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Big Hope for Tiny Particles

Nanoparticles that deliver two or more drugs simultaneously can significantly shrink pancreatic cancer tumors and also reduce its spread, say researchers at Massachusetts General Hospital. Tayyaba Hasan, who is also a professor of dermatology at Harvard Medical School, led the development and testing of two "nanocells." These nanocells combine light-based therapy with molecules that inhibit the growth of cancer cells or of the blood vessels that feed them.

Though the particles have only been studied in mice so far, the cancer-research community is excited. Pancreatic cancer remains one of the deadliest and hardest cancers to treat; mortality rates have changed very little in the last 30 years. After diagnosis, patients tend to live only six months, and less than 5 percent survive for five years. "In terms of a patient population, there is very little we can do for them once we find the cancer," says Craig Thompson, director of the Abramson Cancer Center at the University of Pennsylvania.

Hasan and two research fellows in her lab, Prakash Rai and Lei Z. Zheng, presented their initial results on November 17 at the International Conference on Molecular Targets and Cancer Therapeutics, held jointly by the American Association for Cancer Research, the U.S. National Cancer Institute (NCI), and the European Organization for Research and Treatment of Cancer.

The team's first type of nanocell is designed to effectively starve tumors by cutting off their blood supply. They trapped a photosensitive drug called verteporfin, which creates toxic oxygen radicals when exposed to specific wavelengths of light, inside solid polymer nanoparticles. Those nanoparticles were then encapsulated in lipid particles along with bevacizumab, an antibody that specifically inhibits the growth of new blood vessels by blocking a protein called VEGF. Both verteporfin and bevacizumab are already approved by the U.S. Food and Drug Administration. Bevacizumab is approved for the treatment of advanced cancers of the colon, breast, lung, and kidney; it's marketed by Genentech as Avastin. Verteporfin is used to eliminate abnormal blood vessels in wet-form macular degeneration. It's sold as Visudyne by Novartis.

In a previous small-scale clinical trial, verteporfin alone increased the median survival of pancreatic cancer patients from six months to nine months. Adding Avastin, however, did not increase survival time--possibly because the Avastin killed off the tumor's blood vessels, making it difficult to get enough of the photosensitive drug to the cancer.

In contrast, when the nanocells are injected intravenously, they deliver both drugs directly to the inside of cancer cells. Blood vessels in normal tissue are impermeable to the nanoparticles, but blood vessels in tumors are "leakier," with much larger pores that allow the nanoparticles to pass through. As a result, the nanoparticles accumulate inside tumors and deliver more of their payload to the cancer cells than to healthy cells. The nanocells provide a higher effective dose of drug to the tumors as well as fewer side effects because the researchers used a lower dose of both drugs than usual.

The team implanted human pancreatic cancer cells in mice and allowed tumors to grow. They then injected the mice with a single dose of the nanocells and exposed the tumor to long-wavelength light. Mice given this single treatment showed a greater reduction in their tumor size than mice treated with either drug alone. The mice treated with the nanocells also had at least two times fewer metastases to the liver, lungs, and lymph nodes. "Injecting these things as separate entities is not as effective as combining them into one construct," says Hasan.

Hasan believes that's because the nanocells actually fuse with the tumor cells and deliver the Avastin inside the cell, instead of just to the outside. And though Hasan's lab has not done any toxicity studies, she hopes that the nanocells' preferential accumulation inside of tumors may decrease the drug's side effects, which can be quite dangerous. As many as 30 percent of patients receiving Avastin suffer cardiovascular side effects, including dangerously high blood pressure, stroke, and heart failure.

Shiladitya Sengupta, an assistant professor of medicine and health sciences and technology at Harvard Medical School, calls the results of Hasan's mouse experiments "dramatic." He says, "In the context of pancreatic cancer, [the results are] outstanding, because there's no therapy."

Sengupta did not participate in Hasan's research, but he originated the idea of drug delivery using nanocells. Technology Review recognized him for this idea with a 2005 TR35 award. He cofounded Cerulean Pharma to commercialize the nanocell platform and other nanopharmaceutical delivery methods. But one tricky aspect of the technology is that it must be individually optimized for every new combination of drugs, he notes.

Hasan's team has already developed a second nanocell designed to prevent pancreatic cancers from developing resistance to chemotherapy, a very common problem. Other researchers have identified two proteins, EGFR and MET, as particularly important in the development and growth of pancreatic cancer. In fact, in cancer cell lines in the lab, when biologists block EGFR, the cells increase their production of MET, and vice versa. So to better control the tumors, Hasan's team set out to target EGFR and MET simultaneously, while again hitting the tumor with light to increase the effectiveness of the treatment.

This second nanocell required a more sophisticated design. Rai started with a small molecule called PHA-66572, which inhibits the MET protein, and confined it in the same sort of solid polymer nanoparticle used in the first nanocell. He then surrounded those nanoparticles with cetuximab, an antibody that blocks EGFR. Finally, he incorporated Visudyne into a lipid sphere that he used to encapsulate these two layers.

Zheng says that tumors shrank dramatically in mice that had been implanted with pancreatic cancers and then given a single injection of the nanocells followed by light therapy. He is still measuring the effects on metastasis, but since the MET protein is active in most cancers that have metastasized (not just pancreatic cancer), the researchers are optimistic that the growth-factor nanocells will significantly decrease the number and size of metastases as well.

Zheng says that these results are particularly encouraging because of the apparent reduction in toxicity of the drugs. Pfizer developed PHA-66572 specifically to block MET in cancer cells, but it proved so toxic that the company abandoned the drug. In contrast, Zheng says that the animals that he gave the nanocell maintained normal activity levels and didn't lose weight.

Hasan hopes that both nanocells will be tested in pancreatic cancer patients within just a few years. Because Avastin and Visudyne are already FDA-approved, their two-part nanocell will likely be the first tested, probably in about two years, but perhaps as soon as a year from now, she says.

The NCI is already conducting toxicology tests of the Avastin-Visudyne nanocell as part of a new drug application to the FDA. The growth factor nanocell should enter the clinic "soon after," Hasan says. The key is finding the best MET inhibitor, and Hasan says that other researchers are already testing several promising candidates.

By Erika Jonietz

Arming the Immune System against H1N1

Viruses multiply incredibly quickly once they've infected their victim--so fast that antiviral medications such as Tamiflu are only effective if given during the first few days of an infection. After that, the viral load is just too high for a single drug to fight off. But researchers are working on a treatment for the H1N1 virus (or swine flu) that uses a different approach. Rather than disabling the virus with a drug, they're creating a vaccine that can activate and steer a patient's own immune cells to attack the invader.

Defense mechanism: Researchers creating a new vaccine against H1N1 hope to harness the power of the immune system's dendritic cells (one such cell is shown above in blue), which are responsible for directing the body's immune response.

Scientists at the Vienna, VA-based Cel-Sci have created a screening platform, called LEAPS (Ligand Epitope Antigen Presentation System) that identifies epitopes--small pieces of a virus that can be used to elicit very specific immune reactions. The DNA segments that make up these epitopes are so short--just eight to 30 amino acids long--that they can be re-created in the lab. Then the Cel-Sci researchers take those segments and attach them to another small molecule--an immune-cell-binding ligand that guides the complex straight to the immune cells in charge of initiating and directing an immune reaction.

The ligand-bound epitope is guided directly to immature dendritic cells, so named for tiny tentacles that reach out in every direction from the main cell body. Dendritic cells are the immune system's conductors, responsible for initiating and guiding the fight against invaders like the influenza virus. Immature dendritic cells are prompted to mature by the presence of these invaders; the mature dendritic cells then activate T cells, which in turn stimulate very specific immunity against the virus.

"It's like a live virus vaccine--and more effective--but without the live virus," says Kenneth Rosenthal, an immunologist at Northeastern Ohio Universities Colleges of Medicine and Pharmacy who has collaborated with the Cel-Sci team.

So far, the company has tested the LEAPS system in mice with herpes and arthritis, and found the approach to be successful in modulating the rodents' immune responses.

"The LEAPS technology allows you to drive an immune response in a desired direction," says Cel-Sci director and CEO Geert Kersten. "It's about modulating an immune response. That's important, because it's also possible to rev up the immune system and have no effect whatsoever."

Now the company is turning its attention to H1N1. In research that has been fast-tracked by the U.S. Food and Drug Administration, Cel-Sci has created a peptide that it believes will direct the human immune system to fight the virus directly. In collaboration with physicians at Johns Hopkins University's School of Medicine, researchers are collecting blood from 20 patients hospitalized with H1N1, and 20 healthy controls, then stimulating the blood with their peptide to see if they can initiate the appropriate immune responses.

