Biodegradable Transistors

Biodegradable chip: After 50 days under conditions that mimic those inside the body, this transistor array is mostly dissolved. Credit: Christopher Bettinger

Electronics that break down in the body could be useful in temporary medical implants and drug delivery.

By Katherine Bourzac

Fully biodegradable organic transistors, recently fabricated by researchers at Stanford University, could be used to control temporary medical implants placed in the body during surgery.

Biodegradable electronics “open up opportunities for implants in the body,” especially if the electronics prove inexpensive, says Robert Langer, institute professor at MIT, who was not involved with the research. Implants might incorporate the organic electronics with biodegradable drug-delivering polymers. Doctors might implant such a device during surgery, then activate it from outside the body with radio frequencies to release antibiotics if needed during recovery. The electronics could also help monitor the healing process from inside the body. After healing is complete, the entire device would dissolve in the body.

Earlier this month, researchers at Tufts University and the University of Illinois at Urbana-Champaign reported building silicon electronics on biodegradable silk substrates. Silicon electronics generally have much better performance than those made from organic semiconductors, but silicon isn’t biodegradable. The Stanford group, led by chemical engineering professor Zhenan Bao, is the first to make electronics from fully biodegradable semiconducting materials. Though the devices are stable in water, all that’s left of the devices after 70 days are metal electrical contacts just tens of nanometers thick.

So far, the group has proved that it can build organic electronics that work when wet and that break down under conditions that mimic those inside the body. The degradation of these devices is triggered by conditions similar to those found in the body: a salty solution with a slightly basic pH slowly breaks down the transistors. In order to be stable and maintain their performance while they’re in use, these devices will need to be encapsulated in another layer whose composition is tuned to expose the device once it has outlived its usefulness. The prototype device, described online in the journal Advanced Materials, is made from biodegradable plastics approved by the U.S. Food and Drug Administration, a biodegradable semiconducting material that resembles the skin pigment melanin, and gold and silver electrical contacts. These metals are also approved for use inside the body.

Article Continues - http://www.technologyreview.com/biomedicine/23940/

Fact or Fiction: Generic Drugs Are Bad for You

GENERIC THREAT?: How do generic versions of drugs differ and does that pose any threat?   ©iStockphoto.com

Because of the recession, among other reasons, more people are turning to generic drugs, often manufactured abroad. Is there any cause for concern?

By Molly Webster

As we cope with the economic recession, we’ve all had to make concessions. It’s been “good-bye” to European vacations, organic milk and magazine subscriptions. But there are those things we can’t give up without risking serious illness or death, one of which is prescription medication.

In 2004 the U.S. Centers for Disease Control estimated that at least 47 percent of Americans had a prescription filled each month. Besides ordering brand-name pills, powders and sprays from Canada, some people are trying to cut costs by turning to generic medications. But don’t worry: unlike switching from a real Louis Vuitton purse to a knockoff bought in Chinatown, this isn’t a switch that will leave you aching for the real thing in a few months time.

“In theory, generics are every bit as high quality as brand name,” says William Hubbard, a former associate commissioner of the U.S. Food and Drug Administration (FDA). “I would readily take a generic if it was prescribed to me.”

A generic drug contains the same active ingredient, which provides therapeutic benefit, as does the brand-name version. But having the same medicinal component does not mean the two pharmaceuticals are identical. They may contain different inactive ingredients, including those for pill coatings and color or to bind the constituents into tablet form. They also may vary in bioequivalency, which is the amount of drug that is available in the bloodstream at any point in time. In fact, a 2009 FDA study showed that of 2,070 orally administered generic drug products approved by the agency between 1996 to 2007, generics differ in bioequivalency from brand names, on average, by about 3.5 percent; less than two percent varied by more than 10 percent. For many, these differences are not significant enough to reduce therapeutic benefits or, on the other hand, cause toxicity.

