Targeting tumors: Two groups of rats were given an infusion of magnetic, drug-coated nanoparticles. Focused ultrasound combined with an active magnetic field allowed more of the anti-tumor drug (yellow and red) to reach the brain (bottom) than did normal blood circulation (top).
Credit: Chang Gung Memorial Hospital

Combining ultrasound with magnetic particles could help advance treatments

MIT Technology Review, August 11, 2010, by Lauren Gravitz  –  The brain and its adjacent blood vessels are separated by a protective barrier–it keeps viruses and other infections out but also limits entry of most medications, making tumors and other diseases of the brain particularly difficult to treat. But researchers in Taiwan have found a way to transport more anticancer therapeutics to the brain than previously possible through a novel combination of ultrasound and magnetic particles.

The new research shows how independently successful approaches can work in concert to be markedly more effective. Focused ultrasound waves, along with a solution of microbubbles injected into the bloodstream, had already been proven to briefly disturb the blood-brain barrier. Now, Kuo-Chen Wei, of Chang Gung University College of Medicine, has combined the ultrasound method with a technique that uses a magnetic field to attract drug-coated, magnetically charged nanoparticles to the precise spot where they’re most needed. The disrupted blood-brain barrier allows far more of these larger nanoparticles to enter the brain, and the magnetic field guides them directly to the tumors.

“Typical anticancer drugs can’t [accumulate in] the brain because of the blood-brain barrier,” Wei says. “If we could increase the local concentration of the drug and decrease the systemic side effects, that would be more practical for treatment.”

In rats, at least, he and his colleagues have done just that. Their results, published online today in Proceedings of the National Academy of Sciences and last month in the journal Neuro-Oncology, show that the ultrasound-magnetic targeting approach drives more therapeutic particles through the blood-brain barrier, increasing drug concentrations in the tumor region of the rat brain by 20-fold over the amount that passively diffused from the bloodstream in untreated rats.

“Right now, there’s a huge limitation on using drugs in the brain for disorders of all kinds–Alzheimer’s, epilepsy, Parkinson’s, anything you can think of,” says Nathan MacDannold, a radiologist who runs the Focused Ultrasound Laboratory at Brigham and Women’s Hospital in Boston. “Opening up a new way to get drugs into the brain could be a very big deal, if we can do it safely and translate it to humans.”

Even executing the technique in rats required a massive amount of effort and technological innovation. Wei and his group had to build their own drug-dosed magnetic nanoparticles, which they made by first coating the particles with iron oxide to make them magnetic and then adding a layer of the brain-tumor drug epirubicin. But they also had to build a platform that combined both focused ultrasound directed only toward the area of the tumor, and a magnetic field immediately over the same spot. (Opening up the blood-brain barrier anywhere else in the brain could allow toxic cancer-killing drugs to kill healthy cells.)

Using magnetic particles has an additional benefit. Magnetic resonance imaging (MRI) scans can detect the therapeutic nanoparticles, potentially allowing researchers to estimate how much of the drug has been absorbed into the brain.

Clinical use of the technique, however, is still a long way off. “If we want to push this method to clinical trial, several problems must be resolved,” Wei says. The system has to be scaled up to be used on larger animals–not an easy proposition, since the magnetic fields must penetrate more deeply to reach their brains. The entire process must also be fine-tuned so it can be replicated precisely, over and over. The magnetic field technology must be honed to make it both more portable and more accurate, to ensure that it doesn’t attract toxic particles to anywhere other than the cancerous tumors. And the focused ultrasound technology has yet to be proven effective at blood-brain barrier disruption in the larger, thicker human brain, let alone safe.

“I applaud them for what they’re doing,” says Pierre Mourad, a physicist who specializes in medical acoustics at the University of Washington in Seattle. “They’ve managed to do an exhaustive first pass at a novel way of addressing the difficult problem of increasing dose delivery into the brain.”

But Mourad says he’s disappointed that the group focused strictly on brain tumors. “For many malignant primary brain tumors, increased uptake of drug into the tumor isn’t the problem.” Rather, he says, even after a malignant tumor has been surgically removed, there are still cancerous cells throughout the brain that can cause a recurrence of disease. The magnetic-targeting method only directs therapy to tumors that are visible, leaving the rogue cells behind.

