Music Activates Genes for Brain Function

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Although music perception and practice are well preserved in human evolution, the biological determinants of music practice are largely unknown.

Photo Credit: Peter Landecker

According to a latest study, music performance by professional musicians enhanced the activity of genes involved in dopaminergic neurotransmission, motor behavior, learning and memory. Interestingly, several of those up-regulated genes were also known to be responsible for song production in songbirds, which suggests a potential evolutionary conservation in sound perception and production across species.

Music performance is known to induce structural and functional changes to the human brain and enhance cognition. However, the molecular mechanisms underlying music performance have been so far unexplored. A Finnish research group has now investigated the effect of music performance (in a 2 hr concert) on the gene expression profiles of professional musicians from Tapiola Sinfonietta (a professional orchestra) and Sibelius-Academy (a music university).

Playing music enhanced the activity of genes involved in dopaminergic neurotransmission, motor function, learning and memory. Some of the up-regulated genes like SNCA, FOS and DUSP1 are known to contribute to song perception and production in songbirds suggesting a potential evolutionary conservation in molecular mechanisms related to sound production across species. In addition, several of the up-regulated genes are known to be involved in biological pathways like calcium ion homeostasis and iron ion homeostasis that are essential for neuronal function, survival and neuroprotection.

“The findings provide a valuable background for molecular studies of music perception and evolution, and music therapy”, tells Dr Irma Järvelä, the leader of the study.

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Antibacterial plastic: Plastic plus egg whites

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Bioplastics made from protein sources such as albumin and whey have shown significant antibacterial properties, findings that could eventually lead to their use in plastics used in medical applications such as wound healing dressings, sutures, catheter tubes and drug delivery, according to a recent study by the University of Georgia College of Family and Consumer Sciences.

Alex Jones, a doctoral student in the department of textiles, merchandising and interiors at the University of Georgia, is studying the antibacterial properties of bioplastics. He’s found that albumin, a protein found in egg whites, looks the most promising. Photo Credit: Cal Powell/UGA

The bioplastic materials could also be used for food packaging.

Researchers tested three nontraditional bioplastic materials—albumin, whey and soy proteins—as alternatives to conventional petroleum-based plastics that pose risks of contamination.

In particular, albumin, a protein found in egg whites, demonstrated tremendous antibacterial properties when blended with a traditional plasticizer such as glycerol.

“It was found that it had complete inhibition, as in no bacteria would grow on the plastic once applied,” said Alex Jones, a doctoral student in the department of textiles, merchandising and interiors. “The bacteria wouldn’t be able to live on it.”

The study appears in the online version of the Journal of Applied Polymer Science.

One of the researchers’ aims is to find ways to reduce the amount of petroleum used in traditional plastic production; another is to find a fully biodegradable bioplastic.

The albumin-glycerol blended bioplastic met both standards, Jones said.

“If you put it in a landfill, this being pure protein, it will break down,” he said. “If you put it in soil for a month—at most two months—these plastics will disappear.”

The next step in the research involves a deeper analysis of the albumin-based bioplastic’s potential for use in the biomedical and food packaging fields.

As noted in the study, 4.5 hospital admissions out of every 100 in the U.S. in 2002 resulted in a hospital-acquired infection. In addition to the risk of contamination in hospitals, food contamination as a result of traditional plastics is a notable risk.

Researchers are encouraged by the antimicrobial properties of albumin-based bioplastics that could potentially reduce these risks through drug elution—loading the bioplastic with either drugs or food preservatives that can kill bacteria or prevent it from spreading.

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Designer’s toolkit for dynamic DNA nanomachines

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The latest DNA nanodevices created at the Technische Universitaet Muenchen (TUM) – including a robot with movable arms, a book that opens and closes, a switchable gear, and an actuator – may be intriguing in their own right, but that’s not the point. They demonstrate a breakthrough in the science of using DNA as a programmable building material for nanometer-scale structures and machines. Results published in the journal Science reveal a new approach to joining – and reconfiguring – modular 3D building units, by snapping together complementary shapes instead of zipping together strings of base pairs. This not only opens the way for practical nanomachines with moving parts, but also offers a toolkit that makes it easier to program their self-assembly.

The authors of the Science paper, “Dynamic DNA devices and assemblies formed by shape-complementary, non-base pairing 3D components”: (left to right) Thomas Gerling, Andrea Neuner, Klaus Wagenbauer, and Prof. Hendrik Dietz, head of the TUM Laboratory for Biomolecular Nanotechnology. Photo Credit: U. Benz / TUM

The field popularly known as “DNA origami,” in reference to the traditional Japanese art of paper folding, is advancing quickly toward practical applications, according to TUM Prof. Hendrik Dietz. Earlier this month, Dietz was awarded Germany’s most important research award, the Gottfried Wilhelm Leibniz Prize, for his role in this progress.

In recent years, Dietz and his team have been responsible for major steps in the direction of applications: experimental devices including a synthetic membrane channel made from DNA; discoveries that cut the time needed for self-assembly processes from a week to a few hours and enable yields approaching 100%; proof that extremely complex structures can be assembled, as designed, with subnanometer precision.

Yet all those advances employed “base-pairing” to determine how individual strands and assemblies of DNA would join up with others in solution. What’s new is the “glue.”

“Once you build a unit with base pairs,” Dietz explains, “it’s hard to break apart. So dynamic structures made using that approach tended to be structurally simple.” To enable a wider range of DNA nanomachines with moving parts and potentially useful capabilities, the team adapted two more techniques from nature’s biomolecular toolkit: the way proteins use shape complementarity to simplify docking with other molecules, and their tendency to form relatively weak bonds that can be readily broken when no longer needed.

Bio-inspired flexibility

For the experiments reported in Science, Dietz and his co-authors – doctoral candidates Thomas Gerling and Klaus Wagenbauer, and bachelor’s student Andrea Neuner from TUM’s Munich School of Engineering – took inspiration from a mechanism that allows nucleic acid molecules to bond through interactions weaker than base-pairing. In nature, weak bonds can be formed when the RNA-based enzyme RNase P “recognizes” so-called transfer RNA; the molecules are guided into close enough range, like docking spacecraft, by their complementary shapes.

The new technology from Dietz’s lab imitates this approach. To create a dynamic DNA nanomachine, the researchers begin by programming the self-assembly of 3D building blocks that are shaped to fit together. A weak, short-ranged binding mechanism called nucleobase stacking can then be activated to snap these units in place. Three different methods are available to control the shape and action of devices made in this way.

“What this has given us is a tiered hierarchy of interaction strengths,” Dietz says, “and the ability to position – precisely where we need them – stable domains that can recognize and interact with binding partners.” The team produced a series of DNA devices – ranging from micrometer-scale filaments that might prefigure technological “flagella” to nanoscale machines with moving parts – to demonstrate the possibilities and begin testing the limits.

For example, transmission electron micrographs of a three-dimensional, nanoscale humanoid robot confirm that the pieces fit together exactly as designed. In addition, they show how a simple control method – changing the concentration of positive ions in solution – can actively switch between different configurations: assembled or disassembled, with “arms” open wide or resting at the robot’s side.

Another method for switching a DNA nanodevice between its different structural states – by simply raising and lowering the temperature – proved to be especially robust. For earlier generations of devices, this required separating and re-joining DNA base pairs, and thus the systems were “worn out” by dilution and side-reactions after just a few cycles of switching. A scissor-like actuator described in the current paper underwent more than a thousand temperature-switched cycles over a four-day period with no signs of degradation.

“Temperature cycling is a way to put energy into the system,” Dietz adds, “so if the reversible conformational transition could be coupled to some continously evolving process, we basically now have a way not just to build nanomachines, but also to power them.”

“A snap” – like child’s play

There is yet another dimension to the flexibility gained by adding shape-complementary components and weak bonding to the DNA nanotechnology toolkit. Programming self-assembly by base-pairing alone is like writing computer code in machine language. The hope is that this new approach will make it easier to bend DNA origami toward practical ends, in much the same way the advent of higher-level computer programming languages spurred advances in software engineering.

Dietz compares it to building with children’s toys like LEGO: “You design the components to be complementary, and that’s it. No more fiddling with base-pair sequences to connect components.”

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Researchers master gene editing technique in mosquito that transmits deadly diseases

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Traditionally, to understand how a gene functions, a scientist would breed an organism that lacks that gene — “knocking it out” — then ask how the organism has changed. Are its senses affected? Its behavior? Can it even survive? Thanks to the recent advance of gene editing technology, this gold standard genetic experiment has become much more accessible in a wide variety of organisms. Now, researchers at Rockefeller University have harnessed a technique known as CRISPR-Cas9 editing in an important and understudied species: the mosquito, Aedes aegypti, which infects hundreds of millions of people annually with the deadly diseases chikungunya, yellow fever, and dengue fever.