“For the vast majority of patients, switching is not an issue,” says Aaron Kesselheim, a physician and drug policy researcher at Harvard’s Brigham and Women’s Hospital. Kesselheim is author of a 2008 study that showed there are no statistically significant therapeutic differences among generic and brand-name heart medications.

The minority of patients for whom a switch might be problematic are those on narrow-margin therapeutic index drugs, such as anticoagulants and antihypertension meds for which there is a fine line between a dosage that is beneficial and one that is toxic. Even when using pioneer (or brand-name) drugs, doctors monitor patients on these types of medications until they find the precise dose that works with each person’s physiology. Switching medication, especially if there’s even a small bioequivalence variability, can introduce a change that throws off therapy.

“If a person is stable on narrow therapeutic index drug, it makes sense to think two times about changing to a generic or to a new brand-name drug,” Kesselheim says.

Despite convincing scientific evidence that generic drugs are largely equivalent to pioneer meds, there remains an undercurrent of fear toward nonbrand names. In fact, as part of Kesselheim’s 2008 study in JAMA The Journal of the American Medical Association, his team reviewed 43 editorials that had been published in peer-review health care journals between 1975 and 2008 concerning generic substitutions for branded cardiovascular disease pharmaceuticals. The study found that 53 percent expressed a negative view toward generics. There’s myriad sources that could explain the worry, including patient case reports and antigeneric advertising by brand name drug companies. But to be fair, much of the concern is rooted in some scary generic drug scandals, in which toxic substances made it into a medication that was produced overseas, such as occurred with heparin in 2008. Today, more than 40 percent of the active ingredients in generic and over-the-counter pharmaceuticals are produced in India and China—and that number is only expected to increase: In the next few years a number of brand-name pharmaceuticals will be going off patent, with the expectation that within 10 years, 80 percent of the prescriptions Americans take will be generic.

And, although generics have thus far been shown to be as effective and safe as branded drugs, there is a concern that they are more likely than brand-name meds to be the target of adulteration with toxic substances, because some companies might be tempted to cut corners in efforts to keep them as cheap as possible.

“FDA requirements are pretty strict,” Hubbard says, “but foreign firms don’t have the same culture of safety and oversight—and they are interested in the lowest price.”

According to the FDA, the rules that it has set to regulate generic drugs are just as tough as for brand-name meds. But keep in mind that the federal agency was originally formed as a domestic watchdog—overseas expansion and the proliferation of pharmaceutical manufacturers have challenged their infrastructure. The New York Times reported that in 2007, out of 500 Chinese facilities the FDA only got around to checking 13. Acknowledging this situation, the agency is looking to expand overseas staff in an attempt to ramp up on-the-ground regulation of manufacturing facilities. In 2008 the FDA opened three offices in China and two in India, not to mention others in Costa Rica and Belgium. Hubbard further suggests that in the future, all foreign facilities with any role in the U.S. pharmaceutical industry should be required to register with the FDA, providing contact information as well as a list of their product lines.

Plus, the U.S. Pharmacopeia (USP), a standard-setting authority for prescription and over-the-counter meds, has recently changed some of the identification tests that manufacturers are required to run on products destined for the U.S. These newer, more stringent analyses are more sensitive to impurities than prior protocols were. (And, for what it’s worth, the USP is also trying to organize momentum for establishing some tougher food tests—think: melamine.)

Today, however, Hubbard says that prescription-takers “don’t need to panic”: 67 percent of Americans take generic medication, and there are few adverse instances to recount. And studies have shown them to be just as effective as branded meds.

So, with the great recession raging, bring on the generics.

http://www.scientificamerican.com/article.cfm?id=are-generic-drugs-bad-for-you

Pharma Deal With White House on Course to Net Industry Billions

Sam Stein – stein@huffingtonpost.com

The deal struck between the pharmaceutical lobby, the White House and Senate Democrats has drastically improved Big Pharma’s expected profits, a private industry report finds.

