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Nerve signal discovery backs Nobel winner’s theory

October 13, 2012

from R&D Magazine:

Scientists have proved a 60-year-old theory about how nerve signals are sent around the body at varying speeds as electrical impulses.

Researchers tested how these signals are transmitted through nerve fibres, which enables us to move and recognise sensations such as touch and smell.

The findings from the University of Edinburgh have validated an idea first proposed by Nobel laureate Sir Andrew Huxley.

It has been known for many years that an insulating layer—known as myelin—which surrounds nerve fibres is crucial in determining how quickly these signals are sent.

This insulating myelin is interrupted at regular intervals along the nerve by gaps called nodes.

Scientists, whose work was funded by the Wellcome Trust, have now proved that the longer the distance between nodes, the quicker the nerve fibres send signals down the nerves.

The theory that the distance between these gaps might affect the speed of electrical signals was first proposed by Sir Andrew Huxley, who won the Nobel Prize in 1963 for his work on electrical signalling in the nervous system, and who died earlier this year.

The study, published in the journal Current Biology, will help provide insight into what happens in people with nerve damage. It will also shed light on how nerves develop before and after birth.

Professor Peter Brophy, Director of the University of Edinburgh’s Centre for Neuroregeneration, said: “The study gives us greater insight into how the central and peripheral nervous systems work and what happens after nerves become injured. We know that peripheral nerves have the capacity to repair, but shorter lengths of insulation around the nerve fibres after repair affect the speed with which impulses are sent around the body.”

The researchers found that when the myelin reached a certain length, the speed with which nerves impulses were conducted reached a peak.

The study, carried out in mice, also confirmed that a protein—periaxin—plays a key role in regulating the length of myelin layers around nerve fibers.

Biobank Collecting Blood Samples for Neuromuscular Disease Research

December 28, 2010

Filed under: Studies and Clinical Trials

People with genetic neuromuscular diseases who want to “do something for science” now have a way to do so, although they’re unlikely to ever know the results of their good deed.

Scientists at the National Institute of General Medical Sciences (NIGMS) Human Genetic Cell Repository at the Coriell Institute for Medical Research in Camden, N.J., are seeking blood samples from people with certain inherited neuromuscular diseases for use in research.

In particular, the biobank needs blood samples from people with muscular dystrophy, motor neuron diseases, metabolic diseases of muscle, peripheral nerve diseases, diseases of the neuromuscular junction and other myopathies. Most of the diseases covered by MDA are included in these categories.

“We try to have a broad representation in the repository of as many different genetic diseases as possible, and within diseases we try to represent as many genotypes/phenotypes as possible,” says Tara Schmidlen, a genetic counselor who coordinates the admittance of samples into the NIGMS biobank.

An exact genetic diagnosis is not required for a sample to be added to the bank, although the more clinical information that can be provided, the more useful the sample will be to researchers, Schmidlen says.

The biobank does not perform individual genetic testing and once a sample is submitted, it cannot be removed.

Numerous measures are taken to protect the privacy and anonymity of the donor, but these measures also prevent any personal information from being derived from the sample. The bank does not provide results of any kind to donors.

Rather, the anonymous samples are used by researchers around the world who use cell lines and DNA to discover new disease-causing genes; study known genes and their expression; and devise new genetic tests.

Samples from the NIGMS biobank, the world’s largest, have been used in more than 5,000 scientific publications and by scientists in more than 50 countries, the organization says.

Participation requires a blood or tissue sample, as well as a completed consent form, a submission form, and a clinical information summary form.

The Coriell Institute for Medical Research mails participants a collection kit and pays for the cost of shipping the sample, but not the costs associated with collecting it.

Volunteer with Dejerine-Sottas to help evaluate business accessibility (Chelsea, Michigan)

September 16, 2010

Filed under: People

Ashley Wiseman didn’t intend on making handicap accessibility in Chelsea’s downtown district her mission.

It just ended up that way.

Earlier this year on the Chelsea native’s 21st birthday, Wiseman wanted to celebrate at Cleary’s Pub because she thinks it has the best atmosphere and food in town.

But there was one problem: Wiseman suffers from a rare neurological disease that has bound her to a power wheelchair, and Cleary’s, like many businesses in Chelsea, is not wheelchair accessible.

“Cleary’s is totally inaccessible to me,” Wiseman said, explaining that while a manual wheel chair user would have less trouble getting into Cleary’s, she would need a portable unfolding step to make it inside from the front entrance.

Cleary’s owner Pat Cleary and other business owners seem more than eager to work with Wiseman and the Downtown Development Authority’s accessibility subcommittee led by Paul Frisinger, who is also Wiseman’s grandfather.

“When we found that Cleary’s only had a five inch step (Ashley and I) began talking about accessibility, and thought that maybe the DDA could help,” Frisinger said.

The committee has had a couple of preliminary meetings and is hosting presenter Carolyn Grawy, director of the Ann Arbor Center for Independent Living, at the Chelsea District Library at 8 a.m. Sept. 17.

