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Shock. Disbelief. Euphoria. Choose your emotion. All these feelings washed over Linda Watkins as she huddled in front of the computer last year in her cramped Boulder office.

Months earlier, the CU-Boulder distinguished professor and her colleagues in the psychology and chemistry/biochemistry departments had injected two rats with a drug that induces multiple sclerosis, a chronic, often disabling disease that attacks the central nervous system.

Once the rats developed severe neurological damage, including paralysis, Watkins injected one of them with a compound called XT101, an anti-inflammatory drug that her CU-Boulder laboratory discovered and was being developed by Xalud Therapeutics to treat chronic pain.

When the results came in the untreated rat remained paralyzed, able to do little more than drag his limp body a few inches. Meanwhile, the other rat was not only apparently pain free but appeared symptom free, able to move naturally.

In other words, Watkins鈥檚 research team had made a paralyzed rat walk.

In the breathless moments that followed, an intriguing possibility entered her mind: Could a drug originally developed to remedy chronic pain actually be capable of treating and reversing the effects of MS? In the United States approximately 400,000 people live with MS and 200 more are diagnosed per week, according to the National Multiple Sclerosis Society. Symptoms can range from numbness in the limbs to paralysis.

鈥淢y reaction was literally, 鈥極h my God. This is huge,鈥� 鈥欌�� she says. 鈥淲e weren鈥檛 looking for a cure to paralysis. We were looking for a way to treat neuropathic pain. It was complete serendipity. There was nothing in the scientific literature at that time that said [the drug] could do this to paralysis.鈥�

Having now seen quite similar results with a second drug, ATL313, that has a similar mechanism of action, there鈥檚 additional promise in this new approach.

A possible breakthrough

The news is spreading fast as Watkins now lays the groundwork for further study, including raising funds from venture capitalists.

But the next challenge is more formidable: determining if MS lesions 鈥� or scars 鈥� are being healed in rats that receive XT101 or ATL313.

We weren鈥檛 looking for a cure to paralysis. We were looking for a way to treat neuropathic pain. It was complete serendipity. There was nothing in the scientific literature at that time that said [the drug] could do this to paralysis.鈥�

Myelin is the protective sheath that surrounds nerve cells in the spinal cord and brain. In a disease of the central nervous system like MS, loss of myelin results in erratic nerve signals that cause weakness or paralysis, impaired sensation, vision problems and lack of coordination. As the disease progresses, myelin develops lesions that result in irreversible damage.

鈥淲hat happens now with MS drugs is they slow or stop the progression, but they don鈥檛 treat it,鈥� she says. 鈥淭hey don鈥檛 take people back to normal because they don鈥檛 heal the lesions. But if we have a drug that can heal the lesions, this treatment could be a major breakthrough in how we treat the symptoms of MS.鈥欌��

Developing a commercial drug to remedy the chronic pain in MS is a more reachable and immediate goal for Watkins, whose remarkable career at CU has combined study of chronic pain and immunology with a maverick鈥檚 boldness. The disease is two to three times more common in women and most people are diagnosed between ages 20-50, although it can appear in young children, teens and older adults.

鈥淭he therapies out there for MS 鈥� while they鈥檙e improving 鈥� still don鈥檛 provide the relief patients want,鈥� says Jayson Rieger of PGxHealth, a company based in Newton, Mass., that develops drugs for central nervous system disorders and cardiovascular diseases, and who works with Watkins on ATL313. 鈥淎s with any sort of pain or neurological disease, not every drug will work with all patients. So adding another one for these patients is always very valuable.鈥欌��

Rieger emphasizes the importance for scientists to push the envelope to see what is and what isn鈥檛 feasible. He notes Watkins listens to and understands the conventional wisdom, thinks about it, then thinks about ways the paradigm can be changed and adapted to look at things differently.

鈥淭he integrity of her scientific data has always been profound,鈥� Rieger says. 鈥淭he approach she has taken to scientific problems has evolved. She鈥檚 developed new hypotheses on why pain exists. That led to the MS [study] where there might be an overlap.鈥欌��

Battling pain

Originally aiming to become a classical musician, Watkins switched to biology and psychology in the mid-1970s at Virginia Tech.

鈥淚 was going to become the next Jane Goodall,鈥欌�� says Watkins who then decided to focus on a research career as an undergraduate student at Virginia [Tech]. 鈥淚 just kind of fell into it. As I started doing it I fell in love with doing research.鈥�

She pursued graduate studies, focusing on chronic pain, first at UCLA and then at the Medical College of Virginia.

