FRIDAY - March 21, 2008--------------------------------------------------News Archive/Return to Today's News Alerts

Eating Habits between Men and Women Are Different

When it comes to what we eat, men and women really are different according to scientific research presented today at the 2008 International Conference on Emerging Infectious Diseases. In general, men are more likely to report eating meat and poultry items and women are more likely to report eating fruits and vegetables.

The findings come from the most recent population survey of the Foodborne Disease Active Surveillance Network (FoodNet). From May 2006 to April 2007 over 14,000 American adults participated in an extensive survey outlining their eating habits, including high risk foods for foodborne illness.

“There was such a variety of data we thought it would be interesting to see whether there were any gender differences. To our knowledge, there have been studies in the literature on gender differences in eating habits, but nothing this extensive,” says Beletshachew Shiferaw, a lead researcher on the study.

Shiferaw and her colleagues found that men were significantly more likely to eat meat and poultry products especially duck, veal, and ham. They were also more likely to eat certain shellfish such as shrimp and oysters.

Women, on the other hand were more likely to eat vegetables, especially carrots and tomatoes. As for fruits, they were more likely to eat strawberries, blueberries, raspberries and apples. Women also preferred dry foods, such as almonds and walnuts, and were more likely to consume eggs and yogurt when compared with men.

There were some exceptions to the general trend. Men were significantly more likely to consume asparagus and brussels sprouts than women while women were more likely to consume fresh hamburgers (as opposed to frozen, which the men preferred).

The researchers also looked at reported behavior in regards to consumption of 6 risky foods: undercooked hamburger, runny or undercooked eggs, raw oysters, unpasteurized milk, cheese made from unpasteurized milk and alfalfa sprouts. Men were significantly more likely to eat undercooked hamburger and runny eggs while women were more likely to eat alfalfa sprouts.

This information is important to public health officials because better understanding of gender differences in eating habits can help them create more targeted strategies for prevention.

“The reason we looked at consumption and risky behaviors was to see if there was a statistically significant difference between men and women and if there is this information could be used by health educators to target interventions,” says Shiferaw.

Presented March 16 - 18, 2008 at the International Conference on Emerging Infectious Diseases
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Tug of War Goes On In Cells






Transport processes in the cells of our body resemble the transport of goods on the roads. Molecular motors, which are special protein molecules, act as trucks. They carry the cellular cargo on piggy-back and transport it along microtubules, which are the roads of the cell. However, the molecular transporters are a billion times smaller than trucks and can only move as far as the beginning or end of the microtubule, depending on their type. They have to fight their way through a crowd that is more like a busy pedestrian area than a motorway, and also have to compete with motors that want to move in the opposite direction, as scientists at the Max Planck Institute of Colloids and Interfaces in Potsdam have now discovered in a computer simulation.

Several motors are always involved in the tug-of-war over a cargo - for example, some of the kinesin type and some of the dynein type. The kinesin motors move to the end of the microtubule that biologists call the positive end, while the dynein motors move to the minus end. The findings of the Potsdam-based scientists show that the stronger motor team determines the direction in which the cargo is moved. It involves a tug-of-war where opposing motors break off from the microtubule. It was previously assumed that there was a system of coordination that allowed for only one team of motors; it was believed this alternated between one team and the other.

"The tug-of-war is the simplest imaginable mechanism," says Melanie Müller, one of the scientists involved in the project. "But it is possible, if you consider the properties of the individual motors measured experimentally. They produce a strong non-linear reaction when they are pulled." A motor from the losing team is subject to a strong force and is quickly removed from the microtubule. The remaining motors must then take the force of the winning team alone and are also removed even more quickly. In a domino effect, the losing motors concede and are removed from the microtubule until no others remain. The winning team is then able to transport the cargo quickly, unopposed. "However, the cell does not leave it to chance to ensure that the cargo arrives at its destination. Regulatory proteins probably intervene," says Melanie Müller.

Researchers into the transport of fat particles in Drosophila embryos examined whether her model applied in reality. It is actually explained by experimental observations that took place previously on the transport mechanism. A cargo in a microtubule does not move directly from one end to the other. It is constantly pulled back in the opposite direction. The losing motors can, however, occasionally remove the winning ones from the microtubule as heat sometimes blows the winning motors away. The cargo particles therefore move in both directions.

"This bi-directional transport process is very flexible," explains Melanie Müller. It can change direction if the cargo passes its destination or change the speed of the transport. The tug-of-war mechanism, where the winning team pulls the opposing motor team as well as the cargo through the cell, also solves another logistical problem in the cell. It always carries the motors to the end of the microtubule from which they are able to move, preventing an accumulation of motors of one kind at their respective destination.

"Despite the simple mechanism, a cargo particle transported by two motor teams reveals very complex motility behavior," said Melanie Müller. There are seven different types of motility behavior. These are various combinations of movements to the positive and minus end as well as pauses to which the cargo particles can be subjected. The probability of movement in a certain direction or stopping, and the time lapses between the changes of direction, depend heavily on the properties and the number of the motors involved. The cell uses these to direct the cargo transport. If a team of motors is pulled harder or faster, the cargo moves in the minus instead of the positive direction or stops.