Frisinger said the public is welcome to come and participate in addressing the task of making Chelsea a more “accessible friendly community.”

The subcommittee intends to discuss ways to mitigate construction costs, assist in planning and aid in securing grants and lower interest financing to pay for the architectural improvements that will be necessary to make the downtown more accessible to visitors with special needs.

Chelsea’s downtown has already seen improvements to sidewalks and the removal of old electrical wires that were out in the open on Main Street. Future redesigns of the downtown could include significant ramping as a result of the subcommittee’s study.

Frisinger said the timing is perfect with initiatives like Think Chelsea First and other efforts promoting Chelsea around the state and across the country.

That’s why Wiseman and Shana Mote, both members of the DDA study committee on accessibility went on a “roll thru” town this summer to evaluate the state of accessibility in the downtown as it currently stands.

Wiseman said she feels privileged to be able to help out.

Born with Dejerine-Sottas syndrome, Wiseman has gradually lost mobility since birth, which has given her experience with a broad range of accessibility issues.

“I haven’t always used wheelchairs, but it got worse as I was growing up,” Wiseman said.

Those born with Dejerine-Sottas syndrome have trouble moving because of interference between the central and peripheral nervous systems. The central nervous system cannot communicate with the peripheral nervous system that extends throughout the whole body.

“As I grew up and grew taller, that interference increased, and as I’ve grown up my disability has worsened,” she said. “After my spine was fused to treat my scoliosis I couldn’t bend, so I started using a power wheelchair on a full-time basis.

“Before that I was able to get out of my manual wheelchair and conquer that one step at Cleary’s. But you can’t easily lift a power wheelchair like you can a manual one.”

Any business with a step out front is a literal roadblock to Wiseman and others.

During the “roll thru,” Wiseman said that she was pleased to find that many businesses have back entrances often accessible through alleyways, but she said that one of the committee’s goals should be to make those paths friendlier.

Despite many businesses having some accessible entrances, there are two problems that Wiseman noted: the first is that they’re hidden and rarely indicated with signage and secondly they are not given the same aesthetic consideration as the storefronts facing major traffic on Main Street.

“A lot of them require you to go through an alleyway where the businesses keep their trash and the walls aren’t as well kept,” Wiseman said. “It also presents an issue of dignity and safety. It just doesn’t feel very nice using this alternative entrance that no one puts as much care into. And quite frankly at night it doesn’t necessarily feel comfortable going into an alley that isn’t very well lit.”

Another concern is whether or not there is someone who can help open the door. Wiseman has a helper dog, but sometimes she still needs assistance.

Signage, better lighting, general improvements like plantings and even art murals and other amenities similar to those in the alleyway near the Pottery Shed and Pierce’s Pastries would go a long way to making Wiseman and others feel better about Chelsea’s accessibility.

“If we can give those businesses that do have rear accessible entryways the resources to improve them, I think the will is there to do so,” Wiseman said. “Ideally I would like to see people with not just disabilities use the alleyway. Able-bodied people could have their pick.

“I’ve talked to women about strollers and how they can be a real pain getting into some of these places.”

She also said that the committee would be brainstorming on how to help businesses like Cleary’s, which do not have a rear or alley entrance.

Frisinger said the committee has a lot of work ahead of it due to the historical designation that blankets much of Chelsea’s downtown district.

Historical districts are not subject to the same Americans with Disabilities Association guidelines that businesses outside of such boundaries are subject to.

The Chelsea business community’s participation will be voluntary and based on willingness stemming from good will and a common interest to bring more people to downtown busi-nesses.

Wiseman, who works with the Ann Arbor Center for Independent Living, said she has seen accessibility draw customers to businesses in town.

Frisinger pointed out that Chelsea also has a large senior population due to the Chelsea Community Hospital and various senior living facilities in town.

“The number of people locally who accessibility is a concern for or is going to be a concern for in coming years is growing as well as tourism,” Frisinger said.

Stanford study first to show antibodies involved in nerve repair in injuries

June 15, 2010

Filed under: Uncategorized

In a new study conducted in mice, to be published online June 14 in Proceedings of the National Academy of Sciences, the Stanford scientists show for the first time that antibodies are critical to the repair of nerve damage to the peripheral nervous system — nervous tissue that extends outside the brain and spinal cord, such as the sciatic nerve, where circulating antibodies have access. The study also shows that some, but not all, antibodies get the job done. Harnessing those proteins’ unanticipated nurturing qualities may lead to new ways of repairing damage from stroke or spinal-cord injury, as well.

“Nobody has known why, but nerve cells in the central nervous system fail to regenerate after injury whereas those in the peripheral nervous system regenerate robustly,” said senior study author Ben Barres, MD, PhD, professor and chair of neurobiology. So his group was intrigued by one major difference between the two nervous systems: Antibodies, which are large bulky proteins, have limited access to the brain and spinal cord (these organs are surrounded by an interface called the blood-brain barrier or, in the spinal cord, the blood-spinal cord barrier), while they have ready access to the peripheral nervous system.