IMS Health, a company that supplies the pharmaceutical companies with sales data, predicts that new health reform legislation — combined with a projected upswing in the economy — will result in a net gain of more than $137 billion in total market sales over the next four years. The new assessment was contained in document obtained by the Huffington Post.

Back in March, that same firm projected a compound annual growth rate of -0.1 percent in the period of 2008 through 2013. In October, with the general outlines of health care reform clearly in place, it revised that number to a positive 3.5 percent for over the same period.

What happened in those seven months? The economy started looking up, for one, as did the overall prospects of health care reform. But the industry also won a major lobbying victory.

PhRMA, the lobby entity for the industry’s heavy hitters, reached a secret deal with the White House and the Senate Finance Committee in June. As detailed in a memo first published by The Huffington Post, the Obama administration agreed to oppose congressional efforts to use government leverage to bargain for lower drug prices. The White House also agreed not to shift some drugs from Medicare Part B to Medicare Part D, which would have cost the industry billions in reduced reimbursements. All this in exchange for $80 billion over ten years to help push for reform.

The Senate version of the healthcare bill still conforms to the deal (that the White House has still never officially confirmed). The House bill is in the same ballpark, although it would cost Big Pharma an extra $14 billion.

The IMS, in its revised October findings, did not reference the deal specifically, but rather made note of what it called a “NEW EVENT” — mainly that health care reform “could lead to higher priced branded products and increased healthcare coverage across the USA.”

“Branded drug price increases are expected to continue,” the firm concluded, before citing the specific reforms of the PhRMA deal.

America’s Affordable Health Choices Act of 2009 (HR 3200) has proposed several changes to the Medicare Part D program that would impact federal spending. Firstly, it would create a new rebate program that would require manufacturers of brand-name drugs to pay the federal government a rebate equaling 15% of the average manufacturer price. The finer details of the rebate will be determined as the reform legislation develops. Secondly, it would phase out the doughnut hole by simultaneously extending the benefits initial coverage limit and lowering the catastrophe threshold at specified rates leading to removal of the doughnut hole by 2022. Thirdly, as the doughnut hole is being phased out drug makers would be required to provide beneficiaries who are not eligible for the low-income subsidiary programme with a 50% discount on their spending in the doughnut hole for covered branded drugs. This initiative could create new business for pharmaceutical companies and also give seniors a price break, but only if they were paying full price on the brand product in the first instance. For pharmaceutical companies the agreement will lead to a loss if the senior was paying full price, but a win if the senior was not buying brand products at all. By making branded drugs in the doughnut hole more affordable patients may be able to afford to continue with treatment.

As explained by The New Republic’s Jonathan Cohn (who got the IMS document first):

Health reform, as currently envisioned, wouldn’t merely bring coverage to the uninsured. It would also fill in the “donut hole” in Medicare Part D–the gap in coverage that leaves beneficiaries with serious health problems paying for hundred if not thousands of dollars in out-of-pocket prescription costs.In addition, because it will take several years to close the donut hole, reform relies on voluntary discounts from the pharmaceutical industry to make drugs more affordable in the intervening years. But those discounts would apply only to name-brand drugs, not generics.

Put it all together, and you have more demand for name-brand drugs.

The structure of health care reform, as IMS goes on to note, will have benefits for the federal government, which could save an estimated $30 billion from 2010 through 2019. Patients, meanwhile, would be paying higher premiums — roughly five percent more by 2011 — in return for what the report calls greater “protection against incurring higher drug costs.” The real beneficiaries of reform, however, would evidently be the pharmaceutical industry.

IMS’s conclusions are one of the clearest affirmations yet of various media reports that PhRMA is coming out of its negotiations with the White House and the Senate as a big winner — though, as Cohn notes, the numbers IMS uses are simply projections and they may not necessarily bear out.

