SUNDAY - December 16, 2007----------------------------------------------News Archive/Return to Today's News Alerts

Aging Gracefully Requires Taking Out the Trash

All cells undergo autophagy, which means self-eating. In the cell, when structures and proteins become damaged, vesicles called autophagosomes engulf and put the “bagged garbage” into a second group of vesicles, which use digestive enzymes to eat the "trash." This process escalates when animals are placed on a calorie-restricted diet which also extends lifespan.

Scientists at the Salk Institute for Biological Studies now report for the first time that boosting autophagy in the nervous system of fruit flies prevents age-dependent accumulation of cell damage in neurons and promotes longevity.

The age-related accumulation of proteins and lipids damaged by oxygen is considered a normal part of aging. In most age-associated diseases, such as Alzheimer’s, damaged proteins accumulate in excessive amounts leading to progressive cell death in the brain.

“The activation of autophagy facilitates the removal of damaged molecules that accumulate during cellular aging,” says senior author Kim Finley, Ph.D., a scientist in the Cellular Neurobiology Laboratory at the Salk Institute. “This may be particularly important in the nervous system since neurons produce damaged molecules at a much higher rate than most cell types.”

Keeping cells free of damaged molecules is critical for neurons because unlike many cells, they don't divide or replace themselves once created. “They rely on autophagy together with other clearance and detoxification pathways to keep themselves healthy and functioning for decades,” explains Finley.

Salk researchers focused on one particular protein in the fruit fly Drosophila, Atg8a, a protein essential for the formation of new autophagosomes. Finley and her team found that levels of Atg8a were significantly reduced by four weeks of age - middle age for a fruit fly - at the same time that proteins were not being cleared away by the cellular clean-up crew and starting to accumulate.

Without Atg8a things went from bad to worse, as damaged proteins tagged for degradation piled up - life expectancy plummeted.

“The abnormal accumulation of protein aggregates had striking similarities to those seen in the most common human neurodegenerative diseases,” says first author Anne Simonsen, Ph.D., a visiting scientist from the University of Oslo, Norway.

When the researchers kept the neuronal levels of Atg8a high, the genetically engineered flies were spared the ravages of time.

Insulin signaling and caloric restriction are two major determinants of longevity - they also impact the activity level of autophagy. Regulating autophagy, the cleanup work, may be the key factor in controlling the aging process, the researchers think. “By maintaining the expression of a rate-limiting autophagy gene in the aging nervous system there is a dramatic extension of lifespan and resistance to age-associated oxidative stress,” says Finley.

Published February 16, 2008 in the journal Autophagy



Immune Molecules Prune Synapses in Developing Brain

The complement cascade is part of the body's innate immune defense: a protein work crew that tags bacteria and other bad guys for elimination. A new study suggests that complement proteins may do similar work in the early brain, tagging unwanted synapses for removal. They may also induce synapse loss in early stages of many neurodegenerative diseases.

"This is part of a growing body of evidence that many molecules of the immune system have a second set of jobs in the brain," says Lisa Boulanger, a neurobiologist at the University of California, San Diego.

The new study began to determine whether astrocytes have a role in refining synaptic connections between neurons during development, says senior author Ben Barres of Stanford University in Palo Alto, California.

To their surprise, astrocytes spurred the neurons to produce a complement protein called C1q, which elsewhere in the body kicks off a cascade of chemical events ending in the destruction of any intruder cell. In mice, C1q concentrations in the retina and brain peak a week or so after birth and drop dramatically as mice mature. The peak coincides with the time unwanted synapses are being pruned. Likewise, C1q seems to concentrate on puny, immature-looking synapses in the developing nervous system.

In the brains of mice lacking a functional C1q gene, brain development had gone awry in the lateral geniculate nucleus, an area that receives input directly from retinal neurons. In normal mice, early geniculate neurons start off receiving input from both eyes. But then the neurons are pruned so that they receive input from only one eye. In mutant mice, geniculate neurons maintained input from both eyes even as adults.

Boulanger says: "When you get rid of these proteins that we thought just functioned in the immune system, it disrupts a very specific event that we think is involved in making the precise, final connections in the developing visual system."

Finally, Barres and colleagues are collaborating with Simon John's group at the Jackson Laboratory in Bar Harbor, Maine, to investigate C1q's role in synapse loss in a mouse model of glaucoma. Compared to normal adults, adult glaucoma mice exhibit elevated C1q levels - and again, the protein accumulates at retinal synapses early, even before synapses disappear and neurons die off.

Synapse loss precedes cell death in Alzheimer's and other neurodegenerative diseases, Barres notes. He wonders whether blocking this complement cascade may stall neurodegeneration in a number of disorders. Says Monica Vetter, a neurobiologist at the University of Utah in Salt Lake City: "There's good evidence that these complement components are upregulated in other diseases."

Published December 14, 2007 issue of the journal Cell.



How Molecular Muscles Help Cells Divide

Time-lapse videos and computer simulations provide the first concrete molecular explanation of how a cell flexes tiny muscle-like structures to pinch itself into two daughter cells at the end of each cell division.

Cell biologists at Yale and physicists at Columbia teamed up to model and then observe the way a cell assembles this “contractile ring” - a short-lived force-producing structure - that physically divides cells and is always located precisely between the two daughter cell nuclei.

“This contractile ring is thought to operate like an old-fashioned purse string,” said senior author Thomas D. Pollard, Sterling Professor and Chair of the Department of Molecular, Cellular & Developmental Biology at Yale. “It constricts the cell membrane into a cleavage furrow that eventually pinches the cell in two.”

Living cells divide into two daughter cells to reproduce themselves. In one-celled organisms like yeast, each cell division yields a new creature. In humans and other multicellular species, cell division creates an adult from an embryo.

In fully developed adults, it provides necessary replacements for cells that are continuously dying in the course of natural wear and tear.

