Friday, December 17, 2004

Stem Cell Researcher Makes Paralyzed Rats Walk

IRVINE, Calif. - So far, not a single person has been helped by human embryonic stem cells.

But in cramped university labs, a young neurobiologist with movie star good looks, a Carl Sagan-like fondness for the popular media and an entrepeneur's nose for profits is getting tantalizingly close.

Hans Keirstead is making paralyzed rats walk again by injecting them with healthy brain cells sussed from a reddish soup of human embryonic stem cells he and his colleagues have created.

Keirstead hopes to apply his therapy to humans by 2006. If his ambitious timetable keeps to schedule, Keirstead's work will be the first human embryonic stem cell treatment given to humans.

"I have been shocked, thrilled and humbled at the progress that I have made," Keirstead, 37, said in an interview in his University of California-Irvine office, which is dominated by a 4- by 8-foot collage of famous rock stars created by his artist brother. "I just want to see one person who is bettered by something that I created."

Keirstead has been turning stem cells into specialized cells that help the brain's signals traverse the spinal cord. Those new cells have repaired damaged rat spines several weeks after they were injured.

For the last two years, he has shown dramatic video footage of healed rats walking to scientific gatherings and during campaign events to promote California's $3 billion bond measure to fund stem cell work, which passed in November.

Keirstead and his colleagues are continuing to experiment with rats to ensure the injected cells do what they're supposed to without any side effects.

"You don't want toenails growing in the brain," he said.

Meanwhile, Keirstead and his corporate sponsor - Menlo Park-based Geron Corp. - are designing the initial human experiments, which will test for safety and involve just a handful of volunteers. The volunteers likely will be patients who have been recently injured.

Keirstead's work was at first met by derision and disbelief at the Society of Neuroscience's annual meeting in 2002.

"We upset a lot of people," said Dr. Gabriel Nistor, who was the first researcher to join Keirstead's lab five years ago. "No one believed us at first." Keirstead and Nistor were stars at the same gathering in October, and their research will be published next month in a scientific journal.

Kierstead is as close as anyone in the stem cell research world could be to celebrity, and that can be dangerous in a profession noted as much for its petty jealousies of individual fame as it is for scientific breakthroughs. (Sagan, the noted astronomer who for years hosted the PBS series "Cosmos," was denied membership in the prestigious National Academy of Sciences, a slight that his supporters insist was based on his mass appeal).

Reporters have beaten a well-worn path to Keirstead's lab. The fact that he's wealthy only adds to his growing luster.

Keirstead recently sold a biotech company he co-founded, unrelated to his stem cell work, in a deal that could be worth as much as $8 million.

"We all love Hans - for various reasons," giggled Karen Miner, whose advocacy organization helps fund Keirstead's work.

Miner and her colleagues at Research for Cure, based in Escalon in California's Central Valley, have contributed $170,000 over the last four years to the Reeve-Irvine Research Center where Keirstead works. The center is named for its founding donor, actor Christopher Reeve, who died in October of complications related to his paralysis.

"We all feel he is on the cutting edge of spinal cord research," said Miner, 53, who was paralyzed below the neck after an automobile accident 12 years ago. "I have to think it's the most promising thing out there."

She toured Keirstead's labs two years ago and watched once-paralyzed rats walk inside their cages.

"The adrenaline that I felt was almost enough to get me out of the chair," Miner said. "When you are sitting in a wheelchair and see those rats running around, all you can think is, 'I want some of those now.'"

Human embryonic stem cells are created in the first days after conception and are the building blocks of the human body. Scientists believe they will someday be able to coax stem cells to turn into healthy cells to treat a wide range of ailments, including diabetes, heart disease and spinal cord injuries. Many social conservatives who believe life begins at conception view the work as immoral because days-old embryos are destroyed during research.

Critics complain privately that Keirstead is beholden to Menlo Park-based Geron, which claims a Microsoft-like grip on any commercial stem cell market that emerges.

Geron funded the work of University of Wisconsin researcher Jamie Thomson, who discovered human embryonic stem cells in 1998, and the company funds Keirstead's lab at $500,000 a year. Geron owns the commercial rights to any drug Keirstead may develop.

Keirstead doesn't apologize for his funding source, which he said is more generous than he could have expected from the federal government and with fewer research restrictions. He said he's not interested in profits, but rather in speeding the development of new spinal cord treatments.