"We need to find the kinds of responses that have commonly been associated with an ultimate positive outcome," Kersten says. "If we see those kinds of responses, then, based on FDA discussions, we expect to be able to do a randomized clinical trial." The group hopes to be able to move forward as soon as their results come in.

Kersten is optimistic. "We have a way, at least in other diseases, of directing the cellular immune response without the production of pro-inflammatory cytokines," he says, referring to signaling molecules that can incite unwanted inflammation. Cytokines are produced by the body's own immune cells, but when their production goes unchecked and ramps up too high, they can cause the body to overreact to a virus. Cel-Sci's approach circumvents such a response.

Cel-Sci creates its peptide using epitopes from the small segments of flu virus that don't mutate, and which could therefore be used to treat H1N1 even as it changes over the course of the year--such an approach could also be effective against other strains of flu, such as avian (H5N1) and even 1918 pandemic influenza.

Using dendritic cells to direct immune response is an attractive mechanism, says Noel Rose, director of the Center for Autoimmune Disease Research at the Johns Hopkins Bloomberg School of Public Health. "This would have applications far beyond H1N1," he says. "It would be a nice way of having a person make his own vaccine."

Rose was not involved in the trial, but his lab will analyze the cytokine results. "I have no idea what to expect, because we don't know what cytokines are going to be produced." Even so, he says, "I think it could be really interesting."

By Lauren Gravitz

First-Ever Blueprint of 'Minimal Cell' Is More Complex Than Expected

ScienceDaily (Nov. 27, 2009) — What are the bare essentials of life, the indispensable ingredients required to produce a cell that can survive on its own? Can we describe the molecular anatomy of a cell, and understand how an entire organism functions as a system? These are just some of the questions that scientists in a partnership between the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and the Centre de Regulacio Genòmica (CRG) in Barcelona, Spain, set out to address.

In three papers published back-to-back in Science, they provide the first comprehensive picture of a minimal cell, based on an extensive quantitative study of the biology of the bacterium that causes atypical pneumonia, Mycoplasma pneumoniae. The study uncovers fascinating novelties relevant to bacterial biology and shows that even the simplest of cells is more complex than expected.

This image represents the integration of genomic, metabolic, proteomic, structural and cellular information about Mycoplasma pnemoniae in this project: one layer of an Electron Tomography scan of a bottle-shaped M. pneumoniae cell (grey) is overlaid with a schematic representation of this bacterium's metabolism, comprising 189 enzymatic reactions, where blue indicates interactions between proteins encoded in genes from the same functional unit. Apart from these expected interactions, the scientists found that, surprisingly, many proteins are multifunctional. For instance, there were various unexpected physical interactions (yellow lines) between proteins and the subunits that form the ribosome, which is depicted as an Electron microscopy image (yellow).

Mycoplasma pneumoniae is a small, single-cell bacterium that causes atypical pneumonia in humans. It is also one of the smallest prokaryotes -- organisms whose cells have no nucleus -- that don't depend on a host's cellular machinery to reproduce. This is why the six research groups which set out to characterize a minimal cell in a project headed by scientists Peer Bork, Anne-Claude Gavin and Luis Serrano chose M. pneumoniae as a model: it is complex enough to survive on its own, but small and, theoretically, simple enough to represent a minimal cell -- and to enable a global analysis.

A network of research groups at EMBL's Structural and Computational Biology Unit and CRG's EMBL-CRG Systems Biology Partnership Unit approached the bacterium at three different levels. One team of scientists described M. pneumoniae's transcriptome, identifying all the RNA molecules, or transcripts, produced from its DNA, under various environmental conditions. Another defined all the metabolic reactions that occurred in it, collectively known as its metabolome, under the same conditions. A third team identified every multi-protein complex the bacterium produced, thus characterising its proteome organisation.

"At all three levels, we found M. pneumoniae was more complex than we expected," says Luis Serrano, co-initiator of the project at EMBL and now head of the Systems Biology Department at CRG.

When studying both its proteome and its metabolome, the scientists found many molecules were multifunctional, with metabolic enzymes catalyzing multiple reactions, and other proteins each taking part in more than one protein complex. They also found that M. pneumoniae couples biological processes in space and time, with the pieces of cellular machinery involved in two consecutive steps in a biological process often being assembled together.

Remarkably, the regulation of this bacterium's transcriptome is much more similar to that of eukaryotes -- organisms whose cells have a nucleus -- than previously thought. As in eukaryotes, a large proportion of the transcripts produced from M. pneumoniae's DNA are not translated into proteins. And although its genes are arranged in groups as is typical of bacteria, M. pneumoniae doesn't always transcribe all the genes in a group together, but can selectively express or repress individual genes within each group.

Unlike that of other, larger, bacteria, M. pneumoniae's metabolism doesn't appear to be geared towards multiplying as quickly as possible, perhaps because of its pathogenic lifestyle. Another surprise was the fact that, although it has a very small genome, this bacterium is incredibly flexible and readily adjusts its metabolism to drastic changes in environmental conditions. This adaptability and its underlying regulatory mechanisms mean M. pneumoniae has the potential to evolve quickly, and all the above are features it also shares with other, more evolved organisms.

"The key lies in these shared features," explains Anne-Claude Gavin, an EMBL group leader who headed the study of the bacterium's proteome: "Those are the things that not even the simplest organism can do without and that have remained untouched by millions of years of evolution -- the bare essentials of life".

This study required a wide range of expertise, to understand M. pneumoniae's molecular organisation at such different scales and integrate all the resulting information into a comprehensive picture of how the whole organism functions as a system -- an approach called systems biology.

"Within EMBL's Structural and Computational Biology Unit we have a unique combination of methods, and we pooled them all together for this project," says Peer Bork, joint head of the unit, co-initiator of the project, and responsible for the computational analysis. "In partnership with the CRG group we thus could build a complete overall picture based on detailed studies at very different levels." Bork was recently awarded the Royal Society and Académie des Sciences Microsoft Award for the advancement of science using computational methods. Serrano was recently awarded a European Research Council Senior grant.

First 'Genetic Map' of Han Chinese May Aid Search for Disease Susceptibility Genes

ScienceDaily (Nov. 26, 2009) — The first genetic historical map of the Han Chinese, the largest ethnic population in the world, as they migrated from south to north over evolutionary time, was published online November 25 in the American Journal of Human Genetics by scientists at the Genome Institute of Singapore (GIS).

Based on genome-wide DNA variation information in over 6,000 Han Chinese samples from 10 provinces in China, this new map provides information about the population structure and evolutionary history of this group of people that can help scientists to identify subtle differences in the genetic diversity of Asian populations.

DNA on abstract background. Researchers have published the first genetic historical map of the Han Chinese, the largest ethnic population in the world, as they migrated from south to north over evolutionary time.

Understanding these differences may aid in the design and interpretation of studies to identify genes that confer susceptibility to such common diseases as diabetes in ethnic Chinese individuals. Understanding these differences also is crucial in exploring how genes and environment interact to cause diseases.

With the genetic map, the GIS scientists were able to show that the northern inhabitants of China were genetically distinguishable from those in the south, a finding that seems very consistent with the Han Chinese's historical migration pattern.

The genetic map also revealed that the genetic divergence was closely correlated with the geographic map of China. This finding suggests the persistence of local co-ancestry in the country.

"The genome-wide genetic variation study is a powerful tool which may be used to infer a person's ancestral origin and to study population relationships," said Liu Jianjun, Ph.D., GIS Human Genetics Group Leader.

"For example, an ethnic Chinese born and bred in Singapore can still be traced back to his or her ancestral roots in China," Dr. Liu said. "By investigating the genome-wide DNA variation, we can determine whether an anonymous person is a Chinese, what the ancestral origin of this person in China may be, and sometimes which dialect group of the Han Chinese this person may belong to.

"More importantly, our study provides information for a better design of genetic studies in the search for genes that confer susceptibility to various diseases," he added.

Of particular interest to people in Singapore are the findings that while the majority of Singaporean Chinese hail from Southern China as expected, some have a more northern ancestral origin.

GIS Executive Director Edison Liu, M.D., said, "Genome association studies have provided significant insights into the genes involved in common disorders such as diabetes, high cholesterol, allergies, and neurological disorders, but most of this work has been done on Caucasian populations.

"More recently, Dr. Liu Jianjun from our institute has been working with his Chinese colleagues to define the genetic causes of some of these diseases in Asian populations," the GIS Executive Director added. "This work refined those tools so that the results will not be obscured by subtle differences in the genetic diversity of Asian populations. In the process, Dr. Liu has reconstructed a genetic historical map of the Chinese people as they migrated from south to north over evolutionary time."

"There are definite differences in genetic architecture between populations," noted Chia Kee Seng, M.D., Head, Department of Epidemiology & Public Health, National University of Singapore (NUS), and Director, NUS-GIS Centre for Molecular Epidemiology.