Researchers led by postdoctoral fellow Benjamin J. Matthews adapted the CRISPR-Cas9 system to Ae. aegypti and were able to efficiently generate targeted mutations and insertions in a number of genes. The immediate goal of this project, says Matthews, is to learn more about how different genes help the species operate so efficiently as a disease vector, and create new ways to control it. “To understand how the female mosquito actually transmits disease,” says Matthews, “you have to learn how she finds humans to bite, and how she chooses a source of water to lay her eggs. Once you have that information, techniques for intervention will come.”

In the study, published March 26 in Cell Reports, Matthews and research assistant Kathryn E. Kistler, both in Leslie B. Vosshall’s Laboratory of Neurogenetics and Behavior, adapted the CRISPR-Cas9 system to introduce precise mutations in Ae. aegypti. Previously, to create these types of mutations, scientists relied on techniques that used engineered proteins to bind to specific segments of DNA they wanted to remove, a process that was both expensive and unreliable. CRISPR-Cas9, in contrast, consists of short stretches of RNA that bind to specific regions of the genome where a protein, Cas9, cleaves the DNA. Scientists have been studying how RNA binds to DNA for decades and “the targeting is done with rules that we have a good handle on,” says Matthews, which makes it easy to reprogram CRISPR-Cas9 to target any gene.

“This amazing technique has worked in nearly every organism that’s been tried,” says Vosshall, who is Robin Chemers Neustein Professor and a Howard Hughes Medical Institute investigator. “There are lots of interesting animal species out there that could not be studied using genetics prior to CRISPR-Cas9, and as a result this technique is already revolutionizing biology.”

This work opens the door to learning more about the role of specific genes the Vosshall lab suspects may help mosquitoes propagate, perhaps by finding the perfect spot to lay their eggs. Their protocols will likely also help other scientists apply the same technique to study additional organisms, such as agricultural pests or mosquitoes that carry malaria.

“Before starting this project, we thought it would be difficult to modify many genes in the mosquito genome in a lab setting” Matthews says. “With a little tweaking, we were able to make this technique routine and it’s only going to get easier, faster, and cheaper from here on out.”

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Carbon nanotube fibers make superior links to brain

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Carbon nanotube fibers invented at Rice University may provide the best way to communicate directly with the brain. The fibers have proven superior to metal electrodes for deep brain stimulation and to read signals from a neuronal network. Because they provide a two-way connection, they show promise for treating patients with neurological disorders while monitoring the real-time response of neural circuits in areas that control movement, mood and bodily functions.

New experiments at Rice demonstrated the biocompatible fibers are ideal candidates for small, safe electrodes that interact with the brain’s neuronal system, according to the researchers. They could replace much larger electrodes currently used in devices for deep brain stimulation therapies in Parkinson’s disease patients.

They may also advance technologies to restore sensory or motor functions and brain-machine interfaces as well as deep brain stimulation therapies for other neurological disorders, including dystonia and depression, the researchers wrote.

The paper appeared online this week in the American Chemical Society journal ACS Nano.

The fibers created by the Rice lab of chemist and chemical engineer Matteo Pasquali consist of bundles of long nanotubes originally intended for aerospace applications where strength, weight and conductivity are paramount.

Flavia Vitale, a postdoctoral researcher at Rice, prepares carbon nanotube fibers for testing. Vitale is lead author of a new study that determined the thread-like fibers made of millions of carbon nanotubes may be suitable as electrodes to stimulate the brains of patients with neurological diseases. Photo credit: Jeff Fitlow

The individual nanotubes measure only a few nanometers across, but when millions are bundled in a process called wet spinning, they become thread-like fibers about a quarter the width of a human hair.

“We developed these fibers as high-strength, high-conductivity materials,” Pasquali said. “Yet, once we had them in our hand, we realized that they had an unexpected property: They are really soft, much like a thread of silk. Their unique combination of strength, conductivity and softness makes them ideal for interfacing with the electrical function of the human body.”

The simultaneous arrival in 2012 of Caleb Kemere, a Rice assistant professor who brought expertise in animal models of Parkinson’s disease, and lead author Flavia Vitale, a research scientist in Pasquali’s lab with degrees in chemical and biomedical engineering, prompted the investigation.

“The brain is basically the consistency of pudding and doesn’t interact well with stiff metal electrodes,” Kemere said. “The dream is to have electrodes with the same consistency, and that’s why we’re really excited about these flexible carbon nanotube fibers and their long-term biocompatibility.”

Weeks-long tests on cells and then in rats with Parkinson’s symptoms proved the fibers are stable and as efficient as commercial platinum electrodes at only a fraction of the size. The soft fibers caused little inflammation, which helped maintain strong electrical connections to neurons by preventing the body’s defenses from scarring and encapsulating the site of the injury.

The highly conductive carbon nanotube fibers also show much more favorable impedance – the quality of the electrical connection — than state-of-the-art metal electrodes, making for better contact at lower voltages over long periods, Kemere said.

The working end of the fiber is the exposed tip, which is about the width of a neuron. The rest is encased with a three-micron layer of a flexible, biocompatible polymer with excellent insulating properties.

The challenge is in placing the tips. “That’s really just a matter of having a brain atlas, and during the experiment adjusting the electrodes very delicately and putting them into the right place,” said Kemere, whose lab studies ways to connect signal-processing systems and the brain’s memory and cognitive centers.

Doctors who implant deep brain stimulation devices start with a recording probe able to “listen” to neurons that emit characteristic signals depending on their functions, Kemere said. Once a surgeon finds the right spot, the probe is removed and the stimulating electrode gently inserted. Rice carbon nanotube fibers that send and receive signals would simplify implantation, Vitale said.

The fibers could lead to self-regulating therapeutic devices for Parkinson’s and other patients. Current devices include an implant that sends electrical signals to the brain to calm the tremors that afflict Parkinson’s patients.

“But our technology enables the ability to record while stimulating,” Vitale said. “Current electrodes can only stimulate tissue. They’re too big to detect any spiking activity, so basically the clinical devices send continuous pulses regardless of the response of the brain.”

Kemere foresees a closed-loop system that can read neuronal signals and adapt stimulation therapy in real time. He anticipates building a device with many electrodes that can be addressed individually to gain fine control over stimulation and monitoring from a small, implantable device.

“Interestingly, conductivity is not the most important electrical property of the nanotube fibers,” Pasquali said. “These fibers are intrinsically porous and extremely stable, which are both great advantages over metal electrodes for sensing electrochemical signals and maintaining performance over long periods of time.”

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Common Bacteria Poised to Become Superbugs

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Antibiotic resistance is poised to spread globally among bacteria frequently implicated in respiratory and urinary infections in hospital settings, according to new research at Washington University School of Medicine in St. Louis.

Bacteria that cause many hospital-associated infections are ready to quickly share genes that allow them to resist powerful antibiotics. The illustration, based on electron micrographs and created by the Centers for Disease Control and Prevention, shows one of these antibiotic-resistant bacteria. Photo Credit: CDC/JAMES ARCHER

The study shows that two genes that confer resistance against a particularly strong class of antibiotics can be shared easily among a family of bacteria responsible for a significant portion of hospital-associated infections.

Drug-resistant germs in the same family of bacteria recently infected several patients at two Los Angeles hospitals. The infections have been linked to medical scopes believed to have been contaminated with bacteria that can resist carbapenems, potent antibiotics that are supposed to be used only in gravely ill patients or those infected by resistant bacteria.

“Carbapenems are one of our last resorts for treating bacterial infections, what we use when nothing else works,” said senior author Gautam Dantas, PhD, associate professor of pathology and immunology. “Given what we know now, I don’t think it’s overstating the case to say that for certain types of infections, we may be looking at the start of the post-antibiotic era, a time when most of the antibiotics we rely on to treat bacterial infections are no longer effective.”

Dantas and other experts recommend strictly limiting the usage of carbapenems to cases in which no other treatments can help.

The study, conducted by researchers at Washington University, Barnes-Jewish Hospital and the National University of Sciences and Technology in Pakistan, is available online in Emerging Infectious Diseases.

The researchers studied a family of bacteria called Enterobacteriaceae, which includes E. coli, Klebsiella pneumoniae and Enterobacter. Some strains of these bacteria do not cause illness and can help keep the body healthy. But in people with weakened immune systems, infections with carbapenem-resistant versions of these bacteria can be deadly.

The Centers for Disease Control and Prevention named carbapenem-resistant Enterobacteriaceae as one of the three most urgent threats among emerging forms of antibiotic-resistant disease. Studies have shown the fatality rate for these infections is above 50 percent in patients with weakened immune systems.

Two genes are primarily responsible for carbapenem-resistant versions of these disease-causing bacteria. One gene, KPC, was detected in New York in 2001 and quickly spread around most of the world, with the exception of India, Pakistan and other South Asian countries. This gene was present in the bacteria that recently contaminated medical equipment in a Los Angeles hospital where two patients died.

A second carbapenem resistance gene, NDM-1, was identified in 2006 in New Delhi, India. It was soon detected throughout South Asia, and most patients infected by bacteria with NDM-1 have had an epidemiological link to South Asian countries.