Scientists have studied the structure of the cellular machinery, how it assembles and how the machine works, for a long timge. Since the 1970s, it was known that the contractile ring is made up of muscle-like actin and myosin - contractile proteins that are in some ways similar to the muscles used to move arms or legs. However, there was no mechanism to explain how it worked.

“We found that fission yeast cells assemble their contractile ring using a ‘search, capture, pull and release’ mechanism,” said Pollard. “This is important because it shows for the first time how the contractile machinery assembles and how all the pieces get to the right place to get the job done.”

Time-lapse images and computer models demonste that cells in mitosis set up small clusters of protein nodes on the inside of the cell membrane around the equator of the cell. Proteins in these nodes begin to put out a small number of actin filaments. These filaments grow in random directions until they meet another node, then myosin motors in that node pull on the actin filament and bring the two nodes together.

However, each connection only lasts about 20 seconds. "Release and capture" appears essential to the assembly process, say the scientists. Contractile ring assembly involves many episodes of search-release-capture. Eventually the nodes form into a condensed contractile ring around the equator, ready to pinch the mother into two daughters at the end stage.

“A novel and important aspect of this work was that we used computer simulations at every step to test what is feasible physically and to guide our experiments,” said author Ben O’Shaughnessy, professor of chemical engineering at Columbia.

“Future work will involve testing the concepts learned from fission yeast in other cells to learn if the mechanism is universal,” said Pollard. “Since other cells, including human cells, depend on similar proteins for cytokinesis [cell division], it is entirely possible that they use the same strategy.”

Published Online December 13, 2007 in the Science Express


SATURDAY - December 15, 2007-------------------------------------------News Archive/Return to Today's News Alerts

Stem Cells Overpower Duchenne Muscular Dystrophy

Duchenne muscular dystrophy, which predominantly strikes boys, is caused by a mutation in the gene for a protein called dystrophin that is essential for proper muscle function.

The condition leads to muscle degeneration, and patients usually die in their 30s.

A particular type of stem cell found in muscle can give rise to new muscle tissue, so a team led by geneticist Luis Garcia of Généthon, a nonprofit biotechnology firm in Évry, France, investigated whether these cells could be used to reverse the dystrophin problems.

The stem cells were obtained from patients via a muscle biopsy. Then a virus was used to insert a gene into the cells to correct the mutation in the dystrophin gene. The modified stem cells were then injected into arteries of the legs of mice with muscular dystrophy.

In just 3 weeks, muscles in the foot, shin, and thigh began expressing human dystrophin protein, indicating that the stem cells had induced the production of new muscle cells in the mice.

The real proof came in treadmill tests when treated mice were able to run longer, maxing out at 15 minutes, than untreated ill animals, which managed only 10 minutes before becoming exhausted.

Garcia says his team now plans to test the strategy in people with muscular dystrophy. He adds that the technique could be used to treat a variety of genetic diseases, including other muscle and skin disorders.

Stem cell scientist Robert Lanza of Advanced Cell Technology in Worcester, Massachusetts, calls the strategy promising. He adds that the stem cells used in the study have advantages over reprogrammed skin cells, including eliminating the tricky business of inducing the cells to become muscle cells, but he notes that both types of cells could pose risks because the virus used to modify them could cause cancer.

Published December 13, 2007 in the journal Cell Stem Cell


Female Sex Hormones Merit Better Research

Countless movies and TV shows make light of women's so-called "moodiness", often jokingly attributing it to their menstrual cycle or, conversely, to menopause.

In fact, mood disorders are a serious and pervasive health problem, and large-scale population studies have found women are 1.5 to 3 times more likely to suffer from major depressive disorder than are men.

In a newly published study, women's health experts from the University of Alberta argue there is an urgent need for carefully designed, gender-specific research to better understand the relationship of female sex hormones to mood states and disorders.

"The reasons for the gender disparity in rates of depression are not completely understood," says Kathy Hegadoren, the Canada Research Chair in Stress Disorders in Women at the University of Alberta.

"But there is growing evidence that estrogens have powerful effects beyond their role in reproduction-that they play a critical role in mood disorders in women-and this opens new avenues for research into the underlying biological mechanisms and treatment of depression."

Estrogen can be used to treat various mood disturbances in women-such as perimenopausal, postmenopausal and postpartum depression-but the results of these treatments can be difficult to interpret because researchers are only beginning to recognize the complex interactions among estrogens, serotonin and mood. "Right now, clinical use of sex-hormone therapies for the treatment of mood disorders is severely hampered by the inability to predict which women would respond well to such therapies," explains study co-author and U of A nursing professor Gerri Lasiuk.

"Most animal studies looking at the causes of depression have been conducted with male animals and use chronic-stress models, which are assumed to be similar to depression."

Hegadoren and Lasiuk's study recognizes that multiple factors may be at play in the development of mood disturbances, with individual, psychosocial and environmental factors interacting in complicated ways to create differential vulnerability in women and men. But they also point out that the link to sex hormones is hard to deny.

"Previous research has found that, before puberty, the rates of mood and anxiety disorders are similar in boys and girls. It's only after females begin menstrual function that a gender differential in mood disorders manifests itself. This, coupled with the observation that women appear to be especially vulnerable to mood disturbances during times of hormonal flux, certainly lends support to the claim that a relationship exists between sex hormones and mood," says Hegadoren.

Published October, 2007 issue of the journal Biological Research for Nursing.


UK Wants Fewer IVF Twin Births in Order to Save Lives

The fertility regulator in the UK, the Human Fertilisation and Embryology Authority (HFEA) has called for a reduction in the number of twin births from IVF.

Walter Merricks, the interim chair of the government fertility regulatory body says a new strategy is needed to reduce from 25% to 10% the number of twin and triplet births caused by fertility treatment.

