MIT researcher Mark Bear thinks that some forms of autism and mental retardation may be treatable with drugs already on laboratory shelves., November/December 2010, by Robert Langreth —  Mark Bear, 53, has been fixated on understanding the brain since he was 6–when he saw news commentators speculating about John F. Kennedy’s brain functioning after the shooting. He later became a neuroscientist, now at the Massachusetts Institute of Technology, spending most of his career doing basic research on how the brain’s cells form connections during learning.

Today researchers are buzzing about Bear and his radical new theory that offers a real glimmer of hope that some forms of autism may be treatable with drugs. The causes of autism have mystified scientists for decades. It has been blamed on everything from genes to environmental toxins to the discredited concept that childhood vaccines are the culprit.

Bear’s work suggests that a specific class of drug already sitting on drug company shelves may help patients with an inherited disease called fragile X syndrome, a common cause of autism. It hits one in 5,000 kids and causes mental retardation, anxiety and autism-like symptoms. While years of research remain, Bear theorizes those types of drugs might have application beyond fragile X and into autism in general.

In the wake of his results Roche ( RHHBY.PKnews people ) and Novartis ( NVSnews people ) have begun testing an old class of experimental anxiety drugs called mGluR5 inhibitors in fragile X patients. Seaside Therapeutics, which Bear cofounded, licensed a similar drug from Merck ( MRKnews people ) that is set to enter tests in fragile X patients early next year. Another Seaside drug showed promising early results in a study of 28 autism patients. (Bear owns 5% of the company.)

“I have been in this field for 25 years, and these last two years have been the most exciting in my career,” says Randi Hagerman, a developmental pediatrician at the MIND Institute at UC, Davis who is testing several of the drugs.

Bear’s work in fragile X started with a chance encounter a decade ago with Emory University geneticist Stephen Warren, who discovered the gene for fragile X in 1991. Bear gave a speech about how protein production was needed for certain basic cellular processes involved in memory. That grabbed Warren’s attention. He knew that the same gene that caused fragile X also helped control protein production. “After his talk I leaned over and said, ‘I have a mouse you have to look at,'” Warren says.

Bear’s subsequent experiments with mice with fragile X indicate that the brain makes too much of key proteins that prevent proper learning from occurring. By adjusting protein levels with a drug, he realized, it just may be possible to reverse the problem. Better yet, drugs that could do the trick already existed in pharmaceutical laboratories–a class of medications called mGluR5 antagonists that had been originally developed as antianxiety medicines. “I remember the moment. I was sitting in my office at home–and it occurred to me that excessive mGluR could prove a thread that connects what seems to be unrelated symptoms” of fragile X, he recalls. “The hair stood up on the back of my neck.”

When Bear proposed this concept, even his own students were skeptical. His first talk detailing the theory was at an invitation-only conference of fragile X experts in 2002. Bear, an outsider to the field, fretted about how his theory would be received. “The initial reaction was stunned silence. It was like a chin-scratching,” Bear says. “No one could immediately see what was wrong with the idea.”

He founded Seaside Therapeutics in 2005 with Randall Carpenter, who leads the company. It has attracted $60 million in funding from a private family trust. “We were thinking if this is something that has gone wrong in autism we have to do it. Big Pharma was not going to do it because it was too risky,” Bear says. After getting a cool reception from several drug companies, Bear leveraged an MIT connection into a meeting with scientists from Merck, which agreed to license its mGluR5 drug to Seaside.

So far his intuition has proved right. The theory got a huge boost in 2007. Bear and Gül Dölen took mice with the defective fragile X gene and then crossed them with mice that were missing half their copies of the brain receptor mGluR5, which stimulates protein production. The fragile X symptoms disappeared, suggesting that drugs that blocked the receptor–and thus reduced the amount of protein produced–might do the same thing.

UNC-Chapel Hill psychologist Geraldine Dawson, chief science officer for nonprofit Autism Speaks, calls Bear’s work “the first demonstration that it is possible” that drugs based on gene research could help treat autism-like symptoms. “It is like lightning to have something in clinical trials” so fast, says former Bear postdoc Kimberly Huber, who did the early lab work leading to the theory and is now a professor at UT Southwestern Medical Center.

The latest version of Bear’s theory, published in 2008, holds that similar protein production problems may be at play in many cases of autism of unknown cause. There may be an optimal level of protein production inside brain cells needed for learning. If there is too much or too little, learning disabilities may occur and grow over time. Under this view, rather than an unfixable problem, many forms of autism may be more like a chronic disease that starts at birth and gradually gets worse. Tweaking protein levels with various drugs may be able to help.

Initial tests of mGluR5 drugs are being conducted on adults with fragile X, but companies ultimately hope to move to treating kids, where the drugs could have a bigger impact. “My dream would be to apply the treatments early enough in life so we could change the course of the disease,” says Roche Vice President Luca Santarelli.