"The simple and efficient tug-of-war mechanism could be used for the transport in micro-laboratories on chips," relates Melanie Müller. In the same way as with the biological model, teams of motors can transport certain molecules to specific reaction locations on the chip and then also bring back the reaction product. "Our quantitative tug-of-war theory allows motor properties to be optimized for this purpose," according to Müller.

Published March 17, 2008 in the journal PNAS - Early Edition
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Neuron Regulator Potential Target For Cancer Control

Being too brainy can be a bad thing in a junior high cafeteria, where the social hierarchy favors other traits. "Braininess" also causes problems for cells. When a breast cell begins making the proteins normally produced in neurons, for example, it can acquire cancerous properties. Now, researchers in Stephen Elledge's laboratory at Harvard Medical School (HMS) have identified some of the switches that control this transformation, providing promising new therapeutic targets in some types of cancer.

"These switches play an important physiologic role in neural development and pathologic role in cancer," says first author Thomas Westbrook, who is now an assistant professor at Baylor College of Medicine. "I'm optimistic that we can use small molecules to control them."

In a previous study, Westbrook showed that a protein called REST - which keeps neural programs silent in most parts of the body - serves as a tumor suppressor. "He's now identified a protein that promotes tumor growth by tagging REST for destruction, thereby activating neural programs," says Elledge.

If the protein REST worked at a club, he would be a bouncer, preventing dozens of rowdy patrons from causing trouble. REST serves as a "master repressor," keeping numerous neural genes silent in breast cells, lung cells, etc, where they could wreak havoc. When REST disappears, these genes roar to life, pushing cells to become more like neuron precursor cells. But cells outside the nervous system keep neural genes silent for a reason. When neural genes get switched on in breast cells anchored to surfaces, for example, they acquire the ability to live without the anchoring that is essential for normal cells to survive. That is, they can grow in suspension, which is a classical characteristic of cancer cells.

After uncovering this role, Westbrook used a technique called RNA interference (RNAi) to search for proteins that reduce REST levels. He reasoned that these proteins might promote tumor formation if expressed outside the nervous system. The RNAi screen netted a known tumor promoter called β-TRCP. Further genetic tests revealed that β-TRCP binds directly to REST, tagging it for destruction. But REST must be primed with a particular molecule called phosphate for this interaction to occur.

"If we can prevent β-TRCP from binding to REST, we may be able to treat certain tumors that display neuronal gene expression profiles," says Elledge, who is also a member of the HMS-Partners HealthCare Center for Genetics and Genomics and investigator with the Howard Hughes Medical Institute. "Such profiles are remarkably common in epithelial cancers, such as breast cancer and ovarian cancer."

"This discovery is particularly exciting because the scientific community knows how to target enzymes that add and remove phosphate groups from proteins with small molecules," says Westbrook. "Big pharmaceutical companies have devoted lots of resou²²-TRCP from tagging REST for destruction, one could potentially keep embryonic stem cells from turning into neurons. Alternatively, one might be able to make neurons more efficiently by quickening REST destruction."

Published March 20, 2008 in the journal Nature

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THURSDAY - March 20, 2008--------------------------------------------------News Archive/Return to Today's News Alerts

Folate May Be Just As Necessary For Men As For Women

Healthy men who report lower levels of the nutrient folate in their diets have higher rates of chromosomal abnormalities in their sperm, according to a new study by researchers at the University of California, Berkeley, and the Lawrence Berkeley National Laboratory.

Women of child-bearing age are encouraged to maintain adequate levels of folate in their diet, but the new findings provide evidence that what men eat may also affect reproductive health.

"Recent studies have suggested that paternal diet affects sperm count and motility, which is important for conception, but this new study takes it further to say that male diet may be important for healthy offspring as well," said study coordinator Suzanne Young, a researcher at UC Berkeley's School of Public Health. "Our study is the first to look at the effects of diet on chromosomal abnormalities in sperm. These abnormalities would cause either miscarriages or children with genetic syndromes if the sperm fertilized an egg."

Folate is a water-soluble B vitamin that occurs naturally in a wide range of foods, particularly liver, leafy green vegetables, citrus fruits and legumes. It is needed during the synthesis of DNA, RNA and proteins, and it is necessary for the production of new cells. Folate also helps keep in check levels of homocysteine, an amino acid that, when elevated, is linked to heart disease. Studies have shown that adequate intake of folate by women just before and during pregnancy significantly reduces the risk of neural tube birth defects, such as spina bifida or anencephaly. To ensure women get the recommended daily intake of 400 micrograms, the U.S. government in 1998 began requiring food manufacturers to add folic acid to breads, cereals, flours and other grain products. At least one study suggests that there has been a significant reduction in neural tube birth defects in this country since the folic acid fortification program began.

"What we're finding now is that a nutritious diet, specifically folate intake, may be beneficial for men as well when it comes to producing healthy offspring," said Brenda Eskenazi, professor of epidemiology and maternal and child health at UC Berkeley's School of Public Health and co-principal investigator of the study.

