Naked Mole Rat Wins the War on Cancer

By Jocelyn Kaiser
ScienceNOW Daily News
26 October 2009

With its wrinkled skin and bucked teeth, the naked mole rat isn't going to win any beauty contests. But the burrowing, desert rodent is exceptional in another way: It doesn't get cancer. The naked mole rat's cells hate to be crowded, it turns out, so they stop growing before they can form tumors. The details could someday lead to a new strategy for treating cancer in people.

In search of clues to aging, cell biologists Vera Gorbunova, Andrei Seluanov, and colleagues at the University of Rochester have been comparing rodents that vary in size and life span, from mice to beavers. The naked mole rat stands out because it's small yet can live more than 28 years--seven times as long as a house mouse. Resistance to cancer could be a major factor; whereas most laboratory mice and rats die from the disease, it has never been observed in naked mole rats.

Gorbunova's team looked at the mole rat's cells for an answer. Normal human and mouse cells will grow and divide in a petri dish until they mash tightly against one another in a single, dense layer--a mechanism known as "contact inhibition." Naked mole rat cells are even more sensitive to their neighbors, the researchers found. The cells stop growing as soon as they touch. The strategy likely helps keep the rodents cancer-free, as contact inhibition fails in cancerous cells, causing them to pile up.

The reason, the researchers discovered, is that naked mole rat cells rely on two proteins--named p27Kip1 and p16Ink4a--to stop cell growth when they touch, whereas human and mouse cells rely mainly on p27Kip1. "They use an additional checkpoint," says Gorbunova, whose study appears online today in the Proceedings of the National Academy of Sciences (PNAS). When the team mutated the naked mole rat cells so that they grew much closer together than they had before, levels of p16Ink4a dropped.

The naked mole rat's kind of cancer prevention may prove relevant to humans because the same genes are involved, says Brown University cancer biologist John Sedivy. The rat's defenses "evolved separately but use the same nuts and bolts," he says. Sedivy writes in an accompanying commentary in PNAS that it may be possible to "tweak the entire network [of tumor-suppressing pathways] to develop new prevention strategies."

The next step, Gorbunova says, is to find other proteins and molecules that make up this new contact inhibition pathway. One obstacle is that little is known about the naked mole rat's genes. The critter has been proposed for genome sequencing but so far has been turned down. "I hope Vera's study will put the naked mole rate higher up in the queue," says George Martin, a researcher who studies aging and a professor emeritus at the University of Washington.

Secrets of frog killer laid bare

By Richard Black Environment correspondent,
BBC News website

Scientists have unravelled the mechanism by which the fungal disease chytridiomycosis kills its victims.

The fungus is steadily spreading through populations of frogs and other amphibians worldwide, and has sent some species extinct in just a few years.

Researchers now report in the journal Science that the fungus kills by changing the animals' electrolyte balance, resulting in cardiac arrest.

The finding is described as a "key step" in understanding the epidemic.

Karen Lips, one of the world authorities on the spread of chytridiomycosis, said the research was "compelling".

"They've done an incredible amount of work, been very thorough, and I don't think anybody will have problems with this.

"We suspected something like this all along, but it's great to know this is in fact what is happening," the University of Maryland professor told BBC News.

Skin deep

Amphibian skin plays several roles in the animals' life.

Most species can breathe through it, and it is also used as a membrane through which electrolytes such as sodium and potassium are exchanged with the outside world.

The mainly Australian research group took skin samples from healthy and diseased green tree frogs, and found that these compounds passed through the skin much less readily when chytrid was present.

Samples of blood and urine from infected frogs showed much lower sodium and potassium concentrations than in healthy animals - potassium was down by half.

In other animals including humans, this kind of disturbance is known to be capable of causing cardiac arrest.

The scientists also took electrocardiogram recordings of the frogs' hearts in the hours before death; and found changes to the rhythm culminating in arrest.

Drugs that restore electrolyte balance brought the animals a few hours or days of better health, some showing enough vigour to climb out of their bowls of water; but all died in the end.

Grail quest

Lead scientist Jamie Voyles, from James Cook University in Townsville, said the next step was to look for the same phenomenon in other species.

"This is lethal across a broad range of hosts, whether terrestrial or aquatic, so it's really important to look at what's happening in other susceptible amphibians," she said.

Another step will be to examine how the chytrid fungus (Batrachochytrium dendrobatidis - Bd) impairs electrolyte transfer.

"What this work doesn't tell us is the mechanism by which chytrid causes this problem with sodium," said Matthew Fisher from Imperial College London.

"It could be that Bd is excreting a toxin, or it could be causing cell damage. This causative action is actually the 'holy grail' - so that's another obvious next step."

The finding is unlikely to plot an immediate route to ways of preventing or treating or curing the disease in the wild.

