Electronic Implant Dissolves in the Body

Researchers at the University of Illinois at Urbana-Champaign, Tufts University, and others have created fully biodegradable electronics that could allow doctors to implant medical sensors or drug delivery devices that dissolve when they're no longer needed. The transient circuits, described in today's issue of Science, can be programmed to disappear after a set amount of time based on the durability of their silk-protein coating. 

 Soluble silicon: This electronic circuit dissolves when exposed to water. 

"You want the device to serve a useful function, but after that function is completed, you want it to simply disappear by dissolution and resorption into the body," says John Rogers, a physical chemist at the University of Illinois at Urbana-Champaign and senior author on the study.  

The authors demonstrate this possibility with a resorbable device that can heat the area of a surgical cut to prevent bacterial growth. They implanted the heat-generating circuit into rats. After three weeks, the authors examined the site of the implant and found that the device had nearly completely disappeared, leaving only remnants of the silk coating, which is eliminated more slowly than the silicon and magnesium of the circuit itself.

The work builds upon previous efforts from Tufts University's Fiorenzo Omenetto (whose work won a 10 Emerging Technologies award in 2010) on using silk as a body-friendly mechanical support for electronics as well as a tunable coating that can be made to last days or months depending on chemical processing. By combining that technology with their own thin and flexible circuitry, Omenetto, Rogers, and the rest of their team were able to develop silicon-based electronics that completely biodegrade. Other groups are also working to develop biodegradable electronics, some with different materials that may not perform as reliably as the silicon device but might dissolve faster.

"The basic idea is to fabricate implants that are not only electronically active but that can degrade over time," says Chris Bettinger, a materials scientist at Carnegie Mellon University who is also developing such electronics. "Integration, I think, is the achievement here," he says of the study. "It's really impressive, with regards to how they were able to integrate all the materials."

The circuits themselves are made from magnesium electrodes and thin sheets of silicon. They are built on a support substrate of protein purified from silkworm silk. The thin silicon sheets, or nanomembranes, are an important part of the integrated technology, says Bettinger, because they are more flexible and easily broken down and eliminated by the body than other forms of the semiconductor.

The technology could be useful in a variety of biomedical implants, from treating surgical infections, as demonstrated, to drug delivery or disease diagnostics. But the potential extends beyond the body, says Rogers. "Environmental monitors or even consumer electronics might be interesting to build in this fashion, because it would help to eliminate a lot of waste streams with discarded electronics," he says.

By Susan Young  
From Technology Review

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Gene Control, Delivered Directly to the Brain

A biotech company called Alnylam announced today that a small clinical trial for a genetic therapy based on RNA interference, or RNAi, suggests that the technique can have a powerful effect on its target gene. The therapeutic effect lasted for over a month with just one dose. The company is also working with a medical device maker, Medtronic, on a way to deliver RNAi treatment directly to the brain, in order to treat the degenerative brain disease Huntington's.

 RNA Rx: An Alynlam chemist prepares RNA molecules.

The patients in the trial have a genetic disorder that originates in the liver and leads to the buildup of protein deposits in many organs. Alnylam, a Cambridge, Massachusetts-based company, says its RNAi therapeutic, given at its highest dose, reduces the amount of the faulty protein that spurs the disease by almost 94 percent.

The positive results add weight to the notion that RNAi therapeutics could eventually help patients with a range of genetic diseases. RNAi therapy involves researchers producing snippets of RNA, a close relative of DNA, that match a portion of a gene of interest. When administered, this so-called small interfering RNA (siRNA) causes the destruction of that gene's products before it can be turned into a protein. The specificity of RNAi for targeting particular genes has attracted a lot of interest from people who want to use it as a clinical treatment (see "Prescription RNA").

"Today's platforms target the protein that causes the disease and bind to that protein. We stop the protein from being made in the first place," says Barry Greene, president and chief operating officer of Alnylam.

But a recurring challenge for the therapeutic RNAi field is how to deliver the siRNAs to the right place in the body. On their own, the small molecules do not survive long in the bloodstream, so simply injecting a patient with a solution of unprotected siRNAs is not effective. "The key technical hurdle is getting the siRNA [inside] the right cells," says Greene.

For several of its projects, Alnylam uses nanoparticles to protect and deliver its siRNAs, which can then be delivered by injection. But for genetic diseases that originate in the brain, the body's own defenses, namely the blood-brain barrier, complicate delivery further. To circumvent the blood-brain barrier, which prevents most molecules from leaving the bloodstream and entering the brain, Alnylam has looked to a different delivery mechanism: direct dosing of unpackaged siRNAs.

Medtronic, a Minneapolis company that designs and manufactures medical devices, has devised a way to allow this. Together, the companies have developed a treatment that combines Alnylam's RNAi therapeutic with Medtronic's drug delivery technology to treat Huntington's.

Huntington's, for which there is no cure, is caused by the loss of neurons due to a toxic protein made by a tainted gene. The idea behind the new treatment is to stop at least some of that protein's production so that it cannot damage the brain. 

The treatment would use a device made by Medtronic that is already implanted in more than 250,000 patients to treat chronic pain and spasticity. The device features a catheter connected to a drug pump that's surgically implanted into the abdomen. The pump pushes drugs through the device and into the fluid around the spinal cord. In the case of the Huntington's RNAi work, the system is adapted to deliver liquids directly into the brain tissue.

"To create pressure, it actively pumps the drug into the brain, and that pressure really moves the drug into the brain and further away than the drugs would otherwise go based on diffusion," says Lothar Krinke, vice president and manager of Medtronic's deep brain stimulation projects.

In a study published earlier this year, the researchers showed that the device can distribute the siRNA to around six cubic centimeters of brain tissue in a rhesus monkey. The results of the study suggest the treatment was safe over 28 days of infusion and showed that the protein product of the Huntington's-type gene in the monkeys was nearly halved, says Krinke.

Medtronic is currently leading the effort to push the device-drug treatment into the clinic. Although the company will not say when it anticipates initiating clinical trials, the work has been funded by CHDI, a nonprofit foundation focused on developing cures for Huntington's.

By Susan Young 
From Technology Review

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Microspheres Could Save Patients Whose Lungs Have Stopped Working

Researchers have developed a way to deliver oxygen to the body's organs safely—via gas-filled microparticles—even when the patient's lungs have stopped working. Doctors could one day use the method to quickly reverse oxygen deprivation in patients with acute loss of lung function while longer-term fixes such as heart-lung bypass support are put in place. 

 Air bubble: An intravenous infusion of oxygen-filled microparticles (the yellow sphere in this composite image) could carry the life-sustaining gas to red blood cells in patients with sudden loss of lung function.

Even short periods of oxygen deprivation put the vital organs of the body at risk. Typically, doctors feed oxygen-deprived patients the gas through ventilators such as tubes in the mouth or nose, but the treatment depends on functioning lungs. In situations where the airway is blocked or the lungs do not work, few options exist. 

In such cases, injecting pure oxygen into the body is not an option because it can form bubbles in blood vessels and block blood flow. Some hospitals have machines that can oxygenate a patient's blood outside of the body, but the surgical procedure to hook up such a bypass machine is complicated and can take too long in an emergency, says study author John Kheir. 

