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Week Ending FRIDAY June 5, 2009---------------------------News Archive

The Origin and Evolution of Lactation
Lactation appears to be an ancient reproductive feature pre-dating the origin of mammals

A compelling theory for the evolution of the mammary gland and lactation has been provided by Olav Oftedal, Research Nutritionist at the National Zoological Park of the Smithsonian Institution in Washington, DC.

The mammary gland is believed to have evolved from apocrine-like glands which secrete through a plasma membrane and are associated with hair follicles. Oftedal suggests that these glands evolved from providing primarily moisture and antimicrobials to parchment-shelled eggs to the role of supplying nutrients for live birth offspring. Fossil evidence indicates that some of the mammal like forms present during the Triassic period more than 200 million years ago, produced a nutrient-rich milk-like secretion.

The ability to supply fluid and nutrients to eggs would be enhanced by incorporating antimicrobials. Antimicrobials may already have been produced in the skin, as they are on amphibian skin, and evolutionary pressure would probably have fostered incorporating molecules such as lysozyme and iron-binding proteins into these secretions as well; such components are still prevalent in milk.

Disaccharide lactose (galactose β1–4 glucose) is contained in all milks, except for some marine mammals. Its is catalyzed in the mammary gland by lactose synthetase, an enzyme that is part of β1–4-galactosyl transferase and the regulatory subunit α-lactalbumin. Because α-lactalbumin evolved from lysozyme before the division of amniotes into synapsids and sauropsids, the capacity to produce lactose was an ancient trait that preceded its use in milk production. Probably early milks primarily contained antimicrobial oligosaccharides - with lactose as a component of milk arising only after α-lactalbumin was produced in greater quantity.

With the synthesis of lactose, this modified secretion would have provided nutrients to the egg. The evolution of the casein family of milk proteins in particular would provide calcium, phosphate and protein to hatchlings. Fossil records suggest that caseins were present during the Triassic, because the extensive bone and tooth development evident in certain species before independent feeding, would have required delivery of ample calcium.

Given this evolutionary scenario, the composition of mammary secretions during early lactation in monotremes and marsupials is likely to be similar to that of the primitive milk of early pre-mammals. Their milk then converts to a more nutrient-rich source during later stages of lactation. The evolution of placenta-based reproduction displaced the function of milk as a source of water and nutrients for the egg, leading to secretion of a complex milk throughout lactation in eutherians or placental mammals.

Milk also improves the survival of offspring by promoting immunological resistance and endocrine maturation in the neonate. These needs can be highly species-specific. Also, the behavioral and 'psychological' aspects of suckling and nurturing between mother and offspring produces bonds that promote neonate survival. An aspect of lactation independent of the chemical and physical characteristics of milk.

Systemic and local control of mammary function
In mammals, development of the mammary gland during gestation generates abundant alveolar secretory cells regulated to begin functioning after the delivery of the offspring. The combination of prolactin, insulin, glucocorticoids, growth hormone and estradiol, act as endocrine stimulators and are kept in check by the negative influence of progesterone. The decline in progesterone at parturition (birth) largely determines the onset of copious milk secretion.

But regulation of milk production in marsupials differs from that in eutherian or placental mammals. The reproductive cycle in marsupials is characterized by a short gestation and a long lactation. Lactation in the tammar wallaby has been studied and, consistent with the marsupial reproductive strategy, is found to be insensitive to inhibition by progesterone. The Marsupial offspring is born in a very immature state. At birth it remains attached to the nipple while it obtains a dilute, carbohydrate-rich milk. However, the composition of the milk changes significantly during lactaton to meet the demands of the developing offspring. Marsupials can have asynchronous concurrent lactation, during which the dam provides milk of differing composition from adjacent teets to feed two offspring of different ages and nutritional needs.

Study of the bovine genome compared with human, dog, mouse and rat (eutherians), opossum (marsupial) and platypus (monotreme) shows that in general, cow milk and mammary genes are more conserved, evolving more slowly than other genes in the bovine genome, despite the cow having been selectively bred for milk production. This supports the idea that lactation has evolved to minimize the energy cost to the mother while maximizing survival of the neonate, and thereby promoting survival of the pair.

The most divergent proteins in the lactome (milk genome) were those with nutritional or immunological attributes, which suggests a continuing ability on the part of the cow to select from those genes to meet changing nutritional and pathogen needs incurred by diverse environments and reproductive strategies.

Ottawa Scientists Discover New Way to Enhance Stem Cells to Stimulate Muscle Regeneration
Scientists at the Ottawa Hospital Research Institute (OHRI) and the University of Ottawa have discovered a powerful new way to stimulate muscle regeneration, paving the way for new treatments for debilitating conditions such as muscular dystrophy

The research, to be published in Cell Stem Cell, shows for the first time that a protein called Wnt7a increases the number of stem cells in muscle tissue, leading to accelerated growth and repair of skeletal muscle.

“This discovery shows us that by targeting stem cells to boost their numbers, we can improve the body’s ability to repair muscle tissue,” said senior author Dr. Michael Rudnicki. Dr. Rudnicki is the Scientific Director of Canada’s Stem Cell Network and a Senior Scientist at OHRI and Director of OHRI’s Sprott Centre for Stem Cell Research, as well as a Professor of Medicine at the University of Ottawa.

Stem cells give rise to every tissue and organ in the body. Satellite stem cells are specialized muscle stem cells that live in adult skeletal muscle tissue and have the ability to both replicate and differentiate into various types of muscle cells. Dr. Rudnicki’s team found that the Wnt7a protein, when introduced into mouse muscle tissue, significantly increased the population of these satellite stem cells and fueled the regeneration process, creating bigger and stronger muscles. Muscle tissue mass was increased by nearly 20 per cent in the study.

“Our findings point the way to the development of new therapeutic treatment for muscular diseases such as muscular dystrophy, sarcopenia and muscle wasting conditions resulting from extended hospital stays and surgeries,” said Dr. Rudnicki.

This project was funded by the Canadian Institutes of Health Research, the Muscular Dystrophy Association, the National Institutes of Health, the Howard Hughes Medical Institute, Canada’s Stem Cell Network and the Canada Research Chairs Program.


Sleuths Follow Lung Stem Cells for Generations
More than one kind of stem cell is required to support the upkeep and repair of the lungs, according to a new study published in the journal Cell Stem Cell

Scientists at Duke University Medical Center painstakingly followed and counted genetically labeled cells in the mouse lung for over a year, under differing conditions, to learn more about natural renewal and healing processes. This information may shed light on what goes wrong in conditions like lung cancer, chronic bronchitis and asthma.

"We are learning the exact processes that maintain the various regions of the lung in tip-top condition and what happens when things go wrong," said Brigid Hogan, Ph.D., chair of the Duke Department of Cell Biology and senior author of the study. "Normally, the lung is beautifully organized, with the exact proportion of secretory and ciliated cells lined up next to each other to get their jobs done." The secretory cells lubricate and protect, while the hair-like projections of the ciliated cells waft the secretions up and out of the lungs.

In humans, under conditions of heavy smoking, or infection or inflammation due to asthma or cystic fibrosis, repeated cycles of damage and repair lead to a messy arrangement, she said. "You can get patches of cells building up in a stacked, flattened formation like skin cells. Some cells multiply too fast; others may make too much mucus."

The team tagged secretory cells, called Clara cells, found in both the trachea and bronchioles, the airway branches inside the lung. They followed them in normal mice and during the amazingly efficient repairs after damage by too much oxygen or other environmental stresses.

They tested the theory that there are BASCs (bronchioalveolar stem cells). These purportedly are on the border between the bronchioles and alveoli, which are the small air sacs where gas exchange takes place. BASCs were thought to replenish both regions of the lung.

Instead, the cells they labeled and followed in the bronchioles only renewed the airways and not the alveoli; they found no evidence for a special BASC population.

The Duke team was also surprised to find that the proportion of tagged Clara cells in the airways stayed the same for over a year. What's more, the genetic tag slowly appeared in ciliated cells, which told them that the secretory cells both make more of themselves and give rise to ciliated cells - a switch that had been suspected but never shown directly. Since the tagged cells renew over a long time and give rise to ciliated cells, they behave like long-term stem cells even though they are differentiated.

When the scientists tagged secretory cells in the trachea and followed them for a year, they found that the labeled cells gradually were lost. They could multiply and make ciliated cells but didn't do this for long. As the tagged cells were lost by wear and tear they were replaced by the descendants of unlabeled cells. From other experiments, Hogan and her colleagues think these replenishing cells are basal cells.

"In the wider trachea, there is a population of basal cells that are more like classical stem cells in being undifferentiated," Hogan said. Cells like these basal stem cells are found in the airways and bronchioles of human lungs. "It is important to know what these stem cells are doing in the human lung," Hogan said.

Until now, the lineage labeling tools had not been available for lung Clara cells. Postdoctoral fellow Emma Rawlins' efforts to tag the cells and count the daughters for over a year were "heroic," Hogan said.

"You really need this particular genetic flag to know exactly what a cell's fate is," Hogan said. "If you just stain the cells, this tells you only what they look like. It doesn't say who the parents are, and who begets whom, if you will. You have to count and work out the family tree."

Many questions remain. "While we know secretory cells can give rise to ciliated cells, we don't know what controls this switch so that the correct proportion is always made," Hogan said. "In the airways of people with asthma there are many goblet cells that make mucus, but we don't know where these cells come from. We also need to search for the specialized stem cell that gives rise to alveolar cells."


Bleeding Disorders in Women Going Undiagnosed
Nearly one percent of the population suffers from bleeding disorders, yet many women don't know they have one because doctors aren't looking for the condition, according to researchers at Duke University Medical Center

That's about to change, now that an international expert consortium specifically outlined the definitive signs that may signal the presence of a bleeding disorder in women. The recommendations are published online and will appear in the July issue of the American Journal of Obstetrics and Gynecology.

The new guidelines aren't just for doctors. Women who suffer from heavy menstrual cycles should be on the lookout for these signs as well, says Andra James, MD, a Duke obstetrician, who says about 25 percent of women with heavy menstruation may have an undiagnosed bleeding disorder.

"Heavy bleeding should not be ignored," says James, the paper's lead author. "When a woman's blood can't clot normally the most obvious sign is a heavy period."

Yet when faced with these scenarios, most doctors aren't suspecting a blood clotting problem is to blame. "Sometimes they think hormones are the cause, or fibroids," says James. "In some cases they recommend removal of the uterus or offer another gynecologic explanation when the real contributing factor is a blood clotting disorder."

In previous studies, women who ultimately were treated for a bleeding disorder reported waiting 16 years, on average, before being diagnosed. In extreme cases, James says undiagnosed bleeding disorders have led to women bleeding to death during menstruation, childbirth and surgical procedures.