Dantas and his collaborators were curious about why the two resistance genes seemed to be geographically exclusive. For the study, they compared the genomes of carbapenem-resistant bacteria isolated in the United States with those of carbapenem-resistant bacteria isolated in Pakistan.

Based on the apparent geographic exclusivity of the two resistance genes, the scientists expected to find that bacteria from the two regions were genetically different. Such differences could explain why the two resistance genes weren’t intermingling. But the researchers’ results showed otherwise. The bacteria’s high genetic similarity suggests that the antibiotic resistance genes could be shared easily between bacteria from the two geographic regions.

The researchers also sequenced a special portion of bacterial genetic material called plasmids. Most of a bacteria’s DNA is found in its chromosome, but bacteria also have many extra, smaller and circular bits of DNA known as plasmids that easily can pass from one bacterial strain to another. A plasmid is like a bacterial gene delivery truck; it is the primary way antibiotic resistance genes spread between bacteria.

The researchers identified a few key instances in which the plasmids carrying NDM-1 or KPC were nearly identical, meaning they easily could facilitate the spread of antibiotic resistance between disease-causing bacteria found in the United States and South Asia. Recent evidence suggests that this intermingling already may be happening in parts of China.

“Our findings also suggest it’s going to get easier for strains of these bacteria that are not yet resistant to pick up a gene that lets them survive carbapenem treatment,” Dantas said. “Typically, that’s not going to be a problem for most of us, but as drug-resistant forms of Enterobacteriaceae become more widespread, the odds will increase that we’ll pass one of these superbugs on to a friend with a weakened immune system who can really be hurt by them.”

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Nanorobotic agents open the blood-brain barrier

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Magnetic nanoparticles can open the blood-brain barrier and deliver molecules directly to the brain, say researchers from the University of Montreal, Polytechnique Montréal, and CHU Sainte-Justine. This barrier runs inside almost all vessels in the brain and protects it from elements circulating in the blood that may be toxic to the brain.

Seyed Nasrollah Tabatabaei, first author and co-inventor

The research is important as currently 98% of therapeutic molecules are also unable to cross the blood-brain barrier. “The barrier is temporary opened at a desired location for approximately 2 hours by a small elevation of the temperature generated by the nanoparticles when exposed to a radio-frequency field,” explained first author and co-inventor Seyed Nasrollah Tabatabaei. “Our tests revealed that this technique is not associated with any inflammation of the brain. This new result could lead to a breakthrough in the way nanoparticles are used in the treatment and diagnosis of brain diseases,” explained the co-investigator, Hélène Girouard. “At the present time, surgery is the only way to treat patients with brain disorders. Moreover, while surgeons are able to operate to remove certain kinds of tumors, some disorders are located in the brain stem, amongst nerves, making surgery impossible,” added collaborator and senior author Anne-Sophie Carret.

Although the technology was developed using murine models and has not yet been tested in humans, the researchers are confident that future research will enable its use in people. “Building on earlier findings and drawing on the global effort of an interdisciplinary team of researchers, this technology proposes a modern version of the vision described almost 40 years ago in the movie Fantastic Voyage, where a miniature submarine navigated in the vascular network to reach a specific region of the brain,” said principal investigator Sylvain Martel. In earlier research, Martel and his team had managed to manipulate the movement of nanoparticles through the body using the magnetic forces generated by magnetic resonance imaging (MRI) machines.

To open the blood-brain barrier, the magnetic nanoparticles are sent to the surface of the blood-brain barrier at a desired location in the brain. Although it was not the technique used in this study, the placement could be achieved by using the MRI technology described above. Then, the researchers generated a radio-frequency field. The nanoparticles reacted to the radio-frequency field by dissipating heat thereby creating a mechanical stress on the barrier. This allows a temporary and localized opening of the barrier for diffusion of therapeutics into the brain.

The technique is unique in many ways. “The result is quite significant since we showed in previous experiments that the same nanoparticles can also be used to navigate therapeutic agents in the vascular network using a clinical MRI scanner,” Martel remarked. “Linking the navigation capability with these new results would allow therapeutics to be delivered directly to a specific site of the brain, potentially improving significantly the efficacy of the treatment while avoiding systemic circulation of toxic agents that affect healthy tissues and organs,” Carret added. “While other techniques have been developed for delivering drugs to the blood-brain barrier, they either open it too wide, exposing the brain to great risks, or they are not precise enough, leading to scattering of the drugs and possible unwanted side effect,” Martel said.

Although there are many hurdles to overcome before the technology can be used to treat humans, the research team is optimistic. “Although our current results are only proof of concept, we are on the way to achieving our goal of developing a local drug delivery mechanism that will be able to treat oncologic, psychiatric, neurological and neurodegenerative disorders, amongst others,” Carret concluded.

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Study announces a durable vaccine for Ebola

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A new study shows the durability of a novel ‘disseminating’ cytomegalovirus (CMV)-based Ebola virus (Zaire ebolavirus; EBOV) vaccine strategy that may eventually have the potential to reduce ebolavirus infection in wild African ape species.

The multi-institutional study is led by Dr Michael Jarvis at Plymouth University, and is published today, 25th March 2015, in Vaccine.

African apes serve as a main source of ebolavirus transmission into the human population. As a consequence, the prevention of ebolavirus infection in African apes could reduce the incidence of future human ebolavirus outbreaks. Ebolavirus is also highly lethal to African apes, and is regarded as a major threat to the survival of these populations in the wild. Such a ‘disseminating’ vaccine offers hope for both stabilizing these endangered ape populations and protecting humans against the devastating effects of Ebola.

The innovative approach may overcome the major hurdle to achieving high vaccine coverage of these animals. They live in of some of the most remote, inaccessible regions of the world which makes conventional, individual vaccination near impossible.

Apart from being very immunogenic (able to provoke an immune response) and species-specific, CMV can also spread easily from individual to individual, a process which remains remarkably unaffected by prior CMV immunity. This is the basis of the team’s current innovative strategy of using a CMV-based ebolavirus vaccine that can spread through wild ape populations as a means to provide high levels of protective ebolavirus-specific immunity without the need for direct vaccination.

The current publication expands on a 2011 study, in which the same collaborative research team first showed the ability of a CMV-based vaccine to provide protection against Ebola virus in a mouse challenge model.

Most Ebola virus vaccine mouse studies, including this earlier 2011 study, have only assessed protection against Ebola virus infection shortly after vaccination (generally within six weeks post-vaccination). The present study showed that immunity induced by CMV is extremely long-lasting, with Ebola virus-specific immune responses being maintained for greater than 14 months (equivalent to half the life span of a mouse) following only a single dose of the vaccine.

Importantly, immunity induced by the CMV vaccine was able to provide protection against Ebola virus at least until 119 days (approximately four months) post-vaccination. Long-lasting immunity will be critical for the eventual success of this disseminating vaccine approach. It is also an attractive characteristic for a (albeit non-disseminating) CMV-based Ebola virus vaccine for direct use in humans, which is an additional area of development of the current collaborative research group.

The next step, which is nearing completion, is to trial the vaccine using CMV in the macaque EBOV challenge model (regarded as the ‘gold standard’ for testing vaccines in a model translatable to Ebola infection in great apes and humans). The results from this study further support the utility of this approach and will be published in the next few months. Many questions clearly remain, including the nature of the immunity conferred by disseminated CMV vaccines (in the current study mice were directly inoculated).

“We must walk before we can run, but this study provided a little skip,” said Dr. Michael Jarvis, corresponding author on the study from Plymouth University Peninsula Schools of Medicine and Dentistry. “However, this disseminating approach does potentially provide a workable solution to a currently intractable problem of achieving high vaccine coverage in inaccessible ape populations. Given the impact of ebolavirus on African ape numbers in the wild, and the role of apes as a route of ebolavirus transmission to humans via the bush meat trade, such a vaccine would be a win-win for humans and wild apes alike.”

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Prices of cancer drugs have soared since 1995

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The prices of leading cancer drugs have risen at rates far outstripping inflation over the last two decades, according to a new study co-authored by an MIT economist — but the exact reasons for the cost increases are unclear.

Photo credits: iStock via MIT News

Since 1995, a group of 58 leading cancer drugs has increased in price by 10 percent annually, even when adjusted for inflation and incremental health benefits, the study finds. More specifically, in 1995, cancer drugs in this group cost about $54,100 for each year of life they were estimated to add; by 2013, such drugs cost about $207,000 per each additional year of life.

Those increases have sparked criticism in recent years from doctors, among other groups, who have questioned the pricing of major drugs. But the empirical results may also show, the researchers say, that rising price levels reflect a greater social tolerance for significant health-care costs.

“I think the value of good health has really increased enormously over the last few decades,” says Ernst Berndt, the Louis E. Seley Professor in Applied Economics at the MIT Sloan School of Management, and co-author of a new paper detailing the study’s findings. “We treasure it and are willing to pay a fair bit for that.”

