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They say method may end ethical debate, save lives

By Bill Scanlon, Rocky Mountain News
June 7, 2007

Scientists hailed a breakthrough in stem cell research that they said Wednesday could end the ethical debate over research involving embryos while saving thousands of lives.
The new technique turns mature cells into primitive cells, the type that are able to be coaxed -into any kind of specialized cell to fight maladies such as Alzheimer's and Parkinson's disease. And the technique does so without involving the embryo, so it has a better chance of withstanding criticism from groups who equate embryonic stem cell research to abortion.

"This is fantastic," University of Colorado researcher Chris Hogan said about techniques that reversed development in adult mice cells, bringing them back to the stem cell state, where they could be coaxed into being any kind of cell.

The research is reported in today's issue of the British science journal Nature.

"I would be quite surprised if this didn't work as well in human cells, because it is really quite simple," Hogan said.

And that would be the golden apple researchers have been looking for.

It would mean that a person with a brain disease could donate some of his own skin cells, which then would be coaxed into any type of cell to treat the illness, Hogan said.

"Now we can pick out cells that have really been reprogrammed to be embryonic stem cells. This has huge implications if we can get it to work in the human system," said one the co-authors of the new study, Kathrin Plath, a biological chemist at the University of California, Los Angeles School of Medicine.

The Bush administration has made it difficult for scientists who work with embryonic cells to get federal funding, or to even work at centers that get federal funds.

The prevailing position among the world's scientists is that stem cells from embryos are more useful for fighting disease than are adult stem cells.

But those views could change, now that three different research groups have dosed mature stem cells with four "time-machine" genes, converting them to the embryonic state in which they could become any cell in the body.

The three teams built on work by Japanese researcher Shinya Yamanaka, who developed a way to dose millions of cells with the four genes, and to sift through them to find the few that had reverted to a primitive state.

When enough of the stem cells are produced, they can be put back into the person's body to help heal a wound or restore cells that can slow diseases.

The beauty of it is that the person's body wouldn't reject the injected cells, because they have the same DNA markers as the rest of the person's body, Hogan said. No need for anti-rejection medicines.

"Three independent groups have done the same thing," said Hogan, who is confident that the easy duplication of the principle means there won't be a repeat of 2005's South Korea stem cell breakthrough that turned out to be fraudulent.

It's not time, yet, for a standing ovation, scientists say.

For example, will the process work as well in humans as it seems to in mice? But the overwhelming reaction was enthusiastic.

"This may replace Dolly," Jeanne Loring, a researcher at the Burnham Institute in La Jolla, Calif., who wasn't involved in the studies, said, referring to the famous cloned Scottish sheep. "I'm very impressed and I don't impress easily."

By Tom Avril
INQUIRER STAFF WRITER
Posted on Wed, Jun. 13, 2007

Diseases that ravage the nervous system - Alzheimer's, Huntington's, Lou Gehrig's and so on - are marked by a toxic buildup of faulty proteins, overwhelming our cells' natural ability to take out the trash.
Today, University of Pennsylvania researchers said they had made headway with what might seem like an obvious idea: sending more cellular trash trucks to the rescue.

Through sophisticated genetic manipulation, the scientists got this trick to work for five such diseases in fruit flies, and have begun experimenting on mice. The results are reported in tomorrow's issue of the British journal Nature.

Medical research is littered with examples of potential treatment pathways that looked promising in lab animals but hit a dead end when tried in more complex human patients. Yet the new approach takes advantage of cellular machinery that is already known to exist in people, offering hope that these killer diseases might someday be attacked with a universal weapon.

At the very least, the paper's authors are helping to solve a longstanding mystery about the workings of the cell.

The machinery they exploited is called autophagy, from Greek roots that mean "self-eating." It is a process in which the cell forms bubble-like vacuoles around some of its worn-out parts. The bubbles then fuse with a cellular apparatus called the lysosome, which chops up the trash and spits it out for recycling.

Scientists have known about these vacuoles since at least the 1950s, when they were found in mice kidneys. But the process remains poorly understood. Until recently, it had received so little study that there's still no consensus on how to pronounce it.

The new paper's senior author, Penn neurogeneticist J. Paul Taylor, favors "AUTO-fay-gee." Some scientists say "aw-TOFF-uh-gee."