Nerve cells convey electrochemical impulses over long distances by means of long, tubular projections called axons. These axons are typically wrapped in an insulating layer of a fatty substance called myelin.

“After nerve injury, the degenerating myelin downstream from the injury is rapidly cleared in the peripheral, but not the central, nervous system,” said Barres. “In fact in an injured human brain or spinal cord, the degenerating myelin just sits there for the rest of the person’s lifetime. But after injury to, say, the sciatic nerve, the degenerating myelin is cleared within a week or less.”

The two first authors, Mauricio Vargas, MD, PhD, a former student in Barres’ lab, and Junryo Watanabe, PhD, a postdoctoral researcher in the lab, wondered whether antibodies to components of degenerating myelin might play a role in that clearance. The researchers obtained mutant laboratory mice that can’t make antibodies, and demonstrated that, in those mice, repair of injury to the sciatic nerve is substantially impeded, as is the removal of degenerating myelin downstream from the injury site. Simply injecting the injured mutant mice with antibodies from healthy, uninjured ones restored both myelin removal and sciatic-nerve repair capability in the mice.

While antibodies have been found to play a role in the disposal of aging red blood cells, this is the first time they’ve been implicated in injury repair, said Vargas, now in his internship at White Memorial Medical Center in Los Angeles pending the start of his residency in ophthalmology at UCLA.

What’s more, the investigators threw light on the way in which this happens. “We showed that antibodies grab onto degenerating myelin downstream from the site of the nerve injury, coating the myelin and tagging it for clearance by voracious immune cells called macrophages,” Vargas said.

The word macrophage roughly translates from Greek as “big eater.” These roving gourmands are especially prone to gobble up antibody-tagged bacteria and diseased cells. “It’s analogous to spreading cream cheese on a bagel,” said Vargas.

Using various standard laboratory tools, including special staining techniques, the study’s authors observed that macrophages do indeed chew up antibody-tagged degenerating myelin downstream from the nerve-injury site. Myelin clearance in the antibody-lacking mice was substantially enhanced when antibodies from healthy mice were provided.

Surprisingly, it made no difference whether the antibodies came from normal mice that had suffered similar injuries or mice that had suffered none. This suggests that the antibodies binding to degenerating myelin and flagging it for demolition by squads of macrophages are already present in uninjured mice, rather than summoned into service only after injury. These “off-the-shelf” natural antibodies save the week or two that it would have taken the body to generate the more sophisticated, precisely shaped antibodies that are produced in response to a particular viral or bacterial infection.

In an additional experiment, the Barres team injected the injured mice with a dose of an antibody that specifically targets a protein known to occur only on myelin. Doing so restored nerve-injury repair, whereas administering antibodies that bind to targets not associated with myelin didn’t help. This proved that not just any antibodies, but rather antibodies that associate with degenerating myelin, are the ones that expedite nerve repair in the peripheral nervous system.

It wouldn’t be helpful if naturally occurring antibodies were unable to distinguish between working and worthless myelin — this could result in debilitating autoimmune disease. But, Barres said, degenerating myelin has structural features on its surface that are quite different from those exposed to the immune system on the surface of functioning myelin.

Although these findings all involve the peripheral nervous system, they offer a tantalizing hint as to a possible way to instigate repair to damaged nerve cells in the central nervous system after, say, a stroke or spinal cord injury. “One idea,” said Barres, “would be to bypass the blood-brain barrier by delivering anti-degenerating-myelin proteins directly into the spinal fluid. We’re hoping that these antibodies might then coat the myelin, signaling to microglia — macrophages’ counterparts in the central nervous system — to clear the degenerating myelin.” That might, in turn, jump-start the regeneration of damaged nervous tissue, he added.

“This is really important, elegant work,” said Zhigang He, PhD, associate professor of neurology at Harvard Medical School whose lab focuses on the intrinsic regenerative ability of nervous tissue and who did not participate in the study but is familiar with it. “Everybody’s trying to understand what accounts for the difference between the capacities for repair in the peripheral versus the central nervous system. Now we have a possible mechanism, so we can start to think about some kind of strategy to speed up myelin clearance in the brain.”

Provided by Stanford University Medical Center

Neurologists Come Together to Tackle Charcot-Marie-Tooth

June 13, 2010

(From the University of Rochester Medical Center.)
Neurologists around the nation are working together in a nationwide study focusing on Charcot-Marie-Tooth disease, a painful nerve condition that affects more than 100,000 Americans. The team and its Inherited Neuropathies Consortium is supported with $6.25 million through the National Institutes of Health Rare Diseases Clinical Research Network for the next five years.

CMT is one of the most common genetic nerve disorders and is the most common inherited form of neuropathy, but there is no effective treatment.

