A genetic tweak can make light work of some nervous disorders. Using flashes of light to stimulate modified neurons can restore movement to paralysed muscles. A study demonstrating this, carried out in mice, lays the path for using such "optogenetic" approaches to treat nerve disorders ranging from spinal cord injury to epilepsy and motor neuron disease.

Optogenetics has been hailed as one of the most significant recent developments in neuroscience. It involves genetically modifying neurons so they produce a light-sensitive protein, which makes them "fire", sending an electrical signal, when exposed to light.

So far optogenetics has mainly been used to explore how the brain works, but some groups are exploring using it as therapy. One stumbling block has been fears about irreversibly genetically manipulating the brain.

In the latest study, a team led by Linda Greensmith of University College London altered mouse stem cells in the lab before transplanting them into nerves in the leg this means they would be easier to remove if something went wrong.

"It's a very exciting approach that has a lot of potential," says Ziv Williams of Harvard Medical School in Boston.

Greensmith's team inserted an algal gene that codes for a light-responsive protein into mouse embryonic stem cells. They then added signalling molecules to make the stem cells develop into motor neurons, the cells that carry signals to and from the spinal cord to the rest of the body. They implanted these into the sciatic nerve which runs from the spinal cord to the lower limbs of mice whose original nerves had been cut.

After waiting five weeks for the implanted neurons to integrate with the muscle, Greensmith's team anaesthetised the mice, cut open their skin and shone pulses of blue light on the nerve. The leg muscles contracted in response. "We were surprised at how well this worked," says Greensmith.

Most current approaches being investigated to help people who are paralysed involve electrically stimulating their nerves or muscles. But this can be painful because they may still have working pain neurons. Plus, the electricity makes the muscles contract too forcefully, making them tire quickly.

Using the optogenetic approach, however, allows the muscle fibres to be stimulated more gently, because the light level can be increased with each pulse. "It gives a very smooth contraction," says Greensmith.

To make the technique practical for use in people, the researchers are developing a light-emitting diode in the form of a cuff that would go around the nerve, which could be connected to a miniature battery pack under the skin.

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Muscle paralysis eased by light-sensitive stem cells

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This is wild. Chasing the elusive dream of curing paralysis, a team of scientists used stem cells and optogenetics to circumvent the central motor system of lab mice whose nerves had been cut. This enabled them to blast individual motor neurons with a laser, triggering movement in the legs of the mice.

Okay, so it's a little bit complicated, if you're not familiar with how optogenetics work (and honestly, why would you be?). The cutting-edge technique enables neuroscientists to modify specific neurons so that they're light sensitive. Shining light on the neuron then makes it fire, telling the brain to move a muscle or stop feeling pain.

In the case of the paralyzed mice, researchers modified the animals' stem cells so they'd produce a light-sensitive protein. The stem cells were then programmed to turn into motor neurons and engrafted onto the sciatic nerves of the mice. All the reserachers had to do then was shine a light on the light sensitive motor neurons andboomthe mice weren't paralyzed any more. To be specific, the neurons fired and caused the once-paralyzed leg muscles to move. "We were surprised at how well this worked," says Linda Greensmith of University College London who led the team.

There's obviously a lot of work to be done before we start implanting stem cells and lasers into human legs, but this is an encouraging start. At the very least, it will help researchers better understand crippling neurological conditions like epilepsy. It's also a perfect entry in the annals of mad science. [Science via Science News]

Image via Shutterstock, Science

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Scientists Cured Paralysis in Mice with Stem Cells and Lasers

Laminine What is a Stem Cells
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Contact: B.D. Colen bd_colen@harvard.edu 617-413-1224 Harvard University

Harvard stem cell scientists have discovered that a recently approved medication for epilepsy may possibly be a meaningful treatment for amyotrophic lateral sclerosis (ALS)Lou Gehrig's disease, a uniformly fatal neurodegenerative disorder. The researchers are now collaborating with Massachusetts General Hospital to design an initial clinical trial testing the safety of the treatment in ALS patients.

The investigators all caution that a great deal needs to be done to assure the safety and efficacy of the treatment in ALS patients, before physicians should start offering it.