However you say it, the word is now the title of a new academic journal, founded in 2005 in response to a flurry of research. The discovery that autophagy might be harnessed to fight brain diseases, for example, has emerged only in the past few years, said journal editor Daniel J. Klionsky, a University of Michigan life sciences professor.

"The results are just so tantalizing," Klionsky said of ongoing research by Taylor's lab and others. "We have to continue working in this area."

In tomorrow's Nature paper, the Penn team said it had used autophagy to "rescue" fruit flies after engineering them to develop versions of these human neurodegenerative diseases.

One is a rare ailment called Kennedy's disease, which attacks neuron cells and causes muscle deterioration. Like humans with the disease, the mutant insects had difficulty getting around, said Udai Bhan Pandey, Taylor's post-doctoral fellow and the paper's lead author. The impaired behavior is evident in a lab video of flies trying to climb up a wall.

Using a subtle genetic trick, Pandey also created flies that expressed the disease only in their eyes. That way, he could tell at a glance whether they were healthy or not.

After months of carefully breeding engineered flies, the scientists identified a key gene that seems to communicate between the cell's two systems of trash disposal: autophagy and another called the proteasome.

The proteasome - a cylindrical trash compactor in the cell - is unable to digest large clumps of "misfolded" and worn-out proteins that are common in neurodegenerative disease. So the scientists boosted levels of autophagy instead, adding extra copies of the key gene to compensate.

This strategy worked in flies with the mutation for Kennedy's, Alzheimer's and three other diseases, Taylor said. It also worked for several more disorders when they applied it to individual cells in a lab dish.

"We can just shovel just about anything over to the autophagy," said Taylor, who collaborated with scientists at Duke, Stanford, the University of Maryland, the National Institutes of Health, and Novartis Institutes for Biomedical Research.

Alan E. Moses
June 14, 2007

The one major point that is always forgotten is that medical science is not an exact science. This is and will always be an ever changing science. Something new is on the horizon and as of yet unforeseen. New discoveries, ideas and thoughts are revealed on a daily basis.

The Institute of Medicine (IOM) is currently conducting a 32 million dollar study to determine the effectiveness of chealation therapy. The question is just how does this help past heart attack sufferers to avoid a relapse? How does heavy metal removal avoid future attacks or damage? Some scientist and doctors have achieved this goal and so the IOM wants to replicate the results.

Chealation therapy is the removal of heavy metals and toxins from the patient’s body. These include mercury, lead and aluminum as well as others. This will study the plausibility of the intravenous (IV) chealation method. Some doctors and scientist have found that the less intrusive footpads using natural additives may be more beneficial. This lowers stress and slows stirring of these toxins and therefore reaction. Dr. Michael Sichel of Australia may have the answer. He admits that this method may take longer but without as many adverse reactions involved.

Many of those that suffer from Lou Gehrig's Disease (ALS) have been advised to remove any dental amalgams that contain mercury. They are also instructed how to identify and avoid other toxins. Eliminating heavy metals and toxins has proven to be beneficial and achieved positive results.

Cancer patients that await chemotherapy or radiation treatments are advised to build up their immune systems before hand. This is to ensure that their system or body can handle the onslaught of these toxic substances. Vitamins, change of eating habits and lifestyle are the most common ways to achieve this. Also proves that our immune system when healthy is able to deny toxic adversity.

Leaded gasoline, paints and plumbing have all been banned. The government has recognized that lead can and will cause neurological problems. Lead, mercury, aluminum, cooper and cadmium as well as others all have similar effects upon the human system. These are mostly neurological and central nervous system disruptions. Verbal, social and motor skill failures are noted. However some immunity issues are also involved.

The honeybees that are required to pollinate many of the crops we need have begun to disappear. The question remains that it may be a mite or the fact that our crops are so heavily juiced or modified with pesticide resistance that we in fact are killing this natural ally. The estimate is that 1/3 of all honeybees have been eliminated within the past five years.

Atrazine is/was the most widely used corn insecticide in the United States. Many European countries had banned its use well before now. The U.S. response has been to put stricter regulation upon this proven neurodevelopment causing toxin. This chemical has proven to find its way into land water and surface water sources. Atrazine also has the ability to travel up to 600 miles by air. This has been a truly concerning toxin.

The specially treated wood products that are designed to resist fungus and insect damage also have been found to be toxic to humans. Those beautiful decks and the fashionable log homes are of major concern. Unfortunately the park related swings and obstacles that our children enjoy also are on this list.

