Monday, December 14, 2009

New Hope for Brain, Spinal Cord Injuries

Deletion of key gene could help nerve fibers regenerate, researchers say


Deleting a gene that suppresses natural growth factors enables regeneration of injured nerve fibers (axons) in mice, a new study shows.

The finding may lead to new treatments for people with brain and spinal cord injuries.

Researchers at Children's Hospital Boston deleted the gene SOCS3 -- an inhibitor of a growth pathway called mTOR -- in the retinal ganglion cells of mice. These cells are in the optic nerve, which carries signals from the eyes to the brain.

Removel of SOCS3 resulted in vigorous growth of injured axons. The greatest improvement was seen after one week, when the researchers also detected signs that the mTOR pathway was re-activated. Axon growth increased even more when the researchers applied a growth factor called ciliary neurotrophic factor (CNTF) directly to the eye of mice in which SOCS3 had been deleted. But CNTF only modestly boosted axon growth in mice that still had SOCS3.

"CNTF and other cytokines [cellular signaling molecules] have been tested for promoting axon regeneration previously, but with no success," study leader Zhigang He, of the F.M. Kirby Neurobiology Center at Children's Hospital Boston, said in a university news release. "Now we know that this is due to the tight negative control of SOCS3. Inhibiting SOCS3, using small molecule compounds or RNA interference, might allow these cytokine growth factors to be functional."

The study appears in the Dec. 10 issue of Neuron.

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Monday, September 21, 2009

Scientists Make Paralyzed Rats Walk Again After Spinal Cord Injury

UCLA researchers have discovered that a combination of drugs, electrical stimulation and regular exercise can enable paralyzed rats to walk and even run again while supporting their full weight on a treadmill.

Published Nov. 20 in the online edition of Nature Neuroscience, the findings suggest that the regeneration of severed nerve fibers is not required for paraplegic rats to learn to walk again. The finding may hold implications for human rehabilitation after spinal cord injuries.

"The spinal cord contains nerve circuits that can generate rhythmic activity without input from the brain to drive the hind leg muscles in a way that resembles walking called 'stepping,'" explained principal investigator Reggie Edgerton, a professor of neurobiology and physiological sciences at the David Geffen School of Medicine at UCLA.

"Previous studies have tried to tap into this circuitry to help victims of spinal cord injury," he added. "While other researchers have elicited similar leg movements in people with complete spinal injuries, they have not achieved full weight-bearing and sustained stepping as we have in our study."

Edgerton's team tested rats with complete spinal injuries that left no voluntary movement in their hind legs. After setting the paralyzed rats on a moving treadmill belt, the scientists administered drugs that act on the neurotransmitter serotonin and applied low levels of electrical currents to the spinal cord below the point of injury.

The combination of stimulation and sensation derived from the rats' limbs moving on a treadmill belt triggered the spinal rhythm-generating circuitry and prompted walking motion in the rats' paralyzed hind legs.

Daily treadmill training over several weeks eventually enabled the rats to regain full weight-bearing walking, including backwards, sideways and at running speed. However, the injury still interrupted the brain's connection to the spinal cord-based rhythmic walking circuitry, leaving the rats unable to walk of their own accord.

Neuro-prosthetic devices may bridge human spinal cord injuries to some extent, however, so activating the spinal cord rhythmic circuitry as the UCLA team did may help in rehabilitation after spinal cord injuries.

The study was funded by the Christopher and Dana Reeve Foundation, Craig Nielsen Foundation, National Institute of Neurological Disorders and Stroke, U.S. Civilian Research and Development Foundation, International Paraplegic Foundation, Swiss National Science Foundation and the Russian Foundation for Basic Research Grants.

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Tuesday, July 28, 2009

Stem-Cell Breakthrough

It's a chilling thought. In the coming year, 130,000 people worldwide will suffer spinal-cord injuries?in a car crash, perhaps, or a fall. More than 90 percent of them will endure at least partial paralysis. There is no cure. But after a decade of hype and controversy over research on embryonic stem cells?cells that could, among other things, potentially repair injured spinal cords?the world's first clinical trial is about to begin. As early as this month, the first of 10 newly injured Americans, paralyzed from the waist down, will become participants in a study to assess the safety of a conservative, low-dose treatment. If all goes well, researchers will have taken a promising step toward a goal that once would have been considered a miracle?to help the lame walk.

