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Two new Paths to the Dream: Regeneration
August 8, 2010
5:55 am
Forum Posts: 3858
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December 4, 2009
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In recent years, most research in the field of regenerative medicine has focused on the hope that stem cells, immature cells that give rise to any specific type of cell needed in the body, can somehow be trained to behave as normal adult cells do. Nature’s method of regeneration is quite different in that it starts with the adult cells at the site of a wound and converts the cells to a stemlike state in which they can grow and divide.

The Stanford team has taken a step toward mimicking the natural process. “What I like is that it’s built on what’s happening in nature,” Dr. Blau said. “We mammals lost this regenerative capacity in order to have better tumor suppression, but if we reawaken it in a careful way we could make use of it in a clinical setting.”

Dr. Pomerantz, a clinician, hopes the technique can be applied to people, though many more animal experiments need to be done first. “We have shown we can recapitulate in mammalian cells behavior of lower vertebrate cells that is required for regeneration,” he said. “We would propose using it in amputations of a limb or part of a limb or in cardiac muscle.” After a heart attack, the muscle cells do not regenerate, so any method of making them do so would be a possible treatment.

Interfering with tumor suppressor genes is a dangerous game, but Dr. Pomerantz said the genes could be inhibited for just a short period by applying the right dose of drug. When the drug has dissipated, the antitumor function of the gene would be restored.

Finding the right combination of genes to suppress was a critical step in the new research. One of the two tumor suppressor genes is an ancient gene, known as Rb, which is naturally inactivated in newts and fish when they start regenerating tissue. Mammals possess both the Rb gene and a backup, called the Arf gene, which will close down a cancer-prone cell if Rb fails to do so.

The Stanford team found that newts did not have the Arf backup gene, which mammals must have acquired after their lineage diverged from that of amphibians. This suggests that the backup system “evolved at the expense of regeneration,” the Stanford researchers say in Friday’s issue of Cell Stem Cell.

The Stanford team shut off both Rb and Arf with a chemical called silencing-RNA and found the mouse muscle cells started dividing. When injected into a mouse’s leg, the cells fused into the existing muscle fibers, just as they are meant to.

The Stanford researchers have learned how to block two genes thought to inhibit the natural regenerative capacity of cells, but it is somewhat surprising that the regenerative mechanism should still exist at all if mammals have been unable to use it for 200 million years. “One school of thought is that regeneration is a default mechanism and doesn’t require its own program,” Dr. Pomerantz said.

Dr. Brockes believes that this is true in part. Regeneration “depends on a largely conserved cellular machinery,” he said, meaning that it is present in all animals. The machinery comes into play in wound healing and tissue maintenance. But specific instances of regeneration, like regrowing a whole limb, are invoked by genes specific to various species. He has found a protein specific to salamanders that coordinates regrowth of a salamander limb.

If the regeneration of a whole limb is a special ability that salamanders have evolved, then humans would not have any inherent ability to do the same. “I would beware of suggesting that this sort of manipulation is capable of unlocking ‘the newt within,’ ” Dr. Brockes said.

A second, quite different approach to regenerating a tissue is reported in Friday’s issue of Cell by Deepak Srivastava and colleagues at the University of California, San Francisco. Working also in the mouse, they have developed a way of reprogramming the ordinary tissue cells of the heart into heart muscle cells, the type that is irretrievably lost in a heart attack.

“Living backwards!” Alice repeated in great
astonishment. “I never heard of such a thing!”
“—but there’s one great advantage in it, that one’s
memory works both ways.”
— Lewis Carroll, Through the Looking-Glass

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