View Full Version : Missing Limb? Salamander May Have Answer

09-24-2002, 01:23 PM
Missing Limb? Salamander May Have Answer


IRVINE, Calif. - In a closetlike room at the "Leg Lab" here, salamanders stare blankly out of clear plastic drinking cups. The lab is so named because many of the animals have had, or will have, a leg cut off. But the salamanders recover, with perfect new limbs growing back in weeks.

Salamanders are the superstars of regeneration. They can grow back not only limbs but also tails, parts of their hearts and the retinas and lenses in their eyes. Humans cannot do any of that. So scientists here hope that the salamander's tricks may one day be applied to people.

"I really do believe it's just a matter of time before you're going to regenerate an arm or at least a finger," said Dr. David M. Gardiner, a biologist who runs the laboratory at the University of California at Irvine with Dr. Susan V. Bryant, the dean of biological sciences and his wife. "I'd like to see that in my lifetime."

Regenerative medicine, regrowing or repairing damaged organs, has become a hot topic. Almost all the attention has focused on stem cells. The idea is to grow stem cells outside the body, turn them into particular types of tissue and transplant them into patients.

But a few scientists theorize that a better approach is to induce the same regeneration in people that occurs in salamanders and some other animals. Natural regeneration, which might be accomplished with drugs or genes, would be easier than transplanting, they say. And the tissue would be the patient's own, doing away with the problem of rejection. Even if salamanders' feats cannot be reproduced in humans, those scientists say, studying regenerating animals will at least provide clues for stem cell scientists.

So far, natural regeneration remains a medical backwater, garnering little attention. That may be understandable. Scientists have been studying natural regeneration for 200 years and have not gotten far in understanding it. Regrowing human arms in the lifetime of Dr. Gardiner, who is 53, will be difficult.

"I'd like to say we've made tremendous progress, but that would be a lie," said Dr. Catherine Tsilfidis, an assistant professor at the University of Ottawa Eye Institute, who is studying regeneration in newts.

Now, though, genetic techniques are starting to allow scientists to fathom the mechanisms of regeneration. That and the excitement surrounding regenerative medicine are creating new scientific and even commercial interest in regeneration.

Eli Lilly is supporting research aimed at finding genes that help amphibians regenerate, and venture capitalists recently invested $9 million in starting what is perhaps the first company that wants to replicate natural regeneration in people.

The company, Hydra Biosciences, is largely based on the work of Dr. Mark T. Keating, a company founder and a biologist at Harvard who studies regeneration in zebrafish. Hydra of Cambridge, Mass., is named after a pond-dwelling creature that can grow two wholes after being sliced in two. That creature was in turn named for the mythical multiheaded serpent that regrew new heads when one was cut off.

"What we're trying to do is stimulate the body's natural ability to regenerate," Dr. Keating said.

"There's no evidence that human cells are fundamentally different" from those of zebrafish.
Humans can regenerate some parts like livers, muscles and bones, but human regeneration is generally limited to single types of tissues.

Salamanders can regrow multiple types of tissue to make complete structures like limbs. The planarian, a small flatworm, can be cut into pieces as small as one-279th of the whole, and entire new worms will grow from the segments.

The one possible example of multitissue regeneration in people is that young children can regrow fingertips above the top joint, including the bone, skin and nail. That was discovered by accident in England in 1974, when a child who lost a fingertip in a farm accident was taken to a hospital. The doctor was too busy to provide the standard treatment, sewing the skin closed. When she got around to it over a day later, she saw that it was regrowing.

Still, some experts say, that may not be true regeneration but rather a continuation of the fast growth that normally occurs in children's fingers.

Scientists say animals that regenerate do not do it the way scientists are now hoping to do it in people - by finding stem cells in the body that can be extracted or induced to turn into specific types of tissue. "The reason they can do this, we think, is not because they are chock-full of stem cells waiting to blast forth after an injury," said Prof. Jeremy Brockes of University College London.

Rather, he said, it appears that cells near the site of the injury that are already specialized like muscle cells lose their specialized properties and revert to a primordial state in a process called de-differentiation. The animal, in effect, creates its own stem cells when they are needed.

Those stem cells form a mound called a blastema and multiply rapidly. They then redifferentiate to form the tissue needed to rebuild the limb or organ.