An estimated 1 to 4 percent of a healthy male's sperm have abnormal numbers of chromosomes, or aneuploidy, that are caused by errors during cell division (meiosis) in the testis. However, the causes of these errors are not well understood. If these abnormal sperm fertilize a normal egg, there would either be a miscarriage or a fetus with a chromosomal disorder such as trisomy, also called Downs syndrome. After accounting for factors such as age, alcohol use and medical history, researchers found that men reporting the highest intake of folate had 19 percent lower rates of sperm with abnormal numbers of chromosomes than men with moderate folate intake, and 20 percent lower rates than men in the low folate intake group.

"We can't yet say that increasing folate in your diet will lead to healthier sperm," said study co-principal investigator Andrew Wyrobek, chair of the Radiation Biosciences Department at Lawrence Berkeley National Laboratory. "But we did come up with enough evidence to justify a larger, clinical and pharmacological trial in men to examine the causal relationships between dietary folate levels and chromosomal abnormalities in their sperm. This information will help us set dietary folate levels that may reduce the risk of miscarriage or birth defects linked to the fathers."

If future studies verify higher folate intake with lower rates of sperm abnormalities, it may be worthwhile to increase the U.S. recommended daily allowance of folate for men considering fatherhood from the current level of 400 micrograms per day, the researchers said..

Published March 20, 2008 in the journal Human Reproduction
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'Designer Enzymes' Created at UCLA and Univ. of Washington

Chemists from UCLA and the University of Washington have succeeded in creating "designer enzymes," a major milestone in computational chemistry and protein engineering.

The research, by a UCLA chemistry group led by professor Kendall Houk and a Washington group headed by biochemist David Baker, is reported March 19 in the advance online publication of the journal Nature. The Defense Advanced Research Projects Agency (DARPA) supported the study.

Designer enzymes will have applications for defense against biological warfare, by deactivating pathogenic biological agents, and for creating more effective medications, according to Houk.

"The design of new enzymes for reactions not normally catalyzed in nature is finally feasible," Houk said. "The goal of our research is to use computational methods to design the arrangement of groups inside a protein to cause any desired reaction to occur." "Enzymes are such potent catalysts; we want to harness that catalytic ability," said research co-author Jason DeChancie, an advanced UCLA chemistry graduate student working with Houk's group. "We want to design enzymes for reactions that naturally occurring enzymes don't do. There are limits on the reactions that natural enzymes carry out, compared with what we can dream up that enzymes can potentially do."

Combining chemistry, mathematics and physics, the scientists report in the Nature paper that they have successfully created designer enzymes for a chemical reaction known as the Kemp elimination, a non-natural chemical transformation in which hydrogen is pulled off a carbon atom. In a previous paper, published in the journal Science on March 7, the chemists reported another successful chemical reaction that uses designer enzymes to catalyze a retro-aldol reaction, which involves breaking a carbon-carbon bond. The aldol reaction is a key process in living organisms associated with the processing and synthesis of carbohydrates. This reaction is also widely used in the large-scale production of commodity chemicals and in the pharmaceutical industry, Houk said.

"Previous reports of designed enzymes have not been very successful, and some have been withdrawn," said Houk, UCLA's lead author of both papers. "That is hardly surprising, considering the challenge of designing in days or weeks what nature has perfected over billions of years of evolution. The rate enhancements by our designer enzymes are modest and hardly competitive, so far, with those observed for their natural counterparts."

"We hope with improvements in technology, that we can close the gap between designer enzymes and natural enzymes," DeChancie said.

"Most scientists thought this would be impossible, and we felt the same way after many failures," said Fernando Clemente, a former UCLA postdoctoral scholar and co-author of the Science paper. "But improvements in design and sophistication eventually led to success." Clemente is now at Gaussian Inc., the company that created the software used in the Houk group's research.

The implementation of the aldol reaction in the active site of an enzyme has been an important challenge. The reaction involves at least six chemical transformations, requiring UCLA scientists to compute all six chemical steps with their corresponding transition states. The structures were then combined in such a way to allow all six steps to occur.

Both studies were funded by DARPA, the U.S. Defense Department's central research and development organization, with additional federal support from the National Science Foundation.

Natural enzymes, which are relatively large protein molecules, are the powerful catalysts that control the reactions that sustain life. They play a central role in the chemical reactions involved in the transformation of food into the essential nutrients that provide energy, among many other critical functions.

Houk's team of 30 computational chemists uses quantum mechanical calculations to explore chemical reactions with supercomputers. Quantum mechanics is the fundamental theory that can predict all chemistry.

Houk and Baker's research groups have worked together for three years. Using algorithms and supercomputers, the UCLA chemists design the active site for the enzymes — the area of the enzymes in which the chemical reactions take place — and give a blueprint for the active site to their University of Washington colleagues. Baker and his group then use their computer programs to design a sequence of amino acids that fold to produce an active site like the one designed by Houk's group; Baker's group produces the enzymes.

Houk's group uses modern computational methods based on the physical laws of quantum mechanics to study in detail the mechanisms of chemical reactions. They have been involved in the DARPA-funded Protein Design Processes program, whose goal is to develop the technology that would make possible the design and creation of man-made working enzymes. The role of UCLA chemists has been the design of the active sites of the enzymes. By exploring multiple combinations of chemical groups, they can determine those that are most suitable to facilitate any given chemical transformation. Then, they determine the precise three-dimensional arrangement of these chemical groups, which is critical for the specificity and activity of the enzyme, with an accuracy of less than a hundredth of a nanometer.