As a first-year fellow at Boston Children's Hospital a few years ago, Kheir treated a nine-month-old girl whose lungs had been damaged by pneumonia and were filled with blood. In the 20 or so minutes it took for Kheir and his colleagues to put her on the heart-lung bypass machine, she suffered severe brain injury from low oxygen levels and died. The experience led Kheir to work toward developing a fast-acting, intravenous treatment that could help patients like her with acute, severe lung injury. "The only way to save someone like that would be to inject oxygen directly into the vein," he says. 

Blood substitutes that carry oxygen are available for transfusion, but are known to cause dangerous side effects and furthermore typically rely on functioning lungs. "There really is a need for something that you can pull off the shelf, and give to people to pull them through these critical periods," says Ann Weinacker, a lung and critical care doctor at the Stanford Chest Clinic. 

Kheir's oxygen-filled microspheres, reported today in Science Translational Medicine, are around three micrometers in diameter and are diluted in a solution commonly used in transfusions so that the particles can flow through even small capillaries in the body. In test tubes, the researchers found the oxygen transferred from the microspheres to hemoglobin, the protein in red blood cells that carries oxygen, within four seconds. They then tested the microspheres in anesthetized rabbits with blocked windpipes. Although the rabbits were asphyxiated, their bodies were oxygenated and did not show signs of major injury to organs. 

More research is necessary to determine how long the therapy can work and for how many patients it could be useful. "Situations where you have a short-term need [for oxygen] and everything else is working are not that common," says Gail Weinmann, a lung disease expert with the National Heart Lung and Blood Institute. But when those situations arise, a quick infusion of oxygen could be life-saving, she says. "As a bridge, even 15 minutes could make a difference in some situations." 

Kheir says the intravenous oxygen delivery could help not only in the critical moments when heart-lung bypass machines are being set up, but also when patients are being put in intensive care on ventilators. Unstable patients with low lung function are also at risk of severely low oxygen levels, he says. "[The goal] is not to make ventilators obsolete, but to make patients healthier," says Kheir.

Kheir says that more lab animal work is needed to explore the clinical utility of the microsphere technology, which he and some of the study coauthors are patenting. "We are testing the ability of these particles to deliver oxygen in other clinical circumstances, such as cardiac arrest and severe bleeding," he says. 

The team is also working on making the microspheres more stable, with the ultimate goal of creating an off-the-shelf solution that could be ready for quick use in emergency situations.

By Susan Young  
From  Technology Review

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Fine-tuning Nanotech to Target Cancer

The results of the human trials are startling. Even at a lower-than-usual dose, multiple lung metastases shrank or even disappeared after one patient received only two-hour-long intravenous infusions of an experimental cancer drug. Another patient saw her cervical tumor reduce by nearly 60 percent after six months of treatment. Though the drug trial—by Bind Biosciences in Cambridge, Massachusetts—of an experimental nanotechnology-based technique was designed simply to show whether the technology is safe, the encouraging results revive hopes that nanomedicine could realize its elusive promise.

Programmable particle: Bind's drug-delivery nanoparticle (artist's rendering).

For more than a decade, researchers have been trying to develop nanoparticles that would deliver drugs more effectively and safely. The idea is that a nanoparticle containing a drug compound could selectively target tumor cells or otherwise diseased cells, and avoid healthy ones. Antibodies or other molecules can be attached to the nanoparticle and used to precisely identify target cells. "One of the largest advantages of nanotechnology is you can engineer things in particle form so that chemotherapeutics can be targeted to tumor cells, protecting the healthy cells of the body and protecting patients from side effects," says Sara Hook, nanotechnology development projects manager with the National Cancer Institute.  But executing this vision has been difficult. One challenge: a drug's behavior in the body can change dramatically when it's combined with nanoparticles. A nanoparticle can change a drug's solubility, toxicity, speed of action, and more—sometimes beneficially, sometimes not. If a drug's main problem is that it's toxic to off-target organs, then nanotechnology can ensure that it's delivered to diseased cells instead of healthy cells. But if a drug depends on being absorbed quickly by diseased cells to be effective, a nanoparticle may slow the process and turn an optimal therapeutic into second best.

Bind, which was launched in 2007, has attempted to overcome this problem by building its drug-targeting nanoparticles in a way that allows the company to systematically vary their structures and composition. Typically, targeted drug nanoparticles are produced in two steps: first, a drug is encapsulated in a nanoparticle, and second, the external surface of the particle is bound with targeting molecules that will steer the therapeutic ferry to diseased cells. Generating such nanoparticles can be difficult to control and replicate, which limits a researcher's ability to fine-tune the nanoparticle's surface properties. To avoid this pitfall, Bind synthesizes its drug-carrying nanoparticles using self-assembly.

Under the right conditions, the subunits of its nanoparticles—some of which already contain targeting molecules—assemble on their own. No complex and variable chemical reactions are needed to produce the nanoparticles, and the properties of each subunit can be tweaked. This also allows the company's researchers to test a variety of nanoparticle-drug combinations and identify the best candidates for a particular task. "We make hundreds of combinations to evaluate in order to optimize the performance of each drug," says Jeff Hrkach, senior vice president of technology research and development. 

Bind cofounder Omid Farokhzad, associate professor at Brigham Women's Hospital and Harvard Medical School, came up with the novel method for building nanoparticles while he was a postdoctoral researcher in the lab of Robert Langer, an MIT chemical engineering professor. Langer's group had already developed nanoparticles capable of releasing drugs in a controlled manner, but the particles did not yet seek out cancer cells specifically. Farokhzad's first challenge was to create nanoparticles whose molecular instructions would bring them to cancer cells, but which remained anonymous within the bloodstream so that the immune system wouldn't destroy them. The second was coming up with a robust and reproducible manufacturing process.

Instead, Farokhzad and Langer devised a method by which the building blocks of the nanoparticle and the drug self-assemble into a final product. Two types of polymer combine to form the tangled mesh of Bind's drug-laden spherical nanoparticle. One of these polymers has two chemically and structurally distinct regions, or "blocks": a water-insoluble block that forms part of the mesh that encapsulates the drug, and a water-soluble block that gives the final product a stealthy corona to evade the immune system. The other type of polymer has three blocks: the same two as the first, as well as a third region that contains a targeting molecule—the signal that will ensure the final particles attach to the desired cell types. The drug-carrying nanoparticles are formed by simply mixing these polymers together with the drug in the appropriate conditions.

The self-assembling polymers can be produced in a repeatable and scalable fashion. But the method has an additional benefit, one that may be the real key to Bind's success. The method by which the nanoparticles are built—from individual preparations of the two-block and three-block polymers—would also let researchers use high-throughput screening approaches, akin to how medicinal chemists design and test new drug compounds. Each block could be tweaked—extend one block, change the charge on another—and the relative amounts of each polymer could be varied. With so many parameters for tinkering, Bind's scientists can screen many combinations.