“I’d want to solve movement disorders with these procedures,” Mourad says–diseases such as Parkinson’s and Alzheimer’s, in which very discrete bits of the brain go bad. Parkinson’s, for instance, typically affects distinct, well-known locations. “There are decent drugs to address it, but delivery and dose is the big problem,” says Mourad. “That’s where I would go first with this exciting technology.”

Brigham and Women’s McDannold also sees broader applications. “Technology that can get drugs into the brain where we currently can’t, and deliver them in a controlled way, opens up possibilities for drugs of all types,” he says.

New Delhi metallo-ß-lactamase-1, or NDM-1, is an  emerging enzyme that can confer resistance to certain gram negative bacteria like E.coli and Klebsiella against a class of antibiotics called carbapenems.

Carbapenems are newer generation beta-lactam antibiotics (a class that includes penicillins, cephalosporins, cephamycins, and carbapenems) that are usually reserved as an antibiotic of last resort.

 

FORBES.com, August 11, 2010, LONDON — British scientists have found a new gene that allows any bacteria to become a superbug, and are warning that it is widespread in India and could soon appear worldwide.

The gene, which can be swapped between different bacteria to make them resistant to most drugs, has so far been identified in 37 people who returned to the U.K. after undergoing surgery in India or Pakistan.

The resistant gene has also been detected in Australia, Canada, the U.S., the Netherlands and Sweden. The researchers say since many Americans and Europeans travel to India and Pakistan for elective procedures like cosmetic surgery, it was likely the superbug gene would spread worldwide.

In an article published online Wednesday in the journal Lancet Infectious Diseases, doctors reported finding a new gene, called NDM-1. The gene alters bacteria, making them resistant to nearly all known antibiotics. It has been seen largely in E. coli bacteria, the most common cause of urinary tract infections, and on DNA structures that can be easily copied and passed onto other types of bacteria.

The researchers said the superbug gene appeared to be already circulating widely in India, where the health system is much less likely to identify its presence or have adequate antibiotics to treat patients.

“The potential of NDM-1 to be a worldwide public health problem is great, and coordinated international surveillance is needed,” the authors wrote.

Still, the numbers of people who have been identified with the superbug gene remains very small.

“We are potentially at the beginning of another wave of antibiotic resistance, though we still have the power to stop it,” said Christopher Thomas, a professor of molecular genetics at the University of Birmingham who was not linked to the study. Thomas said better surveillance and infection control procedures might halt the gene’s spread.

Thomas said while people checking into British hospitals were unlikely to encounter the superbug gene, they should remain vigilant about standard hygiene measures like properly washing their hands.

“The spread of these multi-resistant bacteria merits very close monitoring,” wrote Johann Pitout of the division of microbiology at the University of Calgary, Canada, in an accompanying Lancet commentary.

Pitout called for international surveillance of the bacteria, particularly in countries that actively promote medical tourism.

“The consequences will be serious if family doctors have to treat infections caused by these multi-resistant bacteria on a daily basis,” he wrote.

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2810%2970143-2/fulltext

Read the Lancet research paper

A magnified view of E. coli bacteria

The superbug gene has been found in the bacteria.

The NDM-1 gene was first identified last year 

Slow decline: In young mice (top), the part of a motor neuron that releases chemical signals (green) and the receptors on the muscle that receive those signals (red) align to create a structure known as the neuromuscular junction. The overlap between these two components is shown as yellow. As the animals age (bottom), the structure begins to deteriorate.   Credit: Copyright National Academy of Sciences

Caloric restriction and exercise slow muscle decline in mice

MIT Technology Review, August 11, 2010, by Emily Singer  –  The connections between your nerves and muscle deteriorate with age–a phenomenon that may help explain the serious loss of muscle that often strikes old people. New evidence suggests that caloric restriction–a nutritionally complete but low-calorie diet–could help prevent these changes. According to a study published this week in the Proceedings of the National Academy of Sciences, a very-low-calorie diet, and to a lesser extent exercise, can prevent or slow some aspects of muscle decline in aging mice.

