University of Rochester Medical Center

Human brain cells in a mouse glow green because researchers have tagged them with a gene that looks green under fluorescent light. Mice with the human cell transplants were smarter than normal mice, the researchers report.

Researchers who transplanted human brain cells into newborn mice said the rodents grew up to be smarter than their normal littermates, learning how to associate a tone with an electric shock more quickly and finding escape hatches faster.

The experiments are aimed at making models to study human brain diseases such as Huntington’s and schizophrenia, as well as nerve diseases such as multiple sclerosis. But the team at the University of Rochester say their findings also suggest that these brain cells, called glial cells, may very well be one of the important factors that make humans different from other animals.

“Human cognitive evolution might be the product of glial evolution,” said Dr. Steven Goldman, who worked with his partner and wife Dr. Maiken Nedergaard on the study. Their findings also support the growing theory that glia cells, one of the important components of the brain’s so-called white matter, are far from being passive support cells and are in fact actively involved in brain function.

Down the road, Goldman hopes the findings might lead to procedures to transplant brain cells to treat diseases as diverse as multiple sclerosis, bipolar disease and even the brain shrinkage that causes memory loss in aging.

“There are a number of diseases that are specific to humans -- neuropsychiatric diseases, schizophrenia, bipolar disease. Animals don’t get these,” Goldman said in a telephone interview. Apes might – it’s not clear. “One of the possibilities is that neuropsychiatric disorders may have evolved with glial evolution.”

Writing in the journal Cell Stem Cell, Nedergaard and Goldman said they were trying to find ways to cure mice of multiple sclerosis, which is caused when nerve cells lose their fatty coating of myelin and stop working properly. They used immature cells called glial progenitor cells taken from aborted fetuses, infused them into the brains of newborn mice, and watched what happened.

Progenitor cells are partly along the path to from undefined to “adult” cells, and seem to have a better ability to flourish when transplanted. The human glial cells not only survived in the brains of the mice – they thrived, Goldman says.

"The human glia cells essentially took over to the point where virtually all of the glial progenitor cells and a large proportion of the astrocytes in the mice were of human origin, and essentially developed and behaved as they would have in a person's brain," said Goldman.

Human glia are far more complex than mouse glia, and they help form many, many more connections, called synapses, between neurons. The more synapses, the faster and better the brain works. Tests in lab dishes showed the mouse brains with human cells transmitted signals much more quickly than normal mouse brains.

“So here we have these brains where most of the glia are human. And we know that human glia are different from those of most of other species,” Goldman says. “Have their cognitive abilities been enhanced?”

They put the animals to the test -- first a simple one called a conditioned fear response. “You expose the animals to a tone and a very mild shock,” Goldman said. “Mice don’t like to get shocked and they learn to associate the tone with the shock. Mice, when they are afraid, they freeze.” The mice with the human glia froze faster and stayed frozen longer than thieir littermates without human glia, Goldman and Nedergaard found.

“It is a really dramatic effect,” Goldman said. Some learned after just one shock to fear the tone.

Another test involved learning to find and use an escape hatch. Again, the mice with human glial cells learned faster.

To make sure it wasn’t just the transplant of fresh cells that was improving learning, the researchers transplanted mouse progenitor glial cells into newborn mice. These animals did not learn any faster.

Goldman isn’t worried that he is somehow making mice with human brains. “We are not humanizing the mice,” he says. “We were affecting the brain activity with human glial cells ... These are still mouse brains, bottom line.” Transplanting neurons might be a different matter, he said.

There are many animals that carry human cells -- from the millions of lab mice injected with human tumor cells to study cancer, to sheep engineered to produce human liver cells. But the experiment raises a red flg, says bioethicist Arthur Caplan of New York University medical center.

"This experiment is the ethical equivalent of Superstorm Sandy," Caplan says. "It brings together a controversial source of stem cells -- obtained from aborted fetuses to create human-animal chimeras which frighten many members of the public and Congress.  The utility of the work for understanding diseases and the development of therapies for them is enormous but it is vitally important that an agreed upon, transparent and enforced set of rules and review processes be instituted to govern further research using stem cells from humans in animal brains or vice versa."