The work, laid out in two related papers in the April 3 online editions of Cell Stem Cell and Cell Reports, is the long-term fruition of studies by Harvard Stem Cell Institute (HSCI) Principal Faculty member Kevin Eggan, PhD, who, in a 2008 Science paper, first raised the possibility of using ALS patient-derived stem cells to better understand the disease and identify therapeutic targets for new drugs.

Now Eggan and HSCI colleague Clifford Woolf, MD, PhD, have found that the many independent mutations that cause ALS may be linked by their ability to trigger abnormally high activity in motor neurons. Using neurons derived from stem cells made from ALS patient skin cells, the two research teams conducted clinical trials of the anti-epilepsy medication on neurons in laboratory dishes, finding that it reduced the hyperexcitability of the cells.

ALS is a devastating and currently untreatable degradation of motor neurons, the long nerve cells that connect the spinal cord to the muscles of the body. While several potential treatments have looked promising in mice, all proved disappointing in the clinic.

"The big problem in ALS is that there are more than a hundred mutations in dozens of genes that all cause the disease, but almost all of the therapeutics that have gone forward in the clinic have done so for just one of those mutations, SOD1, which almost everyone studies in mice," said Eggan, a professor in Harvard's Department of Stem and Regenerative Biology.

"And so," he continued, "the key question that we really wanted to address wasare clinical efforts failing because the mouse is taking us on a wild goose chase, or is it simply that people haven't had the opportunity to pre-test whether their ideas are true across lots of forms of ALS?"

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Patient stem cells help identify common problem in ALS

Just weeks after invalidating a groundbreaking paper describing a simple technique for generating pluripotent stem cells, professor Kenneth Ka Ho Lee now believes he has identified the correct approach.

Lee, chief of stem cell research at the Chinese University of Hong, spoke to Wired.co.uk in March about his tentative excitement when he read the Nature study in question, published at the start of the year. The proposed Stap cells (stimulus-triggered acquisition of pluripotency) in it were a revelation, because they suggested there was a simple way to generate embryonic-like stem cells that could potentially be used in the treatment of diseases such as Parkinson's. The method involved reprogramming a donor's own adult blood and skin cells (in this case, mice) by exposing them to extreme trauma, such as an acid bath.

Lee could see its potential, but like the rest of the community he had his doubts. While reports circulated that the images published in the Nature study also featured in older papers penned by lead researcher Haruko Obokata of Japan's Riken Centre, Lee set about trying to replicate the experiment himself.

It didn't work.

Since then the Riken Centre has launched an investigation into the legitimacy of the trial, and that investigation today revealed Obokata had indeed falsified information, including results and images of DNA fragments used.

"Actions like this completely destroy data credibility," commented Shunsuke Ishii, head of the investigative committee and a Riken molecular geneticist, at a press conference. "There is no doubt that she was fully aware of this danger. We've therefore concluded this was an act of research misconduct involving fabrication." Obokata has denied the allegations, but Riken says its own research team will be the one to verify the results and carry out the experiment again.

In the interim however, a coauthor on the paper at the centre of the debacle,Charles Vacanti published yet another protocol for the Stap technique, fairly different from the original. Vacanti, of ear-on-a-mouse fame, is a professor at Harvard Medical School and published online what he said was found to be "an effective protocol for generating Stap cells in our lab, regardless of the cell type being studied". It was a combination of the two approaches mentioned in the Naturepaper -- the acid bath, and the trituration process (the application of pressure on the cells using pipettes to induce stress). He describes the latter process as being exerted with force, more so than in the original paper, and over a lengthy period -- twice a day for the first week.

Nature had already rejected Lee's version of experiments for publication last month. Undeterred, he set about applying Vacanti's technique. Liveblogging the experiments on ResearchGate, the open source platform where Lee had published his first set of experiments, the Hong Kong researcher immediately saw the excess stress was leading to rapid cell death among the lung fibroblast cells used.

"The Vacanti protocol put a deal of emphasis on mechanically passing the cells through narrow bore glass pipettes for 30 minutes before acid treatment and then growing the cells on non-adhesive culture plates," Lee told Wired.co.uk. "We conducted these experiments, but it did not induce expression of the pluripotent stem cell markers (Oct4, Sox2 and Nanog)."

Nevertheless, things appeared to turn around. In his preliminary studies Lee has concluded that it could be the extreme stress through trituration, and not the acid bath, that was responsible for creating the Stap cells.

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'Fabricated' stem cell paper technique may yet be proven valid