Viruses: You’ve heard the bad — here’s the good

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“The word, virus, connotes morbidity and mortality, but that bad reputation is not universally deserved,” said Marilyn Roossinck, PhD, Professor of Plant Pathology and Environmental Microbiology and Biology at the Pennsylvania State University, University Park. “Viruses, like bacteria, can be important beneficial microbes in human health and in agriculture,” she said. Her review of the current literature on beneficial viruses appeared ahead of print April 24 in the Journal of Virology, which is published by the American Society for Microbiology.

In sharp contrast to the gastrointestinal distress it causes in humans, the murine (mouse infecting) norovirus plays a role in development of the mouse intestine and its immune system, and can actually replace the beneficial effects of certain gut bacteria when these have been decimated by antibiotics. Normal, healthy gut bacteria help prevent infection by bacteria that cause gastrointestinal illness, but excessive antibiotic intake can kill the normal gut flora, and make one vulnerable to gastrointestinal disease. However, norovirus infection of mice actually restored the normal function of the immune system’s lymphocytes and the normal morphology of the intestine, said Roossinck.

Mammalian viruses can also provide immunity against bacterial pathogens. Gamma-herpesviruses boost mice resistance to Listeria monocytogenes, an important human gastrointestinal pathogen, and to Yersinia pestis, otherwise known as plague. “Humans are often infected with their own gamma-herpes viruses, and it is conceivable that these could provide similar benefits,” said Roossinck.

Latent herpesviruses also arm natural killer cells, an important component of the immune system, which kill both mammalian tumor cells, and cells that are infected with pathogenic viruses.

The gastrointestinal tracts of mammals are plush with viruses. So far, little is known about how these viruses affect their hosts, but their sheer number and diversity suggest that they have important functions, said Roossinck. For example, GI viruses that infect bacteria–known as phage–may modulate expression of bacterial genes involved in host digestion.

Recent research shows that bacteriophage stick to the mucus membranes of many metazoans (the class “Animalia,” which includes everything from worms to wombats). And mucus membranes, Roossinck points out, are the points of entry for many bacterial pathogens, suggesting that they provide the first line of defense against invading bacteria.

Viruses also provide a variety of services for plants. A few plants grow in the hot soils surrounding the geysers and the “Artists’ Paintpots” of Yellowstone National Park. One such plant, which is a type of tropical panic grass, is a symbiosis that includes a fungus that colonizes the plant, and a virus that infects that fungus. All three members of this symbiosis are necessary for survival in soils simmering at more than 122 degrees Fahrenheit.

In the laboratory, Roossinck has created symbioses between the same virus-infected fungus and other plants. This has enabled every plant her group has tested to survive at these elevated soil temperatures, including tomato, she says, noting that she has pushed the soil temperature to 140 degrees without killing the plant.

Investigators have also found that certain viruses can render some plants drought tolerant, and at least one example of virally-conferred cold tolerance has been discovered– discoveries that could become useful for expanding the ranges of crops.

Plants are often infected with “persistent viruses” that are passed down from generation to generation, perhaps over thousands of years, with viruses that are transmitted to nearly 100 percent of their plant progeny, but that have never been shown to be transmitted from one plant to another. “One such virus, white clover crytpic virus, suppresses formation of nitrogen-fixing nodules when adequate nitrogen is present in the soil, saving the plant from producing a costly organ when it is not needed” said Roossinck.

Other beneficial viruses are the ancient retroviruses that long ago made a permanent home in the genome, or that left genes therein, said Roossinck. “The mammalian genes for syncitin, essential in the establishment of the placenta, are retroviral env genes that were incorporated on several different occasions,” Roossinck writes. “They even function differently in ruminants compared to other mammals… these elements are considered viral fossils that can help us understand the deep evolution of viruses.”

“Viruses are beyond a doubt the coolest things I have ever encountered,” said Roossinck. “They do truly amazing things with very little genetic information. I was always a little disturbed at the bad rap they get, so it was very exciting for me to find good ones.”

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Scientists discover key driver of human aging

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A study tying the aging process to the deterioration of tightly packaged bundles of cellular DNA could lead to methods of preventing and treating age-related diseases such as cancer, diabetes and Alzheimer’s disease, as detailed April 30, 2015, in Science.

Salk Institute researchers discovered that a proteinmutated in the premature aging disorder, Werner syndrome, plays a key rolein stabilizing heterochromatin, a tightly packaged form of DNA. Moregenerally, the findings suggest that heterochromatin disorganization maybe akey driver of aging. This image shows normal human cells (left) andgenetically modified cells developed by the Salk scientiststo simulate Werner syndrome (right), which showed signs of aging,including their larger size. Credit: Salk Institute

In the study, scientists at the Salk Institute and the Chinese Academy of Science found that the genetic mutations underlying Werner syndrome, a disorder that leads to premature aging and death, resulted in the deterioration of bundles of DNA known as heterochromatin.

The discovery, made possible through a combination of cutting-edge stem cell and gene-editing technologies, could lead to ways of countering age-related physiological declines by preventing or reversing damage to heterochromatin.

“Our findings show that the gene mutation that causes Werner syndrome results in the disorganization of heterochromatin, and that this disruption of normal DNA packaging is a key driver of aging,” says Juan Carlos Izpisua Belmonte, a senior author on the paper. “This has implications beyond Werner syndrome, as it identifies a central mechanism of aging–heterochromatin disorganization–which has been shown to be reversible.”

Werner syndrome is a genetic disorder that causes people to age more rapidly than normal. It affects around one in every 200,000 people in the United States. People with the disorder suffer age-related diseases early in life, including cataracts, type 2 diabetes, hardening of the arteries, osteoporosis and cancer, and most die in their late 40s or early 50s.

The disease is caused by a mutation to the Werner syndrome RecQ helicase-like gene, known as the WRN gene for short, which generates the WRN protein. Previous studies showed that the normal form of the protein is an enzyme that maintains the structure and integrity of a person’s DNA. When the protein is mutated in Werner syndrome it disrupts the replication and repair of DNA and the expression of genes, which was thought to cause premature aging. However, it was unclear exactly how the mutated WRN protein disrupted these critical cellular processes.

In their study, the Salk scientists sought to determine precisely how the mutated WRN protein causes so much cellular mayhem. To do this, they created a cellular model of Werner syndrome by using a cutting-edge gene-editing technology to delete WRN gene in human stem cells. This stem cell model of the disease gave the scientists the unprecedented ability to study rapidly aging cells in the laboratory. The resulting cells mimicked the genetic mutation seen in actual Werner syndrome patients, so the cells began to age more rapidly than normal. On closer examination, the scientists found that the deletion of the WRN gene also led to disruptions to the structure of heterochromatin, the tightly packed DNA found in a cell’s nucleus.

This bundling of DNA acts as a switchboard for controlling genes’ activity and directs a cell’s complex molecular machinery. On the outside of the heterochromatin bundles are chemical markers, known as epigenetic tags, which control the structure of the heterochromatin. For instance, alterations to these chemical switches can change the architecture of the heterochromatin, causing genes to be expressed or silenced.

The Salk researchers discovered that deletion of the WRN gene leads to heterochromatin disorganization, pointing to an important role for the WRN protein in maintaining heterochromatin. And, indeed, in further experiments, they showed that the protein interacts directly with molecular structures known to stabilize heterochromatin–revealing a kind of smoking gun that, for the first time, directly links mutated WRN protein to heterochromatin destabilization.

“Our study connects the dots between Werner syndrome and heterochromatin disorganization, outlining a molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by disrupting epigenetic regulation,” says Izpisua Belmonte. “More broadly, it suggests that accumulated alterations in the structure of heterochromatin may be a major underlying cause of cellular aging. This begs the question of whether we can reverse these alterations–like remodeling an old house or car–to prevent, or even reverse, age-related declines and diseases.”

Izpisua Belmonte added that more extensive studies will be needed to fully understand the role of heterochromatin disorganization in aging, including how it interacts with other cellular processes implicated in aging, such as shortening of the end of chromosomes, known as telomeres. In addition, the Izpisua Belmonte team is developing epigenetic editing technologies to reverse epigenetic alterations with a role in human aging and disease.

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Using nature to grow batteries

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Inspired by an abalone shell, Angela Belcher programs viruses to make elegant nanoscale structures that humans can use. Selecting for high-performing genes through directed evolution, she’s produced viruses that can construct powerful new batteries, clean hydrogen fuels and record-breaking solar cells. In her talk, she shows us how it’s done.

I thought I would talk a little bit about how nature makes materials. I brought along with me an abalone shell. This abalone shell is a biocomposite material that’s 98 percent by mass calcium carbonate and two percent by mass protein. Yet, it’s 3,000 times tougher than its geological counterpart. And a lot of people might use structures like abalone shells, like chalk. I’ve been fascinated by how nature makes materials, and there’s a lot of sequence to how they do such an exquisite job. Part of it is that these materials are macroscopic in structure, but they’re formed at the nanoscale. They’re formed at the nanoscale, and they use proteins that are coded by the genetic level that allow them to build these really exquisite structures.