These new mice might be used to study ways to treat a range of human diseases. The technique of transplanting progenitor cells into newborns might hold special promise in treating genetic diseases such as Niemann-Pick or Tay-Sachs disease, Goldman says.

These diseases both are marked by abnormal brain cells, including glia. “It is possible that by introducing normal glial cells in these kids we may well be able to treat these disorders with cell transplants,” he said.  

The technique is most definitely not a way to make people smarter, he said. But it could restore some of the normal damage caused in aging. Some cases of vascular dementia are in fact not caused by little strokes in the brain, but are age-related white matter loss, Goldman asserts. “As we get older we lose more and more white matter,” he said.

It’s possible glial cell transplants could help. But transplants of brain cells into adult mice don’t work as well. The cells take up residence but they don’t multiply and take over the way they do in the newborns, whose brains are still developing, Goldman said.

Last month, Goldman and Nedergaard reported they made human glial progenitor cells out of ordinary human skin cells that had been reprogrammed so they acted like embryonic stem cells. These so-called induced pluripotent stem cells – iPS cells for short – might one day be used as grow-your-own transplants, made using a patient’s own cells. They’d be a perfect genetic match.

The science isn’t quite there yet but researchers hope iPS cells, which are made without creating a human embryo, would be a more ethically acceptable alternative to human embryonic stem cells. That would be the route to making brain cells to treat human adults, Goldman said.

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By Rachael Rettner
MyHealthNewsDaily

Very obese children and teens may be at risk for multiple sclerosis, a new study suggests.

In the study, very obese girls (those who had a body mass index (BMI) of 35 or higher) were nearly four times more likely to be diagnosed with multiple sclerosis (MS) within the study period, compared with girls who were normal weight. The link was strongest among teenagers.

No link between obesity and multiple sclerosis was found for girls in other weight classes, or for boys.

In people with MS, the immune system attacks the nerve cells of the brain and spinal cord, producing symptoms such as numbness, loss of balance, weakness and tremors. MS is rare in children — about one to two kids out of every 100,000 will develop the condition. Symptoms are similar in children and adults, although youngsters may also experience symptoms not typical of MS, such as seizures or lethargy, according to the National Multiple Sclerosis Society.

The findings suggest that, as the prevalence of childhood obesity increases, so will cases of multiple sclerosis, said study researcher Dr. Annette Langer-Gould, of Kaiser Permanente Southern California Department of Research & Evaluation in Pasadena, Calif.

"Our study suggests that parents or caregivers of obese girls and teenagers should pay attention to symptoms such as tingling and numbness or limb weakness, and bring them to a doctor's attention," said Langer-Gould.

However, the study only found an association, and cannot prove that obesity causes multiple sclerosis. It could be that an aspect of the condition itself — such as having trouble exercising before the condition is diagnosed — predisposes youngsters to obesity. But if this were the case, researchers would expect to see the same link in girls and boys, which the study did not find, Langer-Gould said.

The researchers analyzed information from 75 children and teens ages 2 to 18 who were diagnosed with pediatric MS, and compared them with more than 913,000 children and teens who did not have MS. For those with MS, BMI was measured before the condition was diagnosed.

Obesity is known to increase inflammation in the body, which may be involved in the development of MS, Langer-Gould said. Estrogen, a female hormone, also increases inflammation, and together with other inflammatory factors released from fat cells, could accelerate the development of MS, Langer-Gould said. The involvement of estrogen might explain why the link was only seen in girls.

"The authors certainly have opened the door to an interesting association," said Dr. Michael Duchowny, a pediatric neurologist and director of academic affairs at Miami Children's Hospital Research Institute, who was not involved in the study. "These findings need to be repeated, expanded and clarified further" with additional research, including studies that test the estrogen hypothesis, Duchowny said.