“This disease can really have a severe impact on a person’s health, yet there just isn’t as much awareness about it as there is for some other conditions,” said neurologist David Herrmann, MBBCh, associate professor in the Department of Neurology at the University of Rochester Medical Center and the lead investigator for the CMT Research Network in Rochester. “Nevertheless, Charcot-Marie-Tooth can be devastating for patients.”

The project, which is based at Wayne State University, brings together experts who are learning more about the disease and searching for new treatments. Herrmann and colleagues are part of a group compiling a database of people in North America who have CMT and who have volunteered to make their information available to researchers. The team is also working to pinpoint more precisely the different genes at work in the disease and how each affects the health of patients; scientists are aware of more than three dozen gene mutations that can cause CMT.

Currently Herrmann and colleagues from Wayne State University and Johns Hopkins are conducting a study in 110 people measuring the effectiveness of high doses of Vitamin C for treating CMT. With the new funding, the expanded team plans to conduct a new study aimed at testing a potential treatment.

In late 2008 neurologists created the first diagnostic guidelines for neuropathy. Herrmann himself is also an expert in the use of skin biopsy to identify sensory neuropathies like CMT and track their progression. He is currently developing a new non-invasive technique that uses a specialized microscope to look beneath the skin to gauge the condition of a person’s nerves in the fingers, as a way to possibly eliminate the need for a biopsy in some patients.

Variety appeal to set Chantelle Lawrence free

June 4, 2010

Filed under: People — Tags: ,

Chantelle Lawrence

Chantelle Lawrence is hoping the Variety appeal will help finance her electronic wheelchair so that she can get around unassisted.


by Josephine Gillespie for The Queensland Times

At only 13, Chantelle Lawrence has already seen the inside of more hospitals than most people will in a lifetime.

Born with a rare progressive neuromuscular condition known as Dejerine-Sottas Syndrome, Chantelle has endured 10 operations, including two hip reconstructions.

The West Moreton Anglican School year nine student is among the local children who Variety Queensland hopes to assist as part of its Variety Friday Radio Appeal on River 94.9 on Friday, June 11.

Mother Kerri said her daughter has inherited the condition from her father Raymond, who through a spontaneous gene mutation was diagnosed with the same condition close to 30 years ago.

Mrs Peters said while the family had received assistance to purchase an electric wheelchair through the Medical Aids Subsidy Scheme, they still faced a gap payment of more than $700.

The Brassall resident said the family also recently had to modify their home to better accommodate their daughter’s needs.

“We have renovated the bathroom and still have to do the kitchen,” Mrs Peters said.

“It is all ongoing costs.

“Raymond had to have his hip done last year and I had heart problems.

“It all mounts up and it can be difficult.”

Mrs Peters said monetary assistance through the appeal would mean her daughter could enjoy the freedom others took for granted, such as going to class on her own unassisted.

The Queensland Times general manager Steve Portas said the QT was fully supportive of the Variety Friday Appeal.

The children’s charity supports sick, disabled and disadvantaged children.

Variety Queensland has received more than $60,000 worth of requests for support in the region.

“The Variety appeal provides assistance to quite a number of needy Ipswich families and it is a great feeling to be able to make a difference to somebody’s life,” he said.

For more information about making a donation or hosting a Variety Friday event at your school or workplace in support of local kids, phone Variety Queensland on 3367 6999 or log on to www.varietyqld.org.au.

Girl with Dejerine-Sottas receives Children of Courage award

June 1, 2010

Filed under: People — Tags: ,

From the Macedon Ranges Leader, by Barry Kennedy:

Amber Jepsen

Amber Jepsen was one of 10 children to receive a Lions Club Children of Courage award

CARLSRUHE’S Amber Jepsen has a growing set of hobbies including horse riding, playing the keyboard, card games, drawing, painting and writing.

The seven-year-old is confident she will be a famous author and knows the full dimensions of her parent’s farm because she loves taking her dog for a walk in her electric wheelchair.

Amber’s many passions come despite some crippling setbacks caused by Charcot Marie Tooth disease of which she has an even rarer strand, Dejerine Sottas.

The neurological disorder affects signals from the brain to the spine and muscles making joints and muscles loose and fragile.

The disorder has prompted a range of physical impairments and health scares with hip and ankle surgery as well as having her spine stapled.

Amber’s mother Shelley said her daughter has no concept she even has a problem.

“She has lots of friends at Newham Primary School and at home she just hangs off everything as she criss-crosses the house,” she said.

Mrs Jepsen said the family knew the Royal Children’s Hospital too well especially as her health issues spanned many specialists.

Amber’s plucky attitude was last month honoured in the Lions Club Children of Courage award under the special needs category for children who have endured lengthy periods in hospital or with pain and trauma.

Chairperson of the awards Julie Starec said all of the nominees, aged between five and 15 had attempted to overcome their obstacles and improve the quality of their lives.