Curing infected amphibians in captivity is straightforward using antifungal chemicals; but currently there is no way to tackle it outside.

Various research teams are exploring the potential of bacteria that occur naturally on the skin of some amphibians, and may play a protective role.

Understanding the genetics of how Bd disrupts electrolyte balance might lead to more precise identification of protective bacteria, suggested Professor Lips, and so eventually play a role in curbing the epidemic.

Gene therapy transforms eyesight of 12 born with rare defect

A single injection in a patient's eye brings 'astounding' results. The findings may offer hope for those with macular degeneration and retinitis pigmentosa.

By Thomas H. Maugh II
October 25, 2009

Pennsylvania researchers using gene therapy have made significant improvements in vision in 12 patients with a rare inherited visual defect, a finding that suggests it may be possible to produce similar improvements in a much larger number of patients with retinitis pigmentosa and macular degeneration.

The team last year reported success with three adult patients, an achievement that was hailed as a major accomplishment for gene therapy. They have now treated an additional nine patients, including five children, and find that the best results are achieved in the youngest patients, whose defective retinal cells have not had time to die off.

The youngest patient, 9-year-old Corey Haas, was considered legally blind before the treatment began. He was confined largely to his house and driveway when playing, had immense difficulties in navigating an obstacle course and required special enlarging equipment for books and help in the classroom.

Today, after a single injection of a gene-therapy product in one eye, he rides his bike around the neighborhood, needs no assistance in the classroom, navigates the obstacle course quickly and has even played his first game of softball.
The results are "astounding," said Stephen Rose, chief scientific officer of Foundation Fighting Blindness, which supported the work but was not involved directly. "The big take-home message from this is that every individual in the group had improvement… and there were no safety issues at all."

The study "holds great promise for the future" and "is appealing because of its simplicity," wrote researchers from the Nijmegen Medical Center in the Netherlands in an editorial accompanying the report, which was published online Saturday by the journal Lancet.

The 12 patients had Leber's congenital amaurosis, which affects about 3,000 people in the United States and perhaps 130,000 worldwide. Victims are born with severely impaired vision that deteriorates until they are totally blind, usually in childhood or adolescence. There is no treatment.Leber's is a good candidate for gene therapy because most of the visual apparatus is intact, particularly at birth and in childhood. Mistakes in 13 different genes are known to cause it, but all 12 of the patients suffered a defect in a gene called RPE65. This gene produces a vitamin A derivative that is crucial for detecting light.

About five children are born each year in the United States with that defect, which was chosen because researchers at the Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine had cloned the gene, making copies available for use.

The study, led by Dr. Katherine A. High, Dr. Albert M. Maguire and Dr. Jean Bennett of those two institutions, enrolled five people in the United States, five from Italy and two from Belgium. Five were children, and the oldest was 44.
The good copy of the RPE65 gene was inserted into a defanged version of a human adenovirus. The engineered virus then invaded retinal cells and inserted the gene into the cells' DNA.

Maguire used a long, thin needle to insert the preparation into the retina of the worst eye in each of the patients. Within two weeks, the treated eyes began to become more sensitive to light, and within a few more weeks, vision began to improve. The younger the patients were, the better they responded. That was expected, Bennett said, because similar results had been observed in dogs and rodents.

By both objective and subjective measures, vision improved for all the patients. They were able to navigate obstacle courses, read eye charts and perform most of the tasks of daily living. The improvement has now persisted for as long as two years.

The children who were treated "are now able to walk and play just like any normally sighted child," Maguire said.

Bennett noted that the oldest patient in the trial, a mother, had not been able to walk down the street to meet her children at school. "Now she can. She also achieved her primary goal, which was to see her daughter hit a home run."

There are clear limitations to the study. The patients' vision was not corrected to normal because of the damage that had already been done to the retina, and only one eye was treated.

"The big elephant in the room is: Can you treat the other eye?" Rose said.
The foundation will put more funding into the research "to make sure that if you go back and treat the other eye, it won't ablate the positive results in the first eye due to an immune reaction or something else."

Researchers also have not optimized the dosage of the adenovirus used to carry the gene into the eye. Those issues will be studied in Phase 2, a larger clinical trial that they hope to begin soon.

Meanwhile, the team has begun treating some patients at the University of Iowa.
Researchers also hope they will be able to translate the results to other congenital conditions using different genes.

Leber's is one form of retinitis pigmentosa, which affects an estimated 100,000 Americans.

The findings might be applicable to macular degeneration, which affects an estimated 1.25 million Americans and is the major cause of visual impairment in the elderly.

World’s oldest human-linked skeleton found

‘Ardi’ predates Lucy by a million years, changes scientific view of origins

By Randolph E. Schmid
updated 6:23 p.m. CT, Thurs., Oct . 1, 2009

WASHINGTON - The story of humankind is reaching back another million years with the discovery of “Ardi,” a hominid who lived 4.4 million years ago in what is now Ethiopia.

