Neuroscientists illuminate role of autism gene

Neuroscientists illuminate role of autism linked gene. Loss of Shank gene prevents neuronal synapses from properly maturing.

Scientia — A new study from MIT neuroscientists reveals that a gene mutation associated with autism plays a critical role in the formation and maturation of synapses — the connections that allow neurons to communicate with each other.

Many genetic variants have been linked to autism, but only a handful are potent enough to induce the disorder on their own. Among these variants, mutations in a gene called Shank3 are among the most common, occurring in about 0.5 percent of people with autism.

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Scientists know that Shank3 helps cells respond to input from other neurons, but because there are two other Shank proteins, and all three can fill in for each other in certain ways, it has been difficult to determine exactly what the Shank proteins are doing.

“It’s clearly regulating something in the neuron that’s receiving a synaptic signal, but some people find one role and some people find another,” says Troy Littleton, a professor in the departments of Biology and of Brain and Cognitive Sciences at MIT, a member of MIT’s Picower Institute for Learning and Memory, and the senior author of the study. “There’s a lot of debate over what it really does at synapses.”

Key to the study is that fruit flies, which Littleton’s lab uses to study synapses, have only one version of the Shank gene. By knocking out that gene, the researchers eliminated all Shank protein from the flies.

“This is the first animal where we have completely removed all Shank family proteins,” says Kathryn Harris, a Picower Institute research scientist and lead author of the paper, which appears in the May 25 issue of the Journal of Neuroscience.

Synaptic organization

Scientists already knew that the Shank proteins are scaffold proteins, meaning that they help to organize the hundreds of other proteins found in the synapse of a postsynaptic cell — a cell that receives signals from a presynaptic cell. These proteins help to coordinate the cell’s response to the incoming signal.

“Shank is essentially a hub for signaling,” Harris says. “It brings in a lot of other partners and plays an organizational role at the postsynaptic membrane.”

In fruit flies lacking the Shank protein, the researchers found two dramatic effects. First, the postsynaptic cells had many fewer boutons, which are the sites where neurotransmitter release occurs. Second, many of the boutons that did form were not properly developed; that is, they were not surrounded by all of the postsynaptic proteins normally found there, which are required to respond to synaptic signals.

The researchers are now studying how this reduction in functional synapses affects the brain. Littleton suspects that the development of neural circuits could be impaired, which, if the same holds true in humans, may help explain some of the symptoms seen in autistic people.

“During critical windows of social and language learning, we reshape our connections to drive connectivity patterns that respond to rewards and language and social interactions,” he says. “If Shank is doing similar things in the mammalian brain, one could imagine potentially having those circuits form relatively normally early on, but if they fail to properly mature and form the proper number of connections, that could lead to a variety of behavioral defects.”

Pinpointing an exact link to autism symptoms would be difficult to do in fruit fly studies, however.

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“Although the core molecular machines that allow neurons to communicate are highly conserved between fruit flies and humans, the anatomy of the various circuits that are formed during evolution are quite different,” Littleton says. “It’s hard to jump from a synaptic defect in the fly to an autism-like phenotype because the circuits are so different.”

An unexpected link

The researchers also showed, for the first time, that loss of Shank affects a well-known set of proteins that comprise the Wnt (also known as Wingless) signaling pathway. When a Wnt protein binds to a receptor on the cell, it initiates a series of interactions that influence which genes are turned on. This, in turn, contributes to many cell processes including embryonic development, tissue regeneration, and tumor formation.

When Shank is missing from fruit flies, Wnt signaling is disrupted because the receptor that normally binds to Wnt fails to be internalized by the cell. Normally, a small segment of the activated receptor moves to the cell nucleus and influences the transcription of genes that promote maturation of synapses. Without Shank, Wnt signaling is impaired and the synapses do not fully mature.