The paper notes that there have been some cases of political backlash in recent years — in Oregon, for instance — in response to proposed policies that would limit the ability of public insurance programs to buy expensive, life-extending cancer drugs. On the other hand, as the authors observe, patient cost-sharing in medical plans has also increased since 1995, limiting the extent to which demand can explain the changes.

Patients do seem to be paying for improved quality, to an extent: The study found a positive correlation between the effectiveness of drugs and their prices. Cancer drug prices rise about 120 percent for each additional year of life gained by a patient, in aggregate.

“We found that the greater the improvement of the drug over the existing therapies, the higher the price,” Berndt explains. “So price was related to quality — but price increased more than did quality.”

So what else is driving prices?

The paper, “Pricing in the Market for Anticancer Drugs,” is published in the latest issue of the Journal of Economic Perspectives. In addition to Berndt, the co-authors are Peter B. Bach, a physician at Memorial Sloan Kettering Cancer Center in New York; Rena M. Conti, an assistant professor of health policy at the University of Chicago; and David H. Howard, an associate professor at Emory University’s Rollins School of Public Health.

Globally, cancer drugs are the class of pharmaceuticals with the highest sales, at $91 billion in 2013; $37 billion of that spending was in the U.S. As in many major global markets, there is contention about what price levels are justified. The paper notes that in 2013, a group of 100 prominent oncologists claimed that drug companies’ pricing policies involved a “simple formula: start with the price of the most recent similar drug on the market and price the new one within 10-20 percent of that price (usually higher).”

The paper notes that such assertions are at least consistent with “reference price models of demand,” in which consumers’ decisions to pay involve existing prices, rather than a measurement of intrinsic value. Berndt says such challenges are “probably credible,” but notes that it is hard to assess how much money pharmaceutical companies have spent developing specific drugs.

“Typically drug companies and biotech companies simultaneously study all sorts of medicines,” Berndt notes. Therefore, he adds, “It’s extremely difficult to allocate historical costs of drug development to specific new drugs.”

There may be some additional factors entering into the cost of cancer therapeutics today. The “340B” pricing program enacted by Congress in 1992, the paper notes, requires discounts for some hospitals and clinics, which may incentivize companies to raise prices to compensate.

Overall, the authors conclude, “We believe the direction of causation runs from prices to research and development costs — as prices increase, manufacturers are willing to spend more to discover new drugs — rather than the other way around.”

Experts in the field say the authors have shed welcome light on an important trend in medicine.

“This is a really nice paper,” says Jonathan Skinner, an economist at Dartmouth College, who adds that the paper uses “convincing measures” to show how much costs have both increased, and are also associated with effectiveness: “There is at least some attempt to price drugs according to the value they provide patients.”

Skinner also suggests that health-insurance arrangements could be a significant factor behind the overall trend in prices.

“Patients may not be facing the higher prices, either because they have generous insurance, or because the drug companies themselves are jumping in to pick up the co-insurance payments,” Skinner observes. As he notes, drug companies can, in theory, benefit from significantly higher basic prices while waiving patients’ payments, if those waived payments are smaller than the overall price increases.

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After learning new words, brain sees them as pictures

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When we look at a known word, our brain sees it like a picture, not a group of letters needing to be processed. That’s the finding from a Georgetown University Medical Center (GUMC) study published in the Journal of Neuroscience, which shows the brain learns words quickly by tuning neurons to respond to a complete word, not parts of it.

Neurons respond differently to real words, such as turf, than to nonsense words, such as turt, showing that a small area of the brain is “holistically tuned” to recognize complete words, says the study’s senior author, Maximilian Riesenhuber, PhD, who leads the GUMC Laboratory for Computational Cognitive Neuroscience.

“We are not recognizing words by quickly spelling them out or identifying parts of words, as some researchers have suggested. Instead, neurons in a small brain area remember how the whole word looks — using what could be called a visual dictionary,” he says.

This small area in the brain, called the visual word form area, is found in the left side of the visual cortex, opposite from the fusiform face area on the right side, which remembers how faces look. “One area is selective for a whole face, allowing us to quickly recognize people, and the other is selective for a whole word, which helps us read quickly,” Riesenhuber says.

The study asked 25 adult participants to learn a set of 150 nonsense words. The brain plasticity associated with learning was investigated with functional magnetic resonance imaging (fMRI), both before and after training.

Using a specific fMRI technique know as fMRI-rapid adaptation, the investigators found that the visual word form area changed as the participants learned the nonsense words. Before training the neurons responded like the training words were nonsense words, but after training the neurons responded to the learned words like they were real words. “This study is the first of its kind to show how neurons change their tuning with learning words, demonstrating the brain’s plasticity,“ says the study’s lead author, Laurie Glezer, PhD.

The findings not only help reveal how the brain processes words, but also provides insights into how to help people with reading disabilities, says Riesenhuber. “For people who cannot learn words by phonetically spelling them out — which is the usual method for teaching reading — learning the whole word as a visual object may be a good strategy.”

In fact, after the team’s first groundbreaking study on the visual dictionary was published in Neuron in 2009, Riesenhuber says they were contacted by a number of people who had experienced reading difficulties and teachers helping people with reading difficulties, reporting that learning word as visual objects helped a great deal. That study revealed the existence of a neural representation for whole written real words — also known as an orthographic lexicon —the current study now shows how novel words can become incorporated after learning in this lexicon.

“The visual word form area does not care how the word sounds, just how the letters of the word look together,” he says. “The fact that this kind of learning only happens in one very small part of the brain is a nice example of selective plasticity in the brain,”

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Is blood really thicker than water?

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A duel between mathematical models supports the reigning theory of the genetics of altruism

It isn’t that often that a scientific controversy is featured in the New Yorker, but in 2012 an article titled “Kin and Kind” describing a tempest over a biological theory appeared in its pages.

Even Darwin was vexed by the cooperative behavior of insects such as these leaf cutter ants, which didn’t seem to fit with his theory of natural selection. Why would ants help other ants when it didn’t benefit them directly? Photo credit: BANDWAGONMAN AT EN.WIPIDEIA

The tempest was provoked by an article in the Aug. 26, 2010 issue of Nature. Written by Harvard mathematicians Martin A. Nowak and Corina E. Tarnita and Harvard biologist Edward O. Wilson, it questioned the validity of the theory of inclusive fitness.

Inclusive fitness theory, proposed by British biologist W. D. Hamilton in 1964, expanded Darwin’s definition of “fitness” — an organism’s success in passing on its genes — to include the genes of its relatives. This expansion made altruism in the service of kin a competitive strategy.

The Nature article, titled “The Evolution of Eusociality,” asserted that inclusive fitness theory, which has been a cornerstone of evolutionary biology for the past 50 years, had produced only “meagre” results and that mathematical models based on standard natural selection theory provide a “simpler and superior approach.”

This provoked a prolonged argument among evolutionary biologists that is still not resolved. But in ”Relatedness, Conflict and the Evolution of Eusociality” published in the March 31 issue of PLOS Biology David C. Queller, PhD, a well-known evolutionary biologist at Washington University in St. Louis, suggests a way out of the impasse.

Queller, the Spencer T. Olin Professor in the Department of Biology, and his co-authors Stephen Rong, who graduated from Washington University with a bachelor’s degree in math and is now a graduate student at Brown University, and Xiaoyun Liao, a former research assistant at Rice University with expertise in mathematical modeling, adopted the model the Harvard writers had proposed as an alternative to inclusive fitness and tested it to see whether it supported the claims the authors made in the Nature paper.

It didn’t. “They had a modeling strategy that should work and should be fine, but they weren’t careful enough when they made claims about their models’ novel results,” Queller said. But he also argued that the two mathematical models are essentially equivalent in that they ultimately predict the same results.

Inclusive fitness and social insects

Inclusive fitness was originally developed to explain eusociality, a extreme form of altruism found in social insects, where non-reproducing colony members give up their right to reproduce and devote their lives to caring for the offspring of a single reproducing member.

Hamilton’s inclusive fitness theory was invented to solve this paradox, which vexed even Darwin. Hamilton calculated that sterile castes could evolve if altruistic sterility sufficiently benefited relatives also carrying the altruistic gene.

Kin selection and inclusive fitness quickly became the dominant mode of thinking about the evolution of eusocial insects and their success in this area led to their application to many other problems in social evolution.

But the Harvard authors asserted that while “empirical research on eusocial organisms has flourished, revealing rich details of caste, communication, colony life cycles, and other phenomena . . . almost none of this progress has been stimulated or advanced by inclusive fitness theory, which has evolved into an abstract enterprise largely on its own.”

Queller saw nothing wrong with the mathematical models the Harvard authors proposed in Nature but was puzzled by some of the assertions they made. “I went through their paper trying to pull out conclusions that appeared to be different from the conclusions you get from inclusiveness theory,” he said. “He settled on three claims, which he then tried to prove by running ‘experiments’ with the Harvard-style models.”

Do shared genes drive the evolution of social behavior?