"We have seen this in the Singapore Genome Variation Project, a Joint NUH-GIS effort. Understanding these differences is crucial in exploring how genes and environment interact to cause diseases," he added.

The research results published in American Journal of Human Genetics is part of a larger ongoing project on the genome-wide association study of diseases among the Chinese population. The project is a collaboration between GIS and several institutions and universities in China.

In Jan. 2009, Nature Genetics published the findings of researchers at the GIS and Anhui Medical University, China, on psoriasis, a common chronic skin disease. In that study, led by Dr. Liu Jianjun at the GIS and Dr. Zhang Xuejun at the Anhui Medical University, the scientists discovered a genetic variant that provides protection against the development of psoriasis. The collaboration's recent discovery of over a dozen genetic risk variants for systematic lupus erythematosus (SLE) in the Chinese population was published in Nature Genetics in Oct. 2009.

How to mix oil and water

Scientists in Belgium have uncovered a new way to shake things up. Violent bouncing of a water droplet coated with oil causes the oil layer to move inside and fracture into many oily globs. In a paper published in the December Chaos, researchers at the University of Liège in Belgium call this microemulsion of oil and water the mayonnaise droplet.

Bounce and mixWith bouncing, oil coating a water droplet moves inside. A single interior oil glob (far left image) then splinters into many smaller oil globs on later bounces (middle and right panels). Bounce after bounce, oil globs shatter and mingle, creating a microemulsion

From earlier experiments, researchers knew that oily droplets bounce several times on a bed of oil before merging with the oil base. But Denis Terwagne and colleagues wanted to know what would happen to an oil-coated water droplet if the bouncing was prolonged. To find out, the team constructed a moving base that would quickly raise and lower the oil bed, similar to using a horizontal Ping-Pong paddle to keep a ball bouncing.

When the oil-coated water droplet hit the oil surface and deformed, some of the outer oil layer was ushered into the interior of the droplet. Subsequent bounces shattered this interior oil glob, creating a thoroughly mixed oil-in-water-in oil droplet, the researchers found.

Understanding the forces that govern the mayonnaise droplet may help scientists design new microfluidic systems. Bouncing droplets could enable more efficient ways to create complex mixtures of liquids, such as for cosmetics or pharmaceuticals.

By Laura Sanders

A New Spin on Electronics

You're reading this story on a computer whose chips shift tiny packets of electric charge through circuits etched in the ubiquitous semiconductor silicon. But some physicists aim to develop a whole new technology called "spintronics" that would encode information in the directions in which electrons spin as well. Those efforts could lead to ultra-low-power electronics and even futuristic quantum computers. Now, such technologies may be an important step closer to reality thanks to a group of researchers that has managed to polarize the spinning electrons in silicon, the most common commercial semiconductor.

Novel twist. Ordinary electronics uses only the electrons charge; spintronics would also encode information in an electron’s spin, which causes the particle to be magnetized along its axis.

Such "spin injection" had been achieved before in more exotic semiconductors, such as gallium arsenide and indium arsenide. The trick is to lay a patch of magnetic metal such as nickel iron on top of the semiconductor. The whole reason the metal is magnetic is that more of its electrons' spins point in one way than in the opposite way. So if a current can be driven from the metal into the semiconductor, it should deposit spin-polarized electrons in it. Physicists have shown that those electrons will hold their polarization long enough to flow micrometers through the semiconductor, which should be far enough to use them in circuits.

Incorporating both the magnetic leads and the underlying semiconductor, a spintronics circuit could hold its memory when turned off, as the magnetic elements remain magnetized. Manipulating spin could also require far less power than steering charges does, says Ron Jansen of the University of Twente in Enschede, Netherlands. Some physicists even aspire to create a spooky quantum connection called "entanglement" between spin-polarized currents to make a quantum computer that could crack problems that stymie an ordinary one.

Spin injection had been achieved at room temperature, however, only in materials like gallium arsenide. In silicon it had been done only at temperatures below 150 kelvin. Now Jansen, Saroj Dash, and colleagues at Twente have brought silicon in from the cold, too. To do that, they relied on a simple and elegant scheme to inject and detect the spins with a single nickel iron electrode separated from the silicon with a very even layer of aluminum oxide. As current flowed out of the electrode, it produced a puddle of polarized electrons in the silicon below it. But the researchers could dissipate this polarized puddle by applying a magnetic field, which for a fixed current would cause the voltage across the contact to decrease in a telltale way. And that's exactly what they observed, as the team reports tomorrow in Nature.

To prove that the voltage change wasn't caused by something else, the researchers conducted a control experiment in which they separated the aluminum oxide and the nickel iron with a layer of the metal ytterbium, which destroyed the spin polarization. In that case, the voltage across the contact remained constant even when the magnetic field was ramped up, proving that polarized electrons caused the original effect.

It's a "compelling demonstration," says Paul Crowell, a physicist at the University of Minnesota, Twin Cities. The next step, he says, is to conduct multielectrode measurements that show spin-polarized currents actually flowing through the silicon. The result raises the possibility of quick and simple spintronics applications, he says. "For a chip that needs a relatively simple memory, I think this could be realized in silicon fairly easily." But the grand goals of spintronics, such as ultralow power consumption, remain years away, Crowell says--and Jansen agrees.

By Adrian Cho
ScienceNOW Daily News
25 November 2009

Wind Turbines Take a Lesson From Lance Armstrong

Arranging wind turbines like a school of fish could reduce the amount of land they take up by 100-fold while maintaining their electrical output, say researchers. Wind farms based on the approach might also be considerably safer for migrating birds.

Whether it's Lance Armstrong bicycling behind his teammates in the Tour de France or a storm of fish slicing their way through the ocean, animals benefit from drafting. The leader breaks through the calm air or water, while the followers enjoy the reduced resistance in the leader's wake.

Wind school. Placing vertically aligned turbines closer together gives more wattage for the buck.

The same doesn't hold true for horizontal-axis wind turbines(HAWTs), the most common kind of windmill. Placing one HAWT in another's draft drastically reduces the efficiency of the trailing windmill. That's because the turbulent breeze created by the leading turbine's blades can't propel the trailing blades as well as an unobstructed airflow. So engineers spread the giant fans across hundreds of hectares of land--a practice that has created a backlash from people who find the turbines unsightly.

Turn a windmill on its side, so to speak, and the drafting benefit returns. That's what two fluid dynamicists from the California Institute of Technology in Pasadena have discovered. Robert Whittlesey and John Dabiri decided to study how a new type of generator, called a vertical-axis wind turbine (VAWT), stacked up against its more conventional counterpart. VAWTs resemble giant versions of the lawn ornaments that gardeners install to scare away birds and other veggie-loving critters (see picture). The researchers measured airflows at a prototype VAWT array in Glendora, California. They then compared that data with existing studies of how water flows through schools of swimming fish to see how geometrically arranging the arrays affected their performance.

Bunching up the vertical-axis turbines behind a leader pays off, Whittlesey and Dabiri reported yesterday at the annual meeting of the American Physical Society in Minneapolis, Minnesota. In fact, using a new mathematical model they developed from the Glendora data, the researchers found that arranging the VAWT arrays just like schools of fish produced the best results. Such tightly packed VAWT arrays can produce as much electricity as conventional windmills, all while using as little as one-hundredth of the land area. "I don't think I expected to see as great an improvement in the land use," says Whittlesey.

The study revealed that the most efficient arrangement involved alternating the rotational direction of the turbines: a clockwise rotation in the lead turbine, say, with two counterclockwise rotators next in line, followed by three clockwise rotators, and so on. Whittlesey notes that the models are preliminary, so even greater improvements might be possible with further study. And he says that the VAWT arrays could be much less deadly to birds because "the faster they spin, the more solid they appear," thereby allowing birds to see the turbines more easily and navigate around them.

The study shows "great promise," says mechanical engineer Lex Smits of Princeton University. Even if VAWT configurations achieve only half of the land-use gain as suggested, he says, "it would be a major improvement."

By Phil Berardelli
ScienceNOW Daily News
24 November 2009

A Cancer-Fighting Implant

In a new approach to fighting cancer, scientists from Harvard University have engineered an implantable disc designed to attract immune cells and prep them to attack tumors. Mice with melanoma tumors were much more likely to survive if they'd been implanted with the device, and tumors disappeared in up to half of the vaccinated animals, according to research published today in the journal Science Translational Medicine. Researchers believe that the implant elicits a broader immune response than traditional vaccines, and may therefore prove more effective. A startup called InCytu, based in Lincoln, RI, is now developing the technology for human testing.

Cancer killer: A cross section of a polymer matrix designed to prime the immune system against cancer. Immune cells crawl through the pores and are activated by chemical signals and tumor molecules.