Its first drug in clinical trials, Bind-014, carries a widely used chemotherapeutic called docetaxel through the bloodstream to cancer cells. The drug is packaged inside a ball-like nanostructure made of biodegradable polymers that protect the drug and shield it from the body's immune system. The external surface of each nanoparticle is dotted with molecules that target cancerous cells. Once the nanoparticle has reached its target, it sticks to the outside of the cell, which triggers the cell to engulf the particle. The drug diffuses out of the particle at a controlled rate and is released into the deranged cell.

Mark Davis, a professor of chemical engineering at Caltech, is hopeful that the few ongoing trials of targeted nanoparticle therapeutics, which include one developed in his lab as well as Bind-014, will demonstrate the technology's potential. "The medical community isn't going to get excited until there is [an advanced human trial] where we can show what these targeted nanoparticles actually do for patients in a statistically significant way." For now, the results from the 17 patients enrolled in the phase I trial of Bind-014 look promising, but a real test of efficacy will have to wait until phase II trials, which are likely to start later this year.

The "programmable" design used by Bind may be key to bringing more nanoparticle-targeted drugs to trial. The company's methods could be applied to any existing drugs or compounds, including those that may have been shelved by pharmaceutical companies because they proved too toxic to the whole body. "We believe we can have a very broad platform of drugs that we can develop," says Hrkach.

By Susan Young
From Technology Review

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Spinning Spare Parts

Thin off-white threads of human cellular material spiral around the spindle of a machine that is braiding them into a sturdy rope. It sounds macabre, but the inspiration for the material, made by San Francisco–based Cytograft Tissue Engineering, is health, not horror: the biological strands could be used to weave blood vessel patches and grafts that a patient's body would readily accept for wound repair. The process is faster and could be more cost-effective than other methods of producing biological tissue replacements.

Clean crochet: A specialist weaves a blood vessel graft from human threads on a sterile tubular loom.

Much of today's tissue engineering depends on biodegradable but synthetic scaffolds for cells that will rebuild a piece of organ or tissue. Typically, the scaffolding is eventually destroyed by the body. Cytograft's woven tissues, however, seem to remain in the body and become populated with cells. "A long time ago we decided we were going to make strong tissues without any scaffolding," says Nicolas L'Heureux, Cytograft's cofounder and chief scientific officer. "Once you get it in the body, your body doesn't see it as foreign."

The company developed the "human textile" idea from earlier work using sheets of biological material to reconstruct blood vessels. Basically, researchers grow human skin cells in a culture flask under conditions that encourage the cells to lay down a sheet of what is known as extracellular matrix—a structural material produced by animal cells that makes up our connective tissue. Cytograft can harvest these sheets from the culture flasks and then roll them into tubes that become replacement blood vessels. Blood vessels produced in this manner are still being tested—but they have performed well, with no signs of rejection, in a few patients in Europe and South America.

The rolling process, however, is expensive and time-consuming, in part because cells must be used to fuse the tube together so that it is sturdy enough for transplantation. Slicing the sheets into thin ribbons that can be spooled into threads makes it possible to use automated weaving and braiding machines to create three-dimensional structures that do not require fusing.  Cytograft's technique draws upon a long history of medical textiles, which are typically produced with synthetic fibers like polyester. "Creating textiles is an ancient and powerful technique, and combining it with biomaterials is exciting because it has so much more versatility than the sheet method," says Christopher Breuer, a surgeon, scientist, and tissue engineer at the Yale School of Medicine. "The notion of making blood vessels or more complex shapes like heart valves, or patches for the heart, is much easier to do with fibers," he says. "If you can make fibers of any length, then there is no limit to the size or shape that you can make." 

 Biological braids: A machine braids together 48 threads of human extracellular material. 

Cytograft has long focused on building replacement blood vessels for people who need dialysis, which cleans the blood of patients with kidney failure. This treatment is severely damaging to the vein (usually in the forearm) through which the patient's blood is transferred.

Cytograft is not yet testing its woven blood vessels in patients, but it has approximated the needs of dialysis patients in dogs with vessel grafts implanted in their legs. The preclinical dog work has shown that the grafts are resistant to puncture damage and that very little blood leaks from the weave, says L'Heureux.

Cytograft's implants remain intact after months, suggesting that the body accepts the grafts and does not try to break them down. "Other materials get remodeled very aggressively," says L'Heureux. "With our tissue, it is so innocuous the body does not see a danger."

That's partly because Cytograft's implants contain no cells. Though the company's earlier implants were made of extracellular matrix produced from a patient's own cells, its researchers can now harvest the material from cells unrelated to the person receiving the graft and remove the "donor" cells completely. "We don't need the cells," says L'Heureux. "The cells can come from the patients after implantation."

Without any foreign cells to alert a patient's immune system, the company could produce blood vessels ahead of time for use in any patient. Such replacement vessels would be less expensive and more readily accessible than what's available today. "One of Cytograft's biggest advantages will be off-the-shelf availability," says Breuer.

The company is also working on a technique in which the cell-produced sheets are processed into particles instead of threads. The biological bits can then be molded together, says L'Heureux, giving tissue engineers two advantages. Molding the particles together leaves a complex network of channels behind—exactly what tissues engineers will need in order to produce, eventually, something like a liver, pancreas, or kidney. With most other technology, there is "no guarantee that the channels will be maintained," says L'Heureux. The particles could also be injected, he says, which could add volume to tissues for cosmetic or reconstructive purposes. 

By Susan Young
From Technology Review

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Why a Portable DNA Device Could Yield Better Data

Oxford Nanopore Technologies announced recently that it has two products capable of sequencing DNA by reading the chemical bases in a DNA molecule directly, as it is threaded through a nanoscopic hole in a protein. The U.K.-based company will begin selling a simple, disposable, portable $900 DNA-reading device, and a more comprehensive desktop model, by the end of the year.

 Mini sequencer: The MinION from Oxford Nanopore plugs into a computer like a USB memory stick. The single-use sequencer will be on the market for under $900 sometime this year.

If Oxford Nanopore's technology can do what the company claims, it will be "a total game-changer," says Jeffery Schloss, director for technology development at the National Human Genome Research Institute, part of the National Institutes of Health. 

The technology relies on the fact that a DNA base, or a combination of bases on a DNA strand creates a characteristic disruption in a current as it passes through the nanopore. Electrodes measure the change in current flow as DNA molecules are fed through protein nanopores; an electrical gradient drives the DNA through the pore, while molecular "controllers" attached to the molecules mechanically slow them down so that their electrical signals may be recorded. 

This approach has two important advantages.

First, the system is compact and doesn't require a supply of expensive reagents. That means sequencing can come out of the lab, making it useful for personalized medicine or for use in resource-poor clinics. Indeed, the disposable sequencer the company is about to introduce is the size of a USB memory stick. 

Second, the technology reads much longer stretches of DNA than other rapid sequencing approaches, which means it has the potential to be better at spotting important "structural variants" related to disease. These variants occur when a whole segment of chromosome is moved, inverted, duplicated, or otherwise changed. When DNA is chopped into shorter stretches to be sequenced and then put back together on a computer, it is easier to miss, or misinterpret, such variants.

The best way to identify variants is still to use conventional sequencing methods, which are highly accurate but also expensive and slow. Other rapid sequencers released in recent years are fast and inexpensive, but Schloss believes Oxford Nanopore's may have an edge when it comes to spotting structural variants.