This list can go on and on as the amount of neurological, immune and central nervous system toxins are growing by the hour. How can we wonder why we are seeing so many chronic illnesses? I really must ask, what is it that you don’t understand?

DDT, asbestos, Agent Orange, phosphates etc. were all once considered safe. It took time to realize the effects. It took more time for these effects to be admitted. The ever changing science that we create has to be acknowledged. There is no junk science and no perfect science.

Exclude the financial losses or gains and just may be you can find science and all of its mysteries again. We have an obligation to provide our children with the hope of a good future. At the rate we are going we are offering no hope and therefore no future. Honesty, fairness and acceptance are the only answers. Medical science must move on despite our self imposed restrictions. As human nature is bound to do we must explore all possibilities not by numbers but by facts.

Thu, June 14, 2007
By GLYNNIS MAPP, SUN MEDIA

Scientists believe a breakthrough discovery could help them better understand and eventually treat "one of the worst aging diseases."

Dr. Michael Strong, a clinical neurology professor at the University of Western Ontario, unveiled a new protein at an annual conference.

He said yesterday the discovery will help clarify the symptoms of nerve-destroying amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

The protein, TDP-43, is a key player in the facilitation of riboneuclaic acid, which carries genetic instructions to the body's motor neurons.

Lou Gehrig's disease affects the nerves in the brain, affecting the cells controlling voluntary muscle activities such as speaking, walking and breathing. It often causes paralysis.

Strong said the disease's progression is much like a neurological game of broken telephone.

"Think of your cells like building a house," he said. "It's as if the suppliers gave you 2x4 planks to build the outer walls when you asked for 2x6. They don't fit. "

Strong said these "suppliers," or riboneuclaic acid, give instructions like blueprints to motor neurons to build protein in the body.

"Your genes send the wrong messages and the random dysregulation of this information to produce the wrong proteins," he said. "We've now found the protein that may contribute to this blockage."

His new findings appear in the June issue of the scientific journal Molecular and Cellular Neuroscience.

Of the three main age-related diseases affecting Canadians -- Parkinson's, Alzheimer's and Lou Gehrig's disease -- Strong said the latter is the most aggressive.

The ALS Society of Canada says about 3,000 Canadians live with the illness.

In discovering the TDP-43 protein, researchers also believe they may have found a key to unlocking why some people experience dementia

Strong hopes a $250,000 research project will lead to gene therapy treatment.

"This means a lot to the people who are suffering with the disease and their families," he said. "Now, we're just one step closer to understanding the connection between ALS symptoms and and other diseases."

By Toni Clarke

June 22, 2007

BOSTON - Genzyme Corp. is expanding its research into gene therapy, a controversial and cutting-edge approach to treating disease which most companies avoid.
The company, which built itself into one of the world's biggest biotechnology companies by developing drugs for rare genetic disorders, said on Thursday it has entered a partnership with Ceregene Inc. to develop a treatment for Parkinson's disease.

Gene therapy is a controversial method of injecting genes into cells to make proteins that can fight disease, typically using a genetically engineered virus to carry the gene to the cell.

So far, no gene therapy product has been approved, and research has shriveled following the death in 1999 of Jesse Gelsinger, an 18-year-old participant in a gene therapy clinical trial.

"Gene therapy makes everyone nervous and there are only a limited number of players," said Dr. Harry Tracy, publisher of the monthly journal NeuroInvestment. "This is a daring area of research, and Ceregene's program is one of the most sophisticated out there."

Genzyme began work on gene therapy in the early 1990s as a potential treatment for cystic fibrosis. That program didn't work, but the company continued its research and is now in mid-stage clinical trials with a treatment which stimulates blood vessel growth and could be valuable for patients with conditions characterized by poor circulation, such as peripheral artery disease.

Ceregene's program, CERE-120, is composed of an adeno-associated virus vector carrying the gene for neurturin, a protein known to protect or repair nerve cells which secrete a brain chemical known as dopamine that is involved in movement. Parkinson's disease is caused by a reduction in dopamine-containing nerve cells.

Gene therapy, in theory, represents an attractive technology for treating neurological disorders because the treatment circumvents the blood-brain barrier, a cell structure that protects the brain from foreign substances in the blood - including large molecules such as therapeutic proteins.