Previous studies in adults have suggested that obesity, or related factors, such as levels of appetite hormones, play a role in the development of MS, said Dr. Steven Mandel,  a neurologist at Lenox Hill Hospital in New York City.

"It doesn't mean that if you're obese or overweight ,you're going to develop MS," but rather, that a link between the two conditions exists, Mandel said. The findings may be another reason to bring childhood obesity under control, he said.

Although preliminary, some saw the findings as hopeful.

"We're beginning to accumulate a good deal of information about some of the environmental factors that may play a role in MS, and environmental factors that are possible to be modified," such as smoking and obesity, said Dr. Nicholas LaRocca, vice president of health care delivery at the National Multiple Sclerosis Society. "That’s a very exciting possibility," LaRocca said.

The study will be published today (Jan. 30) in the journal Neurology.

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Researchers trying to find a way to treat multiple sclerosis think they’ve come up with an approach that could not only help patients with MS, but those with a range of so-called autoimmune diseases, from type-1 diabetes to psoriasis, and perhaps even food allergies.

So far it’s only worked in mice, but it has worked especially well. And while mice are different from humans in many ways, their immune systems are quite similar.

“If this works, it is going to be absolutely fantastic,” said Bill Heetderks, who directs outside research at the National Institute of Biomedical Imaging and Bioengineering, part of the National Institutes of Health, which helped pay for the research. “Even if it doesn’t work, it’s going to be another step down the road.”

In autoimmune disease, the body’s immune cells mistakenly attack and destroy healthy tissue. In MS, it’s the fatty protective sheath around the nerves; in type-1 or juvenile diabetes it’s cells in the pancreas that make insulin; in rheumatoid arthritis it’s tissue in the joint. 

Currently, the main treatment is to suppress the immune system, an approach that can leave patients vulnerable to infections and cancer. The new treatment re-educates the immune cells so they stop the attacks.

The approach uses tiny little balls called nanoparticles made of the same material used to make surgical sutures that dissolve harmlessly in the body. They’re attached to little bits of the protein that the immune cells are attacking, the researchers report in Sunday’s issue of the journal Nature Biotechnology.

Stephen Miller of the Northwestern University Feinberg School of Medicine in Chicago had been trying a slightly different approach to treating MS. When normal cells die naturally through a self-destruction process called apoptosis, immune cells called macrophages come in and eat up the mess.

The macrophages are carried to the spleen where they show these ground-up bits of cells to other immune cells called T-cells. It’s a kind of introduction that familiarizes the T-cells with the body’s normal cells. Then T-cells know not to attack healthy cells.

Miller’s team had been trying to find ways to use this process to re-educate the T-cells. They have been attaching bits of the myelin that T-cells mistakenly attack to healthy cells from MS patients that were self-destructing, then infusing the concoction back into MS patients.

The idea would be to “introduce” the myelin to the T-cells at the same time they were “meeting” the healthy tissue, and educate them to leave the myelin alone.

So far the team has only shown the process is safe – a phase 1 clinical trial. But Miller says the experiment also seemed to show they were beginning to repair the patients’ immune systems. However, it was hideously expensive. “It cost probably about a million dollars to treat 10 patients using live cells,” he said.

Obviously, the researchers needed something cheaper. Miller got together with Lonnie Shea, a professor of chemical and biological engineering at Northwestern. They substituted cheap little balls of plastic called polystyrene nanoparticles for the self-destructing cells.

These new nanoparticles stopped the course of a MS-like disease in mice, the researchers found. But polystyrene is no good to use in people. It doesn’t break down and contains a compound, styrene, that may cause cancer.

Shea had another possibility, called poly(lactide-co-glycolide) or PLG for short. “It turns out this is an FDA approved substance that is used in resorbable sutures,” said Miller.

“There is nothing rare or exotic or strange here,” said NIBIB’s Heetderks. The particles are easy to produce, he said.