Following a public consultation process the HFEA is calling for a three-year national strategy to change the way fertility clinics operate, so that fewer women have two or three embryos implanted simultaneously.

Merricks says current techniques were leading to hundreds of unnecessary baby deaths and he wants clinics to use fewer embryos and the NHS to pay for more IVF cycles to maintain success rates.

Very often clinics will implant more than one fertilised embryo in order to boost the chances of a pregnancy, with the result that 40% of IVF babies are either twins or triplets, compared with approximately 1% of those conceived naturally.

As twins and triplets tend to be born earlier they often face far greater health problems and as many as 60% need to spend some time in neonatal units, compared to 20% of singletons.

Multiple births represent the single biggest risk factor for babies born by IVF as they significantly increase the risk of premature birth and cerebral palsy, and pose long-term risks including heart disease.

Merricks says research has shown that in 2003 alone, the deaths of 126 IVF twins could have been avoided, had they been born as singletons.

The HFEA wants to see many women offered just one fertilised embryo, a step which would minimise the chances of a twin birth and would reduce the rate of multiple births.

Refinements in fertility treatment techniques now means that in many cases the chances of pregnancy are as good with a single embryo.

But the HFEA has not called for a total ban on the use of more than one embryo as some women who are older or have certain fertility problems may still need more than one embryo implanted to stand a reasonable chance of success.

At present the National Health Service (NHS) usually funds just one IVF cycle.

The HFEA also wants funding for fertility treatment to be increased, and treatments such as donor insemination and fertility hormone injections which also contribute to twin and triplet births to be regulated.

The British Fertility Society has welcomed the results of the consultation saying there was an "overwhelming case for change."

Published Online December 4, 2007 by the Human Fertilisation and Embryology Authority (HFEA)

FRIDAY - December 14, 2007-----------------------------------------------News Archive/Return to Today's News Alerts

Menopause in Chimps?

At about 35 years of age, fertility steeply decreases in women as their "pool" of oocytes steadily shrinks. And at an average age of 51 - when women have only about 1000 eggs left - they stop ovulating and enter menopause, typically living an additional 3 decades..

Wild female chimpanzees have a much shorter life span: More than 90% die by the age of 40, and scant data exists regarding whether survivors experience what's known as "reproductive senescence" - menopause.

Harvard University anthropologist Melissa Emery Thompson and colleagues - a who's who in chimpanzee research, including Richard Wrangham and Jane Goodall - followed 185 wild female chimpanzees for several decades.

Only 34 mothers survived past the age of 40, but nearly half of them gave birth, and one had a baby at the age of 55. In contrast to humans, says Emery Thompson, fertility in wild chimpanzees seems to senesce at the same pace as the rest of the body. "It's a completely normal mammalian pattern, just like cardiac function will decline with age."

Anthropologist Kristen Hawkes of the University of Utah in Salt Lake City says the new data adds compelling support for her long-held belief that the important difference between female chimpanzees and women is not the rate of oocyte depletion - but adult mortality.

"Do most adult female chimpanzees go through menopause?" asks Hawkes. "No, they die first. It's all a definitional thing."

Although Thompson agrees with Hawkes's mortality argument, she remains perplexed that so many of the surviving elderly chimpanzees her group followed were fertile. "We don't know at what age reproduction would stop in chimps because there's no indication of an age at which they cannot reproduce."

Wild elephants, which live about 10 years longer than chimpanzees, give birth into their 60s, indicating that the age of oocytes does not limit reproduction.

The uniquely long, postreproductive life span of women might have come about because of natural selection. Hawkes believes that human grandmothers who help provide food and care for their daughters, ultimately sustain a reproductive advantage as this care leads to more descendants from that grandmother.

"With chimpanzees, there's no real grandmothering," Emery Thompson notes.

Published December 13, 2007 in the journal Current Biology


How Women Bend Over Backwards for Babies

When human ancestors made the switch from walking on four legs to walking on two, they had to make several skeletal adjustments.

Vertebrae increased in number and thickness to provide added support to the upper body. The spine took on a curved shape in the lower back, to shift the shoulders backwards and move the centre of mass above the hips.

But the added bulk of pregnancy shifts that centre of mass forwards again, making a woman more likely to tip over towards the front. Pregnant women bring their centre of mass back over their hips by leaning back, deepening the curve at the base of their spine.

Katherine Whitcome and Daniel Lieberman from Harvard University in Cambridge, together with their colleague Liza Shapiro of the University of Texas at Austin, measured the centre of mass of 19 pregnant women and found that they leaned back by as much as 28º beyond the normal curve of the spine. This lowers the torque around the hip created by the baby's weight by roughly eight times.

Exaggerating the curve in the lower back can place more stress on the spine: vertebrae are more likely to slip against each other, leading to back pain or fractures. Whitcome and her colleagues found that a woman’s spine has several features that help to prevent that damage. In women, the curve in the lower back spans three vertebrae; in men, it encompasses just two. The added vertebra helps distribute the strain over a wider area.

Also, specialized joints located behind the spinal cord in women, called zygapophyseal joints, are 14% larger relative to vertebrae size in men, suggesting that the joints are well adapted to resist the higher force. The joints are also oriented at a slightly different angle in women, allowing them to better brace the vertebrae against slipping.

The researchers looked for, and found, the same trends between males and females in two Australopithecus fossils.

“Imagine strapping seven kilos to your belly and then leading a really active life hunting, gathering, running away from predators,” Lieberman says. Adaptation to upright walking on two legs meant the lower back of females had to adapt to vertical pregnancy - a key for survival.

Whitcome is now looking at the effect of child rearing on vertebrae, and Ward notes that it would be interesting to see how these changes integrate with adaptations made for long-distance running as some think the need for long-distance running provided a key selective advantage in human evolution

“But as anybody who’s been 9-months' pregnant knows, running is not the thing you want to be doing,” says Ward.

Published December 13, 2007 in the journal Nature.