Testing whether the drugs work in people with fragile X will take years, and it’s far from clear that they could work with other forms of autism. “That’s the billion-dollar question,” says Santarelli, who is holding off testing his drug in autism until researchers know more. Says Bear: “If we are right, this could have a profound effect on human health.”

An array of dissolving microneedles is shown on a fingertip. Researchers have been awarded $10 million to develop a microneedle patch for immunizing against influenza. (Credit: Courtesy of Mark Prausnitz), November 2010 — The National Institutes of Health (NIH) has awarded $10 million to the Georgia Institute of Technology, Emory University and PATH, a Seattle-based nonprofit organization, to advance a technology for the painless, self-administration of flu vaccine using patches containing tiny microneedles that dissolve into the skin.

The five-year grant will be used to address key technical issues and advance the microneedle patch through a Phase I clinical trial. The grant will also be used to compare the effectiveness of traditional intramuscular injection of flu vaccine against administration of vaccine into the skin using microneedle patches. In animals, vaccination with dissolving microneedles has been shown to provide immunization better than vaccination with hypodermic needles.

“We believe that this technology will increase the number of people being vaccinated, especially among the most susceptible populations of children and the elderly,” said Mark Prausnitz, a professor in the Georgia Tech School of Chemical and Biomolecular Engineering, and the project’s principal investigator. “If we can make it easier for people to be vaccinated and improve the effectiveness of the vaccine, we could significantly reduce the number of deaths caused every year by influenza.”

Vaccine-delivery patches contain hundreds of micron-scale needles so small that they penetrate only the outer layers of skin. Their small size would allow vaccines to be administered without pain — and could allow people to apply the patches themselves without visiting medical facilities.

While the ability to immunize large numbers of people without using trained medical personnel is a key advantage for the microneedle patch, the researchers have learned that administering the vaccine through the skin creates a different kind of immune response — one that may protect vaccine recipients better.

“We have seen evidence that the vaccine works even better when administered to the skin because of the plethora of antigen presenting cells which reside there,” said Ioanna Skountzou, co-principal investigator for the project and an assistant professor in Emory University’s Department of Microbiology and Immunology. “This study will allow us to determine how we can optimize the vaccine to take advantage of those cells that are important in generating the body’s immune response.”

Among the issues to be addressed in the five-year study are:

  • Developing an administration system that will be simple to use, intuitive and reliable. “Our goal is to make these patches suitable for self-administration, so that anybody could take a patch out of an envelope, put it on, and have it work with high reliability,” Prausnitz said.
  • Studying the long-term stability of vaccine used in the patches, and optimizing technology for incorporating it into the dissolving microneedles. “We need to put the vaccine into a dry form in this patch,” said Prausnitz. “That will require different processing than is normally done with vaccines. We expect that this dry vaccine will provide enough stability that the patches can be stored without refrigeration.”
  • Evaluating the economic, regulatory, social and medical implications of a self-administered vaccine. PATH, an international nonprofit organization, will assist with this work, and will help strategically address any issues. “We will be assessing the barriers that may exist to introduction of a self-administered flu vaccine so we can anticipate those issues and develop possible solutions,” said Darin Zehrung, leader of the vaccine delivery technologies group at PATH.

The funding will come from the Quantum program of the National Institute of Biomedical Imaging and Bioengineering (NBIB), which is part of the NIH. The initiative is designed to bring new medical technologies into clinical use.

While the funding focuses specifically on influenza vaccination, the lessons learned may advance other microneedle applications — including vaccination efforts in developing countries where skilled medical personnel are limited and concerns about re-use of hypodermic needles are significant.

Additional design and development of the microneedle patch will largely be done at Georgia Tech, with vaccine development, immunological studies and the Phase I trial carried out at Emory University. The trial, to be conducted by the Hope Clinic of the Emory Vaccine Center, is expected to take place during the final year of the grant, setting the stage for Phase II and Phase III clinical trials that would be required to obtain FDA approval.

Ultimately, the goal will be to produce an influenza vaccine delivery patch that could be made widely available. Prausnitz expects that will be done by an established company with the ability to manufacture and market the devices.

Microneedle drug and vaccine delivery systems have been under development at Georgia Tech and elsewhere since the 1990s. The technology got a significant boost in July of 2010 with publication of a study in Nature Medicine that showed mice vaccinated with dissolving microneedles were protected against influenza at least as well as mice immunized through traditional hypodermic needle injections.

The patches used in that study contained needles just 650 microns long, assembled into arrays of 100 needles. Pressed into the skin, the needles quickly dissolved into bodily fluids thanks to their hydrophilic polymer material, carrying the vaccine with them and leaving only a water-soluble backing. In contrast, use of hypodermic needles leaves the problem of “sharps” disposal.

Prausnitz hopes that the $10 million in NIH funding will help accelerate development of the microneedle patches to make them available for general use within five to ten years.