In a twist of sorts, it was the March IMS study that served as a small pillar in PhRMA’s push to get a deal with the White House and Senate Democrats in the first place. In the press release touting its $80 billion commitment, the lobbying entity, along with affiliated institutions, warned that, “Medicines have already begun to play a key role in bending the cost curve in the U.S,”

“In 2009, IMS projects that the U.S. market for prescription medicines will contract, declining 1-2% below 2008 levels. Going forward till 2014, IMS projects annual growth rate for prescription medicines to remain essentially flat.”

At the time, PhRMA was making the case that the $80 billion it was offering for reform was a major concession to the White House and Senate Dems. Compared to the new numbers, however, it doesn’t look like such a big concession anymore.

http://www.huffingtonpost.com/2009/11/11/pharma-deal-with-white-ho_n_353499.html

Embryonic Stem Cell Therapy Restores Walking Ability In Rats With Neck Injuries

Illustration of rat with spinal injury. (Credit: Image courtesy of University of California – Irvine)

The first human embryonic stem cell treatment approved by the FDA for human testing has been shown to restore limb function in rats with neck spinal cord injuries — a finding that could expand the clinical trial to include people with cervical damage.

In January, the U.S. Food & Drug Administration gave Geron Corp. of Menlo Park, Calif., permission to test the UC Irvine treatment in individuals with thoracic spinal cord injuries, which occur below the neck. However, trying it in those with cervical damage wasn’t approved because preclinical testing with rats hadn’t been completed.

Results of the cervical study currently appear online in the journal Stem Cells. UCI scientist Hans Keirstead hopes the data will prompt the FDA to authorize clinical testing of the treatment in people with both types of spinal cord damage. About 52 percent of spinal cord injuries are cervical and 48 percent thoracic.

“People with cervical damage often have lost or impaired limb movement and bowel, bladder or sexual function, and currently there’s no effective treatment. It’s a challenging existence,” said Keirstead, a primary author of the study. “What our therapy did to injured rodents is phenomenal. If we see even a fraction of that benefit in humans, it will be nothing short of a home run.”

A week after test rats with 100 percent walking ability suffered neck spinal cord injuries, some received the stem cell treatment. The walking ability of those that didn’t degraded to 38 percent. Treated rats’ ability, however, was restored to 97 percent.

UCI’s therapy utilizes human embryonic stem cells destined to become spinal cord cells called oligodendrocytes. These are the building blocks of myelin, the biological insulation for nerve fibers that’s critical to proper functioning of the central nervous system. When myelin is stripped away through injury or disease, paralysis can occur.

Lead author and doctoral student Jason Sharp, Keirstead and colleagues discovered that the stem cells not only rebuilt myelin but prevented tissue death and triggered nerve fiber regrowth. They also suppressed the immune response, causing an increase in anti-inflammatory molecules.

“The transplant created a healing environment in the spinal cord,” said Keirstead, who is co-director of the Sue & Bill Gross Stem Cell Research Center and on the faculty of the Reeve-Irvine Research Center — named for late actor Christopher Reeve, who became a quadriplegic after a cervical spinal cord injury.

In addition to Keirstead and Sharp, Jennifer Frame, Monica Siegenthaler and Dr. Gabriel Nistor of UCI worked on the study, which was supported by Geron Corp., a University of California Discovery Grant, the Roman Reed Spinal Cord Injury Research Fund of California, Research for Cure, and individual donations to the Reeve-Irvine Research Center.

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Adapted from materials provided by University of California – Irvine.

http://www.sciencedaily.com/releases/2009/11/091109121345.htm

New Synthetic Molecules Trigger Immune Response To HIV And Prostate Cancer

Artist’s rendering of viruses. Scientists have developed synthetic molecules capable of enhancing the body’s immune response to HIV and HIV-infected cells, as well as to prostate cancer cells. (Credit: iStockphoto/Henrik Jonsson)

Researchers at Yale University have developed synthetic molecules capable of enhancing the body’s immune response to HIV and HIV-infected cells, as well as to prostate cancer cells. Their findings, published online in the Journal of the American Chemical Society, could lead to novel therapeutic approaches for these diseases.