How Semen May Boost HIV Transmission

Peptides clustered into long fibres in semen can enhance HIV transmission by as much as 100,000-fold, researchers have found. The results, if verified in a clinical setting, could identify a new way to help prevent the spread of the disease.

Over 80% of HIV infections are transmitted through sexual intercourse, primarily via semen from HIV-positive men.

Researchers studying the role of semen in HIV transmission, focus primarily on the quantity and type of virus contained in semen. "We’ve looked at everything except the semen itself," says Christopher Pilcher, an HIV researcher at the University of California, San Francisco, who was not affiliated with the study.

Peptide fibres are the latest in a growing list of naturally produced products in the body that impact HIV infection. Earlier this year, Frank Kirchhoff of the University of Ulm in Germany, together with Wolf-Georg Forssmann of IPF PharmaCeuticals in Hannover, Germany, reported the isolation of a peptide found in blood that inhibits HIV entry into cells (see Natural peptide protects against HIV).

Now, Kirchhoff and Forssmann have found that fragments of a protein called 'prostatic acidic phosphatase' strongly enhanced HIV transmission. The peptides were most active when they clustered together to form fibres called amyloid fibrils.

Depending on the laboratory assay being used, the fibres enhanced transmission of the virus by as little as 30-fold or as much as 400,000-fold.

Many human proteins can form amyloid fibrils, which are associated with several diseases including Alzheimer’s, Parkinson’s and diabetes. But none had been previously shown to affect virus transmission, says Per Westermark, who studies the fibrils at Uppsala University in Sweden.

The seminal fibres physically capture the HIV virus and help HIV to interact with host cells in culture. This suggests that drugs that prevent HIV from binding to the fibres could slow HIV spread, says Westermark.

Robin Shattock, an HIV researcher at St. George's, University of London, who has also been studying HIV transmission, says the results are promising but cautions against reading too much into them without additional clinical studies. “The definitive experiments have not been done,” says Shattock. Shattock argues that the peptide fibres need to be tested in a non-human primate by exposing mucosal surfaces to HIV in the presence or absence of semen.

Meanwhile, Pilcher estimates that clinical studies in humans could evaluate the relationship between seminal peptide-fibre content and HIV transmission within the next few years.

Published December 14, 2007 in the journal Cell.


THURSDAY - December 13, 2007-------------------------------------------News Archive/Return to Today's News Alerts

Walking Tall to Protect the Species

The transition from apes to humans may have been partially triggered by the need to stand on two legs, in order to safely carry heavier babies, according to Lia Amaral from the University of São Paulo in Brazil.

For safety, all nonhuman primate babies cling to their mother's fur from birth, species survival depends on this ability even though the pattern of carrying changes somewhat as the infant grows.

Newborns apes cling to their mother’s stomach, often with the additional support of one of mom's arms.

Months later, infants are carried slung over or around the adult body usually on the mother’s back, a position lasting for years in some primates.

However, carrying infants safely imposes limits on the weight of the infant. An adult gorilla is much heavier than an adult human, but its infant is only half the weight of a human baby.

Through a detailed mechanical analysis of how different types of apes - gibbons, orangutans and gorillas - carry their young, and while looking at the properties of ape hair and density, infant grip and carrying position - Amaral demonstrates that a relationship between infant weight, hair friction and body angle exists to ensure primate infants are carried safely.

She also shows how the usual pattern of primate carrying of heavy infants is incompatible with bipedalism. African apes have to persist with knuckle-walking on all fours, or ‘quadruped’ position, in order to stop their young from slipping off their backs.

Amaral believes that the reduction in body hair in the primates on their way to becomming early humans, would have forced bipedality in mothers as the only means to safely carry newborns, as overall body hair loss left babies with nothing to cling to.

The evolution to bipedality may have generated other important consequences for females. Carrying an infant restricts movement and places limits on food gathering for the mothers, and may have led to more group cooperation to support mothers and their young.

Published September 6, 2007 in the journal Naturwissenschaften


The Granddaddy of ALL Human Blood Cells

Researchers at the Stanford University School of Medicine have isolated a human blood cell representing the great-grandparent of all blood cells, a finding that could lead to new treatments for blood cancers and other blood diseases.

This cell, called the multipotent progenitor, is the first offspring of the much-studied blood-forming stem cell that resides in bone marrow and gives rise to all types of blood cells. It's also the cell that may give rise to acute myelogenous leukemia if mutated.

Isolating this cell, which is well known in mice but had yet to be isolated in humans, fills in an important gap in the human blood cell family tree.

Irving Weissman, MD, director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine, spent his early career identifying each cell in the mouse blood family tree. The progression went from the stem cell through the progenitor cell through progressively more specialized cells, ending up with the red blood cells, platelets and immune cells that make up the bulk of the blood.

This detailed information has helped researchers understand the origins of blood diseases and cancers and has led to advances in bone marrow transplantation. But studies in mice are never a perfect substitute for understanding those same cells in humans, said Ravindra Majeti, MD, PhD, an instructor in hematology and co-lead author of the paper.

Majeti isolated the human progenitor cell by grouping human blood cells according to proteins on their cell surface. He and co-lead author Christopher Park, MD, PhD, an instructor in pathology, then looked for a pool of cells that could form all the final cells of the blood, but lacked the ability to constantly renew their own supplies - a trait that is unique to the stem cell. Those characteristics are what distinguish the mouse progenitor cell, and, they thought, would likely be shared by the human equivalent.

One pool of cells fulfilled those requirements. Knowing the proteins on the surface of that cell, researchers can now reliably identify, isolate and study the cell in the lab.

Being able to isolate and study this cell has many implications for human disease, according to Majeti. First, this progenitor cell is also thought to be the cell that, after a number of mutations, eventually becomes the acute myelogenous leukemia stem cell. That's the cell that lies at the heart of the leukemia and that must be destroyed in order to cure the disease.

