Author Archives: Arielle Duhaime-Ross

Bundled RNA balls silence brain cancer gene expression

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{credit}Mirkin lab, Northwestern{/credit}

Scientists have developed a nanotechnology-based way to silence a key genetic switch involved in the formation of glioblastoma brain cancer. The technique, which delayed tumor growth in mice, consists of an injection of synthetic balls of RNA with a gold nanoparticle core. Researchers think similarly engineered RNA blobs, called spherical nucleic acids (SNAs), could eventually be used to treat Alzheimer’s disease and other neurodegenerative ailments.

“We are really excited about this,” says Alexander Stegh, a cancer biologist at the Northwestern University Feinberg School of Medicine in Chicago who helped develop the new cancer-killing SNA platform. “It’s a really novel approach.”

One of the biggest challenges for researchers wishing to treat brain-related diseases is crossing the blood-brain barrier, a separation of circulating blood that blocks bacteria and large molecules from entering the brain. Recent attempts to address this issue in brain cancer have involved injecting gene-silencing RNA directly into brain tumors. This method, called RNA interference (RNAi), is designed to neutralize the expression of important oncogenes. But injecting RNA through the skull poses a number of safety and logistical issues, and is inefficient in cases involving more than one tumor site.

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Seeing through the smoke with the help of research: a conversation with Helen Meissner

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{credit}NIH{/credit}

Most people stopped doubting the dangers of tobacco long ago. And yet, tobacco products continue to adorn the checkout kiosks of convenience stores and appear in the pages of magazines. The question is: which of these products should be allowed and which should not? It’s no longer a theoretical question: the US Food and Drug Administration (FDA) was granted the power to regulate these products four years ago.

More research will help the FDA make tough decisions in this area, says Helen Meissner, the director of the Tobacco Regulatory Science Program at the US National Institutes of Health (NIH). Meissner is leading a joint effort with the FDA to study how to bring science-based regulation to the manufacturing, marketing and distribution of products such as cigarettes. On 19 September, the two agencies announced that they would grant a total of $53 million to 14 research teams working on tobacco-related projects across the US. Nature Medicine asked Meissner about the newly formed Tobacco Centers of Regulatory Science (TCORS) and the challenges of government-funded research in this space.

What are the biggest research goals of this new funding effort, broadly speaking?

The FDA [needs] to understand tobacco products in order to review tobacco products. They need product standards. They need to know how best to monitor compliance and enforcement, say with advertising or youth access. And they also need information on the best ways to communicate about tobacco products through media and education campaigns.

And how will the 14 centers come together and communicate?

They will be coming together through grantee meetings, so there will be collaborative activities across the centers. Although each is independent and they have different seams—as I mentioned they cover different areas—there is synergy as well across the centers. So that is the role of NIH: to convene the groups.

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Centipede venom trumps morphine in mouse study of pain

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Centipede picturePlacing a Chinese red headed centipede on a burn can speed up the healing process, according to ancient Chinese medicine. But a mouse study published today suggests that what the Chinese interpreted as a healing effect may in fact have been the handiwork of a pain-inhibiting peptide contained within this centipede’s venom, which kills insects but is harmless in humans. The results indicate that the peptide, called m-SLPTX-Ssm6a, is a powerful analgesic that, in some cases, surpasses the effect of morphine. Given its apparent lack of side effects, Ssm6a is seen by scientists as an attractive candidate drug compound that might prove suitable for treating chronic pain.

Researchers first discovered Ss6ma’s effect by screening it, and other peptides, for the ability to inhibit Nav 1.7, a channel located on the surface of nerve cells that allows sodium to transmit pain signals when the cell membrane is depolarized. Nav 1.7’s importance in pain signaling came to light in 2006 when researchers linked mutations in the channel to a rare genetic condition in which people are unable to perceive pain. The finding led many researchers to suggest developing pain medications composed of small molecules that could block the channel.

But there was a problem with this approach: Nav 1.7 is one of nine types of so-called ‘voltage-gated sodium channels’, all endowed with similar channel entrances that, if blocked all at once, would lead to major neurological malfunctions including cardiac arrest. “This makes it really hard to get selectivity,” explains Glenn King, a structural biologist of the University of Queensland, Australia, and a co-author of the study, which appears in the Proceedings of the National Academy of Sciences. Luckily, he says, “toxins found in venoms are much bigger,” so their action does not take place at the channel entrance.

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Months after an injury has healed, receptors involved in modulating pain remain active

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shutterstock_139125542Pain researchers know that, in the immediate aftermath of a severe injury, pain sensitization pathways become active, causing the body to produce opioids—naturally occurring chemicals that inhibit pain by activating receptors. But a mouse study published today in Science reveals that a specific type of opioid receptor found on the surface of nerve cells remains hyperactive months after an injury has healed—a period much longer than previously thought. Moreover, blocking this receptor from binding opioids can produce opioid withdrawal, much like that experienced by people addicted to heroin or codeine. This finding suggests that opioids only serve to mask underlying pain, shedding light on why some chronic nature of pain disorders.

