Scientists Find New Way to Regenerate Tissue

Chop off a newt's tail and it regenerates. Carve out a piece of a zebra fish's heart and it grows back. Why can't humans do similar tricks?

Some scientists believe that mammals once had such newt-like regenerative ability but lost it as they evolved. Now, by taking a leaf from nature's book of oddities, scientists have shown that mammals can also be coaxed into using the newt's unusual technique to make fresh tissue.

In a study being published Friday in the journal Cell Stem Cell, scientists at Stanford University describe how they got muscle tissue in mice to regenerate, essentially re-awakening what had been thought lost over evolutionary time. Such mature tissues normally don't divide and proliferate.

The Stanford scientists hope this novel approach will one day offer a way to make fresh tissue and help repair damaged organs. The research is at a very early stage and years away from any potential human application. Indeed, many other techniques in regenerative medicine are much further along in the lab.

In 2006, for example, scientists re-grew the wing of a chicken embryo. Earlier this year, another team made partly functioning rat lungs in a lab dish. The most common approach to regenerating tissue is to harness the power of stem cells: In late July, Geron Corp. got U.S. government approval to move forward with the world's first human clinical trial using stem cells derived from an embryo to treat spinal-cord injuries.

The most remarkable feats of regeneration, though, belong to nature, and this is the path taken in the latest study. For years, scientists have tried to figure out why mammals can't regenerate body parts in the same way that, say, salamanders can. The reason is that most mature mammalian cells are locked into a steady state that prevents them from dividing. Without cell division there's no regeneration.

"The trick was to get them to go back into the cell cycle" and kick-start the regenerative process, said Helen Blau, a stem-cell biologist at Stanford University and senior author of the Cell Stem Cell paper.

Dr. Blau and her colleagues homed in on a class of proteins called tumor suppressors. These prevent cells from dividing willy-nilly, possibly an evolutionary response aimed at preventing tumor growth. Past research had shown that one such protein, retinoblastoma, or Rb, prevented inappropriate cell division in many mammalian cells. Dr. Blau and her colleagues then found another called ARF that similarly threw the brakes on the mammalian cell cycle.

The researchers were able to identify ARF thanks to clues left behind on the evolutionary tree. The protein is missing in lower species such as newts, but exists in birds and mammals. Another useful sign was that the protein is found in less-than-normal levels in the human liver, the only organ that humans can regenerate.

The scientists started with individual mouse cells and blocked both Rb and ARF. They hoped this would release the brakes, re-start cell division, and regenerate tissue.

The experiment worked. Colonies of fresh mouse muscle cells proliferated in the lab and when they were returned to a live mouse, they got incorporated into the animal's body and contributed to its function.

A risk of such a technique, of course, is that it could lead to uncontrolled cell division and thus cancerous tumors. To prevent that, the scientists said they released the "brakes" only temporarily.

The Stanford scientists now plan to make functional cells in large quantities and see if they can repair tissue-related injuries in animals. A planned project is to treat muscular dystrophy, a muscle-wasting disease, in a mouse model.

Jason Pomerantz, co-author of the paper and now a reconstructive plastic surgeon at the University of California, San Francisco, added: "If a person has a heart attack and loses heart muscle, we could use this technique to induce heart cells in the surrounding area to start the cell cycle." He said a drug could be used to inhibit Rb and ARF to start the regenerative process.