J.H. Matternes
An artist's rendering shows Ardipithecus ramidus as it might have looked in life.

The 110-pound, 4-foot female roamed forests a million years before the famous Lucy, long studied as the earliest skeleton of a human ancestor.
This older skeleton reverses the common wisdom of human evolution, said anthropologist C. Owen Lovejoy of Kent State University.
Rather than humans evolving from an ancient chimplike creature, the new find provides evidence that chimps and humans evolved from some long-ago common ancestor — but each evolved and changed separately along the way.
“This is not that common ancestor, but it’s the closest we have ever been able to come,” said Tim White, director of the Human Evolution Research Center at the University of California, Berkeley.
The lines that evolved into modern humans and living apes probably shared an ancestor 6 million to 7 million years ago, White said in a telephone interview.
But Ardi has many traits that do not appear in modern-day African apes, leading to the conclusion that the apes evolved extensively since we shared that last common ancestor.
A study of Ardi, under way since the first bones were discovered in 1994, indicates the species lived in the woodlands and could climb on all fours along tree branches, but the development of their arms and legs indicates they didn’t spend much time in the trees. And they could walk upright, on two legs, when on the ground.
Formally dubbed Ardipithecus ramidus — which means root of the ground ape — the find is detailed in 11 research papers published Thursday by the journal Science.
“This is one of the most important discoveries for the study of human evolution,” said David Pilbeam, curator of paleoanthropology at Harvard’s Peabody Museum of Archaeology and Ethnology.
“It is relatively complete in that it preserves head, hands, feet and some critical parts in between. It represents a genus plausibly ancestral to Australopithecus — itself ancestral to our genus Homo,” said Pilbeam, who was not part of the research teams.
Scientists assembled the skeleton from 125 pieces.

The area where "Ardi" was found is rich in sites where the fossils of human ancestors have been found.
Lucy, also found in Africa, thrived a million years after Ardi and was of the more humanlike genus Australopithecus.
“In Ardipithecus we have an unspecialized form that hasn’t evolved very far in the direction of Australopithecus. So when you go from head to toe, you’re seeing a mosaic creature that is neither chimpanzee, nor is it human. It is Ardipithecus,” said White.
White noted that Charles Darwin, whose research in the 19th century paved the way for the science of evolution, was cautious about the last common ancestor between humans and apes.
“Darwin said we have to be really careful. The only way we’re really going to know what this last common ancestor looked like is to go and find it. Well, at 4.4 million years ago we found something pretty close to it,” White said. “And, just like Darwin appreciated, evolution of the ape lineages and the human lineage has been going on independently since the time those lines split, since that last common ancestor we shared.”
J.H. Matternes
An artist's rendering shows Ardipithecus ramidus as it might have looked in life.
Some details about Ardi in the collection of papers:

• Ardi was found in Ethiopia’s Afar Rift, where many fossils of ancient plants and animals have been discovered. Findings near the skeleton indicate that at the time it was a wooded environment. Fossils of 29 species of birds and 20 species of small mammals were found at the site.


• Geologist Giday WoldeGabriel of Los Alamos National Laboratory was able to use volcanic layers above and below the fossil to date it to 4.4 million years ago.


• Ardi’s upper canine teeth are more like the stubby ones of modern humans than the long, sharp, pointed ones of male chimpanzees and most other primates. An analysis of the tooth enamel suggests a diverse diet, including fruit and other woodland-based foods such as nuts and leaves.


• Paleoanthropologist Gen Suwa of the University of Tokyo reported that Ardi’s face had a projecting muzzle, giving her an ape-like appearance. But it didn’t thrust forward quite as much as the lower faces of modern African apes do. Some features of her skull, such as the ridge above the eye socket, are quite different from those of chimpanzees. The details of the bottom of the skull, where nerves and blood vessels enter the brain, indicate that Ardi’s brain was positioned in a way similar to modern humans, possibly suggesting that the hominid brain may have been already poised to expand areas involving aspects of visual and spatial perception.


• Ardi’s hand and wrist were a mix of primitive traits and a few new ones, but they don’t include the hallmark traits of the modern tree-hanging, knuckle-walking chimps and gorillas. She had relatively short palms and fingers which were flexible, allowing her to support her body weight on her palms while moving along tree branches, but she had to be a careful climber because she lacked the anatomical features that allow modern-day African apes to swing, hang and easily move through the trees.


• The pelvis and hip show the gluteal muscles were positioned so she could walk upright.


• Her feet were rigid enough for walking but still had a grasping big toe for use in climbing.

The research was funded by the National Science Foundation, the Institute of Geophysics and Planetary Physics of the University of California, Los Alamos National Laboratory, the Japan Society for the Promotion of Science and others.