In inclusive fitness theory, relatedness is essential to the evolution of eusociality. But the Harvard authors claimed it is a consequence of eusociality rather than a cause. “Once eusociality has evolved, colonies consist of related individuals because daughters stay with their mothers to raise further offspring,” they wrote.

“Although they said relatedness was not important, in their mathematical models they didn’t actually vary relatedness,“ Queller said. “To test their claim we allowed some mixing between the offspring of different mothers before the offspring decided to stay with the colony to help her or to abandon her and leave,” he said.

“When you ‘lower’ relatedness,” he said, “it makes eusociality hard to evolve, and if you make it zero, you never get eusociality. So varying relatedness in their model takes us back to what we thought we already knew from inclusive fitness theory.”

Are the queen and the workers in conflict?

“It follows from inclusive fitness theory is that unless all members of a colony are genetically identical, there will be a region of the benefit/cost space where the queen and workers are in conflict,” Queller said. What’s good for the inclusive fitness of one may not be good for the inclusive fitness of the other.”

But the Harvard authors wrote that “the queen and her workers are not engaged in a standard cooperative dilemma.” The workers, they said, are “robots,” built by the queen as part of her reproductive strategy rather than independent agents.

But, Queller said, they tested only “offspring control models” (models where the decision to stay with the colony or to leave was controlled by genes expressed by workers). To check for conflict Queller compared models with offspring agency to ones with maternal agency (where the decision to stay to help is controlled by genes expressed by the queen).

As predicted by inclusive fitness theory, he said, the two cases evolve quite differently, and mothers benefit from stay-at-home offspring under conditions where offspring would be better off leaving.

“So as inclusive fitness theory predicts, you get regions of conflict where the queen would like her workers to stay but the workers want to leave. The mathematics says they’re not robots,” Queller said.

How hard is it to evolve eusociality?

Finally, the Harvard authors wrote, their model showed that it was very difficult for a solitary species to evolve to become eusocial despite the intuitive advantages of cooperation among members of a group.

This claim is less fundamental than the two others, Queller said, and it is true that eusociality has evolved only 10 or 20 times in the course of evolution.

“But we also showed that this result hinged on heavily biased assumptions,” Quellers said. “We showed that modifying either the fitness function in their model or the worker decision rule made it easier to achieve eusociality. “

“So the essence of my paper,” Queller said, ”is that there really isn’t much disagreement. The things we thought were important from inclusive fitness theory show up as important in their models as well.”

Fully aware of the irony of a fight over selflessness, he hopes that his assertion that the dueling models are essentially equivalent will help resolve the debate.

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The above story is based on materials provided by Washington University in St. Louis

Ovarian Cancer: Predicting Response to Chemo

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Queen’s University cancer researcher Madhuri Koti has discovered a biomarker that will help lead to better predictions of the success of chemotherapy in ovarian cancer patients. This discovery could lead to better treatment options in the fight against ovarian cancer.

“Recent successes in harnessing the immune system to combat cancer are evidence for the significant roles of a cancer patient’s immune responses in fighting cancer,” explains Dr. Koti (Biomedical and Molecular Sciences). “Many of these success are based on boosting anti-cancer immunity via different therapies. Such therapies would prove to be most effective when coupled with markers predicting a patient’s eventual response to a specific therapy.”

Dr. Koti conducted the study in retrospective cohorts of over 200 ovarian cancer patients.

The study utilized a combination of recent cutting-edge and more established detection technologies for identifying such markers. Initial discovery of these markers was made in frozen tumor tissues accrued from tumor banks such as the Ontario Tumor Bank and the Ottawa Health Research Institute and Gynecology-Oncology and Pathology services of the CHUMHospital Notre-Dame, Montreal.

Phase II validations are currently under way in retrospective cohorts of over 500 ovarian cancer patient tumors accrued from the Terry Fox Research Institute-Ovarian Cancer Canada partnered, Canadian Ovarian Experimental Unified Resource.

A major impact of this discovery is that these novel markers, when used at the time of treatment initiation in the specific type of ovarian cancer patient, will help gynecologic oncologists make decisions on additional treatment needed in these patients, thus increasing the potential for patient survival.

Ovarian cancer leads to approximately 152,000 deaths among women worldwide each year, making it a leading cause of gynecological cancer related deaths in women.

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Scientists coax stem cells to form 3-D mini lungs

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Human lung organoids may help scientists learn more about lung diseases, test new drugs

The panel on the left is a cross section through an organoid, viewed through a microscope and stained to visualize the lung tissue. Lung tissue in organoids is organized in a similar manner to the adult lung, shown in the right panel.

Previous research has focused on deriving lung tissue from flat cell systems or growing cells onto scaffolds made from donated organs. In a study published in the online journal eLife the multi-institution team defined the system for generating the self-organizing human lung organoids, 3D structures that mimic the structure and complexity of human lungs.

“These mini lungs can mimic the responses of real tissues and will be a good model to study how organs form, change with disease, and how they might respond to new drugs,” says senior study author Jason R. Spence, Ph.D., assistant professor of internal medicine and cell and developmental biology at the University of Michigan Medical School.

The scientists succeeded in growing structures resembling both the large airways known as bronchi and small lung sacs called alveoli.

Since the mini lung structures were developed in a dish, they lack several components of the human lung, including blood vessels, which are a critical component of gas exchange during breathing.

Still, the organoids may serve as a discovery tool for researchers as they churn basic science ideas into clinical innovations. A practical solution lies in using the 3-D structures as a next step from, or complement to, animal research.

Cell behavior has traditionally been studied in the lab in 2-D situations where cells are grown in thin layers on cell-culture dishes. But most cells in the body exist in a three-dimensional environment as part of complex tissues and organs.

Researchers have been attempting to re-create these environments in the lab, successfully generating organoids that serve as models of the stomach, brain, liver and human intestine.

The advantage of growing 3-D structures of lung tissue, Spence says, is that their organization bears greater similarity to the human lung.

How to make a human lung in a dish

To make these lung organoids, researchers at the U-M’s Spence Lab and colleagues from the University of California, San Francisco; Cincinnati Children’s Hospital Medical Center; Seattle Children’s Hospital and University of Washington, Seattle manipulated several of the signaling pathways that control the formation of organs.

First, stem cells – the body’s master cells — were instructed to form a type of tissue called endoderm, which is found in early embryos and gives rise to the lung, liver and several other internal organs.

Scientists activated two important development pathways that are known to make endoderm form three-dimensional tissue. By inhibiting two other key development pathways at the same time, the endoderm became tissue that resembles the early lung found in embryos.

In the lab, this early lung-like tissue spontaneously formed three-dimensional spherical structures as it developed. The next challenge was to make these structures expand and develop into lung tissue. To do this, the team exposed the cells to additional proteins that are involved in lung development.

The resulting lung organoids survived in the lab for over 100 days.

“We expected different cells types to form, but their organization into structures resembling human airways was a very exciting result,” says lead study author Briana Dye, a graduate student in the U-M Department of Cell and Developmental Biology.

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Artificial Hand: Sensitive Touch

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Artificial hand able to respond sensitively thanks to muscles made from smart metal wires

Engineers at Saarland University have taken a leaf out of nature’s book by equipping an artificial hand with muscles made from shape-memory wire. The new technology enables the fabrication of flexible and lightweight robot hands for industrial applications and novel prosthetic devices. The muscle fibres are composed of bundles of ultrafine nickel-titanium alloy wires that are able to tense and flex. The material itself has sensory properties allowing the artificial hand to perform extremely precise movements. The research group led by Professor Stefan Seelecke will be showcasing their prototype artificial hand and how it makes use of shape-memory ‘metal muscles’ at HANNOVER MESSE – the world’s largest industrial fair – from April 13th to April 17th. The team, who will be exhibiting at the Saarland Research and Innovation Stand in Hall 2, Stand B 46, are looking for development partners.

Filomena Simone, an engineer in the research team led by Professor Stefan Seelecke, is working on the prototype of the artificial hand. Photo Credit: Oliver Dietze

The hand is the perfect tool. Developed over millions of years, its ‘design’ can certainly be said to be mature. The hand is extraordinarily mobile and adaptable, and the consummate interaction between the muscles, ligaments, tendons, bones and nerves has long driven a desire to create a flexible tool based upon it. The research team led by Professor Stefan Seelecke from Saarland University and the Center for Mechatronics and Automation Technology (ZeMA) is using a new technology based on the shape memory properties of nickel-titanium alloy. The engineers have provided the artificial hand with muscles that are made up from very fine wires whose diameter is similar to that of a human hair and that can contract and relax.