The most common inherited bleeding disorder is von Willebrand disease, says James, author of 100 Questions and Answers About von Willebrand Disease (Jones and Bartlett).

Common criteria for diagnosis include the presence of a family history of bleeding, personal history of bleeding and laboratory tests that indicate the lack of a protein called von Willebrand factor which is essential for clotting.

Without the laboratory test, the consortium says women and doctors should be on the lookout for the following:

Heavy blood loss during menstruation
Family history of bleeding disorder
Notable bruising without injury
Minor wound bleeding that lasts more than five minutes
Prolonged or excessive bleeding following dental extraction
Unexpected surgical bleeding
Hemorrhaging that requires blood transfusion
Postpartum hemorrhaging, especially if occurs more than 24 hours after delivery

"Too often women think heavy bleeding is okay because the women in their family -- who may also have an undiagnosed bleeding disorder -- have heavy periods as well," says James.

"We want women who continually experience abnormal reproductive tract bleeding, specifically heavy menstrual bleeding, to be alert to these other signs and approach their physicians about being evaluated."

In addition, she says doctors should be asking the right questions and ordering appropriate laboratory tests in suspected patients.

"Not every patient who has abnormal reproductive tract bleeding has a bleeding disorder, and most don't," James says. "But since up to one-quarter do, this needs to be recognized. Once treated, these women can expect to have normal periods and go through childbirth safely."

Simple Drug Treatment May Prevent Nicotine-Induced SIDS
A new study has identified a specific class of pharmaceutical drugs that could be effective in treating babies vulnerable to Sudden Infant Death Syndrome (SIDS), because their mothers smoked during pregnancy

According to researchers at McMaster University, exposure of the fetus to nicotine results in the inability to respond to decreases in oxygen—known as hypoxia—which may result in a higher incidence of SIDS. In the same study on rats, they found that the diabetic medication 'glibenclamide' can reverse the effects of nicotine exposure, increasing the newborn's ability to respond to hypoxia and likely reducing the incidence of SIDS.

The findings are published today in the Journal of Neuroscience.

"During birth the baby rapidly changes its physiology and anatomy so that it can breathe on its own," explains Josef Buttigieg, lead author who conducted his research as a PhD graduate student in the department of Biology. "The stress of being born induces the release of the hormones adrenaline and noradrenaline—collectively called catecholamines—from the adrenal glands. During birth, these hormones in turn signal the baby's lungs to become ready for air breathing."

For some months after birth, the adrenal glands act as a critical oxygen sensor. A drop in blood oxygen levels will stimulate the release of catecholamines, which in turn signals the baby to take a deep breath, when an infant rolls on its face or has an irregular breathing pattern during sleep, for example. However, the ability to release those hormones during moments of apnea or asphyxia is impaired due to nicotine exposure.

During those episodes, specific proteins sensitive to hypoxia stimulate the cell to release catecholamines. A secondary class of proteins then acts as a 'brake', ensuring the cells do not over excite themselves during this stressful time. However, exposure of the fetus to nicotine results in higher levels of this brake protein.

"The result is like trying to drive your car with the parking brake on. You might go a little bit, but the brakes hold you back," explains Buttigieg. "In this case, the adrenal glands do not release catecholamines during hypoxia –for example during birth or a self-asphyxiation episode—often resulting in death."

But when researchers administered the drug glibenclamide in laboratory rats, which override the brake protein, the adrenal glands were able to respond to oxygen deprivation, therefore reversing the lethality of hypoxia.

"Our initial goal was really to understand how the nervous system regulates oxygen sensitivity of cells in the adrenal gland at a basic research level," says Colin Nurse, academic advisor on the study and a professor in the department of Biology.

"We speculated that chemicals released from nerves might interact with adrenal cells and cause them to lose oxygen sensitivity. It turns out that nicotine mimics the effects of one of these chemicals, thereby allowing us to test the idea. The present study was significant in that it led to a mechanistic understanding of how nicotine works in this context."


Boy or Girl? In Lizards, Egg Size Matters
Whether baby lizards will turn out to be male or female is a more complicated question than scientists would have ever guessed, according to a new report published online on June 4th in Current Biology, a Cell Press publication

The study shows that for at least one lizard species, egg size matters.

"We were astonished," said Richard Shine of the University of Sydney. "Our studies on small alpine lizards have revealed another influence on lizard sex: the size of the egg. Big eggs tend to give girls, and small eggs tend to give boys. And if you remove some of the yolk just after the egg is laid, it's likely to switch to being a boy, even if it has female sex chromosomes; and if you inject a bit of extra yolk, the egg will produce a girl, even if it has male sex chromosomes."

In many animals, the sex of offspring depends on specialized sex chromosomes. In mammals and many reptiles, for instance, males carry one X and one Y chromosome, while females have a pair of X chromosomes. In contrast, animals such as alligators depend on environmental cues like temperature to set the sex of future generations.

The new findings add to evidence that when it comes to genetic versus environmental factors influencing sex determination, it doesn't have to be an either/or proposition. In fact, Shine and his colleagues earlier found in hatchlings of the alpine-dwelling Bassiana duperreyi that extreme nest temperatures can override the genetically determined sex, in some cases producing XX boys and XY girls. His group had also noticed something else: large lizard eggs were more likely to produce daughters and small eggs to produce sons.

Despite the correlation, Shine said he had assumed that the association was indirect. In fact, his colleague Rajkumar Radder conducted studies in which he removed some yolk from larger eggs, more likely to produce daughters, to confirm that assumption.

"We were confident that there would be no effect on hatchling sex whatsoever," Shine said. "When those baby boy lizards started hatching out, we were gob-smacked."

Shine thinks there will be much more to discover when it comes to lizard sex determination.

"I suspect that the ecology of a species will determine how it makes boys versus girls, and that our yolk-allocation effect is just the tip of a very large iceberg," he said.

THURSDAY June 4, 2009---------------------------News Archive

Low-Carb Diet Burns More Liver Fat than Low-Cal Diet
People on low-carbohydrate diets are more dependent on the oxidation of fat in the liver for energy than those on a low-calorie diet, researchers at
UT Southwestern Medical Center have found in a small clinical study.

The findings, published in the journal Hepatology, could have implications for treating obesity and related diseases such as diabetes, insulin resistance and nonalcoholic fatty liver disease, said Dr. Jeffrey Browning, assistant professor in the UT Southwestern Advanced Imaging Research Center and of internal medicine at the medical center.

“Instead of looking at drugs to combat obesity and the diseases that stem from it, maybe optimizing diet can not only manage and treat these diseases, but also prevent them,” said Dr. Browning, the study’s lead author.

Drs. Jeffrey Browning and Shawn Burgess have found that people on low-carbohydrate diets depend more on the oxidation of fat in the liver for energy than those on a low-calorie diet.

Although the study was not designed to determine which diet was more effective for losing weight, the average weight loss for the low-calorie dieters was about 5 pounds after two weeks, while the low-carbohydrate dieters lost about 9½ pounds on average.

Glucose, a form of sugar, and fat are both sources of energy that are metabolized in the liver and used as energy in the body. Glucose can be formed from lactate, amino acids or glycerol.

In order to determine how diet affects glucose production and utilization in the liver, the researchers randomly assigned 14 obese or overweight adults to either a low-carbohydrate or low-calorie diet and monitored seven lean subjects on a regular diet.

After two weeks, researchers used advanced imaging techniques to analyze the different methods, or biochemical pathways, the subjects used to make glucose.

“We saw a dramatic change in where and how the liver was producing glucose, depending on diet,” said Dr. Browning.

Researchers found that participants on a low-carbohydrate diet produced more glucose from lactate or amino acids than those on a low-calorie diet.

“Understanding how the liver makes glucose under different dietary conditions may help us better regulate metabolic disorders with diet,” Dr. Browning said.

The different diets produced other differences in glucose metabolism. For example, people on a low-calorie diet got about 40 percent of their glucose from glycogen, which is comes from ingested carbohydrates and is stored in the liver until the body needs it.

The low-carbohydrate dieters, however, got only 20 percent of their glucose from glycogen. Instead of dipping into their reserve of glycogen, these subjects burned liver fat for energy.

The findings are significant because the accumulation of excess fat in the liver — primarily a form of fat called triglycerides — can result in nonalcoholic fatty liver disease, or NAFLD. The condition is the most common form of liver disease in Western countries, and its incidence is growing. Dr. Browning has previously shown that NAFLD may affect as many as one-third of U.S. adults. The disease is associated with metabolic disorders such as insulin resistance, diabetes and obesity, and it can lead to liver inflammation, cirrhosis and liver cancer.

“Energy production is expensive for the liver,” Dr. Browning said. “It appears that for the people on a low-carbohydrate diet, in order to meet that expense, their livers have to burn excess fat.”

Results indicate that patients on the low-carbohydrate diet increased fat burning throughout the entire body.

Hydrogen Peroxide Ignites Immune System
Using the zebrafish as an animal model, researchers have discovered that the body uses hydrogen peroxide to sound the alarm when a tissue has been injured

As a direct result of this hydrogen-peroxide red alert, white blood cells come to the aid of the wounded site.

Prior research has indicated that white blood cells produce hydrogen peroxide to kill bacteria, but never before has it been know to act as a kind of “first responder” that alerts healing cells to bodily trauma. This is important because scientists know very little about how tissue detects that it’s been damaged, and what sorts of signals it sends as a result. Although these findings occurred in zebrafish, they offer new ways to begin thinking about certain human conditions, like asthma, which are associated with elevated levels of hydrogen peroxide and white blood cells in the affected areas.

When you were a kid your mom poured it on your scraped finger to stave off infection. When you got older you might have even used it to bleach your hair. Now there’s another possible function for this over-the-counter colorless liquid: your body might be using hydrogen peroxide as an envoy that marshals troops of healing cells to wounded tissue.

Using the zebrafish as an animal model, researchers in the lab of Harvard Medical School professor of systems biology Timothy Mitchison and Dana Farber Cancer Institute professor Thomas Look have discovered that when the tail fins of these creatures are injured, a burst of hydrogen peroxide is released from the wound and into the surrounding tissue. Teams of rescue-working white blood cells respond to this chemical herald, crawl to the site of damage, and get to work.

“We’ve known for quite some time that when the body is wounded, white blood cells show up, and it’s really a spectacular piece of biology because these cells detect the wound at some distance,” says Mitchison. “But we haven’t known what they’re responding to. We do know something about what summons white blood cells to areas that are chronically inflamed, but in the case of an isolated physical wound, we haven’t really known what the signal is.”

