Monday, July 25, 2005

Nerve Damage Repair Agent Hope

Scientists say they have discovered a protein that could be injected to repair damaged nerves and brain cells.

The protein, KDI tripeptide, works by blocking the harmful effects of a substance present in degenerative brain diseases and spinal cord injuries.

By blocking this substance, called glutamate, KDI prevents permanent cell death and helps the body heal itself.

The Finnish work from the University of Helsinki will be published online by the Journal of Neuroscience Research.

Human trials

So far the researchers have tested KDI in the lab on animals and nerve cells from humans.

The findings have been promising and they hope to be able to begin treating people with nerve and degenerative brain diseases, such as Alzheimer's and Parkinson's disease, using KDI injections within a year.

Since KDI occurs naturally in some form in the body, researchers do not believe it will have major toxic side effects. None have been noted during their work to date.

Lead researcher Dr Päivi Liesi said: "We have had such good results with animals that I think it is totally feasible we would be ready to start human clinical trials within a year."

Currently, KDI has to be injected as a solution directly to the damaged area.

However, in the future it might be possible to make the treatment as an oral drug or an intravenous injection, said Dr Liesi.

Future promise

Her work builds on that of Dr George Martin from the National Institute on Ageing, at the US National Institutes of Health, who first discovered the molecule that KDI is derived from.

Dr Martin said: "This represents a new approach and one with considerable promise.

"When you look at the potential for preventing spinal cord injury progressing to total lack of physical control, to the fact that people could regenerate and regain their lives, this could be enormously important."

Dr Hugh Pearson, from the Alzheimer's Research Trust and the School of Biomedical Sciences at Leeds University, said: "This is an interesting study, though while the peptide has some significance for Alzheimer's disease treatment, it would be in slowing the mental decline associated with the disease. It does not represent a cure.

Side effects

"KDI will not generate new neurons but will increase the connections between the remaining neurons in the patient's brain.

"There is some evidence that this can improve cognition in Alzheimer's disease patients."

He said there might be problems with delivery of KDI - the tripeptide would be broken down by the body if given orally or intravenously.

Although the researchers do not expect side effects, he said the peptide could upset the balance of electrical activity in neurons and this might have some short to long term side effects.

"While there are some benefits, this approach is perhaps more significant for spinal cord repair than for Alzheimer's disease, where neurite outgrowth and reconnection of nerve cells with their target will provide long-lasting repair of damage."
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Sunday, July 17, 2005

Stem Cell Research May Be Money Game

After the back-to-back cloning breakthroughs by Seoul National University professor Hwang Woo-suk, Koreans may look at stem cell research as divine work to help hopeless patients.

Experts here argue, however, that the reality might be different because stem cell research is already associated with that most secular of causes - money.

Studies on stem cells fall into two fields: embryonic and adult stem cell experiments, and Korea is at the forefront of both fields thanks to the nation?s top-tier scientists.

In embryonic stem cell research, Hwang is indisputably leading the best team in the world. He has stunned the world by cloning a human embryo and extracting a stem cell line from it in 2003.

The 52-year-old made further headlines in May by announcing that his team cloned 11 stem cell batches, genetically matched to patients with critical diseases or disabilities.

Hailing the breakthroughs, many scientists expected the medical feat to open the door to gene therapy, transplanting developed stem cells back into the patients with degenerative diseases such as Alzheimer?s or Parkinson?s.

But University of Ulsan professor Koo Young-mo points out that the therapeutic cloning research will only help the rich, who have the luxury of being able to pay the high fees.

He contends the cloning research will benefit a handful of millionaires because the operation requires many human eggs, which need to be extracted from women, as well as the technology to develop stem cells into specific organs and to transplant the organs into a human body.

"Let?s assume Hwang or other scientists succeed in creating a miracle cloning therapy in the future,?? Koo said. ``However, the new cure will only save the rich and not all of those suffering from devastating diseases."

He predicted that things will not change drastically, even with the development of new technologies since embryologists cannot mass produce the patient-specific stem cells.

Adult Stem Cell Therapy

Korean scientists have also pioneered studies of adult stem cells, the parent cells capable of growing into other cells and found in the grown bodies or umbilical cord blood.

In particular, Chosun University professor Song Chang-hun and Seoul Cord Bank head Han Hoon surprised the world late last year by successfully treating a female patient with a spinal cord injury via stem cells from umbilical cord blood.

Hwang Mi-soon, whose lower limbs had been paralyzed for 19 years due to a back injury, stood up from her wheelchair and took a few steps with the help of a walking frame.

Some billed the cure as a new-concept treatment for spinal cord injuries, but many are skeptical as the research was not reported to a peer-viewed journal but was announced via a press conference.

In addition, it was just a one-time success that must be replicated to gain the global recognition and to do that Song?s team prepared follow-up clinical tests and applied for government approval for the second-round tests with four spinal cord patients last December.

When the application was under review by the Korea Food Drug Administration (KFDA), the scheme fell apart because the Seoul Cord Bank refused to offer cord blood stem cells.