Better structural information could be useful for personalized medicine. Among other things, it could identify cases of translocation, a chromosomal abnormality in which large stretches of DNA break away from the chromosome where they belong and reattach someplace else. These mutations can cause cancer and other diseases. 

The company's portable nanopore sequencers could be used in the field—for example, to quickly identify or sequence a new strain of bacteria. A spokesperson for Oxford Nanopore says the portable sequencers might be used to monitor wound care in hospitals or to aid in on-site monitoring of agricultural sites for food safety.

At a research conference last week in Marco Island, Florida, Oxford Nanopore reported continuously sequencing 100,000-base stretches of DNA in the lab—sequences about 10 to 100 times longer than any other company has read. Pacific Biosciences' newest commercial machines are capable of sequencing up to 3,000 bases at once, says the company's director of product management, Edwin Hauw. 

But nanopore sequencing could go way beyond this. In theory, the only limit on the length the system can sequence is researchers' ability to prepare the inherently fragile samples. Human chromosomes encompass a million or so DNA bases.

The Oxford Nanopore system so far has a raw error rate of 4 percent. In the short term this might be improved by sequencing the same strand of DNA multiple times, threading it back and forth through the pore. However, the company says that in the coming months it will make improvements to the nanopore and the algorithms associated with the DNA analysis that will also reduce the error rate. 

By Katherine Bourzac
From Technology Review

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Fluorescent Protein Lights Up the Inner Workings of the Brain

Interactions between neurons involve both chemical and electrical signaling. For decades, neuroscientists have searched for a noninvasive way to measure the electrical component. Achieving this could make it easier to study how the brain works, and how neurological disease impairs its functioning.

 Light up: Applying voltage to the neurons shown here caused an increase in fluorescence.

One promising approach is tracking neuronal electrical activity with fluorescence, which can be integrated into cells fairly easily through genetics or by being attached to antibodies, but which can be toxic and slow to work. Last week, researchers introduced a new candidate—a fluorescent protein from a Dead Sea microbe—that appears to be better equipped for the challenge.

The protein, called archaerhodopsin-3, or Arch, was discovered more than 10 years ago, but scientists are just now starting to realize its potential as a research tool. In a study published last year, researchers used light to trigger an electrical response from Arch that silenced overactive neurons—an approach that could lead to new therapeutics for epilepsy and other seizure disorders.

In this study, the researchers took the opposite tack and used electricity to elicit changes in Arch's fluorescence. The approach could lead to more accurate methods for recording electrical signals from the brain.

The results, published in Nature Methods, indicate that Arch could be the noninvasive voltage sensor neuroscientists have been looking for: It's not toxic to cells, and it's sensitive and fast enough to pick up the rapid electrical changes that accompany neuronal activity. 

"It looks order of magnitudes better than any of the other optical imaging methods I've seen before," says Darcy Peterka, a neuroscientist at Columbia University who was not involved with the study.

The standard method for recording electrical activity in neurons in cell culture—which involves sticking an electrode into the cell—remains the most accurate for measuring voltage at a single point in the cell. But puncturing a neuron with an electrode eventually kills it, whereas Arch would let researchers follow the electrical signal as it propagates throughout the cell. It would also allow researchers to record from the same cell again and again, allowing for long-term experiments that would not be possible with the standard method.

"It really depends on what scientific questions you're trying to answer," says Adam Cohen, a biophysics researcher at Harvard University and the lead author of the new study.

The study was conducted in cultured mouse neurons, but Cohen and his colleagues plan to use Arch to measure neuronal activity in live animals, starting with simple organisms, such as the zebrafish and the worm C. elegans. One advantage of these animals is that they're transparent, making it easy to see the fluorescent signal through a microscope. 

Arch could also prove useful for imaging electrical signals in the mammalian brain, especially for experiments in mice, which could be genetically engineered to express the protein in specific neurons or at specific times in development, for example. 

The challenge of transferring the approach to animals is making sure the fluorescent signal stays strong and consistent. "In the living brain, light gets absorbed—for example, by blood—so you lose light," says Ed Boyden, the researcher at MIT who led the study that used Arch to silence neurons.

The fluorescence given off by Arch also isn't as bright as some of the other available dyes, but its low toxicity makes this less of a concern, because researchers could compensate by using higher concentrations. "The fact that they got it to work well in mouse neurons bodes well," says Peterka.

By Erica Westly
From Technology Review

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An Ultrathin Brain Implant Monitors Seizures

A new, ultrathin, ultraflexible implant loaded with sensors can record the electrical storm that erupts in the brain during a seizure with nearly 50-fold greater resolution than was previously possible. The level of detail could revolutionize epilepsy treatment by allowing for less invasive procedures to detect and treat seizures. It could also lead to a deeper understanding of brain function and result in brain-computer interfaces with unprecedented capacity.

 Brain map: An ultrathin array of electrodes, shown at top being inserted into the brain of a cat, allows for data acquisition far greater than ever before possible. At bottom, the electrode array is so flexible that it can fold around even the slimmest objects, allowing for easy insertion and good coverage of uneven surfaces.

For epilepsy patients who don't respond to medication, neurologists will often try to map where in the brain the seizure originated so that region can be surgically removed. The doctor removes a section of skull and places a bulky sensor array on the surface of the patient's frontal cortex. 

"These clinical devices haven't changed much since the '50s or '60s," says Brian Litt, an epilepsy specialist and bioengineer at the University of Pennsylvania and one of the scientists who led the new research. Because the device has to accommodate wires for each electrode, it only has space for fewer than 100 electrodes and gives a poor resolution picture of the electrical activity. "It's like trying to understand what's going on in a crowd in Manhattan with a single microphone suspended from a helicopter," Litt says. 

 Out of control: An epileptic seizure in a cat, as measured by the new electrode-dense implant, shows a never-before-seen spiral wave of electrical activity.

Current technology has stalled out at a sensor array with about eight sensors per square centimeter; the new array—built in collaboration with John Rogers, a professor of materials science and engineering at the University of Illinois Urbana-Champaign—can fit 360 sensors in the same amount of space. To create a small device so densely packed with sensors, Rogers integrated electronics and silicon transistors into the array itself, drastically reducing the amount of wiring.

"This is more like an array of 360 microphones, lowered closer to the surface and recorded from much smaller regions: a couple of people at the street corner, a couple by the mailbox," Litt says. "This new technique could be the key to understanding functional networks in the brain, and could even be the key to treating and potentially curing some diseases."

In their first test of the device, on a cat with epilepsy, Litt, Rogers, and graduate student Jonathan Viventi (now an assistant professor studying translational neuroengineering at New York University),  saw something striking: a storm of activity that looked like a self-propagating spiral wave. The pattern, only apparent with incredibly high-resolution recording, is remarkably similar to one seen in cardiac muscle during a life-threatening condition called ventricular fibrillation. 

Rather than large sections of the brain being responsible for seizures, something Litt says has traditionally been thought to occur, it appears to instead stem from multiple clusters of very small areas, or "microdomains," in the cortex. The research was published online last week in Nature Neuroscience.