Enzymes are the ultimate "green" catalysts by performing under ambient conditions in water, Houk said, "This technology will find tremendous applications."

How far off are designer enzymes with important applications? "I think we're there," DeChancie said. "These papers are showing the technology is now in place."

Published March 19, 2008 in the journal Nature
First reference to article published March 7, 2008 in the journal Science

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Scientists Find Color Vision System Independent of Motion Detection

The vision system used to process color is separate from that used to detect motion, according to a new study by researchers at New York University’s Center for Developmental Genetics and in the Department of Genetics and Neurobiology at Germany’s University of Würzburg. The findings, which appear in the latest issue of the Proceedings of the National Academy of Sciences, run counter to previous scholarship that suggested motion detection and color contrast may work in tandem.

The study’s authors are: Claude Desplan of NYU’s Center for Developmental Genetics; Reinhard Wolf and Martin Heisenberg of the University of Würzburg; and Satoko Yamaguchi, who holds appointments at both institutions.

Whether motion vision uses color contrast is a controversial issue that has been investigated in several species--from insects to humans. In human vision, it had been widely believed that color and motion were processed by parallel pathways. More recently, however, the complete segregation of motion detection and color vision came into question.

To explore this matter, the NYU and University of Würzburg researchers examined the fruit fly Drosophila. Fruit flies’ development is well-understood by biologists and therefore serves as an appropriate focus for analyses. Specifically, they monitored Drosophila’s optomotor response to moving color stimuli in both normal and mutant flies, with some of the mutant flies lacking the photoreceptors necessary for motion detection and others without the photoreceptors needed to process color.

The results showed that flies lacking the photoreceptors for detecting color showed the same ability to detect motion as normal flies. The researchers then concluded that the color channel does not contribute to motion detection.

“The finding that motion detection is independent of color contrast is somewhat counterintuitive,” said NYU’s Desplan. “Color is thought to increase the salience of objects, such as red fruits in the green foliage of trees.”

“However, our results in the fly demonstrate that color is strictly excluded from processing directional motion information, which suggests two separate functional pathways,” he added. “Whether, inversely, the motion detection system is involved in color vision in Drosophila remains to be determined.”

Published March 19, 2008 in the journal Proceedings of the National Academy of Sciences - PNAS
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WEDNESDAY - March 19, 2008------------------------------------------------News Archive/Return to Today's News Alerts

How We Judge the Thoughts of Others

New research suggests we use the same brain region when thinking about ourselves - when we judge the thoughts of another person we feel is similar to ourselves.

When guessing the opinions and feelings of someone unlike ourselves, this brain region does not get involved. This may mean we are more likely to fall back on stereotyping - potentially helping to explain the causes of social tensions such as racism or religious disputes.Reya's team i

Neuroscientists led by Adrianna Jenkins of Harvard University in Cambridge, Massachusetts, made the discovery. As Jenkins explains, judging how others are feeling is a valuable social skill. "How do we go about bridging the gap between our minds and others' minds?" Jenkins asks. The answer seems to be that it depends on whether we identify with that person or not.

Jenkins and her colleagues studied a brain region called the ventral medial prefrontal cortex (vMPFC), which is known to be involved in thinking about oneself. If you are asked, for example, whether you like baseball, this brain region will kick into life as you reflect on your love (or not) of the sport. To find out what happens when considering the opinions of others, the researchers introduced college students from the Boston area to photographs and descriptions of similar and dissimilar people. They then asked the students to answer a range of questions, such as "do you like mushrooms on pizza?", and guess the responses of the two fictitious people.

Volunteers showed vMPFC activity when weighing up the opinions of those from similar backgrounds. When considering the pizza preferences of the dissimilar person, this brain region did not come into play. "The more you consider the other person like yourself, the more you empathize with them," Jenkins explains. "We might be seeing dissimilar others as less human," she suggests. Although the questions in the study were deliberately apolitical, the results might nonetheless shed light on social conflicts between groups of people who view each other as very different, Jenkins says.

Psychological theory suggests that another way to deduce the feelings of others, without reference to one's own feelings, is to rely simply on social assumptions. This, she suggests, might be the cause of racial or religious tensions. "It's quite plausible that we use stereotypes for people dissimilar to ourselves," says Jenkins. "Whether that's useful or detrimental is an open question."

Jenkins and her colleagues are now investigating this effect using people from different races, to see whether they get the same results. So far they have chosen volunteers from white and oriental backgrounds - using racial groups with a history of tension, such as Israelis and Palestinian Arabs, may change the results, she says.

However this research pans out, there is hope for creating stronger empathy with people unlike ourselves. Other research by Jenkins and her team suggests that you can 'put yourself in another's shoes' fairly effectively by simply spending five minutes writing about them in the first person - perhaps suggesting that you really can see another person's point of view if you try.

