Scientists Implant Monkeys’ Cells Back Into Their Own Brains
The research is a step along the way to personalized stem cell therapies.
A Neuron This is a photo of neuron created from a stem cell, but it is not one of the cells that was implanted in the monkeys in the study below. Courtesy Yan Liu and Su-Chun Zhang, Waisman Center, University of Wisconsin–Madison
Scientists have taken cells from rhesus monkeys’ skin, turned them into neural cells, then implanted them successfully into the monkeys’ brains. After six months, the transplanted cells showed no scarring and looked healthy and normal—except that they glowed green, a characteristic the scientists added to the cells so they could find the cells later.
The feat is a basic step toward personalized stem cell therapies, in which people might get treated for diseases using their own healthy cells. Of course, a study in monkeys—and one that didn’t cure any disease—is a long way from something your doctor could order. But that’s the eventual aim of studies like this.
The research team, from the University of Wisconsin in Madison, first took skin samples from three rhesus monkeys. They used the famed Yamanaka cocktail to transform those skin cells into pluripotent stem cells, a kind of “blank slate” cell that’s able to develop into any type of cell in the body. It was just the kind of experiment that Popular Science predicted would take off in 2013.
After making stem cells from skin cells, the Wisconsin team coaxed the stem cells into becoming something completely different: early-stage neural cells. At this point, the researchers implanted the cells back into the monkeys, in which they had artificially induced a Parkinson’s-like disorder.
Once inside the monkey brains, the neural cells finished their maturation, got great jobs and their own apartments… I mean, they turned into specialized brain cells called neurons, astrocytes and oligodendrocytes. They didn’t die, get rejected by the monkeys’ brains as foreign, or appear cancerous, all of which have happened in some previous stem cell implant studies.
Although the new brain cells settled well into the monkeys’ brains, there weren’t enough of them to improve the monkeys’ Parkinson’s symptoms. The researchers will still have to see if they can implant cells that actually help with symptoms. And they’ll need to keep checking on the monkeys’ brains in the months and years to come, to make sure the implants don’t cause problems later on.
The Wisconsin team published their work today in the journal Cell Reports.
[University of Wisconsin-Madison]
Advance in tuberous sclerosis brain science
May is Tuberous Sclerosis Complex awareness month
Doctors often diagnose tuberous sclerosis complex (TSC) based on the abnormal growths the genetic disease causes in organs around the body. Those overt anatomical structures, however, belie the microscopic and mysterious neurological differences behind the disease’s troublesome behavioral symptoms: autism, intellectual disabilities, and seizures. In a new study in mice, Brown University researchers highlight a role for a brain region called the thalamus and show that the timing of gene mutation during thalamus development makes a huge difference in the severity of the disease.
TSC can arise in humans and mice alike when both alleles (the one from mom and the one from dad) of the TSC1 gene are deleted. One bad gene is often inherited and the other accumulates a mutation some time during embryonic development. This happens to one in 6,000 people.
“We don’t know when during development the mutations are occurring in the patients,” said Elizabeth Normand, a Brown neuroscience graduate student and lead author of the paper in the journal Neuron. “That’s why we chose to look at the timing. It can give us some insight into the role of genes during embryonic development.”
Normand and adviser Mark Zervas, assistant professor of biology, not only wanted to assess the timing but also to probe the role the thalamus might have in contributing to the neurological symptoms of the disease. To do both, their team genetically engineered a clever mouse model in which they could, with a dose of the drug tamoxifen, delete both alleles exclusively in thalamus neurons at the developmental stage of their choosing.
Their interest in the thalamus comes from its role in forging strong but intricate links to the cortex, which is where most other TSC researchers have focused. As for timing, they tested the effect of controlling allele deletions on day 12 of gestation in some mice and day 18 (just before birth) in others. Still other mice were left healthy as experimental controls.
Overall, the researchers found they could indeed generate TSC-like behavioral symptoms in the mice, such as seizures, by deleting TSC1 alleles in developing cells of the thalamus. They also found that the timing of the deletion mattered tremendously to the extent of the disease in the brain, the degree of abnormality, and the severity of TSC-like symptoms.
The mice whose alleles were deleted on embryonic day 12 fared much worse behaviorally than the mice whose alleles were deleted on embryonic day 18.
At two months of age, the mice with the embryonic day 12 deletion exhibited excessive self-grooming to the point where they experienced lesions. Among those mice, 10 of 11 experienced seizures at an average rate of more than three per hour.
The mice with the embryonic day 18 deletion, on the other hand, fared better without any over-grooming. By eight months of age, however, four of 17 of the mice did exhibit rare seizures.