This worked just as well in mice. It only takes an hour in a chemical bath to attach little bits of myelin to the nanoparticles of PLG. When infused into a vein, they’re carried by the blood right to the spleen, where the nanoparticles “meet” the T-cells.

If the treatment was done as soon as the mice had their first MS-like attack, the attacks stopped. The effects lasted for the entire lives of the mice, Miller said.

What’s great about the approach,  Miller says, is that it can be used to treat any autoimmune disease. For diabetes, little bits of pancreatic beta cells could be attached to the nanoparticles. For a food allergy, the part of the food that causes the allergic response could be attached.  “You can try to induce tolerance to peanuts or eggs or shellfish or whatever you are allergic to,” he said.

One shortcoming is that scientists don’t always know what’s causing an autoimmune disease. “We know that in rheumatoid arthritis, your joints get attacked, but what we don’t know really well is what specific protein in your joints is being attacked. We really need to know that before we can apply this therapy,” Miller said.

Now the researchers are looking for funding so they can test this new approach in people. They’re in discussions with the Juvenile Diabetes Research Foundation to test it in people with type-1 diabetes, and the Myelin Repair Foundation to test it in MS patients, Miller said. They may form their own company to develop it as a medical treatment, something that would be years away.

Mice don’t live very long, and it’s not clear if human patients would need repeat treatments. But the T-cells that are re-educated usually live for a long time in the body, and have long memories, Miller said.

It’s also clear the approach would not repair any damage already done by the disease, so the best candidates would be patients having their very first symptoms. But it might be possible down the road to combine the nanoparticle treatment with another treatment to replace the damaged tissue in more advanced patients, Miller said.

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Multiple sclerosis is a horrible disease afflicting an estimated 400,000 Americans. There is no cure and little understanding of the cause, even though the patterns of MS leave many tantalizing clues.

An experimental drug called BG-12 helps reduce the number of “flare-ups" in the disease, researchers reported on Wednesday -- much like the nine other drugs already approved to treat MS.

MS occurs because the immune system – mostly disease-fighting T-cells – destroy the myelin sheath, the coating on the outside of brain and spinal nerve cells. This doesn’t happen continually, but in separate attacks or flare-ups, often a year or more apart. No part of the brain or spinal cord seems resistant. Although people with MS can appear very healthy, these autoimmune attacks often inflict severe damage.

“MS can affect vision, movement, strength, sensation, bowel, bladder, sexual function, mood, cognition," says Dr. Robert Fox, a neurologist at the Cleveland Clinic who headed the BG-12 study. "Everything the brain does can be impaired from MS.”

Like most autoimmune diseases, it's possible MS is set off by a viral infection. After the infection, the immune system starts to mistake neurons for virus or infected cells and destroys them. The evidence for a viral role comes from studies done in the Orkney, Shetland and Faroe Islands off Scotland. All these islands share similar geography and ethnic makeup. Prior to 1943, the Orkneys and Shetlands had a high incidence of MS, and the Faroe Islands almost none. Then it evened out. The best guess is that the movement of British troops spread a virus.

Despite this and similar other areas that became infected at a certain time, scientists have yet to identify the virus.

There also strong evidence for genetic susceptibility. Much of that comes from the incidence of MS among various ethnic groups. Caucasians have the highest incidence. Some ethic groups have almost no MS. These include the Inuit of Canada, Yakuts of Russia, the Hutterites, a religious group in Montana, Hungarian Romani, Norwegian Lapps, Australian Aborigines and New Zealand Maoris.

Many populations in Africa almost never suffer MS, but when they migrate to Europe or the U.S. their rates go up. Many Asian populations have almost no MS, and for them migration does not seem to increase susceptibility. In general, MS seems to occur far more often in cooler climates than closer to the equator. Also like many autoimmune diseases, hormones seem to play a role. MS occurs about three times as often in women as men — especially for cases diagnosed for people in their 20s, 30s, and 40s.