“The Shank protein and the Wnt protein family are thought to be involved in autism independently, but the fact that this study discovered that Wnt and Shank are interacting brings the story into better focus,” says Bryan Stewart, a professor of cell and systems biology at the University of Toronto at Mississauga, who was not involved in the research. “Now we can look and see if those interactions between Wnt and Shank are potentially responsible for their role in autism.”

The finding raises the possibility of treating autism with drugs that promote Wnt signaling, if the same connection is found in humans.

“Because the link to Wnt signaling is new and hasn’t been picked up in mammalian studies, we really hope that that can inspire people to look for a connection to Wnt signaling in mammalian models, and maybe that can offer another avenue for how loss of Shank could be counteracted,” Harris says.

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– Credit and Resource –

The research was funded by the National Institutes of Health and the Simons Center for the Social Brain at MIT.

Anne Trafton | MIT News Office

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Neuroscientists illuminate role of autism gene

Programming language for living cells

A programming language for living cells. New programming language lets researchers design novel biological circuits.

Scientia — MIT biological engineers have created a programming language that allows them to rapidly design complex, DNA-encoded circuits that give new functions to living cells.

Using this language, anyone can write a program for the function they want, such as detecting and responding to certain environmental conditions. They can then generate a DNA sequence that will achieve it.

“It is literally a programming language for bacteria,” says Christopher Voigt, an MIT professor of biological engineering. “You use a text-based language, just like you’re programming a computer. Then you take that text and you compile it and it turns it into a DNA sequence that you put into the cell, and the circuit runs inside the cell.”

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Voigt and colleagues at Boston University and the National Institute of Standards and Technology have used this language, which they describe in the April 1 issue of Science, to build circuits that can detect up to three inputs and respond in different ways. Future applications for this kind of programming include designing bacterial cells that can produce a cancer drug when they detect a tumor, or creating yeast cells that can halt their own fermentation process if too many toxic byproducts build up.

The researchers plan to make the user design interface available on the Web.

No experience needed

Over the past 15 years, biologists and engineers have designed many genetic parts, such as sensors, memory switches, and biological clocks, that can be combined to modify existing cell functions and add new ones.

However, designing each circuit is a laborious process that requires great expertise and often a lot of trial and error. “You have to have this really intimate knowledge of how those pieces are going to work and how they’re going to come together,” Voigt says.

Users of the new programming language, however, need no special knowledge of genetic engineering.

“You could be completely naive as to how any of it works. That’s what’s really different about this,” Voigt says. “You could be a student in high school and go onto the Web-based server and type out the program you want, and it spits back the DNA sequence.”

The language is based on Verilog, which is commonly used to program computer chips. To create a version of the language that would work for cells, the researchers designed computing elements such as logic gates and sensors that can be encoded in a bacterial cell’s DNA. The sensors can detect different compounds, such as oxygen or glucose, as well as light, temperature, acidity, and other environmental conditions. Users can also add their own sensors. “It’s very customizable,” Voigt says.

The biggest challenge, he says, was designing the 14 logic gates used in the circuits so that they wouldn’t interfere with each other once placed in the complex environment of a living cell.

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In the current version of the programming language, these genetic parts are optimized for E. coli, but the researchers are working on expanding the language for other strains of bacteria, including Bacteroides, commonly found in the human gut, and Pseudomonas, which often lives in plant roots, as well as the yeast Saccharomyces cerevisiae. This would allow users to write a single program and then compile it for different organisms to get the right DNA sequence for each one.

Biological circuits

Using this language, the researchers programmed 60 circuits with different functions, and 45 of them worked correctly the first time they were tested. Many of the circuits were designed to measure one or more environmental conditions, such as oxygen level or glucose concentration, and respond accordingly. Another circuit was designed to rank three different inputs and then respond based on the priority of each one.

One of the new circuits is the largest biological circuit ever built, containing seven logic gates and about 12,000 base pairs of DNA.

Another advantage of this technique is its speed. Until now, “it would take years to build these types of circuits. Now you just hit the button and immediately get a DNA sequence to test,” Voigt says.