"Parkinson's is very attractive because you can deliver the gene to a localized area, the cells will make the protein and hopefully do the job," said David Meeker, head of Genzyme's rare genetic diseases unit.

Meeker said its Parkinson's research is the cornerstone for what the company expects will be a growing central nervous system disorders program, including work on treatments for ALS, also known as Lou Gehrig's disease, and Huntington's disease, a condition in which the degeneration of brain cells causes uncontrolled movement and loss of intellectual function.

"This is an area of high interest for us," Meeker said.

Cambridge, Massachusetts-based Genzyme said it will pay Ceregene $25 million up front, make as much as $125 million in payments as the companies reach development milestones, and provide 50 percent reimbursement for late-stage development costs.

Genzyme will gain marketing rights in all markets outside the United States and Canada.

Ceregene, which was launched in January 2001 and is a former subsidiary of Cell Genesys Inc., is currently conducting a Phase II, or mid-stage, clinical trial which is enrolling 51 patients.

In an early-stage trial, CERE-120 showed a 36 percent reduction in Parkinson's symptoms at 12 months following administration.

"This is early data which is very encouraging," Meeker said, "but it is too early to draw meaningful conclusions about the relative efficacy to other treatments."

Trophos Describes Identification, Characterization and Broad Neuroprotective Properties of TRO19622 in Journal of Pharmacology and Experimental Therapeutics

Neurodegenerative Disease Specialists Publish Details of a Novel Drug Candidate for ALS That Targets Mitochondrial Proteins

MARSEILLE, June 19th, 2007 - Trophos SA, a biopharmaceutical company specializing in the discovery and development of drugs for neurological disorders, announced today that a publication entitled "Identification and characterization of TRO19622 (cholest-4-en-3-one, oxime), a novel drug candidate for amyotrophic lateral sclerosis" has been accepted and published online May 11, 2007 in the Journal of Pharmacology And Experimental Therapeutics (J Pharmacol. Exp. Ther. 2007 May 11; [Epub ahead of print]).

Amylotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig's disease in the USA, is a progressive and fatal neurological disease that is estimated to affect about 100,000 people worldwide. There is no cure for ALS. The only drug approved for ALS is riluzole (Rilutek(R), Sanofi-Aventis), which has been demonstrated to confer some survival benefit to ALS patients.

The studies reported in the paper by Bordet et al., (see below) identify two protein targets of TRO19622 present in the outer mitochondrial membrane suggesting that the compound has potential in a range of additional commercially attractive therapeutic indications involving mitochondrial dysfunction, including painful neuropathies. The publication describes the models of motor neuron disease employed to support the use of this compound to treat ALS, as well as spinal muscular atrophy. TRO19622 is currently in a Phase IIa clinical trial to establish its efficacy as a treatment for painful diabetic neuropathy.

TRO19622 is representative of novel compounds identified using the proprietary neuronal cell screening platform developed at Trophos. In vitro, TRO19622 promotes motor neuron survival in the absence of trophic support in a dose-dependent manner. In preclinical models in vivo, TRO19622 rescues motor neurons from axotomy-induced cell death in neonates and promotes nerve regeneration following sciatic nerve crush. Furthermore, in the SOD1G93A model of familial ALS, TRO19622 treatment improves motor performance, delays the onset of the clinical disease, and extends survival.

TRO19622 binds directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel (VDAC) and the translocator protein (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity.

TRO19622 has successfully completed Phase I/Ib studies in both healthy volunteers and ALS patients demonstrating the product is well tolerated, has an excellent safety profile and that once-a-day dosing achieves the predicted exposure level required for efficacy, based on preclinical models. These data support the further clinical evaluation of TRO19622 as a potential treatment for ALS.

"Trophos is proud to have this body of work accepted for publication in a well recognized journal such as JPET," said Rebecca Pruss, CSO at Trophos. "Given the significant unmet medical need in ALS, it is tremendously encouraging that TRO19622 promotes the survival of motor neurons in this extensive battery of preclinical models. These studies, along with the excellent clinical safety profile of TRO19622, provide the basis upon which Trophos plans to initiate a pivotal Phase II/III trial to establish the clinical efficacy of TRO19622 in ALS patients."