So something I think is very fascinating is what if you could give life to non-living structures, like batteries and like solar cells? What if they had some of the same capabilities that an abalone shell did, in terms of being able to build really exquisite structures at room temperature and room pressure, using non-toxic chemicals and adding no toxic materials back into the environment? So that’s the vision that I’ve been thinking about. And so what if you could grow a battery in a Petri dish? Or, what if you could give genetic information to a battery so that it could actually become better as a function of time, and do so in an environmentally friendly way?

And so, going back to this abalone shell, besides being nano-structured, one thing that’s fascinating, is when a male and a female abalone get together, they pass on the genetic information that says, “This is how to build an exquisite material. Here’s how to do it at room temperature and pressure, using non-toxic materials.” Same with diatoms, which are shown right here, which are glasseous structures. Every time the diatoms replicate, they give the genetic information that says, “Here’s how to build glass in the ocean that’s perfectly nano-structured. And you can do it the same, over and over again.” So what if you could do the same thing with a solar cell or a battery? I like to say my favorite biomaterial is my four year-old.

But anyone who’s ever had, or knows, small children knows they’re incredibly complex organisms. And so if you wanted to convince them to do something they don’t want to do, it’s very difficult. So when we think about future technologies, we actually think of using bacteria and virus, simple organisms. Can you convince them to work with a new toolbox, so that they can build a structure that will be important to me?

Also, when we think about future technologies, we start with the beginning of Earth. Basically, it took a billion years to have life on Earth. And very rapidly, they became multi-cellular, they could replicate, they could use photosynthesis as a way of getting their energy source. But it wasn’t until about 500 million years ago — during the Cambrian geologic time period — that organisms in the ocean started making hard materials. Before that, they were all soft, fluffy structures. And it was during this time that there was increased calcium and iron and silicon in the environment, and organisms learned how to make hard materials. And so that’s what I would like be able to do — convince biology to work with the rest of the periodic table.

Now if you look at biology, there’s many structures like DNA and antibodies and proteins and ribosomes that you’ve heard about that are already nano-structured. So nature already gives us really exquisite structures on the nanoscale. What if we could harness them and convince them to not be an antibody that does something like HIV? But what if we could convince them to build a solar cell for us? So here are some examples: these are some natural shells.

There are natural biological materials. The abalone shell here — and if you fracture it, you can look at the fact that it’s nano-structured. There’s diatoms made out of SIO2, and they’re magnetotactic bacteria that make small, single-domain magnets used for navigation. What all these have in common is these materials are structured at the nanoscale, and they have a DNA sequence that codes for a protein sequence that gives them the blueprint to be able to build these really wonderful structures. Now, going back to the abalone shell, the abalone makes this shell by having these proteins. These proteins are very negatively charged. And they can pull calcium out of the environment, put down a layer of calcium and then carbonate, calcium and carbonate. It has the chemical sequences of amino acids, which says, “This is how to build the structure. Here’s the DNA sequence, here’s the protein sequence in order to do it.” And so an interesting idea is, what if you could take any material that you wanted, or any element on the periodic table, and find its corresponding DNA sequence, then code it for a corresponding protein sequence to build a structure, but not build an abalone shell — build something that, through nature, it has never had the opportunity to work with yet.

And so here’s the periodic table. And I absolutely love the periodic table. Every year for the incoming freshman class at MIT, I have a periodic table made that says, “Welcome to MIT. Now you’re in your element.” And you flip it over, and it’s the amino acids with the PH at which they have different charges. And so I give this out to thousands of people. And I know it says MIT, and this is Caltech, but I have a couple extra if people want it. And I was really fortunate to have President Obama visit my lab this year on his visit to MIT, and I really wanted to give him a periodic table. So I stayed up at night, and I talked to my husband, “How do I give President Obama a periodic table? What if he says, ‘Oh, I already have one,’ or, ‘I’ve already memorized it’?” (Laughter) And so he came to visit my lab and looked around — it was a great visit. And then afterward, I said, “Sir, I want to give you the periodic table in case you’re ever in a bind and need to calculate molecular weight.” And I thought molecular weight sounded much less nerdy than molar mass. And so he looked at it, and he said, “Thank you. I’ll look at it periodically.” (Laughter) (Applause) And later in a lecture that he gave on clean energy, he pulled it out and said, “And people at MIT, they give out periodic tables.”

So basically what I didn’t tell you is that about 500 million years ago, organisms starter making materials, but it took them about 50 million years to get good at it. It took them about 50 million years to learn how to perfect how to make that abalone shell. And that’s a hard sell to a graduate student. (Laughter) “I have this great project — 50 million years.” And so we had to develop a way of trying to do this more rapidly. And so we use a virus that’s a non-toxic virus called M13 bacteriophage that’s job is to infect bacteria. Well it has a simple DNA structure that you can go in and cut and paste additional DNA sequences into it. And by doing that, it allows the virus to express random protein sequences.

And this is pretty easy biotechnology. And you could basically do this a billion times. And so you can go in and have a billion different viruses that are all genetically identical, but they differ from each other based on their tips, on one sequence that codes for one protein. Now if you take all billion viruses, and you can put them in one drop of liquid, you can force them to interact with anything you want on the periodic table. And through a process of selection evolution, you can pull one out of a billion that does something that you’d like it to do, like grow a battery or grow a solar cell.

So basically, viruses can’t replicate themselves; they need a host. Once you find that one out of a billion, you infect it into a bacteria, and you make millions and billions of copies of that particular sequence. And so the other thing that’s beautiful about biology is that biology gives you really exquisite structures with nice link scales. And these viruses are long and skinny, and we can get them to express the ability to grow something like semiconductors or materials for batteries.

Now this is a high-powered battery that we grew in my lab. We engineered a virus to pick up carbon nanotubes. So one part of the virus grabs a carbon nanotube. The other part of the virus has a sequence that can grow an electrode material for a battery. And then it wires itself to the current collector. And so through a process of selection evolution, we went from being able to have a virus that made a crummy battery to a virus that made a good battery to a virus that made a record-breaking, high-powered battery that’s all made at room temperature, basically at the bench top. And that battery went to the White House for a press conference. I brought it here. You can see it in this case — that’s lighting this LED. Now if we could scale this, you could actually use it to run your Prius, which is my dream — to be able to drive a virus-powered car.

But it’s basically — you can pull one out of a billion. You can make lots of amplifications to it. Basically, you make an amplification in the lab, and then you get it to self-assemble into a structure like a battery. We’re able to do this also with catalysis. This is the example of photocatalytic splitting of water. And what we’ve been able to do is engineer a virus to basically take dye-absorbing molecules and line them up on the surface of the virus so it acts as an antenna, and you get an energy transfer across the virus. And then we give it a second gene to grow an inorganic material that can be used to split water into oxygen and hydrogen that can be used for clean fuels. And I brought an example with me of that today. My students promised me it would work. These are virus-assembled nanowires. When you shine light on them, you can see them bubbling. In this case, you’re seeing oxygen bubbles come out. And basically, by controlling the genes, you can control multiple materials to improve your device performance.

The last example are solar cells. You can also do this with solar cells. We’ve been able to engineer viruses to pick up carbon nanotubes and then grow titanium dioxide around them — and use as a way of getting electrons through the device. And what we’ve found is through genetic engineering, we can actually increase the efficiencies of these solar cells to record numbers for these types of dye-sensitized systems. And I brought one of those as well that you can play around with outside afterward. So this is a virus-based solar cell. Through evolution and selection, we took it from an eight percent efficiency solar cell to an 11 percent efficiency solar cell.

So I hope that I’ve convinced you that there’s a lot of great, interesting things to be learned about how nature makes materials — and taking it the next step to see if you can force, or whether you can take advantage of how nature makes materials, to make things that nature hasn’t yet dreamed of making.

Thank you.

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Transforming all donated blood into a universal type

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Every day, thousands of people need donated blood. But only blood without A- or B-type antigens, such as type O, can be given to all of those in need, and it’s usually in short supply. Now scientists are making strides toward fixing the situation. In ACS’ Journal of the American Chemical Society, they report an efficient way to transform A and B blood into a neutral type that can be given to any patient.

Stephen G. Withers and colleagues note that currently, blood transfusions require that the blood type of the donor match that of the recipient. If they aren’t the same, a patient can suffer serious side effects, and could even die. The exception is the universal-donor blood type O, which can be given to anyone because it doesn’t have the A or B antigens that could provoke an immune reaction. For years, scientists have been searching for a way to convert types A and B into type O. They found that some enzymes from bacteria can clip the sugars off red blood cells that give blood its “type.” But the enzymes are not very efficient. Withers’ team wanted to see if they could boost the enzymes’ activity.

The researchers tweaked one of those enzymes and improved its ability to remove type-determining sugars by 170-fold, rendering it antigen-neutral and more likely to be accepted by patients regardless of their blood type. In addition to blood transfusions, the researchers say their advance could potentially allow organ and tissue transplants from donors that would otherwise be mismatched.