Ten children were nominated this year for the region incorporating the Macedon Ranges, Melton, Sunbury and Castlemaine including Ingrid Gersbeck from Clarkefield, 8 and Shae Benfell, 5, from Riddells Creek.

Sunburys Sophie Geytenbeek,12, also received an award for her strength suffering congenital heart disease. Molly Clohessy, 9, was awarded for her resilience in treatment for Dravet Syndrome. Patty Carlyon, 13, was awarded for an inspirational battle with leukaemia and Bulla’s Nathan Smith, 14, was awarded for his achievement over coming asthma to compete at a national level in swimming.

Why medical discoveries don’t become cures

May 16, 2010

Desperately Seeking Cures
How the road from promising scientific breakthrough to real-world remedy has become all but a dead end.

By Sharon Begley and Mary Carmichael | NEWSWEEK
Published May 14, 2010
From the magazine issue dated May 31, 2010

From 1996 to 1999, the U.S. food and Drug Administration approved 157 new drugs. In the comparable period a decade later—that is, from 2006 to 2009—the agency approved 74. Not among them were any cures, or even meaningfully effective treatments, for Alzheimer’s disease, lung or pancreatic cancer, Parkinson’s disease, Huntington’s disease, or a host of other afflictions that destroy lives.

Also not among the new drugs approved was A5G27, or whatever more mellifluous name a drug company might give it. In 2004 Hynda Kleinman and her colleagues at the National Institutes of Health discovered that this molecule, called a peptide, blocks the metastasis of melanoma to the lungs and other organs, at least in lab animals. The peptide also blocks angiogenesis, the creation of blood vessels that sustain metastatic tumors, they reported six years ago in the journal Cancer Research. Unfortunately, A5G27 has not been developed beyond that discovery. Kleinman was working at NIH’s dental-research institute, and, she says, “there was not a lot of support for work in cancer there at the time. They weren’t interested.” She did not have the expertise to develop the peptide herself. “I continued doing cancer research on it, but I couldn’t take it to the next level because I’m not a cancer specialist,” she says. “I was trained as a chemist.”

No one is saying A5G27 would have cured metastatic cancers, which account for some 90 percent of all cancer deaths; the chance of FDA approval for a newly discovered molecule, targeting a newly discovered disease mechanism, is a dismal 0.6 percent. Diseases are complicated, and nature fights every human attempt to mess with what she has wrought. But frustration is growing with how few seemingly promising discoveries in basic biomedical science lead to something that helps patients, especially in what is supposed to be a golden age of genetics, neuroscience, and biomedical research in general.

From 1998 to 2003, the budget of the NIH—which supports such research at universities and medical centers as well as within its own labs in Bethesda, Md.—doubled, to $27 billion, and is now $31 billion. There is very little downside, for a president or Congress, in appeasing patient-advocacy groups as well as voters by supporting biomedical research. But judging by the only criterion that matters to patients and taxpayers—not how many interesting discoveries about cells or genes or synapses have been made, but how many treatments for diseases the money has bought—the return on investment to the American taxpayer has been approximately as satisfying as the AIG bailout. “Basic research is healthy in America,” says John Adler, a Stanford University professor who invented the CyberKnife, a robotic device that treats cancer with precise, high doses of radiation. “But patients aren’t benefiting. Our understanding of diseases is greater than ever. But academics think, ‘We had three papers in Science or Nature, so that must have been [NIH] money well spent.’?”

More and more policymakers and patients are therefore asking, where are the cures? The answer is that potential cures, or at least treatments, are stuck in the chasm between a scientific discovery and the doctor’s office: what’s been called the valley of death.

The barriers to exploiting fundamental discoveries begin with science labs themselves. In academia and the NIH, the system of honors, grants, and tenure rewards basic discoveries (a gene for Parkinson’s! a molecule that halts metastasis!), not the grunt work that turns such breakthroughs into drugs. “Colleagues tell me they’re very successful getting NIH grants because their experiments are elegant and likely to yield fundamental discoveries, even if they have no prospect of producing something that helps human diseases,” says cancer biologist Raymond Hohl of the University of Iowa. In 2000, for instance, scientists at four separate labs discovered a gene called ABCC6, which, when mutated, causes PXE (pseudoxanthoma elasticum), a rare genetic disease in which the skin, eyes, heart, and other soft tissue become calcified—rock hard. By 2005, scientists had genetically engineered lab mice to develop the disease. The next step would be what’s called screening, in which scientists would laboriously test one molecule after another to see which had any effect on ABCC6. But “academic scientists aren’t capable of creating assays [test systems] to do that,” says Sharon Terry, CEO of the Genetic Alliance, which supports research on rare genetic diseases (her children have PXE). “It’s time-consuming drudgery and takes an expertise that hasn’t trickled down to the typical academic scientist.” Ten years later, there is still no cure for PXE.