"We can compare the leukemic stem cell to this progenitor cell and from that find out what makes the leukemic stem cell different," Weissman said. That difference could very well be a target for leukemia treatments.

Another use for this cell could be in bone marrow transplantation, according to Majeti. Having the human progenitor cell means researchers can then produce all the cells of the blood in a lab dish. They can then take their pick of which cells would be most beneficial for possible transplantation.

Published December 13, 2007 in the journal Cell Stem Cell.


South Koreans Clone Glow in the Dark Cats

South Korean scientists have cloned cats by manipulating a fluorescent protein gene, a procedure which could help develop treatments for human genetic diseases, officials said Wednesday.

In a side-effect, the cloned cats glow in the dark when exposed to ultraviolet beams.

A team of scientists led by Kong Il-keun, a cloning expert at Gyeongsang National University, produced three cats possessing altered fluorescence protein (RFP) genes, the Ministry of Science and Technology said.

"It marked the first time in the world that cats with RFP genes have been cloned," the ministry said in a statement.

"The ability to produce cloned cats with the manipulated genes is significant as it could be used for developing treatments for genetic diseases and for reproducing model (cloned) animals suffering from the same diseases as humans," it added.

The cats were born in January and February. One was stillborn while two others grew to become adult Turkish Angoras, weighing 3.0 kilogrammes (6.6 pounds) and 3.5 kilogrammes.

"This technology can be applied to clone animals suffering from the same diseases as humans," the leading scientist, Kong, told AFP.

"It will also help develop stemcell treatments," he said, noting that cats have some 250 kinds of genetic diseases that affect humans, too.

The technology can also help clone endangered animals like tigers, leopards and wildcats, Kong said.

South Korea's bio-engineering industry suffered a setback after a much-touted achievement by cloning expert Hwang Woo-Suk turned out to have been faked.

The government banned Hwang from research using human eggs after his claims that he created the first human stem cells through cloning were ruled last year to be bogus.

Hwang is standing trial on charges of fraud and embezzlement.

Published December 12, 2007 by the Ministry of Science and Technology, Seoul, South Korea.


WEDNESDAY - December 12, 2007-----------------------------------------News Archive/Return to Today's News Alerts

The Strange Case of the Radiation-Resistant Bacteria

Fifty years ago, scientists experimenting with gamma radiation to sterilize canned foods were surprised to find spoiled meat in cans zapped with lethal levels of ionizing radiation (IR). Inside the bulging cans, they discovered a strain of bacteria now called Deinococcus radiodurans.

It turns out that this extremely resilient microbe can endure 100 times the IR levels that kill other bacteria and levels 2,000 times higher than the lethal human dose.

Efforts to understand D. radiodurans’s resistance have focused on how DNA repairs itself. Surprisingly, this extremophile relies on a set of apparently universal DNA repair proteins. As DNA repair and synthesis depends on proteins, which also suffer radiation damage, how does the protein manage to resurrect a radiation-shattered genome?

Turns out that in a 2004 study by Michael Daly, IR-resistant and IR-sensitive cells were found to have 300 times more manganese and three times less iron than more sensitive cells. Daly showed that high cytosolic manganese and low iron concentrations protected proteins, but not DNA, from IR damage. Their findings shifted the focus of toxicity and resistance away from DNA repair towards protein protection.

Exposing cells to IR generates molecules called reactive oxygen species (ROS). These molecules can accumulate faster than cellular scavengers can neutralize them, causing oxidative stress and killing cells. Hydroxyl radicals, one of the primary ROS products of irradiated water (the major component of cells), are particularly toxic to DNA, and can generate other ROS, including hydrogen peroxide and superoxide (a simple peroxyl radical).

High concentrations of manganese ions alleviate oxidative stress in several bacterial species. Daly tested manganese’s ability to scavenge hydroxyl and superoxide radicals to determine whether it protects DNA or proteins. The researchers irradiated DNA and a DNA-modifying enzyme and found that, although manganese ions failed to protect DNA from hydroxyl radicals generated during irradiation, the ions did prevent enzyme damage and preserved enzyme activity.

These results suggest that D. radiodurans relies on a detoxifying mechanism based on its unusual intracellular environment. Most organisms contain near-millimolar concentrations of iron, which when irradiated will form hydroxyl radicals and superoxide radicals killing the cells' repair proteins.

In resistant D. radiodurans, millimolar Mn(II) concentrations appear to protect proteins from oxidative damage by eliminating superoxide and its derivatives. This oxidative protection shields proteins involved in DNA repair, and allows them to quickly heal DNA lesions.

This new model of radiation toxicity opens up novel possibilities for radioprotection. Individuals exposed to chronic or acute doses of radiation might benefit from treatments delivering purified D. radiodurans Mn complexes into their cells. Or, the toxic effects of radiation therapy in cancer patients might be lesssened by antioxidant drugs based on this new protection paradigm.

How D. radiodurans survives radiation might even prove useful in our efforts to contain toxic runoff from the immense radioactive - and heavy-metal-contaminated waste sites left over from the Cold War.

Published March 20, 2007 in the journal PLoS - Public Library of Sciences Biology.


Protein-Dependent "Switch" Regulates Traffic in Epithelial Cells

Epithelial cells line the outside of nearly all organs. Now, researchers at Weill Cornell Medical College in New York City have discovered a molecular "switch" in epithelial cells that allows specific "motor proteins" (called kinesins) to transport surface markers produced inside the cell to reach the cell's surface.

"Not only are many more kinesins present in cells than previously thought, but their selectivity helps direct which packages of surface proteins are transported, as well as their ultimate destinations," explains lead researcher Dr. Geri Kreitzer, assistant professor in the department of cell and developmental biology at Weill Cornell Medical College.

