ScienceNow

Enlarge Image

Monkey business.
By blocking tiny pieces of RNA called microRNA in African green monkeys, researchers have shown the potential of using the strategy for fighting disease in humans.

Credit: RxGen Inc.

Scientists have taken a big step toward developing therapies based on naturally occurring tiny RNA molecules called microRNAs. In the first successful experiment with primates, researchers have blocked microRNAs to lower cholesterol levels in monkeys. This achievement builds hope that the strategy could one day be used to attack human diseases. Safety concerns still linger, however.

MicroRNAs regulate gene expression and play key roles in many biological processes, such as cell death and metabolism. Scientists have eyed microRNAs as potential targets for disease-fighting treatments because their malfunction has been implicated in cancer, heart disease, viral infections, and other disorders. Ailing mice have recovered thanks to microRNA-based therapies, but researchers have worried whether blocking overactive microRNAs in people will be feasible and safe. The new tests were led by Santaris Pharma, a biotech company in Horsholm, Denmark, focused on developing microRNA-based therapies. The company, which has developed a way to block microRNAs that is different from the strategies previously used in mice, put their method to the test by targeting a microRNA called miR-122 that regulates cholesterol levels.

Sakari Kauppinen, a molecular geneticist at Santaris, teamed with collaborators from Stanford University and RxGen, a biotech company in Hamden, Connecticut. They generated a short sequence of DNA that would bind to and block the function of miR-122. The DNA sequence was combined with a piece of RNA designed to increase its binding power to the microRNA. The researchers then injected the modified DNA sequence into African green monkeys at varying doses. In the five healthy monkeys that received the highest dose, cholesterol levels dropped by a maximum of 40% within 23 days, a strong indication that the therapy had stymied miR-122. Five animals that received a lower dose had a cholesterol drop of 20%. Of the 15 animals injected with the microRNA blocker, none showed any signs that the treatment was toxic, the researchers report online today in Nature. Kauppinen says his company's goal is to develop a hepatitis C treatment based on miR-122, because this microRNA is involved in replication of the virus in people.

John Rossi, a molecular geneticist at the City of Hope in Duarte, California, says the findings open the door for using microRNA-based therapies in people. That's because the research shows it is possible to get these microRNA blockers into the cells where they are needed, without causing apparent harm to the animal. This approach could now be adopted for developing treatments for other conditions, by generating DNA sequences that target specific microRNAs involved in diseases, he says.

Although no serious side effects were detected in the monkeys, both Rossi and Peter Kang, a neurologist at Children's Hospital Boston, say the safety of blocking microRNAs in humans must be carefully studied. Many microRNAs regulate numerous genes, so knocking down the expression of just one could have untold effects on the body, Rossi says.

Related sites

• More about microRNAs
• Video showing how microRNAs are formed and their function in the body

Enlarge Image

The eyes have it.
Scientists have discovered a new form of vision--the ability to see circularly polarized light--in the eyes of mantis shrimp, a reef-dwelling crustacean.

Credit: Justin Marshall/University of Queensland

When it comes to versatile vision, the mantis shrimp reigns supreme. Its specialized eyes can pick up several types of light, including infrared and ultraviolet, and its color vision tops ours. Now scientists report that this reef-dwelling crustacean has done itself one better: It can see a type of polarized light that no other animal is known to be able to detect. The function of this new form of vision is still a mystery, but researchers speculate that the crustacean may use it in mating displays or as a secret form of communication.

The key to the mantis shrimp's (Odontodactylus scyllarus) extraordinary vision is in the structure of its eyes, which consist of six rows of numerous smaller eyes called ommatidia. Justin Marshall first suspected that the shrimp could see a new type of light based on the way light-sensing cells in some ommatidia are arranged. They sit at just the angle to convert circularly polarized light (CPL)--a type of light wave that travels in a spiral--to a form that other cells underneath can detect, says Marshall, a sensory neurobiologist at the University of Queensland in Brisbane, Australia. Certain beetles have shells that change color when various types of CPL are shone on them, but no animal is known to have the ability to see this type of light. (To humans using special goggles, CPL appears as a bright light.)

Marshall and colleagues tested the mantis shrimp to see if they could distinguish between various forms of the light. Three of four animals learned to correctly identify a tube emitting left-handed CPL (corkscrewing to the left) in exchange for a bite of food, whereas two of three did the same for right-handed CPL, the researchers report online today in Current Biology. Although these sample sizes are small, co-author Roy Caldwell, an invertebrate biologist at the University of California, Berkeley, says they are sufficient to demonstrate that the shrimp can detect CPL. The question now is what they use it for.

Marshall says CPL vision may play a role in mating displays. Males--but not females--of at least three mantis shrimp species have body parts that reflect CPL. Another possibility is a mode of secret communication: Reflections of CPL off mantis shrimp bodies would likely be invisible to predators and competitors.

