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Manufacturing Dopamine in the Brain with Gene Therapy

Parkinson’s patients who take the drug levodopa, or L-Dopa, are inevitably disappointed. At first, during a “honeymoon” period, their symptoms (which include tremors and balance problems) are brought under control. But over time the drug becomes less effective. They may also need ultrahigh doses, and some start spending hours a day in a state of near-frozen paralysis.

A biotech company called Voyager Therapeutics now thinks it can extend the effects of L-Dopa by using a surprising approach: gene therapy. The company, based in Cambridge, Massachusetts, is testing the idea in Parkinson’s patients who’ve agreed to undergo brain surgery and an injection of new DNA.

Parkinson’s occurs when dopamine-making neurons in the brain start dying, causing movement symptoms that afflicted boxing champ Muhammad Ali and actor Michael J. Fox, whose charitable foundation has helped pay for the development of Voyager’s experimental treatment.

The cause of Parkinson’s isn’t well understood, but the reason the drug wears off is. It’s because the brain also starts losing an enzyme known as aromatic L-amino acid decarboxylase, or AADC, that is needed to convert L-Dopa into dopamine.

Voyager’s strategy, which it has begun trying on patients in a small study, is to inject viruses carrying the gene for AADC into the brain, an approach it thinks can “turn back the clock” so that L-Dopa starts working again in advanced Parkinson’s patients as it did in their honeymoon periods.

Videos of patients before and after taking L-Dopa make it obvious why they’d want the drug to work at a lower dose. In the ‘off’ state, people move in slow motion. Touching one’s nose takes an effort. In an ‘on’ state, when the drug is working, they’re shaky, but not nearly so severely disabled.

“They do well at first but then respond very erratically to L-Dopa,” says Krystof Bankiewicz, the University of California scientist who came up with the gene-therapy plan and is a cofounder of Voyager. “This trial is to restore the enzyme and allow them to be awakened, or ‘on,’ for a longer period of time.”

Voyager was formed in 2013 and later went public, raising about $86 million. The company is part of a wave of biotechs that have been able to raise money for gene therapy, a technology that is starting to pay off: after three decades of research, a few products are reaching the market.

Unlike conventional drug studies, those involving gene therapy often come with very high expectations that the treatment will work. That’s because it corrects DNA errors for which the exact biological consequences are known. Genzyme, a unit of the European drug manufacturer Sanofi, paid Voyager $65 million and promised hundreds of millions more in order to sell any treatments it develops in Europe and Asia.

“We’re working with 60 years of dopamine pharmacology,” says Steven Paul, Voyager’s CEO, and formerly an executive at the drug giant Eli Lilly. “If we can get the gene to the right tissue at the right time, it would be surprising if it didn’t work.”

But those are big ifs. In fact, the concept for the Parkinson’s gene therapy dates to 1986, when Bankiewicz first determined that too little AADC was the reason L-Dopa stops working. He thought gene therapy might be a way to fix that, but it wasn’t until 20 years later that he was able to test the idea in 10 patients, in a study run by UCSF.

In that trial, Bankiewicz says, the gene delivery wasn’t as successful as anticipated. Not enough brain cells were updated with the new genetic information, which is shuttled into them by viruses injected into the brain. Patients seemed to improve, but not by much.

Even though the treatment didn’t work as planned, that early study highlighted one edge Voyager’s approach has over others. It is possible to tag AADC with a marker chemical, so doctors can actually see it working inside patients’ brains. In fact, ongoing production of the dopamine-making enzyme is still visible in the brains of the UCSF patients several years later.

It is possible to tag AADC with a marker chemical, so doctors can actually see it working inside patients’ brains. Image Source: MIT Technology Review.

In some past studies of gene therapy, by contrast, doctors had to wait until patients died to find out whether the treatment had been delivered correctly. “This is a one-and-done treatment,” says Paul. “And anatomically, it tells us if we got it in the right place.”

A new trial under way, this one being carried out by Voyager, is designed to get much higher levels of DNA into patients’ brains in hopes of achieving better results. To do that, Bankiewicz developed a system to inject the gene-laden viral particles through pressurized tubes while a patient lies inside an MRI scanner. That way, the surgeon can see the putamen, the brain region where the DNA is meant to end up, and make sure it’s covered by the treatment.

There are other gene therapies for Parkinson’s disease planned or in testing. A trial developed at the National Institutes of Health seeks to add a growth factor and regenerate cells. A European company, Oxford BioMedica, is trying to replace dopamine.

Altogether, as of this year, there were 48 clinical trials under way of gene or cell replacement in the brain and nervous system, according to the Alliance for Regenerative Medicine, a trade group. The nervous system is the fourth most common target for this style of experimental treatment, after cancer, heart disease, and infections.