"These proteins are essentially 'trains' pulling packets (vesicles) of essential proteins and lipids from production sites in the heart of the cell up to areas on the outer surface, where the cell interacts with its environment," Dr. Kreitzer explains.

The kinesin "trains" work by moving their cargoes along filamentous tracks, known as microtubules. "When everything is working right, appropriate surface markers end up where they need to go. However, in rare cases, mix-ups occur, and they can be devastating - causing sickness not only of cells but of the organ of which those cells are a part," Dr. Kreitzer explains.

Scientists have spent decades investigating vesicular trafficking. But the exact role for each of the 41 members of the kinesin family has remained unclear.

"We discovered something exciting: that the journey a particular surface marker makes depends on a specific member of the kinesin family. What worked for one protein did not work for the others," Dr. Kreitzer says.

Dr. Kreitzer's team also discovered that selectivity of the motor for its cargo (passenger) switches after the epithelial cell has fully matured. "When we worked with immature, developing cells, the type of kinesin used was clearly different."

The type of kinesin selected is a key piece of information determining where a particular surface protein will go. "That's great news for drug development, because it means that we might use this selectivity to target the appropriate motor protein whenever a specific pathway goes wrong," Dr. Kreitzer says. "That could potentially mean more effective, targeted therapies with fewer side effects."

"Right now, most chemotherapy targets the whole microtubule 'track'- that's a really heavy-handed approach that typically affects the cell as a whole and causes serious side effects."

"Imagine, though, that we could use what we now know about kinesins to target only the specific trafficking machinery that's gone awry," she says. "The result could be better, safer cancer care. And that paradigm holds true for a myriad of other diseases, as well."

Published October 9, 2007 in the journal Developmental Cell.


Like a Virgin ... Fly

The female fruit fly is a faithful lover, at least for several days. As soon as she mates, she rejects all other suitors and spends her time laying eggs. Now biologists have found the switch that turns on coy female behavior, to the delight of male flies and curious disease researchers.

The female fly's temporary monogamy is due to a mood-killing protein called sex peptide (SP). Male flies inject SP, along with their semen, into the female as a guard against potential competitors and to induce her into egg-laying. But the peptide's target goal has eluded researchers for decades.

To find SP's molecular partner, a team led by Barry Dickson, a biologist at the Research Institute of Molecular Pathology (IMP) in Vienna, Austria, introduced 13,000 virgin female flies to 13,000 eager males. In each female fly, a different gene had been turned off using a technique known as RNA interference. After every mating, the researchers counted the number of eggs that the females produced in 48 hours. Then they matched each female with another randy male. "If we managed to turn off the receptor for SP in a female," says IMP graduate student Nilay Yapici, "then she should lay few or no eggs and be as receptive as a virgin when she meets another male."

Of the 13,000 female flies tested, only one glowed with the antibodies used to home in on the location of the SP receptor (SPR) gene. It lit up in the female's sperm-storing organ and nervous system. Specifically, SPR clustered in neurons known to be involved in sexual behaviors. (SPR also showed up in males' nervous systems, though it is not clear what it does in males.) Blocking the production of SPR in just those brain cells made females behave like virgins, even if they were already impregnated. If a drug can be found that blocks SPR in mosquitoes, the researchers say, it could help combat malaria: Mosquito populations might crash as ever-frisky females mate instead of laying eggs.

"This is a major breakthrough," says Eric Kubli, a biologist at the University of Zurich in Switzerland. Whether mosquitoes use the same sexual behavior switches as fruit flies isn't certain, says Kubli. But a gene very similar in sequence to SPR is known in mosquitoes so the next step will be to knock it out too.

Published December 9, 2007, in the journal Nature.


TUESDAY - December 11, 2007---------------------------------------------News Archive/Return to Today's News Alerts

Findings Suggest We Are Becoming More Different, Not Alike

Researchers discovered genetic evidence that human evolution is speeding up – and has not halted or proceeded at a constant rate, as had been thought – indicating that humans on different continents are becoming increasingly different.

“We used a new genomic technology to show that humans are evolving rapidly, and that the pace of change has accelerated a lot in the last 40,000 years, especially since the end of the Ice Age roughly 10,000 years ago,” says research team leader Henry Harpending, a distinguished professor of anthropology at the University of Utah.

“We aren’t the same as people even 1,000 or 2,000 years ago,” he says, which may explain, for example, part of the difference between Viking invaders and their peaceful Swedish descendants. “The dogma has been these are cultural fluctuations, but almost any temperament trait you look at is under strong genetic influence.”

“Human races are evolving away from each other,” Harpending says. “Genes are evolving fast in Europe, Asia and Africa, but almost all of these are unique to their continent of origin. We are getting less alike, not merging into a single, mixed humanity.” He says that is happening because humans dispersed from Africa to other regions 40,000 years ago, “and there has not been much flow of genes between the regions since then.”

“Our study denies the widely held assumption or belief that modern humans [those who widely adopted advanced tools and art] appeared 40,000 years ago, have not changed since and that we are all pretty much the same. We show that humans are changing relatively rapidly on a scale of centuries to millennia, and that these changes are different in different continental groups.”

“The increase in human population from millions to billions in the last 10,000 years accelerated the rate of evolution because “we were in new environments to which we needed to adapt,” Harpending adds. “And with a larger population, more mutations occurred.” Study co-author Gregory M. Cochran says: “History looks more and more like a science fiction novel in which mutants repeatedly arose and displaced normal humans – sometimes quietly, by surviving starvation and disease better, sometimes as a conquering horde. And we are those mutants.”

Harpending conducted the study with Cochran, a New Mexico physicist, self-taught evolutionary biologist and adjunct professor of anthropology at the University of Utah; anthropologist John Hawks, a former Utah postdoctoral researcher now at the University of Wisconsin, Madison; geneticist Eric Wang of Affymetrix, Inc. in Santa Clara, Calif.; and biochemist Robert Moyzis of the University of California, Irvine.

