Wednesday, January 20, 2010

NEW AND IMPROVED RNA INTERFERENCE

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Ever since RNA interference was discovered, in 1998, scientists have been pursuing the tantalizing ability to shut off any gene in the body — in particular, malfunctioning genes that cause diseases such as cancer.

Researchers at MIT and Alnylam Pharmaceuticals report that they have successfully used RNA interference to turn off multiple genes in the livers of mice, an advance that could lead to new treatments for diseases of the liver and other organs.

The new delivery method, described in the Proceedings of the National Academy of Sciences, is orders of magnitude more effective than previous methods, says Daniel Anderson, senior author of the paper and a biomedical engineer at the David H. Koch Institute for Integrative Cancer Research at MIT. It’s also the first method that can deliver as many as five genes — previous delivery vehicles could carry only one or two genes.

“This greatly improved efficacy allows us to dramatically decrease the dose levels, and also opens the door to formulations that can simultaneously inhibit multiple genes or pathways,” says Anderson.

RNA interference works by disrupting the flow of genetic information from a cell's nucleus to the protein-building machinery of the cell. The key to success is finding a safe and effective way to deliver the short strands of RNA that can bind with and destroy messenger RNA, which carries instructions from the nucleus.

Anderson and his colleagues believe the best way to do that is to wrap short interfering RNA (siRNA) in a layer of fat-like molecules called lipidoids, which can cross cells’ fatty outer membrane. Anderson and others in Institute Professor Robert Langer’s lab at MIT, along with Alnylam researchers, have developed methods to rapidly produce, assemble and screen a variety of different lipidoids, allowing them to pick out the most effective ones.

In a previous study, the researchers created more than 1,000 lipidoids. For their latest study, they picked out one of the most effective and used a novel chemical reaction to create a new library of 126 similar molecules. The team focused on one that appeared the most promising, dubbed C12-200.

Using C12-200, the researchers achieved effective gene silencing with a dose of less than 0.01 milligrams of siRNA per kilogram of solution, and 0.01 milligrams per kilogram in non-human primates. If the same dosing were translated to humans, a potential therapy would only require an injection of less than 1 milliliter — about a fifth of a teaspoon — to specifically inhibit a gene, compared with previous formulations that would have required hundreds of milliliters, says Anderson.

In studies with mice, the researchers were able to successfully deliver five snippets of RNA at once, and Anderson believes the lipidoids have the potential to deliver as many as 20. That could be a huge advantage in treating diseases such as cancer that result from multiple malfunctioning genes.

Four of the genes shut off in the mouse study are involved in metabolic pathways regulating cholesterol homeostasis; mutations in those genes have been linked to altered cholesterol levels. In a study of non-human primates, the researchers successfully turned off a gene for the protein TTR (transthyretin), which has been implicated in several diseases including senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy, with very low doses of RNA.

The liver is a natural starting point for studies of RNA interference delivered by nanoparticles, according to Anderson, because such particles are often carried to the liver and spleen, which filter the blood. Because of that, the some of the earliest targets for potential treatments will likely be liver diseases such as cancer or hepatitis.

John Rossi, a molecular biologist at the Beckman Research Institute in Duarte, Calif., says the ability to achieve gene silencing with such low doses of siRNA represents a “substantial breakthrough,” for several reasons: It reduces the cost of producing siRNA; offers potentially improved safety for patients who may receive injections over a long period of time; and could lead to new treatments for liver disease that would eliminate the need for liver transplantation.

“It will be of interest to see what other tissues the lipidoids penetrate with siRNA cargo, since this approach could have broad-based applications in the RNAi therapy world,” adds Rossi, who is working on RNAi therapies for AIDS and cancer.

(Photo: MIT)

MIT

TOXICANTS DETECTED IN ASIAN MONKEY HAIR MAY WARN OF ENVIRONMENTAL THREATS

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Testing hair from Asian monkeys living close to people may provide early warnings of toxic threats to humans and wildlife, according to a study published online last week in the American Journal of Physical Anthropology.

In parts of South and Southeast Asia, macaques and people are synanthropic, which means they share the same ecological niche. They drink from identical water sources, breathe the same air, share food sources, and play on the same ground.