Should a lab be so fortunate as to discover a molecule that cures a disease in a lab rat, the next step is to test its toxicity and efficacy in more lab animals. Without that, no company—for companies, not academic scientists, actually develop drugs—will consider buying the rights to it. “A company wants to know, how specific and toxic is the molecule?” says Kenneth Chahine, an expert in patent law at the University of Utah. “It might work great in a mouse, but will it make a rat keel over? Doing this less fun research is not something an academic lab is interested in. The incentive driving academic labs is grants for creative, innovative research, and you’re not going to get one to learn how much of a compound kills a rat.”

How this culture works against finding treatments can be seen in Huntington’s disease, a single-gene, fatal illness. “We have something like 300 targets [genes, pathways, and other mechanisms thought to cause the disease] and almost as many theories,” says an official at a disease foundation, who asked not to be identified so as not to anger scientists he has to work with. “The way science careers are structured, big labs get established based on a theory or a target or a mechanism, and the last thing they want to do is disprove it and give up what they’re working on. That’s why we have so many targets. We’d like people to work on moving them from a ‘maybe’ to a ‘no,’ but it’s bad for careers to rule things out: that kind of study tends not to get published, so doing that doesn’t advance people’s careers.”

For scientists who are willing to push past these obstacles, the next one is the patent system. When Robert Sackstein was a bone-marrow-transplant surgeon in the 1980s, he noticed that fewer than 5 percent of the transplanted blood stem cells reached their target in a patient’s marrow. He therefore decided to study how cells navigate, what beacons they follow. A decade-long search led to the discovery of a molecule on the surface of blood stem cells that turns out to be the master molecule used by those cells to home in on any site in the body.

Sackstein named the molecule HCELL. If stem cells were tagged with HCELL, he thought, they would make a beeline for the correct tissue—say, to regenerate bones in patients with osteoporosis. In 2008 he and colleagues announced in a paper in Nature Medicine that they had managed to do just that: when he injected human bone-forming stem cells tagged with HCELL into mice, the cells headed for the mice’s bones and began forming human bone there. HCELL-tagged stem cells, in other words, could be the long-sought cure for osteoporosis, as well as other diseases that might be treatable with stem cells.

But because Sackstein had described HCELL in a scientific paper, the U.S. patent office told him it was rejecting his application. Ten years of appeals have cost hundreds of thousands of dollars in attorney fees. Sackstein fervently believes his discovery deserves a patent, and it was granted one in Europe and Japan. “You have to persevere,” he says. “I can’t let it go, because I think the impact on patients could be so great. We’ve cured osteoporosis in mice.” But without patent protection, no company will develop HCELL for people, even in Europe or Japan. For a multinational drug company to go forward, it needs patent protection in the U.S. as well.

If a discovery is patented, the next step is for the university or NIH technology licensing office to find a commercial partner to develop its professors’ discoveries. (The institution where a scientist works, not the scientist herself, owns the intellectual-property rights to discoveries, and thus the exclusive right to license it.) Licensing typically involves upfront fees, plus a promised share of royalties should the molecule become a commercial drug. One biotech startup in the Midwest has been trying for three years to license a discovery made when some of its founders worked at the NIH. Vascular surgeon Jeffrey Isenberg, now at the University of Pittsburgh Medical Center, and colleagues were studying how the gas nitric oxide promotes blood flow. They discovered a pathway that inhibits nitric oxide and thus impedes blood flow. By blocking the blocker—to football fans, adding an extra guard to your offensive line—the scientists got nitric oxide to open blood vessels again and increase blood flow, at least in lab animals. The molecule that works this magic is a protein called thrombospondin-1, or TSP1, suggesting that this particular offensive guard might be a potent drug for saving heart-attack victims; restoring blood flow in patients with severe diabetes, in which impaired blood flow leads to gangrene; and treating hypertension.

Unfortunately, attempts to negotiate the rights to develop this discovery were Kafkaesque. NIH’s licensing office demanded payments that the startup—which, unlike the Pfizers of the world, has zero revenue—couldn’t make. “NIH has no skin in the game, so they have no inducement to work with a company” to get a discovery from the lab to patients, says Eric Gulve, president of BioGenerator, a nonprofit in St. Louis that advises and provides seed money for biotech startups. “There isn’t a sense of urgency.” A top lab chief at the NIH laments that when scientists like himself push the licensing office to move a discovery toward commercialization, “it’s just another piece of paper to them.” Without the license, the startup struggles to stay alive. In its defense, Mark Rohrbaugh, the director of NIH’s technology-transfer office, notes that it licensed 215 discoveries last year (though that is down from the 2004–2008 average of 273 a year, with a high of 313 in 2005). “I think we do incredibly well accommodating the needs of a company,” says Rohrbaugh. “We have even linked milestone payments [made when a company achieves a goal such as starting a clinical trial] to a company raising money. The last thing we want to do is slow down the science.”