“For example, in China and most of Africa, few people can digest fresh milk into adulthood. Yet in Sweden and Denmark, the gene that makes the milk-digesting enzyme lactase remains active, so “almost everyone can drink fresh milk,” explaining why dairying is more common in Europe than in the Mediterranean and Africa, Harpending says.

He now is studying if the mutation that allowed lactose tolerance spurred some of history’s great population expansions, including when speakers of Indo-European languages settled all the way from northwest India and central Asia through Persia and across Europe 4,000 to 5,000 years ago. He suspects milk drinking gave lactose-tolerant Indo-European speakers more energy, allowing them to conquer a large area.

But Harpending believes the speedup in human evolution “is a temporary state of affairs because of our new environments since the dispersal of modern humans 40,000 years ago and especially since the invention of agriculture 12,000 years ago. That changed our diet and changed our social systems. If you suddenly take hunter-gatherers and give them a diet of corn, they frequently get diabetes. We’re still adapting to that. Several new genes we see spreading through the population are involved with helping us prosper with high-carbohydrate diet.”

Published December 10, 2007 in the journal Proceedings of the National Academy of Sciences


When She's Turned On, Some of Her Genes Turn Off

When a female swordtail is attracted to a male, entire suites of genes in her brain turn on and off, found biologists from The University of Texas at Austin.

Molly Cummings and Hans Hofmann found that some genes were turned on when females found a male attractive, but a larger number were turned off.

“When females were most excited - when attractive males were around - we observed the greatest down regulation [turning off] of genes,” said Cummings, assistant professor of integrative biology. “It’s possible that this could lead to a release of inhibition, a transition to being receptive to mating.”

The same genes that turned on when the females were with attractive males - turned off when they were with other females.

This is one of few studies to link changes in the expression of genes with changes in an individual’s behavior in different social situations. Cummings and Hofmann suggest that the gene sets they studied could be involved in orchestrating mating responses in all vertebrates.

Female swordtails are attracted to males that are large and have ornaments on their bodies, such as long tails and striking coloration. In experiments, females were placed in the center of a tank separated into three zones for 30 minutes. When an attractive male was in one of the adjacent zones, females behaved indicating they had chosen a male for mating. The females were also tested with other females, with unattractive smaller males, and in empty tanks.

Then researchers immediately extracted RNA from the females and used gene array technology to identify genes that were being up regulated (turned on) and down regulated (turned off) in the females’ brains. Looking at more than 3,000 genes, they found 77 involved in the females’ mating behavior.

The genes turned on or off very quickly during the 30-minute testing period. “What we have not appreciated until now is how dynamic the genome is,” said Hofmann. “It is constantly changing and even in a very short period of time, 10 percent of the protein-coding genome can change its activity. We now have a genomic view of these dynamic processes within a social context.”

The biologists next want to identify specific regions in the brain where the genes are expressed so that they can enhance or inhibit specific genes and observe the resulting behavioral change. “We’d like to take a female who is a ‘high preference gal’ and make her a ‘low preference gal’ and vice versa,” said Cummings.

Understanding behavior and its underlying genetic causes can shed light on how behavior drives and maintains the evolution and diversification of species.

Published December 4, 2007 in the journal Proceedings of the Royal Society of London - Biology.


Pathways that Regulate Growth and Differentiation of Adult Muscle Stem Cells Revealed

During muscle regeneration, a natural response to injury and disease, environmental cues cause adult muscle stem cells (satellite cells) to shift from dormant to active in order to rebuild new muscle.

Although the signaling pathways controlling muscle regeneration are fairly well known, how these signals alter chromatin structure remains unsolved.

Now, a group of scientists at the Burnham Institute for Medical Research in La Jolla, CA, have analyzed the mechanism of specific cellular signals that cause expression of genes regulating growth and differentiation of muscle stem cells that repair injured muscle.

Pier Lorenzo Puri, MD, Ph.D., shows how two signaling pathways, PI3K/AKT and p38, work together to assemble components of protein complexes responsible for muscle-specific transcription, and how each pathway is responsible for a distinct step in the transcription process.

His team was also able to pharmacologically separate these two steps, showing that selective interference with either cascade leads to incomplete assembly of protein complexes, and prevent muscle-specific gene expression.

These results point to a possible pharmacological control of gene expression of adult muscle stem cells that have the therapeutic potential for regenerative medicine.

Published October 26, 2007, in the journal Molecular Cell.


MONDAY - December 10, 2007---------------------------------------------News Archive/Return to Today's News Alerts

US Warns About Bed-Wetting Drug After Two Deaths

U.S. health officials are alerting the public about the deaths of two patients who were treated with a prescription drug to control bed-wetting. One patient was 28 years of age and the other 80 years of age.

The Food and Drug Administration said it was unclear whether the drug, desmopressin, had contributed to the deaths. But nasal versions are no longer approved for treating bed-wetting and doctors should consider other options.

Desmopressin is sold under the names DDAVP Nasal Spray, DDAVP Rhinal Tube, DDVP, Minirin and Stimate Nasal Spray. Makers include Sanofi-Aventis (SASY.PA: Quote, Profile, Research) and several generic companies.

Other forms of the drug "should be used cautiously" in patients at risk of sodium imbalances that can be caused by over-hydration, the FDA said.

The agency reviewed 61 reports of patients treated with desmopressin who developed seizures related to hyponatremia, when sodium is too low. "The direct contribution of desmopressin to the deaths is unclear," the FDA said in a notice posted at the FDA Center for Drug Evaluationa and Research web site. The patients who died were ages 28 and 80, FDA spokeswoman Susan Cruzan said.

Thirty-six seizure reports were associated with intranasal forms of the drug, the FDA said. Those versions should not be used in patients with hyponatremia or a history of the condition, the FDA said.