‘Shape-memory alloy (SMA) wires offer significant advantages over other techniques,’ says Stefan Seelecke. Up until now, artificial hands, such as those used in industrial production lines, have relied on a lot of complex background technology. As a result they are dependent on other devices and equipment, such as electric motors or pneumatics, they tend to be heavy, relatively inflexible, at times loud, and also expensive. ‘In contrast, tools fabricated with artificial muscles from SMA wire can do without additional equipment, making them light, flexible and highly adaptable. They operate silently and are relatively cheap to produce. And these wires have the highest energy density of all known drive mechanisms, which enables them to perform powerful movements in restricted spaces,’ explains Seelecke. The term ‘shape memory’ refers to the fact that the wire is able to ‘remember’ its shape and to return to that original predetermined shape after it has been deformed. ‘This property of nickel-titanium alloy is a result of phase changes that occur within the material. If the wire becomes warm, which happens, for instance, when it conducts electricity, the material transforms its lattice structure causing it to contract like a muscle,’ says Seelecke.

The engineers use ‘smart’ wires to play the role of muscles in the artificial hand. Multiple strands of shape-memory wire connect the finger joints and act as flexor muscles on the front-side of the finger and as extensor muscles on the rear. In order to facilitate rapid movements, the engineers copied the structure of natural human muscles by grouping the very fine wires into bundles to mimic muscle fibres. These bundles of wires are as fine as a thread of cotton, but have the tensile strength of a thick wire. ‘The bundle can rapidly contract and relax while exerting a high tensile force,’ explains Filomena Simone, an engineer who is working on the prototype of the artificial hand as part of her doctoral research. ‘The reason for this behaviour is the rapid cooling that is possible because lots of individual wires present a greater surface area through which heat can be dissipated. Unlike a single thick wire, a bundle of very fine wires can undergo rapid contractions and extensions equivalent to those observed in human muscles. As a result, we are able to achieve fast and smooth finger movements,’ she explains.

Another effect of using the shape-memory metal wires is that the hand can respond in a natural manner when someone intervenes while a particular movement is being carried out. This means that humans can literally work hand-in-hand with the prototype device. A semiconductor chip controls the relative motions of the SMA wires allowing precise movements to be carried out. And the system does not need sensors. ‘The material from which wires are made has sensor properties. The controller unit is able to interpret electric resistance measurement data so that it knows the exact position of the wires at any one time,’ says Seelecke. This enables the hand and the fingers to be moved with high precision. The research team will be exhibiting their system prototypes at HANNOVER MESSE 2015 and showcasing the potential of the technology by performing hand grasps and the controlled movement of individual fingers. The researchers want to continue developing the prototype and improve the way in which it simulates the human hand. This will involve modelling hand movement patterns and exploiting the sensor properties of SMA wire.

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Brain tumor cells decimated by mitochondrial ‘smart bomb’

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An experimental drug that attacks brain tumor tissue by crippling the cells’ energy source called the mitochondria has passed early tests in animal models and human tissue cultures, say Houston Methodist scientists.

As reported on the cover of the April 2015 ChemMedChem (early online), Houston Methodist Kenneth R. Peak Brain & Pituitary Tumor Center Director David S. Baskin, M.D., and Peak Center Head of Research Martyn Sharpe, Ph.D. designed a drug called MP-MUS that destroyed 90 to 95 percent of malignant glioma cells, yet in other experiments did not seem to adversely affect healthy human brain cells (in vitro). This compliments a soon to be published extensive study showing the same drug can treat human brain cancer grown in the brains of mice. Researchers hope to begin testing the drug in human clinical trials in 2016 or 2017

The new drug MP-MUS (yellow) attacks cancer cell mitochondria by infiltrating both inner and outer membranes (green) after being converted from an inactive, non-toxic form to an active, toxic form by the enzyme MAO-B (purple). Once inside, the drug damages mitochondrial DNA, which cannot be repaired. Photo Credit: Dr. David Baskin laboratory, Houston Methodist Hospital

“We are very optimistic that we’ll get there,” said Baskin, also Vice Chair of the Department of Neurosurgery at Houston Methodist Hospital. “Our past work has shown that MP-MUS has very low toxicity until it gets into tumor cells. Once it arrives, it is changed to its active form, doing a lot of damage where we want it to, leaving healthy brain cells alone — a bit like a ‘smart bomb.’ To our knowledge, this is the first known example of selective mitochondrial chemotherapy, which we believe represents a powerful new approach to brain cancer.”

Medical options for brain tumor patients are woeful, Baskin said. “It’s a horrible diagnosis. Because of where the tumors are located, and because of the way they can infiltrate healthy tissue, surgery is often not helpful long term. The most effective chemotherapy drug available right now, temozolomide, only extends life from 9 to 15 months, and patients’ quality of life during that period isn’t very good.”

For that reason, Baskin said, he and researchers around the world have been looking for new treatment approaches, such as vaccines intended to aid the body’s immune system’s recognition and removal of tumor cells, gene therapy and, in the present case, targeting tumor cell mitochondria.

Gliomas (a type of brain tumor) develop from brain cells called astrocytes. Gliomas account for as much as 20 to 30 percent of all tumors of the brain and central nervous system.

Mitochondria are often referred to as the “powerhouses” of cells — including misbehaving cancer cells — because they help cells create energy. In cancer cells this feature is partially switched off, causing cells to rely on other systems that generate energy. The numerous pill-shaped mitochondria in each cell perform a number of other crucial functions, however, and even cancer cells cannot grow and divide without healthy mitochondria.

As luck would have it, an enzyme called MAO-B is over-expressed in brain tumor cells, which is the target of MP-MUS. This means that healthy cells are only exposed to low levels of MP-MUS and their mitochondria to very low levels of P+-MUS, Baskin says. On the other hand, in tumor cells the vast majority of the pro-drug is converted into P+-MUS, which essentially traps the drug inside their mitochondria where it attacks the mitochondrial DNA.

“We found that we could achieve profound effects with MP-MUS at very low concentrations, around 75 micromolar,” said Baskin, Professor of Neurological Surgery, Weill Cornell Medical College. “By contrast, temozolomide must be used at concentrations two to three times that to be of any use to patients. Our approach is designed to capitalize on what is going inside the cells. Tumor cells have much more MAO-B, and when challenged, make even more MAO-B as a sort of defensive response. We hope that we are one step ahead of the cancer cells, as we are using that very fact to kill them.”

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Training your brain to pay attention

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A recent analysis has brought new clarity to the debate over whether brain training exercises can improve people’s ability to pay attention in everyday life.

Dr Megan Spencer-Smith, from Monash University’s School of Psychological Sciences, and Professor Torkel Klingberg from the Karolinska Institute in Stockholm – analysed the results of 12 studies, eleven of which had been conducted with participants who suffered Attention Deficit Hyperactivity Disorder (ADHD).

Dr Megan Spencer-Smith

However, the meta-analysis showed that brain training also worked as a ‘cure’ for inattentiveness in those without the disorder.

“Subgroup analyses showed this significant effect was observed in groups of children and adults as well as users with and without ADHD, and in studies using control groups that were active and non-adaptive, wait-list and passive as well as studies using specific or general measures,” the study states.

“Seven of the studies reported follow-up assessment and a meta-analysis showed persisting training benefits for inattention in daily life,” it continues.

The study, published in prestigious psychology journal PLOS One, examined the results of Cogmed, a program designed to improve the retention and use of verbal and visual information.

Participants who completed 35 minutes of brain training, five times a week for a period of five weeks showed improved attentiveness for up to four months after training was complete.

“Cogmed and programmes like it are expensive and time-consuming, so doctors, parents and individuals will want to see bigger studies that track participants for longer,” Dr Spencer-Smith said.

There was still a long way to go in proving the effectiveness of brain training, Dr Spencer-Smith added.

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Microbes Can Make Anti-Obesity Molecule

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Microbes may just be the next diet craze. Researchers have programmed bacteria to generate a molecule that, through normal metabolism, becomes a hunger-suppressing lipid. Mice that drank water laced with the programmed bacteria ate less, had lower body fat and staved off diabetes — even when fed a high-fat diet — offering a potential weight-loss strategy for humans.

The team will describe their approach in one of nearly 11,000 presentations at the 249th National Meeting & Exposition of the American Chemical Society (ACS), the world’s largest scientific society, taking place here through Thursday.

Photo credit: Joe Howell

Obesity strongly increases the risk for developing several diseases and conditions, such as heart disease, stroke, type 2 diabetes and some types of cancer. One in three Americans is obese, and efforts to stem the epidemic have largely failed. Lifestyle changes and medication typically achieve only modest weight loss, and most people regain the weight. In recent years, numerous studies have shown that the population of microbes living in the gut may be a key factor in determining the risk for obesity and related diseases, suggesting that strategically altering the gut microbiome may impact human health.

One advantage to microbial medicine would be that it’s low maintenance, says Sean Davies, Ph.D. His goal is to produce therapeutic bacteria that live in the gut for six months or a year, providing sustained drug delivery. This is in contrast to weight-loss drugs that typically need to be taken at least daily, and people tend not to take their medications as directed over time. “So we need strategies that deliver the drug without requiring the patient to remember to take their pills every few hours,” Davies says.