A number of vaccines for treating different types of cancer are currently being tested in clinical trials, though none has yet been approved by the U.S. Food and Drug Administration. Unlike traditional vaccines, therapeutic cancer vaccines are designed to halt or reverse the course of the disease after it has developed. Gardasil, Merck's vaccine against the human papillomavirus, is considered a preventative cancer vaccine and acts in a similar way to traditional vaccines. It helps prevent the development of cervical cancer by stopping viral infection--but it cannot treat existing cervical cancer.

While cancer vaccines come in several variations, the general approach is to trigger the immune system to recognize and destroy cells bearing a cancer-specific marker. The immune system can be tuned to cancer cells by injecting patients with specific molecules linked to different types of cancer, or by injecting irradiated cancer cells. Scientists have also tried to enhance this process by training the immune cells in a controlled environment outside the body--the cells are isolated from the patient's blood and exposed to cancer-specific molecules. The primed immune cells are then injected back into the patient, where they travel to the lymph nodes and trigger an immune response against the However, a problem with this approach is that few cells survive the transplant process, making it difficult for the lymph nodes to mount a strong immune response. David Mooney and colleagues at Harvard University have developed an approach that allows this carefully controlled immune training to take place inside the body. A polymer scaffold, made of the same material used in biodegradable sutures and other surgical products, is impregnated with cytokines, signaling molecules produced by the immune system that attract immune cells known as dendritic cells."The cytokines diffuse into the tissue and the [dendritic] cells follow the gradient to the material and crawl right into it," says Mooney.

Vaccine disc: The disc-shaped implant is smaller than a dime.

The polymer is also packed with small fragments of genetic material designed to mimic bacterial DNA. These fragments signal to the dendritic cells that a foreign invader is present. Also present are ground-up pieces of the patient's tumor, which show the cells what to attack. The dendritic cells pick up these molecules as they move through the scaffold. The cells then travel to the lymph nodes, where they introduce the target molecules and generate an immune response. "When the implant is in the body, the immune system sees it as dangerous material and attacks it," says Tarek Fahmy, a bioengineer at Yale University who was not involved in the research.

In mice with established melanoma tumors, the vaccine significantly slowed the growth of the tumors and increased animals' survival time. In addition, tumors completely disappeared in 20 to 50 percent of animals given two vaccinations, depending on how long the tumors had been growing. Researchers say this is significant, given that most cancer vaccines considered to be effective in rodents have been shown to prevent formation of tumors rather than to diminish established tumors. However, it's difficult to compare different rodent models of cancer, which can vary widely.

The implant's effectiveness may lie in the immune response that it triggers, says Mooney. It appears to generate the formation of different types of dendritic cells, which may make the immune response more potent. It also appears to dampen a part of the immune system that typically neutralizes the response once it's been activated--maintaining an activated immune system might be important in preventing tumors from recurring. "That is very novel and extremely important for cancer immunotherapy," says Fahmy.

As is often the case with new cancer treatments, it's difficult to predict how well the findings will translate to humans. A number of cancer vaccines have shown success in animal models and then failed in human clinical trials.

By Emily Singer

Origami Solar Cells

One way to squeeze more power out of sunlight is to ensure that it always hits a solar panel at the ideal angle. This means either tracking the sun and maneuvering a panel to face it, or using complex optics to redirect the sun's rays to hit the panel's surface from above.

Researchers at the University of Illinois have now come up with self-assembling spherical solar cells capable of capturing more sunlight than flat ones. The shape is a simpler way to make more use of the sun's rays, but has been difficult to realize in a solar cell. These new microscale solar cells are made using conventional lithography combined with self-assembly. If they prove practical, the devices could be wired up into large arrays that have the same power output as conventional cells, but that save on materials costs by using less silicon.

Fold-up silicon: In these images, three thin films of silicon fold up into 3-D shapes under the force of surface tension as water droplets placed in their centers evaporate. The top row depicts the first step, when the water droplets are large, and the images below it show a time progression as the water droplets shrinks.

"Instead of a big slab of semiconductor fitted with concentrating lenses and motors to move it around, we want to make compact cells that still have a significant power output," says Ralph Nuzzo, professor of chemistry at the University of Illinois at Urbana-Champaign.

Curved surfaces capture more light than flat ones because they have a greater surface area. But making solar cells that are curved or spherical is challenging, says Nuzzo, because the techniques used to process semiconducting materials such as silicon work best on flat surfaces. Nuzzo's group has overcome this problem by making microscale 3-D structures that self-assemble from flat sheets.

The Illinois researchers start by treating the surface of a thin, high-quality silicon wafer and using conventional lithography to etch out a thin, two-dimensional shape. To make a sphere, the researchers cut the silicon into a flower shape. They then use an adhesive to secure a small piece of glass inside. The glass helps the structure maintain its shape once it is assembled. Finally, as a drop of water placed in the center of the flower shape evaporates, surface tension pulls its petals up, eventually bringing them together to form a sphere.

"The challenge in this is, how do you get things to follow the necessary sequence of steps to fold into the desired shape?" says Nuzzo. The Illinois group came up with mathematical models to help predict the mechanical properties of silicon sheets of different shapes and thicknesses, as well as how they interact with water, which can be tuned by chemically treating their surfaces.

Nuzzo's group used the techniques to make functioning microscopic spherical solar cells, as a proof of the functionality of what he calls "materials origami." Before cutting the silicon into the petal shape, the team treated it to form the conductive regions that make a solar cell work. After the flower had folded up into a sphere, electrical contacts were added. The group used a similar technique to make cylindrical micro-solar cells as well.

These devices convert only about 1 percent of the light that hits them into electricity--a poor return for a solar cell--but this is better than a planar solar cell made using the same relatively crude techniques using the same amount of silicon. The researchers say the technique can be applied to other materials besides silicon, and could be used to make new forms of solar cells. The work is described online this week in the Proceedings of the National Academy of Sciences.

"Folding is very appealing because you can make fantastic, complicated three-dimensional shapes," says George Barbastathis, professor of mechanical engineering at MIT.

There are other ways of improving solar cells' ability to capture light, such as antireflective coatings and surface texturing. The main advantage of the new approach is that it requires less material, says Nuzzo. Planar solar cells just a few micrometers thick can't be textured--there's simply not enough material. And antireflective coatings add more manufacturing costs and complexity. Self-assembly, Nuzzo hopes, could offer an alternative.

The Illinois group will now work to improve the process, and make designs that further improve the cells' light management. "We want to bring forward form factors that rely on high performance materials like silicon but provide a substantial economy" by using as little of these expensive materials as possible, says Nuzzo.

By Katherine Bourzac

IBM's Move in Microfluidics

Researchers at IBM have demonstrated a novel "lab on a chip" that uses capillary action to create a potential one-step diagnostic tool, and which could ultimately test for a wide range of diseases and viruses.

Capillaries in action: The sample collector section of a new microfluidic lab on a chip consists of a network of microscopic channels. Capillary action causes serum from a drop of blood to be drawn into the diagnostic device.

The chip requires only a small drop of blood, which it draws through tiny channels within the device. The blood reacts with different disease markers to provide accurate diagnoses in about 15 minutes, says Emmanuel Delamarche, who codeveloped the device at IBM Zurich Research Laboratory in Switzerland.

A nice thing about the new chip is that it involves no moving parts, says IBM's Luc Gervais, who is also a researcher at the University Hospital Basel. Instead, it works using capillary action to filter blood and pump serum through its various chambers.

IBM is an important player in the field of microfluidics, says Jikui Luo, a microfluidics expert at the UK-based Centre for Materials Research and Innovation at the University of Bolton. However capillary driven microfluidic devices are nothing new, he says. "There is a trend toward this sort of moving-part-free device." With no mechanical parts or membranes to pump the fluid, such devices are potentially more reliable, says Luo.

Within its new device, the IBM team has engineered capillary-driven pumps and valves to precisely control the fluid flowing through it. Consumer pregnancy tests use a similar yet simpler approach, says Gervais. But the IBM chip has the potential to test for multiple diseases simultaneously and can give a quantitative response, rather than a simple yes or no, he says. "If a patient has just had a heart attack, a yes or no test is not going to help determine the best course of action," says Gervais. "This [IBM chip] pushes point-of-care diagnostics to the next level."

In their prototype, the IBM researchers created a network of channels, some as narrow as 30 micrometers, with various detection and reaction chambers. As the filtered serum passes through these sections, antibodies embedded within the walls of the channel bind to any disease markers present in the blood. In the case of the prototype, the researchers used a marker commonly used for detecting inflammation and for assessing myocardial damage following heart attacks.