If a discovery is licensed, the licensee then has to raise enough money to test the compound’s toxicity (does it kill the lab rats? give them seizures?), to figure out how to make it in quantity and with uniform quality, to test the drug in larger lab animals such as dogs, and then to test it in people. Because large drug companies have been merging and retrenching (the industry laid off 90,000 people last year) and have become more interested in buying early-stage research than in doing it themselves, this role has been falling to biotech firms, which are smaller and poorer. It is at this step—turning a discovery into something that can be manufactured and that is safe and effective—that the valley of death has gotten dramatically more fatal over the last few years. “NIH grants don’t support the kind of research needed to turn a discovery into a drug,” says Gulve, so the money has to come from elsewhere. Traditionally, that has been venture capital. But “over the last four or five years VC funding for early-stage drug discovery has decreased dramatically,” says Utah’s Chahine. “You used to be able to go public, raising millions of dollars, based on a couple of genes in a rat. Now you can’t even get a venture capitalist’s business card for that.”

Instead, VCs—essentially the only source of money to move preliminary discoveries forward—are demanding that startups prove themselves far more than in the past. Francis “Duke” Creighton had a eureka moment a few years ago: use magnets to amplify the effects of drugs that dissolve stroke-causing clots. He founded Pulse Therapeutics to develop the discovery, in which tiny magnetic particles would be mixed with a clot-busting drug, and a magnet would be used to get more of the drug to its target. He had enough money to do experiments for six months in vitro, “then we ran out,” says Creighton. “Venture-capital firms said, ‘Show me animal data and we’ll talk,’ but running animal experiments would cost $300,000 at the least.” No money, no animal studies; no animal studies, no money. BioGenerator helped Creighton raise $100,000, but he’s still short of what he needs.

Human testing is even more expensive—tens of millions of dollars—so commercial calculations stalk the decision like Banquo’s ghost. Research funded by the Multiple Myeloma Re–search Foundation at a small biotech led to a promising new drug for multiple myeloma, a cancer of plasma cells in bones. But the firm was bought by a large drug company that decided against testing the drug in that cancer, calculating that the payoff would be greater if it could be shown to work against the big four (breast, lung, prostate, colon) or leukemias. “It’s our feeling that if it had been tested in myeloma only, it would have moved faster,” says Louise Perkins, chief scientific officer of the foundation.

If we are serious about rescuing potential new drugs from the valley of death, then academia, the NIH, and disease foundations will have to change how they operate. That is happening, albeit slowly. Private foundations such as the MMRF, the Michael J. Fox Foundation for Parkinson’s Research, and the Myelin Repair Foundation (for multiple sclerosis) have veered away from the NIH model of “here’s some money; go discover something.” Instead, they are managing and directing scientists more closely, requiring them to share data before it is published, cooperate, and do the nonsexy development work required after a discovery is made.

For instance, the Chordoma Foundation, which supports research into that rare cancer, found that there was only one decent chordoma cell line in the whole world—in a freezer in Germany—and it hadn’t been used for new research since 2001. The foundation obtained the legal rights to it and distributed it to some two dozen researchers, jump-starting studies that otherwise would never have been done. The cell line is being used to, among other things, screen existing drugs to see if they might work against chordoma.

Forcing that kind of cooperation among turf-jealous academics could break a lot of logjams. “There are thousands of researchers working on exactly the same thing,” says Bruce Bloom, whose Partnership for Cures foundation supports research on new uses for existing drugs. “Under the current system they cannot and will not collaborate for fear that it will jeopardize funding, patent protection, and publication. Look at the progress open-source software has made in IT. Imagine the progress open-source research could make in biomedicine.”

Perhaps the greatest sea change is that “more academics are starting to ask, ‘How can I get funding to turn this discovery into something?’ so universities are encouraging the creation of drug-development groups,” says Jeff Ives, president of Satori Pharmaceuticals, a biotech in Cambridge, Mass., that is searching for Alzheimer’s drugs. “The ivory-tower separation from the real world isn’t acceptable anymore.”

Stanford Medical School realized that. Although the NIH has increased support for research intended to help patients, points out Daria Mochly-Rosen of Stanford, there is still very little funding for steps such as testing a compound’s toxicity in several species of lab animals, synthesizing the molecule, and scaling up that synthesis. “What we lack in academia is an understanding that these steps can be intellectually interesting, too,” says Mochly-Rosen. To foster that, she founded Spark four years ago. It scrutinizes discoveries from Stanford scientists that have not been licensed to a company and, with industry input, identifies 20 per year that have promise. The inventor is taught the basics of drug development and gets funding support to carry out the “drudgery.”

In perhaps the clearest sign that patience among even the staunchest supporters of biomedical research is running thin, the health-care-reform bill that became law in March includes a Cures Acceleration Network that Sen. Arlen Specter, a longtime supporter of biomedical research, sponsored. Located at the NIH, the network would give grants ($500 million is authorized this year) to biotech companies, academic researchers, and advocacy groups to help promising discoveries cross the valley of death. It may or may not make a difference. But something had better, and soon.