These findings are reported in the June 4 issue of the journal Nature.

Philipp Niethammer, a postdoc in Mitchison’s lab, and Clemmens Grabber, a postdoc in Look’s lab, initiated this research project with no interest in wound healing. Rather, they were studying a groups of molecules called reactive oxygen species, or ROS. These small oxygen-derived molecules, of which hydrogen peroxide is one, have the potential to be both helpful and hurtful. Niethammer and Grabber were simply curious to find ways to detect ROS molecules in an organism.

To do this, they took a gene engineered to change color in the presence of hydrogen peroxide and inserted it into zebrafish embryos. Once the embryos entered the larvae stage after a few days, this synthetic gene spread throughout the entire body, essentially “wiring” the fish so that any discreet location in which hydrogen peroxide appears would glow.

But how do you coax the fish to produce a reactive chemical like hydrogen peroxide in the first place?

Since white blood cells have long been known to produce hydrogen peroxide, one obvious way to initiate chemical production would be to inflict a small wound onto the fish, and then, using microscopy, observe patterns of this chemical as white blood cells gathered around the wound. But much to the researchers surprise, they found that hydrogen peroxide immediately appeared at the wound site, prior to the arrival of any white blood cell, and quickly disseminated into neighboring tissue.

They repeated the experiment, this time in zebrafish where they’d disabled a protein that was previously discovered to produce hydrogen peroxide in the human thyroid gland. Not only did hydrogen peroxide not appear at the wound site, but white blood cells failed to respond to the injury.

“This was our real eureka! moment,” says Niethammer. “We weren’t too surprised that we could block hydrogen peroxide production through this technique, but what we didn’t expect at all was that white blood cells wouldn’t respond. This proved that the white blood cells *needed* hydrogen peroxide to sense the wound, and move towards it.”

Of course, zebrafish are not people, and while our genomes share many similarities with these tiny fish, it isn’t yet clear that natural selection has conserved this process throughout the evolutionary family tree. Still, these findings offer something of a conceptual shift in how to view human conditions where hydrogen peroxide plays a role.

“When we look at how hydrogen peroxide works in people, this really starts getting intriguing,” says Mitchison.

In the human body, hydrogen peroxide is produced primarily in three places: lung, gut, and thyroid gland. Because hydrogen peroxide, and the proteins responsible for producing other ROS molecules, are especially present in lung and gut, the researchers hypothesize that human diseases relevant to these findings would include any in the lung and gut that involve disproportionate levels of white blood cells, like asthma, chronic pulmonary obstruction, and some inflammatory gut diseases.

“Our lungs are supposed to be sterile; our guts are anything but,” says Mitchison. “It’s very logical that both those tissues produce hydrogen peroxide all the time. Perhaps in conditions like asthma, the lung epithelia is producing too much hydrogen peroxide because it’s chronically irritated, which, if our findings translate to humans, would explain inappropriate levels of white blood cells. This is certainly a question worth pursuing.”


Single Women Gaze at Males Longer
Neuroscientists found woman's partner status relevant for her interest in the opposite sex

A study by neuroscientist Heather Rupp and her team found that a woman's partner status influenced her interest in the opposite sex.

In the study, published in the March issue of Human Nature, women both with and without sexual partners showed little difference in their subjective ratings of photos of men when considering such measures as masculinity and attractiveness.

However, the women who did not have sexual partners spent more time evaluating photos of men, demonstrating a greater interest in the photos. No such difference was found between men who had sexual partners and those who did not.

"These findings may reflect sex differences in reproductive strategies that may act early in the cognitive processing of potential partners and contribute to sex differences in sexual attraction and behavior," said Rupp, assistant scientist at The Kinsey Institute for Research in Sex, Gender and Reproduction at Indiana University in the US.

For the study, 59 men and 56 women rated 510 photos of opposite-sex faces for realism, masculinity/femininity, attractiveness, or affect. Participants were instructed to give their "gut" reaction and to rate the pictures as quickly as possible.

The men and women ranged in age from 17 to 26, were heterosexual, from a variety of ethnic backgrounds and were not using hormonal contraception. Of the women, 21 reported they had a current sexual partner; 25 of the men reported having a sexual partner.

This is the first study to report whether having a current sexual partner influences interest in the opposite sex. Other studies have demonstrated that hormones, relationship goals and social context influence such interest.

"That there were no detectable effects of sexual partner status on women's subjective ratings of male faces, but there were on response times, which emphasizes the subtlety of this effect and introduces the possibility that sexual partner status impacts women's cognitive processing of novel male faces but not necessarily their conscious subjective appraisal," the authors wrote in the journal article.

The researchers also note that influence of partner status in women could reflect that women, on average, are relatively committed in their romantic relationships, "which possibly suppresses their attention to and appraisal of alternative partners."

Cancer Cells Need Normal, Non-Mutated Genes to Survive
Cancer cells rely on normal, healthy genes as much as they rely on mutated genes

Using a technique called RNA interference, researchers dialed down the production of thousands of normal proteins to determine which were required for cancer cells to survive. They found that cancer cells growing in a dish rely heavily on many normal proteins to maintain their deviant state. When some of these protein levels drop, cancer cells die, but normal cells often survive.

If the findings translate to the clinic, they might spur a new therapeutic approach by exposing a hidden set of new drug targets. One could imagine drug cocktails that reduce the activity of normal and aberrant proteins to keep cancer cells in check. The study also reveals the limitations of the Cancer Genome Atlas, a federally-funded effort to sequence cancer genomes. If researchers focus exclusively on DNA sequences, they will miss key aspects of cancer cell biology, including this addiction to normal proteins.

Corrupt lifestyles and vices go hand in hand; each feeds the other. But even the worst miscreant needs customary societal amenities to get by. It's the same with cancer cells. While they rely on vices in the form of genetic mutations to wreak havoc, they must sustain their activity, and that requires equal parts vice and virtue.

According to a new study in the May 29 issue of Cell, cancer cells rely heavily on many normal proteins to deal with stress and maintain their deviant state. Researchers at Harvard Medical School and Brigham and Women's Hospital used a technique called RNA interference (RNAi) to dial down the production of thousands of proteins and determine which were required for cancer cell survival.

Being a cancer cell isn't easy. Think of all the DNA replication and protein production involved, not to mention the abnormal architecture of a tumor, which deprives cells of oxygen. Survival requires a complete kit of stress response tools.

"Researchers often characterize cancer cells as oncogene addicts, but they're just as reliant on normal genes that alleviate stress," explains senior author Stephen Elledge, a professor at HMS and Brigham and Women's Hospital. "These stress management genes deserve attention as potential therapeutic targets."

In recent years, the National Cancer Institute has supported an ambitious effort to understand the molecular basis of cancer by sequencing cancer genomes. Elledge and Luo note that this Cancer Genome Atlas project would miss the stress management genes.

"If these genes are intact, they won't stand out when you compare the DNA sequences of cancer cells with normal cells," says Luo.

So the team took a different approach to test their "non-oncogene addiction" hypothesis. They acquired two human cell lines, identical in every way except for one--the presence or absence of a Ras oncogene. Ras mutations are prevalent in many deadly cancers, and researchers have not been successful in developing drugs against the dangerous gene.

The team used molecules called shRNAs to interfere with the production of thousands of normal, healthy proteins in the two cell lines. They gave the cells time to divide and sifted through the data to determine which proteins were required for survival. (In the past, labs relied on large robots to complete these types of screens, but Elledge and others have refined the technology in an effort to make RNAi affordable and accessible. Luo conducted his genome-wide screen in test tubes without the aid of a robot.)

Despite their similarities, the two cell lines responded differently to a number of shRNAs. That is, normal cells tolerated low levels of a particular protein while cells with the Ras mutation perished. Luo validated 50 of these hits in a second pair of cell lines. Dozens of these represent brand new therapeutic targets.

"This opens the door to using a drug cocktail approach to treat tumors driven by Ras mutations," says Elledge, who is also an investigator with Howard Hughes Medical Institute. "We might be able to tinker with the levels of these proteins and cripple cancer cells without hurting normal cells in the body, though this needs to be tested in tumor models."

"This type of functional approach complements the physical mapping of cancer genomes, but provides a much more direct path to new anti-cancer drug targets," adds Luo. "The genes that are critical for maintaining the malignant state will really crystallize when we combine forces."

Small Molecules Mimic Natural Gene Regulators
In the quest for new approaches to treating and preventing disease, one appealing route involves turning genes on or off at will, directly intervening in ailments such as cancer and diabetes, which result when genes fail to turn on and off as they should

Scientists at the University of Michigan and the University of California at Berkeley have taken a step forward on that route by developing small molecules that mimic the behavior and function of a much larger and more complicated natural regulator of gene expression. The research, by associate professor of chemistry Anna Mapp and coworkers, is described in the current issue of the journal ACS Chemical Biology.

Molecules that can prompt genes to be active are called transcriptional activators because they influence transcription—the first step in the process through which instructions coded in genes are used to produce proteins. Transcriptional activators occur naturally in cells, but Mapp and other researchers have been working to develop artificial transcription factors (ATFs)—non-natural molecules programmed to perform the same function as their natural counterparts. These molecules can help scientists probe the transcription process and perhaps eventually be used to correct diseases that result from errors in gene regulation.

In previous work, Mapp and coworkers showed that an ATF they developed was able to turn on genes in living cells, but they weren't sure it was using the same mechanism that natural activators use. Both natural transcriptional activators and their artificial counterparts typically have two essential parts: a DNA-binding domain that homes in on the specific gene to be regulated, and an activation domain that attaches itself to the cell's machinery through a key protein-to-protein interaction and spurs the gene into action. The researchers wanted to know whether their ATFs attached to the same sites in the transcriptional machinery that natural activators did.

In the current work, the team showed that their ATFs bind to a protein called CBP, which interacts with many natural activators, and that the specific site where their ATFs bind is the same site utilized by the natural activators, even though the natural activators are much larger and more complex.

Then the researchers altered their ATFs in various ways and looked to see how those changes affected both binding and ability to function as transcriptional activators. Any change that prevented an ATF from binding to CBP also prevented it from doing its job. This suggests that, for ATFs as for natural activators, interaction with CBP is key to transcriptional activity.

"Taken together, the evidence suggests that the small molecules we have developed mimic both the function and the mechanism of their natural counterparts," said Mapp, who has a joint appointment in the College of Pharmacy's Department of Medicinal Chemistry. Next the researchers want to understand in more detail exactly how the small molecules bind to that site. "Then we'll use that information to design better molecules."

WEDNESDAY June 3, 2009---------------------------News Archive

Why Dishing Does You Good, Girlfriend
Why does dishing with a girlfriend do wonders for a woman's mood?