Following a brief interlude in private business in California, Watkins used a National Science Foundation grant to move to Boulder in 1988.

鈥淚 wanted to get retrained in immunology,鈥� she says. 鈥淏oulder had a really good lab for that. I could keep my background in pain research but combined with immunology.鈥�

What Watkins and other scientists have known for a long time is that the sensation of pain travels from the site of injury via electrical impulses that hop from one nerve cell to the next, ultimately climbing the spinal cord to the brain, where the pain is perceived.

Pop an aspirin, take a nap and the pain will fade by morning. Break an arm? Morphine will wash away the agony. But imagine the worst possible toothache. Picture the pain spreading throughout your body, pain that persists for years.

That鈥檚 chronic pain, a pathological state afflicting between 15 and 30 percent of the population in some form. Unlike ordinary acute pain, which is a function of a healthy nervous system, chronic pain resembles a disease, a pathology of the nervous system that produces abnormal changes in the brain and spinal cord.

At CU Watkins has become a pioneer in the study of how glial cells in the central nervous system act as key players in pain enhancement by exciting neurons that transmit pain signals. Glial cells don鈥檛 send signals to the brain, but they do release substances that amplify the pain message, like the crowd egging a bully on. Watkins also found glial cells impair the abilities of opiates like morphine to suppress pain.

鈥淲hat has become evident is that glial cells have a Dr. Jekyll and Mr. Hyde personality,鈥� Watkins says. 鈥淯nder normal circumstances they do all these really good things for the neurons, but when they shift into the Mr. Hyde formation they release a whole host of chemicals that cause problems like neuropathic pain and other chronic pain conditions.

鈥淭hat鈥檚 why we think glial cells are very, very critical. That鈥檚 why we think all the drugs out there fail. They鈥檙e targeting neurons.鈥�

Watkins says that blaming drug failure on the wrong target 鈥� neurons 鈥� was a pretty heretical view for a long time But she says it has gone from a very out-there thing 10 years ago to being very much accepted.

Gene therapy to control pain

In 2010 CU signed an option agreement with biotech company Xalud Therapeutics allowing Watkins鈥� research team to work jointly with the California company to move forward with her laboratory鈥檚 discovery of a novel non-viral gene therapy to control chronic pain. The therapy involves giving patients the DNA for interleukin-10, which calms down the 鈥淢r. Hyde鈥� glia back to 鈥淒r. Jekyll鈥� through a nonsurgical lumbar puncture injection once every few months. This is XT101, which Xalud Therapeutics is trying to move into clinical trials once sufficient investment funding is raised. It is hoped that ATL313 will also move into clinical trials for pain and MS.

The secret to both XT101 and ATL313 is that they are delivered by a simple injection right where they are needed around the spinal cord.

鈥淭hat keeps it localized,鈥欌�� Watkins says. 鈥淭hat鈥檚 what鈥檚 so amazing. It鈥檚 a single injection and it completely resolves neuropathic pain for three months. Your back pain would go away for three months. We moved into MS after that. Seventy to 80 percent of MS patients have chronic pain that drugs don鈥檛 treat.鈥欌��

Because rats are inoculated with their own myelin protein, they create antibodies that attack their nervous system after developing MS symptoms. Progressive paralysis begins at the tip of the tail and, when full tail paralysis occurred Watkins鈥� staff injected some of them with the XT101 or ATL313 treatment with the aim of remedying pain.

Watkins鈥檚 team not only saw that MS pain went away with drug treatment but also came up with a different finding 鈥� namely arrest and reversal of paralysis. This infused her and her team spearheaded by senior research associate Lisa Loram with a sense of urgency.

鈥淸Linda] is a very strategic collaborator,鈥欌�� Rieger says. 鈥淪he finds ways of bringing people together and asking questions of the right people at the right time so that new opportunities can be tested.

Sitting in her office in jeans, a wool shirt and running shoes, Watkins is surrounded by plaques and awards, including Spain鈥檚 2010 Prince of Asturias Award, which recognizes world leaders in science and technology.

But waiting down the road could be her signature moment.

鈥淵ou don鈥檛 have many discoveries like this,鈥欌�� she says.

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Get involved with Watkins鈥� research and its potential to transform lives by giving to the .

Clay Latimer is a freelance writer for the Coloradan.

Photo by Ivan Martinez/FPA听