"Macaques are similar to humans anatomically, physiologically and behaviorally," said the senior author on the study, Dr. Lisa Jones-Engel, a senior research scientist at the National Primate Research Center at the University of Washington in Seattle.

"They are also similar in their response to toxic exposures," said lead author Dr. Gregory Engel, a physician at Swedish Cherry Hill Family Medicine in Seattle and a research scientist at the UW National Primate Research Center. When macaques live in environments polluted by motor vehicles, openly disposed garbage, and industrial waste, they can come into contact with toxic substances such as lead, just as their human neighbors might.

Lead toxicity, the authors noted, remains a significant public health problem around the world. Intense exposure to lead can damage the nervous, circulatory, and reproductive systems, as well as the kidneys and liver. Exposure during childhood, according to other studies, may cause more subtle effects, such as decreased intelligence.

According to Jones-Engel, the researchers hypothesized that young macaques, in particular, would be good sentinels for human exposure to lead.

"Young macaques share a propensity for curiosity and have a penchant for picking up objects and inserting them into their mouths, just as young children do," Jones-Engel noted. "A juvenile macaque has all the curiosity and energy of a toddler, and then some! Plus their parents aren't well informed about environmental hazards."

She and her team of primatologists, physicians, epidemiologists, veterinarians and toxicologists decided to test urban macaques as a potential early indicator that their human neighbors, especially the children, are being exposed to lead and other toxic metals. They took hair samples from three groups of free-ranging macaques at the Swoyambu temple overlooking Kathmandu, Nepal. The macaques patrolling the site have abundant contact with people and with human-made environments. This World Heritage Site temple is located in a densely populated urban area with poor infrastructure that leaves point sources like discarded lead batteries, flaking leaded paint, and lead contaminated soil, a by-product of decades of leaded fuel, in the environment.

Hair lead levels differed among the three groups of macaques, and were much higher in younger macaques. The researchers' data did not support the idea that these lead levels were from basic differences in the animals' diet, and instead suggested that, in this population of macaques, behavioral or physiological factors among young macaques might play a significant role in determining exposure to lead and subsequent tissue concentration.

Animal sentinels of poisonous conditions for people have been used for a long time. From the 19th century and well into the 20th century coal miners sent canaries into mining shafts to check if the air was safe to breathe.

"While using animal sentinels is not a new phenomenon, we argue that not all animal species are relevant models for human toxicant exposures, but young macaques that share the same ecological niche with humans may be one of the best animal sentinels we have," Engel said.

Scientists testing for environmental exposures also don't want to hurt the animals they are monitoring. Collecting a few hairs is a gentle, non-invasive approach.

The researchers noted, "All of these factors contribute to making synanthropic macaques -- those that share the environment with humans -- potentially valuable as sentinels for toxic exposures and predictors of physiologic responses in humans."

The research team concluded, "Chemical analysis of hair is a promising, non-invasive technique for determining exposure to toxic elements in free-ranging, non-human primates, and further multidisciplinary research is needed to establish whether it can be used to predict lead levels in humans who live in the same areas."

(Photo: Nantiya Aggimarangsee)

University of Washington

IMAGE REVEALS UNPRECEDENTED VIEW OF UNIVERSE

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Shown in an extremely broad range of color and showcasing more than 12 billion years of cosmic history, Hubble's recent image is a full-glory cosmic renaissance of the history of the Universe. This image provides a record of the Universe's most exciting formative years, from the birth of stars in the early Universe all the way through the materialization of the Milky Way.

Constructed from mosaics taken with the newly installed Wide Field Camera 3 (WFC3) in fall 2009 and Hubble Space Telescope's Advanced Camera for Surveys (ACS) taken in 2004, the final image combines a broad range of colors, from the ultraviolet, through visible light, into the near infrared. Such a detailed multi-color view of the Universe has never been assembled before at such a level of clarity, accuracy and depth.

"It's like taking off rose-colored glasses and seeing the Universe in a whole new light, and what we're seeing is fantastic," says Rogier Windhorst, a professor in the School of Earth and Space Exploration, an academic unit of the College of Liberal Arts and Sciences at Arizona State University, and a member of the WFC3 Science Oversight Committee. "We're seeing stars on a galactic scale being born, we're seeing galaxies in formation, galaxies replenished with new fuel for making stars. We're seeing a messy Universe, a Universe in action, and we're seeing it like astronomers have never seen it before."

