Sitting by the window of a posh coastal hotel in Half Moon Bay, Calif., wearing a baby-blue sweater and khakis, Ian Wilmut doesn’t project the image of a scientist who pulled off one of the most dramatic experiments in modern biology. When he and his collaborators unveiled Dolly the cloned sheep in 1997, they ignited the embryonic stem cell research field, struck awe in the public and set off a panic about the imminent cloning of humans. “Dolly was a big surprise to everyone,” recalls stem cell biologist Thomas Zwaka of the Center for Cell and Gene Therapy at the Baylor College of Medicine. Cloned frogs had refused to grow past the tadpole stage, and a seeming success in mice had proved to be a fake. According to scientific consensus back then, cloning adult mammals by the method Wilmut used was biologically impossible.
As Dolly matured, the cloning technology that created her—called somatic cell nuclear transfer (SCNT)—grew into a rich research enterprise. Scientists hoped to eventually be able to take a patient’s cell, place its nucleus into an unfertilized human egg and then harvest embryonic stem cells to treat intractable conditions such as Parkinson’s disease. But the first human clinical trial continues to seem remote, with embryonic cloning constrained by a federal funding ban, deeply controversial ethical issues and technical challenges. In mid-May safety concerns led the U.S. Food and Drug Administration to put on hold a bid by Geron Corporation in Menlo Park, Calif., to conduct trials on patients who have acute spinal cord injury.
Now the 64-year-old Wilmut is one of several high-profile scientists who remain loyal to SCNT in concept but are leading a wholesale charge out of the field and into an alternative technology. That other approach, first demonstrated in 2006 by Shinya Yamanaka of Kyoto University, restores adult cells back to an embryoniclike state called pluripotency, in which they regain the ability to develop into any kind of cell. Any well-appointed lab can apply the comparatively straightforward technique. “It’s really easy—a high school lab can do it,” says Mahendra Rao, who heads up the stem cell and regenerative medicine business at Invitrogen, a life sciences corporation based in Carlsbad, Calif. Yamanaka’s approach also enables scientists to leap over nuclear transfer’s egg supply problems and sidestep qualms about destroying human embryos.
Such practicalities, rather than a lack of inherent scientific value, seem to be driving the SCNT exodus. Wilmut describes his own switch in approach as a by-product of time-consuming responsibilities at the helm of the Scottish Center for Regenerative Medicine in Edinburgh, a post he assumed last year after nearly three decades at the nearby Roslin Institute. With 20 principal investigators demanding his attention, Wilmut’s research on amyotrophic lateral sclerosis (ALS) had slowed to a crawl. “We thought it would be more likely that things could be made to happen quickly,” he says.
Somatic cell nuclear transfer demands enormous skill and expensive equipment. It is easy to damage the unfertilized egg and hard to get the donated nucleus to operate in concert with its new host. Last fall Oregon Health & Science University researchers announced the first-ever success in primates—but the team went through 304 eggs from 14 rhesus macaque females to generate just two cell lines. And one of those had an abnormal Y chromosome. In humans the ability to collect fresh oocytes also remains a huge roadblock, especially because scientists cannot legally pay donors.
Yamanaka’s ability to convert adult mouse cells into embryoniclike stem cells—called induced pluripotent stem cells (iPS cells)—has pumped fresh excitement into regenerative medicine. In this process, scientists use viruses to deliver three to four genes into an adult cell and to reprogram it back to its unspecialized state, enabling it to grow into any type of cell in the body. In a span of months, Yamanaka’s team and three others reported success using human cells from adult skin and joint tissue and newborn foreskin.