The researchers hope that the findings will point toward new ways to stem loss of muscle mass, one of the most common problems of aging and a major cause of injury. They also say it could help them understand how similar factors affect neural connections in the brain. “Much of the research on aging in the nervous system has been done in the context of neurodegenerative diseases, such as Alzheimer’s,” says Joshua Sanes, a neuroscientist at Harvard Medical School and one of the senior authors of the study. “Remarkably little is known about the basic phenomenon of aging in the nervous system.”

The researchers studied the structure of the neuromuscular junction–the connection between the motor neurons and muscle–in mice that had been genetically engineered to make these neurons glow. Because these junctions are relatively large and tend to have a regular structure, it is easy to see when things go wrong. When the mice were about two years old, roughly the equivalent of a 70- to 80-year-old person, the junctions had clearly deteriorated. “The majority of muscle fibers had abnormal junctions,” says Jeff Lichtman, a neuroscientist at Harvard University and a senior author of the study. The connections were generally smaller, and the nerves and corresponding receptors on the muscle, which are normally aligned, were askew. “They looked old and decrepit, kind of like a person looks old,” says Lichtman.

The findings, hinted at in previous research, could shed light on a major health issue in aging: sarcopenia, or loss of muscle mass. “That is one of the most robust age-related impairments observed across many species, but it’s not really clear what causes it,” says Charles Mobbs, a neuroscientist at Mt. Sinai School of Medicine, in New York, who was not involved in the research. “This study provides evidence that an important mechanism involves neuromuscular junctions and the role of motor neurons.”

To look for factors to stem this decline, the researchers examined animals that had been on a restricted diet most of their lives. This type of diet has previously been shown to extend lifespan in a number of species and to reduce some signs of aging, such as diabetes and heart disease, in some animals. “With caloric restriction, we saw a striking absence of abnormalities,” says Lichtman. “These animals’ synapses looked quite young.”

The findings are among the first to show that caloric restriction has a robust effect on the nervous system, which has been a matter of debate. “This paper demonstrates the protective effect of dietary restriction on muscle and the neurons that regulate muscle function,” says Mobbs. “It’s one of the most convincing papers I have seen demonstrating a protective effect of dietary restriction in neural function.”

Those who are disinclined to diet for their whole lives still have hope, however. Mice that exercised for a month in old age also had healthier neuromuscular junctions, though the findings weren’t as significant as those for caloric restriction. “Just a month of exercise actually seemed to reverse the course of the downward spiral,” says Lichtman.

“If there were ever two scientists who did not want to hear this result, it’s us,” says Lichtman, of himself and Sanes. “We don’t love to exercise, and I find it real torture to starve myself.” Because few people want to or are able to maintain a severely restricted diet, scientists and drug developers are searching for molecules that can mimic these health-boosting effects.

Others say the study gives reason for optimism. “The effects are remarkable, given the short time span and late onset time of exercise,” says Leonard Guarente, a biologist at MIT who was not involved in the research. “It suggests it’s never too late.”

It’s not yet clear how well the findings will translate to humans. Exercise has been shown to have health benefits for older people, but “many studies demonstrate that exercise cannot restore muscle to the same functionality that a young exercised muscle would have,” says Mobbs.

The researchers are now searching for the molecular basis for the decline of neuromuscular junctions, as well as for the benefits of caloric restriction and exercise. “Is there some key molecule that goes away so the synapse falls apart?” says Sanes. “Is it the nerve’s fault and muscle is fine, or vice versa? We won’t be able to find out [how caloric restriction helps] until we know the normal mechanisms of age-related decline.”

It’s also unclear whether the two treatments work via the same mechanism or different ones. “I believe that caloric restriction is fundamentally affecting the processes of aging, whereas exercise training doesn’t really do that,” says Russell Hepple, a scientist at the University of Calgary, in Canada. “An exercise-trained muscle is definitely happier than a sedentary one, but it’s not going to affect the processes of aging like caloric restriction does.”

Researchers hope ultimately to apply the same approach to study nerve connections in the brain, which is more difficult because these nerves are much smaller and more densely packed. Previous research suggests that the number of connections declines with age, and that caloric restriction can help stem memory loss in older mice.