Voyager’s staff is enthusiastic about a study participant they call “patient number 6,” whom they’ve been tracking for several months—ever since he got the treatment. Before the gene therapy, he was on a high dose of L-Dopa but still spent six hours a day in an “off” state. Now he’s off only two hours a day and takes less of the drug.

That patient got the highest dose of DNA yet, covering the largest brain area. That is part of what makes Voyager think higher doses should prove effective. “I believe that previous failure of gene-therapy trials in Parkinson’s was due to suboptimal delivery,” says Bankiewicz.

Image Credit: L.A. JOHNSON

Source: MIT Technology Review (by Antonio Regalado)

The Portuguese man o’ war delivers a powerful sting to its prey—and sometimes to people—through venom-filled structures on its tentacles. It is not a jellyfish, but rather a colony of different types of zooids (small animals). Jean Louis Coutant engraved the plate for this illustration.

(Image caption: Antidepressants move G proteins out of lipid rafts in the cell membrane. Credit: Molly Huttner)

Why do antidepressants take so long to work?

An episode of major depression can be crippling, impairing the ability to sleep, work, or eat. In severe cases, the mood disorder can lead to suicide. But the drugs available to treat depression, which can affect one in six Americans in their lifetime, can take weeks or even months to start working.

Researchers at the University of Illinois at Chicago have discovered one reason the drugs take so long to work, and their finding could help scientists develop faster-acting drugs in the future. The research was published in the Journal of Biological Chemistry.

Neuroscientist Mark Rasenick of the UIC College of Medicine and colleagues identified a previously unknown mechanism of action for selective serotonin reuptake inhibitors, or SSRIs, the most commonly prescribed type of antidepressant. Long thought to work by preventing the reabsorption of serotonin back into nerve cells, SSRIs also accumulate in patches of the cell membrane called lipid rafts, Rasenick observed, and the buildup was associated with diminished levels of an important signal molecule in the rafts.

“It’s been a puzzle for quite a long time why SSRI antidepressants can take up to two months to start reducing symptoms, especially because we know that they bind to their targets within minutes,” said Rasenick, distinguished professor of physiology and biophysics and psychiatry at UIC. “We thought that maybe these drugs have an alternate binding site that is important in the action of the drugs to reduce depressive symptoms.”

Serotonin is thought to be in short supply in people with depression. SSRIs bind to serotonin transporters – structures embedded within nerve-cell membranes that allow serotonin to pass in and out of the nerve cells as they communicate with one another. SSRIs block the transporter from ferrying serotonin that has been released into the space between neurons – the synapse – back into the neurons, keeping more of the neurotransmitter available in the synapse, amplifying its effects and reducing symptoms of depression.

Rasenick long suspected that the delayed drug response involved certain signaling molecules in nerve-cell membranes called G proteins.

Previous research by him and colleagues showed that in people with depression, G proteins tended to congregate in lipid rafts, areas of the membrane rich in cholesterol. Stranded on the rafts, the G proteins lacked access to a molecule called cyclic AMP, which they need in order to function. The dampened signaling could be why people with depression are “numb” to their environment, Rasenick reasoned.

In the lab, Rasenick bathed rat glial cells, a type of brain cell, with different SSRIs and located the G proteins within the cell membrane. He found that they accumulated in the lipid rafts over time — and as they did so, G proteins in the rafts decreased.

“The process showed a time-lag consistent with other cellular actions of antidepressants,” Rasenick said. “It’s likely that this effect on the movement of G proteins out of the lipid rafts towards regions of the cell membrane where they are better able to function is the reason these antidepressants take so long to work.”

The finding, he said, suggests how these drugs could be improved.

“Determining the exact binding site could contribute to the design of novel antidepressants that speed the migration of G proteins out of the lipid rafts, so that the antidepressant effects might start to be felt sooner.”

Rasenick already knows a little about the lipid raft binding site. When he doused rat neurons with an SSRI called escitalopram and a molecule that was its mirror image, only the right-handed form bound to the lipid raft.

“This very minor change in the molecule prevents it from binding, so that helps narrow down some of the characteristics of the binding site,” Rasenick said.

COLORS OF CHEMISTRY

The bright colors of chemistry fascinate people of all ages. Hriday Bhattacharjee, a Ph.D. student in the lab of Jens Mueller at the University of Saskatchewan, assembled this showcase from compounds he prepared as well as from some synthesized by the undergraduate students he teaches. Organometallic and inorganic chemistry—the study of molecules like these that involve metal atoms—is especially colorful.

The table below the picture indicates the chemicals seen in the photo.

Submitted by Hriday Bhattacharjee

Do science. Take pictures. Win money: Enter our photo contest.