His team plans to work on several different applications using this approach: bacteria that can be swallowed to aid in digestion of lactose; bacteria that can live on plant roots and produce insecticide if they sense the plant is under attack; and yeast that can be engineered to shut off when they are producing too many toxic byproducts in a fermentation reactor.

The lead author of the Science paper is MIT graduate student Alec Nielsen. Other authors are former MIT postdoc Bryan Der, MIT postdoc Jonghyeon Shin, Boston University graduate student Prashant Vaidyanathan, Boston University associate professor Douglas Densmore, and National Institute of Standards and Technology researchers Vanya Paralanov, Elizabeth Strychalski, and David Ross.

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– Credit and Resource –

Anne Trafton | MIT News Office

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Programming language for living cells

Process to Accelerate Protein Evolution

Stanford engineers invent process to accelerate protein evolution

A new tool enables researchers to test millions of mutated proteins in a matter of hours or days, speeding the search for new medicines, industrial enzymes and biosensors.

All living things require proteins, members of a vast family of molecules that nature “makes to order” according to the blueprints in DNA.

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Through the natural process of evolution, DNA mutations generate new or more effective proteins. Humans have found so many alternative uses for these molecules – as foods, industrial enzymes, anti-cancer drugs – that scientists are eager to better understand how to engineer protein variants designed for specific uses.

An overview of the directed evolution process using the new Stanford technique: preparing protein libraries, screening them, extracting desired cells, and then inferring their DNA sequence. (Click image to enlarge.)

Now Stanford engineers have invented a technique to dramatically accelerate protein evolution for this purpose. This technology, described in Nature Chemical Biology, allows researchers to test millions of variants of a given protein, choose the best for some task and determine the DNA sequence that creates this variant.

“Evolution, the survival of the fittest, takes place over a span of thousands of years, but we can now direct proteins to evolve in hours or days,” said Jennifer Cochran, an associate professor of bioengineering who co-authored the paper with Thomas Baer, executive director of the Stanford Photonics Research Center.

“This is a practical, versatile system with broad applications that researchers will find easy to use,” Baer said.

By combining Cochran’s protein engineering know-how with Baer’s expertise in laser-based instrumentation, the team created a tool that can test millions of protein variants in a matter of hours.

“The demonstrations are impressive and I look forward to seeing this technology more widely adopted,” said Frances Arnold, a professor of chemical engineering at Caltech who was not affiliated with the study.

Making a million mutants

The researchers call their tool µSCALE, or Single Cell Analysis and Laser Extraction.

The “µ” stands for the microcapillary glass slide that holds the protein samples. The slide is roughly the size and thickness of a penny, yet in that space a million capillary tubes are arrayed like straws, open on the top and bottom.

The microcapillary glass slide, roughly the size and thickness of a penny, holds the protein samples.

The power of µSCALE is how it enables researchers to build upon current biochemical techniques to run a million protein experiments simultaneously, then extract and further analyze the most promising results.

The researchers first employ a process termed “mutagenesis” to create random variations in a specific gene. These mutations are inserted into batches of yeast or bacterial cells, which express the altered gene and produce millions of random protein variants.

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A µSCALE user mixes millions of tiny opaque glass beads into a sample containing millions of yeast or bacteria and spreads the mixture on a microcapillary slide. Tiny amounts of fluid trickle into each tube, carrying individual cells. Surface tension traps the liquid and the cell in each capillary.

The slide bearing these million yeast or bacteria, and the protein variants they produce, is inserted into the µSCALE device. A software-controlled microscope peers into each capillary and takes images of the biochemical reaction occurring therein.

Once a µSCALE user identifies a capillary of interest, the researcher can direct the laser to extract the contents of that tube without disrupting its neighbors, using an ingenious method devised by Baer.

“The beads are what enable extraction,” Baer said. “The laser supplies energy to move the beads, which breaks the surface tension and releases the sample from the capillary.”