These behavioral differences traced to differences in the the way the mice’s brains became wired. A comparison of brain tissue from adult mice — some of which had the early TSC1 deletions and some of which didn’t — revealed differences in the connections between the thalamus and the cortex and in the electrical and physical properties of thalamus cells.
“We’re building off the core idea of the thalamus playing an important role in brain function and showing that if you disrupt the way that the thalamic neurons develop that you can get some of these behavioral consequences such as overgrooming or seizures,” said Zervas, who is affiliated with the Brown Institute for Brain Science.
The extent of mutant neurons was much more severe in the mice with the embryonic day 12 versus day 18 mutations. In embryonic day 12 deleted mice, for example, the deletion disrupted the growth-regulating “mTOR” pathway in 70 percent of neurons versus only 29 percent of neurons in the embryonic day 18 deleted mice. The disruptions occurred in more areas of the thalamus in embryonic day 12 than in day 18 mice as well. The overactivity of mTOR in TSC is what produces the unusual growths around the body, though these new findings indicate additional roles for the mTOR pathway in brain development and function, Zervas said.
In future work, the team plans to study the effects of deleting the TSC1 allele at other days during development as well as to understand whether there is a threshold of mutant neurons with mTOR disruption at which TSC-like symptoms begin to emerge.
Image: Neurons from the thalamus of control mice with healthy genes glow green (left), while those whose two Tsc1 alleles were deleted during embryonic development show a strong red glow (right), indicating disruption of the mTOR pathway that regulates growth.Credit: Zervas Lab/Brown University
Scientists show how nerve wiring self-destructs
Many medical issues affect nerves, from injuries in car accidents and side effects of chemotherapy to glaucoma and multiple sclerosis. The common theme in these scenarios is destruction of nerve axons, the long wires that transmit signals to other parts of the body, allowing movement, sight and sense of touch, among other vital functions.
Now, researchers at Washington University School of Medicine in St. Louis have found a way the body can remove injured axons, identifying a potential target for new drugs that could prevent the inappropriate loss of axons and maintain nerve function.
“Treating axonal degeneration could potentially help a lot of patients because there are so many diseases and conditions where axons are inappropriately lost,” says Aaron DiAntonio, MD, PhD, professor of developmental biology. “While this would not be a cure for any of them, the hope is that we could slow the progression of a whole range of diseases by keeping axons healthy.”
DiAntonio is senior author of the study that appears online May 9 in the journal Cell Reports.
While axonal degeneration appears to be a major culprit in diseases like multiple sclerosis, it also paradoxically plays an important role in properly wiring the nervous systems of developing embryos.
“When an embryo is building its nervous system, there can be inappropriate or excessive axonal sprouts, or axons that are only needed at one time in development and not later,” DiAntonio says. “These axons degenerate, and that’s very important for wiring the nervous system. And in adult organisms, it might be useful to have a clean and quick way to remove a damaged axon from a healthy nerve, instead of letting it decay and potentially damage its neighboring axons.”
DiAntonio compares the process to programmed cell death, or apoptosis, which is also important in embryonic development. Apoptosis culls unnecessary or damaged cells from the body. If cell death programs become overactive, they can kill healthy cells that should remain. And if apoptosis fails to destroy damaged cells in adults, it can lead to cancer.
The new discovery also underscores the relatively recent understanding that loss of axons is not a passive decay process resulting from injury. Just as apoptosis actively destroys cells, axonal degeneration results from a cellular program that actively removes the damaged axon. In certain diseases, the program may be inappropriately triggered.
“We want to understand axonal degeneration at the same level that we understand programmed cell death, in the hopes of developing drugs to block the process when it becomes overactive,” DiAntonio says.
DiAntonio’s major collaborators in this project include Jeffrey D. Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics, and first author Elisabetta Babetto, PhD, postdoctoral research scholar.
Studying mice, the researchers found that a gene called Phr1 plays a major role in governing the self-destruction of injured axons. When they removed Phr1 from adult mice, the severed portion of the axons remained intact for much longer than in genetically normal mice.
In the normal mice, a severed axon degenerated entirely after two days. In mice without Phr1, they found that about 75 percent of the severed axons remained at five days, with a quarter persisting at least 10 days after being cut. The mice showed no side effects and suffered no obvious problems due to the missing Phr1.
The findings raise the possibility that blocking the Phr1 protein with a drug could keep damaged axons alive and functional when the body would normally cause the axons to self-destruct.