Whatever its role, CPL vision must be important to the animals, says Eric Warrant, an invertebrate biologist at Lund University in Sweden. "Evolution wouldn't have gone to all this trouble to develop this if it wasn't playing a role in some vital aspect of their lives," he says.

Related sites

• More about mantis shrimp
• More about the vision of mantis shrimp
• The basics of vision

Letters

• The impression created by this news item is that circularly polarized light (CPL) is invisible to all but the mantis shrimp, that humans need special goggles to see it, and that CPL does not induce a visual response in light receptors of humans or any other animal but this species of shrimp. Your readers should be advised that the wording in the article is misleading. All light can be construed to be composed of different ratios of the two "flavors" of CPL, left- and right-handed CPL. Any animal, plant or microbe sensitive to light is generally sensitive to circularly polarized light, just as they are to any other polarization of light or to unpolarized light. The retina or other visual receptors will respond approximately equally to CPL, linearly polarized light or unpolarized light.

The unique aspect of the mantis shrimp is its ability to discriminate between the two forms of CPL, left- and right-circularly polarized. As described in the Current Biology paper, the additional capability is due to specialized receptors that respond differently based on the polarization state, as opposed to common visual receptors that respond equally to different polarization states and so cannot discriminate between them.

I can certainly attest to my own propensity for seeing light equally, unaided, no matter the polarization, based on my daily interaction with various polarizations of light throughout the visible spectrum. Please do not leave your readers with the false understanding that they cannot see CPL, a small blemish on an otherwise fascinating item of science news.

Daniel Some, Ph.D.
Principal Scientist
Wyatt Technology Corp.
March 24, 2008

Enlarge Image

Premodern?
The shell of this fossil turtle may predate the ancestor of modern turtles.

Credit: (fossil) Juliana Sterli/Biology Letters (turtle) Jorge A.Gonzalez (2008)

As reptiles go, turtles are old--no question. They evolved before snakes and crocodiles and preceded dinosaurs. But establishing when the common ancestor of modern turtles first appeared has recently become controversial. Now a new fossil is backing the idea that modern turtles evolved more recently than previously thought.

Living turtles are divided into two main groups--the Cryptodira and the Pleurodira--based on where on the skull the muscles that close the lower jaw are attached. In the 1970s, paleontologist Eugene Gaffney of the American Museum of Natural History (AMNH) in New York City conducted the first modern analysis of turtle evolution. He proposed that almost all fossil turtles belonged within one or the other of these two modern, or crown, groups. That meant that the common ancestor of these turtles first appeared in the Late Triassic, some 210 million years ago.

Last year, paleontologist Walter Joyce of Yale University outlined a major revision of this classification. After reviewing all of the anatomical features, called characters, of the fossil turtles, he argued in the Bulletin of the Peabody Museum of Natural History that many of the fossil taxa were so different from modern turtles that they don't belong in either the Cryptodira or the Pleurodira groups. The implication is that these two groups only evolved about 150 million years ago. "Joyce's picture of turtle evolution is totally different," says James Parham of the California Academy of Sciences, who is based in Santa Barbara.

The new fossil backs this picture, say Joyce and Parham. It comes from Argentina and was discovered in central Patagonia by a joint expedition of the Museo Paleontológico Egidio Feruglio in Trelew and AMNH. About 35 centimeters long, the fossils of a shell and skull were found in ancient lake rocks, dating to between 160 million and 146 million years old--a period in which turtle fossils are few and far between. Juliana Sterli, a Ph.D. student at the Museo de Historia Natural de San Rafael in Mendoza, Argentina, set about describing and analyzing the fossil, which has been named Condorchelys antiqua. Sterli says her research shows that Condorchelys doesn't belong to the Cryptodira or Pleurodira and fits Joyce's hypothesis that the modern groups are at least 60 million years younger than previously thought.

"It's an important fossil," Gaffney says. "A discovery like this gives an important ... glimpse of early Jurassic turtles" in South America. But Gaffney thinks that the turtle fits within his original classification scheme--as a primitive Cryptodira--and is not evidence for Joyce's reinterpretation of turtle evolution. Sterli disagrees, based on analyses of anatomical details. If Joyce and Sterli are correct, Parham notes, then modern turtles would have taken much less time to evolve.

Related site

• Overview of Gaffney's history of turtle evolution

Talk about a low-down, dirty trick. New research reveals that bacteria deploy duplicates of human proteins to jam our body's early warning system. The results might lead to improved treatments for bacterial infections and for diseases such as arthritis that are caused by an overactive immune system.