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Recruiting the entire immune system to attack cancer

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The human immune system is poised to spring into action at the first sign of a foreign invader, but it often fails to eliminate tumors that arise from the body’s own cells. Cancer biologists hope to harness that untapped power using an approach known as cancer immunotherapy.

An illustration of T Lymphocytes on a Cancer Cell. Photo Credits: iStock via MIT News

Orchestrating a successful immune attack against tumors has proven difficult so far, but a new study from MIT suggests that such therapies could be improved by simultaneously activating both arms of the immune system. Until now, most researchers have focused on one of two strategies: attacking tumors with antibodies, which activate the innate immune system, or stimulating T cells, which form the backbone of the adaptive immune system.

By combining these approaches, the MIT team was able to halt the growth of a very aggressive form of melanoma in mice.

“An anti-tumor antibody can improve adoptive T-cell therapy to a surprising extent,” says Dane Wittrup, the Carbon P. Dubbs Professor in Chemical Engineering at MIT. “These two different parts of the immune therapy are interdependent and synergistic.”

Wittrup, an associate director of MIT’s Koch Institute for Integrative Cancer Research and also a faculty member in the Department of Biological Engineering, is the senior author of a paper describing the work this week in the journal Cancer Cell. Lead authors are graduate students Eric Zhu and Cary Opel and recent PhD recipient Shuning Gai.

Enlisting the immune system

Antibody drugs for cancer, which include rituximab and Herceptin, are believed to work by binding to cancer proteins and blocking the signals that tell cancer cells to divide uncontrollably. They may also draw the attention of cells belonging to the innate immune system, such as natural killer cells, which can destroy tumor cells.

Adoptive T cell therapy, on the other hand, enlists the body’s T cells to attack tumors. Billions of T cells flow through the average person’s bloodstream at any given time, each specialized to recognize different molecules. However, many tumor proteins do not provoke T cells to attack, so T cells must be removed from the patient and programmed to attack a specific tumor molecule.

Wittrup and his colleagues made the discovery that they could generate both types of immune responses while they were experimenting with improving antibody drug performance with a signaling molecule called IL-2, which helps boost immune responses.

Scientists have tried this strategy before, and about a dozen such therapies have gone through phase I clinical trials. However, most of these efforts failed, even though the antibody-IL-2 combination usually works very well against cancer cells grown in a lab dish.

The MIT team realized that this failure might be caused by the timing of IL-2 delivery. When delivered to cells in a dish, IL-2 sticks around for a long time, amplifying the response of natural killer cells against cancer cells. However, when IL-2 is injected into a patient’s bloodstream, the kidneys filter it out within an hour.

Wittrup and his colleagues overcame this by fusing IL-2 to part of an antibody molecule, which allows it to circulate in the bloodstream for much longer. In tests in mice with a very aggressive form of melanoma, the researchers found they could stop tumor growth by delivering this engineered form of IL-2, along with antibody drugs, once a week.

Immune synergy

To their surprise, the researchers found that T cells were the most important component of the anti-tumor response induced by the antibody-IL-2 combination. They believe that the synergy of IL-2-induced cells and cytokines, and the antibody treatment, creates an environment that lets T cells attack more effectively.

“The antibody-driven innate response creates an environment such that when the T cells come in, they can kill the tumor. In its absence, the tumor cells establish an environment where the T cells don’t work very well,” Wittrup says.

Cells called neutrophils, which are considered the immune system’s “first line of defense” because they react strongly to foreign invaders that enter the skin through a cut or other injury, were also surprisingly important.

“They’re a really powerful force in your immune system, but people in immunotherapy don’t usually focus on neutrophils. They don’t really consider them as a viable tool,” Zhu says. “It pointed us to the idea that although T cells and natural killer cells are important, maybe we’re forgetting about a part of the immune system that is also really important and could help us achieve our goals of ultimately curing the tumors.”

The researchers also found that when they delivered an antibody, IL-2, and T cells targeted to the tumor, the adoptively transferred T cells killed cancer cells much more successfully than when only T cells were delivered. In 80 to 90 percent of the mice, tumors disappeared completely; even when tumor cells were reinjected into the mice months after the original treatment, their immune systems destroyed the cells, preventing new tumors from forming

In a related paper that appeared recently in the Proceedings of the National Academy of Science, the MIT team also found that delivering IL-2 bound to any kind of antibody, even if the antibody did not target a protein on the tumor cell surface, would halt or slow tumor growth, especially if additional doses of the antibody alone were also given. Graduate student Alice Tzeng was the lead author of that study.

The researchers are now exploring additional proteins that could be added to the IL-2 and antibody combination to make immunotherapy more effective. In the meantime, simply giving patients more prolonged exposure to IL-2 could improve the effectiveness of existing antibody drugs, Wittrup says.

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The above story is based on materials provided by MIT News, Anne Trafton.

How to identify drugs that work best for each patient

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Implantable device could allow doctors to test cancer drugs in patients before prescribing chemotherapy.

More than 100 drugs have been approved to treat cancer, but predicting which ones will help a particular patient is an inexact science at best.

MIT chemical engineers have designed an implantable device that can deliver many drugs at once, allowing researchers to determine which drugs are the most effective against a patient’s tumor. Photo Credit:Eric Smith (edited by Jose-Luis Olivares/MIT)

A new device developed at MIT may change that. The implantable device, about the size of the grain of rice, can carry small doses of up to 30 different drugs. After implanting it in a tumor and letting the drugs diffuse into the tissue, researchers can measure how effectively each one kills the patient’s cancer cells.

Such a device could eliminate much of the guesswork now involved in choosing cancer treatments, says Oliver Jonas, a postdoc at MIT’s Koch Institute for Integrative Cancer Research and lead author of a paper describing the device in the April 22 online edition of Science Translational Medicine.

“You can use it to test a patient for a range of available drugs, and pick the one that works best,” Jonas says.

The paper’s senior authors are Robert Langer, the David H. Koch Professor at MIT and a member of the Koch Institute, the Institute for Medical Engineering and Science, and the Department of Chemical Engineering; and Michael Cima, the David H. Koch Professor of Engineering at MIT and a member of the Koch Institute and the Department of Materials Science and Engineering.

Putting the lab in the patient

Most of the commonly used cancer drugs work by damaging DNA or otherwise interfering with cell function. Recently, scientists have also developed more targeted drugs designed to kill tumor cells that carry a specific genetic mutation. However, it is usually difficult to predict whether a particular drug will be effective in an individual patient.

In some cases, doctors extract tumor cells, grow them in a lab dish, and treat them with different drugs to see which ones are most effective. However, this process removes the cells from their natural environment, which can play an important role in how a tumor responds to drug treatment, Jonas says.
“The approach that we thought would be good to try is to essentially put the lab into the patient,” he says. “It’s safe and you can do all of your sensitivity testing in the native microenvironment.”

The device, made from a stiff, crystalline polymer, can be implanted in a patient’s tumor using a biopsy needle. After implantation, drugs seep 200 to 300 microns into the tumor, but do not overlap with each other. Any type of drug can go into the reservoir, and the researchers can formulate the drugs so that the doses that reach the cancer cells are similar to what they would receive if the drug were given by typical delivery methods such as intravenous injection.

After one day of drug exposure, the implant is removed, along with a small sample of the tumor tissue surrounding it, and the researchers analyze the drug effects by slicing up the tissue sample and staining it with antibodies that can detect markers of cell death or proliferation.

Ranking cancer drugs

To test the device, the researchers implanted it in mice that had been grafted with human prostate, breast, and melanoma tumors. These tumors are known to have varying sensitivity to different cancer drugs, and the MIT team’s results corresponded to those previously seen differences.

The researchers then tested the device with a type of breast cancer known as triple negative, which lacks the three most common breast cancer markers: estrogen receptor, progesterone receptor, and Her2. This form of cancer is particularly aggressive, and none of the drugs used against it are targeted to a specific genetic marker.

Using the device, the researchers found that triple negative tumors responded differently to five of the drugs commonly used to treat them. The most effective was paclitaxel, followed by doxorubicin, cisplatin, gemcitabine, and lapatinib. They found the same results when delivering these drugs by intravenous injection, suggesting that the device is an accurate predictor of drug sensitivity.

In this study, the researchers compared single drugs to each other, but the device could also be used to test different drug combinations by putting two or three drugs into the same reservoir, Jonas says.
“This device could help us identify the best chemotherapy agents and combinations for every tumor prior to starting systemic administration of chemotherapy, as opposed to making choices based on population-based statistics. This has been a longstanding pursuit of the oncology community and an important step toward our goal of developing precision-based cancer therapy,” says Jose Baselga, chief medical officer at Memorial Sloan Kettering Cancer Center and an author of the paper.

The researchers are now working on ways to make the device easier to read while it is still inside the patient, allowing them to get results faster. They are also planning to launch a clinical trial in breast cancer patients next year.

“This is a stunning advance in the approach to treating complex cancers,” says Henry Brem, a professor of neurosurgery and oncology at Johns Hopkins School of Medicine who was not involved in the research. “This work is transformative in that it now opens the doors to truly personalized medicine with the right drug or drug combination being utilized for each tumor.”

