to be easier to come by than freshly donated eggs, and therefore could allow scientists to test and refine their cloning methods.

But whether that method will solve the egg-donation problem facing stem cell researchers is unknown. “It may be that we need fresh oocytes,” says Daley.

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