Thus µSCALE empties the contents of a single capillary onto a collector plate, where the DNA of the isolated cell can be sequenced and the gene variant responsible for the protein of interest can be identified.

“One of the unique features of µSCALE is that it allows researchers to rapidly isolate a single desired cell from hundreds of thousands of other cells,” said Bob Chen, a doctoral student in Cochran’s lab who wrote the software to examine and detect signs of interesting protein activity within the test tubes.

Promising variants can be collected and reprocessed through µSCALE to further evolve and optimize the protein.

“This is an exciting new tool to answer important questions about proteins,” Cochran said, likening µSCALE to the way that high-throughput tools for gene analysis have allowed researchers to unlock key features of biology underlying human disease.

Genesis and proofs

The project began five years ago when Baer and collaborator Ivan Dimov developed the first instrument. They showed how to identify cell types in a microcapillary array and extract a single capillary’s contents using glass beads and a focused laser.

About three years ago, Cochran and Baer joined forces to develop µSCALE for protein engineering, and the team devised three experiments to showcase µSCALE’s utility and flexibility.

In one experiment, researchers sifted through a protein library produced in yeast cells to select antibodies that bound most tightly to a cancer target. Antibodies with a high target-binding affinity are known to be effective against cancer.

In a second example, they engineered a bright orange fluorescent protein biosensor. Using µSCALE, they did this almost 10 times faster than previous methods. Such biosensors are often used as tags in a wide variety of biology experiments.

A third experiment, carried out with Stanford biochemistry Professor Daniel Herschlag, used µSCALE to improve upon a model enzyme.

“This system will allow us to explore the evolutionary and functional relationships between enzymes, guiding the engineering of new enzymes that can carry out novel beneficial reactions,” Herschlag said.

The Stanford team included graduate students Sungwon Lim and Arvind Kannan, postdoctoral scholar Spencer Alford and researcher Fanny Sunden.

Support for this work included a Wallace H. Coulter Translational Partnership Award, which made this pioneering interdisciplinary research possible.

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– Credit and Resource –

Written by: Ramin Skibba

Provided by: Standford University

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Process to Accelerate Protein Evolution

Hibernating Parasite Could Alter Brain Behavior

‘Hijacking’ and hibernating parasite could alter brain behavior

Researchers from Melbourne’s Walter and Eliza Hall Institute have discovered how a common parasite hijacks host cells and stockpiles food so it can lie dormant for decades, possibly changing its host’s behavior or personality in the process.
The findings could lead to a vaccine to protect pregnant women from Toxoplasma infection, which carries a serious risk of miscarriage or birth defects, as well as drugs to clear chronic infections in people with compromised immune systems, such as cancer patients. Credit: Walter and Eliza Hall Institute

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Scientia — Melbourne researchers have discovered how a common parasite hijacks host cells and stockpiles food so it can lie dormant for decades, possibly changing its host’s behaviour or personality in the process.

The findings could lead to a vaccine to protect pregnant women from Toxoplasma infection, which carries a serious risk of miscarriage or birth defects, as well as drugs to clear chronic infections in people with compromised immune systems, such as cancer patients.

Toxoplasma is a common parasite transmitted by cats and found in raw meat. Around 30 per cent of the population is infected. The research projects were led by Dr Chris Tonkin, Dr Justin Boddey, Dr Alex Uboldi, Mr James McCoy and Mr Michael Coffey from the Walter and Eliza Hall Institute.

Dr Tonkin said Toxoplasma required a human host cell – such as a brain cell (neuron) – to live in. The research team discovered how the parasite hijacks the host cell to enable its own growth and survival, hibernating for decades by creating its own food reserve.

“Toxoplasma infection leads to massive changes in the host cell to prevent immune attack and enable it to acquire a steady nutrient supply,” Dr Tonkin said. “The parasite achieves this by sending proteins into the host cell that manipulate the host’s own cellular pathways, enabling it to grow and reproduce.”

