Research brings hope body parts can regrow: Like lower species, humans possess genes that direct the

Buoyed by recent genetic breakthroughs, researchers at Northwestern University and across the country have hopes of achieving a feat long thought to be impossible: enabling people to replace damaged body parts or even regrow missing limbs.

Like salamanders and other lower species, humans possess genes that direct the body to make new arms and legs after an injury. But in humans, the genes lie dormant, inactivated after evolution favored the swift patching of wounds through scarring over the slow regeneration of body parts.

The discoverer of those genetic switches, Northwestern developmental biologist Hans-Georg Simon, and other researchers think they can find a way to turn on the dormant genes. A person who lost a leg might be able to generate a new one.

"All of a sudden, this becomes not so much science fiction but really a challenging science problem," said Dr. Stephen Badylak of the University of Pittsburgh, who is coordinating one of the research teams. "This particular project to regrow digits and limbs on humans is kind of like saying we're going to go to the moon."

The project, the first national scientific effort of its kind, is financed primarily by the U.S. military, which is seeking better therapies for the unprecedented number of military personnel in Iraq and Afghanistan who are surviving previously mortal wounds, but often without arms or legs.

No one expects amputees to be able to regrow their missing parts any time soon. But there is increasing optimism that therapies can be developed in the next five to 10 years to prevent the formation of scars and to restore damaged or lost tissue from wounds, heart attacks, spinal cord injuries or Alzheimer's disease.

Pediatric surgeons were the first to witness the magical power of regeneration genes about 20 years ago when they began performing daring fetal surgery in early pregnancy. They were astonished to discover the fetus would later be born perfectly healed. No scars.

These same genes allow amphibian species such as salamanders to heal wounds without scars and to perfectly replace lost limbs throughout life. But in humans and other mammals, the genes get turned off shortly before birth.

"There is a transition in us humans where we go from a perfect wound healing phase through regeneration early on, to a later phase where scars begin to form," said Simon, who is working with Badylak's team. "That means we probably also possess the appropriate genes to perfectly heal wounds without scars. And that's the idea my colleagues and I have--to see if we can find the regeneration switch and reactivate it in humans."

Simon, who is also a cell and developmental biologist at Children's Memorial Research Institute, and his colleagues are genetically engineering mice to see if two genes can be turned on: Tbx5 for arms and Tbx4 for legs. They hope that within four years, they will have a mouse that can grow back a "finger."

They already know that when the Tbx genes are inactivated in mice during fetal development, they don't develop fore limbs or hind limbs, and humans born with partially defective Tbx5 genes will have severely stunted arms.

Giving people the salamander's regenerative power has been one of science's oldest dreams, but it has remained just that--a dream thought to be so impossible that research in the area attracted scant funding.

That changed in a major way this spring as the U.S. military sought better ways to repair the disfiguring scars and amputated limbs that are occurring among soldiers in Afghanistan and Iraq at the highest rate ever recorded during war.

The military's Defense Advanced Research Projects Agency, or DARPA, looked at the scattered research going on in regeneration, concluded it could lead to something big and formed two teams of researchers with multimillion dollar grants.

"DARPA would like us to come up with some sort of topical treatment that you could give a wounded soldier on the battlefield or shortly after and get them healing along a regenerative pathway," said Badylak, who has identified proteins that are now commercially available to help people regrow tendons after suffering rotator cuff and Achilles' heel injuries.

One team member may have already taken a step closer to a scarless healing salve. Lorraine Gudas of the Weill Medical College of Cornell University discovered that vitamin A plays an important role in causing one type of cell to differentiate into other cell types, a critical step in regeneration. After a newt limb has been amputated, the amount of vitamin A it is exposed to, for example, will determine if the stump starts regenerating as a whole arm or as an elbow or wrist.

A newt takes six to eight weeks to regenerate a functional limb and a few weeks more to complete a perfect replacement. If humans had the same regenerative capacity, it would probably take a year or more to grow a new arm or leg.

It's this long regeneration time that scientists believe led evolution to favor rapid scar formation in humans and other mammals as a better route to survival in hostile environments. Scars start forming almost immediately after a wound and can be completed in a matter of days or a week or two.

"There are more species on Earth that can regenerate lost appendages than those that can't," Simon said. "We humans are more the exception. The idea is to explore what nature came up with in the first place and then try to find out what genes are inactivated in humans and try to reactivate them."

There is also hope that regeneration in humans, if successful, can be speeded up.

So promising has this line of research become that it is opening the door to "the next evolution of medical treatments," according to a new report, "2020: A New Vision--A Future for Regenerative Medicine," by the U.S. Department of Health and Human Services.

"Regenerative medicine, if driven by a cohesive federal initiative, has the opportunity to begin producing complex skin, cartilage and bone substitutes in as little as five years," it said. "Tissue and organ patches, designed to help regenerate damaged tissues and organs such as the heart and kidneys, are within reach in 10 years. Within 20 years, with appropriate federal funding and direction, the goal of 'tissues on demand' is realistic."

The first regenerated bladders have already made a successful appearance. The bladders, made from a patient's own tissue, have functioned for five years in six patients, Wake Forest's Dr. Anthony Atala reported in April.

"Regenerative medicine definitely is the next generation of treatment, going from the hardware kind of medical devices to a living tissue that can grow and repair with the person," said Christine Kelley, director of the division of discovery science and technology at the National Institute of Biomedical Imaging and Bioengineering.

DARPA awarded Badylak's team $3.7 million for the first year, which can grow to $15 million over four years if certain goals are met. A second team, headed by Ken Muneoka of Tulane University, received similar funding. Muneoka's focus is to find ways to prevent scarring.

Badylak said DARPA became interested in regenerative medicine because of the massive increase in the ratio of wounded military personnel. In all wars from the Revolutionary War up to the first Gulf War the ratio of wounded soldiers to those killed was 2.5 to 1. The early '90s saw a dramatic change with the advent of body armor, which protected the torso and head but left arms, legs and neck exposed. In the Afghanistan and Iraq wars the ratio of wounded to dead is 9 to 1.

"They said let's look at something better than developing prosthetic limbs. Let's see if we can take it further," Badylak said.

The two-year goal for the Badylak team is to have a mouse replicate the kind of biological transformation that occurs in a salamander at the site of an amputation called a blastema. In a blastema, cells in the stump are converted into progenitor cells, which go on to make bone, skin, nerves and other structures that form a new limb.

The four-year goal is to basically have a mouse regenerate a finger. "If we can do that, then I think we are well on the road to understanding how to regrow appendages," Badylak said.

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