For more than 400 years, scientists have studied the amazing regenerative power of salamanders, trying to understand how these creatures routinely repair injuries that would usually leave humans and other mammals paralyzed or worse.

Now, fueled by a highly competitive National Institutes of Health Grand Opportunity grant of $2.4 million, a multi-institutional team of researchers associated with the University of Florida McKnight Brain Institute's Regeneration Project has begun creating genomic tools necessary to compare the extraordinary regenerative capacity of the Mexican axolotl salamander with established mouse models of human disease and injury.

Researchers want to find ways to tap unused human capacities to treat spinal cord injury, stroke, traumatic brain injury and other neural conditions, according to Edward Scott, Ph.D., principal investigator for the GO grant and director of the McKnight Brain Institute's Program in Stem Cell Biology and Regenerative Medicine.

"The axolotl is the champion of vertebrate regeneration, with the ability to replace whole limbs and even parts of its central nervous system," Scott said. "These salamanders use many of the same body systems and genes that we do, but they have superior ability to regenerate after major injuries. We think that studying them will tell us a lot about a patient's natural regenerative capacities after spinal cord injury and nerve cell damage."

The issue of what controls organ regeneration was named among the top 25 major questions facing scientists in the next quarter century by Science magazine in 2005, Scott said. With medical science continually adding years to the human lifespan, the importance of "rebuilding and restoring" old tissues and organs is growing. But science had to enter the 21st century to fully explore the use of the highly regenerative axolotl as a model for human disease.

"Only now have new genetic, molecular and cellular technologies as well as scientific knowledge of the salamander, mouse and human genomes and 'regeneromes' risen to a level where scientists can compare systemwide responses to injury," according to Dennis A. Steindler, Ph.D., excutive director of UF's McKnight Brain Institute and a co-investigator on the grant.

"I am extremely hopeful with the discoveries being made in comparative regenerative biology that the questions surrounding cell and tissue regeneration in the human following injury or disease are going to be answered," Steindler said. "It is going to take broad, multidisciplinary collaborations across a number of scientific fields, but we are making that happen. I think the GO grant shows that these efforts are recognized and valued on a national level."

GO grants are funded through the American Recovery and Reinvestment Act and are intended to support research with high short-term impact and a high likelihood of enabling growth and investment in biomedical research and health-care delivery.

"NIH Grand Opportunity grants support high-impact projects, which lay the foundation for whole new fields of investigation," said Naomi Kleitman, Ph.D., repair and plasticity program director at the National Institute of Neurological Disorders and Stroke. "This important model of regeneration is one of several being developed in organisms that can repair themselves, using genetics to find links to mammals. We'll continue to watch the progress of these exciting studies to ensure that discoveries of genes that promote regeneration are one day applied to improving human health."

The Regeneration Project is also supported by private foundations such as the Thomas H. Maren Foundation and the Jon L. and Beverly A. Thompson Research Endowment, the UF Office of the Vice President for Research, and an anonymous donor, Steindler said. Enhancing the discovery process are Regeneration Project research fellows scientists who work across institutes and universities to advance discoveries in tissue and organ regeneration to the clinic.

Even without help, people are capable of a certain degree of regeneration. Humans can regrow fingertips and even more than half of their liver. But they cannot replace whole limbs and restoring parts of their brain and spinal cord is a daunting challenge. "The axolotl is the highest, most complex organism that can still do this clever trick of completely reconstructing a whole body part in adulthood," said Arlene Chiu, Ph.D., a scientific adviser for the Regeneration Project and director of New Research Initiatives at Beckman Research Institute of the City of Hope. "I like to think of it in construction terms where we need both the materials such as bricks and beams and the architect's plans. In regenerative medicine, can we learn where the biological blueprint resides, and understand the basis of restoring and reorganizing many different types of lost cells and tissues? Muscles, bones, nerves and blood vessels all have to be reconstructed at the right time and in the right place, all in perfect coordination with the original biological master plan.

"It may sound like science fiction, but the reality is the salamander is able to do all of these things," she said. "We are not so far removed that we can't relate to them, learn from them and try to apply their secrets to improve our capacity to regenerate."

As discoveries are made, more researchers will begin using the axolotl as a model for exploring regenerative techniques, according to S. Randal Voss, director of the Salamander Genome Project at the University of Kentucky.

"We've analyzed genes in common between the axolotl salamander and humans, and found out we share about 90 percent of our genes in a one-to-one sense," Voss said. "It could be that small but important changes in the way these genes function in an injury environment affect the repair process, but somehow the salamander is able to use these genes for regeneration, while people are not."

The team has already referenced human and mouse genes with axolotl counterparts.

"We started this with a list of genes in humans and mice that are involved in repair processes and matched them with their counterparts in the axolotl genome," Scott said. "Ultimately, what makes the axolotl a great model for regeneration is that the model systems we are most familiar with mice and humans do not regenerate very well. By comparing how a mammal and a salamander respond to injuries, we can identify genes or proteins that we can now add back to the mammalian system to make it regenerate better."