Published March 15, 2008 in the journal Proceedings of the National Academy of Sciences - PNAS
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Notes From Stanford's 2008 Symposium on Cancer and Stem Cells



On February 4, 2008, a symposium on cancer and stem cells was held at Stanford University, in Palo Alto, California. What follows is a summation of work in worms, flies, cell lines, mice and more as it impacts the future of cancer research.

Tannishtha Reya of Duke University, watched the process of division at the single-cell level and recognized that the Notch signalling pathway is usually shut off in mature cells. To substantiate this, she infused the dividing cells with green fluorescent protein (GFP) which linked to a Notch signal. Stem cells remained green but GFP faded where somatic cell differentiation took place. Imaging the cells every ten minutes for three days, usually long enough for the cells to divide twice, she was able to capture a pattern of cell divisions that establish the path from stem cell to fully differentiated somatic cell - and it appears there are follow three phases, all tightly regulated.

Mike Clarke, Stanford, also believes controlling differentiation might be a way to stall tumors. He transplanted cancer cells into mice and observed that those expressing markers of mature cells could not cause tumor growth. He also observed that the very cells that drive tumors are the ones resisting chemotoxic treatments. Clarke looked at gene expression in human tumors and saw the more related the tumor was to a stem cell, the higher the rate of death and relapse. Clarke's group tracked this to a set of microRNAs. One: ZEB-2, implicated in neural crest stem cell functions. Another: chromatin-remodelling protein (called BMI1) which is already implicated in self-renewal in multiple tissues.

Stanford's Andrew Fire, 2006 Nobel Prize for discovery of RNA interference, found that as a fertilized worm egg divides, a group of maternal RNAs gather into a single cell prior to its division into two germ cells. These RNA transcripts are degraded in other cells which will become somatic cells. Although the fate of somatic cells can be changed simply by moving their position within the embryo, a germ cells' identity is fixed. Fire believes that in the worm, the distinction between germ cells and somatic cells is not through blocking transcription of specific genes, but through blocking "information to become germ cells", noting that reprogramming a differentiated cell into an embryonic-like state requires the addition of oncogenes.

Stanford's Margaret Fuller described the hub of somatic cells that surround a core of germ line stem cells in the Drosophila testes. Cell divisions in the testes hub always produce one cell that remains close to the hub and one that is pushed away. The cell closest to the hub stays a stem cell; the one pushed further away differentiates into a spermatocyte. Knock out a gene called JAX, however, and the system falls apart - no new sperm are made.

Irving Weissman, Stanford, described his work in leukaemia. The cancer can be found in the marrow of any bone in the patient, the cells clearly descend from a single common ancestor. In mice, Weissman tracked leukaemia cells as they arose from multiprogenitor cells - these are not stem cells and are not capable of self-renewal. He found, however, that a stage in chronic myelogenous leukaemia gives the ability of self-renewal to multiprogenitor cells. A marker called CD47 then prevents these cells from being consumed by macrophages. CD47 is a gene also turned on in healthy multiprogenitor cells to protect them from macrophages as they travel to the bone marrow. With these two changes, leukaemia cells can both avoid macrophages and divide repeatedly in the bone marrow.

Owen Witte, University of California, Los Angeles, wanted to understand how biopsies - taken from areas of the prostate that are very close together - can nonetheless show various cell stages from ordered growth to neoplastic growth to full-blown cancer. Witte's team started exploring the roles of fibroblast growth factors, already known to increase the amounts of the androgen receptor in epithelial cells. Not all of the growth factors had an effect, but fibroblast growth factor 10 did when expressed in mesenchymal cells. In some cases, cells from the induced carcinoma could start cancers when transplanted to other mice, suggesting a potential hormone-sensitive target for prostate cancer cells.

Sam Sidi and Tom Look, Dana Farber Cancer Institute, in Boston, think they may have found an ancient form of apotosis. Two known apotosis pathways target an enzyme called caspase-3, but their new pathway relies on caspase-2. Sidi and Look worked with zebrafish lacking functional copies of a gene called p53, which triggers cell death in troubled cells and is turned off in perhaps half of all cancers. Look's team reduced the activity of a series of genes that serve as 'checkpoints' in a cell's life cycle. For most genes, this made no difference in the developing fish embryos - except for one, encoding Chk1. Reducing Chk1 caused the same pattern of cell death as in embryos carrying a normal copy of p53. Cells with defective Chk1 look to be susceptible to replicating damaged DNA and creating malignancies. Drugs that inhibit Chk1, should sensitize human tumor cells to undergo apoptosis after radiation and chemotherapy.

The basic message of the day was that the path from stem cell to fully differentiated cell follows three main phases, all of which are tightly regulated. To maintain a stem cell population, cells must self-renew; cells that differentiate divide a controlled number times to expand cell numbers in specific tissues. Redundant processes and checkpoints keep these activities under control or destroy wayward cells. When these safeguards fail, cancer stem cells emerge.

Published March 13, 2008 in the journal Nature
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Egg Yolk Gene Loss Was Mammals' Gain

Mammals lost their egg yolk genes after acquiring genes for milk proteins, according to a study published yesterday in PLoS Biology. The results pinpoint an important step in how mammals evolved.