"This is absolutely terrific. I was astounded by the technical accomplishment, and the very strong and important results," says Gerwin Schalk, a brain-computer interface researcher at the Wadsworth Center in Albany, New York. Schalk was not involved in the research. "It will be of tremendous value for basic neuroscience and for translational research." Schalk notes that if the technology proves itself in humans, it could open up substantial opportunities for everything from diagnostics to brain-computer interface devices.

The device could also enable less-invasive testing and treatment. Rather than cutting open a large section of skull to place a monitoring device, Litt says, the new implant could allow surgeons to drill just a small hole through which to slip the slim, rolled-up sensor array, and unfurl it onto the brain's surface once it's inside. And instead of removing areas of brain the size of a golf ball, it might be possible to just remove the microdomains and leave the rest of the cortex intact. 

The current version of the device is one square centimeter; for human use, researchers need to expand it to about eight square centimeters. A startup called MC10 will work on making it larger and production-ready.

Litt and Rogers are now working to create an implant with stimulators embedded next to the sensors. If they can build a device that not only detects the onset of a seizure but can just as quickly provide electrical stimulation to quash it, the research could have great clinical impact. "This isn't just a research tool. It has a clearly defined mode of use in the clinical setting," Rogers says. "This is a piece of biointegrated electronics that is unmatched in its functionality, and the proof is in the pudding." 

By Lauren Gravitz
From Technology Review

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Researchers Engineer a Mightier Mouse

Mice that grow larger muscles and can run for twice as long as their unaltered littermates before tiring could point toward new treatments for the muscle loss that can occur with aging.   

 Svelte mice: Animals that lack a molecule called NCOR in their fat cells (bottom) show fewer signs of inflammation (light blue) than their normal counterparts (top).

The mice were engineered to lack a molecule called NCOR in their muscle tissue. In a second, related study, knocking out the same molecule in fat resulted in mice that were overweight but sensitive to insulin, a result that could lead to more targeted treatments for diabetes. Both studies were published in the journal Cell last week.

NCOR acts as a dimmer switch for other molecules in a cell. It is known as a corepressor, slowing the production of transcription factors, which in turn regulate the expression of genes. Dimmer-switch molecules are often good drug targets thanks to this subtle effect, says Johan Auwerx, a researcher at École Polytechnique Fédérale de Lausanne, who led the first study, which involved knocking out NCOR in muscle. "That's better from a medical standpoint, because you don't want to turn a molecule all on or off," he says.

Because NCOR acts on different molecules in many parts of the body, Auwerx and others have been using genetic techniques to create mice that lack the protein in only certain types of tissue. Knocking out the molecule in all tissues from birth is lethal.

According to the second study, eliminating the molecule in fat had a very specific effect: fat cells became more sensitive to insulin, as did cells in the muscle and the liver. Insulin resistance is one of the hallmarks of metabolic syndrome, a precursor to type 2 diabetes, so the findings could inform drug development for the disease.

"The results suggest that adipose is the organizing tissue for metabolic syndrome," says Jerrold Olefsky, a researcher at the University of California, San Diego, who led the second study. "If you can treat it, you get systemic effects on other tissues."

On a molecular level, knocking out NCOR appeared to mimic the effect of a class of diabetes drugs known as thiazolidinediones, or TZDs. These drugs target the same molecule as NCOR, but have significant side effects, including hepatitis, liver failure, water retention, and heart failure. Some have been pulled from the market.

The researchers did not see any of these ill effects in the mice, suggesting that if you target treatment to adipose tissue, "you get rid of unwanted side effects," says Olefsky. "Targeting NCOR is better because it has a much more selective role."

Olefsky's team also identified more than 100 genes that are activated by deleting NCOR in fat. They're now studying these genes as potential drug targets.

The mice that lacked NCOR in their muscles had a different outcome—their muscles had many more mitochondria, the fuel source of the cell, which allowed them to run longer. "That means better capacity to keep energy levels up," says Auwerx. The researchers knocked out the same gene in the muscle tissue of worms, which also grew larger muscles, suggesting that the same trick should work in other animals.

Auwerx is now looking for drugs that can modulate NCOR levels. Fasting brings levels down, while glucose pushes it up. The results could be useful in treating aging-related muscle loss, which occurs even in old people who exercise, as well as diseases such as muscular dystrophy.

By Emily Singer
From Technology Review

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EEG Detects Signs of Awareness in Vegetative Patients

Three brain injury patients diagnosed as being in a vegetative state—meaning they do not respond to their environment—may actually be conscious. Using EEG (electroencephalography) to measure their brain activity, researchers found that the patients could follow simple commands.

 Mind reading: Using EEG to measure brain activity, researchers found that some patients diagnosed as being in a vegetative state could respond to simple commands. The pattern of electrical activity in these patients (one example is shown above) is identical to patterns seen in healthy people.

This supports previous findings from the same group suggesting that some people who appear outwardly unresponsive may have a relatively high level of cognitive capacity. Researchers aim to ultimately develop the approach into a communication tool.

In the study, researchers examined 16 patients with brain injury—some due to traumatic injury and others due to lack of oxygen—and 12 healthy people, asking both groups to imagine moving either their hands or toes while wearing an EEG monitor. They found that, like the healthy people, three of the brain injury patients could reliably generate two distinct brain activity patterns based on the command. One patient did it more than 200 times, which is even more than the healthy participants managed.

The team had previously used functional MRI, or brain imaging, to show that a patient diagnosed as being in a vegetative state could use a similar system to answer yes or no questions. That startling finding rocked the medical world, begging the question of how many of these patients had cognitive function beyond what their outward function indicated.

MRI machines are, however, expensive and largely limited to hospitals, making them a difficult tool to study brain injury patients, who are often in rehabilitation or nursing homes. In the new study, researchers used a standard EEG device, which is relatively inexpensive and highly portable. "It's probably about as sensitive as MRI," says Adrian Owen, a researcher at the University of Western Ontario, who led the study. "That means we have something we can get out into the community and use in hospitals or residential homes."

The researchers can detect when someone is thinking about moving a hand versus a toe because the brain activity originates in a different part of the motor cortex, the part of the brain that controls movement. Owen's team spent much of the last year working out how to accurately decode the electrical signals the brain emits when imaging these movements. The findings of the new study were published this week in The Lancet. 

The three patients who could respond via EEG did not share any obvious features; they varied in age, in time since the original injury, and in the type of injury suffered. Owen's team is now using high-resolution functional MRI machines to study these patients' brains in fine detail in hopes of finding some commonality. "Anything we can do to improve our understanding or to learn more about catastrophic brain injuries can help us understand what's going on," says Owen.

They hope to eventually use the EEG setup to ask patients questions, which had been possible with functional MRI. At the moment, researchers can't read the EEG response in real time, making interaction very difficult. "Our priority now is trying to speed it up; then we'll move on to communication," he says. 

What exactly the new findings indicate about the patients' level of consciousness is still controversial. "I think they were entirely aware and conscious of what's going on," says Owen. "For them to do this, they have to have understood the instructions we gave them, to have sustained attention, to keep on task, and to respond. These are all things we associated with consciousness."