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Dr Boddey said some of these proteins might even influence the behaviour of the host. “There is a fascinating association between Toxoplasma infection and psychiatric diseases including schizophrenia and bipolar disorder. It is now possible to test whether proteins sent from the hibernating parasite into a host neuron disrupt normal brain function and contribute to development of these diseases,” he said.

Once Toxoplasma parasites establish infection, they can lie dormant in our bodies for the rest of our lives. In people with suppressed immune systems, such as cancer patients, the parasite can reactivate and cause neurological damage and even death.

Dr Tonkin said the teams had identified pathways that allow the parasite to establish chronic infections, unveiling potential avenues for treatment that clear the dormant parasite.

“We discovered that, similar to animals preparing for hibernation, Toxoplasma parasites stockpile large amounts of starch when they become dormant,” he said. “By identifying and disabling the switch that drives starch storage, we found that we could kill the dormant parasites, preventing them from establishing a chronic infection.”

Dr Tonkin said the finding could lead to a drug to clear chronic Toxoplasma infections, or even a vaccine to prevent infection in at-risk people, such as pregnant women.

“Cats are one of the primary transmitters of Toxoplasma parasites,” Dr Tonkin said. “If the parasites are transmitted to pregnant women, for example through contact with kitty litter, there is a substantial risk of miscarriage or birth defects.

“We hope to use our discoveries to develop a vaccine that stops cats transmitting the parasite, to prevent these potentially catastrophic consequences.”

Dr Boddey said it had long been a mystery how the Toxoplasma parasite transported proteins into the host. “Our study showed that the parasite includes a signature on the exported proteins that ‘earmark’ them for transport into the host cell,” he said. “Blocking transport makes the parasite much less dangerous in infection models, suggesting this may also be a new way of treating Toxoplasma infections.”

The research findings were published today in the journal Cell Host & Microbe and in the journal eLife.

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– Credit and Resource –

Journal reference: Cell Host & Microbe & eLife

Provided by: Walter and Eliza Hall Institute

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Hibernating Parasite Could Alter Brain Behavior

Drug-resistance Mechanism in Tumor Cells

Biologists unravel drug-resistance mechanism in tumor cells – Targeting the RNA-binding protein that promotes resistance could lead to better cancer therapies.

P53, which helps healthy cells prevent genetic mutations, is missing from about half of all tumors. Researchers have found that a backup system takes over when p53 is disabled and encourages cancer cells to continue dividing. In the background of this illustration are crystal structures of p53 DNA-binding domains.
Image: Jose-Luis Olivares/MIT (p53 illustration by Richard Wheeler/Wikimedia Commons)

Scientia — About half of all tumors are missing a gene called p53, which helps healthy cells prevent genetic mutations. Many of these tumors develop resistance to chemotherapy drugs that kill cells by damaging their DNA.

MIT cancer biologists have now discovered how this happens: A backup system that takes over when p53 is disabled encourages cancer cells to continue dividing even when they have suffered extensive DNA damage. The researchers also discovered that an RNA-binding protein called hnRNPA0 is a key player in this pathway.

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“I would argue that this particular RNA-binding protein is really what makes tumor cells resistant to being killed by chemotherapy when p53 is not around,” says Michael Yaffe, the David H. Koch Professor in Science, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the study, which appears in the Oct. 22 issue of Cancer Cell.

The findings suggest that shutting off this backup system could make p53-deficient tumors much more susceptible to chemotherapy. It may also be possible to predict which patients are most likely to benefit from chemotherapy and which will not, by measuring how active this system is in patients’ tumors.

Rewired for resistance

In healthy cells, p53 oversees the cell division process, halting division if necessary to repair damaged DNA. If the damage is too great, p53 induces the cell to undergo programmed cell death.

In many cancer cells, if p53 is lost, cells undergo a rewiring process in which a backup system, known as the MK2 pathway, takes over part of p53’s function. The MK2 pathway allows cells to repair DNA damage and continue dividing, but does not force cells to undergo cell suicide if the damage is too great. This allows cancer cells to continue growing unchecked after chemotherapy treatment.