Scientists wonder why the ability to regenerate has not spread more widely through evolution. "It seems the higher up you move in terms of evolution," Dr. Tsilfidis said, "the less regenerative ability."

One reason, she speculated, is that higher animals depend more on specialized cells to perform sophisticated functions, and those cells are harder to de-differentiate. Or, she said, the advanced immune systems of higher life forms may mistake rapidly proliferating cells for cancer and kill them.

There are hints that this type of regeneration can occur in higher animals. Dr. Thomas A. Reh, a professor of biological structure at the University of Washington, found that neurons in a chicken retina could be replenished because other nerve cells called glial cells de-differentiated.

In the distant future, Dr. Reh said, that may be used to help heal blindness caused by retinal diseases like macular degeneration.

Regeneration has been found in mammals, in a strain of mice with an altered immune system.

A few years ago, Dr. Ellen Heber-Katz, an immunologist at the Wistar Institute in Philadelphia, was conducting an experiment with those mice, which develop a disease similar to lupus. As is common, Dr. Heber-Katz punched a pattern of holes in each mouse's ear to so she could tell which mouse was which.

Three weeks later, she said, when she checked on the experiment, "there were no ear holes." Dr. Heber-Katz could not tell the mice apart. That ruined her experiment but sent her into a whole new field of study.

She has since found that those mice, unlike other mice, can also regrow parts of their hearts, tails and spinal cords. The fact that the "healer mice" do not form scars appears to be important, she said. Scars block the ability of cells to divide and block signals from the epidermis, a layer of skin, that appear necessary to begin regeneration, she said.

Scientists have been fascinated by regeneration since the 1700's, when a French scientist, René-Antoine Ferchault de Réaumur, for whom a temperature scale is named, noticed at the fish market that some crayfish had legs that were not the same size. He surmised that some legs had grown back after having been cut off. Other scientists around the same time found that hydra, snails and other creatures could regenerate, setting off a frenzy of experimentation.

"Almost everything that moved in Europe was amputated," said Dr. Alejandro Sánchez Alvarado, an associate professor of neurobiology and anatomy at the University of Utah. Even Voltaire decapitated a snail to see its head grow back. He then wrote to friend who was blind that he hoped that a similar process could be harnessed in people.

But that has proved difficult. Dr. Thomas Hunt Morgan studied regeneration at the beginning of the 20th century and basically declared the subject intractable. Dr. Morgan himself moved on to other areas, studying genes and chromosomes in the fruit fly, work that won him a Nobel Prize as the father of modern genetics.

Now, scientists hope to understand regeneration by finding the genes involved. Dr. Heber-Katz has found at least seven locations on the chromosomes of her "healer mice" that appear to contain genes that correlate with the ability to regenerate.

Dr. Sánchez Alvarado is systematically turning off
genes in planaria in hope of discovering which are necessary for regeneration. Dr. David Stocum, a biology professor and the dean of the School of Science at Indiana University-Purdue University Indianapolis, is studying which genes are active in tadpoles, which can regrow limbs, but not in adult frogs, which cannot.

One gene that appears to be important is msx1. It helps keep cells in an embryo from dividing prematurely. Dr. Keating found that when the gene was turned on in mouse muscle cells that were growing in culture, the cells de-differentiated into stem cells. Another tantalizing clue of the importance of msx1, Dr. Keating said, is that the gene is turned off in people, except in the fingertips, the one part of the body where regeneration has been seen.

Dr. Keating has also made mouse muscle cells de-differentiate by using an uncharacterized mixture of proteins extracted from a newt.

Scientists at the Scripps Research Institute did that with a chemical called myoseverin.

The scientists focusing on natural regeneration concede that stem cell scientists are highly likely to make more progress in the near future.

"It's a lot easier to take a stem cell and put it back somewhere than to figure out what's going on here," Dr. Heber-Katz said.

But the salamander types insist that their time will come.

"Given that these mechanisms work so well in
animals that are built like us," Dr. Brockes said,
"it would really surprise me if there wasn't some role for this strategy in the future."


Wise Young
09-24-2002, 08:04 PM
The mouse that Ellen Heber-Katz found is really very interesting. Although they were able to regenerate their ears, they could not regenerate their spinal cord until they prevented fibroblast invasion into the spinal cords: http://carecure.org/forum/showthread.php?t=36765