The trial signals a new energy permeating the field of stem-cell research. More than 3,000 scientists recently met in Barcelona for the annual conference of the International Society for Stem Cell Research, compared with just 600 researchers five years ago. Money from major pharmaceutical companies is following the advances. Former U.S. vice president Al Gore, now a partner in the venture-capital firm Kleiner Perkins Caufield & Byers, has thrown his weight behind the research. In April, the firm joined with Highland Capital Partners to invest $20 million in iZumi Bio (now iPierian), a startup firm working on stem-cell therapies.
Click here to find out more!

Despite the considerable hype surrounding stem cells in recent years, the possibilities now appear to be broader than most people realize. In addition to helping replace damaged cells in patients with diseases like diabetes or Parkinson's, stem cells have the potential to change how we develop drugs and unravel the biology of disease. They may even be used one day to create replacement organs. "There's been a massive injection of optimism into the field," says stem-cell biologist Alan Trounson, president of the California Institute for Regenerative Medicine. "It's remarkable how fast it's progressing."

Much of the excitement comes from the development of a new type of stem cells, called "induced pluripotent" stem cells, or iPS. Shinya Yamanaka first concocted the cells in his Kyoto University lab by inserting four genes into fully formed adult skin cells. They began to behave like embryonic stem cells, capable of forming unlimited copies of any of the body's 220 cell types. Because iPS cells can be derived from a patient's own adult cells, they do not carry the risk of rejection by the immune system. Equally important, because iPS cells are not derived from embryos, they skirt a major ethical and religious problem.

The first iPS cells, however, will not be used as replacement tissue for spinal cords and other organs. Because iPS cells have subtle (and potentially dangerous) differences from true embryonic stem cells, many doctors are leery of putting them directly into patients until more research is done. But the cells could be immensely important in helping scientists understand and treat genetically based diseases.

By the time a full-blown disease has emerged, says Harvard stem-cell biologist Konrad Hochedlinger, it's like an airplane that has crashed. You can examine the wreckage for clues, but what you really want is the plane's black boxes?the flight-data and cockpit voice recorders that tell you exactly how electrical systems failed, hardware malfunctioned, and pilots made crucial errors. That's what doctors think iPS cells could provide. By coaxing some iPS cells into becoming the cell types affected in Huntington's disease, type 1 diabetes, or ALS (Lou Gehrig's disease), scientists will be able to watch in the lab as the disease unfolds. They'll be able to understand how the disease starts, which could lead to new ways of blocking it.

Embryonic stem cells are still regarded as the gold standard. That's why there is intense interest in the U.S. spinal-cord-injury trial. Sponsored by Geron Corp. in California, the trial will recruit patients within one to two weeks of their injuries, before scar tissue has formed. Doctors will inject a derivative of stem cells, called progenitor cells, that manufacture myelin, the substance that coats the long, spindly projections on nerve cells, much the same way that insulation coats electrical wires. Damage to cells that make and maintain the myelin sheath, as happens in spinal-cord injuries, prevents nerves from conveying messages from the brain. Although it's not clear yet whether the treatment is effective or safe, the restoration of even partial function would be a huge advance.

Geron's CEO, Dr. Thomas Okarma, thinks that spinal injury is a logical place to begin. Because patients will be completely paralyzed from the waist down, any improvement will be the result of the therapy, not chance. And the spinal cord is an "immune-privileged site," meaning that the attack cells of the immune system cannot get in and destroy the embryo-derived cells. "If the therapy is safe and effective, the potential impact will extend way beyond spinal-cord injury," says Okarma. "It will mark the start of a new era in medical therapeutics."

Other companies aren't waiting for the results. The U.S. pharmaceutical giant Pfizer is pursuing two other embryonic-stem-cell-based therapies, which it hopes to have in clinical trials by 2011. In April the company partnered with University College London to pursue a therapy for macular degeneration, the principal cause of blindness in the elderly. The disease leads to the gradual destruction of the macula, the sensitive central portion of the retina. But Peter Coffey, professor of cellular therapy and visual sciences at UCL, is using embryonic cells to make the same type of support cells that lie just behind the retina, providing it with nutrients. The goal is to implant a disc-shaped layer of the cells behind the retina. Immune rejection should not be a problem, since the eye is also immune-privileged.