“It only rescues the bad parts of p53’s function, but it doesn’t rescue the part of p53’s function that you would want, which is killing the tumor cells,” says Yaffe, who first discovered this backup system in 2013.

In the new study, the researchers delved further into the pathway and found that the MK2 protein exerts control by activating the hnRNPA0 RNA-binding protein.

RNA-binding proteins are proteins that bind to RNA and help control many aspects of gene expression. For example, some RNA-binding proteins bind to messenger RNA (mRNA), which carries genetic information copied from DNA. This binding stabilizes the mRNA and helps it stick around longer so the protein it codes for will be produced in larger quantities.

“RNA-binding proteins, as a class, are becoming more appreciated as something that’s important for response to cancer therapy. But the mechanistic details of how those function at the molecular level are not known at all, apart from this one,” says Ian Cannell, a research scientist at the Koch Institute and the lead author of the Cancer Cell paper.

In this paper, Cannell found that hnRNPA0 takes charge at two different checkpoints in the cell division process. In healthy cells, these checkpoints allow the cell to pause to repair genetic abnormalities that may have been introduced during the copying of chromosomes.

One of these checkpoints, known as G2/M, is controlled by a protein called Gadd45, which is normally activated by p53. In lung cancer cells without p53, hnRNPA0 stabilizes mRNA coding for Gadd45. At another checkpoint called G1/S, p53 normally turns on a protein called p21. When p53 is missing, hnRNPA0 stabilizes mRNA for a protein called p27, a backup to p21. Together, Gadd45 and p27 help cancer cells to pause the cell cycle and repair DNA so they can continue dividing.

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Personalized medicine

The researchers also found that measuring the levels of mRNA for Gadd45 and p27 could help predict patients’ response to chemotherapy. In a clinical trial of patients with stage 2 lung tumors, they found that patients who responded best had low levels of both of those mRNAs. Those with high levels did not benefit from chemotherapy.

“You could measure the RNAs that this pathway controls, in patient samples, and use that as a surrogate for the presence or absence of this pathway,” Yaffe says. “In this trial, it was very good at predicting which patients responded to chemotherapy and which patients didn’t.”

“The most exciting thing about this study is that it not only fills in gaps in our understanding of how p53-deficient lung cancer cells become resistant to chemotherapy, it also identifies actionable events to target and could help us to identify which patients will respond best to cisplatin, which is a very toxic and harsh drug,” says Daniel Durocher, a senior investigator at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Toronto, who was not part of the research team.

The MK2 pathway could also be a good target for new drugs that could make tumors more susceptible to DNA-damaging chemotherapy drugs. Yaffe’s lab is now testing potential drugs in mice, including nanoparticle-based sponges that would soak up all of the RNA binding protein so it could no longer promote cell survival.

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– Credit and Resource –

Anne Trafton | MIT News Office

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Drug-resistance Mechanism in Tumor Cells

Targeting DNA

Protein-based sensor could detect viral infection or kill cancer cells.

Scientia — MIT biological engineers have developed a modular system of proteins that can detect a particular DNA sequence in a cell and then trigger a specific response, such as cell death.

This system can be customized to detect any DNA sequence in a mammalian cell and then trigger a desired response, including killing cancer cells or cells infected with a virus, the researchers say.

“There is a range of applications for which this could be important,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Department of Biological Engineering and Institute of Medical Engineering and Science (IMES). “This allows you to readily design constructs that enable a programmed cell to both detect DNA and act on that detection, with a report system and/or a respond system.”

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Collins is the senior author of a Sept. 21 Nature Methods paper describing the technology, which is based on a type of DNA-binding proteins known as zinc fingers. These proteins can be designed to recognize any DNA sequence.

“The technologies are out there to engineer proteins to bind to virtually any DNA sequence that you want,” says Shimyn Slomovic, an IMES postdoc and the paper’s lead author. “This is used in many ways, but not so much for detection. We felt that there was a lot of potential in harnessing this designable DNA-binding technology for detection.”