The agency also said treatment with desmopressin tablets should be stopped during episodes that may trigger extra fluid intake, including fever, recurrent vomiting, diarrhea and vigorous exercise.

Sanofi-Aventis spokeswoman Terri Pedone said the company had removed the bed-wetting use and updated the warnings and other sections in the prescribing instructions for its desmopressin products.

Edited from a report by Lisa Richwine, edited by Gerald E. McCormick and Braden Reddall.


Published December 4, 2007 by the US FDA/Center for Drug Evaluation and Research


Antibacterial Chemical Disrupts Hormone Activities

A new UC Davis study shows that a common antibacterial chemical added to bath soaps can alter hormonal activity in rats and in human cells in the laboratory - and does so by a previously unreported mechanism.

The findings come as an increasing number of studies – of both lab animals and humans – are revealing that some synthetic chemicals in household products can cause health problems by interfering with normal hormone action.

Called endocrine disruptors, or endocrine disrupting substances (EDS), such chemicals have been linked in animal studies to a variety of problems, including cancer, reproductive failure and developmental anomalies.

This is the first endocrine study to investigate the hormone effects of the antibacterial compound triclocarban (also known as TCC or 3,4,4'-trichlorocarbanilide), which is widely used in household and personal care products including bar soaps, body washes, cleansing lotions, wipes and detergents. Triclocarban-containing products have been marketed broadly in the United States and Europe for more than 45 years; an estimated 1 million pounds of triclocarban are imported annually for the U.S. market.

The researchers found two key effects: In human cells in the laboratory, triclocarban increased gene expression that is normally regulated by testosterone. And when male rats were fed triclocarban, testosterone-dependent organs such as the prostate gland grew abnormally large.

Also, the authors said their discovery that triclocarban increased hormone effects was new. All previous studies of endocrine disruptors had found that they generally act by blocking or decreasing hormone effects.

“This finding may eventually lead to an explanation for some rises in some previously described reproductive problems that have been difficult to understand,” said one author, Bill Lasley, a UC Davis expert on reproductive toxicology and professor emeritus of veterinary medicine. More analyses of antibacterials and endocrine effects are planned, he said.

Consumers should not take this study as guidance on whether to use triclocarban-containing products, Lasley said. “Our mothers taught us to wash our hands well before the advent of antimicrobial soaps, and that practice alone prevents the spread of disease.”

The new study was published online this week by the journal Endocrinology (“Triclocarban enhances testosterone action: A new type of endocrine disruptor"”) at: http://endo.endojournals.org/rep.shtml).

The nine authors are Lasley; Jiangang Chen; Ki Chang Ahn; Nancy Gee, Mohamed I. Mohamed, Antoni Duleba, Ling Zhao, Shirley Gee and Bruce Hammock. They are associated with these UC Davis programs: Center for Health and the Environment; Department of Entomology; California National Primate Research Center; Division of Reproductive Endocrinology and Infertility at the School of Medicine; Department of Nutrition; and the Cancer Center.

In their disclosure statement, the authors report that six of them have taken steps to patent their findings through the University of California.

Published December 7, 2007 in the journal Endocrinology.


Rapid Chlamydia Test Shows Promise for 'Test and Treat' Strategy

A rapid point-of-care test for Chlamydia has demonstrated good accuracy compared with conventional tests, investigators here found.

Results with the rapid test, not yet approved for use, are available in 30 minutes, enabling physicians to pursue a "test and treat" strategy whenever Chlamydia is suspected.

"The performance of the Chlamydia Rapid Test with self-collected vaginal swabs indicates that it would be an effective same-day diagnostic and screening tool for Chlamydia infection in women," allowing for "immediate treatment and contact tracing, potentially reducing the risks of persistent infection and onward transmission."

The most prevalent sexually transmitted bacterial infection in the world, Chlamydia trachomatis is particularly common in sexually active young women. If undiagnosed and untreated, it can lead to complications that include pelvic inflammatory disease, ectopic pregnancy, and infertility, Dr. Lee and colleagues noted.

Most developed nations have national screening programs for C. trachomatis, and almost all specimens are tested by polymerase chain reaction amplification of nucleic acid. In contrast, screening programs are almost nonexistent in developing countries, even in high-risk populations, such as female sex workers. Obstacles to screening include economic constraints and lack of a simple and reliable rapid test.

Only one rapid test is currently licensed for use with vaginal swabs.

Dr. Lee and colleagues evaluated the sensitivity, specificity, and predictive values of the Chlamydia Rapid Test in comparison with polymerase chain reaction and strand displacement amplification assay. The study involved 1,349 women ages 16 to 54 seen at one of three clinics.

Polymerase chain reaction assay, considered the reference standard, tested positive for C. trachomatis in 8.4%, 9.4%, and 6% of specimens evaluated at the three clinics. In comparison, the rapid test had a positive predictive value of 86.7% and a negative predictive value of 98.6%.

Comparison with the strand displacement assay demonstrated a sensitivity of 81.6% and specificity of 98.3% for the rapid test.

The Chlamydia Rapid Test "is suitable as a primary diagnostic tool for Chlamydia infection and, in settings where access to nucleic acid amplification tests is limited or absent, could also be used as a screening tool, especially for high-risk populations," the authors said.

They also pointed out that the new test is most likely to miss infection in patients with low organism loads. "Given that the organism load of Chlamydia trachomatis in women is associated with multiple symptoms and clinical signs, further research is needed to determine the clinical significance and transmission dynamics of low-load infection in both men and women," they said.

The study was funded by the Wellcome Trust and by the Cambridge Biomedical Research Center. Dr. Lee disclosed that she is an equity holder in a company that markets rapid-test technologies developed at the University of Cambridge.

Published November 30, 2007, in the journal BMJ - British Medical Journal.
Related article published February 6, 2006 on MSNBC: Rare chlamydia strain raising concern