For a therapeutic molecule, Davies and colleagues at Vanderbilt University selected N-acyl-phosphatidylethanolamines (NAPEs), which are produced in the small intestine after a meal and are quickly converted into N-acyl-ethanolamines (NAEs), potent appetite-suppressing lipids. The researchers altered the genes of a strain of probiotic bacteria so it would make NAPEs. Then they added the bacteria to the drinking water of a strain of mice that, fed a high-fat diet, develop obesity, signs of diabetes and fatty livers.

Compared to mice who received plain water or water containing control, non-programmed bacteria, the mice drinking the NAPE-making bacteria gained 15 percent less weight over the eight weeks of treatment. In addition, their livers and glucose metabolism were better than in the control mice. The mice that received the therapeutic bacteria remained lighter and leaner than control mice for up to 12 weeks after treatment ended.

In further experiments, Davies’ team found that mice that lacked the enzyme to make NAEs from NAPEs were not helped by the NAPE-making bacteria; but this could be overcome by giving the mice NAE-making bacteria instead. “This suggests that it might be best to use NAE-making bacteria in eventual clinical trials,” says Davies, especially if the researchers find that some people don’t make very much of the enzyme that converts NAPEs to NAEs. “We think that this would work very well in humans.”

The main obstacle to starting human trials is the potential risk that a treated person could transmit these special bacteria to another by fecal exposure. “We don’t want individuals to be unintentionally treated without their knowledge,” says Davies. “Especially because you could imagine that there might be some individuals, say the very young or old or those with specific diseases, who could be harmed by being exposed to an appetite-suppressing bacteria. So, we are working on genetically modifying the bacteria to significantly reduce its ability to be transmitted.”

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How we’re teaching computers to understand pictures

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When a very young child looks at a picture, she can identify simple elements: “cat,” “book,” “chair.” Now, computers are getting smart enough to do that too. What’s next? In a thrilling talk, computer vision expert Fei-Fei Li describes the state of the art — including the database of 15 million photos her team built to “teach” a computer to understand pictures — and the key insights yet to come.

As Director of Stanford’s Artificial Intelligence Lab and Vision Lab, Fei-Fei Li is working to solve AI’s trickiest problems — including image recognition, learning and language processing.

Why you should listen

Using algorithms built on machine learning methods such as neural network models, the Stanford Artificial Intelligence Lab led by Fei-Fei Li has created software capable of recognizing scenes in still photographs — and accurately describe them using natural language.

Li’s work with neural networks and computer vision (with Stanford’s Vision Lab) marks a significant step forward for AI research, and could lead to applications ranging from more intuitive image searches to robots able to make autonomous decisions in unfamiliar situations.

What others say

“Computer software only recently became smart enough to recognize objects in photographs. Now, Stanford researchers using machine learning have created a system that takes the next step, writing a simple story of what’s happening in any digital image.” — Stanford News, November 18, 2014

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The ‘intraterrestrials': New viruses discovered in ocean depths

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Strange creatures live in the deep sea, but few are odder than the viruses that inhabit deep ocean methane seeps and prey on single-celled microorganisms called archaea.

The least understood of life’s three primary domains, archaea thrive in the most extreme environments on the planet: near hot ocean rift vents, in acid mine drainage, in the saltiest of evaporation ponds and in petroleum deposits deep underground.

Virus in the deep blue sea

While searching the ocean’s depths for evidence of viruses, scientists have found a remarkable new one, a virus that seemingly infects archaea that live beneath the ocean floor.

The researchers were surprised to discover that the virus selectively targets one of its own genes for mutation, and that this capacity is also shared by archaea themselves.

The findings appear today in a paper in the journal Nature Communications.

The project was supported by a National Science Foundation (NSF) Dimensions of Biodiversity grant to characterize microbial diversity in methane seep ecosystems. Dimensions of Biodiversity is supported by NSF’s Directorates for Biological Sciences and Geosciences.

New information about life in ocean depths

“Life far beneath the Earth’s subsurface is an enigma,” said Matt Kane, program director in NSF’s Division of Environmental Biology. “By probing deep into our planet, these scientists have discovered new information about Earth’s microbes and how they evolve.”

“Our study uncovers mechanisms by which viruses and archaea can adapt in this hostile environment,” said David Valentine, a geoscientist at the University of California Santa Barbara (UCSB) and co-author of the paper.

The results, he said, raise new questions about the evolution and interaction of the microbes that call the planet’s interior home.

“It’s now thought that there’s more biomass inside the Earth than anywhere else, just living very slowly in this dark, energy-limited environment,” said paper co-author Sarah Bagby of UCSB.

Using the submersible Alvin, Valentine and colleagues collected samples from a deep-ocean methane seep by pushing tubes into the ocean floor and retrieving sediments.

The contents were brought back to the lab and fed methane gas, helping the methane-eating archaea in the samples to grow.

When the team assayed the samples for viral infection, they discovered a new virus with a distinctive genetic fingerprint that suggested its likely host was methane-eating archaea.

Genetic sequence of new virus holds the key

The researchers used the genetic sequence of the new virus to chart other occurrences in global databases.

“We found a partial genetic match from methane seeps off Norway and California,” said lead author Blair Paul of UCSB. “The evidence suggests that this viral type is distributed around the globe in deep ocean methane seeps.”

Further investigation revealed another unexpected finding: a small genetic element, known as a diversity-generating retroelement, that accelerates mutation of a specific section of the virus’s genome.

Such elements had been previously identified in bacteria and their viruses, but never among archaea or the viruses that infect them.

“These researchers have shown that cutting-edge genomic approaches can help us understand how microbes function in remote and poorly known environments such as ocean depths,” said David Garrison, program director in NSF’s Division of Ocean Sciences.

While the self-guided mutation element in the archaea virus resembles known bacterial elements, the researchers found that it has a divergent evolutionary history.

“The target of guided mutation–the tips of the virus that make first contact when infecting a cell–is similar,” said Paul.

“But the ability to mutate those tips is an offensive countermeasure against the cell’s defenses, a move that resembles a molecular arms race.”

Unusual genetic adaptations

Having found guided mutation in a virus-infecting archaea, the scientists reasoned that archaea themselves might use the same mechanism for genetic adaptation.

In an exhaustive search, they identified parallel features in the genomes of a subterranean group of archaea known as nanoarchaea.

Unlike the deep-ocean virus that uses guided mutation to alter a single gene, the nanoarchaea target at least four distinct genes.

“It’s a new record,” said Bagby.

“Bacteria had been observed to target two genes with this mechanism. That may not seem like a huge difference, but targeting four is extraordinary.”

According to Valentine, the genetic mutation that fosters these potential variations may be key to the survival of archaea beneath the Earth’s surface.

“The cell is choosing to modify certain proteins,” he said. “It’s doing its own protein engineering. While we don’t yet know what those proteins are being used for, learning about the process can tell us something about the environment in which these organisms thrive.”

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The above story is based on materials provided by The National Science Foundation.

Scientists call for caution in using DNA-editing technology

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A group of 18 scientists and ethicists today warned that a revolutionary new tool to cut and splice DNA should be used cautiously when attempting to fix human genetic disease, and strongly discouraged any attempts at making changes to the human genome that could be passed on to offspring.

Among the authors of this warning is Jennifer Doudna, the co-inventor of the technology, called CRISPR-Cas9, which is driving a new interest in gene therapy, or “genome engineering.” She and colleagues co-authored a perspective piece that appears in the March 20 issue of Science, based on discussions at a meeting that took place in Napa on Jan. 24. The same issue of Science features a collection of recent research papers, commentary and news articles on CRISPR and its implications.

“Given the speed with which the genome engineering field is evolving, our group concluded that there is an urgent need for open discussion of the merits and risks of human genome modification by a broad cohort of scientists, clinicians, social scientists, the general public and relevant public entities and interest groups,” the authors wrote.

Doudna, director of UC Berkeley’s Innovative Genomics Initiative, was joined by five current and two former UC Berkeley scientists, plus David Baltimore, a Nobel laureate and president emeritus of the California Institute of Technology, Stanford Nobelist Paul Berg and eminent scientists from UC San Francisco, Stanford, Harvard and the universities of Wisconsin and Utah. Several of these scientists are currently involved in gene therapy to cure inherited diseases.

Such warnings have been issued numerous times since the dawn of genetic engineering in 1975, but until now the technology to actually fix genetic defects was hard to use.

“However, this limitation has been upended recently by the rapid development and widespread adoption of a simple, inexpensive and remarkably effective genome engineering method known as CRISPR-Cas9,” the scientists wrote. “The simplicity of the CRISPR-Cas9 system enables any researcher with knowledge of molecular biology to modify genomes, making feasible many experiments that were previously difficult or impossible to conduct.”

Correcting genetic defects

Scientists today are changing DNA sequences to correct genetic defects in animals as well as cultured tissues generated from stem cells, strategies that could eventually be used to treat human disease. The technology can also be used to engineer animals with genetic diseases mimicking human disease, which could lead to new insights into previously enigmatic disorders.