To study the long-term role of ‘endogenous’ opioids produced naturally by the body, scientists created an inflammatory response in the paws of mice by injecting a dose of toxic bacteria fragments. The researchers then allowed the injury to heal for a period of three weeks or more, all the while monitoring how sensitive the area was by using molecular biomarkers and recording how often the rodents made facial grimaces or withdrew their paws when the injured area was touched.

Six months on, once the injury had healed, the researchers administered naltrexone methobromide, a drug that blocks the receptors that can normally bind to opioids. Surprisingly, blocking the receptor’s activity caused the pain to return, even though considerable time had passed. Moreover, the mice also exhibited the telltale signs of opioid withdrawal, such as jumping, shaking and teeth chattering. “We think it’s possible that the body becomes dependent on the endogenous opioid system after an injury,” says neurobiologist and co-author Bradley Taylor, of the University of Kentucky in Lexington, “but this is speculative.” If these results are further validated, this could be the first recorded expression of what the researchers call ‘endogenous opioid withdrawal’.

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Discovery of distinct peptides in brains of Alzheimer’s patients could help diagnosis

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Alzheimer’s patients with different medical histories might possess distinct variants of amyloid beta fibrils—the basic component of the plaque-like deposits found in the brains of people with the disorder—according to study of two affected individuals published online today in the journal Cell. The findings hint at the existence of Alzheimer’s disease subcategories, and suggest a potential path forward to improving the diagnostic specificity of this devastating illness.

It’s thought by some scientists that the overproduction of amyloid beta peptides, or perhaps the failure to clear this peptide, can cause an accumulation of these molecules and the formation of fibrils in the brain, possibility leading to inflammation and neurotoxic effects.

Previous studies demonstrated that amyloid beta fibrils cultured in a test tube can present different molecular structures and can retain these structures when grown from short fibril fragments. To determine if different structures of these peptide chains are also present in human brains, the study’s researchers gently extracted amyloid fibrils from postmortem brain tissue taken from two Alzheimer’s patients who had different medical histories. One of the individuals received an Alzheimer’s diagnosis while still alive. The other was had initially been diagnosed with another form of dementia, but an autopsy that revealed the hallmark amyloid plaques in his her brain that indicated Alzheimer’s.

The researchers then used the extracted amyloid beta fibrils to seed the growth of isotopically-labeled amyloid samples in sufficient quantity for analysis. A close inspection of the peptides revealed that the fibrils grown from one patient seemed to have a periodic twist in their structure that was absent from those grown from the other patient’s sample, which grew fibrils with a constant diameter of 7 nanometers. Importantly, each of the patients possessed a single type of structure that did not overlap with that found in the other.

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Lasker Awards go to rapid neurotransmitter release and modern cochlear implant

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A very brainy area of research has scooped up one of this year’s $250,000 Lasker prizes, announced today: The Albert Lasker Basic Medical Research Award has gone to two researchers who shed light on the molecular mechanisms behind the rapid release of neurotransmitters—findings that have implications for understanding the biology of mental illnesses such as schizophrenia, as well the cellular functions underlying learning and memory formation.

By systematically analyzing proteins capable of quickly releasing chemicals in the brain, Genentech’s Richard Scheller and Stanford University’s Thomas Südhof advanced our understanding of how calcium ions regulate the fusion of vesicles with cell membranes during neurotransmission. Among Scheller’s achievements is the identification of three proteins—SNAP-25, syntaxin and VAMP/synaptobrevin—that have a vital role in neurotransmission and molecular machinery recycling. Moreover, Südhof’s observations elucidated how a protein called synaptotagmin functions as a calcium sensor, allowing these ions to enter the cell. Thanks to these discoveries, scientists were later able to understand how abnormalities in the function of these proteins contribute to some of the world’s most destructive neurological illnesses. (For an essay by Südhof on synaptotagmin, click here.)

The Lasker-DeBakey Clinical Medical Research Award went to three researchers whose work led to the development of the modern cochlear implant, which allows the profoundly deaf to perceive sound. During the 1960s and 1970s Greame Clark of the University of Melbourne and Ingeborg Hochmair, CEO of cochlear implant manufacturer MED-EL, independently designed implant components that, when combined, transformed acoustical information into electrical signals capable of exciting the auditory nerve. Duke University’s Blake Wilson later contributed his “continuous interleaved sampling” system, which gave the majority of cochlear implant wearers the ability to understand speech clearly without visual cues. (For a viewpoint by Graeme addressing the evolving science of cochlear implants, click here.)

Bill and Melinda Gates were also honored this year with the Lasker-Bloomberg Public Service Award. Through their foundation, the couple has made large investments in helping people living in developing countries gain access to vaccines and drugs. The Seattle-based Bill & Melinda Gates Foundation also runs programs to educate women about proper nutrition for their families and themselves. The organization has a broad mandate in public health; one of its most well known projects is the development of a low-cost toilet that will have the ability to operate without water.

The full collection of Lasker essays, as well as a Q&A between Lasker president Claire Pomeroy and the Gateses, can be found here.