Yamanaka and Gurdon

Two sets of experiments, performed 40 years apart, have been recognized with today's Nobel Prize in Physiology or Medicine. Cambridge University's John Gurdon won for showing that adult cells contain all the genetic information necessary to create every tissue in the body. That work set the stage for Shinya Yamanaka, who demonstrated that a relatively simple process could convert adult cells into embryonic stem cells. That development is already opening new avenues of research, and it holds the promise of new ways to repair tissues damaged by injury or disease.

As an embryo develops from a single fertilized egg, its cells become increasingly specialized. Although the initial cells can form any tissue in the body, groups of them adopt specific fates. A cell might first commit to being a neuron, after which it may be further limited to the roles required in the spinal cord, before finally specializing in the activities needed to control muscles. What doesn't seem to happen, however, is for the cell to switch developmental tracksdeveloping as, for example, a liver cell.

The apparent permanence of these fate decisions left most researchers thinking that they were in fact permanentthat the genomes of the cells undergo irreversible changes. At least in the case of immune cells, that seemed to be true: as part of generating the ability to recognize a diverse array of threats, B and T cells delete large stretches of their DNA and irreversibly commit themselves to recognizing a single threat.

But it's not true of all cells. John Gurdon performed key experiments back in the 1960s that showed how most cells maintain their general capacity to develop in any direction, although it took decades for the significance of his work to be fully appreciated. Using the eggs of a frog, Gurdon carefully removed the nucleus, which contains its genome. He then transferred in the nucleus of a specialized cell from an adult frog. If the general perception turned out to be correct, the DNA from that cell should have been permanently committed to its fate (in this case, intestine). Instead, Gurdon was able to get the hybrid cell to develop into a tadpole and, eventually, a healthy adult.

These results clearly demonstrated that adult cells contain all the genomic ingredients to make every cell in an organism. But it took time to develop the technology that took advantage of the fact. A key step in that development was honored by the Nobel Committee in 2007: the development of embryonic stem cells derived from mice. These cells, derived from early embryos, could divide indefinitely in culture without adopting any particular fate, but given the right chemical nudges, could form any type of adult cell. If injected into an early embryo, they would go on to contribute to every tissueincluding the germ cells, which allowed these cells to go from a culture dish to future generations of mice.

This work led to the controversial development of human embryonic stem cells. But it also allowed people to ask what makes an embryonic stem cell distinct. Over time, scientists created a list of a few dozen genes that were consistently active in stem cells of various types. Some of these would undoubtedly be a consequence of the cells' stem-cell-ness. But others would be responsible for putting the cells there in the first place.

Shinya Yamanaka, an MD who says he got into research because he wasn't any good at surgery, decided to find out which of this list of genes was likely to be in control. Starting with about 20 known regulatory genes on the list, he inserted groups of them into adult cells, seeing which sets could turn them into a stem cell. By process of elimination, he gradually whittled that list down to just four genes. Inserting them into an adult cell would force it to get rid of any specializations and go on to adopt a stem cell fate. Once that was done, the cells could then be induced to form any type of adult cell in culture, or be injected into an embryo and contribute to an adult.

Stem cell work in general has raised the prospect that we could repair injured or damaged tissue with newly generated cells that are just as specialized as the ones they are replacing. But Yamanaka's work has turned that prospect into a vision of on-demand tissues, generated with a simple lab procedure, and a perfect genetic match for their recipient. The cells produced with the procedure he pioneered don't seem to be an exact match for cells derived from embryos, but it appears that they may be close enough that the difference doesn't matter.

It might be hard to imagine that research could take 40 years to come to fruition. But it's widely accepted that Gurdon's work fostered a change in perspective that was necessary for people to even start thinking about the studies that eventually led to stem cell manipulations. A year ago, I spoke to Martin Evans, who was a co-winner of the 2007 prize for stem cells, and he was already describing a long line of developments that led from Gurton through his own work and that of others, and that eventually culminated in Yamanaka's experiments. Two years ago, Gurdon and Yamanaka were honored with a Lasker Prize, which often precedes Nobel status.

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A not-so-simple twist of fate: Nobel awarded for stem cell reprogramming