Bright heat: Nicholas Melosh has developed a device for simultaneously converting the sun’s light and heat into electricity. Melosh makes and tests the device in this vacuum chamber in his lab at Stanford University.  
Credit: Technology Review

Researchers have demonstrated a new mechanism for converting both sunlight and heat into electricity

MIT Technology Review, August 11, 2010, by Katherine Bourzac  –  A new type of device that uses both heat and light from the sun should be more efficient than conventional solar cells, which convert only the light into electricity.

The device relies on a physical principle discovered and demonstrated by researchers at Stanford University. In their prototype, the energy in sunlight excites electrons in an electrode, and heat from the sun coaxes the excited electrons to jump across a vacuum into another electrode, generating an electrical current. The device could be designed to send waste heat to a steam engine and convert 50 percent of the energy in sunlight into electricity–a huge improvement over conventional solar cells.

The most common silicon solar cells convert about 15 percent of the energy in sunlight into electricity. More than half of the incoming solar energy is lost as heat. That’s because the active materials in solar cells can interact with only a particular band of the solar spectrum; photons below a certain energy level simply heat up the cell.

One way to overcome this is to stack active materials on top of one another in a multijunction cell that can use a broader spectrum of light, turning more of it into electrical current instead of heat, for efficiencies up to about 40 percent. But such cells are complex and expensive to make.

Looking for a better way to take advantage of the sun’s heat, Stanford’s Nicholas Melosh was inspired by highly efficient cogeneration systems that use the expansion of burning gas to drive a turbine and the heat from the combustion to power a steam engine. But thermal energy converters don’t pair well with conventional solar devices. The hotter it is, the more efficient thermal energy conversion becomes. Solar cells, by contrast, get less efficient as they heat up. At about 100 °C, a silicon cell won’t work well; above 200 °C, it won’t work at all.

The breakthrough came when the Stanford researchers realized that the light in solar radiation could enhance energy conversion in a different type of device, called a thermionic energy converter, that’s conventionally driven solely by heat. Thermionic converters consist of two electrodes separated by a small space. When the positive electrode, or cathode, is heated, electrons in the cathode get excited and jump across to the negative electrode, or anode, driving a current through an external circuit. These devices have been used to power Russian satellites but haven’t found any applications on the ground because they must get very hot, about 1,500 °C, to operate efficiently. The cathode in these devices is typically made of metals such as cesium.

Melosh’s group replaced the cesium cathode with a wafer of semiconducting material that can make use of not only heat but also light. When light strikes the cathode, it transmits its energy to electrons in the material in a way that’s similar to what happens in a solar cell. This type of energy transfer doesn’t happen in the metals used to make these cathodes in the past, but it’s typical of semiconductor materials. It doesn’t take quite as much heat for these “preëxcited” electrons to jump to the anode, so this new device can operate at lower temperatures than conventional thermionic converters, but at higher temperatures than a solar cell.

The Stanford researchers call this new mechanism PETE, for photon-enhanced thermionic emission. “The light helps lift the energy level of the electrons so that they will flow,” says Gang Chen, professor of power engineering at MIT. “It’s a long way to a practical device, but this work shows that it’s possible,” he says.

The Stanford group’s prototype, described this month in the journal Nature Materials, uses gallium nitride as the semiconductor. It converts just about 25 percent of the energy in light into electricity at 200 °C, and the efficiency rises with the temperature. Stuart Licht, professor of chemistry at George Washington University, says the process would have an “advantage over solar cells” because it makes use of heat in addition to light. But he cautions: “Additional work will be needed to translate this into a practical, more efficient device.”

The Stanford group is now working to do just that. The researchers are testing devices made from materials that are better suited to solar energy conversion, including silicon and gallium arsenide. They’re also developing ways of treating these materials so that the device will work more efficiently in a temperature range of 400 °C to 600 °C; solar concentrators would be used to generate such high temperatures from sunlight.

Even at high temperatures, the photon-enhanced thermionic converter will generate more heat than it can use; Melosh says this heat could be coupled to a steam engine for a solar-energy-to-electricity conversion efficiency exceeding 50 percent. These systems are likely to be too complex and expensive for small-scale rooftop installations. But they could be economical for large solar-farm installations, says Melosh, a professor of materials science and engineering. He hopes to have a device ready for commercial development in three years.