Pfizer's other collaboration, with Novocell in California, aims to devise a treatment for some of the 100 million patients worldwide with insulin-dependent diabetes. Novocell is using embryonic stem cells to help regenerate all five of the pancreas's cell types. But there's a hitch. Unlike the eye or the spinal cord, the pancreas has no immune protection. For this, Novocell has devised a clever solution. It encases the stem-cell-derived progenitor cells in a capsule that can be implanted in the body. The pore size of the fabric is large enough to allow oxygen, glucose, and insulin to pass through but small enough to keep out big immune cells. "If problems should develop, the surgeon can easily remove the capsule," says Liz Bui, director of intellectual property for Novocell.

Some researchers aren't interested in just replacing impaired cells. They're using adult stem cells?which exist within organs to help with minor repairs?to grow entire replacement organs and tissues. Dr. Anthony Atala, director of the Institute for Regenerative Medicine at Wake Forest University in North Carolina, has made human bladders in this way. He starts by taking a small bladder biopsy from the patient and extracting his or her stem cells. After allowing the cells to multiply in the lab for about a month, he spreads them onto a collagen scaffold fashioned in the shape of a bladder. He then incubates the would-be organ in a bioreactor that provides the same temperature, oxygen level, growth factors, and nutrients that would be found in the body. In two weeks, he has a small but functional organ, ready for a patient.

In the early 2000s, Atala completed the procedure on seven children with spina bifida, who never developed fully functional bladders. He has now followed these patients for eight years to make sure there are no drastic failures or side effects. And he has moved on to other possible replacement parts. "We're working on 22 tissues and organs, including kidneys, heart valves, and cartilage," he says.

Because any new therapy is inherently risky, researchers are careful about creating false hopes that cures are just around the corner. Therapies that succeed in the idealized world of the lab can fail in real life or take decades to put into practice. As doctors and regulators begin to consider treating patients, they still have basic questions. Will the cells survive for long in the body? Will they integrate to form functioning tissue? Will the benefits outweigh risks that may become apparent only decades from now? Scientists are daring to hope, though, that after a decade of hype, real progress is imminent. Millions of patients worldwide could one day be the beneficiaries.

By Anne Underwood | NEWSWEEK

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Friday, November 21, 2008

Nanotechnology for Spinal Cord Injury

A cure for spinal injuries that leave people paralyzed, currently incurable, is being developed by Researchers at Northwestern University in Chicago. They are looking into using new nanotechnology that could enable them to completely heal cut and severed spinal cords allowing the previously paralyzed to walk again.

Spinal cord injury often leads to permanent paralysis and loss of sensation below the site of the injury due to damaged nerve fibers which can?t regenerate. These nerve fibers (axons) have the capacity to grow but don?t because they are blocked by scar tissue that have developed around the injury. Northwestern University researchers have shown that a new nano-engineered gel inhibits the formation of scar tissue at the injury site and enables the severed spinal cord fibers to regenerate and grow.

The gel is injected as a liquid into the spinal cord and self -assembles into a scaffold that supports the new nerve fibers as they grow up and down the spinal cord, penetrating the site of the injury. When the gel was injected into mice with a spinal cord injury, after six weeks the animals had a greatly enhanced ability to use their hind legs and walk.

However it was stressed that the results were preliminary and there is no magic bullet and it may not necessarily work on humans, but it helps a new technology to develop treatments for spinal injuries.

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Sunday, July 20, 2008

Stem Cells Identified for Spinal-Cord Repair

A researcher at MIT?s Picower Institute for Learning and Memory has pinpointed stem cells within the spinal cord that, if persuaded to differentiate into more healing cells and fewer scarring cells following an injury, may lead to a new, non-surgical treatment for debilitating spinal-cord injuries.

The work, reported in the July issue of the journal PLoS (Public Library of Science) Biology, is by Konstantinos Meletis, a postdoctoral fellow at the Picower Institute, and colleagues at the Karolinska Institute in Sweden. Their results could lead to drugs that might restore some degree of mobility to the 30,000 people worldwide afflicted each year with spinal-cord injuries.

In a developing embryo, stem cells differentiate into all the specialized tissues of the body. In adults, stem cells act as a repair system, replenishing specialized cells, but also maintaining the normal turnover of regenerative organs such as blood, skin or intestinal tissues.