Central deposition zone: Serum passes through a flow resistor (shown as first coil) to control the speed of the blood’s flow, before passing into a zone lined with biomarker-seeking antibodies.

In the final stage, these tagged markers are captured by a different set of antibodies, which hold them in place so they can be measured. This is done with a separate device called a fluorescence reader, commonly found in hospitals, which illuminates the chip and measures the amount of fluorescent light given off by the markers. The work is published in the latest issue of the journal Lab on a Chip.

"This work is very interesting," says Juan Santiago, head of the Stanford Microfluidics Laboratory. Not only have the IBM researchers shown that their device can cope with filtering blood, but given the chip's precise control over the liquid, it might also carry out multiple tests in parallel, or even in series of multistage reactions, he says.

IBM is working with Belgian diagnostics firm Coris BioConcept to assess the accuracy of the chips by comparing them directly with traditional laboratory-based testing. "The next step is to develop a pilot series of maybe a thousand devices and test them on samples from hospitals," says Delamarche.

By Duncan Graham-Rowe

Practical Nanotube Electronics

Carbon nanotubes are a promising material for making display control circuits because they're more efficient than silicon and can be arrayed on flexible surfaces. Until recently, though, making nanotubes into transistors has been a painstaking process. Now researchers at the University of Southern California have demonstrated large, functional arrays of transistors made using simple methods from batches of carbon nanotubes that are relatively impure.

Nanotube array: This photo shows a three-inch silicon wafer covered with an array of carbon-nanotube transistors. Though these transistors were made using simple processes at room temperature, their performance is good enough to drive display pixels.

The pixels in a computer or television screen, whether it's an LCD or plasma, are each controlled by several transistors. In today's devices, these transistors are made from silicon. Arrays of these transistors need to be made at high temperatures and in a vacuum, so they're very expensive, says Chongwu Zhou, an associate professor of electrical engineering at USC and researcher on the nanotube project.

Transistors have also been made from carbon nanotubes, but that, too, presents challenges. "Many people use one nanotube to make a very small, high-performance transistor" for computer chips, says Zhou. But that one-to-one ratio won't work for displays, in which a large surface must be covered in transistors. "If we use one nanotube for one transistor, the yield will never be high enough" to work for large-scale manufacturing of big screens, he says. Zhou believes his approach will solve this problem by making larger transistors from mats of nanotubes.

The USC researchers make large arrays of carbon nanotube transistors using solution-processing techniques at room temperature. They start by placing a silicon wafer in a chemical bath to coat its surface with a nanotube-attracting chemical, then rinse off the residue. The treated wafer is then immersed in a solution of semiconducting carbon nanotubes, which are attracted to its surface. The wafer, now coated with a carpet of nanotubes, is rinsed clean again. To make transistors from this tangled mess, the researchers put down metal electrodes at selected locations. The electrodes define where each transistor is and carry electrons into and out of the nanotubes that lie between them. Areas of silicon underlying each device act as the transistors' gates. So far, they've built a prototype device on a four-inch silicon wafer and used it to control a simple organic light-emitting diode display. This work is described online in the journal Nano Letters.

Other researchers have made transistors from nanotube carpets using solution-processing, but these projects started from mixtures of conducting and semiconducting nanotubes, leading to very poor performance. And late last year, researchers at IBM and Northwestern University used highly purified semiconducting nanotubes to make higher-performance transistor arrays in which all the nanotubes line up in nearly straight lines, which improves their electrical properties.

The significance of the USC work is that it shows that arrays made from only 95 percent semiconducting nanotubes that aren't aligned still have good enough performance for displays, says Zhou.

"This is the first time someone has shown solution-deposited, purified semiconducting tubes for high-quality transistors," says John Rogers, professor of materials science and engineering at the University of Illinois at Urbana-Champaign. "The accomplishment is in the integration of several promising approaches to demonstrate a full sequence for the fabrication of electronics."

Now that his group has demonstrated the feasibility of these techniques, Zhou says, it's working to build a truly integrated organic LED display that is flexible and transparent. Such a display might be rolled up to fit in a pocket, or mounted on a car windshield to display information to the driver. The first step is eliminating the rigid silicon. Because the nanotubes may be laid down at room temperature, the USC researchers can build them on electrically active plastic sheets that can't tolerate high temperatures. They're also working to replace the stiff metal electrodes with a coating of indium tin oxide, a commonly used, flexible, transparent electrode material. In their prototype, the organic LED pixels are connected to the transistor array by wires; to integrate them they'll need to come up with methods for building the LEDs on top of the control circuit.

Zhou says he is talking with display companies about commercializing these methods. Korean display giant LG has demonstrated interest in carbon nanotube electronics, and IBM researchers have been publishing on the topic. However, the only company to come out with a nanotube electronic product so far is the Menlo Park, CA startup Unidym, which makes electrodes from the material.

Researchers in the field have been talking about nanotube displays for years, and the holdup, says Mark Hersam of Northwestern University, has been the lack of a big enough supply of semiconducting carbon nanotubes. In 2006, materials science professor Hersam developed a simple method for purifying nanotubes based on their properties by centrifuging them in a soapy solution. He then founded a company, called NanoIntegris, which has been supplying semiconducting nanotubes to groups including Zhou's and the research team at IBM. A newly formed company in China and one in Japan are also supplying the semiconducting nanotubes needed for making transistor arrays to control displays.

With this supply in place, says Hersam, it's only a matter of time before a company comes out with a product, whether it's made using a method like Zhou's or some other method. "I'm confident there will be a suite of products in the foreseeable future," says Hersam. "It's a matter of going from prototyping to market."

By Katherine Bourzac

Demonstrating a CO2 Recycler

Researchers at Sandia National Laboratories have successfully demonstrated a prototype machine that uses the sun's energy to convert water and carbon dioxide into the molecular building blocks that make up transportation fuels. The "Sunshine to Petrol" system could ultimately prove a practical way to recycle CO₂ from power and industrial plants into gasoline, diesel, and jet fuel, assuming the process can become at least twice as efficient as natural photosynthesis.

Sun to syngas: This prototype, known as the CR5, was designed by Sandia researchers to convert carbon dioxide into carbon monoxide, or water into hydrogen, using concentrated solar energy. The carbon monoxide and hydrogen can be combined later to produce syngas, a building block for most transportation fuels. The first working prototype, shown above, has demonstrated that the process works, but efforts are underway to make it more efficient.

Until recently, the system had only been validated in a laboratory in small batches. A hand-built demonstration machine was successfully tested this fall. "This is a first-of-its-kind prototype we're evaluating," says Sandia researcher Rich Diver, inventor of the device.

"In the short term we see this as an alternative to sequestration," says James Miller, a chemical engineer with Sandia's advanced materials laboratory. Instead of just pumping CO2 underground for permanent storage, Miller says, the sun's abundant energy can be used to achieve "reverse combustion" that essentially turns carbon dioxide back into a fuel. "It's a productive utilization of CO2 that you might capture from a coal plant, a brewery, and similar concentrated sources."

The cylindrical metal machine, called the Counter-Rotating-Ring Receiver Reactor Recuperator (CR5), relies on concentrated solar heat to trigger a thermo-chemical reaction in an iron-rich composite material. The material is designed to give up an oxygen molecule when exposed to extreme heat, and then retrieve an oxygen molecule once it cools down.

The machine is designed with a chamber on each side. One side is hot, the other cool. Running through the center is a set of 14 Frisbee-like rings rotating at one revolution per minute. The outer edge of each ring is made up of an iron oxide composite supported by a zirconium matrix. Scientists use a solar concentrator to heat the inside of one chamber to 1,500 º C, causing the iron oxide on one side of the ring to give up oxygen molecules. As the affected side of the ring rotates to the opposite chamber, it begins to cool down and carbon dioxide is pumped in. This cooling allows the iron oxide to steal back oxygen molecules from the CO₂, leaving behind carbon monoxide. The process is continually repeated, turning an incoming supply of CO2 into an outgoing stream of carbon monoxide.

Miller says the same process can be used to produce hydrogen, the only difference being that water, instead of carbon dioxide, is pumped into the second chamber. The two separately retrieved gases--hydrogen and carbon monoxide--are then mixed together to make syngas, which can be used to make a "drop-in replacement" for traditional fuels, says Miller.

Diver originally designed the machine with the hydrogen economy in mind. The idea was to avoid the inefficiency of electrolysis and build instead a solar heat engine that could produce hydrogen and oxygen directly, cutting out electricity as the middleman. It's an approach also being pursued by researchers in Japan, France, and Germany.

But the Sandia team soon realized that the same process could turn CO2 into carbon monoxide. Even if the hydrogen economy didn't take off, they still had a way to make the fuels we depend on today in a way that limits the impact of burning coal and natural gas for electricity and other industrial processes.