Sense and respond

To create their new system, the researchers needed to link zinc fingers’ DNA-binding capability with a consequence — either turning on a fluorescent protein to reveal that the target DNA is present or generating another type of action inside the cell.

The researchers achieved this by exploiting a type of protein known as an “intein” — a short protein that can be inserted into a larger protein, splitting it into two pieces. The split protein pieces, known as “exteins,” only become functional once the intein removes itself while rejoining the two halves.

Collins and Slomovic decided to divide an intein in two and then attach each portion to a split extein half and a zinc finger protein. The zinc finger proteins are engineered to recognize adjacent DNA sequences within the targeted gene, so if they both find their sequences, the inteins line up and are then cut out, allowing the extein halves to rejoin and form a functional protein. The extein protein is a transcription factor designed to turn on any gene the researchers want.

In this paper, they linked green fluorescent protein (GFP) production to the zinc fingers’ recognition of a DNA sequence from an adenovirus, so that any cell infected with this virus would glow green.

This approach could be used not only to reveal infected cells, but also to kill them. To achieve this, the researchers could program the system to produce proteins that alert immune cells to fight the infection, instead of GFP.

“Since this is modular, you can potentially evoke any response that you want,” Slomovic says. “You could program the cell to kill itself, or to secrete proteins that would allow the immune system to identify it as an enemy cell so the immune system would take care of it.”

Martin Fussenegger, a professor of biotechnology and bioengineering at the Swiss Federal Institute of Technology in Zurich, described this experiment as an “elegant proof of concept” that could lead to greatly improved treatments for viral infection.

“Sentinel designer cells engineered with the DNA sense-and-response system may one day be able to sense and eliminate viruses in our body. This would represent a quantum leap in antiviral therapy,” says Fussenegger, who was not involved in the study.

The MIT researchers also deployed this system to kill cells by linking detection of the DNA target to production of an enzyme called NTR. This enzyme activates a harmless drug precursor called CB 1954, which the researchers added to the petri dish where the cells were growing. When activated by NTR, CB 1954 kills the cells.

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Future versions of the system could be designed to bind to DNA sequences found in cancerous genes and then produce transcription factors that would activate the cells’ own programmed cell death pathways.

Research tool

The researchers are now adapting this system to detect latent HIV proviruses, which remain dormant in some infected cells even after treatment. Learning more about such viruses could help scientists find ways to permanently eliminate them.

“Latent HIV provirus is pretty much the final barrier to curing AIDS, which currently is incurable simply because the provirus sequence is there, dormant, and there aren’t any ways to eradicate it,” Slomovic says.

While treating diseases using this system is likely many years away, it could be used much sooner as a research tool, Collins says. For example, scientists could use it to test whether genetic material has been successfully delivered to cells that scientists are trying to genetically alter. Cells that did not receive the new gene could be induced to undergo cell death, creating a pure population of the desired cells.

It could also be used to study chromosomal inversions and transpositions that occur in cancer cells, or to study the 3-D structure of normal chromosomes by testing whether two genes located far from each other on a chromosome fold in such a way that they end up next to each other, the researchers say.

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– Credit and Resource –

Anne Trafton | MIT News Office

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Targeting DNA

Quest for organic solar panels and flexible electronics

University of Vermont scientists have invented a new way to create what they are calling an electron superhighway in an organic semiconductor that promises to allow electrons to flow faster and farther — aiding the hunt for flexible electronics, organic solar cells, and other low-cost alternatives to silicon. To explore these organic materials, UVM graduate students (from left) Naveen Rawat and Lane Manning, and professors Randy Headrick and Madalina Furis, deployed this table-top scanning laser microscope. Their latest finding is reported in the journal Nature Communications — and may, someday not too far off, let you roll up your computer like a piece of paper. Credit: Joshua Brown, UVM

Scientia — TV screens that roll up. Roofing tiles that double as solar panels. Sun-powered cell phone chargers woven into the fabric of backpacks. A new generation of organic semiconductors may allow these kinds of flexible electronics to be manufactured at low cost, says University of Vermont physicist and materials scientist Madalina Furis.