Scientists have focused on each of these clues. But none has so far yielded the cause or a cure for the disease. And although people with MS have near-average life expectancies, until there are better medications, they will likely end up in a wheelchair with many other disabilities.

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By Rachael Rettner
MyHealthNewsDaily

Smoking marijuana may improve some symptoms of multiple sclerosis, a new study suggests.

Patients with multiple sclerosis in the study had less muscle tightness, also called spasticity, and less pain after they smoked marijuana, compared with after they took a placebo.

Spasticity is a common symptom of multiple sclerosis (MS) and can cause exaggerated reflexes, spasms and problems walking. Existing medications can ease spasticity, but they cause side effects, and not all MS patients are helped by them.

However, patients in the study experienced short-term decreases in their abilities to pay attention and concentrate after they smoked marijuana. Patients also reported feeling "high" after smoking marijuana, and two patients withdrew from the study because they felt uncomfortably high.

More research is needed to confirm the findings and to investigate whether lower doses of marijuana may have similar benefits with fewer adverse effects, said study researcher Dr. Jody Corey-Bloom, professor of neurosciences and director of the Multiple Sclerosis Center at the University of California, San Diego.

The study is published today (May 14) in the Canadian Medical Association Journal.

Improved symptoms

Previous studies have suggested marijuana use may have benefits for MS patients, but most have investigated oral forms of the drug, including mouth sprays and capsules. In addition, most studies have asked patients to report changes in their symptoms, rather than having a researcher objectively assess them.

In the new study, Corey-Bloom and colleagues evaluated 30 MS patients, 19 of whom were female, and more than half of whom needed walking aids.

Participants were randomly assigned to receive treatment with a marijuana cigarette or a placebo cigarette, which did not contain delta-9-tetrahydrocannabinol (THC), the active ingredient of marijuana. Participants smoked a marijuana cigarette once a day for three consecutive days under the supervision of a researcher. Eleven days later, participants repeated the procedure, but this time, they switched treatment groups so that everyone received the marijuana cigarette and placebo at some point in the study. On average, participants smoked four puffs of their cigarettes at each session.

Shortly after each treatment session, the researchers assessed participants with a test specifically designed to measure spasticity.

After smoking marijuana, participants experienced a 30 percent reduction in spasticity, compared with when they smoked the placebo cigarette, Corey-Bloom said.

However, patients did not see improvements in the time it took them to walk 25 feet. And 45 minutes after their sessions, participants experienced a small but significant decrease in scores on tests designed to measure attention and concentration.

Participants were not told whether they recieved a placebo or a true marijuana cigarette, more than half correctly guessed the sessions when they were given marijuana.

Marijuana prescriptions?

The researchers are not advocating marijuana prescriptions for MS patients, Corey-Bloom said. They undertook the study to investigate whether anecdotal reports from MS patients about the benefits of marijuana smoking held up under the scrutiny of science. "I'm not a proponent for marijuana smoking at all," Corey-Bloom said.

Although cannabis may one day be used to treat spasticity in MS patients, delivery through a marijuana cigarette is "probably not the way that it would be done," because of the side effects patients experience, said Dr. Nicholas LaRocca, vice president of health care delivery at the National Multiple Sclerosis Society, who was not involved in the study. "The majority of people with MS experience cognitive changes at some point in their lives," LaRocca said. "We don’t want to add any additional cognitive deficits with treatment," he said.

Researchers are currently investigating other treatments for spasticity, including exercise and Botox injections. "We need to continue to explore all of those possibilities, because any given person with MS may respond better to one [treatment] than another," LaRocca said.

Because many studies have not found a benefit of marijuana for MS patients, and because the new study was small, it's important for researchers to replicate the findings, said Dr. Karen Blitz-Shabbir, director of the Multiple Sclerosis Center at North Shore-Long Island Jewish Health System in Manhasset, N.Y.

Marijuana cigarettes have disadvantages compared with oral forms of the drug, including potential effects on the lungs and problems with administrating a controlled dose, Blitz-Shabbir said.

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