A University of Michigan study has identified a likely reason: feeling emotionally close to a friend increases levels of the hormone progesterone, helping to boost well-being and reduce anxiety and stress.

"This study establishes progesterone as a likely part of the neuroendocrine basis of social bonding in humans," said U-M researcher Stephanie Brown, lead author of an article reporting the study findings, published in the current (June 2009) issue of the peer-reviewed journal Hormones and Behavior.

A sex hormone that fluctuates with the menstrual cycle, progesterone is also present in low levels in post-menopausal women and in men. Earlier research has shown that higher levels of progesterone increase the desire to bond with others, but the current study is the first to show that bonding with others increases levels of progesterone. The study also links these increases to a greater willingness to help other people, even at our own expense.

"It's important to find the links between biological mechanisms and human social behavior," said Brown, is a faculty associate at the U-M Institute for Social Research (ISR) and an assistant professor of internal medicine at the U-M Medical School. She is also affiliated with the Ann Arbor Veterans Affairs Hospital. "These links may help us understand why people in close relationships are happier, healthier, and live longer than those who are socially isolated."

Progesterone is much easier to measure than oxytocin, a hormone linked to trust, pair-bonding and maternal responsiveness in humans and other mammals. Oxytocin can only be measured through an invasive spinal tap or through expensive and complex brain imaging methods, such as positron emission tomography scans. Progesterone can be measured through simple saliva samples and may be related to oxytocin.

In the current study, Brown and colleagues examined the link between interpersonal closeness and salivary progesterone in 160 female college students.

At the start of the study, the researchers measured the levels of progesterone and of the stress hormone cortisol in the women's saliva, and obtained information about their menstrual cycles and whether they were using hormonal contraceptives or other hormonally active medications.

To control for daily variations in hormone levels, all the sessions were held between noon and 7 p.m.

The women were randomly assigned to partners and asked to perform either a task designed to elicit feelings of emotional closeness or a task that was emotionally neutral.

In the emotionally neutral task, the women proofread a botany manuscript together.

After completing the 20-minute tasks, the women played a computerized cooperative card game with their partners, and then had their progesterone and cortisol sampled again.

The progesterone levels of women who had engaged in the emotionally neutral tasks tended to decline, while the progesterone levels of women who engaged in the task designed to elicit closeness either remained the same or increased. The participants' cortisol levels did not change in a similar way.

Participants returned a week later, and played the computerized card game with their original partners again. Then researchers measured their progesterone and cortisol. Researchers also examined links between progesterone levels and how likely participants said they would be to risk their life for their partner.

"During the first phase of the study, we found no evidence of a relationship between progesterone and willingness to sacrifice," Brown said. "But a week later, increased progesterone predicted an increased willingness to say you would risk your life to help your partner."

According to Brown, the findings are consistent with a new evolutionary theory of altruism which argues that the hormonal basis of social bonds enables people to suppress self-interest when necessary in order to promote the well-being of another person, as when taking care of children or helping ailing family members or friends.

The results also help explain why social contact has well-documented health benefits---a relationship first identified nearly 20 years ago by U-M sociologist James House.

"Many of the hormones involved in bonding and helping behavior lead to reductions in stress and anxiety in both humans and other animals. Now we see that higher levels of progesterone may be part of the underlying physiological basis for these effects," Brown said.

Genes Are 'Fated' In the Earliest Brain Construction
Long before the brain’s neurons can facilitate life’s big decisions, they have to find their own destiny in the rapidly developing embryo

In the lingo of neurobiologists, they are “fated” very early on to become certain types of cells, over time traveling to and organizing the various structures that compose the brain.

These earliest developments are difficult to observe, like the first few moments in the life of the universe following the Big Bang. But by adapting new tools of genetic profiling, researchers at Rockefeller University have peered into the brain as it’s born and teased out genes that shape its aboriginal fate.

Last month in the journal Cerebral Cortex, researchers published a list of 229 genes that they found to be active at the beginning of neurogenesis, specifically those involved in so-called subplate neurons, which form the initial scaffolding for assembling cortical circuits. The genes include a substantial network related to estrogen, a sex hormone whose prominence in the brain differentiates female from male.

“That these sex pathways are involved from the get-go is a particular surprise,” says Mary E. Hatten, Frederick P. Rose Professor and head of the Laboratory of Developmental Neurobiology. “The research provides a new starting point for people to say, ‘what, exactly, are all of these new pathways doing?’”

The experiments, conducted by former graduate student Hilleary Osheroff, now at the American Museum of Natural History, drew on a project developed by Hatten and Nathaniel Heintz, James and Marilyn Simons Professor and head of the Laboratory of Molecular Biology, called the Gene Expression Nervous System Atlas (GENSAT). GENSAT pioneered a genetic engineering technology that employs bacterial artificial chromosomes to visualize the contribution of thousands of genes to the mouse brain with the enhanced green fluorescent protein.

Osheroff screened these genes for involvement in the earliest stages of brain development, when the first neurons begin to stratify across six layers that form the scaffolding of the embryonic brain inside a folding neural tube.

Using fluorescence-activated cell sorting, Osheroff isolated the neurons destined for the layer known as the subplate from the Cajal-Retzius neurons, which carry on beyond the subplate to the layer known as the marginal zone.

She identified 229 genes specifically dedicated to developing the subplate neurons and found that they were involved in a broad range of activities including cortical development, cell and axon motility, protein trafficking, steroid hormone signaling and central nervous system degenerative diseases.

The work indicates the breadth of factors involved in the early development of neurons and provides investigators with a biochemical handle to start investigating the various contributions, says Hatten. “It’s a roadmap, not an answer,” she says. “These results could really change the direction of research.”

Oh Baby!

Early Childhood Conditions that Lead to Adult Health Disorders
The origins of many adult diseases can be traced to early negative experiences associated with social class and other markers of disadvantage

Confronting the causes of adversity before and shortly after birth may be a promising way to improve adult health and reduce premature deaths, researchers argue in a paper published today in JAMA: The Journal of the American Medical Association. These adversities establish biological “memories” that weaken physiological systems and make individuals vulnerable to problems that can lie dormant for years.

“Improving the developmental trajectory of a child by helping the parents and improving the home environment is probably the single most important thing we can do for the health of that child,” says coauthor Bruce S. McEwen, Alfred E. Mirsky Professor and head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at The Rockefeller University. “Adverse childhood experience is one of the largest contributors to such chronic health problems as diabetes and obesity, psychiatric disorders, drug abuse — almost every major public health challenge we face.”

In the report, McEwen and his coauthors distinguish between levels of stress experienced by young children. “Positive” and “tolerable” stress, with the support of adults, help the body and brain learn to cope with brief situations of adversity, while “toxic” stress, which can disrupt brain architecture and other organ systems, increases the risk for stress-related disease and cognitive impairment well into adulthood. Major risk factors for toxic stress include extreme poverty, recurrent physical and/or emotional abuse, chronic neglect, severe maternal depression, parental substance abuse and family violence.

An intervention to relieve toxic stress that children experience early in life could not only affect their own individual well-being and longevity but also improve overall societal health, the report concludes. In particular, the researchers highlight three findings and propose promising applications in health policy and clinical practice:

• Adult disease prevention begins with reducing toxic stress in early childhood, as a reduction in the number and severity of early adverse experiences will lead to a decrease in the prevalence of a wide range of health problems.

• High-quality early care and education programs can benefit lifelong health, not just learning, by providing safe, stable, responsive environments and evidence-based treatments for family mental health problems.

• Child welfare services represent an opportunity for lifelong health promotion by augmenting their exclusive focus on child safety and custody with comprehensive developmental assessments and appropriate interventions by skilled professionals.

“Health care reform is clearly essential for assuring universal access to needed medical care,” says coauthor Jack Shonkoff, founding director of the Center on the Developing Child at Harvard University. “Yet we also know that health disparities linked to social class, race and ethnicity are not primarily about health care access or quality, since these inequalities persist in countries that provide health care for all their citizens. These disparities are rooted in where and how we live, work and play. Science is now telling us that they’re also about how we as a society treat our youngest members.”

McEwen and Shonkoff wrote the report with W. Thomas Boyce, the chair in child development and professor in the College for Interdisciplinary Studies and Faculty of Medicine at the University of British Columbia. All three authors are members of the National Scientific Council on the Developing Child, a multidisciplinary, multi-university collaboration housed at the Center on the Developing Child at Harvard.

Genetically Corrected Blood Cells from Skin Cells of Fanconi Anemia Patients
The new therapeutic strategy could be applied to several other genetic diseases

A collaboration research carried out by the teams of Jordi Surrallés, Universitat Autònoma de Barcelona (UAB); Juan Carlos Izpisúa-Belmonte and Ángel Raya, Centre for Regenerative Medicine of Barcelona (CMRB); and Juan Antonio Bueren, Centre for Energetic, Environmental and Technological Research (CIEMAT), has resulted in the generation of blood cells from skin cells of patients with a genetic disease known as Fanconi anemia. The process is based on gene therapy and cell reprogramming techniques in which cells similar to embryonic stem cells known as induced pluripotent stem (iPS) cells can be generated. The research article was published in this week's digital version of Nature.

The research demonstrates that, for the first time, in the case of a genetic disease such as Fanconi anemia it is possible to correct the genetic defect in patient-specific skin cells by converting them into cells similar to embryonic stem cells (iPS cells) which later can be differentiated towards blood cells.

These results are the proof of concept that this new therapeutic strategy has the potential of generating tissues using the very skin of those affected with these genetic diseases. This observation is particularly important in diseases such as Fanconi anemia, where one of the main problems lies in the lack of blood cell in the bone marrow of those affected. However, according to researchers, this new therapeutic strategy can be applied to many other genetic diseases by differentiating iPS cells towards healthy tissues these patients lack.

The generation of blood cells in this research was carried out in vitro, in cell culture plates, which places the research in a preclinical environment. It remains unknown whether they would generate blood cells after being transplanted. Moreover, the transplant of embryonic stem cells in animals has revealed that these cells can cause tumours. Therefore, the possibility of treating Fanconi anemia patients by transplanting iPS cells must wait until the efficacy and safety of these new discoveries are demonstrated in experimental models.

Researchers taking part in the study are confident that in the next few years it will be possible to improve the efficacy and safety of this new scientific discovery, and that some time in the future, clinical professionals will be able to cure patients suffering from genetic diseases such as Fanconi anemia.