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But the basic science of how to get electrons to move quickly and easily in these organic materials remains murky.

To help, Furis and a team of UVM materials scientists have invented a new way to create what they are calling “an electron superhighway” in one of these materials—a low-cost blue dye called phthalocyanine—that promises to allow electrons to flow faster and farther in organic semiconductors.

Their discovery, reported Sept. 14 in the journal Nature Communications, will aid in the hunt for alternatives to traditional silicon-based electronics.

Hills and potholes

Many of these types of flexible electronic devices will rely on thin films of organic materials that catch sunlight and convert the light into electric current using excited states in the material called “excitons.” Roughly speaking, an exciton is a displaced electron bound together with the hole it left behind. Increasing the distance these excitons can diffuse—before they reach a juncture where they’re broken apart to produce electrical current—is essential to improving the efficiency of organic semiconductors.

Using a new imaging technique, the UVM team was able to observe nanoscale defects and boundaries in the crystal grains in the thin films of phthalocyanine—roadblocks in the electron highway. “We have discovered that we have hills that electrons have to go over and potholes that they need to avoid,” Furis explains.

To find these defects, the UVM team—with support from the National Science Foundation—built a scanning laser microscope, “as big as a table” Furis says. The instrument combines a specialized form of linearly polarized light and photoluminescence to optically probe the molecular structure of the phthalocyanine crystals.

“Marrying these two techniques together is new; it’s never been reported anywhere,” says Lane Manning ’08 a doctoral student in Furis’ lab and co-author on the new study.

The new technique allows the scientists a deeper understanding of how the arrangement of molecules and the boundaries in the crystals influence the movement of excitons. It’s these boundaries that form a “barrier for exciton diffusion,” the team writes.

And then, with this enhanced view, “this energy barrier can be entirely eliminated,” the team writes. The trick: very carefully controlling how the thin films are deposited. Using a novel “pen-writing” technique with a hollow capillary, the team worked in the lab of UVM physics and materials science professor Randy Headrick to successfully form films with jumbo-sized crystal grains and “small angle boundaries.” Think of these as easy-on ramps onto a highway—instead of an awkward stop sign at the top of a hill—that allow excitons to move far and fast.

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Better solar cells

Though the Nature Communications study focused on just one organic material, phthalocyanine, the new research provides a powerful way to explore many other types of organic materials, too—with particular promise for improved solar cells. A recent U.S. Department of Energy report identified one of the fundamental bottlenecks to improved solar power technologies as “determining the mechanisms by which the absorbed energy (exciton) migrates through the system prior to splitting into charges that are converted to electricity.”

The new UVM study—led by two of Furis’ students, Zhenwen Pan G’12, and Naveen Rawat G’15—opens a window to view how increasing “long-range order” in the organic semiconductor films is a key mechanism that allows excitons to migrate farther. “The molecules are stacked like dishes in a dish rack,” Furis explains, “these stacked molecules—this dish rack—is the electron superhighway.”

Though excitons are neutrally charged—and can’t be pushed by voltage like the electrons flowing in a light bulb—they can, in a sense, bounce from one of these tightly stacked molecules to the next. This allows organic thin films to carry energy along this molecular highway with relative ease, though no net electrical charge is transported.

“One of today’s big challenges is how to make better photovoltaics and solar technologies,” says Furis, who directs UVM’s program in materials science, “and to do that we need a deeper understanding of exciton diffusion. That’s what this research is about.”

– Credit and Resource –

More information: Polarization-resolved spectroscopy imaging of grain boundaries and optical excitations in crystalline organic thin films, Nature Communications, 6, Article number: 8201 DOI: 10.1038/ncomms9201

Provided by: University of Vermont

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Quest for organic solar panels and flexible electronics