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The above story is based on materials provided by MIT News, Anne Trafton.

Switching On One-Shot Learning in the Brain

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Most of the time, we learn only gradually, incrementally building connections between actions or events and outcomes. But there are exceptions—every once in a while, something happens and we immediately learn to associate that stimulus with a result. For example, maybe you have had bad service at a store once and sworn that you will never shop there again.

Caltech researchers provide evidence that the amount of uncertainty about the causal relationship between a stimulus and an outcome mediates the switching between incremental learning, in which we gradually acquire knowledge, and one-shot learning, where we rapidly learn from a single pairing of a potential stimulus and an outcome. Neuroimaging findings suggest that the ventrolateral prefrontal cortex may act as a “switch,” selectively turning one-shot learning on and off, as needed. Photo Credit: Sang Wan Lee/Caltech

This type of one-shot learning is more than handy when it comes to survival—think, of an animal quickly learning to avoid a type of poisonous berry. In that case, jumping to the conclusion that the fruit was to blame for a bout of illness might help the animal steer clear of the same danger in the future. On the other hand, quickly drawing connections despite a lack of evidence can also lead to misattributions and superstitions; for example, you might blame a new food you tried for an illness when in fact it was harmless, or you might begin to believe that if you do not eat your usual meal, you will get sick.

Scientists have long suspected that one-shot learning involves a different brain system than gradual learning, but could not explain what triggers this rapid learning or how the brain decides which mode to use at any one time.

Now Caltech scientists have discovered that uncertainty in terms of the causal relationship—whether an outcome is actually caused by a particular stimulus—is the main factor in determining whether or not rapid learning occurs. They say that the more uncertainty there is about the causal relationship, the more likely it is that one-shot learning will take place. When that uncertainty is high, they suggest, you need to be more focused in order to learn the relationship between stimulus and outcome.

The researchers have also identified a part of the prefrontal cortex—the large brain area located immediately behind the forehead that is associated with complex cognitive activities—that appears to evaluate such causal uncertainty and then activate one-shot learning when needed.

The findings, described in the April 28 issue of the journal PLOS Biology, could lead to new approaches for helping people learn more efficiently. The work also suggests that an inability to properly attribute cause and effect might lie at the heart of some psychiatric disorders that involve delusional thinking, such as schizophrenia.

“Many have assumed that the novelty of a stimulus would be the main factor driving one-shot learning, but our computational model showed that causal uncertainty was more important,” says Sang Wan Lee, a postdoctoral scholar in neuroscience at Caltech and lead author of the new paper. “If you are uncertain, or lack evidence, about whether a particular outcome was caused by a preceding event, you are more likely to quickly associate them together.”

The researchers used a simple behavioral task paired with brain imaging to determine where in the brain this causal processing takes place. Based on the results, it appears that the ventrolateral prefrontal cortex (VLPFC) is involved in the processing and then couples with the hippocampus to switch on one-shot learning, as needed.

Indeed, a switch is an appropriate metaphor, says Shinsuke Shimojo, Caltech’s Gertrude Baltimore Professor of Experimental Psychology. Since the hippocampus is known to be involved in so-called episodic memory, in which the brain quickly links a particular context with an event, the researchers hypothesized that this brain region might play a role in one-shot learning. But they were surprised to find that the coupling between the VLPFC and the hippocampus was either all or nothing. “Like a light switch, one-shot learning is either on, or it’s off,” says Shimojo.

In the behavioral study, 47 participants completed a simple causal-inference task; 20 of those participants completed the study in the Caltech Brain Imaging Center, where their brains were monitored using functional Magnetic Resonance Imaging. The task consisted of multiple trials. During each trial, participants were shown a series of five images one at a time on a computer screen. Over the course of the task, some images appeared multiple times, while others appeared only once or twice. After every fifth image, either a positive or negative monetary outcome was displayed. Following a number of trials, participants were asked to rate how strongly they thought each image and outcome were linked. As the task proceeded, participants gradually learned to associate some of the images with particular outcomes. One-shot learning was apparent in cases where participants made an association between an image and an outcome after a single pairing.

The researchers hypothesize that the VLPFC acts as a controller mediating the one-shot learning process. They caution, however, that they have not yet proven that the brain region actually controls the process in that way. To prove that, they will need to conduct additional studies that will involve modifying the VLPFC’s activity with brain stimulation and seeing how that directly affects behavior.

Still, the researchers are intrigued by the fact that the VLPFC is very close to another part of the ventrolateral prefrontal cortex that they previously found to be involved in helping the brain to switch between two other forms of learning—habitual and goal-directed learning, which involve routine behavior and more carefully considered actions, respectively. “Now we might cautiously speculate that a significant general function of the ventrolateral prefrontal cortex is to act as a leader, telling other parts of the brain involved in different types of behavioral functions when they should get involved and when they should not get involved in controlling our behavior,” says coauthor John O’Doherty, professor of psychology and director of the Caltech Brain Imaging Center.

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Breakthrough in 3-D printing of replacement body parts

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QUT biofabrication team has made a major breakthrough by 3D printing mechanically reinforced, tissue engineered constructs for the regeneration of body parts.In an article published in Nature Communications, the biomedical engineers outlined how they had reinforced soft hydrogels via a 3D printed scaffold.

Professor Dietmar W. Hutmacher, from QUT’s Institute of Health and Biomedical Innovation, said nature often used fibre reinforcement to turn weak structures into outstanding mechanically robust ones.

“Such is the case with articular cartilage tissue, which is formed by stiff and strong collagen fibres intertwined within a very weak gel matrix of proteoglycans,” Professor Hutmacher said.

“By bringing this natural design perspective of fibre reinforcement into the field of tissue engineering (TE), we can learn a lot about how to choose an effective combination of matrix and reinforcement structure in order to achieve composite materials with enhanced mechanical properties for engineering body parts.”

Professor Hutmacher said hydrogels were favoured because they had excellent biological properties, however, the hydrogels currently available for tissue regeneration of the musculoskeletal system couldn’t meet the mechanical and biological requirements for successful outcomes.

“Our international biofabrication research team has found a way to reinforce these soft hydrogels via a 3D printed scaffold structure so that their stiffness and elasticity are close to that of cartilage tissues.”

Professor Hutmacher said the team had introduced organised, high-porosity microfiber networks that are printed using a new technique called “melt electrospinning writing”.

“We found that the stiffness of the gel/scaffold composites increased synergistically up to 54 times, compared with hydrogels or microfiber scaffolds alone,” he said.

“Computational modelling has shown that we can use these 3D-printed microfibres in different hydrogels and a large range of tissue engineering applications.”

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Scientists observe deadly dance between nerves, cancer cells

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In certain types of cancer, nerves and cancer cells enter an often lethal and intricate waltz where cancer cells and nerves move toward one another and eventually engage in such a way that the cancer cells enter the nerves.

The photomicrograph shows a nerve (central structure) invaded by cancer cells. Photo Credit: Nisha D’Silva

The findings, appearing in Nature Communications, challenge conventional wisdom about perineural invasion, which holds that cancer cells are marauders that invade nerves through the path of least resistance, said Nisha D’Silva, principal investigator and professor at the University of Michigan School of Dentistry.

D’Silva’s lab discovered that perineural invasion is actually a much more intricately choreographed biochemical give-and-take between the nerves and the cancer cells.

“Once head and neck cancer invades the nerves, it is one of the worst things that can happen,” said D’Silva, who also has a joint appointment at the U-M Medical School Department of Pathology and is a member of the U-M Cancer Center’s Head and Neck Oncology program. “It is highly correlated with poor patient survival, and there is no targeted treatment for it because it is not known why some tumors do this and some don’t.”

Perineural invasion is seen most in head and neck, pancreatic, stomach and colon cancers, and causes severe pain or numbness, tumor spread and recurrence, and loss of function, among other complications.

D’Silva’s lab found that perineural invasion begins when the nerve releases a stimulus that triggers a specific protein receptor in cancer cells. The receptor activates instructions in the cancer and releases the same stimulus back to the nerve.

The nerve recognizes the stimulus, which causes the nerve to ‘reach’ toward the cancer–imagine two dancers recognizing each other across a room and slowly moving closer until they become permanent partners. After this initial pairing up, the loop continues.

“Basically it’s like they are waltzing,” D’Silva said. “It is a very elegant dance, if you will.”

It is extremely difficult to study perineural invasion in head and neck cancer, so D’Silva’s lab had to develop a way to observe these interactions in live samples. First, researchers implanted the nerve in chick egg membranes, and after the nerve integrated, they studied the interactions between the nerve and head and neck cancer cells.

D’Silva said the next steps in the research are to find out, “when and how we can interrupt the dance.”

The study is called “Galanin modulates the neural niche to favor perineural invasion in head and neck cancer.”

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A digital field guide to cancer cells

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Using advanced technology and an approach that merges engineering and medicine, a Yale University-led team has compiled some of the most sophisticated data yet on the elaborate signaling networks directing highly invasive cancer cells. Think of it as a digital field guide for a deadly scourge.