UAB and CIEMAT, leading research centres in Fanconi anemia
Fanconi anemia is a rare hereditary disease which mainly affects the bone marrow and causes it to produce less blood cells. The lack of white blood cells makes individuals more vulnerable to infections, while the lack of platelets or red blood cells may prevent clotting or lead to fatigue. Treatment includes transplanting healthy blood stem cells from the bone marrow or umbilical cord of a compatible donor or, if possible, a relative. Unfortunately, few patients can find a healthy and compatible donor.

UAB, through the Research Group directed by Dr Jordi Surrallés, professor at the Department of Genetics and Microbiology, and CIEMAT, through the group led by Dr Juan Antonio Bueren, director of the Hematopoiesis and Gene Therapy Division, are two of the world's leading centres in the research on Fanconi anemia. In recent years they have made many important contributions to help understand the genetic mechanisms of the disease. These past few years, the Office of the Vice-Rector for Strategic Projects at UAB has cofinanced translational research on Fanconi anemia as a model disease in biomedical and biotechnological research.

The research group led by doctors Surrallés and Bueren are part of the Networking Centre of Biomedical Research in Rare Diseases(CIBERER).

CIBERER acts as a vehicle between biomedical research, health services and patients and their families, and therapeutic conferences are the channel through which clinical professionals and patient associations are informed of the research advances taking place. At the same time, the centre gives support and promotes actions aimed at offering research services for rare diseases as a whole..

World First: Chinese Scientists Create Pig Stem Cells
Scientists have managed to induce cells from pigs to transform into pluripotent stem cells – cells that, like embryonic stem cells, are capable of developing into any type of cell in the body

It is the first time in the world that this has been achieved using somatic cells (cells that are not sperm or egg cells) from any animal with hooves (known as ungulates).

The implications of this achievement are far-reaching; the research could open the way to creating models for human genetic diseases, genetically engineering animals for organ transplants for humans, and for developing pigs that are resistant to diseases such as swine flu.

The work is the first research paper to be published online today (Wednesday 3 June) in the newly launched Journal of Molecular Cell Biology [1].

Dr Lei Xiao, who led the research, said: "To date, many efforts have been made to establish ungulate pluripotent embryonic stem cells from early embryos without success. This is the first report in the world of the creation of domesticated ungulate pluripotent stem cells. Therefore, it is entirely new, very important and has a number of applications for both human and animal health."

Dr Xiao, who heads the stem cell lab at the Shanghai Institute of Biochemistry and Cell Biology (Shanghai, China), and colleagues succeeded in generating induced pluripotent stem cells by using transcription factors to reprogramme cells taken from a pig's ear and bone marrow. After the cocktail of reprogramming factors had been introduced into the cells via a virus, the cells changed and developed in the laboratory into colonies of embryonic-like stem cells. Further tests confirmed that they were, in fact, stem cells capable of differentiating into the cell types that make up the three layers in an embryo – endoderm, mesoderm and ectoderm – a quality that all embryonic stem cells have. The information gained from successfully inducing pluripotent stem cells (iPS cells) means that it will be much easier for researchers to go on to develop embryonic stem cells (ES cells) that originate from pig or other ungulate embryos.

Dr Xiao said: "Pig pluripotent stem cells would be useful in a number of ways, such as precisely engineering transgenic animals for organ transplantation therapies. The pig species is significantly similar to humans in its form and function, and the organ dimensions are largely similar to human organs. We could use embryonic stem cells or induced stem cells to modify the immune-related genes in the pig to make the pig organ compatible to the human immune system. Then we could use these pigs as organ donors to provide organs for patients that won't trigger an adverse reaction from the patient's own immune system.

"Pig pluripotent stem cell lines could also be used to create models for human genetic diseases. Many human diseases, such as diabetes, are caused by a disorder of gene expression. We could modify the pig gene in the stem cells and generate pigs carrying the same gene disorder so that they would have a similar syndrome to that seen in human patients. Then it would be possible to use the pig model to develop therapies to treat the disease.

"To combat swine flu, for instance, we could make a precise, gene-modified pig to improve the animal's resistance to the disease. We would do this by first, finding a gene that has anti-swine flu activity, or inhibits the proliferation of the swine flu virus; second, we can introduce this gene to the pig via pluripotent stem cells – a process known as gene 'knock-in'. Alternatively, because the swine flu virus needs to bind with a receptor on the cell membrane of the pig to enter the cells and proliferate, we could knock out this receptor in the pig via gene targeting in the pig induced pluripotent stem cell. If the receptor is missing, the virus will not infect the pig."

In addition to medical applications for pigs and humans, Dr Xiao said his discovery could be used to improve animal farming, not only by making the pigs healthier, but also by modifying the growth-related genes to change and improve the way the pigs grow.

However, Dr Xiao warned that it could take several years before some of the potential medical applications of his research could be used in the clinic.

The next stage of his research is to use the pig iPS cells to generate gene-modified pigs that could provide organs for patients, improve the pig species or be used for disease resistance. The modified animals would be either "knock in" pigs where the iPS or ES cells have been used to transfer an additional bit of genetic material (such as a piece of human DNA) into the pig's genome, or "knock out" pigs where the technology is used to prevent a particular gene functioning.

Commenting on the study, the journal's editor-in-chief, Professor Dangsheng Li, said: "This research is very exciting because it represents the first rigorous demonstration of the establishment of pluripotent stem cell in ungulate species, which will open up interesting opportunities for creating precise, gene-modified animals for research, therapeutic and agricultural purposes."

Researchers engineer metabolic pathway in mice to prevent diet-induced obesity
By Wileen Wong Kromhout | 6/2/2009 9:30:00 AM
In recent years, obesity has taken on epidemic proportions in developed nations, contributing significantly to major medical problems, early death and rising health care costs. According to Centers for Disease Control and Prevention estimates, at least a quarter of all American adults and more than 15 percent of children and adolescents are obese.

While recent research advances and treatment methods have had little effect in reducing obesity levels, researchers at the UCLA Henry Samueli School of Engineering and Applied Science, in collaboration with the David Geffen School of Medicine at UCLA, may have discovered a completely new way to approach the problem.

In a study to be published in the June 3 issue of the journal Cell Metabolism, chemical and biomolecular engineering professor James Liao, associate professor of human genetics and pediatrics Katrina Dipple and their research team demonstrate how they successfully constructed a non-native pathway in mice that increased fatty acid metabolism and resulted in resistance to diet-induced obesity.

"When we looked at the fatty-acid metabolism issue, we noted there are two aspects of the problem that needed to be addressed," Liao said. "One is the regulation; fatty acid metabolism is highly regulated. The other is digestion of the fatty acid; there needs to be a channel to burn this fat."

"We came up with an unconventional idea which we borrowed from plants and bacteria," said Jason Dean, a graduate student on Liao's team and an author of the study. "We know plants and bacteria digest fats differently from humans, from mammals. Plant seeds usually store a lot of fat. When they germinate, they convert the fat to sugar to grow. The reason they can digest fat this way is because they have a set of enzymes that's uniquely present in plants and bacteria. These enzymes are called the 'glyoxylate shunt' and are missing in mammals."

To investigate the effects of the glyoxylate shunt on fatty acid metabolism in mammals, Liao's team cloned bacteria genes from Escherichia coli that would enable the shunt, then introduced the cloned E. coli genes into the mitochondria of liver cells in mice; mitochondria are where fatty acids are burned in cells.

The researchers found that the glyoxylate shunt cut the energy-generating pathway of the cell in half, allowing the cell to digest the fatty acid much faster than normal. They also found that by cutting through this pathway, they created an additional pathway for converting fatty acid into carbon dioxide. This new cycle allowed the cell to digest fatty acid more effectively.

"The significance of this is great. It is a unique approach to understanding metabolism. Perturbing metabolic pathways, such as introducing the glyoxylate shunt and seeing how it affects overall metabolism, is a novel way to understand the control of metabolism," Dipple said.

The team also found that the new pathway decreased the regulatory signal malonyl-CoA. When malonyl-CoA levels are high, a signal is released that tells the body it is too full and that it needs to stop using fat and begin making it. Malonyl-CoA is high after eating a meal, blocking fatty acid metabolism. The new pathway, however, allowed for fat degradation even when the body was full.

Ultimately, the research team found that mice with the glyoxylate shunt that were fed the same high-fat diet — 60 percent of calories from fat — for six weeks remained skinny, compared with mice without the shunt.

"One exciting aspect of this study is that it provides a proof-of-principle for how engineering a specific metabolic pathway in the liver can affect the whole body adiposity and response to a high-fat diet," said Karen Reue, a UCLA professor of human genetics and an author of the study. "This could have relevance in understanding, and potentially treating, human obesity and associated diseases, such as diabetes and heart disease."

"We are very hopeful," said Liao. "This is the first example of how people can build new genes into mammals to achieve a desired function. It's very exciting that we've been able to achieve this new pathway in mammals that could potentially be used to fight a very serious problem."

TUESDAY June 2, 2009---------------------------News Archive

Stem Cell-Gene Therapy Cures Genetic Disease in Vitro
A study led by researchers at the Salk Institute for Biological Studies, has catapulted the field of regenerative medicine significantly forward, proving in principle that a human genetic disease can be cured using a combination of gene therapy and induced pluripotent stem (iPS) cell technology

The study, published in the May 31, 2009 early online edition of Nature, is a major milestone on the path from the laboratory to the clinic.

"It's been ten years since human stem cells were first cultured in a Petri dish," says the study's leader Juan-Carlos Izpisúa Belmonte, Ph.D., a professor in the Gene Expression Laboratory and director of the Center of Regenerative Medicine in Barcelona (CMRB), Spain. "The hope in the field has always been that we'll be able to correct a disease genetically and then make iPS cells that differentiate into the type of tissue where the disease is manifested and bring it to clinic."

Although several studies have demonstrated the efficacy of the approach in mice, its feasibility in humans had not been established. The Salk study offers the first proof that this technology can work in human cells.

Belmonte's team, working with Salk colleague Inder Verma, Ph.D., a professor in the Laboratory of Genetics, and colleagues at the CMRB, and the CIEMAT in Madrid, Spain, decided to focus on Fanconi anemia (FA), a genetic disorder responsible for a series of hematological abnormalities that impair the body's ability to fight infection, deliver oxygen, and clot blood. Caused by mutations in one of 13 Fanconi anemia (FA) genes, the disease often leads to bone marrow failure, leukemia, and other cancers. Even after receiving bone marrow transplants to correct the hematological problems, patients remain at high risk of developing cancer and other serious health conditions.

After taking hair or skin cells from patients with Fanconi anemia, the investigators corrected the defective gene in the patients' cells using gene therapy techniques pioneered in Verma's laboratory. They then successfully reprogrammed the repaired cells into induced pluripotent stem (iPS) cells using a combination of transcription factors, OCT4, SOX2, KLF4 and cMYC. The resulting FA-iPS cells were indistinguishable from human embryonic stem cells and iPS cells generated from healthy donors.