A doctor who joined the operation on Hwang said the Seoul Cord Bank only focuses on commercialization of the stem cell research rather than making breakthroughs that can heal the spinal cord patients.

"Late last year, Han said it will be the best option to make Hwang walk through another operation to commercialize the umbilical cord blood therapy. He seems intent merely on making money with this research without continuing more clinical tests," he said.

In fact, the Seoul Cord Bank offered stem cells to Hwang for her second therapy in April free of charge while refusing to do so for other four expected patients.

In response to the claim, Han said Chosun University is responsible for the split because it had provoked the Seoul Cord Bank by setting up its own venture start-up that provides umbilical cord blood.

But the four patients who were supposed to receive the cord blood stem cells pinned blame on Han?s side, claiming they attempted to receive money for providing the cells.

"In March, an official of a fund affiliated with the Seoul Cord Bank made a call and asked me to pay 16 million won ($15,000) for stem cells. I protested, and received a cold response," said one of the four patients, who wanted to be identified by his surname Ok.

When contacted, the fund acknowledged that one of its officials placed the call. But it said the call was the official?s mistake because she just tried to notify patients of the exact stem cell price without knowing they were subjects of clinical tests. Subjects of clinical tests don?t have to pay for stem cells.

However, Ok countered that the official knew everything about the stem cell research.

"She said the relationship between the Seoul Cord Bank and Chosun University is over, and then urged me to pay to obtain the harvested stem cells that were specifically for me," Ok said.

The Seoul Cord Bank eventually refused to provide the stem cells to patients and the four people had to find another umbilical cord blood institute, Medipost, for stem cell operations.

The KFDA gave the green light for clinical tests on the four patients last week with the Medipost cells and they are waiting for the stem cell therapy.

By: Kim Tae-gyu - The Korea Times
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Air Filters May Be Key to Human Organ Regeneration

Industrial air filters may harbor key to human organ regeneration

The rat in Sally Meiners' New Jersey lab stood on its hind legs, spied food and darted to the other end of the cage to grab the morsel. Just four days earlier, the rat had sat motionless, its spine severed and hind legs paralyzed.

The latest medical miracle? Perhaps.

In a bizarre twist, the rat appears to owe its quick recovery to the same material that Donaldson Co. Inc. of Bloomington, Ill., has been using for 25 years in the industrial air filters it makes for factories, trucks and airplanes.

Three years ago, Meiners' husband, Michigan State University molecular biologist Melvin Schindler, discovered that the tiny fibers in Donaldson's synthetic filters looked just like the natural collagen surface on which animal cells grow. And when Schindler placed a few human breast cells on the tiny fibers, they grew perfectly, rather than in the flat, misshapen way cells usually grow when placed in a glass petri dish. Soon Schindler was growing functioning, three-dimensional breast cells, stem cells and nerve cells in his lab on Donaldson's fibers.

This spring, Meiners, a spinal cord injury researcher, decided to give the fibers a try. When she inserted them in the gap in her rat's severed spine, its nerve cells grew over the fibers, connected the severed area and enabled the rat to walk again.

At least five more years of research are needed before anyone expects that the results of this lab work could be applied to humans. But the preliminary discoveries were encouraging enough to lead to a partnership with Schindler that is propelling Donaldson into the multimillion-dollar cellular science business for the first time.

Cell researchers and drug companies around the world are now studying Donaldson's synthetic filter fibers. The Mayo Clinic, National Institutes of Health and 800 university labs have snatched up samples for their own cell experiments. And scientists in China, India, Australia, Israel, South Africa and across Europe are using Donaldson's fibers to grow cell cultures.

"It's a total hoot that fibers that make (Army) tanks go through the desert and that filter air in tractors can now be used for cell research," Schindler said.

For Donaldson, the new demand for its filter material was entirely unforeseen.

"It's just by coincidence that the fine fibers do mimic the ... cellular matrix," Donaldson spokesman Rich Sheffer said. "It was on our Donaldson website as a filtration enhancer."

Donaldson created the product to go into the air filter systems it makes for Mack trucks, bulldozers, farm equipment, airplanes, factories and even Army vehicles. The fibers in the filters create a screen-like barrier that traps tiny pollutants. But Donaldson's designers also unknowingly created a replica of the "cell matrix" naturally found in animals.

An online Google search is responsible for bringing Donaldson's fibers to Schindler's attention.

Long frustrated with how poorly mammalian cells grow on glass petri dishes, Schindler wondered if they might grow better on synthetic "nanofibers" that mimic what is naturally found in the body. Schindler hit the Internet to do more research. What he found surprised him.

"I came to the (Donaldson) website and said, 'Oh, my God, this must be a Google mistake.' There was an article about air filters showing nanofibers, but not for bioscience (use)," Schindler said.

Unlike plant cells, mammalian cells need a realistic structure to grow on, one that mimics the body. One look at what his Google search turned up sent Schindler reaching for the phone and Donaldson's number.

When Schindler put a human breast cell on the Donaldson fibers for the first time, his microscope not only revealed that it had attached to the fibers and grown round and plump, just like it would in the body, but the cell even grew a hole in the middle, as normal milk-duct cells do.