DiAntonio emphasizes that he is not trying to save axons that have no connection to the rest of the nerve. The paradigm is simply a good way to model nerve injury. In many instances, such as a crush injury or disease processes in which the axon is not severed, blocking the Phr1 protein could potentially preserve an attached axon that would otherwise self-destruct.
Importantly, the research team also looked at optic nerves of the central nervous system, which are damaged in glaucoma, and found similar protective effects from the loss of Phr1.
“This is not the first gene identified whose loss protects mammalian axons from degeneration,” DiAntonio says. “But it is the first one that shows evidence of working in the central nervous system. So it could be important in conditions like glaucoma, multiple sclerosis and other neurodegenerative diseases where the central nervous system is the primary problem.”
DiAntonio also points out possible ways to help cancer patients. Many chemotherapy drugs cause damage to peripheral axons, which may limit the doses a patient can tolerate.
As part of the new study, the researchers showed that intact axons without Phr1 were protected from the damage caused by vincristine, a chemotherapy drug used to treat leukemia, neuroblastoma, Hodgkin’s disease and non-Hodgkin’s lymphoma, among other cancers.
“In this case, the loss of axons is not caused by disease,” DiAntonio says. “It’s caused by the drug doctors are giving. You know the date it will start. You know the date it will stop. This is probably where I am most optimistic that we could make an impact.”
Image: Many medical issues affect nerves, from injuries in car accidents and side effects of chemotherapy to glaucoma and multiple sclerosis. The common theme in these scenarios is destruction of nerve axons, the long wires that transmit signals to other parts of the body, allowing movement, sight and sense of touch, among other vital functions. Now, researchers at Washington University School of Medicine in St. Louis have found a way the body can remove injured axons, identifying a potential target for new drugs that could prevent the inappropriate loss of axons and maintain nerve function. Mouse nerve axons (green) connect to muscle synapses (red) to coordinate movement. Three days after injury, these axons are protected from degeneration because they are missing Phr1, a gene involved in removing damaged axons from the body. In mice that have the gene, injured green axons fragment and disappear by the third day, leaving the red muscle synapses without nerve connections. Credit: Elisabetta Babetto, Ph.D.
Adventures in Neurohumanities
At Stanford University in 2012, a young literature scholar named Natalie Phillips oversaw a big project: a new way of studying the nineteenth-century novelist Jane Austen. No surprise there—Austen, a superstar of English literature and the inspiration for an endless array of Hollywood and BBC productions based on her work, has been the subject of thousands of scholarly papers.
But the Stanford study was different. Phillips used a functional magnetic resonance imaging (fMRI) machine to track the blood flow of readers’ brains when they read Mansfield Park. The subjects—mostly graduate students—were asked to skim an excerpt and then read it closely. The results were part of a study on reading and distraction.
The “neuro novel” story was quickly picked up by the mainstream media, from NPR to The New York Times. But the Austen project wasn’t merely a clever one-off—the brainchild, so to speak, of one imaginatively interdisciplinary scholar. And it wasn’t just the result of ambitious academics crossing brain science with “the marriage plot” in unholy matrimony simply to grab headlines. The Stanford study reflects a real trend in the humanities. At Yale University, Lisa Zunshine, now a literature scholar at the University of Kentucky, was part of a research team that studied modernist authors using fMRI, also in order to better understand reading. Rather than a cramped office or library carrel, the researchers got to use the Haskins Laboratory in New Haven, with funding by the Teagle Foundation, to carry out their project, in which twelve participants were given texts with higher and lower levels of complexity and had their brains monitored. (via Adventures in Neurohumanities | The Nation)
People provided with a real-time readout of activity in specific regions of their brains can learn to control that activity and lessen their anxiety, say Yale researchers.
They used functional magnetic resonance imaging (fMRI), to display the activity of the orbitofrontal cortex (a brain region just above the eyes) to subjects while they lay in a brain scanner.
Through a process of trial and error, these subjects were gradually able to learn to control their brain activity. This led both to changes in brain connectivity and to increased control over anxiety. These changes were still present several days after the training.
Extreme anxiety associated with worries about dirt and germs is characteristic of many patients with obsessive-compulsive disorder (OCD). Hyperactivity in the orbitofrontal cortex is seen in many of these individuals.
I’ll be at the Toronto Comics Arts Festival this weekend!
Primates isn’t officially out yet, but I have 10 copies of the book that I’m giving away for free. There’s a slight catch; if you want a book, you have to do a little work (I promise that it’s FUN work). Come see me for more info!
I’ll also have a bunch of other stuff (books and prints)!
Food artist Michelle Wibowo Creates Edible Beyonce Portrait from 3780 Oreo Pops