Since bone marrow failure as a result of the progressive decline in the numbers of functional hematopoietic stem cells is the most prominent feature of Fanconi anemia, the researchers then tested whether patient-specific iPS cells could be used as a source for transplantable hematopoietic stem cells. They found that FA-iPS cells readily differentiated into hematopoietic progenitor cells primed to differentiate into healthy blood cells.

"We haven't cured a human being, but we have cured a cell," Belmonte explains. "In theory we could transplant it into a human and cure the disease."

Although hurdles still loom before that theory can become practice—in particular, preventing the reprogrammed cells from inducing tumors—in coming months Belmonte and Verma will be exploring ways to overcome that and other obstacles. In April 2009, they received a $6.6 million from the California Institute Regenerative Medicine (CIRM) to pursue research aimed at translating basic science into clinical cures.

"If we can demonstrate that a combined iPS–gene therapy approach works in humans, then there is no limit to what we can do," says Verma.

Wet Ear Wax/Unpleasant Body Odors May Signal Breast Cancer Risk
New research in the FASEB Journal shows that a “breast cancer gene” causes osmidrosis and makes earwax wet and sticky

If having malodorous armpits (called osmidrosis) and goopy earwax isn't bad enough, a discovery by Japanese scientists may add a more serious problem for women facing these cosmetic calamities. That's because they've found that a gene responsible for breast cancer causes these physical symptoms. The report describing this finding is featured on the cover of The FASEB Journal's June 2009 print issue (http://www.fasebj.org), and should arm physicians with another clue for detecting breast cancer risk.

"We do strongly hope that our study will provide a new tool for better predication of breast cancer risk by genotyping," said Toshihisa Ishikawa, Ph.D., a professor from the Department of Biomolecular Engineering at the Tokyo Institute of Technology and the senior researcher involved in the work. "Using a rapid and cost-effective typing method presented in this study would provide a practical tool for pharmacogenomics-based personalized medicine."

To draw their conclusions, Ishikawa and colleagues monitored the activities of a protein created by a gene associated with breast cancer, called "ABCC11." By studying this gene and its complex cellular and molecular interactions in the body, the researchers discovered a distinct link between the gene and excessively smelly armpits and wet, sticky earwax. Specifically, the researchers expressed the ABCC11 gene and variant proteins in cultured human embryonic kidney cells and showed exactly how the ABCC11 gene produces the wet-type earwax and excessive armpit odor. This discovery could lead to practical tools for clinicians—especially those in developing nations—to rapidly identify who may have a higher risk for breast cancer.

"Wet, sticky earwax might not be easily noticed, but most people can't miss unpleasant body odors," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal, "As it turns out, the type of ear wax one has is linked to a gene that leads to bad odors from one's armpit. These may become lifesaving clues to the early detection and treatment of breast cancer."

Oh Baby!

Newly Rediscovered, Selenium May Lead to New Antibiotics
A mineral found at health food stores could be the key to developing a new line of antibiotics for bacteria that commonly cause diarrhea, tooth decay and, in some severe cases, death

The trace mineral selenium is found in a number of proteins in both bacterial cells and human cells called selenoproteins. University of Central Florida Associate Professor William Self’s research shows that interrupting the way selenoproteins are made can halt the growth of the super bug Clostridium difficile and Treponema denticola, a major contributor to gum disease.

Infections of Clostridium difficile (commonly known as C-diff) lead to a spectrum of illnesses ranging from severe diarrhea to colitis, which can cause death. It’s a life-threatening problem in hospitals and nursing homes worldwide, and the number of cases is on the rise. There are an estimated 500,000 cases per year in the United States alone. Between 15,000 to 20,000 people die each year while infected with this superbug. Treponema denticola is one of leading causes of gum disease and costs individuals thousands of dollars in dental care each year.

Self’s findings are published in the May and June editions of the Journal of Biological Inorganic Chemistry and the Journal of Bacteriology. The National Institutes of Health and the Florida Department of Health funded the research, which was conducted at UCF during the past three years.

“It’s the proof of principle that we are excited about,” Self said from his research lab at UCF. “No one has ever tried this approach, and it could potentially be a source for new narrow spectrum antibiotics that block bacteria that require selenium to grow.”

The key discovery occurred when the team found that the gold drug Auranofin, used to treat arthritis, impacted selenium's metabolism process. The chemical reaction changes the selenium, which prevents bacteria from using it to grow. Auranofin is an FDA-approved gold salt compound that is used to control inflammation and is already known to inhibit the activity of certain selenoproteins. Since certain bacteria, such as C. difficile, require selenoproteins for energy metabolism, the drug acts as a potent antimicrobial halting the growth of the bacteria.

The initial studies with C. difficile led to studies with T. denticola, known for several years to require selenium for growth. While testing the gold salt, Self’s group also uncovered another surprise; the stannous salts found in many antimicrobial toothpastes in the form of stannous fluoride also inhibited the synthesis of selenoproteins. Previous independent research had already established that stannous salts are more effective at preventing tooth decay and inhibiting growth of T. denticola, but the mechanism of this inhibition of growth was not yet known. These findings could lead to new approaches to preventing gum disease.

“No one has tried to block the metabolism of selenium before as a therapeutic approach,” Self said. “That’s what’s new and exciting and could lead to a whole host of other possibilities, including a better understanding of how the gold salt works for arthritis.”

Self said more research is needed, and he already has another grant proposal before the NIH that would move his research forward.

Study Reveals Broad, Hidden Network Where Tumors Thrive
Howard Hughes Medical Institute researchers have identified many potential new drug targets for cancers long deemed “untouchable” due to the type of genetic mutation they contain. These studies are beginning to reveal new ways of attacking cancer by targeting a largely hidden network of normal genes that cancer cells rely on for survival

Independent research teams led by Howard Hughes Medical Institute (HHMI) investigators D. Gary Gilliland of Brigham and Women’s Hospital (now senior vice president at Merck Research Laboratories) and Stephen J. Elledge at Harvard Medical School, used RNA interference (RNAi) technology to identify a host of genes that cancer cells depend on for survival. The researchers studied cells with mutations in KRAS, the most commonly mutated gene in human cancers.

KRAS, which was discovered nearly 30 years ago, is mutated in 30 percent of human tumors, including 90 percent of pancreatic cancers, 50 percent of colon cancers, and 30 percent of non-small cell lung cancers.

“Efforts to develop drugs that inhibit oncogenic RAS proteins have been largely unsuccessful, despite the fact that RAS gene family members are mutated in about 30 percent of human tumors,” said Gilliland, who directs the oncology program at Merck.

More than 18 months ago, Elledge and Gilliland decided to see if they could use the powerful RNAi technology to seek out genes that KRAS-mutant cancer cells need for survival. Their efforts, culminating in two reports in the May 29, 2009, issue of the journal Cell, have led to the identification of potentially promising drug targets: serine/threonine kinase 33 (STK33) and polo-like kinase 1 (PLK-1), as well as a host of other proteins.

“These targets represent a potential Achilles heel for tumors,” said Gilliland. “In the case of STK33, it is absolutely required for survival of cancer cells. Normal cells don’t require it.”

“The translational implications of both reports are important and immediate,” wrote Charles L. Sawyers, an HHMI investigator at Memorial Sloan-Kettering Cancer Center. Sawyers discussed the implications of the research in a Preview article published in the same issue of Cell.

Sawyers points to the identification of the two kinases as validation of the approaches taken by Elledge and Gilliland. With the dramatic clinical success of cancer drugs, such as Gleevec and dasatinib, which target rogue kinases, Sawyers says any screen that turns up new kinases is worthy of further investigation.

“The new mantra, quite simply, is that cancers bearing oncogenic mutations in a kinase are dependent on that kinase for growth and survival,” writes Sawyers in Cell. “With rare exception, patients with such tumors have derived significant benefit (that is, their tumors shrink) when treated with an inhibitor of that mutant kinase. The probability of success in such patients is so high that drug discovery programs can (and should) be launched when a new kinase mutation is discovered in a subset of human cancers.”

“Hopefully drugs that target non-mutant, but synthetic lethal kinases will be similarly effective,” Sawyers added.

The concept of synthetic lethality – which is part of the intellectual framework of these two studies -- has its roots in yeast genetics. Synthetic lethality is defined as a genetic interaction where the combination of mutations in two or more genes leads to cell death. For example, two different strains of yeast may each harbor a mutation that is not lethal on its own. But when both mutations are combined in a single strain of yeast, death occurs – hence the name, synthetic lethality. “Synthetic lethality is actually co-lethality,” said Elledge.

During the last few years cancer researchers have become increasingly interested in developing synthetic lethality screens as a tool for uncovering genetic dependencies in cancer cells. The rationale behind the strategy is as follows: A mutated cancer-causing gene, or oncogene, causes a cell to grow abnormally. That abnormal growth can lead to the development of a tumor. But oncogenes do not cause cancer by themselves – they depend on the activity of other genes. These genes are considered “dependents,” in the sense that the cancer cell’s survival also depends on the activity of the oncogenes and its dependent genes. Many of these so-called dependent genes are not mutated in cancer cells, but they contribute to abnormal cell growth and cancer. By using RNAi to knock down the expression of individual genes in cells bearing mutations in an oncogene, such as KRAS, researchers can see which gene knock-downs affect cancer cells’ viability. Gene dependencies are uncovered in cancer cells that fail to thrive.


Until recently, however, researchers simply did not have the tools to undertake a large-scale, systematic analysis to uncover genetic dependencies in mammalian cells. The discovery of RNAi a little more than a decade ago is making it possible to do genetics in mammalian cells. The cellular machinery involved in RNAi first identifies short segments of suspicious-looking RNA, and then destroys all identical copies of that RNA. The result: None of the protein that the RNA encodes for gets made.

While the natural function of RNAi is to prevent viruses from replicating inside cells and to control endogenous gene expression, scientists discovered they could exploit the process to squelch individual gene products. To do so, they introduce a short segment of RNA that looks like one of the cell's normal genes. The RNA interference machinery grinds into action and shuts down production of the protein made from that gene.

Gilliland’s team, which included first authors, Claudia Scholl and Stefan Fröhling, as well as HHMI investigator Tyler Jacks at MIT, began their studies about two years ago. The team’s interest in leukemias informed their decision to focus on using short hairpin RNAs (shRNAs) -- single strands of RNA that fold back on themselves -- to selectively knock down the activity of serine/threonine kinases and tyrosine kinases. In recent years, kinase inhibitors have emerged as highly successful therapy for a subset of leukemias.