The molecules — called “antibody-recruiting molecule targeting HIV” (ARM-H) and “antibody-recruiting molecule targeting prostate cancer” (ARM-P) — work by binding simultaneously to an antibody already present in the bloodstream and to proteins on HIV, HIV-infected cells or cancer cells. By coating these pathogens in antibodies, the molecules flag them as a threat and trigger the body’s own immune response. In the case of ARM-H, by binding to proteins on the outside of the virus, they also prevent healthy human cells from being infected.

“Instead of trying to kill the pathogens directly, these molecules manipulate our immune system to do something it wouldn’t ordinarily do,” said David Spiegel, Ph.D., M.D., assistant professor of chemistry and the corresponding author of both papers.

Because both HIV and cancer have methods for evading the body’s immune system, treatments and vaccinations for the two diseases have proven difficult. Current treatment options for HIV and prostate cancer — including antiviral drugs, radiation and chemotherapy — involve severe side effects and are often ineffective against advanced cases. While there are some antibody drugs available, they are difficult to produce in large quantities and are costly. They also must be injected and are accompanied by severe side effects of their own.

By contrast, the ARM-H and ARM-P molecules, which the team has begun testing in mice, are structurally simple, inexpensive to produce, and could in theory be taken in pill form, Spiegel said. And because they are unlikely to target essential biological processes in the body, the side effects could be smaller, he noted.

“This is an entirely new approach to treating these two diseases, which are extraordinarily important in terms of their impact on human health,” Spiegel said.

HIV is a global pandemic that affects 33 million people worldwide, while prostate cancer is the second leading cause of cancer-related death among American men, with one out of every six American men expected to develop the disease.

Funding for this research was provided by the National Institutes of Health.

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Adapted from materials provided by Yale University.

http://www.sciencedaily.com/releases/2009/11/091105165527.htm

Spraying on Skin Cells to Heal Burns

Spray-on skin: In a unique treatment for second-degree burns, surgeons harvest a small number of skin cells through a skin biopsy, suspend them in solution, and then spray the resulting mixture onto a burn wound. Once in place, skin stem cells, called basal cells, proliferate to create a new layer of skin.   Credit: ReCell

A new technique in burn treatment provides an alternative to skin grafts in the operating room.

By Lauren Gravitz

Traditionally, treatment for severe second-degree burns consists of adding insult to injury: cutting a swath of skin from another site on the same patient in order to graft it over the burn. The process works, but causes more pain for the burn victim and doubles the area in need of healing. Now a relatively new technology has the potential to heal burns in a way that’s much less invasive than skin grafts. With just a small skin biopsy and a ready-made kit, surgeons can create a suspension of the skin’s basal cells–the stem cells of the epidermis–and spray the solution directly onto the burn with results comparable to those from skin grafts.

The cell spray is intended to treat severe second-degree burns, in which the top two layers of skin are damaged but the subcutaneous tissue is left intact. Third-degree burns, which are more severe, still require a skin graft. The spray, already approved for use in some countries, has garnered interest from the United States Army, whose Armed Forces Institute of Regenerative Medicine is funding a trial, slated to begin before the end of this year, of more than 100 patients.

The technology, developed by Australian surgeon Fiona Wood, relies on cells, such as skin progenitor cells and the color-imparting melanocytes, that are most concentrated at the junction between the skin’s top two layers. With a small step-by-step kit dubbed ReCell, surgeons can harvest, process and apply these cells to treat a burn as large as 10.5 square feet. The kit, marketed by Avita Medical, a United Kingdom-based regenerative-medicine company, is a tiny, self-contained lab about the size and shape of a large sunglasses case.