Lactation is "what makes us mammals, basically," said Henrik Kaessmann, who led the study. "Using egg yolk genes as markers, we found a unique way to put a timeframe on how key transitions in mammals occurred."

There are three types of mammals: true placental mammals, marsupials and monotremes. Though each type nourishes its young in a different way, they all use milk to some extent, and their eggs have far less yolk than their reptilian and bird-like ancestors. But in the evolution of mammals, there's a longstanding "chicken and egg" question, or rather, a milk and egg question: What came first in the mammalian lineage — genes involved in lactation, or the loss of genes for making egg proteins? Now researchers at the University of Lausanne in Switzerland have cracked the problem.

Kaessmann and his colleagues compared the sequences of genes encoding vitellogenin, an essential egg yolk protein, in the different mammalian lineages. They found that the three genes present in the mammalian ancestor were progressively lost in all lineages except for the monotremes, which have retained one working gene. These primitive mammals, which include platypuses and echidnas, lactate, yet lay small, parchment-shelled eggs. So the presence of both functional and non-functional vitellogenin genes is consistent with this intermediate reproductive state, said Kaessmann.

The researchers also found that all three groups of mammals shared major milk resource genes, called caseins, indicating that these genes arose over 200 million years ago, before the split of the mammalian lineages. Putting findings from both sets of genes together, Kaessmann argues that lactation in the common mammalian ancestor, followed by the emergence of placentas in some mammals, probably allowed for the loss of yolk-nourishment in mammals.

"Everything makes sense," said Jay Storz of the University of Nebraska in Lincoln, who was not involved in the research. He told The Scientist he was "surprised that the progressive loss of the yolk genes coincided so nicely with the origins of lactation and placental development." Nigel Finn of the University of Bergen in Norway agreed that the evidence was "quite convincing," but he thinks the picture of mammalian evolution is still incomplete.

The transition to mammalian reproduction was not just about nutrition, he argues, mammals had to overcome a water problem as well, the evolution of amniotic fluid, which nourishes the embryo and keeps it moist.

Published March 17, 2008 by the journal PLoS Biology

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TUESDAY - March 18, 2008----------------------------------------------------News Archive/Return to Today's News Alerts

Another Path Found to Controlling Blood Vessel Growth

One of the most intensive pursuits in medical science is the hunt for ways to control the formation of new blood vessels - angiogenesis. This process has been called the common denominator of disease because of its influence on many different conditions, from cancer to heart disease to tissue injury and degeneration. Millions of patients stand to benefit from angiogenic therapies.

But building new vessels or tearing them down is not a simple process as there are at least 50 known factors in the body that govern vessel formation. Several therapies targeting a single though central factor have failed, for example, because the new vessels remain leaky and immature. Researchers are now looking for targets that coordinate multiple factors in the angiogenic process.

Bruce Spiegelman, HMS professor of cell biology at the Dana–Farber Cancer Institute, and his colleague Zoltan Arany, HMS instructor in medicine at Beth Israel Deaconess Medical Center, recognized that a gene known for regulating metabolism also behaves like the conductor of a grand angiogenic orchestra, they were pleasantly surprised. The gene, PGC-1 alpha, “turns on a whole program of angiogenesis,” said Spiegelman. “It puts things in the right place and in the right balance.”

The researchers are quick to point out that another angiogenic orchestral conductor of sorts, hypoxia-inducible factor (HIF), also exists and is well understood. What they have found in PGC-1 alpha is a second, completely independent pathway to new blood vessel growth.

Spiegelman discovered PGC-1 alpha 10 years ago and identified it as a key regulator of metabolic processes such as energy production and respiration. He and HMS professor of cell biology Alfred Goldberg later uncovered its role in protecting against muscle atrophy. This most recent study began when Spiegelman and Arany decided to explore the gene’s role in ischemia, resulting when tissue is deprived of oxygen and nutrients. The condition can occur, for example, when a blocked artery cuts off the blood supply to an organ or limb.

“This study raises the dream that one might design drugs that act through this pathway to turn angiogenesis on or off,” said Arany. PGC-1 alpha is a very attractive target because it also has therapeutic potential in several other arenas. For instance, PGC-1 alpha–knockout mice tend to exhibit neurodegeneration, suggesting that the gene protects against this condition. The same holds for cardiovascular disease, as well as muscle atrophy.

Published February 21, 2008 in the journal Nature

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How The Zebrafish Regrows Its' Tail

Biologists have discovered a molecular circuit breaker that controls a zebrafish's remarkable ability to regrow missing fins, according to a new study from Duke University Medical Center.

Tiny wonders of the aquarium world, zebrafish can regenerate organs and tissues, including hearts, eye parts and fins. When a fin is lost, the fish regenerates a perfect copy in two weeks by orchestrating the growth of many tissue types, including bone, nerves, blood vessels, connective tissue and skin.

Scientists hope that understanding how zebrafish repair themselves will lead to new treatments for human conditions caused by damaged tissue, such as heart failure, diabetes and spinal cord injuries.

The regeneration regulator is one of a group of recently discovered molecules called microRNAs: small pieces of ribonucleic acid (RNA) that each can potentially control the activity of dozens of different genes. In humans, microRNAs play important roles in cell growth and death, among other functions. There are hundreds of kinds of microRNAs, and scientists are constantly discovering new roles they play.