“This is a very complex set of interactions and processes,” said Andre Levchenko, a Yale systems biologist and biomedical engineer, and director of the Yale Systems Biology Institute. “The systems biology approach acknowledges that complexity by analyzing how cancer cells migrate together and separately in response to complex cues.”

In a study published April 8 in the journal Nature Communications, Levchenko and his colleagues describe the intricate ways breast cancer cells respond to chemical cues in the human body. The idea is to determine which cues cause cancer cells to disperse and metastasize, how these cues are combined with other cues directing the invasion, and which cues hold sway when there are conflicting orders.

Until now, little has been known about how cells decide when and where to turn while traveling through the complex tissues. These cells often encounter contradictory directional cues — begging the questions: Which cues are stronger, and in what situations?

Scientists are mapping the habits of cancer cells, turn by microscopic turn. Photo Credit: Yale University

In this study, researchers focused on several cues. One is a protein called Epidermal Growth Factor (EGF), which acts as a strong, directional guidance signal to individual cancer cells. Another cue mediates a poorly understood phenomenon called “contact inhibition of locomotion” (CIL), in which cells act almost like bumper cars, stopping their forward motion on contact and moving away from each other.

Levchenko’s team found that when both EGF and CIL signals act upon a breast cancer cell, the cell acts as a tiny computer, making decisions about which cue dominates. If the EGF cue is weak, the cell can turn around if it encounters another cell; if the EGF cue is strong enough, the two cells will travel together. The researchers unraveled the molecular network that allows the cells to follow these cues and make appropriate decisions. In particular, they found the critical role of proteins called ephrins in mediating the CIL cue. These proteins, also found in other cell types, allow breast cancer cells to be repelled from each other, while ignoring other cells, such as fibroblasts. This knowledge allowed the investigators to suppress CIL, so that even weak EGF inputs could lead to coordinated movement of many cells.

“We have shown that migrating cells prioritize certain cues in the presence of others and thus can switch their migration mode, depending on what they see from the environment,” said first author Benjamin Lin, a postdoctoral associate in biomedical engineering at Yale.

Understanding the interplay of these signals may allow researchers to devise strategies for interfering with, or redirecting, cancer cells in motion. For example, if a traveling cancer cell received strong, artificial CIL cues so that its movement became less directed and invasive, and more chaotic, could that slow the onset of metastasis?

Historically, experiments on cancer cell movement have been unable to mimic the dynamic complexity of the human body. Now, using advanced biosensors and other technology, such experiments come much closer to replicating a realistic, biological environment.

“Scientists have studied quite well how individual cues affect cell migration. But in reality, cells are subject to multiple cues at the same time,” said co-author Takanari Inoue, an associate professor at Johns Hopkins University. “Our work is significant because we clearly demonstrated that cells do integrate multiple pieces of information and that the integration occurs at a place fairly upstream of the signal processing. I think we have been underestimating these cells’ capability to integrate different cues.”

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What can brain-controlled prosthetics tell us about the brain?

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The ceremonial opening kick of the 2014 FIFA World Cup in Sao Paolo, Brazil, which was performed—with the help of a brain-controlled exo-skeleton—by a local teen who had been paralyzed from the waste down due to a spinal cord injury, was a seminal moment for the area of neuroscience that strives to connect the brain with functional prosthetics. The public display was a representative of thousands of such neuroprosthetic advances in recent years, and the tens of years of brain research and technological development that have gone into them. And while this display was quite an achievement in its own right, a Drexel University biomedical engineer working at the leading edge of the field contends that these devices are also opening a new portal for researchers to understand how the brain functions.

Karen Moxon, PhD, a professor in Drexel’s School of Biomedical Engineering Science and Health Systems, was a postdoctoral researcher in Drexel’s medical school when she participated in the first study ever to examine how the brain could be connected to operate a prosthetic limb. More than 15 years after that neuroscience benchmark, Moxon’s lab is showing that it’s now possible to glean new insight about how the brain stores and accesses information, and into the causes of pathologies like epilepsy and Parkinson’s disease.

In a perspective published in the latest edition of the neuroscience journal Neuron Moxon and her colleague, Guglielmo Foffani from San Pablo University in Spain, build a framework for how researchers can use neuroprosthetics as a tool for examining how and where the brain encodes new information. The duo highlights three examples from their own research where the brain-machine-interface technology allowed them to isolate and study new areas of brain function.

“We believe neuroprosthetics can be a powerful tool to address fundamental questions of neuroscience,” Moxon said. “These subjects can provide valuable data as indirect observers of their own neural activity that are modulated during the experiments they are taking part in. This allows researchers to pinpoint a causal relationship between neural activity and the subject’s behavior rather than one that is indirectly correlative.”

The challenge faced by all scientists who study the brain is proving a direct relationship between the action of the subject and the behavior of brain cells. Each experiment is designed to chisel away at the uncertainty in this relationship with the goal of establishing causality—proof that the behavior of neurons in the brain is actually what is causing a subject to perform a certain action. Or, conversely, that a certain neural behavior is the direct result of an external stimulus.

Neuroprosthetics, according to Moxon, could be the way around this obstacle. This is because the prosthetic, as a stand-in for an actual body part or set of them, is also a vehicle for getting real-time feedback from the brain.

“Subjects can be viewed as indirect observers of their own neurophysiological activity during neuroprosthetic experiments,” Moxon said. “To move the prosthesis they must think both about the motor functions involved and the goal of the movement. As they see the movement of the prosthetic their brain adjusts in real time to continue planning the movement, but doing it without the normal feedback from the moving body part—as the prosthetic technology is standing in for that part of the body.”

This separation of planning and movement control was pivotal to Moxon’s research on how the brain encodes for the passage of time, which she recently reported in the Journal of Neuroscience. But this is just one example of how brain-machine-interface technology can be used to experimentally tease out and observe new certainties about the brain.

Moxon, who was recently elected a fellow of the American Association for the Advancement of Science and the American Institute for Medical and Biological Engineers, suggests that in addition to the study of how neurons encode and decode information in real time, incorporating neuroprosthetics into experiments could also show how this coding process changes with learning and is altered in pathological conditions like the ones that cause epilepsy and Parkinson’s disease.

“While the past 15 years have witnessed tremendous advancements in neuroprosthetic technology and our basic understanding of brain function, the brain-machine-interface approach is still expanding the landscape of neuroscienctific inquiry,” Moxon said. “By circumventing classical object-observer duality, the BMI research paradigm opens doors for a new understanding of how we control our own brain function including neural plasticity—and this has the potential to lead to new treatments and therapies for epilepsy, Parkinson’s and other pathologies.”

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Chromosome-folding theory shows promise

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Human chromosomes are much bigger and more complex than proteins, but like proteins, they appear to fold and unfold in an orderly process as they carry out their functions in cells.

Rice University biophysicist Peter Wolynes and postdoctoral fellow Bin Zhang have embarked upon a long project to define that order. They hope to develop a theory that predicts the folding mechanisms and resulting structures of chromosomes in the same general way Wolynes helped revolutionize the view of protein folding through the concept of energy landscapes.

The first fruit of their quest is a new paper in the Proceedings of the National Academy of Sciences that details a coarse-grained method to “skirt some of the difficulties” that a nucleotide-level analysis of chromosomes would entail.

Essentially, the researchers are drawing upon frequently observed crosslinking contacts among domains – distinct sequences that form along folding strands of DNA – to apply statistical tools. With these tools, they can build computational models and infer the presence of energy landscapes that predict the dynamics of chromosomes.

How macromolecules of DNA fold into chromosomes is thought to have a crucial role in biological processes like gene regulation, DNA replication and cell differentiation. The researchers argue that unraveling the dynamics of how they fold and their structural details would add greatly to the understanding of cell biology.

“It’s inevitable that there’s a state of the chromosome that involves having structure,” Wolynes said. “Since the main theme of our work is gene regulation, it’s something we would naturally be interested in pursuing.”

But it’s no small task. First, though a chromosome is made of a single strand of DNA, that strand is huge, with millions of subunits. That’s much longer than the average protein and probably a lot slower to organize, the researchers said.

Second, a large “team of molecular players” is involved in helping chromosomes get organized, and only a few of these relevant proteins are known.

Third, chromosome organization appears to vary from one cell to the next and may depend on the cell’s type and the phase in its lifecycle.

All those factors led Wolynes and Zhang to conclude that treating chromosomes exactly as they do proteins — that is, figuring out how and when the individual units along the DNA strand attract and repel each other — would be impractical.

“But the three-dimensional organization of chromosomes is of critical importance and is worthy of study by Rice’s Center for Theoretical Biological Physics,” Wolynes said. He holds out hope that the theory developed in this study will lead to a more detailed view of chromosome conformations and will result in a better understanding of the relationships of the structure, dynamics and function of the genome.

He said there is already evidence for the idea that actual gene regulatory processes are influenced by the chromosomes’ structures. He noted work by Rice colleague Erez Lieberman Aiden to develop high-resolution, three-dimensional maps of folded genomes will be an important step toward specifying their structures.