Any good military defense employs radar, and our immune system is no exception. Immune cells known as macrophages and dendritic cells carry so-called Toll-like receptors, which raise the alarm if they detect bits of bacterial membrane or other telltale signs of microbial invasion. A portion of the Toll-like receptor called the TIR domain transmits the warning signal to another protein called MyD88, which passes it on to other molecules. The end result is the release of chemicals such as tumor necrosis factor (TNF) that summon infection-fighting cells.

Microbes have devised a few ways to escape detection. Two years ago, for example, researchers found that Salmonella bacteria manufacture proteins that are dead ringers for the TIR domain and that short-circuit the Toll-like alarm system. However, scientists didn't know how widespread this countermeasure was.

To find out, immunologist Thomas Miethke of the Technical University of Munich in Germany and colleagues scanned bacterial genome databases for genes that encode TIR-like proteins. The team reports online this week in Nature Medicine that it has identified these mimics in several bugs, including a strain of the intestinal bacterium Escherichia coli that can trigger urinary infections, and in a penicillin-resistant strain of Staphylococcus aureus. The proteins gave the bacteria an edge. E. coli that produce TIR mimics triggered more severe kidney infections in mice than did bacteria lacking the proteins. Likewise, in patients with E. coli-induced urinary tract infections, the more serious the illness, the more likely the microbes were copying human TIR.

What's going on? The fake TIRs act as decoys, the researchers report. They latch onto MyD88 and prevent it from receiving the alarm signal from the Toll-like receptors, but they don't alert immune cells. A drug that shut down the bacteria's ability to secrete these copycat proteins restored normal TNF release from macrophages in the culture dish, suggesting that it might prove effective against some infections.

"I think it's a great piece of work," says immunologist Bruce Beutler of the Scripps Research Institute in San Diego, California. The finding could have therapeutic benefits beyond fighting bugs, adds immunologist Luke O'Neill of Trinity College Dublin in the U.K. He notes that the copycat proteins might help researchers design drugs to quell autoimmune diseases such as arthritis and lupus, in which hyperactive Toll-like receptors provoke immune attacks on the body's own tissues.

Related site

• Science news story on Toll-like receptors

Enlarge Image

Old for her age.
Scientists are learning more about the molecular mechanisms behind progeria.

Credit: Progeria Research Foundation

Researchers have unearthed new clues behind a disease that effectively turns young children into senior citizens. A protein called progerin prods stem cells to go astray, causing them to mature into the wrong cell types. The findings may have implications for understanding normal aging as well.

Children with Hutchinson-Gilford progeria syndrome (HGPS) develop late-life ailments such as osteoporosis and atherosclerosis, and they usually die from heart disease in their early teens. In 2003, scientists identified the wrongdoer as progerin, a faulty version of the protein lamin A. Normally, lamin A helps strengthen the cell nucleus, but progerin leads to misshapen nuclei and higher-than-normal amounts of DNA damage. Beyond that, researchers didn't know much about how progerin results in illness.

To learn more, cell biologists Paola Scaffidi and Tom Misteli of the U.S. National Cancer Institute in Bethesda, Maryland, engineered cultured skin cells to manufacture progerin and then measured changes in gene activity. Of the more than 1000 genes whose activity levels changed in response to progerin, several belonged to a biochemical circuit known as the Notch pathway, which helps coax stem cells to specialize into a variety of cell types. That was an interesting clue because many progeria symptoms involve tissues derived from mesenchymal stem cells, which give rise to bone, muscle, and fat cells.

So Scaffidi and Misteli tested whether progerin disrupted development of cultured mesenchymal stem cells. As the researchers report online this week in Nature Cell Biology, the mutant protein prodded some stem cells to take an alternative path and become blood vessel cells. Stem cells that did transform into bonemakers were hyperactive, a result that gibes with recent clinical findings that HGPS patients build up and break down bone more rapidly than normal, says Misteli.

The researchers also found that progerin-producing stem cells were loath to mature into fat cells, which could explain why HGPS patients typically lose the fat layer beneath the skin, leading to thin skin. Cells that carried an overactive form of Notch showed similar developmental disruptions, suggesting that progerin makes trouble by turning up the Notch pathway. The work "links the cellular and molecular defects with symptoms in these patients," says Misteli.

The results might also provide insight into aging itself. Scaffidi and Misteli previously demonstrated that even normal cells fashion some progerin (Science, 19 May 2006, p. 1059), and the new data suggest that this small quantity might promote aging by undermining stem cells' capacity to replace damaged or dead cells.

"The results make a lot of sense," says developmental biologist Thomas Gridley of the Jackson Laboratory in Bar Harbor, Maine. The first trials of drugs to alleviate HGPS symptoms have just begun. However, notes developmental biologist Colin Stewart of the Institute of Medical Biology in Singapore, these medicines target progerin, and the findings suggest that compounds that intervene in the Notch pathway are also worth investigating.

Related sites

• More on HGPS from the National Center for Biotechnology Information
• The Progeria Research Foundation