In zebrafish, one or more microRNAs appear to be important to keep regeneration on hold until the fish needs new tissue, the Duke researchers say. In response to an injury, the fish then damp down levels of these microRNAs to aid regrowth. The team discovered that the ability of zebrafish to replace amputated fins is particularly sensitive to levels of a particular microRNA called miR-133.

The discovery makes sense because any animal that can rapidly grow new tissue needs to keep the system in check, said senior author Kenneth Poss, Ph.D., assistant professor of cell biology. "They probably need to have mechanisms to reduce the potential for unwelcome growth. The implication is that in order to make human tissue regenerate more effectively, we might want to look at some of these microRNAs as potential targets."

The results appear in the March 15, 2008 issue of the journal Genes & Development. Postdoctoral scholar Viravuth Yin, Ph.D., a member of Poss' lab, is first author on the study. Funding was provided by the National Institutes of Health, the American Heart Association, the Whitehead Foundation and Pew Charitable Trusts.

Poss and many other cell biologists believe that mammals may have the same tissue regeneration capability as zebrafish, salamanders and newts, but that it is locked away somewhere in our genome, silenced in the course of evolution. "The key is finding a way to turn on this regenerative ability in humans," Poss said.

The Duke researchers began their study by ferreting out any microRNAs present in fins at different stages of regrowth, then measuring whether there was a lot or a little of each molecule.

Dr. Poss' team eventually zeroed in on some of the most important microRNAs for regrowth by studying genetically modified zebrafish. The modification allows a critical signaling pathway to be shut down during regeneration. The pathway sends biochemical cues called growth factors that stimulate cell division and organ growth.

Levels of one microRNA in particular, miR-133, dropped during normal regeneration. But when the scientists blocked the signaling pathway briefly during regeneration, the amount of miR-133 jumped back up to the level found in uninjured fins. Further experiments showed that tweaking the concentration of miR-133 affected fin growth. When levels were raised, fin regrowth slowed; when they were dropped, regeneration sped up.

"Our work shows microRNAs appear to have an important role in regenerating complex tissues. Further studies could help us discover potential ways to stimulate this ability in mammals," Poss said.

Published March 15, 2008 in the journal Genes & Development


Two Scientists Begin Company Using Zebrafish to Study Regeneration

Dr. Jeff S. Mumm, biologist at the Medical College of Georgia, along with his partner in science and life, Dr. Meera Saxena, have founded Luminomics, Inc., to help fellow scientists unlock the capacity of the zebrafish to regenerate essentially any cell type in it's body. “This little fish is telling us what biology is capable of. With the same general set of genetic tools, these animals can do something we can’t - regenerate lost cells and tissues.”

“If you have a cell type in your body that you lose, a lot of times, the end result is a particular degenerative disease state,” Dr. Mumm says.  “So if you lose dopaminergic neurons in your brain, you end up with Parkinson’s. If you lose the insulin-producing cells of your pancreas, you begin to develop diabetes. There are literally hundreds of degenerative diseases. Still very little is known about how individual cell types are regenerated.”

Using a fluorescent protein, Dr. Mumm developed a way to light up cells of interest - for example the insulin-producing cells of the pancreas - destroy them, then see what it takes for the fluorescent protein to be turned back on. The same fluorescent protein that illuminates the cells links them to an enzyme, nitroreductase, which can kill them when a particular drug is introduced.

Because the zebrafish’s genome is mapped and easily altered, scientists can produce mutant fish that can no longer spontaneously regenerate a cell type. “What the system we have developed does is provide us inroads to understanding the genetics and chemicals that can modify the genetics.”

Humans have much in common with zebrafish as do most animals. “For the most part, we are all a piano with the same 88 keys. The PAX6 gene, for example, makes an eye in a fish, makes an eye in a drosophila, or fruit fly, and makes an eye in us. But the way those genes are combined in time and space creates many different tunes, and that is how many different body plans come out the other end,” says Dr. Mumm. The tune of the nimble zebrafish allows indeterminate growth capacity. Put a full-grown zebrafish in a bigger tank with more food and it gets bigger. “The fish appear to have resident stem cells for every single tissue component of their bodies that they are able to regulate,” says Dr. Mumm.

Harvard researchers reported amazing evidence of their regenerating ability in 2002 in the journal Science when they showed that within two months of removing 20 percent of a zebrafish’s heart, it had grown back.

Published March 17, 2008 by the Medical College of Georgia
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MONDAY - March 17, 2008-----------------------------------------------------News Archive/Return to Today's News Alerts

Fetal Form of Enzyme Energizes Tumor Cell Growth

Normal cells and cancer cells use glucose differently. Normal cells prefer to oxidate glucose - or burn it up in the mitochodria to make fuel; cancer cells prefer to glycolysize - or use the cell membrane to process smaller amounts of glucose in a less efficient manner.

This metabolic switch, known as the "Warburg effect" (after the German chemist Otto Warburg who discovered the difference 80 years ago), is now believed to be triggered by a fetal form of the enzyme pyruvate kinase, PKM2 - an enzyme responsible for the explosive growth in the fetus.