“This research will focus on optimizing the microneedle-based delivery of vaccines into the skin and understanding how this method affects immune responses both at the mucosal surfaces of the body and through the systemic response inside the body,” added Skountzou. “Combined with the convenience of self-administration, painless application and absence of sharps waste, this novel immunization route could make the microneedle patch a powerful new weapon against infectious diseases.”

Sections of neurons captured with new imaging technology from Stanford researchers., November/December 2010  —  While large pharmaceutical companies like Pfizer, Eli Lilly and Bristol-Myers Squibb spend millions of dollars pursuing new treatments for neurological diseases like Alzheimer’s, a huge impediment to their success lies in the fact that the brain and diseases affecting it are still not well understood. As my colleague Bob Langreth has pointed out several times, including here, there is still quite a bit of controversy about what causes Alzheimer’s.

New research by scientists at Stanford University may help to change that. The researchers created a state-of-the-art imaging system and used it to look at brain tissues of mice (see the photo at right) –and were able to quickly and accurately count the high number of connections between the brain’s nerve cells with a level of detail not attained before. The research results were published today in the journal Nature.

There are some 200 billion nerve cells (neurons) in the brain, linked together by trillions of contacts called synapses. “In a human, there are more than 125 trillion synapses just in the cerebral cortex area [a thin layer of tissue on the brain’s surface],” said Stephen Smith, PhD, a professor of molecular and cellular physiology and a senior author of the new research paper. Smith said that up to now, scientists have been guessing when they attempt to map the circuitry of the cerebral cortex. The synapses in the brain are smashed so close together that traditional microscopes couldn’t make them out. “Now we can actually count them and, in the bargain, catalog each of them according to its type.”

The method Smith and others in his lab developed is called array tomography. The researchers took slabs of tissue from a mouse’s cerebral cortex, sliced it into sections 70 nanometers thick, stained them with antibodies designed to match certain proteins and attached molecules that responded to glowing light.

After taking very high resolution photographs of the tissue slices, the information in the photos was virtually stitched together using new computational software designed by study co-author Brad Busse. The result: Researchers could move through a 3-D mosaic created by the software. Different colors represent different synaptic types.

The promise is great, and the researchers are optimistic. “I anticipated that within a few years, array tomography will have become an important mainline clinical pathology technique and a drug research tool,” said Smith. Let’s hope that it ultimately leads to unraveling the many mysteries of crippling neurological diseases like Alzheimer’s.

Image by blitzmaerker via Flickr, November 29, 2010, by Terry Waghorn  —  Micro solutions hold the answer to sustainability in developing countries. Advanced infrastructure often taken for granted in the developed world does not exist in many of these countries. This means sustainability innovations must include what isn’t available in these regions must make use of what little is available.

One way this is being accomplished is through txteagle, which uses the mobile phone phenomenon to provide micro-work for people in developing countries. Only 18% of people in the developing world have access to the internet, but more than 50% owned a mobile phone at the end of 2009.

Txteagle, started by Nathan Eagle a research scientist with MIT, distributes small jobs via text messaging in return for small payments. These jobs often involve local knowledge and range from things like checking what street signs say for a satellite-navigation service, to translating words into local dialects for companies trying to spread their marketing.

Meanwhile, others are tackling one of the biggest problems in the developing world’s rural areas – the lack of an electrical grid to provide lighting. In many areas, highly polluting kerosene is burned to generate light, contributing significantly to the earth’s carbon dioxide levels.

For example, the Lumina Project, an initiative of the U.S. Department of Energy, and Lighting Africa conducted tests using solar LED lighting in a broiler chicken operation at an off-grid farm in Kenya. The test achieved lower operating costs, produced substantially more light, improved the working environment and had no adverse effect on yields.

Providing light with the solar LED systems is far more economical than connecting to a grid, the cost of which was estimated at 1.7 million Kenya Schillings (about 21,350 USD). This is about 35 times the cost of the LED system. Furthermore, switching to the LED system avoids over one metric ton of carbon dioxide emissions per (broiler) house on an annual basis compared to kerosene.

There is potential for replication of this particular LED lighting strategy in the developing world. But there is also potential for non-industrial use. Solar LED could help produce much-needed light for millions of people in the developing world who do not have access to traditional electrical grids.

Australian company Barefoot Power uses this simple post-industrial technology to bring alternatives to fuel-consuming appliances, specifically lights, to poverty stricken areas. This reduces the drain on the very limited money impoverished individuals have.

More than $10 billion is spent each year on kerosene for lighting in the homes of the poor in developing countries. Barefoot Power provides LED lights driven by fuel cells that collect solar power to help poor families stop spending their scarce cash by giving them a better and cheaper option.

Carbon emissions from burning kerosene are also heavily cut. Kerosene consumption for lighting is equal to 1.7 million barrels of oil per day, which is greater than the annual oil production of Libya. The Lawrence Berkley Laboratories state that the “single greatest way to reduce the green house gas emissions associated with lighting energy use is to replace kerosene lamps with white LED light systems in developing countries.”