After removing a small swatch of skin near the burn site (the closer the biopsy, the better for precise matching of color and texture), the surgeon places it in the kit’s tiny incubator along with an enzyme solution. The enzyme loosens the critical cells at the skin’s dermal-epidermal junction, and the surgeon harvests them by scraping them off the epidermal and dermal layers and suspending them in solution. The resulting mixture is then sprayed onto the wound, repopulating the burn site with basal cells from the biopsy site.

“Currently, treating any burn that requires a skin graft is the same technology we were routinely using 30 years ago,” says James Holmes, a surgeon and the medical director of the Burn Center at Wake Forest University Baptist Medical Center. Current practice with larger burns requires grafts from donor skin that are anywhere from one-quarter to the complete size of the burn area. ReCell requires only as much as four square centimeters. “This allows you to take a very small skin biopsy and process it at the table there in the operating room using a fully prepackaged device,” Holmes says. “You’re able to cover an area that’s 80 times the size of your biopsy.”

Holmes is the lead investigator on an upcoming multicenter trial that will compare skin grafts and ReCell. Patients in the trial will act as their own controls: If a burn victim has a second-degree burn severe enough for surgeons to deem treatable by skin graft, half of the burn will be treated that way, while the other half will be treated with the cell spray.

Article Continues - http://www.technologyreview.com/biomedicine/23876/

Next-generation Microcapsules Deliver ‘Chemicals On Demand’

A new generation of microcapsules, shown above, promise to deliver “chemicals on demand” for a wide range of uses, including medicine and personal care.

Scientists in California are reporting development of a new generation of the microcapsules used in carbon-free copy paper, in which capsules burst and release ink with pressure from a pen. The new microcapsules burst when exposed to light, releasing their contents in ways that could have wide-ranging commercial uses from home and personal care to medicine.

ean Fréchet, Alex Zettl and colleagues note that liquid-filled microcapsules have many other uses, including self-healing plastics. Those plastics contain one group of microscapsules filled with monomer and another with a catalyst. When scratches rip open the capsules, the contents flow, mix, and form a seal. Microcapsules that burst open when exposed to light would have great advantages, the scientists say. Light could be focused to a pinpoint to kill cancer cells, for instance, or shined over an large area to print a pattern.

The new microcapsules consist of nylon spheres about the size of a grain of sand. They enclose a liquid chemical sprinkled with carbon nanotubes. The nanotubes convert laser light to heat that bursts the nylon capsule, releasing the chemical. Using such a system, doctors, for example, might inject microcapsules containing anti-cancer drugs to specific cells and make the capsules burst upon exposure to laser light, delivering their contents precisely where and when they are needed in the body.

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Journal reference:

1. Pastine et al. Chemicals On Demand with Phototriggerable Microcapsules. Journal of the American Chemical Society, 2009; 131 (38): 13586 DOI: 10.1021/ja905378v

Adapted from materials provided by American Chemical Society, via EurekAlert!, a service of AAAS.

http://www.sciencedaily.com/releases/2009/10/091028114027.htm

Regeneration Can Be Achieved After Chronic Spinal Cord Injury

Scientists at the University of California, San Diego School of Medicine report that regeneration of central nervous system axons can be achieved in rats even when treatment delayed is more than a year after the original spinal cord injury.

“The good news is that when axons have been cut due to spinal cord injury, they can be coaxed to regenerate if a combination of treatments is applied,” said lead author Mark Tuszynski, MD, PhD, professor of neurosciences and director of the Center for Neural Repair at UC San Diego, and neurologist at the Veterans Affairs San Diego Health System. “The chronically injured axon is not dead.”

While there are more than 10,000 new spinal cord injuries annually in the United States, nearly 250,000 patients are living in the chronic stages of injury. Yet nearly all previous spinal cord injury studies have attempted to stimulate regeneration when treatment is begun almost immediately after injury — because, in part, scientists considered it very difficult to achieve regeneration at such long time points after injury. None had shown successful regeneration in the late, chronic stages.