Diver says the challenge now is to improve the efficiency of the system. If the Sandia team can demonstrate higher efficiency, "it could be a significant step forward," said Vladimir Krstic, director of the Centre for Manufacturing of Advanced Ceramics and Nanomaterials at Queen's University in Kingston, Ontario.

Scientists figure it will be 15 to 20 years before the technology is ready for market. In the meantime, the goal is to develop a new generation prototype every three years that shows an increase in solar-to-fuel conversion efficiency and a decrease in cost. Part of that will come from the development of new ceramic composites that release oxygen molecules at lower temperatures, allowing for more of the sun's energy to be converted into hydrogen or carbon monoxide.

"Our short-term goal is to get this to a few percent efficiency," says Miller. "It might seem like a low number, but we like to compare that to photosynthesis, which is actually a very inefficient way to use sunlight."

He says the theoretical maximum efficiency for photosynthesis is around 5 percent, but in the real world it tends to fall to around 1 percent. "So we may be starting very low, but we'd like to keep it in the context of what we have to beat. Ultimately, we believe we have to get in the range of 10 percent sunlight-to-fuels, and we're a long way from doing that."

By Tyler Hamilton

How Crystals Get Their Groove Back

If you ever took a chemistry lab class in college, chances are you once stared desperately at a flask of liquid, crossing your fingers for tiny crystals to appear. Your lab instructor may have offered advice that sounded like voodoo: "Scratch the inside of the flask to make the crystal grow." But the trick worked--and now scientists have uncovered new details behind it.

Better angle. Computer-simulated molecules crystallize faster in the more comfy 70-degree groove (left) than the cramped 45-degree wedge (right).

Compared with the fast wiggling and whizzing of molecules, crystallization takes forever. A crystal has a specific, ordered pattern, and it’s quite unlikely that a disorganized soup of molecules will suddenly reach that state. But once the molecules start to organize themselves, a process called nucleation, they act as a template for others to get in line--and crystallization takes off. Grooves and pits in glass surfaces help crystals grow faster, because they act as nucleation hot spots. Chemists have known why for decades: The interface between crystal and liquid is unstable, and grooves minimize this interface.

To learn more about how these grooves aid nucleation, physical chemists Amanda Page and Richard Sear of the University of Surrey in the United Kingdom ran computer simulations of droplets of simple molecules such as argon or methane inside v-shaped grooves. The researchers recorded how long nucleation took as they changed the groove's angle. The optimal angle was about 70 degrees, the scientists report online this month in the Journal of the American Chemical Society. Nucleation occurs 48 orders of magnitude faster at this angle than it does on a flat surface.

The reason why one angle is optimal, the researchers found, has to do with the three-dimensional repeating pattern the molecules make in the crystal. The simulated argon and methane molecules in this study, for example, like to assemble into a type of pattern called a face-centered cubic lattice, which fits comfortably into the 70-degree wedges. Other groove angles, such as 45 degrees, force the molecules to disrupt their preferred pattern (see picture), slowing crystallization. "The crystal says, 'I want to be 70 degrees,' and the wedge says, 'No, you have to be 45 degrees,' " Sear says. "So there's frustration."

A surprising result from these simulations is that crystals of simple molecules need only a simple-shaped template to help them nucleate, says theoretical chemist Peter Harrowell of the University of Sydney in Australia: "It will be an eye opener for people."

Still, notes Sear, a 70-degree groove won't work for all molecules. Complex molecules such as drugs can crystallize into more than one pattern, for example. That has practical consequences; because some crystal lattices are more soluble than others, the right crystalline shape can influence how much of a drug enters the bloodstream. In 1998, the drug company Abbott discovered that a less-soluble crystalline form of the HIV drug ritonavir was rampant in their production lines, forcing them to rework how they made the drug. Designing apparatuses that have nano-sized grooves with specific shapes might help favor the crystals drugmakers want over those they don't, Sear says.

By Michael Torrice
ScienceNOW Daily News
20 November 2009

Ants Eat Well, Thanks to Bacteria

Tropical leaf-cutter ants can't eat without a little help from their microbial friends. The insects drag inedible leaves into their massive subterranean lairs, where "gardens" of fungi break them down into a palatable, spongy white material. Meanwhile, bacteria keep the fungi healthy by secreting antibiotics. Now, it turns out that another microbe is needed to ensure that the ant has a balanced diet.

Microbial farm. A leaf-cutter queen ant tends her colony's fungus garden filled with a hodgepodge of microbes.

Leaves are rich in sugars, but they're low in a crucial nutrient: nitrogen. Some experts wondered whether the ants met their nitrogen needs by simply harvesting tons of leaves and then throwing away the excess. But evolutionary biologist Cameron Currie of the University of Wisconsin, Madison, couldn't believe that insects so efficient in their division of labor would be so inefficient in their eating habits. So he and colleagues decided to look for another source of nitrogen.

To rule out that nitrogen wasn't coming from the ground, the researchers collected ant colonies with their gardens and put them in plastic containers. Here, the only nitrogen source was the air, yet the leaves' nitrogen content still increased by 77% after passing through the garden. Further investigation revealed two genera of nitrogen-fixing bacteria living in the fungal gardens. These bacteria convert nitrogen from the air into ammonia, which organisms can use to synthesize proteins. "We expected the fixers to be inside the ants' guts," as with the microbes termites use to get nitrogen, says Currie. "But ... the garden really is an external digestive system, so it makes sense for the fixers to be in the garden."

To see how much nitrogen the ants get from these microbes, Currie and colleagues measured the ants' levels of an isotope, nitrogen-15, which accumulates as organisms move up the food chain. The insects receive between 45% and 61% of their nitrogen from their bacterial friends, the team reports tomorrow's issue of Science. Over a year, a mature leaf-cutter colony may pull down about 1.8 kilograms of nitrogen from the air--equivalent to the nitrogen in 10,000 square meters of surrounding tropical soil. That may be why trees in the tropics clump around leaf-cutter nests, snaking their roots into the ants' dumps, Currie says.

The discovery of another symbiotic microbe in leaf-cutter ant fungal gardens is "very exciting," says etymologist Ted Schultz of the Smithsonian Institution in Washington, D.C. "When I first got into this stuff, we thought it was a ... two-partner symbiosis. It's turning out to be very complicated."

By Michael Torrice
ScienceNOW Daily News
19 November 2009

Herpes Never Sleeps

Genital herpes comes and goes--at least that's what it looks like to patients. But a mathematical model published in the 18 November issue of Science Translational Medicine suggests that herpes never slumbers. Instead, nerve cells continuously pump out the virus in minuscule quantities over a sufferer's lifetime. If the findings hold, it may be much harder to stop patients from passing on the infection than researchers thought.

Busybody. A new study suggests HSV-2, seen here as orange particles, is constantly active even when patients don't have symptoms.

As many as one in five people is permanently infected with herpes simplex virus 2 (HSV-2), the most common cause of genital skin ulcers. The virus is transmitted during sex; after infection, it retreats into nerve cells that have their endings in the genital skin. HSV-2 causes no problems in up to 80% of those infected, but a minority suffers from blisters and sores once or twice a month. For decades, most scientists believed that the virus was simply "off" in the intervals between outbreaks, says William Halford, who studies herpes at Southern Illinois University School of Medicine in Springfield.

But that view has come under fire the past decade or so, as researchers showed that the virus is sometimes present in the genital skin even when no lesions are apparent. The new work, by infectious diseases researcher Lawrence Corey and his colleagues at the University of Washington and the Fred Hutchison Cancer Research Center, both in Seattle, goes even further.

Joshua Schiffer, a clinician and mathematical modeler in Corey's group, constructed mathematical models from a large amount of virological and patient data--including the amount of virus present in the skin of patients who took four swabs daily for 60 days. This is what appears to be going on: Nerve cells shed tiny amounts of virus almost constantly inside the genital skin. Frequently, a virus will infect an epithelial cell, which compared with a nerve cells are "real virus factories," says Schiffer: They produce massive amounts of virus that can infect other nearby epithelial cells and can presumably also infect sexual partners. In most cases, infected epithelial cells are quickly killed by CD8+ cells, a type of white blood cells; only occasionally does the infection overwhelm the immune system, resulting in a lesion.

"It's impressive that they were able to build a model that makes sense of a large amount of clinical data," says Philip Krause, a herpes researcher at the U.S. Food and Drug Administration. "It's a very thoughtful way of looking at the data." Halford says the paper should help dispel the notion, still supported by many herpes scientists, that the virus "does nothing" between clinical episodes.