The tiny number of stem cells in the adult spinal cord proliferate slowly or rarely, and fail to promote regeneration on their own. But recent experiments show that these same cells, grown in the lab and returned to the injury site, can restore some function in paralyzed rodents and primates.

The researchers at MIT and the Karolinska Institute found that neural stem cells in the adult spinal cord are limited to a layer of cube- or column-shaped, cilia-covered cells called ependymal cells. These cells make up the thin membrane lining the inner-brain ventricles and the connecting central column of the spinal cord.

?We have been able to genetically mark this neural stem cell population and then follow their behavior,? Meletis said. ?We find that these cells proliferate upon spinal cord injury, migrate toward the injury site and differentiate over several months.?

The study uncovers the molecular mechanism underlying the tantalizing results of the rodent and primate and goes one step further: By identifying for the first time where this subpopulation of cells is found, they pave a path toward manipulating them with drugs to boost their inborn ability to repair damaged nerve cells.

?The ependymal cells? ability to turn into several different cell types upon injury makes them very interesting from an intervention aspect: Imagine if we could regulate the behavior of this stem cell population to repair damaged nerve cells,? Meletis said.

Upon injury, ependymal cells proliferate and migrate to the injured area, producing a mass of scar-forming cells, plus fewer cells called oligodendrocytes. The oligodendrocytes restore the myelin, or coating, on nerve cells? long, slender, electrical impulse-carrying projections called axons. Myelin is like the layer of plastic insulation on an electrical wire; without it, nerve cells don?t function properly.

?The limited functional recovery typically associated with central nervous system injuries is in part due to the failure of severed axons to regrow and reconnect with their target cells in the peripheral nervous system that extends to our arms, hands, legs and feet,? Meletis said. ?The function of axons that remain intact after injury in humans is often compromised without insulating sheaths of myelin.?

If scientists could genetically manipulate ependymal cells to produce more myelin and less scar tissue after a spinal cord injury, they could potentially avoid or reverse many of the debilitating effects of this type of injury, the researchers said.

Provided by MIT

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Tuesday, April 08, 2008

Nanotechnology May Help Reconnect Nerves

U.S. researchers say they have created a nano-engineered gel that can enable severed spinal cord fibers to regenerate and grow.

Mice paralysed by spinal injuries have been able to walk again thanks to a treatment developed by scientists in the US. The therapy uses proteins that self-assemble into nano-fibers at the site of the injury, encouraging nerves to regrow.

Spinal cord injuries often lead to permanent paralysis and loss of sensation because the damaged nerve fibers can't regenerate, Northwestern University scientists said. Although nerve fibers or axons have the capacity to re-grow, they don't because they're blocked by scar tissue that develops around the injury.

The nanogel developed at the university's Feinberg School of Medicine inhibits formation of scar tissue and enables the severed spinal cord fibers to regenerate and grow, the scientists said.

The gel is injected as a liquid into the spinal cord and self-assembles into a scaffold that supports new nerve fibers. When the gel was injected into mice with a spinal cord injury, after six weeks the animals had a greatly enhanced ability to use their hind legs and walk.

"It's important to understand that something that works in mice will not necessarily work in human beings," said study leader Dr. John Kessler, who noted that if the gel is eventually approved for humans, a clinical trial could begin within several years.

The research is reported in the Journal of Neuroscience.

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Monday, April 07, 2008

Experimental Russian Stem Cell Treatments Credited for Woman's Progress

Experimental Russian stem cell treatments for spinal injury credited for woman's progress


Notice: The following excerpts are taken from the Grand Rapids Press. A link the the entire article is listed below, and is well worth the time to read.
When Kadi DeHaan took her first steps in December, two years after a car accident forced her into a wheelchair, she did it in typical Kadi style: low-key, nonchalant and with a confident grin.


Apparently, she knew all along she would walk away from her pink and black wheelchair and her customized leg braces, despite a spinal cord injury at chest level and a grim prognosis that she would never walk again.

It happened after two years of intensive therapy and six trips to Russia, where her stem cells were harvested and then injected into her spinal cord to restore nerves.

Kadi's progress is "very much a unique and wonderful thing," said physical therapist Sandy Burns, director of the Center for Spinal Cord Injury Recovery in Rockford, a clinic affiliated with the Detroit Medical Center.