Pruss added: "Moreover, we are particularly excited that there is increasing preclinical evidence that the mitochondria-mediated mechanism of action of TRO19622, and other compounds in this class, will have huge commercial potential in other chronic neurological disorders, such as neuropathic pain, and non-neurological conditions, such as ischemia-reperfusion injury and hepatitis."

Author List: Thierry Bordet, Bruno Buisson, Magali Michaud, Cyrille Drouot, Pascale Galea, Pierre Delaage, Esther-Marie Steidl, Delphine Maux, Michel Delaage, Rebecca M. Pruss (Trophos), Natalia P. Akentieva, Alex S. Evers, Douglas F. Covey (Washington University School of Medicine), Mariano A. Ostuni, Jean-Jacques Lacapere (U773 Inserm), Charbel Massaad, Michael Schumacher (UMR788 Inserm), Christopher E. Henderson (Center for Motor Neuron Biology, Columbia University)

About Trophos: <http://www.trophos.com>www.trophos.com Trophos is a biopharmaceutical company committed to the discovery and development of novel therapeutic compounds to treat neurological disorders and other diseases with high unmet medical needs. Trophos has pioneered an innovative phenotypic screening platform which has enabled it to develop a proprietary portfolio of products, such as our lead product TRO19622, that confer a survival benefit upon both neuronal and non-neuronal cell types (such as cardiomyocytes & hepatocytes) through a mitochondria-based mechanism of action with a robust therapeutic rationale, one that is predicted to exhibit a therapeutic benefit in diseases such as neuropathic pain, ischemia-reperfusion injury and hepatotoxicity. The company is focusing its efforts on the orphan indications, ALS, SMA & Huntington's disease, while seeking to establish clinical proof of concept in indications such as neuropathic pain, ischemia-reperfusion injury and hepatotoxicity.

Trophos was founded in 1999, is based in Marseille, France and currently has 32 employees. -- -- Best regards,

Katie Ollerenshaw ANDREW LLOYD & ASSOCIATES http://www.ala.com katie@ala.com

Brighton Business Centre 95 Ditchling Road Brighton BN1 4ST ENGLAND Tel: +44 1273 675100 Fax: +44 1273 675400

55 rue Boissonade 75014 Paris FRANCE Tel: +33 1 56 54 07 00 Fax: +33 1 56 54 07 01

INTERNATIONAL TECHNOLOGY MARKETS, STRATEGY & COMMUNICATION

Thursday, 28 June '07
By Jennifer O'Brien

Mike Homer has been one of the leading forces in Silicon Valley for more than two decades. In May, he was diagnosed with the rare neurodegenerative disease Creutzfeldt-Jakob disease, known as CJD. Now, the 49-year-old husband and father of three young children is fighting for his life, with the assistance of physicians at UCSF Medical Center. And he's taken the fight beyond his own predicament.

Homer, his wife Kristina and two of his closest friends in Silicon Valley are spearheading a fundraising campaign, "Fight for Mike," that aims to provide the UCSF team — the world's leading cadre of scientists and physicians researching and exploring treatments for the brain-wasting disease — with the funding they need to expand and accelerate clinical trials for a drug strategy they are investigating.

The UCSF team includes Stanley Prusiner, MD, who won the Nobel Prize in Physiology or Medicine in 1997 for discovering the abnormally shaped protein, known as a prion (PREE-on), that causes CJD and related diseases in humans and animals, including "mad cow" disease in cattle.

In 2001, Prusiner's lab discovered that quinacrine, once used to treat malaria, kills prions in mouse cells in the culture dish. Then the team found interesting results in mice. In 2005, UCSF began testing the drug in a human clinical trial. Today, the team is working to improve quinacrine's effectiveness, expand the current clinical trial and discover and validate new treatments.

Homer and his wife have learned that what the team needs to accelerate their progress is financial support. He is working with his friends in Silicon Valley to raise money to fight the disease. The goal, says the former marketing executive at Apple Computer and Netscape, is "to be around for my kids," and to help "a whole lot of other people who come after me."

On June 14, 2007, 300 of Silicon Valley's top leaders gathered at the invitation of the Homers and their friends to hear the UCSF team discuss the disease and what needs to be done to accelerate progress in treating it. The event was hosted by Bill Campbell, chair of the board and former CEO of Intuit Inc. and a leading advisor to technology companies, and Ron Conway, founder and general partner of Angel Investors, a major investor in technology companies and vice chair of the board of the UCSF Foundation. The goal – turn out for Mike, in a fight for one of their own.

