"Reprogramming"—the erasure of a cell's developmental history— enables it to start over as an uncommitted embryonic cell. The process is central to cloning, which creates an exact copy of an adult organism from the genetic material in one of its cells. A notable example was the birth of Dolly the lamb in 1996, the first mammalian clone. She developed from a fully differentiated adult cell whose nucleus had been turned back in time, developmentally speaking, so that its full set of genes was once again in its original, embryonic state—and capable of giving rise to a new animal genetically identical to Dolly's donor.

First observed and confirmed in a series of experiments from the late 1950s to the mid-1970s, reprogramming is still something of a "black box" to scientists. It appears that unknown factors in the egg's cytoplasm signal the nucleus to erase its specialized genetic program and reactivate previously silenced genes that support the development of a new embryo. But little is known about what these essential factors are or how they turn back the developmental clock.

"It's a wonderful problem and an incredibly fascinating subject," says Allan C. Spradling, a developmental biologist and HHMI investigator at the Carnegie Institution of Washington in Baltimore. "You're talking about one of the most fundamental of the processes that make life possible."

But limited understanding of the process explains why cloning is still an inefficient and error-prone technology. And that hampers the promise of "regenerative medicine"—generating rejection-free repair tissues by cloning a patient's own body cells. The hope is to improve treatments for neurodegenerative diseases like Alzheimer's and Parkinson's, diabetes, heart disease, and spinal cord injuries, for example.

Following the birth of Dolly, pigs, mice, calves, and other animals have been cloned through the transfer of adult-cell nuclei into unfertilized eggs. In addition to nuclear transfer, reprogramming can also be induced by the fusion of certain cells. In 2005, biologist Kevin Eggan and HHMI investigator Douglas A. Melton at Harvard University succeeded in reprogramming human adult skin cells to revert to an embryonic state by fusing them with stem cells removed from embryos. Evidently, the embryonic stem cells contained something that could reawaken the embryonic genes in the skin cells. But there was a problem: The resulting embryonic cells contained a double set of chromosomes, an abnormality that made them unsuitable for practical cloning.

Using his own approach, Yuri Verlinsky, of the Reproductive Genetics Institute in Chicago, reported in the January issue of the journal Reproductive BioMedicine Online that he had fused several types of human somatic cells with human embryonic stem cells, and that in some instances the adult nuclei had completely replaced the stem cell nuclei, leaving only one set of chromosomes.

These were patient-specific embryonic stem cells, Verlinsky notes. But when grown in culture, some of the cells had both donor and recipient nuclei, so they'll need further purification before they have any practical value.

These studies and many other lines of research aim to elucidate the factors needed for reprogramming, and eventually free the cloning process from the need for unfertilized eggs or embryos, which are scarce and expensive, and raise ethical concerns.

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