No one can say for sure if nearly two years of experimental treatments or hours upon hours of physical therapy -- a trio of three-hour sessions every week -- led Kadi to where she is today.

Probably both, said Burns, whose clients sometimes head to Russia or Portugal or China for treatments that aren't approved in the U.S. and generally aren't covered by insurance.

The physical therapy is a very important component, "but it's definitely Russia," that put Kadi back on her own two feet, Kadi's mom, Bonnie, insisted. "There are just too many coincidences. Kadi knows that what she's got she got from Russia."

After fundraising dollars ran out more than a year ago, Kadi's parents took out a loan to pay for the trips to Russia. The three-year protocol recommended by Moscow doctors will cost in excess of $150,000.

At the time, Kadi had just a bit of feeling in her feet and could walk only with lots of help from custom-built leg braces and a walker.

Since then, she's given up the braces and is "tons stronger" and "a lot more independent," she said. She's a full-time student at Davenport University who quaffs Mountain Dew and confesses to sending text messages during class.

"I've seen a lot of changes. I've seen motor return, sensory return, everything," Kadi said.

She's so convinced of the gains made at the NeuroVita Clinic that she's planning her seventh trip there in August. Quite a change of attitude after she declared the first trip "the worst three weeks of my life."

Burns, who is quick to say her clinic does not endorse any of the alternative treatments, acknowledged that the stem cell injections do seem to make a difference, at least for Kadi.

"Folks that have gone there have, I think, consistently reported that they are noticing changes. They are feeling more," Burns said.

She tempers her optimism with the reality of what she sees every day: some of her clients will never accomplish half as much as Kadi has. Progress often depends upon the severity of the spinal injury, not just the region of the spine that was damaged.

That's why Burns doesn't make predictions about what her clients will eventually accomplish. But of course, she hopes Kadi continues to make great strides.




The Neurovita Clinic


Where: Moscow, Russia
What: Treats spinal cord injuries, degenerative disorders and some cancers with patient's own stem cells, which are harvested, grown and re-injected. Clinic moved away from use of embryonic stem cells because of compatibility issues.
Insurance: Because treatment is experimental and not performed here, U.S. insurance policies don't cover it.
Website: neurovita.ru/eng_index.html

The NeuroVita clinic was founded by neurologist Andrey S. Bryukhovetskiy in 2002. It's located on the campus of the Russian State Medical University and can accommodate 35 patients.

The clinic dabbled in embryonic stem cell treatments but now uses only autologous material -- that which is obtained from the patient -- because there are no problems with compatibility, not to mention politics and religion, according to the Web site.

About 11 of every 100 patients with spinal cord injuries walk again after the stem cell treatments, Bryukhovetskiy told them.

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Sunday, February 17, 2008

Spinal Cord Injury Regeneration Hope

Scientists believe they are close to a significant breakthrough in the treatment of spinal injuries.

The University of Cambridge team is developing a treatment which could potentially allow damaged nerve fibers to regenerate within the spinal cord.

It may also encourage the remaining undamaged nerve fibers to work more effectively.

Spinal injuries are difficult to treat because the body cannot repair damage to the brain or spinal cord.

Although it is possible for nerves to regenerate, they are blocked by the scar tissue that forms at the site of the spinal injury.

Scientists believe they are close to a significant breakthrough in the treatment of spinal injuries.

The Cambridge team has identified a bacteria enzyme called chondroitinase which is capable of digesting molecules within scar tissue to allow some nerve fibers to regrow.

The enzyme also promotes nerve plasticity, which potentially means that remaining undamaged nerve fibers have an increased likelihood of making new connections that could bypass the area of damage.

Boosts rehabilitation

In preliminary tests, the researchers have shown that combining chondroitinase with rehabilitation produces better results than using either technique alone.

However, trials have yet to begin in patients.

Lead researcher Professor James Fawcett said: "It is rare to find that a spinal cord is completely severed, generally there are still some nerve fibers that are undamaged.

"Chondroitinase offers us hope in two ways; firstly it allows some nerve fibers to regenerate and secondly it enables other nerves to take on the role of those fibers that cannot be repaired.

"Along with rehabilitation we are very hopeful that at last we may be able to offer paralyzed patients a treatment to improve their condition."