What they learned: Most cases of CJD develop sporadically, for no apparent reason. A minority of cases are inherited. One percent of cases develop as a result of infection, such as from eating the prion-tainted beef diagnosed in cattle beginning in the mid 1980s in Great Britain. Homer, who most likely has the sporadic form of the disease, definitely does not have the infectious form.

They also learned that Prusiner's discovery that an abnormally shaped protein can cause disease has galvanized scientists' understanding of more common neurodegenerative diseases, such as Alzheimer’s disease and amyotrophic lateral sclerosis, known as ALS, which are now known to be diseases of misshapen or misprocessed proteins.

It is possible that CJD will be the first neurodegenerative disease to be conquered, says one of Homer's physicians, Bruce Miller, MD, director of the UCSF Memory and Aging Center, and that the cure will catalyze drug strategies against these other diseases.

It is a fight that will require the ongoing rapid translation of discoveries made in the lab to the patient bedside, says Homer's primary physician, Michael Geschwind, MD, PhD, recruited from Johns Hopkins University in 2000.

It is a fight that Homer is determined to help win.

Public release date: 27-Jun-2007
Contact: Stuart Wolpert
swolpert@support.ucla.edu
310-206-0511
University of California - Los Angeles

Chemists from UCLA and the University of Florence in Italy may have solved an important mystery about a protein that plays a key role in a particular form of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, a progressive, fatal neurodegenerative disorder that strikes without warning.

Joan Selverstone Valentine, UCLA professor of chemistry and biochemistry, has studied the protein — copper-zinc superoxide dismutase — since the 1970s, long before it was implicated in ALS in 1993. Since the link was discovered, Valentine’s laboratory has made more than two dozen mutant, ALS-causing enzymes, most of which have only one wrong amino acid out of 153, to try to understand their properties and learn what makes them toxic.

“Some of the mutant proteins are very different from the normal protein, but others are virtually identical to the normal protein — yet they all cause the disease,” said Valentine, a member of UCLA’s Molecular Biology Institute. “That was the real mystery. You wrack your brain: What is similar among all these proteins" They seem so different. How can they all cause the same disease"”

Now Valentine and her colleagues, including Ivano Bertini, professor of chemistry at the University of Florence and director of the European Magnetic Resonance Center, think they know. In ALS patients, the protein’s copper and zinc may not be there at all. They present evidence for this hypothesis in new research published in Proceedings of the National Academy of Sciences, currently online and available in the journal’s July 3 print edition.

“If we keep the metals entirely out of the protein, we can explain the toxicity, since even the normal protein forms aggregate at physiological conditions when the metals are gone,” Valentine said. “It was such a puzzle, but this hypothesis can solve it.”

If scientists can figure out why ALS patients lack the copper and zinc, that would be a major advance that could lead to treatment, she said.

The research team is testing the hypothesis. Valentine, who was elected to the National Academy of Sciences in 2005 and to the American Academy of Arts and Sciences this year, praised her colleagues. “This research is the result of a long, successful international collaboration between UCLA and the University of Florence,” she said. “Our colleagues in Italy are exceptional scientists.”

Co-authors on the Proceedings of the National Academy of Sciences research are Lucia Banci, a professor of chemistry at the University of Florence who is affiliated with the FiorGen Foundation; Armando Durazo, a UCLA graduate student of chemistry and biochemistry; Stefania Girotto, a postdoctoral scholar at the University of Florence; Edith Butler Gralla, a senior research chemist at UCLA; Manuele Martinelli and Miguela Vieru, graduate students at the University of Florence; and Julian P. Whitelegge, an adjunct professor at the Semel Institute for Neuroscience and Human Behavior at UCLA and UCLA’s Brain Research Institute.

Copper-zinc superoxide dismutase, which was discovered in the 1960s, is an antioxidant enzyme that protects cells from free radicals, unstable atoms or molecules that can cause cell damage. The link with ALS came when researchers sequenced the genes of people who have the inherited form of ALS and found that some of them have mutations in the gene that codes for this enzyme. While the inherited form represents only a fraction of all ALS cases, this marked the first time there was any indication of a cause for any form of ALS, Valentine said.