It was "extremely dramatic," Schindler recalled. "Right away I saw the difference, and that was striking."

Schindler ultimately convinced Donaldson sales manager Tim Grafe that he wasn't crazy or pulling a prank with this talk of filter material giving cells a new lease on life. They signed a confidentially agreement in 2003 that led to this year's breakthrough into a new market for Donaldson.

Donaldson's new division, which began operations last month, sells its flat fiber wafers for $70 a pack. Sales will be less than $1 million this year, but they should go higher as the company builds its profile in what is estimated to be an annual $100 million university research market and a $500 million pharmaceutical lab market, Grafe said.

Dr. Scott Nyberg, a Mayo Clinic liver transplant surgeon who has been trying to develop an artificial liver made of pig or rat liver cells, got his first sample of Donaldson's nanofibers two months ago.

He placed liver cells from a healthy rat on the wafer and waited for the cells to start the usual bizarre mutations that had occurred in previous experiments. Instead, the cells kept their normal function and shape.

"It's exciting," Nyberg said. "It's still early along to know for sure if it's going to replace the (expensive) biological products that are out there ... but I think this could make a huge difference."

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Wednesday, July 13, 2005

Researchers Find Molecule that Inhibits Regrowth of Spinal Nerve Cells

A molecule that helps the body's motor nerve cells grow along proper paths during embryonic development also plays a major role in inhibiting spinal-cord neurons from regenerating after injury, researchers at UT Southwestern Medical Center have found. In cultured cells, the researchers found that a component of myelin - a substance that normally insulates and stabilizes long nerve fibers in adult vertebrates - chemically blocks the ability of nerve cells to grow through myelin that is released when the spinal cord is damaged. While other myelin components also block nerve growth, a component called ephrin-B3 inhibits such activity as well or better than that of other known blocking agents combined, UT Southwestern researchers report in an upcoming issue of the Proceedings of the National Academy of Sciences.

"I believe that to the extent that overcoming myelin-based inhibition is going to provide some sort of functional recovery for spinal cord injury patients, understanding ephrins is a major step forward," said Dr. Luis Parada, senior author on the paper and director of the Center for Developmental Biology and the Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration at UT Southwestern. A mixture of molecules and proteins, myelin insulates nerve fibers and impedes them from having contact with other nerve cells. After a spinal-cord injury, myelin is released into the tissues. Not only does myelin encourage the growth of scars - called glial scars - which physically block nerve cells from regrowing in the damaged area, but components of myelin also chemically prevent nerve cells from regrowing there as well.

Considerable research has been done in the past 10 years to identify elements in myelin that chemically inhibit the regeneration of nerve cells, Dr. Parada said. Three individual components - the molecules Nogo, MAG and OMgp - have been shown to do so in isolation. Developmental biologists at UT Southwestern have been studying how ephrin-B3 helps control how and where nerve fibers grow during early development. They previously showed that the molecule throws up "fences" that repel developing nerves and guide them along the pathways to their appropriate connections to muscles.

In 2002 Dr. Mark Henkemeyer, associate professor in the Center for Developmental Biology and of cell biology and one of the authors of the PNAS study, found that such a "fence" is erected specifically down the middle of the cortical spinal tract, which is damaged during spinal-cord injury.

In the current study, Dr. Parada and his colleagues asked: What is this molecule, whose normal function is to be repellent during embryonic development, doing in the mature system?

"To our surprise, we found that ephrin-B3, which normally is present as a 'wall' down the middle of adult spinal cords, also is found in very high levels in adult myelin," said Dr. Parada.

The researchers knew from previous work that ephrin-B3 interacts with receptors on neurons in the cortical spinal cord. So, in the lab, led by the study's lead author Dr. M. Douglas Benson, a postdoctoral research fellow, they cultured neurons together with isolated ephrin-B3 and confirmed that the molecule activated the neuron's receptors. They then cultured normal myelin together with the neurons and got the same results.

However, when they cultured neurons with myelin from which the ephrin-B3 had been removed, the receptors were not activated. The findings suggest that there is much more to be learned about myelin-based inhibition, Dr. Parada said. "We firmly believe that ephrin-B3 is an important, functional, relevant component of myelin, although there may be other elements that are left to be discovered," he said.

Dr. Parada added that several factors must be overcome before spinal-cord regeneration and recovery from injury can occur in a meaningful way for patients.

"We have to figure out how to dissolve the glial scars or impede their formation," he said. "We also need to get mature neurons to be better at growing, similar to the way they do during embryonic development. And finally, we have to remove myelin-based inhibition. If and when we achieve those three things, then we'll have robust regeneration of injured nerves."

Other Center for Developmental Biology researchers involved with the study were Dr. Mark Lush, postdoctoral research fellow, and Dr. Q. Richard Lu, assistant professor. Dr. Mario Romero, assistant professor of neurology, also contributed.

The research was supported by the National Institute of Neurological Disorders and Stroke and the Christopher Reeve Paralysis Foundation Consortium on Spinal Cord Injury.
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