Reporting in the October 29 issue of the Cell Press journal Neuron, the UC San Diego team demonstrated successful regeneration of adult spinal cord axons into, and then beyond, an injury site in the cervical spinal cord, the middle region of the neck. Treatment was begun at time periods ranging from six weeks to as long as 15 months after the original injury in rats.

A number of mechanisms create formidable barriers to regeneration of injured axons in chronic spinal cord injury. These include scar formation at the injury site, a partial deficiency in the intrinsic growth capacity of adult neurons, the presence of inhibitors to growth, and, sometimes, extensive inflammation. Chronically injured neurons show a loss of expression of regeneration-promoting genes, and there is progressive degeneration of spinal cord white matter beyond lesion sites — all contributing to a poor environment for axonal re-growth.

Even under ideal laboratory circumstances, axonal re-growth is complex, requiring a combination of three things: a cellular bridge in the lesion site; a nervous system growth factor to guide axons to the correct target; and a stimulus to the injured neuron that turns on regeneration genes. Using this combinatorial treatment, the research team achieved axonal bridging beyond the original lesion site in rats when treatment was delayed for up to 15 months after the original spinal cord injury. Animals lacking the full combination treatment did not exhibit axonal regrowth.

The scientists also conducted genetic studies to measure how broad sets of genes in cells can be activated when treatment is delayed after injury. They discovered that, despite considerable delays, most genes could still be turned on to support regeneration, indicating that a chronically injured cell can still be “primed” to grow.

The studies were done in sensory systems that relay the sense of touch from the body to the brain. In ongoing studies, the scientists are testing these approaches for regenerating axons that control movement in chronically injured rats.

“Our findings indicate that there is potential for promoting repair of the injured spinal cord even in chronic stages of injury,” said Tuszynski. “While the regenerating axons grow for relatively short distances, even this degree of growth could be useful. For example, restoration of nerve function even one level below an injury in the neck might improve movement of a wrist or hand, providing greater quality of life or independence.”

Contributors to the study include first authors Ken Kadoya and Shingo Tsukada, UCSD Department of Neurosciences; Paul Lu, UCSD Neurosciences and Veterans Affairs Medical Center, San Diego; Giovanni Coppola and Dan Geschwind, UCLA Department of Neurology; Marie Filbin, Hunter College, NY; and Armin Blesch, UCSD Department of Neurosciences. The study was funded by the National Institutes of Health, the Veterans Administration, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Bernard and Anne Spitzer Charitable Trust.

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Adapted from materials provided by University of California – San Diego.

http://www.sciencedaily.com/releases/2009/10/091028134620.htm

HIV Tamed By Designer ‘Leash’

This thin-section transmission electron micrograph (TEM) depicted the ultrastructural details of a number of human immunodeficiency virus (HIV) virus particles, or virions. (Credit: CDC/Dr. A. Harrison; Dr. P. Feorino)

Researchers have shown how an antiviral protein produced by the immune system, dubbed tetherin, tames HIV and other viruses by literally putting them on a leash, to prevent their escape from infected cells. The insights, reported in the October 30th issue of the journal Cell, a Cell Press publication, allowed the research team to design a completely artificial protein — one that did not resemble native tetherin in its sequence at all — that could nonetheless put a similar stop to the virus.

“Tetherin is essentially a rod with anchors at either end that are critical for its function,” says Paul Bieniasz of Howard Hughes Medical Institute and the Aaron Diamond AIDS Research Center at The Rockefeller University. Either one of those anchors gets incorporated into the envelope surrounding HIV or other viruses as they bud through the plasma membrane of an infected cell. “One anchor gets into the virus and the other in the cell membrane to inevitably form a tether.

“We showed we could design a completely different protein with the same configuration — a rod with lipid anchors at either end — and it worked very well,” he continued. The finding helped to confirm that tetherin is capable of acting all on its own, he added.