'Ground-breaking'

Dr Yolande Harley, of the charity Action Medical Research which funded the work, said: "This is incredibly exciting, ground-breaking work, which will give new hope to people with recent spinal injuries."

Paul Smith, of the Spinal Injuries Association, said medical advances meant that spinal injuries had ceased to be the terminal conditions that they often once were, but they still had a huge impact on quality of life.

However, he warned against raising expectation before the treatment was fully tested on patients.

He said: "What often happens in a clinical setting is that you don't get to see the results you would have liked."

In the UK there are more than 40,000 people suffering from injuries to their spine, which can take the form of anything from loss of sensation to full paralysis.

The average age at the time of injury is just 19.

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Wednesday, November 28, 2007

Scientists Identify Gene that Helps Salamanders Regrow Limbs

University of Montreal researchers have identified a gene that allows limb regeneration in the axolotl, a salamander that lives in Mexican lakes.

The gene, called TGF-beta 1, controls the generation and movement of new cells, and allows the axolotl to regrow complex structures like limbs, tail, jaw, spinal cord and even parts of its brain.

Humans also have this gene. The difference is that in humans, instead of telling a limb to regenerate, the gene tells the wounded area to heal and form a scar. If scientists can find a way to manipulate TGF-beta in humans, it could lead to the ability to regrow organs and limbs, as well as treatments for spinal cord injury and severe burns.

In the study, the scientists used a drug that inhibited the gene in axolotls. The treated axolotls couldn't regrow their limbs, proving that TGF-beta plays a role in regeneration.

The salamander study is published in the November 28 issue of PLoS ONE.

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Tuesday, April 24, 2007

Simple Injection Shows Promise for Treating Paralysis

Paralyzed lab rodents with spinal cord injuries apparently regained some ability to walk six weeks after a simple injection of biodegradable soap-like molecules that helped nerves regenerate.

The research could have implications for humans with similar injuries.

"It will take a long time, but we want to offer at least some improvement, to improve quality of life for people with these injuries," materials scientist Samuel Stupp at Northwestern University in Evanston, Ill., told LiveScience. "Anything would be considered a breakthrough, because there's nothing right now."

The soap-like molecules contain a small piece of laminin, a natural protein important in brain development. After these molecules are injected into the body, they react with chemicals there, assembling themselves instantly into scaffolds of super-thin fibers just six billionths of a meter wide, roughly a hundredth a wavelength of orange light. They biodegrade after roughly eight weeks.

The scientists experimented with their molecules on dozens of mice and rats that experienced spinal cord injuries that paralyzed their hind legs, "the kind of very hard blow people might experience after falling off skiing slopes or getting in car accidents," Stupp said. His colleague, neurologist John Kessler, became active in this work after Kessler's daughter was paralyzed in a skiing accident.

After six weeks, damaged nerves regenerated enough for the paralyzed legs of the rodents to regain some ability to walk.

"There's a special scale to monitor how much function they regained, ranging from 0 to 21," Stupp explained. "At 21, function is perfect. At 6 or 7, limbs are just paralyzed, and the mice were just dragging them along. If you go to 9 to 12, the animal can now actually move the limbs. Not perfectly?awkwardly?but they move. So two or three points on that scale makes a huge difference."

"We've been able to go from a 7 to a 9 in the mouse, and in the rat, the highest was 12," he said. The findings are to be presented today at a meeting of the Project on Emerging Nanotechnologies in Washington, D.C.

The researchers are currently in talks with the FDA regarding their work and hope to start phase I clinical trials (for toxicity and safety testing) in humans two years from now, Stupp said. The idea he and his colleagues have for these molecules is to administer them within a day or so after spinal cord injuries, before scar tissue begins to form that can suppress healing. Past experiments have shown these molecules can actually turn neural stem cells (which might otherwise become scar cells) into neurons instead.

"Recovering every function a person had before an injury will probably be very hard," Stupp cautioned. "Even if people couldn't walk, if they could recover bladder function, that'd be a good thing. It's the first thing I'd want to recover."

The researchers now are developing versions of these soap-like molecules that could help with regeneration when it comes to other maladies such as Parkinson's disease, stroke, heart attacks, bone trauma or diabetes.

By Charles Q. Choi

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