One result of the new study was the observation that, at least during the interphase state the Rice team primarily studied, chromosome domains take on the characteristics of liquid crystals. In such a state, the domains remain fluid but become ordered, allowing for locally funneled landscapes that lead to the “ideal” chromosome structures that resemble the speculative versions seen in textbooks.

Wolynes and Rice colleague José Onuchic, a biophysicist, began developing their protein-folding theory nearly three decades ago. In short, it reveals that proteins, which start as linear chains of amino acids, are programmed by genes to quickly fold into their three-dimensional native states. In doing so, they obey the principle of minimal frustration, in which interactions between individual acids guide the protein to its final, stable form.

Wolynes used the principle to conceptualize folding as a funnel. The top of the funnel represents all of the possible ways a protein can fold. As individual stages of the protein come together, the number of possibilities decreases. The funnel narrows and eventually guides the protein to its functional native state.

He hopes the route to understanding chromosome folding will take much less time than the decades it took for his team’s protein-folding work to pay off.

“We’re not the first in this area,” he said. “A lot of people have said the structure of the chromosome is an important problem. I see it as being as big a field as protein folding was – and when you look at it from that point of view, you realize the state of our ignorance is profound. We’re like where protein folding was, on the experimental side, in 1955.

“The question for this work is whether we can leapfrog over the dark ages of protein folding that led to our energy-landscape theory. I think we can.”

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A CRISPR antiviral tool

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Emory scientists have adapted an antiviral enzyme from bacteria called Cas9 into an instrument for inhibiting hepatitis C virus in human cells.The results were published April 27, 2015 in Proceedings of the National Academy of Sciences.

Cas9 is part of the CRISPR genetic defense system in bacteria, which scientists have been harnessing to edit DNA in animals, plants and even human cells. In this case, Emory researchers are using Cas9 to put a clamp on RNA, which hepatitis C virus uses for its genetic material, rather than change cells’ DNA.

Although several effective drugs are now available to treat hepatitis C infection, the approach could have biotechnology applications.

“We can envision using Cas9-based technology to prevent viral infections in transgenic animals and plants, for example,” says co-senior author David Weiss, PhD, assistant professor of medicine (infectious disease) at Emory Vaccine Center and Emory University School of Medicine. “This is a proof of principle that we can re-engineer Cas9 to target RNA in human or other mammalian cells. Here, we’re targeting a viral RNA, for which there is no corresponding DNA in the cells.”

Co-first authors of the paper are Microbiology and Molecular Genetics graduate students Aryn Price and Tim Sampson. Sampson is now a postdoctoral fellow at Caltech. Price and associate professor Arash Grakoui, PhD, who together study hepatitis C virus immunology, teamed up with Weiss and Sampson, who specialize in pathogenic bacteria, to develop the hybrid approach.

Other scientists have already modified CRISPR/Cas9 technology to target RNA in a test tube, or to prevent RNA production in cells. What’s distinctive about the technique described in the PNAS paper is that Cas9 is being directed against viral RNA.

In the laboratory, Cas9 and a “guide RNA” directing Cas9 against hepatitis C virus could slow down viral infection of cultured liver cells. These tools could inhibit, but not completely shut down, an established infection.

The RNA-targeting technique resembles RNA interference, which scientists use as a tool for shutting off selected genes in cells, animals and plants. RNA interference is part of an experimental drug aimed at fighting Ebola virus infection, as well as other potential drugs aimed at treating high cholesterol or liver diseases.

However, RNA interference hijacks machinery human and animal cells use to control their own genes, and many viruses have developed sophisticated mechanisms to manipulate this machinery in their host cells.

“Since Cas9 is a bacterial protein and eukaryotic viruses have likely not encountered it, they would not have ways to evade Cas9,” Weiss says. “Thus, Cas9 could be effective in inhibiting viruses when the RNAi system cannot.”

With CRISPR, bacteria incorporate small bits of DNA from phages (viruses that infect bacteria) and use that information to fight off the phages by chewing up their DNA. The system was originally discovered by dairy industry researchers seeking to stop phages from ruining the cultures used to make cheese and yogurt.

The Emory researchers obtained the Cas9 enzyme from Francisella novicida, a relative of the bacterium that causes tularemia. Weiss and his colleagues previously discovered that in F. novicida and other bacteria, Cas9 plays roles in gene regulation and in evading the mammalian immune system.

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Understanding the body’s response to worms and allergies

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Research from The University of Manchester is bringing scientists a step closer to developing new therapies for controlling the body’s response to allergies and parasitic worm infections.

In a paper published in Nature Communications, Professor Andrew MacDonald and his team at the Manchester Collaborative Centre for Inflammation Research discovered a new way that immune cells control inflammation during worm infection or an allergic response like asthma. It’s important to understand how this type of inflammation is controlled as it can be very damaging and in some cases lead to long term conditions.

Professor MacDonald explains the reasons behind his work: “Although both worm infections and allergies exert a devastating global impact and lack effective vaccines or refined treatments, basic knowledge of the key cell types and mediators that control immunity and inflammation against either condition is currently limited.”

To study how inflammation is controlled the team looked at dendritic cells – a particular type of cell in the immune system that is a vital first responder to worms or allergies. The main function of dendritic cells is to recognise infection and switch on channels to combat it, including inflammation.

What isn’t known is precisely how immune cells switch on the kind of inflammation found during worm infections or allergies.

Professor MacDonald and his team studied dendritic cells in the lab and animal models to see how they were activated by parasitic worms, or lung allergens such as house dust mites.

They found that a particular protein called Mbd2 is central to the ability of dendritic cells to switch on inflammation in these kinds of settings. When the protein was removed it resulted in very different cells with a dramatically impaired ability to switch on inflammation.

The team also identified that Mbd2 is able to influence a wide range of genes important for multiple aspects of dendritic cell function without altering their DNA sequence, meaning that Mbd2 is an ‘epigenetic’ regulator.

Professor MacDonald explains: “For the first time we have identified that this protein is a key controller of dendritic cells during inflammation against parasitic worms or allergens. It’s an important step, as all inflammation is not identical, and scientists try to understand which specific cells and chemicals are more important in the body’s response to particular infections. In the past, medicines have had a broad approach, affecting all aspects of a condition rather than being targeted. In the future it might be possible to create medicines that control the inflammation caused specifically by an allergy or a parasitic worm, rather than by a virus such as a common cold.”

Professor MacDonald continues: “With billions of people affected by both allergies and worm infections around the world it is vital that we develop better methods of treatment. It’s also important to tackle the inflammation caused by these conditions, as it has been shown to play a role in the development of longer term diseases such as asthma.”

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New material for creating artificial blood vessels

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Blocked blood vessels can quickly become dangerous. It is often necessary to replace a blood vessel – either by another vessel taken from the body or even by artificial vascular prostheses. Together, Vienna University of Technology and Vienna Medical University have developed artificial blood vessels made from a special elastomer material, which has excellent mechanical properties. Over time, these artificial blood vessels are replaced by endogenous material. At the end of this restorative process, a natural, fully functional vessel is once again in place. The method has already been used successfully in rats.

Long term tests show: the artificial blood vessel works perfectly. Photo Credit: Helga Bergmeister, MedUni Wien

Arteriosclerotic vascular disorders are one of the most common causes of death in industrialized countries. In this situation a bypass operation is often the only solution. Normally, blood vessels are taken from another part of the patient’s body and used to replace the damaged vessel. Thanks to a joint project undertaken by TU Wien and the Medical University of Vienna, artificially manufactured vessels should be used more frequently in future.

The most important thing is to find a suitable material. The artificial materials that have been used so far are not ideally compatible with body tissue. The blood vessel can easily become blocked, especially if it is only small in diameter.

TU Wien has therefore developed new polymers. “These are so-called thermoplastic polyurethanes,” explains Robert Liska from the Institute of Applied Synthetic Chemistry of Vienna University of Technology. “By selecting very specific molecular building blocks we have succeeded in synthesizing a polymer with the desired properties.”

A thin polymer thread spun into tubes

To produce the vascular prostheses, polymer solutions were spun in an electrical field to form very fine threads and wound onto a spool. “The wall of these artificial blood vessels is very similar to that of natural ones,” says Heinz Schima of the Medical University of Vienna. The polymer fabric is slightly porous and so, initially, allows a small amount of blood to permeate through and this enriches the wall with growth factors. This encourages the migration of endogenous cells. The interaction between material and blood was studied by Martina Marchetti-Deschmann at TU Wien using spatially resolved mass spectrometry.

The new method has already proved very successful in experiments with rats. “The rats’ blood vessels were examined six months after insertion of the vascular prostheses,” says Helga Bergmeister of MedUni Vienna. “We did not find any aneurysms, thromboses or inflammation. Endogenous cells had colonized the vascular prostheses and turned the artificial constructs into natural body tissue.” In fact, natural body tissue re-grew much faster than expected so that the degradation period of the plastic tubes can be even shorter. Further adaptations are currently being made to the material.

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Finding the body clock’s molecular reset button

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An international team of scientists has discovered what amounts to a molecular reset button for our internal body clock. Their findings reveal a potential target to treat a range of disorders, from sleep disturbances to other behavioral, cognitive, and metabolic abnormalities, commonly associated with jet lag, shift work and exposure to light at night, as well as with neuropsychiatric conditions such as depression and autism.