Warburg's belief that his observation of a metabolic switch between the two forms of glucose use was responsible for triggering cancer, was ignored until last year, when experiments with a drug called dichloroacetate showed that it could switch energy production from the cell wall back to the mitochondria and reverse cancer in rats. A human trial to test DCA is under way at the University of Alberta in Edmonton, Canada.

Lewis Cantley and colleagues at Harvard Medical School in Boston resolved the question by showing that PKM2 is important for aerobic glycolysis in tumors. They've discovered that cancer cells switch over to glycolysis by re-activating PKM2. In healthy adult cells, energy production involves PKM1, the adult form of pyruvate kinase. But in all cancer cells studied by Cantley, the fetal form of the enzyme had been reactivated and the adult form silenced.

Cantley's team showed that if they used molecular blockers called small hairpin RNAs to reverse the switch, the cancer cells stopped growing, both in the lab and in animals.

Evangelos Michelakis, the researcher in Edmonton who is testing DCA, says that the new results vindicate Warburg. "They support the concept of metabolism being a driver of cancer, not a consequence," he says.

Published March 13, 2008 in the journal Nature

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Male Fertility 'Determined in the Womb'

Common genital disorders, low sperm count and testicular cancer could all be linked to hormone levels early in pregnancy, studies in rats suggest.

Testes not descending properly into the scrotum (cryptorchidism) or the urinary tract opening in the wrong place on the penis (hypospadias) are fairly common in young boys. Using a mouse model, researchers at the Medical Research Council Human Reproductive Sciences Unit found the disorders resulted from low levels of male hormones - or androgens - at the equivalent to 8-12 weeks human gestation.

They also found that the level of androgen hormone in this time period was related to the distance between the base of the penis and the anus, a measurement that could become an early period for recognizing future reproductive problems in baby boys.

It could also give insights into links between hormones in the womb and fertility problems in later life. Study leader, Dr Michelle Welsh, said: "We know from other studies that androgens work during fetal development to program the reproductive tract. "But our assumption was that it would be much later in pregnancy." She added the anogenital measurement would be a useful tool. "Say a clinician were to examine a 30-year-old man with testicular cancer - previously there would have been no way of knowing what hormones he was exposed to in the womb.

"We would suggest that this measurement, even at this later stage in life, could offer an indication of hormone exposure."

"For example, the shorter the distance, the less confident we can be that hormones have acted correctly and at the right time."

Co-author, Professor Richard Sharpe, said around 7% of boys had cryptorchidism and low sperm counts affect as many as one in five young men.

Dr Allan Pacey, senior lecturer in andrology at the University of Sheffield, said scientists had been worried for many years about the increasing incidence of problems resulting from disrupted development of the male reproductive system during pregnancy.

"Understandably, this is almost impossible to study in humans directly and so animal models are needed to unravel the precise details.

"To use the adult anogenital distance as a proxy marker of foetal exposure in utero is a good suggestion and I would encourage studies to investigate how well this correlates with problems of the male reproductive system."

Published March 13, 2008 in the Journal of Clinical Investigation


Discovered: Two Proteins that Regulate Potassium in Stem Cells

Researchers at Texas Tech University and the University of Wisconsin have discovered two proteins that control potassium regulation in stem cells found in the embryonic brain of rats.

Understanding this potassium regulation and how these proteins work can help researchers develop better detection and treatment methods for diseases of nervous system and the heart, said Dean O. Smith, vice president for research at Texas Tech. The findings were published in the journal PLoS ONE.

Since these stem cells had not yet developed specialized properties of nerve or muscle cells, the potassium regulated by these proteins is probably required for the stem cell to divide, Smith said.

“These voltage-gated, potassium-channel proteins are vitally important in the brain and in muscle, including the heart,” Smith said. “If we can understand how and when they develop in stem cells as they change into nerve and muscle cells, then we can open the door to further exploitation of this knowledge in the detection and treatment of diseases that include Alzheimer’s, Parkinson’s and cardiovascular diseases, just to name a few.”

All cells, including stem cells, need potassium to divide, Smith said. When grown, muscle and nerve cells require potassium to contract and to relay information throughout the brain. The availability of this potassium is highly regulated in mature cells, and disruption can lead to serious health disorders. Therefore, scientists want to understand this regulatory mechanism and learn when it appears in the developing embryo.

“We kind of discovered these proteins by accident,” Smith said. “Originally, we intended to make these stem cells differentiate into nerve cells that might then be suitable for transplanting into another animal to repair brain damage. To be sure the cells had differentiated, we examined the potassium channels that are normally found in mature nerve cells. As a control, we did the same tests on undifferentiated stem cells expecting not to find them. But, to our surprise, they too had the same potassium channels.”

Other tests indicated that these stem cells were clearly not differentiated into nerve cells and could not function as such, Smith said. Therefore, these potassium channels must play some other role in stem cells development.

“We’re not sure what yet,” he said. “But we think it might relate to cell replication. These two proteins are found in all mammals, and similar ones are found in animals such as fruit flies and frogs."

Published 2008 in the journal PLoS ONE
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