Morten Storm Overgaard, head of the Cognitive Neuroscience Research Unit at Aalborg University in Denmark, disagrees. "I think their study is very interesting, but it's hard to argue that there is a link between command-following and consciousness. And there's no independent way of making sure," says Overgaard, who wrote a commentary accompanying the paper. Overgaard does agree, however, that someone who can reliably answer questions via brain activity is likely conscious.

Both Overgaard and Owen say a new classification system is required to accurately reflect the state these patients are in. "While they do meet all the clinical criteria for the vegetative state, we know they are not actually vegetative," says Owen. One suggestion that has yet to catch on is "behavioral unresponsiveness syndrome."

By Emily Singer
From Technology Review

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Researchers Create a Pituitary Gland from Scratch

Last spring, a research team at Japan's RIKEN Center for Developmental Biology created retina-like structures from cultured mouse embryonic stem cells. This week, the same group reports that it's achieved an even more complicated feat—synthesizing a stem-cell-derived pituitary gland.

 New gland: After 13 days in culture, mouse embryonic stem cells had self-assembled the precursor pouch, shown here, that gives rise to the pituitary gland.

The pituitary gland is a small organ at the base of the brain that produces many important hormones and is a key part of the body's endocrine system. It's especially crucial during early development, so the ability to simulate its formation in the lab could help researchers better understand how these developmental processes work. Disruptions in the pituitary have also been associated with growth disorders, such as gigantism, and vision problems, including blindness. 

The study, published in this week's Nature, moves the medical field even closer to being able to bioengineer complex organs for transplant in humans.

The experiment wouldn't have been possible without a three-dimensional cell culture. The pituitary gland is an independent organ, but it can't develop without chemical signals from the hypothalamus, the brain region that sits just above it. With a three-dimensional culture, the researchers could grow both types of tissue together, allowing the stem cells to self-assemble into a mouse pituitary. "Using this method, we could mimic the early mouse development more smoothly, since the embryo develops in 3-D in vivo," says Yoshiki Sasai, the lead author of the study.

The researchers had a vague sense of the signaling factors needed to form a pituitary gland, but they had to figure out the exact components and sequence through trial and error. The winning combination consisted of two main steps, which required the addition of two growth factors and a drug to stimulate a developmental protein called sonic hedgehog (named after the video game). After about two weeks, the researchers had a structure that resembled a pituitary gland.

Fluorescence staining showed that the cultured pituitary tissue expressed the appropriate biomarkers and secreted the right hormones. The researchers went a step further and tested the functionality of their synthesized organs by transplanting them into mice with pituitary deficits. The transplants were a success, restoring levels of glucocorticoid hormones in the blood and reversing behavioral symptoms, such as lethargy. Mice implanted with stem-cell constructs that hadn't been treated with the right signaling factors, and therefore weren't functional pituitary glands, did not improve.

Next, Sasai and his colleagues will attempt the experiment with human stem cells. Sasai suspects it will take them another three years to synthesize human pituitary tissue. Perfecting the transplantation methods in animals will likely take another few years. 

Still, researchers in the stem-cell field are impressed with what Sasai's team has accomplished. "This is just an initial step toward generating viable, transplantable human organs, but it's both an elegant and illuminating study," says Michael G. Rosenfeld, a neural stem-cell expert at the University of California, San Diego. 

By Erica Westly
From Technology Review

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Light-Based Therapy Destroys Cancer Cells

For more than two decades, researchers have tried to develop a light-activated cancer therapy that could replace standard chemotherapy, which is effective but causes serious negative side effects. Despite those efforts, they've struggled to come up with a light-activated approach that would target only cancer cells.

Now scientists at the National Cancer Institute have developed a possible solution that involves pairing cancer-specific antibodies with a heat-sensitive fluorescent dye. The dye is nontoxic on its own, but when it comes into contact with near-infrared light, it heats up and essentially burns a small hole in the cell membrane it has attached to, killing the cell. 

Light touch: Researchers treated the tumor on the right-hand side of this mouse’s body with a light-activated therapy. The top image is before treatment; the bottom is after. 

To target the tumor cells, the researchers used antibodies that bind to proteins that are overexpressed in cancer cells. "Normal cells may have a hundred copies of these antibodies, but cancer cells have millions of copies. That's a big difference," says Hisataka Kobayashi, a molecular imaging researcher at the National Cancer Institute and the lead author of the new study, published this week in Nature Medicine. The result is that only cancer cells are vulnerable to the light-activated cascade.

The researchers tested the new treatment in mice and found that it reduced tumor growth and prolonged survival. 

There are a few kinks to work out before the system can be adapted for humans, though. For instance, the researchers couldn't test the treatment's effect on large tumors, since killing off too many cells at once caused cardiovascular problems in the mice. Finding the right cancer-cell markers to pair with the dye may also prove difficult. For example, HER-2, one of the proteins targeted in the study, is only expressed in 40 percent of breast-cancer cells in humans.

Still, the lack of toxicity associated with the treatment is a huge advantage, says Karen Brewer, a chemist at Virginia Tech who also works on light-activated cancer therapies. "What's interesting about this study is that they're applying a traditional method of targeting cancer cells to a light-activated treatment," she says. "This is really where the field is headed."

The dye used in the study offers another bonus because it lights up—allowing clinicians to track the treatment's progress with fluorescence imaging. In the mice, the fluorescence visibly declined in tumor cells a day after administration of the near-infrared light. Kobayashi suspects the approach could also prove valuable as a secondary therapy by helping surgeons label cancer cells that may remain after a tumor has been excised. "It could help clean up the tumor cells that are harder for surgeons to get to," he says.

By Erica Westly 
From Technology Review

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New Method for Making Neurons Could Lead to Parkinson's Treatment

A new method of synthesizing dopamine-producing neurons, the predominant type of brain cell destroyed in Parkinson's, offers hope for creating cell-replacement therapies that reverse the damage.

The method provides an efficient way of making functional cells. When transplanted into mice and rats with brain damage and movement problems similar to Parkinson's, the cells integrated into the brain and worked normally, reversing the animals' motor issues.

 Revamping the brain: Human dopamine-producing cells (marked in red and green) survive and function when transplanted into the brain of rats with brain damage that resembles Parkinson’s disease.

The finding brings researchers a step closer to testing a stem-cell-derived therapy in patients with this disorder. "We finally have a cell that seems to survive and function and a cell source that we can easily scale up," says Lorenz Studer, a researcher at the Sloan Kettering Institute and senior author on the new study. "That makes us optimistic that this could potentially be used in patients in the future."

The research also highlights the challenges of generating cells for tissue-replacement therapy, showing that subtle differences in the way the cells are made can have a huge impact on how well they work once implanted.

Many of the symptoms of Parkinson's disease—which include tremor, muscle rigidity, and loss of balance—are linked to loss of dopamine in the brain. While medications exist to replace some of the lost chemical, they do not alleviate all of the symptoms and can lose their effectiveness over time. Scientists hope that replacing lost cells with new ones will provide a more complete and long-term solution.

In the new study, researchers started with human embryonic stem cells, which by definition can differentiate into any cell type. To make a specific type of cell in high numbers, scientists expose the stem cells to a cocktail of chemicals that mimic what they would experience during normal development.