The CRISPR-Cas9 tool is still being refined to ensure that genetic changes are precisely targeted, Doudna said. Nevertheless, the authors met “… to initiate an informed discussion of the uses of genome engineering technology, and to identify proactively those areas where current action is essential to prepare for future developments. We recommend taking immediate steps toward ensuring that the application of genome engineering technology is performed safely and ethically.”

Of particular concern are changes to genes in “germline cells” – sperm and egg – that can be passed on to offspring. Even a germline modification that eliminated a genetic disease that has plagued a family for generations could have unintended consequences, given current limitations on our knowledge of human genetics.

“We believe that initiating these fascinating and challenging discussions now will optimize the decisions society will make at the advent of a new era in biology and genetics,” the authors concluded.

The UC Berkeley authors are Michael Botchan, a professor of molecular and cell biology and IGI co-director; G. Steven Martin, dean of biological sciences and a professor of molecular and cell biology; chemistry researcher Samuel Sternberg; IGI scientific director Jacob Corn; and IGI program director Marsha Fenner. Edward Penhoet, a former dean of the UC Berkeley School of Public Health, and Martin Jinek, a co-inventor of CRISPR now at the University of Zurich, also signed the commentary.

Doudna is also the Li Ka Shing Chancellor’s Chair in Biomedical and Health Sciences and a Howard Hughes Medical Institute investigator at UC Berkeley.

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The above story is based on materials provided by Berkeley.

Shape-shifting frog discovered

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A frog in Ecuador’s western Andean cloud forest changes skin texture in minutes, appearing to mimic the texture it sits on.

Skin texture variation in one individual frog (Pristimantis mutabilis) from Reserva Las Gralarias. Note how skin texture shifts from highly tubercular to almost smooth; also note the relative size of the tubercles on the eyelid, lower lip, dorsum and limbs. Credit: Zoological Journal of the Linnean Society

Originally discovered by a Case Western Reserve University PhD student and her husband, a projects manager at Cleveland Metroparks’ Natural Resources Division, the amphibian is believed to be the first known to have this shape-shifting capability.

But the new species, called Pristimantis mutabilis, or mutable rainfrog, has company. Colleagues working with the couple recently found that a known relative of the frog shares the same texture-changing quality—but it was never reported before.

The frogs are found at Reserva Las Gralarias, a nature reserve originally created to protect endangered birds in the Parish of Mindo, in north-central Ecuador.

The researchers, Katherine and Tim Krynak, and colleagues from Universidad Indoamérica and Tropical Herping (Ecuador) co-authored a manuscript describing the new animal and skin texture plasticity in the Zoological Journal of the Linnean Society this week. They believe their findings have broad implications for how species are and have been identified. The process may now require photographs and longer observations in the field to ensure the one species is not mistakenly perceived as two because at least two species of rain frogs can change their appearance.

Katherine Krynak believes the ability to change skin texture to reflect its surroundings may enable P. mutabilis to help camouflage itself from birds and other predators.

The Krynaks originally spotted the small, spiny frog, nearly the width of a marble, sitting on a moss-covered leaf about a yard off the ground on a misty July night in 2009. The Krynaks had never seen this animal before, though Tim had surveyed animals on annual trips to Las Gralarias since 2001, and Katherine since 2005.

They captured the little frog and tucked it into a cup with a lid before resuming their nightly search for wildlife. They nicknamed it “punk rocker” because of the thorn-like spines covering its body.

The next day, Katherine Krynak pulled the frog from the cup and set it on a smooth white sheet of plastic for Tim to photograph. It wasn’t “punk “—it was smooth-skinned. They assumed that, much to her dismay, she must have picked up the wrong frog.

“I then put the frog back in the cup and added some moss,” she said. “The spines came back… we simply couldn’t believe our eyes, our frog changed skin texture!

“I put the frog back on the smooth white background. Its skin became smooth.”

“The spines and coloration help them blend into mossy habitats, making it hard for us to see them,” she said. “But whether the texture really helps them elude predators still needs to be tested.”

During the next three years, a team of fellow biologists studied the frogs. They found the animals shift skin texture in a little more than three minutes.

Juan M. Guayasamin, from Universidad Tecnológica Indoamérica, Ecuador, the manuscript’s first author, performed morphological and genetic analyses showing that P. mutabilis was a unique and undescribed species. Carl R. Hutter, from the University of Kansas, studied the frog’s calls, finding three songs the species uses, which differentiate them from relatives. The fifth author of the paper, Jamie Culebras, assisted with fieldwork and was able to locate a second population of the species. Culebras is a member of Tropical Herping, an organization committed to discovering, and studying reptiles and amphibians.

Guayasamin and Hutter discovered that Prismantis sobetes, a relative with similar markings but about twice the size of P. mutabilis, has the same trait when they placed a spiny specimen on a sheet and watched its skin turn smooth. P. sobetes is the only relative that has been tested so far.

Because the appearance of animals has long been one of the keys to identifying them as a certain species, the researchers believe their find challenges the system, particularly for species identified by one or just a few preserved specimens. With those, there was and is no way to know if the appearance is changeable.

The Krynaks, who helped form Las Gralarias Foundation to support the conservation efforts of the reserve, plan to return to continue surveying for mutable rain frogs and to work with fellow researchers to further document their behaviors, lifecycle and texture shifting, and estimate their population, all in effort to improve our knowledge and subsequent ability to conserve this paradigm shifting species.

Further, they hope to discern whether more relatives have the ability to shift skin texture and if that trait comes from a common ancestor. If P. mutabilis and P. sobetes are the only species within this branch of Pristimantis frogs to have this capability, they hope to learn whether they retained it from an ancestor while relatives did not, or whether the trait evolved independently in each species.

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The above story is based on materials provided by University of Case Western Reserve University.

Early Diagnosis Opportunities for Alzheimer’s Through Simple Blood Test

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By the time most people receive a diagnosis of Alzheimer’s disease — based on clinical signs of mental decline — their brains have already suffered a decade or more of damage. But although the mechanisms that spur the destruction of neurons in Alzheimer’s disease are not yet fully understood, two well-documented signs of the condition are accumulation of the amyloid-β peptide (the main component of plaques found in Alzheimer’s patient brains) and chronic inflammation.

Sidney Strickland, head of the Patricia and John Rosenwald Laboratory of Neurobiology and Genetics. Photo Credits: The Rockefeller University

New research from Rockefeller University, published March 16 in the Proceedings of the National Academy of Sciences, identifies a bridge between the two. That bridge, a molecular cascade known as the contact system, may provide opportunities for early diagnosis of the disease through simple blood tests.

“People have been looking for a long time for markers for Alzheimer’s disease,” says Sidney Strickland, head of the Patricia and John Rosenwald Laboratory of Neurobiology and Genetics. But current diagnostic tests for pre-symptomatic Alzheimer’s leave much to be desired. Evaluating the level of amyloid-β in the cerebral spinal fluid, for instance, requires an invasive spinal tap procedure.

“Finding a blood biomarker that would let us know through a simple test whether someone is on their way to developing the disease would be a significant advance,” says first author Daria Zamolodchikov, a postdoctoral associate in the Strickland lab.

The new study grew from the lab’s ongoing work that looks at how the vascular system is involved in Alzheimer’s disease. It has been shown that amyloid-β can activate a protein in plasma called factor XII, the first step in a pathway known as the contact system. When activated, this system leads to the release of a small peptide called bradykinin, a molecule known to promote potentially damaging inflammation. Although some studies have found these molecules in the cerebral spinal fluid and brain tissue of Alzheimer’s patients, no one had studied them in Alzheimer’s patient plasma.

Using plasma from people with and without diagnosed Alzheimer’s disease, the researchers measured the activation levels of the contact system. They found increased activation of this system in the plasma of Alzheimer’s patients, potentially implicating it in the inflammatory pathology of the disease. Moreover, in a subset of patients whose amyloid-β levels in the cerebral spinal fluid were known, the researchers demonstrated a positive correlation between activation of the contact system and changes in cerebral spinal fluid amyloid-β levels, which as mentioned above are correlated with the development of Alzheimer’s.

The researchers found similar activation of the contact system in mouse models of Alzheimer’s, which are genetically modified to overproduce amyloid-β. They then conducted a follow-up experiment with healthy mice. “We went one step further and took completely normal wild-type mice and injected them with amyloid-β. We found that on its own, injection with amyloid-β can activate this system. It’s a proof of principle in a complex environment,” says Zamolodchikov.

These findings will need to be supported by studies in larger patient populations and longitudinal studies, but they could eventually open the door to diagnosis of pre-symptomatic Alzheimer’s based on blood levels of these molecules.

The contact system may also offer a new approach to therapies for Alzheimer’s disease, since inhibition of the pathway could blunt some of the inflammatory aspects of the disease. One concern is that the contact system is also involved in blood clotting and inhibition might carry a risk of bleeding. However, people with a defect in this system do not have hemophilia. Thus, inhibition of this pathway might slow progression of the disease without increasing the risk of hemorrhage.

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The above story is based on materials provided by The Rockefeller University.