And he has an answer for those who say he's moving too fast and that his experiments with rats are dangling false hope before the 15,000 people paralyzed in the United States each year.

"This is extremely promising," Keirstead said. "Why the hell would we wait?"

By: PAUL ELIAS - Associated Press
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Monday, December 13, 2004

New Hope for Spine Injury Victims

Damaged spinal cord nerves are encouraged to grow again
People paralysed by spinal injury may one day be able to walk again thanks to pioneering work by British scientists.

Researchers at Cambridge University and Kings College London have found a way to encourage damaged nerves to re-grow. That in turn prompts any surviving nerves to help out, bringing back some useful muscle function.

The basic techniques in the new therapy were developed by Dr James Fawcett and his team at the Brain Repair Centre at the University of Cambridge.

Spinal cord injury experiments were then conducted with colleagues in Professor Steve McMahon's laboratory at King's College London.

Regaining lost function
Dr Fawcett said: "This technology could lead to the first successful treatment for spinal cord injury and should increase the chance of patients regaining some of their lost function after an injury has occurred."

To encourage damaged nerves to grow again the researchers had to overcome an aspect of the body's natural defences, which prevents nerves from recovering.

Damage to nerves in the spinal cord cuts signals from the brain to the muscles, leading to paralysis.

To protect itself from infection the body creates molecules in the scar tissue that actually block nerve regeneration.

The scientists discovered a way of using enzymes - proteins made by cells - that can "eat" the blocking molecules, allowing some nerve fibres to regenerate.

The universities have now licensed their discoveries to American pharmaceutical company, Acorda Therapeutics, in the hope they can use them to develop treatments for people with spinal injuries.

In return the academics would get a share of future profits from the sale of any drugs.
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Spinal-Cord Chip Implants Underway

You may not think you have much in common with the lamprey eel, arguably the most primitive vertebrate, but the truth is, it's got your back. Though the bones are different, the neural components of a lamprey eel's spinal cord are much the same as humans' but are simpler and easier to understand. By studying these animals, researchers from Johns Hopkins University and the University of Maryland hope to develop an implantable chip, replicating spinal-cord nerves, which could someday help people with spinal-cord injuries walk again.

When a person has a spinal-cord injury, the nerve bundles below the spinal column are generally still intact. The problem is that the brain can no longer send them instructions to fire or stop firing. The implantable chip being developed?measuring just 4 mm by 4 mm, and requiring just 10 to 20 microwatts of power?attempts to control them in place of the brain. "We let the spinal cord do its thing, we just control circuits that make that spinal cord do its thing," says lead researcher Ralph Etienne-Cummings, an associate professor of electrical and computer engineering at Johns Hopkins.

Etienne-Cummings says designing the chip isn't the hard part of the project; understanding and controlling the lamprey eel's spinal cord is. He is working with University of Maryland biology professor Avis H. Cohen, a neuromorphic engineer who specializing in systems and motor control. Cohen has been studying spinal-cord regeneration in lampreys since 1977.

"Designing the chip is not that difficult," Etienne-Cummings says. "It is a very standard technology that has been around for a long time, used to develop microprocessors. The technical difficulty is in understanding the spinal cord, where to stimulate it, and so on. If you understand the organism, then you can replicate that in some sense in silicon."

The chip contains a number of silicon circuits that behave the same way neurons do. For now, these neurons are connected together and integrated into motors that control walking in robots. Iguana Robotics, Inc. president M. Anthony Lewis is collaborating on this part of the project. The researchers will continue to study lamprey eels until they have enough detail to make a good model of its neurons on the silicon chip.

The next step in the process will be to implant the chip in rodents with spinal-cord injuries. Once the researchers successfully stimulate rodents' spinal cords, they can begin to test the chip in humans. If the project succeeds, they anticipate starting human testing in about 10 years. It will be used to treat people with thoracic lesions (who still have control of their upper bodies) rather than treating those with cervical lesions, the kind the late Christopher Reeve had, which are higher up on the spinal cord and thus impair more of the body.

The chip-building aspect of the project is nothing new, Etienne-Cummings says, but his research team has taken it a step further. "People have implemented silicon neurons before," he says. "The first report was back in the early 1990s. The aspect that's new is we put together networks of these neurons and create signals for locomotary control."