While stem-cell researchers had previously been able to create dopamine-producing neurons from human stem cells, these cells did little to alleviate movement problems in animals engineered to mimic the symptoms of Parkinson's. In 2009, Studer and others developed a method of making the cells that more closely mimics the way they form during development. The resulting cells also carry more of the molecular markers that characterize dopamine-producing cells in the brain.

In the new research, published Sunday in the journal Nature, Studer's team found a way to make these cells even more efficiently. This is significant in terms of ultimately testing the therapy in humans; many methods for making specific types of cells are complex and yield small amounts of the desired product.

They could scale up the process to make enough material to transplant into monkeys, whose larger brains are more akin to humans' than other animals used in testing. 

In addition, the researchers demonstrated that transplants of the cells could correct Parkinson's-like problems in mice and rats. Three different tests of motor function "all very dramatically improved when you put the cells in," says Studer.

While the two monkeys in the study also had brain damage reminiscent of Parkinson's, not enough time has passed to determine whether the transplants will help, Studer says. It took five months post-transplant for the cells to have a visible effect in rodents. 

The findings demonstrate the challenges of developing treatments based on living cells. "Previously, I think, many people thought of cell therapy [for Parkinson's] as a dopamine-producing biological pump," says Ole Isacson, a neuroscientist at Harvard Medical School. But in reality, it requires a very specific replacement of nerve cells. Unless you have a specific differentiation protocol, you won't get functional recovery in rodent models." Isacson was not involved in the research but has collaborated with Studer on other projects.

Researchers mostly used embryonic stem cells in these experiments, because tissue derived from these cells is already being used in human trials for treating spinal cord injury and certain types of blindness. They also showed that the protocol works on induced pluripotent stem (iPS) cells, which are derived from adult cells that are turned back to an embryonic-like state using a combination of genetic or chemical factors. iPS cells are genetically matched to the cell donor, and might ultimately provide a preferable source of tissue for therapy. However, these cells are further from human testing because they are much less studied than embryonic cells.

Studer's team now plans to make the cells on an even larger scale in a facility that meets conditions set by the U.S. Food and Drug Administration for human therapies. "We need to be able make enough cells to graft 100 patients," says Studer. He predicts that will take a year or two, followed by extensive safety testing to make sure the differentiated cells do not behave in unexpected ways once implanted. 

By Emily Singer
From Technology Review

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Company Decodes Cancers to Target Treatment

Just 18 months after its launch, cancer diagnostic startup Foundation Medicine has already developed a clinical diagnostic test, forged partnerships with several pharmaceutical companies, and discovered a number of novel mutations that may point toward new drug treatments for cancer.

Cancer reader: Foundation Medicine has developed a diagnostic test for cancer that reads the genome sequence of hundreds of cancer-linked genes. The results help oncologists pick the best drugs for that patient.

The company is at the forefront of a growing trend in cancer: choosing drugs based on the genetic profile of a patient's tumor cells. The plunging cost of gene sequencing means scientists can read the entire genome of an individual's cancer, leading to the rapid discovery of more and more cancer-linked mutations. Foundation Medicine is putting those findings—and cheap sequencing technology—to work to detect these mutations in newly diagnosed cancers. 

The startup was formed last year by a handful of cancer and genomics experts in Boston, including genomics pioneer Eric Lander, with funding from Boston-based venture capital group Third Rock Ventures. They have since raised $33.5 million from several investors, including Google Ventures. 

While most cancer diagnostics focus on individual genes or specific mutations, Foundation Medicine developed a diagnostic test to read the entire sequence of hundreds of cancer-linked genes. The company has yet to finalize the price of the test, but says it will be similar to the cost of testing five or six individual molecular markers. 

Foundation Medicine has so far processed several thousand tumor samples provided by academic medical centers, pharmaceutical companies, and clinical oncologists. The analysis detects whether the individual has mutations tied to existing drugs—both drugs that are approved for the patient's specific cancer, and those that are approved for other conditions. The test, which takes about two weeks, will also highlight whether a patient has mutations that make him a candidate for experimental drugs in clinical trials. While the test is currently available to some oncologists, the company doesn't plan an international launch until later next year.

The number of genes analyzed in the test will grow as the number of cancer-linked genes expands. The company will release an updated version of the test once or twice a year, says Michael Pellini, the company's chief executive officer. "That's why our work with pharma and academic medical centers is so important, because we get great insight into new therapeutics coming down the pike," he says. "If a new therapy targeting a specific molecular profile is getting ready for human testing, we want to make sure we are adding that gene to our test."

A number of pharmaceutical companies are using the test in clinical trials of new drugs. For example, if a study of a specific new drug failed to show a benefit in the patient population overall but did appear to work in a subset of patients, researchers can use Foundation Medicine's test to determine if there is a particular genetic alteration that predicts who is most likely to respond. 

Companies are also using the technology to direct patients into specific studies of drugs designed to target different mutations; it can often be difficult to enroll enough patients in such studies. Furthermore, if researchers collect multiple tumor samples from the same patient over time, they can use the test to understand how the tumor evolves and try to predict why one person's tumor might recur more quickly than another's.

Pellini says at least two pharmaceutical companies are considering using the technology in all cancer clinical trials going forward. "Pharma's willingness to accept this type of molecular approach has been my single greatest surprise since joining Foundation Medicine," he says. Historically, the pharmaceutical industry has been reluctant to test drugs in only a subset of patients, because this limits the number of people who might buy the drug. 

"There has been a transformation among many pharmaceutical companies to where they understand that targeted therapeutics is the new paradigm," says Pellini. Targeting clinical trials to only the patients who are most likely to respond to a drug makes it faster and cheaper to show that a drug works. "As everyone works to turn cancer into a chronic disease, as an industry, we will have the ability to treat patients for years rather than months—pharma has caught on to those concepts," he says.

Because Foundation Medicine's test is based on sequencing genes, rather than detecting known mutations, it can also find novel genetic changes. "As a by-product, a lot of novel discovery is coming out of these efforts," says Pellini. "We are identifying novel gene fusions, translocations, and mutations, many of which have clinical significance."

For example, researchers at Foundation Medicine identified a genetic translocation—where a segment of DNA is flipped around—in cancer tissue from a patient with non-small-cell lung cancer. Subsequent studies found that this mutation, which lies in a part of the genome that is being targeted by pharmaceutical companies, is present in about 5 percent of small-cell lung cancers. Pellini says the company is still working on how to deal with such new discoveries. "We are not a therapeutic company, and our primary interest tends to be on the diagnostic side," he says. "But we recognize that some findings may have strong therapeutic implications."

By Emily Singer
From Technology Review

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Improved characterization of nanoparticle clusters for EHS and biosensors research

A good example of the potential application of the work, says NIST biomedical engineer Justin Zook, is in the development of nanoparticle biosensors for ultrasensitive pregnancy tests. Gold nanoparticles can be coated with antibodies to a hormone produced by an embryo shortly after conception. Multiple gold nanoparticles can bind to each hormone, forming clusters that have a different color from unclustered gold nanoparticles. But only certain size clusters are optimal for this measurement, so knowing how light absorbance changes with cluster size makes it easier to design the biosensors to result in just the right sized clusters.