Clear as Day

The more light your eyes can take in, the better the picture you see, and the lens at the front of your eye is transparent to help this. Most body cells contain lots of membranes – they have important roles like manufacturing cellular components, but they scatter light and aren’t transparent. Cells in the lens become transparent by losing all but their most vital internal membranes as they develop and move towards the middle of the lens: the central cells (shown here in a chick’s eye) are flatter, with rounder nuclei (blue). It wasn’t known how the membranes were lost until recently, when scientists discovered a structure called the excisosome. This forms inside cells and breaks down the membranes, possibly by stripping them apart into the proteins and lipids they’re made of. Current research implies that excisosomes form in the lenses of all animals, helping us understand how our eyes develop.

Written by Esther Redhouse White

Image from work by M.Joseph Costello and colleagues

Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA

Image originally published under a Creative Commons Licence (BY 4.0)

Published in PLOS One, August 2016

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Quote from #JaneGoodall primatologist and anthropologist. More quotes like this to inspire you in my new journal I Love Science, in stores March but ready for preorder now! #womeninscience #ilovescience #anthropology #scientificliteracy

Science Fact Friday: Tetrodotoxin, ft. a small gif because I’m avoiding my real obligations. Why does tetrodotoxin not affect its host? More studies need to be done but at least a few species possess mutated sodium ion channels. The tetrodotoxin can’t interact efficiently with the altered channels.

Another interesting tidbit: Animals with tetrodotoxin can lose their toxicity in captivity. It is suspected that the animals accumulate the toxic bacteria as a side-effect of their diet. After several years of captivity on a tetrodotoxin-bacteria-free diet, the bacterial colonies living in the animals die, residual toxin is cleared from the system, and the animal is safe to handle.

Shocking New Role Found for the Immune System: Controlling Social Interactions

In a startling discovery that raises fundamental questions about human behavior, researchers at the University of Virginia School of Medicine have determined that the immune system directly affects – and even controls – creatures’ social behavior, such as their desire to interact with others.

So could immune system problems contribute to an inability to have normal social interactions? The answer appears to be yes, and that finding could have significant implications for neurological diseases such as autism-spectrum disorders and schizophrenia.

“The brain and the adaptive immune system were thought to be isolated from each other, and any immune activity in the brain was perceived as sign of a pathology. And now, not only are we showing that they are closely interacting, but some of our behavior traits might have evolved because of our immune response to pathogens,” explained Jonathan Kipnis, chair of UVA’s Department of Neuroscience. “It’s crazy, but maybe we are just multicellular battlefields for two ancient forces: pathogens and the immune system. Part of our personality may actually be dictated by the immune system.”

Evolutionary Forces at Work

It was only last year that Kipnis, the director of UVA’s Center for Brain Immunology and Glia, and his team discovered that meningeal vessels directly link the brain with the lymphatic system. That overturned decades of textbook teaching that the brain was “immune privileged,” lacking a direct connection to the immune system. The discovery opened the door for entirely new ways of thinking about how the brain and the immune system interact.

(Image caption: Normal brain activity, left, and a hyper-connected brain. Credit: Anita Impagliazzo, UVA Health System)

The follow-up finding is equally illuminating, shedding light on both the workings of the brain and on evolution itself. The relationship between people and pathogens, the researchers suggest, could have directly affected the development of our social behavior, allowing us to engage in the social interactions necessary for the survival of the species while developing ways for our immune systems to protect us from the diseases that accompany those interactions. Social behavior is, of course, in the interest of pathogens, as it allows them to spread.

The UVA researchers have shown that a specific immune molecule, interferon gamma, seems to be critical for social behavior and that a variety of creatures, such as flies, zebrafish, mice and rats, activate interferon gamma responses when they are social. Normally, this molecule is produced by the immune system in response to bacteria, viruses or parasites. Blocking the molecule in mice using genetic modification made regions of the brain hyperactive, causing the mice to become less social. Restoring the molecule restored the brain connectivity and behavior to normal. In a paper outlining their findings, the researchers note the immune molecule plays a “profound role in maintaining proper social function.”

“It’s extremely critical for an organism to be social for the survival of the species. It’s important for foraging, sexual reproduction, gathering, hunting,” said Anthony J. Filiano, Hartwell postdoctoral fellow in the Kipnis lab and lead author of the study. “So the hypothesis is that when organisms come together, you have a higher propensity to spread infection. So you need to be social, but [in doing so] you have a higher chance of spreading pathogens. The idea is that interferon gamma, in evolution, has been used as a more efficient way to both boost social behavior while boosting an anti-pathogen response.”