Some other treatments are being developed to treat spinal-cord injuries as well, and the project researchers say these varying approaches can complement each other. Functional electrostimulation involves electronic stimulators that act in lieu of the spinal cord, activating nerves so that muscles contract at the appropriate location. Stem cell-based regeneration, for which the research is still in a very early stage, attempts to regrow the actual nerve that has been cut.

Though much progress has been made, the researchers have a long way to go. The project team says they believe lamprey research indicates that other treatments, such as regeneration, will not be sufficient by themselves. Their implantable chip is intended to work with other methods.

"Lampreys automatically regenerate," Etienne-Cummings says. "If you cut their spinal cord and put it back together, it will regrow eventually. However, when you do that, 75 percent of the time their swimming will not be back to normal. That's why we think electrostimulation will have to complement regeneration to make things really work."

By Natalie Goel
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Tuesday, December 07, 2004

Spine therapy works on dogs, may help humans

Researchers have successfully tested injections of a liquid polymer to heal spinal injuries in dogs in an experiment that also offers hope for preventing human paralysis.

The liquid, called polyethylene glycol (PEG), if administered within 72 hours of serious spinal injury, was able to prevent three out of four dogs in a test group from suffering permanent spinal damage. Even when the spine was damaged to the point of paralysis, the PEG solution prevented nerve cells from rupturing irreversibly, allowing them to heal themselves.

"Nearly 75 percent of the dogs we treated with PEG were able to resume a normal life," said Richard Borgens, director of the center for Paralysis Research at Purdue University's School of Veterinary Medicine in West Lafayette, Ind., which developed the treatment. "Some healed so well that they could go on as though nothing had happened."

The polymer has been safely ingested and injected in humans as a component of other medicines, and Borgens thinks it shows great promise as a human therapy. But he cautions: "This is very promising research, but it won't be available in your hospital for some time."

The research is described in the December issue of the Journal of Neurotrauma.

When nerve cells suffer trauma, their membranes weaken and rupture. Even when the cells survive, they lose their ability to produce and carry nerve impulses along the membranes from one cell to the next.

"Worse yet, chemicals seeping out of the dying spinal cord cells send a 'suicide signal' to other nearby cells, causing a chain reaction that kills off more cells than the initial injury did," Borgens said. "Until now, the end result has been irreparable damage to the spinal cord, causing partial or complete paralysis."

PEG is able to stop this cascade of injury by repairing initial membrane damage, or by fusing two damaged cells together into a larger functional nerve cell. Significantly, the polymer is attracted only to damaged nerve cells and tissue when it's injected into the blood stream. It doesn't move into undamaged regions nearby.

About five years ago, Borgens and colleague Riyi Shi found that they could fuse hundreds to thousands of severed nerve fibers in a guinea pig spinal cord with just a two-minute PEG treatment. That put them on the path toward using the polymer as a repair agent to mend spinal nerve cells after traumatic injury.

In the new study, 19 paraplegic dogs between 2 and 8 years of age were treated with a PEG injection within 72 hours of injury in addition to getting standard veterinary therapy for spinal injury.

Standard treatment includes injection of steroids, surgical removal of any potentially damaging bone chips from the spinal area and physical rehabilitation, such as swimming. The group of 19 dogs was compared with a second group of dogs that had gotten only the standard treatment.

"This control group was taken from historical cases of dog injury that were similar to those in the 19 dogs we treated," Borgens said. "We didn't want to tell dog owners who walked in with injured dogs that their pets were not going to receive something that might help."

After treatment, the improvement was measured based on criteria including desire to move.

"More than half the dogs (in the PEG group) in this study were standing or walking within two weeks of treatment," Borgens said. "In most cases, you could notice positive signs within three to five days. These results are unprecedented in paralysis research."

According to the Centers for Disease Control and Prevention, about 11,000 Americans sustain disabling spinal cord injuries each year, mainly from car crashes and sports mishaps, and more than half of them are younger than 30.

Researchers still are not certain how the polymer works to heal cells, but they think it has to do with removing the excess water that floods into the cell after it's been damaged. And the polymer needs to be refined to a high level of purity before it's effective, a manufacturing process that will have to clear tough government standards.

Borgens also noted that there are considerable differences between dog and human spinal cords that need to be addressed before the treatment can be tried in people. "In dogs, for example, some of the control of walking actually takes place in the spine, while in humans, all of this control resides in our brains."

The researchers are working toward developing the product as an emergency drug along the lines of treatments used today for strokes and heart attacks.

By: Lee Bowman, Scripps Howard News Service
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