They also explain tetherin’s broad specificity to protect against many viruses. “It is just targeting lipids,” Bieniasz said. “It’s not about viral proteins.” That’s conceptually important, he continued, because there is no specific interaction between tetherin and any viral protein, which makes it a more difficult problem for viruses to evolve resistance. Rather than tweaking an existing protein-coding gene, “the virus has to make the more difficult adjustment of acquiring a new gene antagonist [of tetherin].”

Unfortunately, many viruses have managed to do just that. In the case of HIV, a protein called Vpu counteracts tetherin. They now show it does so by sequestering the host protein, which prevents its incorporation into the virus. The new insight into tetherin’s and Vpu’s modes of action, however, may lead to the development of Vpu blockers that could free up the innate host defense and inhibit HIV’s spread, Bieniasz suggests.

Bieniasz said there is some possibility that tetherin exists in different forms that might explain differences among people in the progression of HIV or other viral infections. However, the only common variation they’ve seen in the tetherin gene so far does not appear to affect its function. The tetherin sequence does vary quite a lot from one species to the next, he added, as is often the case due to strong selection when host defense genes meet viral inhibitors.

To place the findings in context, Bieniasz says it is worth noting that tetherin is encoded by just one of more than 900 genes that get switched “on” in response to interferon, a cell signaling protein of the immune system.

“There are hundreds of interferon-induced genes,” he said. “The functions are known for only a very small number — less than a dozen. There are potentially a large number of antiviral mechanisms we still know nothing about.”

Going forward, his team intends to look more closely at many of those others, and Bieniasz suspects more surprising mechanisms will be in store.

The researchers include David Perez-Caballero, The Rockefeller University, New York, NY; Trinity Zang, The Rockefeller University, New York, NY, Howard Hughes Medical Institute, Aaron Diamond AIDS Research Center, New York, NY; Alaleh Ebrahimi, The Rockefeller University, New York, NY; Matthew W. McNatt, The Rockefeller University, New York, NY; Devon A. Gregory, University of Missouri School of Medicine, Columbia, MO; Marc C. Johnson, University of Missouri School of Medicine, Columbia, MO; and Paul D. Bieniasz, The Rockefeller University, New York, NY, Howard Hughes Medical Institute, Aaron Diamond AIDS Research Center, New York, NY.

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Adapted from materials provided by Cell Press, via EurekAlert!, a service of AAAS.

http://www.sciencedaily.com/releases/2009/10/091029125530.htm

Fending Off the Flu

If H1N1 vaccine supplies fall short, people may have to turn to supplements, statins, and laser-coupled vaccination.

By Emily Singer

A number of common supplements and drugs can boost the immune system’s ability to ward off the flu and reduce symptoms once you have it, said Jeffrey Gelfand, a physician at Massachusetts General Hospital at the CIMIT (Center for Integration of Medicine and Innovative Technology) Innovation Congress this morning in Boston. Gelfand suggested that in the absence of adequate supplies of vaccine against the H1N1 flu strain, we’ll need to turn to less conventional measures. Clinical research shows that L-theanine, which is found in tea, and quercetin, a plant polyphenol, can reduce chances of getting an upper respiratory infection, he said. Both are available at stores that sell vitamin supplements.

Statins, the cholesterol-lowering blockbuster drug, can reduce symptoms of the flu, especially in younger people, the group hardest hit by H1N1. The drugs, many of which are available generically, reduce the “cytokine storm”–part of the immune reaction that occurs during sepsis and influenza infection. “I believe this could significantly reduce mortality,” said Gelfand.

Gelfand also said that changing our approach to vaccination could help extend limited vaccine supplies. One method currently under study is delivering vaccines to the skin, rather than to the muscle, as is done with current injections. Directly targeting the skin enhances the response from immune cells in the skin. His team is testing a laser-coupled injection system, in which a precise dose of laser light is used to briefly irritate the skin, attracting the target immune cells even more effectively. Initial studies show that this approach generates the same antibody response with only 20 percent of the amount of vaccine.

http://www.technologyreview.com/blog/editors/24324/