The findings may also explain some properties of antiherpes drugs like acyclovir, says Schiffer. For instance, in a trial where herpes patients took acyclovir to prevent their partners from becoming infected, the drug was only 50% effective. If virus shedding never stops, these drugs have a much harder job, says Schiffer, especially compounds like acyclovir that quickly disappear from a patient's body. To really prevent transmission, drugs would have to last longer or stop the shedding by the nerve cells, he adds--but that's a tall order.

By Martin Enserink
ScienceNOW Daily News
18 November 2009

Meditation Halves Risk of Heart Attack

Meditation can cut the risk of heart attack, stroke, and death by almost 50% in patients with existing coronary heart disease, according to a new clinical trial. The findings indicate that relaxation and mental focusing can be as effective as powerful new drugs in treating heart disease.

Over the past 4 decades, scientists have found many hints that transcendental meditation--the most widely used meditation technique--can confer a variety of health benefits. The technique, which was invented by an Indian guru named Maharishi Mahesh Yogi and grew to popularity after the Beatles practiced it in the 1960s, requires the practitioner to focus on repetitions of a single sound or mantra, such as a phrase from Hindu scripture. Transcendental meditation has been shown to decrease blood pressure, reduce stress, and improve mental focus in college students. It's unclear, however, whether any of these benefits translate to overall health.

In the first study to test the effect of transcendental meditation on the risk of heart attack, preventive medicine specialist Robert Schneider of the Maharishi University of Management in Fairfield, Iowa, collaborated with endocrinologist Theodore Kotchen of the Medical College of Wisconsin in Milwaukee. They enlisted 201 patients with narrowed coronary arteries--a risk factor for heart attack and stroke. All volunteers were African American, a high-risk group for heart disease.

The patients were randomly assigned to two groups, both of which were given a standard treatment of prescription drugs for high blood pressure and atherosclerosis, as well as an educational course in cardiovascular health. The team asked one of the groups to also practice transcendental meditation for 15 to 20 minutes a day, following instructions from meditation experts.

Over 5 years (and up to 9 years for some patients), the patients who practiced transcendental meditation on top of standard treatment experienced 47% fewer heart attacks, strokes, and deaths compared with the control group. For comparison, statin drugs, which reduce cholesterol levels, tend to lower the risk of life-threatening events by 30% to 40% relative to existing treatments. Common blood pressure drugs reduce these outcomes by 25% to 30%. In all, transcendental meditation has proved as powerful as any new class of heart disease medications entering the market, says Schneider.

The reason for such a dramatic improvement isn't obvious, but the researchers note that the meditating patients had lower blood pressure, a key risk factor for heart attacks and stroke. Past studies have also indicated that meditation reduces stress hormone levels and dampens the sympathetic nervous system, which triggers the body's stress response. "We've shown that the brain has a direct positive influence on clinical outcomes," says Schneider, whose team presents its findings today at the annual meeting of the American Heart Association in Orlando, Florida.

The study is "excellent work" and a "great start," says cardiologist Sabahat Bokhari of the Columbia University College of Physicians and Surgeons in New York City. However, the dramatic improvements seen in the trial may not translate to other ethnic groups, he cautions, especially those at much lower risk of heart disease than African Americans.

Cardiologist Herbert Benson of the Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital in Boston also praises the study, but he says that other stress-reducing techniques, such as yoga or even prayer, may have just as powerful an effect.

By Jue Wang
ScienceNOW Daily News
16 November 2009

A 25-Year Battery

Batteries that harvest energy from the nuclear decay of isotopes can produce very low levels of current and last for decades without needing to be replaced. A new version of the batteries, called betavoltaics, is being developed by an Ithaca, NY-based company and tested by Lockheed Martin. The batteries could potentially power electrical circuits that protect military planes and missiles from tampering by destroying information stored in the systems, or by sending out a warning signal to a military center. The batteries are expected to last for 25 years. The company, called Widetronix, is also working with medical-device makers to develop batteries that could last decades for implantable medical devices.

Nuclear power: The package inside this prototype betavoltaic battery contains layers of silicon carbide and metal foil embedded with the radioactive isotope tritium. When high-energy electrons emitted by the decay of tritium hit the silicon carbide, it produces an electrical current that exits the cell through the metal pins. Such batteries are designed to last 25 years.

Widetronix's batteries are powered by the decay of a hydrogen isotope called tritium into high-energy electrons. While solar cells use semiconductors such as silicon to capture energy from the photons in sunlight, betavoltaic cells use a semiconductor to capture the energy in electrons produced during the nuclear decay of isotopes. This type of nuclear decay is called "beta decay," for the high-energy electrons, called beta particles, that it produces. The lifetimes of betavoltaic devices depend on the half-lives, ranging from a few years to 100 years, of the radioisotopes that power them. To make a battery that lasts 25 years from tritium, which has a half-life of 12.3 years, Widetronix loads the package with twice as much tritium as is initially required. These devices can withstand much harsher conditions than chemical batteries. This, and their long lifetimes, is what makes betavoltaics attractive as a power source for medical implants and for remote military sensing in extremely hot and cold environments.

The concept of betavoltaics is about 50 years old. The first pacemakers used betavoltaics based on the radioactive element promethium, but these betavoltaics were phased out when cheaper lithium-ion batteries were developed. The technology is now reemerging, says Peter Cabauy, CEO of another betavoltaic company, Miami-based City Labs, because semiconducting materials have improved so much. Early semiconducting materials weren't efficient enough at converting electrons from beta decay into a usable current, so they had to use higher energy, more expensive--and potentially hazardous--isotopes. More efficient semiconducting materials can be paired with relatively benign isotopes such as tritium, which produce weak radiation.

Widetronix's batteries are made up of a metal foil impregnated with tritium isotopes and a thin chip of the semiconductor silicon carbide, which can convert 30 percent of the beta particles that hit it into an electrical current. "Silicon carbide is very robust, and when we thin it down, it becomes flexible," says Widetronix CEO Jonathan Greene. "When we stack up chips and foils into a package a centimeter squared and two-tenths of a centimeter high, we have a one microwatt product." The prototype being tested by Lockheed Martin produces 25 nanowatts of power.

Betavoltaics aren't very powerful. They don't have nearly enough power to drive a laptop or a cell phone. But their energy density is high: they store a lot of energy in films just micrometers thick and can be made in very small packages. "We're focusing on places where you need a very long life and energy density," says Greene.

One such place is the monitoring of military equipment. "Everything the Department of Defense puts out has to have antitamper protection so that if someone gets their hands on the seeker head of a missile, or an entire aircraft, it would be very difficult to reverse-engineer it," says Christian Adams, a chemist at Lockheed Martin Missiles and Fire Control. The memory chips that control such antitamper systems, says Adams, require very low continuous power over a long time. Military specifications also require that these devices withstand extreme conditions that normal batteries can't tolerate: they must operate in temperatures from -65 to 150 ˚C and withstand high-frequency vibrations, high humidity, and blasts of salt. "If the battery freezes out or dies out, the memory circuit loses its configuration," and the device fails, says Adams.

"Widetronix is the first out of the gate with something that can be tested to military specifications," says Adams. Lockheed received the company's prototypes last week. If the betavoltaics pass the test, Lockheed will probably have them in antitamper products in about a year's time, he says. Lockheed is also working with the company to develop higher-power betavoltaics for remote monitoring of missiles. Sending out a radio signal to say "I'm healthy" requires microwatts of power, says Adams. Widetronix is also testing its batteries with medical-device company Welch Allyn. It expects to sell the batteries for $500.

City Lab's Cabauy says that though the prospect of nuclear batteries, especially for medical implants, may raise eyebrows, tritium is safe. Besides the beta particle, other products of tritium's decay are an antineutrino and an isotope of helium that is not radioactive. "A piece of paper can stop the radiation from tritium," says Cabauy.

The future promise of betavoltaics might be in very cheap sensors embedded in buildings and bridges where "you don't ever want to change the battery," says Amit Lal, professor of electrical and computer engineering at Cornell University. However, this would require companies such as Widetronix to move to longer half-life materials, such as nickel isotopes that last 100 years. While tritium has a half-life of only 12.3 years, one of its chief advantages, besides safety, is that it can be secured cheaply from Canadian nuclear reactors that produce heavy water as a by-product. Longer half-life isotopes such as nickel-63 must be purchased abroad at high prices. "Since the end of the Cold War, there is no government support for radioisotope infrastructure in the United States," says Lal. "Making batteries that last forever is probably good reason to build that infrastructure."

By Katherine Bourzac

New Hope for Neuron Protection

Finding a cure for amyotrophic lateral sclerosis (ALS)--also known as Lou Gehrig's disease--has been a frustrating and elusive quest. Even after decades of research, the biological roots of ALS are only partially understood. Now a new form of treatment offers fresh hope.

