Reproductive Health · 1997
Dolly the Cloned Sheep
The prevailing view in developmental biology through most of the twentieth century held that cellular differentiation was a one-way process. Once a cell committed to becoming a mammary epithelial cell, its nucleus was permanently reprogrammed; the genes needed for totipotency were locked away or deleted. Cloning from embryonic cells had been achieved in frogs in the 1960s, but adult somatic nuclei were considered incompatible with normal development. Ian Wilmut's team at the Roslin Institute in Edinburgh set out to test that assumption using sheep.
The Roslin group's approach depended on a technique Keith Campbell had refined: inducing quiescence in the donor cell by serum starvation before nuclear transfer, which appeared to synchronize the cell cycle in a way that improved reprogramming after fusion with an enucleated egg. Nuclei from mammary gland cells of a six-year-old Finn Dorset ewe were transferred into enucleated Scottish Blackface oocytes. Of 277 reconstructed embryos, one produced a live lamb. Dolly was born on July 5, 1996, at the Roslin Institute. She was not announced publicly until February 1997, when the paper appeared in Nature.
The finding was immediately recognized as overturning a foundational assumption of developmental biology. If the nucleus of an adult mammary cell retained the full genomic information necessary to direct development of a complete organism, then differentiation involved epigenetic rather than genetic changes, and those changes were reversible under the right conditions. That conclusion opened experimental approaches that had previously been considered impossible.
The public and political response was rapid and intense. Within days of the Nature paper, President Clinton asked the National Bioethics Advisory Commission to review the implications for human cloning, and several governments announced bans or moratoria. Scientists working on the basic biology found themselves fielding questions about therapeutic cloning and reproductive cloning in humans, two applications that the Roslin researchers had not pursued and did not endorse.
Dolly developed arthritis and a progressive lung disease caused by a retrovirus; she was euthanized in February 2003 at age six, roughly half the normal lifespan for the breed. Whether premature aging was caused by the cloning process or by the viral infection was debated without resolution. The more lasting scientific legacy was the conceptual foundation it provided for Shinya Yamanaka's work on induced pluripotent stem cells, published in 2006, which showed that adult cells could be reprogrammed to a pluripotent state by introducing just four transcription factors.
Key People
- Ian Wilmut — Lead researcher at the Roslin Institute who directed the cloning experiment
- Keith Campbell — Cell biologist who developed the nuclear transfer protocol
- Harry Griffin — Roslin Institute deputy director who coordinated the public announcement
- Alan Colman — PPL Therapeutics research director, commercial partner in the Dolly project
Nature. 1997;385(6619):810-813.
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