 Clusters of roughly 30-nanometer gold nanoparticles imaged by transmission electron microscopy.

The NIST team first prepared samples of gold nanoparticles—a nanomaterial widely used in biology—in a standard cell culture solution, using their previously developed technique for creating samples with a controlled distribution of sizes. The particles are allowed to agglomerate in gradually growing clusters and the clumping process is "turned off" after varying lengths of time by adding a stabilizing agent that prevents further agglomeration.

They then used a technique called analytical ultracentrifugation (AUC) to simultaneously sort the clusters by size and measure their light absorption. The centrifuge causes the nanoparticle clusters to separate by size, the smaller, lighter clusters moving more slowly than the larger ones. While this is happening, the sample containers are repeatedly scanned with light and the amount of light passing through the sample for each color or frequency is recorded. The larger the cluster, the more light is absorbed by lower frequencies. Measuring the absorption by frequency across the sample containers allows the researchers both to watch the gradual separation of cluster sizes and to correlate absorbed frequencies with specific cluster sizes.

Most previous measurements of absorption spectra for solutions of nanoparticles were able only to measure the bulk spectra—the absorption of all the different cluster sizes mixed together. AUC makes it possible to measure the quantity and distribution of each nanoparticle cluster without being confounded by other components in complex biological mixtures, such as proteins. The technique previously had been used only to make these measurements for single nanoparticles in solution. The NIST researchers are the first to show that the procedure also works for nanoparticle clusters.

From physorg

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New Technique Turns Viruses Into Useful Tools

Researchers have demonstrated a simple, one-step process in which genetically engineered viruses arrange themselves into extremely ordered patterns with distinctive properties, such as color or strength. The technique could be used to make novel optical devices or biological scaffolds to grow soft tissue, teeth, and bone.

The researchers, led by Seung-Wuk Lee, a bioengineering professor at the University of California, Berkeley, used the technique to make structured films. "We want to mimic nature and create many different types of functional structures with a very simple building block," Lee says.

 Viral films: Complex, highly structured films made using viruses could be used as optical devices and as templates for engineering tissue, bone, and teeth.

This work is part of a broader effort to make new types of materials using viruses as microscopic building blocks. Researchers at MIT, led by Angela Belcher, a biological engineering and materials science professor, have previously engineered viruses to bind to inorganic materials—something they would never do naturally—and have them assemble into battery components.

Lee and his colleagues have found a way to fine-tune the arrangement of individual viruses to create sophisticated structures with complex designs all on their own. Using a single virus as a building unit is "pretty exquisite," says Belcher, because its traits can be genetically modified and you can attach many different useful materials to its surface. What's even more important about the new work, which was published in the journal Nature last week, is the precise control over viral self-assembly, resulting in large-scale structures with multiple levels of organization. "This is very beautifully laid out," she says. "They can do so much with a single virus." 

The researchers used a rod-shaped bacterial virus, called M13, for their work. First, they dip a flat glass sheet into a saline solution containing the viruses. As they pull the glass out slowly at a controlled speed, the viruses spontaneously configure themselves on the glass surface into orderly patterns. This assembly happens as the solvent evaporates. "Self-assembly is hard to achieve in a systematic way, but what the authors have come up with shows a potentially powerful route to do this," says George Schatz, a chemistry professor at Northwestern University.

By changing the virus concentration in the solution and the pulling speed, the researchers were able to create different structured films. One has regularly placed stripes made of virus bundles in which the viruses are aligned and twisted like corkscrews. 

The most complex film has a "ramen-noodle-like" structure that bends light in certain ways. Various pulling speeds change the spacing and width of the viruses in this wavy structure, so that it shows distinct colors. Such films could be used as light reflectors and filters found in displays and photography. The technique could also be used to fabricate photonic crystals and organic photovoltaics.

The researchers also showed that the material could be made into a scaffold to engineer complex tissues. To do this, they genetically tweaked the virus to make it express certain proteins on its surface, which influence the growth of the tissue. They cultured cells on top of the films and found that the cells aligned themselves with the microstructure. What's more, when the films were dipped in a solution of calcium and phosphate ions, the ions mineralized on the film to form a tough material similar to tooth enamel. 

"Developing a system like this that could regenerate bone or could be used for growth of materials for teeth is a very possible application," says Belcher. 

By Prachi Patel
From Technology Review

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Researchers Engineer Mice with Anomalies Linked to Autism, Schizophrenia

Family studies suggest a strong genetic component to autism and schizophrenia, but the disorders are thought to arise during early development, making it difficult to study the underlying genetics. 

Now researchers at Cold Spring Harbor Laboratory in New York have created mice with chromosomal abnormalities that mirror those seen in humans with these disorders, which should make it easier to study the role of genetics in the development of the brain.

 Mouse minds: This image, created from an MRI scan, shows areas of a mouse's brain affected by chromosomal variations that are tied to autism and schizophrenia in humans.

In 2008, several research groups identified a section of DNA on chromosome 16 that appeared to be important for brain development in humans. Deletions of this section were tied to autism and developmental delays, while extra copies were linked to autism and schizophrenia. 

The new mouse model should let scientists evaluate the effects of genetic variants at different developmental stages, starting in the womb. The hope is that these experiments will provide new clues about the biology of autism and schizophrenia and possibly identify new tests that could help clinicians diagnose these conditions. "We're especially interested in finding early biomarkers for these disorders," says Alea Mills, the lead author of the new study, which appears today in the Proceedings of the National Academy of Sciences.

The researchers used a relatively new genetic technique called chromosome engineering to target the mouse equivalent of the relevant section of chromosome 16. They then used standard methods to generate mice that either lacked the section or had extra copies of it. 

The chromosomal deletion appeared to have more severe effects than the duplication, which is consistent with what clinicians have observed in humans. About half of the mice with the deletion died shortly after birth, suggesting that this chromosomal section is essential for proper development. Whether the deletion also contributes to infant mortality in humans is unknown.

The mice with the deletion also exhibited behaviors associated with autism, such as restricted, repetitive movements and sleep deficits. When the researchers conducted MRI scans on the mice, they found the deletion was associated with increased volume in several brain areas, particularly in the hypothalamus, the brain region that regulates eating and sleeping behaviors. The mice with the duplication tended to have smaller brain areas compared to controls, but the effect was less pronounced. 

The next step for Mills and her colleagues is to figure out the mechanisms behind the behavioral and anatomical differences they observed. Most mouse models are created by manipulating a single gene, but the human and mouse versions of the chromosome 16 section each contain more than 20 genes, and it's unclear which are the most important. "There's going to be a need to refine this area down to fewer genes," says David Miller, a genetics researcher at Children's Hospital Boston who has researched the chromosome 16 deletion in humans but was not involved with this study. 

Toward this end, Mills and her team are working on dividing the chromosomal section into smaller pieces and creating subgroups of their deletion and duplication in mice. Studying the interactions of so many genes will be challenging, but it may be necessary to understand complex, heterogeneous disorders such as autism and schizophrenia. Many clinics, including Children's Hospital Boston, already have a test that can detect chromosome 16 deletions or duplications. "The trick is knowing what it means when you find them," says Miller.

By Erica Westly  
From Technology Review

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