Trophos, a company based in Marseilles, France, has discovered a drug compound that appears to protect neurons from the effects of ALS, a rapidly debilitating degeneration of motor neurons in the brain and spinal cord. These effects lead to muscle atrophy and, ultimately, complete loss of motor control. The company's researchers have found that a compound named olesoxime promotes survival and regeneration of neurons deprived of neurotrophic factors--proteins essential for maintaining healthy neurons. This deprivation is similar to what occurs in the neurons of ALS patients.

The company is currently conducting Phase II clinical trials to test the drug's efficacy in ALS patients. Although the compound's mechanism of action isn't exactly clear, researchers believe it acts like a molecular "stopper," preventing motor neurons from dying off by blocking a key structure that triggers the degeneration of nerve cell mitochondria.

For the past decade, researchers have increasingly focused on mitochondria as a potential target for treating ALS and other neurodegenerative diseases. Often referred to as the powerhouse of cells, mitochondria churn out ATP, a nucleotide that transfers the energy needed by cells. Researchers have found that in ALS patients, something causes the mitochondria to swell up and burst. Scientists believe that the accumulation of dead mitochondria deprives neurons of energy. This causes the neurons to die and thus lose their connection with associated muscles.

It's unclear how mitochondria become dysfunctional in ALS patients in the first place, but over the past two years, scientists have identified a tiny pore within a membrane that may act as a fatal floodgate, letting in unwanted molecules that destabilize mitochondria. This gateway, called the mitochondrial permeability transition pore (mPTP), forms when two proteins within the inner and outer membrane come together. The resulting channel lets in a flood of calcium and other molecules, the source of the swelling in mitochondria.

Lee Martin, a professor of pathology and neuroscience at Johns Hopkins University in Baltimore, who was not involved with the research, says this mitochondrial opening may have evolved in order to get rid of damaged cells and make way for new, healthy cells. However, in diseases such as ALS, membrane proteins may come together more often, and the resulting pore may stay open longer than normal, causing otherwise healthy mitochondria and neurons to die off. "Normally this pore is in a state of flicker," says Martin. "However, in disease states, this flicker may be transformed into a more permanent, more stable opening, and this is really bad."

Martin and others believe that designing drugs to block mPTP from forming may prevent neuron death, and thus slow the progression of diseases such as ALS, Huntington's, and Parkinson's disease. Scientists at Trophos have found that olesoxime binds with a membrane protein in mitochondria that is responsible for forming mPTP. "Our compound binds to the outer membrane of mitochondria, and prevents the pore from opening in pathological conditions," says Trophos CEO Damian Marron. "This is how we believe [the compound] prevents neuronal cell death."

The company screened thousands of compounds before discovering the drug. The researchers' method involved depriving motor neurons of their neurotrophic factors in order to produce neurons that resemble those found in ALS. They then studied the effects of thousands of compounds on these neurons, and found that olesoxime, a cholesterol-like molecule, was best at promoting neuron survival and growth.

In tests on mice with ALS, olesoxime significantly improved survival rates. Researchers went on to determine the drug's safety performance in healthy volunteers and ALS patients. The company determined the drug to be safe in both groups, and is now going forward with an 18-month clinical trial in Europe, testing the drug's efficacy in 480 ALS patients.

Marron says that in the European trial, the compound will be used in combination with riluzole, the only drug currently approved by the U.S. Food and Drug Administration to treat ALS. Riluzole, which is marketed as Rilutek in the United States, has been found to increase survival in patients by three to five months. "What we're looking for is a 12 percent improvement over 18 months, which is a six-to-nine-month increase in survival in patients," says Marron. "We've set a high hurdle, but we feel that if that could be provided, it would be clinically worthwhile."

Other researchers caution that there is more work to be done to tease out the exact mechanism of the drug. "This molecule has great potential for delaying the disease progress in ALS patients, but still, there is a lot more to be done," says Hemachandra Reddy, assistant professor of physiology and pharmacology at Oregon Health and Science University, who investigates the role of mitochondria in neurodegenerative diseases. "If we know the mechanism, then this molecule can be used not just for ALS patients, but also for a broad range of diseases like Parkinson's and Huntington's."

By Jennifer Chu

P4P Remodels File Sharing

"Peer-to-peer" (P2P) is synonymous with piracy and bandwidth hogging on the Internet. But now, Internet service providers and content companies are taking advantage of technology designed to speed the delivery of content through P2P networks. Meanwhile, standards bodies are working to codify the technology into the Internet's basic protocols.

Rather than sending files to users from a central server, P2P file-sharing networks distribute pieces of a file among thousands of computers and help users find and download this data directly from one another. This is a highly efficient way to distribute data, resistant to the bottlenecks that can plague centralized distribution systems, but it uses large amounts of bandwidth. Even as P2P traffic slowly declines as a percentage of overall Internet traffic, it is still growing in volume. In June, Cisco estimated that P2P file-sharing networks transferred 3.3 exabytes (or 3.3 billion trillion bytes) of data per month.

While a PhD student at Yale University in 2006, Haiyong Xie came up with the idea of "provider portal for peer-to-peer," or P4P, as a way to ease the strain placed on networking companies by P2P. This system reduces file-trading traffic by having ISPs share specially encoded information about their networks with peer-to-peer "trackers"--servers that are used to locate files for downloading. Trackers can then make file sharing more efficient by preferentially connecting computers that are closer and reducing the amount of data shared between different ISPs.

During its meetings last week in Japan, the Internet Engineering Task Force, which develops Internet standards, continued work on building P4P into standard Internet protocols. However, Xie believes that those efforts will take two or three more years to come to fruition. In the meantime, he says, many P2P application makers and Internet carriers are already implementing their own versions of P4P.

Pando Networks, which facilitates Internet content delivery, was the first company to adopt P4P techniques. In collaboration with Xie, Pando worked with Verizon, Telefónica, AT&T, and Comcast to run two sets of P4P tests last year; the results showed that P4P could speed up download times for file sharers by 30 percent to 100 percent, while also reducing the bandwidth costs for ISPs. Since then, Verizon and Telefónica have both implemented versions of P4P within their networks, though the network maps may not be available in all regions or to every P2P provider. Several other ISPs are considering implementing P4P, Xie says; Comcast, for instance, publicly stated its interest in the technology following last fall's trial.

Robert Levitan, Pando's CEO, says that the company used the expertise it gained through those trials to develop algorithms that automatically derive network maps, based on information gathered from software installed on individual users' machines (more than 30 million computers have Pando's media booster software installed). The company uses the maps to help route content more quickly to those same computers. The company's clients include Nexon America, one of the largest free-to-play online video-game companies, and, which uses P4P to deliver full-length HD shows over the Internet.

Indeed, Xie says, as multimedia becomes more and more dominant on the Internet, demand for P4P implementations will grow, particularly from ISPs seeking to lower the amount of money they need to spend on new fiber and inter-ISP data transmissions. Video and audio streaming from sites such as YouTube and Hulu already accounts for almost 27 percent of global Internet traffic, according to a report by network-management systems vendor Sandvine. Cisco predicts that by 2013, video alone will account for over 60 percent of all consumer Internet traffic. With this kind of increase in high-bandwidth traffic, Levitan says, "we're not going to be able to have the Internet we all want" without P4P, or a similar technology, to help scale the physical networks at a reasonable cost.

Xie and Levitan see two main difficulties for the continued growth of P4P. The first is P2P's association with software, music, and video piracy. ISPs want to make sure that working with P2P companies to improve their service won't make them liable for any illegal file sharing. But Levitan is optimistic that increasing numbers of legal uses for P2P technology will help reform its image. For example, Internet telephony service Skype relies on P2P connections, as does Blizzard Entertainment, maker of the popular online game World of Warcraft. began using Octoshape's P2P technology to boost its delivery of live streaming video earlier this year, and the PGA, NBA, and NASCAR all use it to support live webcasts of sporting events.

The other potential problem is perhaps trickier: even though P4P benefits both consumers and ISPs, because it treats P2P traffic differently than other data flowing over the Internet, it could technically violate the Federal Communications Commission's proposed net neutrality regulations. In fact, one of Xie's original motivations in developing the P4P protocols was to help carriers avoid having to limit P2P traffic for cost reasons, as Comcast did--much to consumers' ire--in 2006. He admits that P4P would seem to violate the letter of net neutrality, if not the spirit, by "helping" P2P applications preferentially. "I don't have a good, clear answer to those concerns," Xie says. Still, he and other P4P proponents remain optimistic that the technology's advantages will win the day.

Levitan thinks that the benefits such companies are seeing will allow P4P to move forward. "On a technology basis, and even from a policy basis, I think the FCC could see--wow--this could really help networks, and maybe it changes the network neutrality debate," Levitan says-- because there wouldn't be a scarcity of network capacity anymore.

By Erika Jonietz