For many years, Valentine’s laboratory has studied the normal version of the protein. While the normal protein has copper and zinc, scientists can make it with no metals. When it is first made inside the cell, it has no metals and only acquires them later, Valentine said.

“We studied what happens to the protein if you have the metals, if you have no metals and if you have part of the metals,” she said.

The research of the UCLA–University of Florence team has indicated it is the metal-free protein that is likely to be toxic. The protein misfolds when the copper and zinc are not present, but folds properly when they are there.

“Before copper and zinc are inserted, the protein can misfold under physiological conditions,” Valentine said.

There is evidence that ALS is associated with this misfolding of the protein, which becomes toxic in some way that is not known and has properties similar to misfolded proteins associated with other neurodegenerative disorders like Alzheimer’s and Parkinson’s diseases, Valentine said.

Is there a way to slow down this process to give the cell more time to eliminate the misfolded proteins in all of these diseases" Would a strategy to reduce or prevent protein misfolding work against these and other diseases" These are avenues for further investigation by researchers.

When Valentine first began working on copper-zinc superoxide dismutase, she was not a biochemist but a biological inorganic chemist and hardly knew what ALS was. She was interested in the enzyme, which is unique in that it has copper and zinc so close together.

Her laboratory isolated and characterized the enzyme, but Valentine was less interested in its biological properties than in the inorganic chemistry. She was more interested, for example, in how the protein influenced the reactivity of the copper or zinc, or how the copper and zinc influenced the structure of the enzyme. She and her colleagues were among the pioneers in taking the copper and zinc out and putting other metals in to see what would happen. Her laboratory put more emphasis on biological factors over time.

“When I moved to UCLA in 1980, we started working on copper-zinc superoxide dismutase in yeast, a model organism, using the then new tools of molecular biology to redesign the protein and make new mutant forms of the protein that would have different inorganic properties,” she said. “We were making mutant forms of this enzyme to study, but with no connection to disease.

“I remember the day in March 1993 that the announcement came — it was on the front page of The New York Times — that ALS has been linked to superoxide dismutase (SOD), but the article didn’t say which superoxide dismutase; I was hoping it was our enzyme. It took me all day to track down the scientists to find out which SOD it actually was. It was our SOD. It was a very exciting day.”

“When we made the mutant proteins, each one seemed to be totally different,” she said. “Some of the mutant proteins that cause the disease are identical to the normal protein in every property we measure.”

Valentine and Bertini have known each other since she was a graduate student and he was a research associate at Princeton University. Initially, they were both inorganic chemists who did not intend to do biological research. They have just published an authoritative new textbook called “Biological Inorganic Chemistry: Structure and Reactivity,” with co-authors Harry Gray at the California Institute of Technology and the late Edward Stiefel from Princeton University. The textbook is designed for both undergraduate and graduate students.

“All of us who work in the field hope our research will lead to a treatment of ALS,” Valentine said. “What we really want is to diagnose and prevent ALS before its onset. We’re still a long way from that, but we’re making progress.”

###
Valentine’s research was federally funded by the National Institutes of Health.

UCLA is California’s largest university, with an enrollment of nearly 37,000 undergraduate and graduate students. The UCLA College of Letters and Science and the university’s 11 professional schools feature renowned faculty and offer more than 300 degree programs and majors. UCLA is a national and international leader in the breadth and quality of its academic, research, health care, cultural, continuing education and athletic programs. Four alumni and five faculty have been awarded the Nobel Prize.

LA JOLLA, CA – Like any new kid on the block that tries to fit in, newborn brain cells need to find their place within the existing network of neurons. The newcomers jump right into the fray and preferentially reach out to mature brain cells that are already well connected within the established circuitry, report scientists at the Salk Institute for Biological Studies in the online edition of Nature Neuroscience.

Neurons make contact via specialized structures

 called synapses. As a signal traveling along a

nerve branch arrives at the pre-synaptic area, it

releases a chemical signal. The signaling

molecules travel across the synapse and induce

a signal on the neighboring, receiving nerve

fiber or dendrite. A typical neuron sports about

7,000 synapses through which it stays in touch with roughly 1,000 other cells. But just how young neurons make their presence known and hook up with already well-connected elders has been unclear.

“If you have hopes that one day neuronal stem cells can replace damaged neurons in neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease you have to ensure that these cells make proper connections, form functional synapses and integrate into the rest of the brain,” says postdoctoral fellow Nicolas Toni, Ph.D., who headed the current study.