Understanding the Implications

The researchers note that a malfunctioning immune system may be responsible for “social deficits in numerous neurological and psychiatric disorders.” But exactly what this might mean for autism and other specific conditions requires further investigation. It is unlikely that any one molecule will be responsible for disease or the key to a cure. The researchers believe that the causes are likely to be much more complex. But the discovery that the immune system – and possibly germs, by extension – can control our interactions raises many exciting avenues for scientists to explore, both in terms of battling neurological disorders and understanding human behavior.

“Immune molecules are actually defining how the brain is functioning. So, what is the overall impact of the immune system on our brain development and function?” Kipnis said. “I think the philosophical aspects of this work are very interesting, but it also has potentially very important clinical implications.”

Findings Published

Kipnis and his team worked closely with UVA’s Department of Pharmacology and with Vladimir Litvak’s research group at the University of Massachusetts Medical School. Litvak’s team developed a computational approach to investigate the complex dialogue between immune signaling and brain function in health and disease.

“Using this approach we predicted a role for interferon gamma, an important cytokine secreted by T lymphocytes, in promoting social brain functions,” Litvak said. “Our findings contribute to a deeper understanding of social dysfunction in neurological disorders, such as autism and schizophrenia, and may open new avenues for therapeutic approaches.”

The findings have been published online by the prestigious journal Nature.

Giant Artwork Reflects The Gorgeous Complexity of The Human Brain

The new work at The Franklin Institute may be the most complex and detailed artistic depiction of the brain ever.

Your brain has approximately 86 billion neurons joined together through some 100 trillion connections, giving rise to a complex biological machine capable of pulling off amazing feats. Yet it’s difficult to truly grasp the sophistication of this interconnected web of cells.

Now, a new work of art based on actual scientific data provides a glimpse into this complexity.

The 8-by-12-foot gold panel, depicting a sagittal slice of the human brain, blends hand drawing and multiple human brain datasets from several universities. The work was created by Greg Dunn, a neuroscientist-turned-artist, and Brian Edwards, a physicist at the University of Pennsylvania, and goes on display at The Franklin Institute in Philadelphia. 

“The human brain is insanely complicated,” Dunn said. “Rather than being told that your brain has 80 billion neurons, you can see with your own eyes what the activity of 500,000 of them looks like, and that has a much greater capacity to make an emotional impact than does a factoid in a book someplace.”

To reflect the neural activity within the brain, Dunn and Edwards have developed a technique called micro-etching: They paint the neurons by making microscopic ridges on a reflective sheet in such a way that they catch and reflect light from certain angles. When the light source moves in relation to the gold panel, the image appears to be animated, as if waves of activity are sweeping through it.

First, the visual cortex at the back of the brain lights up, then light propagates to the rest of the brain, gleaming and dimming in various regions — just as neurons would signal inside a real brain when you look at a piece of art.

That’s the idea behind the name of Dunn and Edwards’ piece: “Self Reflected.” It’s basically an animated painting of your brain perceiving itself in an animated painting.

To make the artwork resemble a real brain as closely as possible, the artists used actual MRI scans and human brain maps, but the datasets were not detailed enough. “There were a lot of holes to fill in,” Dunn said. Several students working with the duo explored scientific literature to figure out what types of neurons are in a given brain region, what they look like and what they are connected to. Then the artists drew each neuron.

Dunn and Edwards then used data from DTI scans — a special type of imaging that maps bundles of white matter connecting different regions of the brain. This completed the picture, and the results were scanned into a computer. Using photolithography, the artists etched the image onto a panel covered with gold leaf.

“A lot of times in science and engineering, we take a complex object and distill it down to its bare essential components, and study that component really well” Edwards said. But when it comes to the brain, understanding one neuron is very different from understanding how billions of neurons work together and give rise to consciousness.

“Of course, we can’t explain consciousness through an art piece, but we can give a sense of the fact that it is more complicated than just a few neurons,” he added.

The artists hope their work will inspire people, even professional neuroscientists, “to take a moment and remember that our brains are absolutely insanely beautiful and they are buzzing with activity every instant of our lives,” Dunn said. “Everybody takes it for granted, but we have, at the very core of our being, the most complex machine in the entire universe.”

Image 1: A computer image of “Self Reflected,” an etching of a human brain created by artists Greg Dunn and Brian Edwards.

Image 2: A close-up of the cerebellum in the finished work.

Image 3: A close-up of the motor cortex in the finished work.

Image 4: This is what “Self Reflected” looks like when it’s illuminated with all white light.

Image 5: Pons and brainstem close up.

Image 6: Putkinje neurons - color encodes reflective position in microetching.

Image 7: Primary visual cortex in the calcarine fissure.

Image 8: Basal ganglia and connected circuitry.

Image 9: Parietal cortex.

Image 10: Cerebellum.

Credit for all Images: Greg Dunn - “Self Reflected”

Source: The Huffington Post (by Bahar Gholipour)