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How Can a Skin Cell Become a Nerve Cell?

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Science  01 Jul 2005:
Vol. 309, Issue 5731, pp. 85
DOI: 10.1126/science.309.5731.85

Like Medieval alchemists who searched for an elixir that could turn base metals into gold, biology's modern alchemists have learned how to use oocytes to turn normal skin cells into valuable stem cells, and even whole animals. Scientists, with practice, have now been able to make nuclear transfer nearly routine to produce cattle, cats, mice, sheep, goats, pigs, and—as a Korean team announced in May—even human embryonic stem (ES) cells. They hope to go still further and turn the stem cells into treatments for previously untreatable diseases. But like the medieval alchemists, today's cloning and stem cell biologists are working largely with processes they don't fully understand: What actually happens inside the oocyte to reprogram the nucleus is still a mystery, and scientists have a lot to learn before they can direct a cell's differentiation as smoothly as nature's program of development does every time fertilized egg gives rise to the multiple cell types that make up a live baby.

Scientists have been investigating the reprogramming powers of the oocyte for half a century. In 1957, developmental biologists first discovered that they could insert the nucleus of adult frog cells into frog eggs and create dozens of genetically identical tadpoles. But in 50 years, the oocyte has yet to give up its secrets.

The answers lie deep in cell biology. Somehow, scientists know, the genes that control development—generally turned off in adult cells—get turned back on again by the oocyte, enabling the cell to take on the youthful potential of a newly fertilized egg. Scientists understand relatively little about these on-and-off switches in normal cells, however, let alone the unusual reversal that takes place during nuclear transfer.

Cellular alchemist.

A human oocyte.

CREDIT: DON W. FAWCETT/VISUALS UNLIMITED

As cells differentiate, their DNA becomes more tightly packed, and genes that are no longer needed—or those which should not be expressed—are blocked. The DNA wraps tightly around proteins called histones, and genes are then tagged with methyl groups that prevent the proteinmaking machinery in the cell from reaching them. Several studies have shown that enzymes that remove those methyl groups are crucial for nuclear transfer to work. But they are far from the only things that are needed.

If scientists could uncover the oocyte's secrets, it might be possible to replicate its tricks without using oocytes themselves, a resource that is fairly difficult to obtain and the use of which raises numerous ethical questions. If scientists could come up with a cell-free bath that turned the clock back on already-differentiated cells, the implications could be enormous. Labs could rejuvenate cells from patients and perhaps then grow them into new tissue that could repair parts worn out by old age or disease.

But scientists are far from sure if such cell-free alchemy is possible. The egg's very structure, its scaffolding of proteins that guide the chromosomes during cell division, may also play a key role in turning on the necessary genes. If so, developing an elixir of proteins that can turn back a cell's clock may remain elusive.

To really make use of the oocyte's power, scientists still need to learn how to direct the development of the rejuvenated stem cells and guide them into forming specific tissues. Stem cells, especially those from embryos, spontaneously form dozens of cell types, but controlling that development to produce a single type of cell has proved more difficult. Although some teams have managed to produce nearly pure colonies of certain kinds of neural cells from ES cells, no one has managed to concoct a recipe that will direct the cells to become, say, a pure population of dopamine-producing neurons that could replace those missing in Parkinson's disease.

Scientists are just beginning to understand how cues interact to guide a cell toward its final destiny. Decades of work in developmental biology have provided a start: Biologists have used mutant frogs, flies, mice, chicks, and fish to identify some of the main genes that control a developing cell's decision to become a bone cell or a muscle cell. But observing what goes wrong when a gene is missing is easier than learning to orchestrate differentiation in a culture dish. Understanding how the roughly 25,000 human genes work together to form tissues—and tweaking the right ones to guide an immature cell's development—will keep researchers occupied for decades. If they succeed, however, the result will be worth far more than its weight in gold.

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