In a study published online April 27 in Nature Neuroscience, the authors, led by researchers at McGill and Concordia universities in Montreal, report that the body’s clock is reset when a phosphate combines with a key protein in the brain. This process, known as phosphorylation, is triggered by light. In effect, light stimulates the synthesis of specific proteins called Period proteins that play a pivotal role in clock resetting, thereby synchronizing the clock’s rhythm with daily environmental cycles.

Shedding light on circadian rhythms

“This study is the first to reveal a mechanism that explains how light regulates protein synthesis in the brain, and how this affects the function of the circadian clock,” says senior author Nahum Sonenberg, a professor in McGill’s Department of Biochemistry.

In order to study the brain clock’s mechanism, the researchers mutated the protein known as eIF4E in the brain of a lab mouse so that it could not be phosphorylated. Since all mammals have similar brain clocks, experiments with the mice give an idea of what would happen if the function of this protein were blocked in humans.

Running against the clock

The mice were housed in cages equipped with running wheels. By recording and analyzing the animals’ running activity, the scientists were able to study the rhythms of the circadian clock in the mutant mice.

The upshot: the clock of mutant mice responded less efficiently than normal mice to the resetting effect of light. The mutants were unable to synchronize their body clocks to a series of challenging light/dark cycles – for example, 10.5 hours of light followed by 10.5 hours of dark, instead of the 12-hour cycles to which laboratory mice are usually exposed.

“While we can’t predict a timeline for these findings to be translated into clinical use, our study opens a new window to manipulate the functions of the circadian clock,” says Ruifeng Cao, a postdoctoral fellow in Dr. Sonenberg’s research group and lead author of the study.

For co-author Shimon Amir, professor in Concordia’s Department of Psychology, the research could open a path to target the problem at its very source. “Disruption of the circadian rhythm is sometimes unavoidable but it can lead to serious consequences. This research is really about the importance of the circadian rhythm to our general well-being. We’ve taken an important step towards being able to reset our internal clocks — and improve the health of thousands as a result.”

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Brain-machine interface to control prosthetic hand

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A research team from the University of Houston has created an algorithm that allowed a man to grasp a bottle and other objects with a prosthetic hand, powered only by his thoughts.

The technique, demonstrated with a 56-year-old man whose right hand had been amputated, uses non-invasive brain monitoring, capturing brain activity to determine what parts of the brain are involved in grasping an object. With that information, researchers created a computer program, or brain-machine interface (BMI), that harnessed the subject’s intentions and allowed him to successfully grasp objects, including a water bottle and a credit card. The subject grasped the selected objects 80 percent of the time using a high-tech bionic hand fitted to the amputee’s stump.

Previous studies involving either surgically implanted electrodes or myoelectric control, which relies upon electrical signals from muscles in the arm, have shown similar success rates, according to the researchers.

Jose Luis Contreras-Vidal, a neuroscientist and engineer at UH, said the non-invasive method offers several advantages: It avoids the risks of surgically implanting electrodes by measuring brain activity via scalp electroencephalogram, or EEG. And myoelectric systems aren’t an option for all people, because they require that neural activity from muscles relevant to hand grasping remain intact.

The results of the study were published March 30 in Frontiers in Neuroscience, in the Neuroprosthetics section.

Contreras-Vidal, Hugh Roy and Lillie Cranz Cullen Distinguished Professor of electrical and computer engineering at UH, was lead author of the paper, along with graduate students Harshavardhan Ashok Agashe, Andrew Young Paek and Yuhang Zhang.

The work, funded by the National Science Foundation, demonstrates for the first time EEG-based BMI control of a multi-fingered prosthetic hand for grasping by an amputee. It also could lead to the development of better prosthetics, Contreras-Vidal said.

Beyond demonstrating that prosthetic control is possible using non-invasive EEG, researchers said the study offers a new understanding of the neuroscience of grasping and will be applicable to rehabilitation for other types of injuries, including stroke and spinal cord injury.

The study subjects – five able-bodied, right-handed men and women, all in their 20s, as well as the amputee – were tested using a 64-channel active EEG, with electrodes attached to the scalp to capture brain activity. Contreras-Vidal said brain activity was recorded in multiple areas, including the motor cortex and areas known to be used in action observation and decision-making, and occurred between 50 milliseconds and 90 milliseconds before the hand began to grasp.

That provided evidence that the brain predicted the movement, rather than reflecting it, he said.

“Current upper limb neuroprosthetics restore some degree of functional ability, but fail to approach the ease of use and dexterity of the natural hand, particularly for grasping movements,” the researchers wrote, noting that work with invasive cortical electrodes has been shown to allow some hand control but not at the level necessary for all daily activities.

“Further, the inherent risks associated with surgery required to implant electrodes, along with the long-term stability of recorded signals, is of concern. … Here we show that it is feasible to extract detailed information on intended grasping movements to various objects in a natural, intuitive manner, from a plurality of scalp EEG signals.”

Until now, this was thought to be possible only with brain signals acquired invasively inside or on the surface of the brain.

Researchers first recorded brain activity and hand movement in the able-bodied volunteers as they picked up five objects, each chosen to illustrate a different type of grasp: a soda can, a compact disc, a credit card, a small coin and a screwdriver. The recorded data were used to create decoders of neural activity into motor signals, which successfully reconstructed the grasping movements.

They then fitted the amputee subject with a computer-controlled neuroprosthetic hand and told him to observe and imagine himself controlling the hand as it moved and grasped the objects.

The subject’s EEG data, along with information about prosthetic hand movements gleaned from the able-bodied volunteers, were used to build the algorithm.

Contreras-Vidal said additional practice, along with refining the algorithm, could increase the success rate to 100 percent.

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‘Chemo brain’ is real, say UBC researchers

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UBC research shows that chemotherapy can lead to excessive mind wandering and an inability to concentrate. Dubbed ‘chemo-brain,’ the negative cognitive effects of the cancer treatment have long been suspected, but the UBC study is the first to explain why patients have difficulty paying attention.

Breast cancer survivors were asked to complete a set of tasks while researchers monitored their brain activity. Photo Credit: Julia Kam

Breast cancer survivors were asked to complete a set of tasks while researchers in the Departments of Psychology and Physical Therapy monitored their brain activity. What they found is that the minds of people with chemo-brain lack the ability for sustained focused thought.

“A healthy brain spends some time wandering and some time engaged,” said Todd Handy, a professor of psychology at UBC. “We found that chemo brain is a chronically wandering brain, they’re essentially stuck in a shut out mode.”

Handy explains that healthy brains function in a cyclic way. People can focus on a task and be completely engaged for a few seconds and then will let their mind wander a bit.

The research team that included former PhD student Julia Kam, the first author of the study, found that chemo brains tend to stay in that disengaged state. To make matters worse, even when women thought they were focusing on a task, the measurements indicated that a large part of their brain was turned off and their mind was wandering.

The researchers also found evidence that these women were more focused on their inner world. When the women were not performing a task and simply asked to relax, their brain was more active compared to healthy women.

Kristin Campbell, an associate professor in the Department of Physical Therapy and leader of the research team, says these findings could help health care providers measure the effects of chemotherapy on the brain.

“Physicians now recognize that the effects of cancer treatment persist long after its over and these effects can really impact a person’s life,” said Campbell.

Tests developed for other cognitive disorders like brain injury or Alzheimer’s have proven ineffective for measuring chemo brain. Cancer survivors tend to be able to complete these tests but then struggle to cope at work or in social situations because they find they are forgetful.

“These findings could offer a new way to test for chemo brain in patients and to monitor if they are getting better over time,” said Campbell, who also conducts research to measure how exercise can improve cognitive function for women experiencing chemo brain.

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Dead feeder cells support stem cell growth

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Stem cells naturally cling to feeder cells as they grow in petri dishes. Scientists have thought for years that this attachment occurs because feeder cells serve as a support system, providing stems cells with essential nutrients.

A) Stem cell colonies adhere to and grow on live feeder cells. B) This phenomenon is unaltered when feeder cells are fixed, or dead. Photo Credit: Kiralise Silva / UTEP

But a new study that successfully grew stem cells with dead, or fixed, feeder cells suggests otherwise.

The discovery, described in the Journal of Materials Chemistry B, challenges the theory that feeder cells provide nutrients to growing stem cells. It also means that the relationship between the two cells is superficial, according to Binata Joddar, Ph.D., a biomedical engineer at The University of Texas at El Paso (UTEP).

“We’ve proved an important phenomenon,” said Joddar, who runs UTEP’s Inspired Materials and Stem-Cell Based Tissue Engineering Lab. “And it suggests that these feeder cells, which are difficult to grow, may not be important at all for stem cell growth.”

In the study, feeder cells were chemically fixed before living stem cells were placed in the same dish. Like organs that are preserved with formaldehyde, this kept the feeder cells’ physical appearance the same, but essentially killed them.

Even though the feeder cells were dead, the stem cells still latched on and grew successfully.

