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The ideal, says Melton, who is co-director of the Harvard Stem Cell Institute, "would be if you could take a specialized, differentiated cell from an individual and use some chemical compounds to reprogram it, turning it into an embryonic stem cell" without having to resort to nuclear transfer or cell fusion. "But we are many steps and years away from that."
Each of our cells contains the full set of DNA instructions, or genome, for making all the proteins that build and operate a human being. According to current estimates, the genome of a human cell carries 25,000 to 30,000 genes on its 46 chromosomes within the nucleus. But the function of any particular cell—skin, nerve, or blood, for example—requires the activity of only a small subset of the genome. It would be not only superfluous but also harmful if a nerve cell made proteins, say, for bone or intestine. So how do cells prevent this from occurring? For many years scientists pondered whether a cell specialized for one role permanently inactivates, or even loses, its genes for making other types of cells—as well as the genes that were essentially in its own embryonic past.
In 1975, John Gurdon and colleagues at the MRC Molecular Biology Laboratory in Cambridge, England, carried out a series of experiments that built on those first observations, in the 1950s, of nuclear reprogramming. Gurdon transferred the nuclei from adult-frog skin cells into an egg whose own nucleus had been removed. Of all the nuclei placed in the eggs, 4 percent generated fully developed tadpoles, though none of them led to adult frogs. Inefficient and incomplete as the process was, it nailed an important point: Genes in the nuclei of differentiated cells could be reactivated to direct the development of a normal embryo—at least, up to a point. The reprogramming was clearly induced by the cytoplasm of the egg, and it was accomplished within a few hours after nuclear transfer.
Before the work of Gurdon and others, "One might have thought that a cell is locked in—that a blood cell can only be a blood cell—and can never be changed," says Leonard I. Zon, an HHMI investigator and stem cell researcher at Harvard Medical School and Children's Hospital Boston. But the nuclear-transfer experiments suggested that the differentiated cell's chromosomal DNA hadn't been permanently altered; nothing had been discarded, and no part of the genetic sequence had been edited or rewritten.
When Eggan was at the Whitehead Institute in Cambridge, Massachusetts, with Rudolf Jaenisch in 2004, they partnered with HHMI's Richard Axel at Columbia University and brilliantly demonstrated this capacity for the reawakening of genes in even the most specialized of cells. To be attuned to specific odors, mice have hundreds of different types of olfactory sensory neurons: In each nerve cell, just 1 of 1,500 olfactory genes is turned on, while the rest are silenced. The researchers extracted one such cell from an adult mouse and cloned it, through nuclear transfer, to create a mouse that had a full repertoire of smell-sensitive neurons. Clearly, the process had reactivated the entire set of silenced olfactory genes.
That's why reprogramming can occur: The unexpressed DNA is dormant but intact, and can be awakened. These reversible changes in gene activity are due to so-called "epigenetic modifications." Epigenetics, the study of changes in gene silencing that occur without changes in the genes themselves, has become a highly active field—a journal devoted entirely to the subject was just launched in January—and scientists are steadily discovering more about its role in development, reprogramming, and diseases. Most of the events that occur during development, they've learned, are orchestrated by epigenetic modifications triggered by signals from the cell's environment.
"Epigenetics explains many things that happen between development and death," says Jeannie T. Lee, an HHMI investigator at Harvard Medical School and Massachusetts General Hospital. "Not only is epigenetics responsible for setting up a developmental program, it determines whether you are going to get cancer or develop autoimmunity, or get prion diseases such as mad cow."