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Home , Dolly (sheep), Ian Wilmut, Scientific American

INSIGHTS ■ ■ ■ ■ STEM CELLS No More Around Like many pioneers, , the creator of the , has jumped to an alternative approach. Is this the beginning of the end for embryonic cloning? BY SALLY LEHRMAN

itting by the window of a posh coastal hotel in Half Moon Bay, S 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 fi eld, 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 Thom- as Zwaka of the Center for Cell and Gene Therapy at the Baylor College of Medicine. Cloned 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 IAN WILMUT adult by the method Wilmut SHIFT CHANGE: A pioneer in (SCNT), or cloning—a way to used was biologically impossible. create embryonic stem cells—he now focuses on induced pluripotent stem cells (iPS cells). As Dolly matured, the cloning technol- HYBRID SOLUTION: To get around the egg-supply problem, Wilmut proposed inserting ogy that created her—called somatic cell human DNA into animal oocytes. Recently approved in England, such chimeric unions have nuclear transfer (SCNT)—grew into a rich fueled political debate in the U.S. and hampered SCNT work. research enterprise. Scientists hoped to eventually be able to take a patient’s cell, place its nucleus into an unfertilized human an alternative technology. That other Such practicalities, rather than a lack of egg and then harvest embryonic stem cells approach, fi rst demonstrated in 2006 by inherent scientifi c value, seem to be driv- to treat intractable conditions such as Par- of Kyoto University, ing the SCNT exodus. Wilmut describes kinson’s disease. But the fi rst human clini- restores adult cells back to an embryonic- his own switch in approach as a by-prod- cal trial continues to seem remote, with like state called pluripotency, in which they uct of time-consuming responsibilities at embryonic cloning constrained by a federal regain the ability to develop into any kind the helm of the Scottish Center for Regen- funding ban, deeply controversial ethical of cell. Any well-appointed lab can apply erative Medicine in , a post he issues and technical challenges. In mid- the comparatively straightforward tech- assumed last year after nearly three May safety concerns led the U.S. Food and nique. “It’s really easy—a high school lab decades at the nearby . Drug Administration to put on hold a bid can do it,” says Mahendra Rao, who heads With 20 principal investigators demand- by Geron Corporation in Menlo Park, up the stem cell and regenerative medicine ing his attention, Wilmut’s research on

Calif., to conduct trials on patients who business at Invitrogen, a life cor- amyotrophic lateral sclerosis (ALS) had have acute spinal cord injury. poration based in Carlsbad, Calif. Yamana- slowed to a crawl. “We thought it would Now the 64-year-old Wilmut is one of ka’s approach also enables scientists to leap be more likely that things could be made to several high-profi le scientists who remain over nuclear transfer’s egg supply problems happen quickly,” he says. loyal to SCNT in concept but are leading a and sidestep qualms about destroying Somatic cell nuclear transfer demands

wholesale charge out of the fi eld and into human embryos. enormous skill and expensive equipment. Reuters/Corbis MITCHELL J. JEFF

100 August 2008 INSIGHTS ■ ■ ■ ■

It is easy to damage the unfertilized egg ers must speed up disease development and hard to get the donated nucleus to and co-culture the various cells involved operate in concert with its new host. Last in the condition. Scientists would like to fall Oregon Health & University avoid retroviral vectors, risky because researchers announced the fi rst-ever suc- they deliver the genes randomly into the cess in —but the team went chromosome. Moreover, the new genes through 304 eggs from 14 rhesus might vary in activity level, turn on in sur- females to generate just two cell lines. And prising ways or negatively infl uence other one of those had an abnormal Y chromo- genes. Some teams succeeded in making some. In humans the ability to collect fresh iPS cells without the tumor-producing oocytes also remains a huge roadblock, gene that Yamanaka used, but they also especially because scientists cannot legally found that, as a result, they ended up with pay donors. many fewer iPS cells. Yamanaka’s ability to convert adult Scientists do not fully understand how mouse cells into embryoniclike stem cells— iPS reprogramming works—the inserted called induced pluripotent stem cells (iPS genes might represent a core regulatory cir- cells)—has pumped fresh excitement into cuit, or they might activate other genes. It regenerative medicine. In this process, sci- is also not clear whether the results subtly entists use viruses to deliver three to four differ from embryonic stem cells. No one genes into an adult cell and to reprogram yet has grown the two and made a side-by- it back to its unspecialized state, enabling side comparison, and survival after trans- it to grow into any type of cell in the body. plantation remains an unknown for both. In a span of months, Yamanaka’s team and The iPS cells may force biologists to GOOD-BYE, DOLLY: Ian Wilmut, who ushered three others reported success using human throw out accepted ideas about what it in a new era by creating the world’s most cells from adult skin and joint tissue and means to be a differentiated cell, says famous sheep in 1997, fully supports clon- newborn foreskin. Zwaka, whose lab is studying characteris- ing research despite having left the fi eld. Now it’s hard to fi nd a lab concentrat- tics of embryonic stem cells. Perhaps, he ing solely on embryonic cloning. Jamie suggests, it is not necessary to take an ety for Stem Cell Research. His lab is using Thomson, the fi rst to pluck viable cells embryonic cell through every step of devel- both SCNT and iPS to understand pluri- from a human embryo and grow them in opment to create a particular cell type. potency. Daley fears that public sentiment culture, for instance, recently took charge There may be a set of “master regulators” may turn against embryonic work and of an institute focusing primarily on iPS that would enable, say, a skin cell to dash hopes that a new U.S. administration cells. Although the technique is ineffi cient become an adult neuron without passing will open up opportunities to new so far—less than 1 percent of cells become through the embryonic state. cell lines for research. pluripotent—scientists see the iPS approach Despite leaping on the iPS bandwagon, Indeed, as scientists turn their atten- as a speedier path to cells suitable for dis- Wilmut and other cloning pioneers insist tion elsewhere, opponents of embryonic ease research and, ultimately, the clinic. that embryonic stem cell research should cell research have seized on the moment to With iPS, Wilmut enthuses, his team continue. SCNT has offered important attack. “There is no valid reason for any can study cell lines instead of wrestling to lessons about basic biology and will con- ” or embryo destruction, get them. “All you have to do is take some tinue to enable studies of cell program- wrote Tony Perkins of the Family Research skin cells from somebody who apparently ming and reprogramming outside the Council. It is hard to escape the sense that has inherited the disease, scatter some genome. Only embryonic cells can answer SCNT research is on the wane. The ethi- ‘magic dust’ on them and wait for three questions about fertility and very early cal barriers and short egg supply remain weeks,” he says. “And you’ve got pluripo- human development. Scientists will also daunting. If iPS pans out, Wilmut pre- tent cells.” Wilmut and his collaborators, likely rely on SCNT to produce mammali- dicts, nuclear transfer to produce cell lines including George Daley of Children’s Hos- an models of diseases such as cystic fi brosis may one day become a history lesson. ■

pital Boston and Chris Shaw of King’s and for agricultural applications such as College London, hope to use iPS cells to producing human proteins in animal milk. Sally Lehrman is based in the pinpoint mutations involved in ALS. “It’s simply too early to start putting San Francisco Bay Area. A Q&A The method still does not promise one avenue over another,” says Daley, who version of her interview with Wilmut

quick cures. In ALS, for instance, research- is also president of the International Soci- is at www.SciAm.com/aug2008 Corbis WALLIS ROBERT

102 SCIENTIFIC AMERICAN August 2008