Hubble's sharp resolution and new color versatility, accomplished by combining data from the two cameras, is allowing astronomers to sort out the various stages of galaxy assembly, from the mature spiral and elliptical galaxies in the foreground, to smaller, fainter, irregularly shaped galaxies that are in general farther away, and hence existed farther back into time. These smaller galaxies are considered the building blocks of the larger galaxies that we see today. The wide range of new colors now observed with WFC3 also allows astronomers to estimate a galaxy's distance from Earth, and reveal information about its stellar populations.

Acquiring this image was much more time intensive than simply pointing and shooting. The data that comes off the telescope is in a raw form that requires processing. The Science Oversight Committee designed a science program to test and demonstrate the science capabilities of the WFC3, referred to as Early Release Science (ERS) data. Windhorst and students in the School of Earth and Space Exploration have been involved in the processing and analyzing the ERS data, spending the better part of July and August calibrating the data and removing background artifacts.

"Certain instrumental effects and cosmetic problems have to be taken out," explains Seth Cohen, a postdoctoral research associate in SESE. "Some artifacts are due to cosmic rays or satellites, while others are due to the detectors themselves. You have to remove all these things before you can do the science. You don't want to mistake the residual effects of these in your image if they are not due to something in your galaxy of interest."

"Your eye is very good at picking out the artifacts, but you have to train a computer to do this and use software to reduce these out," says Michael Rutkowski, a graduate student in SESE who has worked on preparing the image.

The image shows a rich tapestry of 7,500 galaxies stretching back through most of cosmic history. The closest galaxies seen in the foreground emitted their observed light only 0.9 billion years ago. The farthest galaxies, a few of the very faint red specks, are seen as they appeared more than 13 billion years ago, or roughly 650 million years after the Big Bang. This mosaic spans a slice of space that is 10 arc minutes across in its largest diameter, or about one-third of the diameter of the full Moon in the sky.

The new Hubble view highlights a wide variety of stages in the galaxy assembly process. The WFC3 ultraviolet light shows the blue glow of hot, young stars in galaxies teeming with star-birth. The orange light reveals the nearly final assembly stages of massive galaxies about 8 billion to 10 billion years ago. The near infrared reveals the red glow of very distant galaxies – in a few cases as far as 12 billion to 13 billion light years away – whose light has been stretched, like a toy Slinky, from ultraviolet light to longer-wavelength infrared light due to the expansion of the Universe.

The region covers a portion of the Great Observatories Origins Deep Survey's (GOODS) Southern field, first observed by Hubble with the ACS in 2004, and now with Hubble's new WFC3 from September to October 2009.

In this ambitious use of Hubble's observing time, the 2004 ACS exposures totaled over 100 orbits in the optical in this portion of the sky, and the new WFC3 exposures total 104 orbits in the ultraviolet and near-infrared. The image was made from a mosaic of 2x4 WFC3 ultraviolet pointings, and 2x5 WFC3 near-infrared pointings. In just two orbits per pointing, the WFC3 peered deeper into the Universe than comparable near-infrared observations from ground-based telescopes. This set of unique new Hubble observations reveals galaxies to about 27th magnitude in brightness over a factor of 10 in wavelength.

"Having this broad spectrum wavelength coverage allows us to do many different things that we couldn't do before without having deep observations at all these wavelengths at the Hubble resolution," Cohen says.

Astronomers are using this multi-color panorama to trace many details of galaxy formation over cosmic time: the star-formation rate in galaxies, the rate of mergers among galaxies, and the abundance of weak active galactic nuclei, along with many other measurable quantities.

Rutkowski is most excited about the panchromatic nature, particularly the UV capabilities since UV astronomy can't be done from the ground.

"My interest is in elliptical galaxies known as "red and dead galaxies." We believed that there wasn't much going on by way of current star formation in these galaxies, but as the UV becomes more accessible, there are a lot of red and dead galaxies that are actually quite blue. This image suggests that they're neither as red nor as dead as we originally thought."

(Photo: ASU)

Arizona State University

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