To figure out how the newcomers do it, the Salk researchers injected a virus carrying the gene for green fluorescent protein into the hippocampus, a brain region harboring neural stem cells that give rise to new neurons. Newly born neurons infected with virus were marked by a fluorescent dye enabling the researchers to follow their fate over time as they tried to get accepted into the existing circuitry.

With the help of a whole arsenal of high-tech imaging technology and the electron tomography expertise of Mark. H. Ellisman, Ph.D., a professor at the National Center for Microscopy and Imaging Research at the University of California, San Diego, Toni then zoomed in at a nanometer scale and watched how the young and the old got acquainted.

He observed that between three and four weeks after injection of the virus newborn neurons sent out dendritic filopodia—tiny feelers that probe the environment. “When we analyzed them in three dimensions, the tip of the filopodia was preferentially associated with synapses already connected to other neurons,” explains Toni.

However, as the new neurons matured, the tiny tips filled out and started to monopolize the synaptic connections. “That’s what we believe is the crux of the study: the survival of new neurons may depend on the ability to compete out the older existing neurons,” says Gage. Earlier studies had shown that if young neurons fail to receive signals from other brain cells they wither and die. By connecting to functional synapses, the newborn neurons ensure that they are not reaching out to deadbeats.

The Gage lab previously identified a subunit of the NMDA receptor, a protein complex that transduces signals sent by neighboring cells, as the newborn neurons’ life-saving equipment. The NMDA receptor is activated by the neurotransmitter glutamate, a chemical released by neurons in order to transmit information to neighboring cells. Whenever the receptor picks up a glutamate signal it is stimulated and relays the signal. For young neurons that signal means survival.

As a matter of fact, only about half of all newly born neurons manage to successfully integrate into the existing network of brain cells, at least in mice living in bare standard cages. Providing the mice with a stimulating, enriched environment—large cages filled with running wheels, colored tunnels and playmates—boost the number of neurons that manage to hook up with the existing network to 80 percent, reinforcing the observation that using one’s brain cells is the best way to optimize brain function throughout one’s lifetime.

Also contributing to the study where postdoctoral researchers E. Matthew Teng, Ph.D., James B. Aimone, Ph.D., Chunmei Zhao, Ph.D., Antonella Consiglio, Ph.D., staff scientist Henriette van Praag, Ph.D., all at the Salk Institute, and postdoctoral fellows Eric A. Bushong , Maryann E. Martone, Ph.D., and Mark H. Ellisman at the National Center for Microscopy and Imaging Research at the University of California, San Diego.

The Salk Institute for Biological Studies in La Jolla, California is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health, and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

La Jolla, CA – The Salk Institute for Biological Studies was awarded a $2.3 million share of the stem cell research facilities grants approved by the governing board of the California Institute for Regenerative Medicine (CIRM) on June 5.

At the Salk, the grant will support the development of shared laboratory space to be used by multiple investigators, and provide an environment for scientific research on human embryonic stem cells (hESCs) under CIRM’s medical and ethical standards. The grant will also provide funds for equipment and operating expenses over three years.

“The availability of this shared research laboratory will allow Salk researchers to initiate research on human embryonic stem cells and to contribute to this very exciting field of biology,” says Program Project Director Inder Verma, Ph.D., a professor in the Laboratory of Genetics, who spearheads the stem cell facility project at the Salk Institute.

“The Salk faculty is also very grateful for the invaluable expertise and help during the planning stages provided by Garry Van Gerpen, senior director of Facility Services, and his staff members, who are the ones who ultimately make it happen,” Verma said.

To date, the Salk Institute has received more than $7.5 million in stem cell research grants from CIRM. Earlier this year, Salk professor Fred H. Gage received $2.9 million for research to develop methods of turning hESCs into neural stem cells; and professors Senyon Choe, Beverly Emerson and Sam Pfaff received seed funding totaling $2.28.

The latest round of CIRM grants, totaling more than $50 million, will finance construction of shared research laboratories at 17 academic and non-profit institutions for the culture of human embryonic stem cells (hESCs), particularly those that fall outside federal guidelines. (Current federal policy prohibits research involving hESCs isolated after August 2001 from being conducted in laboratories constructed with any federal funding). These facilities are scheduled to be complete and available to researchers within six months to two years of the grant awards.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.