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Mar 15, 2007 (Vol. 27, No. 6)

Ten Years After Dolly: Where Are We?

Famous Sheep Left Scientific Legacy That Has Yet to be Fulfilled

  • It has been more than 10 years since the birth of a lamb called Dolly knocked one of cell biology’s most entrenched principles on the head by providing living proof that a fully differentiated somatic cell nucleus could be reprogrammed within the environment of an enucleated egg, divide, and develop de novo into a whole new animal.

    A decade on, we are still a ways off from the first clinical embodiment of Dolly’s inheritance, but she did represent the springboard for a new era of research in fields ranging from therapeutic cloning to xenotransplantation and the use of transgenic animals as human protein factories, suggests (www.roslin.ac.uk) team that represented Dolly’s technological dad.

    According to Prof. Wilmut, now director of the Scottish Centre for Regenerative Medicine at the University of Edinburgh, Dolly was the ultimate proof that nuclear transfer—essentially putting the nucleus from a nonreproductive cell into an enucleated egg—could be used to clone animals from diverse somatic cell types: in Dolly’s case, even a fully differentiated mammary gland cell from a different sheep.

    Cloning from an adult cell was not the researchers’ original goal however, he admits. “We had actually envisaged cloning from sheep embryonic stem (ES) cells. Researchers had for years been able to genetically alter mouse ES cells and inject these into early mouse embryos to generate genetically modified mice. But by the mid-1990s, ES cells hadn’t been isolated from large mammals, such as sheep.

    “While the nuclear transfer technology was proving to be remarkably powerful, the inability to isolate sheep ES cells meant we had to find new donor cells. The adult cell cloning project grew from this, and Dolly was the result.”

    Since the birth of Dolly, ES cells have been isolated from many relevant mammalian species, including humans, and the availability of human ES cell lines derived from donated embryos, combined with nuclear transfer-based cloning, has spurred new avenues of therapeutic research, Prof. Wilmut points out.

  • Advances in Disease Research

    “Despite these new technologies, disappointingly little progress has been made in fundamental disease research,” he says. “Cloning human embryos using cells taken from patients suffering inherited genetic diseases will allow us to study the basis of disease in affected ES-derived cell types taken from cloned embryos. Such cells can also form the basis of high-throughput cell-based screens to investigate the activity of new drug candidates. It is a field that has great potential, but which has still to really get off the ground.”

    Conversely, the concept of cloning human embryos from an individual patient to generate patient-specific cell types for cell therapy may be more newsworthy, but is a more tenuous prospect, he suggests. “The idea of cloning embryos from a patient’s own cells in order to generate ES cells that can be differentiated into cell types required for reimplantation is attractive, but fraught with pitfalls,” Prof. Wilmut stresses.

    “Not only would it be incredibly expensive, but technically difficult in terms of ensuring the integrity of the millions of cells being put back into the patient. You would have to be sure that every single one of those cells is genetically and functionally ‘correct,’ and not able to cause disease or tissue damage in any way. The scientific and regulatory minefield would be considerable. Far more valuable will be the accelerated use of this technology to derive stem cells for studying diseases, unravelling disease pathways and designing and testing new therapeutics.”

    Although Prof. Wilmut maintains somatic cell cloning for disease research has made relatively little headway, he highlights the generation of human polyclonal antibodies in cattle as one of the most clinically important successes of nuclear transfer.

    Since Dolly, cloning animals using genetically modified donor cells has generated sheep, pigs, and cattle that carry targeted genetic alterations. The nuclear transfer-based technology pioneered by Jim Robl and South Dakota-based Hematech (www.hematech.com) requires not just genetic modification of the donor cell’s nucleus, but the construction of a whole microchromosome containing the human immunoglobulin sequences. The microchromosome is then introduced into fetal cells used as nuclear donors.

    “Using this technology it may ultimately be possible to generate large quantities of human antibodies for routine use in the diagnosis of human diseases, or even for treating a wide range of disorders, such as infectious diseases and cancer, for which antibody therapy is not feasible today,” explains Prof. Wilmut.

    Nuclear transfer-based cloning is separately being exploited in the field of xenotransplantation, and although the potential to use pigs as organ donors for humans is still, understandably, a distant goal, the principle is sound, he continues.

    “Nuclear transfer has made it possible to generate transgenic pigs that lack a cell surface sugar responsible for causing acute graft vs. host rejection following transplantation of pig organs into other species. Animal trials to date have shown that grafts from genetically modified pigs can function in baboons for up to six months, and future clinical applications in therapy are not unreasonable.”

    Now immortalized in a glass case in Edinburgh’s National Museum of Scotland (Dolly was put to sleep following a lung infection in 2003), one sheep has thus left a scientific legacy that has yet to be completely fulfilled. Nevertheless, with a number of U.K.-based research organizations already licensed to carry out human embryo cloning for research purposes, progress will surely continue, Prof. Wilmut believes.

    “On a personal note, Dolly has also provided me with completely new opportunities for research, and through my travels and invitations to speak at meetings, exposure to exciting new scientific disciplines. Moreover, she has helped change the public’s perception of the word ‘cloning’. Dolly introduced people to the concept of cloning as the vast majority of researchers intend it—for human therapeutic rather than reproductive purposes. Hopefully, public acceptance will do much to ensure this valuable technology is exploited to the full.”

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