Find this article at http://www.newsweek.com/id/238078
© 2010

Cellular characterization of MPZ mutations presenting with diverse clinical phenotypes.

J Neurol. 2010 May 12
Lee YC, Lin KP, Chang MH, Liao YC, Tsai CP, Liao KK, Soong BW.

Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.

Abstract
Mutations in MPZ, which encodes myelin protein zero (P(0)), may lead to different subtypes of Charcot-Marie-Tooth disease (CMT). The aim of this study was to characterize the cellular manifestations of various MPZ mutations associated with CMT1, Dejerine-Sottas syndrome (DSS) and CMT2, and to correlate their cellular and clinical phenotypes.

Nine P(0) mutants associated with CMT1 (P(0)S63F, R98H, R277S, and S233fs), DSS (P(0) I30T and R98C), and CMT2 (P(0)S44F, D75V, and T124M), were investigated. Wild-type and mutant P(0) fused with fluorescent proteins were expressed in vitro to monitor their intracellular localization.

An adhesiveness assay was used to evaluate the adhesiveness of the transfected cells. Protein localization and cell adhesiveness of each mutant protein were compared and correlated with their clinical phenotypes.

Three different intracellular localization patterns of the mutant P(0) were observed. Wild-type P(0), P(0)I30T, S44F, S63F, D75V, T124M, and R227S were mostly localized on the cell membrane, P(0)R98H, and R98C were found in the endoplasmic reticulum (ER) or Golgi apparatus, and P(0)S233fs formed aggregates within the ER.

Cells expressing mutant P(0), as compared with those expressing wild-type P(0), demonstrated variable degrees of reduction in the cell adhesiveness.

The molecular patho-mechanisms of MPZ mutations are likely very complex and the clinical phenotype must be influenced by many genetic or environmental factors.

This complexity may contribute to the highly variable clinical manifestations resulting from different MPZ mutations.

Nerves under control

May 13, 2010

Filed under: Uncategorized

The proper transmission of nerve signals along body nerves requires an insulation layer, named myelin sheath. To be efficient this sheath is designed to have a certain thickness and Swiss researchers from the ETH Zurich have now discovered that proteins Dlg1 and PTEN interact to control the myelin sheath thickness. Recently published in Science their discovery improves our understanding of Charcot-Marie-Tooth neurodegenerative diseases and open a new avenue in the potential treatment of these incurable and debilitating diseases.

A crucial factor in the transmission of nerve signals is the myelin layer – also known as the myelin sheath – which surrounds the axons. Axons are nerve cell projections through which the signals are relayed; the myelin sheath is formed by the Schwann cells in the peripheral nervous system, i.e. in the nervous system outside the brain and spinal chord. If it is too thick or too thin, the signal transmission slows down; if the myelin sheath becomes too badly damaged, it can cause diseases like Charcot-Marie-Tooth diseases. Patients suffer from an increasing weakness of the hands and feet, which gradually spreads to the arms and legs, sometimes even making them wheelchair-bound for the rest of their lives.

But which molecules regulate the thickness of the myelin sheath? Scientists at ETH Zurich from the research groups around biologists Ueli Suter and Nicolas Tricaud set about finding out. They have now published their findings in an online article in the journal Science.

The scientists didn’t have to start their search entirely from scratch, however, having already developed a mouse model for a sub-type of Charcot-Marie-Tooth disease; the model is based upon a mutation in the gene for the protein MTMR2 and leads to hypermyelination by the Schwann cells. What’s more, the researchers already knew from other studies that MTMR2 interacts with Dlg1.

In experiments conducted on cell cultures and the sciatic nerve in mice, the researchers were now able to demonstrate that Dlg1 inhibits myelin growth. For this to work, however, it needs to enlist the help of another signal protein: PTEN. Together, they ensure that the growth of the myelin sheath does not go to excess in the mouse’s development. If the brake is “released” by suppressing Dlg1 or PTEN, it results in myelin excess that not only leads to an extra-thick myelin sheath, but also to its degeneration. This process is characteristic of various diseases of the peripheral nervous system and , as it was revealed in the mouse model of Charcot-Marie-Tooth disease the Dlg-PTEN brake no longer works in these diseases. Nicolas Tricaud is convinced that the project helps to understand the basic molecular mechanisms of myelination, as well as offering new opportunities to define how the misdirection of these processes can cause neurodegenerative diseases and how this might be remedied.

More information: Cotter L, Ozçelik M, Jacob C, Pereira JA, Locher V, Baumann R, Relvas JB, Suter U, Tricaud N.: Dlg1-PTEN Interaction Regulates Myelin Thickness to Prevent Damaging Peripheral Nerve Overmyelination. Science. 2010 May 6. [Epub ahead of print] DOI:10.1126/science.1187735

Provided by ETH Zurich

“Nerves under control.” May 12th, 2010. www.physorg.com/news192908075.html

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