Cow Rumen Enzymes for Better Biofuels

When it comes to breaking down plant matter and converting it to energy, the cow has it all figured out. Its digestive system allows it to eat more than 150 pounds of plant matter every day. Now researchers report that they have found dozens of previously unknown microbial enzymes in the bovine rumen -- the cow's primary grass-digestion chamber -- that contribute to the breakdown of switchgrass, a renewable biofuel energy source.

The study, in the journal Science, tackles a major barrier to the development of more affordable and environmentally sustainable biofuels. Rather than relying on the fermentation of simple sugars in food crops such as corn, beets or sugar cane (which is environmentally costly and threatens the food supply) researchers are looking for better ways to convert the leaves and stems of grasses or woody plants to liquid fuel. These "second-generation" biofuels ideally will be "carbon neutral," absorbing as much carbon dioxide from the atmosphere as is emitted in their processing and use.

But breaking down and releasing the energy in the plant cell wall is no easy task.

"The problem with second-generation biofuels is the problem of unlocking the soluble fermentable sugars that are in the plant cell wall," said University of Illinois animal sciences professor Roderick Mackie, an author on the study whose research into the microbial life of the bovine rumen set the stage for the new approach. "The cow's been doing that for millions of years. And we want to examine the mechanisms that the cow uses to find enzymes for application in the biofuels industry."

In previous studies beginning in 2008, Mackie and Washington State University professor Matthias Hess (then a postdoctoral researcher at the U.S. Department of Energy Joint Genome Institute in California) used a decades-old technique for studying ruminant nutrition. They placed small, mesh bags containing either milled alfalfa or switchgrass through a cannula (a permanent, surgically installed portal) into the cow rumen and examined the microbes that adhered to each plant type after two or three days. Visual and chemical analyses showed that microbes in the rumen were efficiently breaking down both types of plant matter, with a different community of microbes attacking each plant type.

This and later experiments proved that the technique could help scientists find the microbes in the cow rumen that were most efficient at degrading a particular type of plant matter, said Mackie, who is a professor in the U. of I. Institute for Genomic Biology.

In the new study, the researchers focused on switchgrass, a promising biofuels crop. After incubating the switchgrass in the rumen for 72 hours, researchers conducted a genomic analysis of all of the microbes that adhered to switchgrass. This "metagenomic" approach, led by Edward Rubin, of the DOE Joint Genome Institute and the Lawrence Berkeley National Laboratory, analyzed all the genes in all the microbes present in a sample, rather than one at a time. This gave a more accurate picture of the processes in the rumen that make plant degradation possible, Mackie said.

"Bacteria are microbes," he said. "They don't live alone. They live in consortia, and they all contribute to the functioning and the services provided."

Using a variety of techniques, the researchers sequenced and analyzed the total DNA in the sample, a huge undertaking that allowed them to identify 27,755 potential "carbohydrate-active" genes. They cloned some of these genes into bacteria, and successfully produced 90 proteins of interest. They found that 57 percent of these proteins demonstrated enzymatic activity against cellulosic plant material.

The researchers also were able to assemble the genomes of 15 previously "uncultured" (never before grown in a lab) microbes, said Hess, who is first author on the new study. Several techniques, including sequencing the genomes of individual cells and comparing those to the assembled genomes, validated this approach, he said.

These results suggest that the bovine rumen is one of the best microbial habitats to explore for sources of plant-degrading enzymes, the researchers reported.

The research team also included scientists from the DOE Joint Genome Institute, the University of California at Berkeley and Illumina Inc. The BP-sponsored Energy Biosciences Institute funded the research carried out at Illinois.

Journal Reference:

1. