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Biomedicine

Human-Animal Cybrids

Biologist Ian Wilmut talks about his cloning plans for the future.

Over the past year, a major ethical debate has raged in the United Kingdom over whether scientists should be allowed to use animal eggs in their attempts to create cloned human embryonic stem cells. Scientists say that these cells could lead to the development of the first-ever human-cell models of complex genetic diseases and, eventually, new tissue-replacement therapies. Lack of human eggs has presented an enormous obstacle: eggs are collected via a lengthy and potentially painful and risky procedure that few women are willing to undergo. (See “Lack of Human Eggs Could Hamper U.S. Cloning Efforts.”)

After Dolly: Biologist Ian Wilmut, who led the group that cloned Dolly the sheep, wants to clone human stem cells, a feat that has eluded many scientists.

Readily available animal eggs could fill that gap. Rather than inserting the DNA of a human cell into a donated human egg, scientists would insert human DNA into a cow or rabbit egg and then collect stem cells from the resulting embryos. The DNA of these cells would be overwhelmingly human, with a tiny percentage of animal DNA from the egg. To date, only one group, in China, has successfully generated human stem cells with this approach, but several groups around the world are trying to repeat it.

Research mixing human and animal eggs and sperm has garnered considerable ethical concern and been banned in several countries. The banning was started in part by fears that scientists will create animals with human genes or other ethically questionable organisms, and in part by concerns that mixing animal and human materials diminishes the sanctity of human life. But researchers say that public outcry has largely failed to distinguish between important medical research, such as therapeutic cloning, and more dubious experiments. For example, in the United Kingdom, proposals to use animal eggs for human cloning sparked outcry from an overzealous media portending half-human creatures.

Last month, after a lengthy debate, the U.K. authority overseeing such research overrode a previous ban, approving specific projects to generate these cells. Much like other embryonic stem-cell research, the embryos the scientists generate–dubbed cybrids rather than hybrids because only the cell cytoplasm from the animal is used–are not allowed to develop beyond 14 days.

Ian Wilmut, the biologist who spearheaded the cloning of the now renowned Dolly the sheep, plans to submit his own proposal for cybrid research in the next few months. Wilmut, now director of the Scottish Center for Regenerative Medicine at the University of Edinburgh, ultimately wants to use stem cells cloned from a patient with ALS, a degenerative movement disorder, to develop a model for studying the disease. At the Stem Cell Summit in Boston this week, Wilmut spoke with Technology Review about the ethical debate over cloning, the slow pace of the research, and his plans for the future.

Technology Review: What do you think of the lengthy public debate that took place in the United Kingdom prior to approval of these experiments?

Ian Wilmut: Our experience in Britain has been that if you go through the detail of what you want to do, most people are okay with it. It’s really a very difficult balance. I do believe we have to explain our research to the public. On the other hand, the process in Britain was complicated and took the better part of a year. That means we lost a year of research. If you look around this conference, you’ll see people who have ALS and are in wheelchairs. I’m sure they are very impatient.

TR: Are there scientific concerns surrounding human stem cells generated with animal eggs? Will they be equivalent to other stem cells?

IW: There’s lots of uncertainty over the normalcy of these cells because the mitochondria [the cell’s energy factory] is from a rabbit. Some people are concerned that if the cells have to work hard, as they would when differentiating into different types of tissue, they won’t be able to generate enough energy and could crash.

TR: Scientists here in the United States have tried cloning using rabbit eggs, with no success. Does that suggest that the method won’t work?

IW: Those results are disappointing, but they aren’t surprising. Very small changes in these procedures can be critical. For example, many labs that successfully cloned farm animals could not get the technique to work in mice.

We’ve already learned certain lessons about how to go about it. One group in Japan has used rabbit eggs to generate stem cells from macaque monkeys. They discovered that cells should first be grown in the medium used for rabbit cells, then later in the medium used for macaque cells. Simple changes like that can dramatically change success.

TR: In the past year, scientists made a breakthrough in “reprogramming”–turning back the clock on an adult cell to produce stem cells without using eggs. Simply triggering expression of four genes seemed to create stem-cell-like cells, which could obviate the need for human eggs. Are you also pursuing this type of research?

IW: I first suggested something like that back in 1997: I said it would be the offspring of Dolly. I’m sure a lot of other people were thinking that way as well, but it’s been a very difficult experiment to do.

The efficiency for that method [the reprogramming method described earlier this year] was very low, so there should be lots of room for improvement. We just developed an assay in which we add an extract from mouse embryonic stem cells onto human cells, which triggers expression of those four genes. We plan to use that system to figure out which factors in the extract are crucial for turning on gene expression.

TR: The U.S. administration, which has hindered embryonic stem-cell research with drastic funding restrictions, has suggested that advancements in reprogramming technologies are a reason to move away from traditional embryonic stem-cell research. What do you think?

IW: In the short term, we don’t know which approach will work best, so I think we should pursue both. But in the end, I think reprogramming will be preferable.

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