“We were looking at genes that we thought we could target easily with drugs,” Gilliland said. “We looked for genes that when knocked down would confer lethality to cells that were KRAS-mutant, but not KRAS-wild-type.” This approach is a particularly attractive concept in cancer research because normal cells don’t have the same dependencies on these genes. “If you find a vulnerability conferred by another gene, you should, in theory, have a great therapeutic window because you’re not going to affect normal cells,” he said.

Gilliland’s group began a collaboration with William C. Hahn at the RNAi Consortium at the Broad Institute to use the Broad’s automated RNAi screening technology to assess about 5,000 shRNAs targeting about 1,000 human genes in a panel of eight human cancer cell lines. The shRNAs were carried in lentiviral vectors, which the researchers used to infect four cell lines carrying KRAS mutations and four lines carrying KRAS-wild-type genes.

At the top of the “hits” identified in the screen was the serine/threonine kinase, STK33, which Gilliland describes as a “totally new gene” in cancer research circles. “There are a couple of older papers describing STK33’s genetic localization and exon structure, but otherwise nothing else is known about it.”

That’s about to change as Gilliland and his team begin to explore why STK33 represents a liability for KRAS-mutant cancer cells. Evidence presented in Cell shows that STK33 is not a part of the RAS signaling pathway, nor is it mutated in human cancer cell lines that were tested. Gilliland said his group’s experiments indicate that STK33 is involved in induction of the cell death pathway in cancer cells. “We don’t have all the answers yet, but STK33 is selectively required for the survival and proliferation of mutant KRAS-dependent cancer cells,” Gilliland said.

In the experiments reported in Cell, Elledge and his colleagues used an RNAi technique developed by Elledge and HHMI investigator Greg Hannon at Cold Spring Harbor Laboratory. “Overall, we were asking very simple questions: What do RAS cells need to survive? And is it different from what normal cells need to survive?” said Elledge.

Elledge’s team generated about 75,000 bits of short hairpin RNAs that can be inserted into retroviruses. When the altered retroviruses infected either normal cells or cells that differed by only a single mutation in KRAS, the shRNA bound to corresponding stretches of RNA in the cells, and prevented their translation into proteins.

If the shRNA knocked down production of a protein essential to keeping the cells alive, then the abundance of that particular shRNA quickly diminished as cells died. The researchers could track the identity of the shRNA – and its corresponding gene – by using a “barcoding” method to track the diverse pool of short hairpin RNAs in parallel. In the barcoding method, every short hairpin RNA that is made carries a unique genetic tag. This tag lets the researchers track the effect of thousands of the RNAs in a single pool of cells in a single lab dish. “These are experiments a single researcher can perform in their own lab without the need for complex robotic platforms,” said Elledge.

By tracking the abundance of each shRNA from the total pool and comparing cancer cells to cells from normal tissues, Elledge and his colleague Ji Luo identified many genes that KRAS is dependent on. In this manner, they were able to do a genome-wide survey, uncovering many new potential drug targets, including PLK-1, STK33, and a number of proteins involved in mitosis. “It will take some time to figure this out, but RAS is clearly having some effect on an important part of mitosis,” said Elledge. “Regardless of that mechanism, it provides a vulnerability that we can attack. And fortunately there are a lot of drugs already available that have anti-mitotic properties – and we showed that some of those drugs are more toxic to the RAS cells.”

Furthermore, Elledge’s group found that the expression levels of some of the genes on their “hit” list correlated with patient survival. “This argues that they really do have an important role in the clinical outcomes observed in cancer patients,” said Elledge.

Sawyers thinks these two studies are an important proof-of-concept, but much more work will be needed to identify all the underlying vulnerabilities of cancer cells. “The ultimate validation of the synthetic lethal screening strategies will be evidence that patients KRAS-mutant tumors benefit from treatment with STK33 or PLK1 inhibitors,” Sawyers said. “Unfortunately, we won’t have that answer for many years.”

MONDAY June 1, 2009---------------------------News Archive

A Window on the Fetus, The Human Placenta
Written by Judy Siegel-Itzkovich for THE JERUSALEM POST
The placenta - or afterbirth - has long been regarded by obstetricians and midwives as an afterthought. The dark reddish-blue or maroon gob about 22 centimeters in diameter and weighing about half a kilo connects the developing embryo/fetus to the wall of the uterus and provides it with nutrients from its mother while removing fetal waste to be eliminated by the mother's kidneys. Tiny blood vessels branch out over its surface and form a network covered by a thin layer of epidermal cells, thus forming finger-shaped structures called chorionic villi

This amazing structure, without which human babies and other mammals could not thrive in the womb, is nevertheless cast away or buried (even though today, the umbilical cord that connects the fetus to the placenta is usually saved for its embryonic stem cells, that could be used for bone marrow transplants). But the placenta is the focus of research by a handful of scientists who believe it can provide a great deal of information about the mother, the fetus and the baby.

One of them, Prof. Harvey Kliman of the Yale University School of Medicine in Connecticut, says: "Behind every healthy baby is a healthy placenta." He has even done research (which must first be corroborated in larger studies) indicating that an examination of the placenta can predict with impressive exactitude whether the baby who was connected to it will show symptoms of autism some two years after birth.

Kliman recently lectured at the Jerusalem conference called "Across the Endometrium and Into the Promised Land of the Placenta" and chaired by Hadassah University Medical Center fetal ultrasound expert Prof. Simcha Yagel at the Inbal Hotel.

Kliman, who was born in Buffalo, grew up on Long Island, New York. Born to young parents (including an engineer father) who did not tie him to their apron strings, Harvey decided in 1970, at the age of 17, that he wanted to drive a motorcycle the length of Israel. When he came, the ride didn't work out, but he did participate in the International Summer Science Institute at the Weizmann Institute in Rehovot and ended up at Kibbutz Sde Boker in the Negev.

"I recall an old man who told me stories there; only later did I learn this was [Israel's first prime minister] David Ben-Gurion." Kliman has visited Israel frequently since then, especially for professional reasons.

Kliman returned to the US and earned his BA at Syracuse University and his MD from the University of Chicago, which also awarded him his doctorate in biochemistry. He was a resident in pathology at the University of Pennsylvania. He delivered about 30 babies as a medical student, but as he liked to sleep through the night, he decided not to specialize in bringing babies into the world, even though he now treats patients with infertility and other problems.

Studying pathology, he researched the placenta and devised a way to purify the stem cells inside. Today his method is used around the world. "I took a full-term placenta - which is a big, bloody thing - cut it up into pieces, then minced the 'meat' and used enzymes to digest it," he said in an interview with The Jerusalem Post during the conference. "Then I peeled away what looked like little peas. The ends of fetal circulation have a skin cover and an inside layer where stem cells are. I learned how to extract them."

PLACENTAS, HE continued, "say a tremendous amount, but you have to be educated about them. The most important thing to know is the gestational age [how much time has passed since conception]. I remember one young pathologist who didn't bother to go up from the lab to the labor floor to see the patient and find out the gestational age of her placenta."

He said he is one of A few - and probably the only - pathologist to be an obstetrician/gynecologist who prefers not to deliver babies. "There are some ob/gyns who left to become pathologists, but I don't know of a pathologist who sees patients today."

The placenta "totally supports the fetus's life. You can have a pregnancy with a placenta and not a fetus, but not the opposite. Today, medicine still focuses almost completely on the fetus rather than on the placenta. We put women through pregnancy without a gasoline gauge. The tank that provides the fuel is the placenta, and we can't tell how much gas is left by the last part of the gestation," he said.

"When a woman is not pregnant, only .5% of her blood goes through these blood vessels in the uterus, but when she is pregnant, it reaches up to 25%. The vessels open up, and this characteristic makes humans different from apes," he explained. But the skin-covered villi, which together look like a hand in a bucket of water, do not allow the woman's blood to leak out into the water. There is no direct connection between the mother's and fetus' blood."

"The placenta is part of the fetus," he explained. "They are made of the same material. When you look at a placenta, it's like a window on the baby. We look for symmetry in the placenta. It's difficult to create symmetry.We can tell off the bat if something is put together perfectly. When genes are abnormal, however, you get abnormal growth patterns and folding in the placenta. Basically a funny-looking placenta."

THE HUMAN brain is also a complex folded tissue. "Whatever is abnormal in the placenta in these cases of genetic defects is likely what's abnormal in the brain. Something is wrong with the way the brain is folded - and we may see the same thing in both the placenta and the brain," he continued. Normally, the villus produces the needed hormones for pregnancy. "I thought I could look at the villi in a placenta to know what problems were in a fetus," he continued. "Irregularities in the fetus are three to four times more likely when there is abnormal folding in the placenta."

He conducted studies on the stored placentas of women whose children were diagnosed with autism - the development disorder causing impaired social interaction and repetitive behavior. His aim was to find a marker that would show up in the afterbirth, so that diagnosis would not have to wait for two or three years. He believes he has found a possible connection between this abnormal folding and autism. "It isn't the irregular folds themselves that cause problems, but a marker, as the fetus and placenta are connected to the same genetic material," Kliman stressed. "The earlier the intervention for autism, even just after birth, the more likely we can see improvements." If confirmed by further studies, it could lead to new medications, he added.

He is not currently recommending that all placentas be checked for autism after birth. "We're doing a prospective multicenter study for five years using women at high risk for having an autistic child. Of those with one such child, 10% will have another."

The placenta has also been used to develop a test during an early stage of pregnancy to determine whether a woman will develop preeclampsia later. A sensitive biomarker called placental protein 13 (PP13) is the first in the world believed to predict preeclampsia, a condition that involves high blood pressure and can lead to complications in the kidneys, liver, blood and brain, as well as to premature delivery.

It was developed at Diagnostic Technologies Ltd. (DTL) in Yokneam, Israel based on the work of an "incubator" project at the Technion-Israel Institute of Technology. Used so far on some pregnant Israeli women, the PP13 diagnostic test will now be tried further in Austria by Prof. Berthold Huppertz, a German-born cell biology expert at the University of Graz who attended the Jerusalem conference and will receive the 2009 award of the International Federation of Placenta Associations (IFPA).

Oh Baby!

PREECLAMPSIA complicates five to seven percent of all pregnancies and is responsible for 18% of all maternal deaths during pregnancy, as well as for a third of all premature births. It remains a mysterious disease, even though it was mentioned in Egyptian and Chinese texts going back 3,000 years. While there is no cure, treating women with bed rest, low-dose aspirin or other substances and monitoring their condition can reduce the risk of preeclampsia. The earlier such intervention is undertaken, the better.