The discovery offers a simpler and more cost-effective way to grow stem cells, which has proved difficult over the years.

“Because feeder cells don’t need to stay alive in the process, we can store them at room temperature and spend less time cultivating them,” Joddar said.

Joddar believes the finding suggests that stem cells may only like the “topology” of feeder cells.

“This makes me think that we use a nanomanufacturing approach to grow stem cells,” she said. “We could mimic feeder cells’ nanotopology with 3-D printing techniques and skip using feeder cells altogether in the future.”

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The above story is based on materials provided by The University of Texas at El Paso.

4-D printing

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4D printing is unfolding as technology that takes 3D printing to an entirely new level.The fourth dimension is time, shape shifting in fact, and the ARC Centre of Excellence for Electromaterials Science (ACES) at the University of Wollongong is helping to set the pace in the next revolution in additive manufacturing.

Another dimension: Professor Marc in het Panhuis and PhD student Shannon Bakarich are building objects using 4-D printing, where time is the fourth dimension. Photo Credit: University of Wollongong/Paul Jones

Just as the extraordinary capabilities of 3D printing have begun to infiltrate industry and the family home, researchers have started to develop 3D printed materials that morph into new structures, post production, under the influence of external stimuli such as water or heat – hence the name, 4D printing.

So, as in 3D printing, a structure is built up layer by layer into the desired shape, but these new materials are able to transform themselves from one shape into another, much like a child’s Transformer toy.

This ground-breaking science promises advancement in myriad fields – medicine, construction, automation and robotics to name a few.

ACES researchers have turned their attention to the medical field of soft robotics, manufacturing a valve that actuates in response to its surrounding water’s temperature.

ACES Professor Marc in het Panhuis said it was the cleverness of the valve’s creation that was remarkable.

“The cool thing about it is, is it’s a working functioning device that you just pick up from the printer,” he said.

“There’s no other assembly required.”

The materials scientist said the valve, a 3D printed structure, possessed actuators that are activated solely by water.

“So it’s an autonomous valve, there’s no input necessary other than water; it closes itself when it detects hot water,” he said.

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The above story is based on materials provided by University of Toronto Faculty of Dentistry.

An end to cancer pain?

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A new study led by University of Toronto researcher Dr. David Lam has discovered the trigger behind the most severe forms of cancer pain. Released in top journal Pain this month, the study points to TMPRSS2 as the culprit: a gene that is also responsible for some of the most aggressive forms of androgen-fuelled cancers.

This is an image of TMPRSS2. Photo Credit: D. Lam

Head of Oral and Maxillofacial Surgery at the Faculty of Dentistry, Lam’s research initially focused on cancers of the head and neck, which affect more than 550,000 people worldwide each year. Studies have shown that these types of cancers are the most painful, with sufferers experiencing pain that is immediate and localized, while pain treatment options are limited to opioid-family pharmaceuticals such as morphine.

It was while conducting clinical research at the University of California San Francisco, though, that Lam noticed something interesting. A majority of head and neck cancer patients are men – leading him to investigate a genetic marker with a known correlation to prostate cancer, TMPRSS2.

“Prostate cancer research already knows that if you have the TMPRSS2 gene marker, the prostate cancer is much more aggressive. They’ve also shown that this is androgen (male hormone) sensitive.”

In his study, Lam, who is jointly appointed as a Consultant Surgeon at the Princess Margaret Cancer Centre and a Clinician at the Mount Sinai Wasser Pain Management Centre, ascertained that TMPRSS2 was not only present in patients suffering from head and neck cancers – it was also prevalent in much greater quantities than in prostate cancer.

But was there a link to pain?

Visible on the surface of the cancer cells, TMPRSS2 comes into contact with the body’s nerve pain receptors, which then triggers the pain. Lam was also able to determine a clear, correlative relationship between the two: the more TMPRSS2 that comes into contact with nerve pain receptors, the greater pain is provoked.

Lam and his fellow researchers followed up this observation by looking at different types of cancers with known pain associations – for instance, certain breast and melanoma cell lines. These cells were grown and labelled for the TMPRSS2 genetic marker.

According to clinical data, head and neck cancer is the most painful form of cancer, followed by prostate cancer, while melanoma, or skin cancer, sits at the bottom of the pain scale.

But what surprised the researchers was that the presence and amount of TMPRSS2 in these cancer cell cultures stood in exact correlation with the known level of pain each cancer causes.

“It was exactly what we know clinically about pain association,” adds Lam.

A New Direction for Drug Research

The startling discovery of TMPRSS2’s role in triggering cancer pain may lead to the creation of targeted cancer pain therapies that effectively shut down the expression of this gene or its ability to infiltrate pain receptors in the body.

Dr. Brian Schmidt, Professor at New York University College of Dentistry, Director of the Bluestone Center for Clinical Research and a co-author of the study states, “The discovery that TMPRSS2 drives cancer pain demonstrates another way that cancers lead to suffering. Inhibition of its activity in patients might provide a new form of treatment for cancer pain.”

“Any cancer that is painful before initiating drug treatment – we can label the cancer cells for TMPRSS2 and look for this particular marker,” explains Lam, who adds that the most effective approach to ending pain would be to target the production and expression of the pain gene.

But there may be other ramifications to the TMPRSS2 study: further research may yet uncover what role the increased expression of TMPRSS2 plays in the aggressiveness and morbidity rates associated with certain aggressive cancers – and whether or not shutting down the pain gene will have any other beneficial side effects than reducing discomfort.

The study also involved researchers from New York University and the Forsyth Institute (Cambridge).

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How the Brain Transforms Sound

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Study captures how 2 brain systems in mammals cooperate to capture sounds and process information. When people hear the sound of footsteps or the drilling of a woodpecker, the rhythmic structure of the sounds is striking, says Michael Wehr, a professor of psychology at the University of Oregon.

Even when the temporal structure of a sound is less obvious, as with human speech, the timing still conveys a variety of important information, he says. When a sound is heard, neurons in the lower subcortical region of the brain fire in sync with the rhythmic structure of the sound, almost exactly encoding its original structure in the timing of spikes.

“As the information progresses towards the auditory cortex, however, the representation of sound undergoes a transformation,” said Wehr, a researcher in the UO’s Institute of Neuroscience. “There is a gradual shift towards neurons that use an entirely different system for encoding information.”

In a new study, detailed in the April 8 issue of the journal Neuron, Wehr’s team documented this transformation of information in the auditory system of rats. The findings are similar to those previously shown in primates, suggesting that the processes involved are at work in the auditory systems of all mammals, the team concluded.

Neurons in the brain use two different languages to encode information: temporal coding and rate coding.

For neurons in the auditory thalamus, the part of the brain that relays information from the ears to the auditory cortex, this takes the form of temporal coding. Neurons fire in sync with the original sound, providing an exact replication of the sound’s structure in time.

In the auditory cortex, however, about half the neurons use rate coding, which instead conveys the structure of the sound through the density and rate of the neurons’ spiking, rather than the exact timing.

But how does the transformation from one coding system to another take place?

To find the answer, Wehr and an undergraduate student — lead author Xiang Gao, now a medical student at the Oregon Health & Science University– used a technique known as whole-cell recording in their rat models to capture the thousands of interactions that take place within a single neuron each time it responds to a sound. The team observed how individual cells responded to a steady of stream of rhythmic clicks.

During the study, Wehr and Gao noted that individual rate-coding neurons received up to 82 percent of their inputs from temporal-coding neurons.

“This means that these neurons are acting like translators, converting a sound from one language to another,” Wehr said. “By peering inside a neuron, we can see the mechanism for how the translation is taking place.”

One of these mechanisms is the way that so-called excitatory and inhibitory neurons cooperate to push and pull together, like parents pushing a playground teeter-totter. In response to each click, excitatory neurons first push on a cell and then inhibitory neurons follow with a pull exactly out of phase with the excitatory neurons. Together, the combination drives cells to fire spikes at a high rate, converting the temporal code into a rate code.

The observation provides a glimpse into how circuits deep within the brain give rise to how the world is perceived, Wehr said. Neuroscientists previously have speculated that the transformation from temporal coding to rate coding may explain the perceptual boundary experienced between rhythm and pitch. Slow trains of clicks sound rhythmic, but fast trains of clicks sound like a buzzy tone.

It could be that these two very different experiences of sound are produced by the two different kinds of neurons, Wehr said.

In the UO study, synchronized neurons, using temporal coding, tracked a click train up to about 20 clicks per second, at which point the non-synchronized, rate-coding neurons began to take over. These non-synchronized neurons could respond to faster speeds — up to about 500 clicks per second — but with a rate code in which neurons fire in a random and disconnected pattern.

Why would the auditory system switch representations? The answer, Wehr said, may lie in the visual cortex, which also uses rate coding.

“This transformation in the auditory system is similar to what has been observed in the visual system,” he said. “Except that in the auditory system, neurons are encoding information about time instead of about space.”

Neuroscientists believe rate codes could support multisensory integration in the higher cortical areas, Wehr said. A rate code, he said, could be a universal language, helping us put together what people see and hear.

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