Preeclampsia is diagnosed when a pregnant woman develops consistent blood pressure readings of 140/90 or more and 300 mg. of protein (proteinuria) in a 24-hour urine sample. Edema (swelling), especially in the face and hands, used to be thought a key sign of preeclampsia, but today only hypertension and proteinuria are needed for a diagnosis. But if a pregnant woman has swelling in her ankles, hands or face and pressing a finger into them leaves a mark, it may be a sign of preeclampsia and should be reported to her doctor. A major problem is that none of the symptoms of preeclampsia are specific only to that condition.

"A healthy baby at term is the product of three important factors - a healthy mother, normal genes and good placental implantation and growth," said Kliman. "Placental thickness and volume have been used to predict chromosomal abnormalities and diseases such as preeclampsia."

THREE-DIMENSIONAL ultrasound has been used to measure these factors, but it's expensive and requires training. Kliman developed a two-dimensional technique and a mathematical equation that, he suggests, is just as accurate and can help rule out, early in pregnancy, the presence of a placenta that's small for gestational age, thus pointing to possible problems. His father, the engineer with 20 patents, helped Kliman calculate the placenta's volume as if it were a rounded skullcap. "After delivery, we weighed the placenta and found that our estimate was accurate. Thanks to this, knowing that the placenta volume was very small in one of my patients, we saved the baby's life. We put the mother in the hospital for two weeks, giving her liquids and rest. Her placenta swelled up like a sponge during that time, and she was able to have a healthy baby."

Kliman, who loves to use metaphors to describe complex biological phenomena, depicts the placenta as a battlefield between two armies. The father, his sperm and his genes naturally want to produce "the biggest baby" so it will survive. To do this the father sends soldiers into the mother to open up the blood vessels supplying the placenta. But a too-large baby might get stuck and could kill her. Therefore the mother tries to fight off the father's soldiers to keep the blood flow to the uterus low. Neither side gets exactly what it "wants," so each has to compromise and a normal baby is born. Preeclampsia is believed to be launched when cells invading the uterus (the father's 'soldiers') fail to transform the uterine arteries into open tubes, leading to decreased maternal blood flow.

Kliman noted that he found PP13 "far away from the arteries in the placenta. When I looked close, I saw a zone of necrosis that looked like mass destruction, with hundreds of thousands of dead soldiers hit by napalm on the battlefield." It looks as if the PP13 is one way the father tricks the mother into not destroying the father's soldiers that are trying to open up the mother's uterine blood vessels.

Kliman aroused quite a bit of controversy about seven years ago when he and colleagues wrote an article in an ob/gyn journal about endometriosis - a condition in fertile women in which endometrial cells migrate outside the uterine cavity and are affected by hormones, causing pain and possibly infertility. The authors maintained that use of tampons or having an orgasm during menstruation can reduce the risk of endometriosis. Feminist and environmental groups didn't like the conclusion, as they worried about the chemical dioxin (a natural substance used for bleaching some tampons in those days). In addition, Orthodox rabbis certainly didn't like it, as sex during menstruation and the week after is strictly barred by Jewish law (although health is not given as the reason).

"The female body was never designed to have 400 menstrual periods during a lifetime. For millennia, females started getting pregnant in early adolescence and then kept getting pregnant, but they died young so they had few periods," Kliman explained. But his retrospective research, he said, proved that tampons serve as a wick to remove menstrual blood from the uterus instead of allowing it to seep into the pelvic area. Orgasms during menstruation, he said, produce wave-like movement that accentuates the release of menstrual blood, which he described as "debris" that should not remain in the body.

"I received threats over it from an endometriosis association. I was accused of academic fraud, but my university backed me up, and since then my opponents have given up their stand. I feel very comfortable about that research," Kliman asserted.

Whether all his colleagues agree with him or not, Kliman's shifting of the focus away from the fetus and closer to the placenta is welcome, and should make it easier to find some answers to the many remaining puzzles about fetal disease.


Stem Cell-Gene Therapy Cures Genetic Disease in Vitro
A study led by researchers at the Salk Institute for Biological Studies, has catapulted the field of regenerative medicine significantly forward, proving in principle that a human genetic disease can be cured using a combination of gene therapy and induced pluripotent stem (iPS) cell technology

The study, published in the May 31, 2009 early online edition of Nature, is a major milestone on the path from the laboratory to the clinic.

"It's been ten years since human stem cells were first cultured in a Petri dish," says the study's leader Juan-Carlos Izpisúa Belmonte, Ph.D., a professor in the Gene Expression Laboratory and director of the Center of Regenerative Medicine in Barcelona (CMRB), Spain. "The hope in the field has always been that we'll be able to correct a disease genetically and then make iPS cells that differentiate into the type of tissue where the disease is manifested and bring it to clinic."

Although several studies have demonstrated the efficacy of the approach in mice, its feasibility in humans had not been established. The Salk study offers the first proof that this technology can work in human cells.

Belmonte's team, working with Salk colleague Inder Verma, Ph.D., a professor in the Laboratory of Genetics, and colleagues at the CMRB, and the CIEMAT in Madrid, Spain, decided to focus on Fanconi anemia (FA), a genetic disorder responsible for a series of hematological abnormalities that impair the body's ability to fight infection, deliver oxygen, and clot blood. Caused by mutations in one of 13 Fanconi anemia (FA) genes, the disease often leads to bone marrow failure, leukemia, and other cancers. Even after receiving bone marrow transplants to correct the hematological problems, patients remain at high risk of developing cancer and other serious health conditions.

After taking hair or skin cells from patients with Fanconi anemia, the investigators corrected the defective gene in the patients' cells using gene therapy techniques pioneered in Verma's laboratory. They then successfully reprogrammed the repaired cells into induced pluripotent stem (iPS) cells using a combination of transcription factors, OCT4, SOX2, KLF4 and cMYC. The resulting FA-iPS cells were indistinguishable from human embryonic stem cells and iPS cells generated from healthy donors.

Since bone marrow failure as a result of the progressive decline in the numbers of functional hematopoietic stem cells is the most prominent feature of Fanconi anemia, the researchers then tested whether patient-specific iPS cells could be used as a source for transplantable hematopoietic stem cells. They found that FA-iPS cells readily differentiated into hematopoietic progenitor cells primed to differentiate into healthy blood cells.

"We haven't cured a human being, but we have cured a cell," Belmonte explains. "In theory we could transplant it into a human and cure the disease."

Although hurdles still loom before that theory can become practice—in particular, preventing the reprogrammed cells from inducing tumors—in coming months Belmonte and Verma will be exploring ways to overcome that and other obstacles. In April 2009, they received a $6.6 million from the California Institute Regenerative Medicine (CIRM) to pursue research aimed at translating basic science into clinical cures.

"If we can demonstrate that a combined iPS–gene therapy approach works in humans, then there is no limit to what we can do," says Verma.

Genes that Influence the Start of Menstruation
Two scientists at the Institute for Aging Research of Hebrew SeniorLife are part of an international team of investigators that has identified genes that influence the start of menstruation, a milestone of female reproductive health that has lifelong influences on overall health

Using several population studies, including the Framingham Heart Study, the researchers analyzed data from more than 17,500 women to determine when menarche, the start of menstruation, begins, typically around age 13 or two years after the onset of puberty.

This study provides the first evidence of common genetic variants that influence the normal variation in the timing of female sexual maturation. The researchers say these findings are significant because girls with an earlier age at menarche tend to have a greater body mass index (BMI) and more body fat than girls who begin menstruating at a later age. In addition, one of the genes is located in a region that influences adult height.

"As earlier age at menarche is associated with shorter stature and obesity later in life, the identified variants may not only clarify the genetic control of female sexual maturation, but may also point to regulatory mechanisms involved in normal human growth and obesity," wrote the scientists, who included Douglas Kiel, M.D., M.P.H., the Institute for Aging Research's director of medical research, and David Karasik, Ph.D., director of its Genetic Epidemiology Program.

Genome-wide association studies have successfully identified many genetic variants associated with multiple diseases and traits such as height and skin color, so the researchers used a similar approach to identify genes involved in determining age at menarche.

MicroRNAs Grease the Cell's Circadian Clockwork
Most of our cells possess an internal clock, a group of genes displaying a cyclic expression pattern that reaches a peak once a day. A large number of circadian genes are expressed by organs such as the liver, whose activity needs to be precisely regulated over the course of the day. A team of researchers of the National Centre of Competence in Research Frontiers in Genetics, based at the University of Geneva, Switzerland, reveals that an important regulator of this molecular oscillator is a specific microRNA

The latter belongs to a class of small RNA molecules that regulate the production of proteins in our cells. Thus far, little was known about their function within the circadian clockwork. The study by Ueli Schibler's team, published in the 1st June edition of Genes & Development, fills in this important gap.

Living beings have adapted to the alternation between night and day by developing an internal clock, located in the brain. It allows synchronising gene expression and physiological functions with geophysical time. In addition, most of our body's cells possess their own subsidiary oscillators, a group of genes displaying a cyclic expression pattern that reaches a peak every twenty-four hours.

More than 350 genes involved in metabolism, including that of cholesterol and lipids, are expressed in liver cells in a cyclic fashion. Many of them are also influenced by rhythmic food intake. Their activity must therefore be fine-tuned and synchronised with precision to ensure cohesion between diverse metabolic processes.

MicroRNAs induce gene silencing
Ueli Schibler, from the Molecular Biology Department of the University of Geneva, focuses on the mechanisms controlling the tiny oscillators in liver cells. MicroRNAs were among the potential factors likely to be involved in clock gene regulation. The common property of these small molecules lies in their ability to inhibit the synthesis of specific proteins, thus allowing cells to reduce the activity of certain genes at a given time.

"We have studied the role of a microRNA called miR-122, which is highly abundant in liver. It has caught considerable attention for its role in regulating cholesterol and lipid metabolism and in aiding the replication of hepatitis C virus" explains David Gatfield, one of Professor Schibler's collaborators.

Performance of the molecular oscillator…
The researchers' team has discovered that miR-122 is tightly embedded in the output system of the circadian clock in hepatocytes. This microRNA regulates numerous circadian genes, impinging on the amplitude and duration of their expression. Conversely, the synthesis of miR-122 involves a transcription factor that is otherwise known for its function in the circadian clock.

…and viral replication
"It will be exciting to investigate whether the connection between circadian rhythms and miR-122 also extends to this microRNA's role in hepatitis C virus replication", points out David Gatfield. Knowing whether viral multiplication is gated to specific times of the day would contribute significantly to our understanding of the life cycle of this formidable pathogen.

Scientists have uncovered over the past years the role of microRNAs in crucial physiological functions such as growth and programmed cell death, as well as carcinogenesis. Ueli Schibler's team adds a stone to this edifice by placing miR-122 within the clock gene machinery.

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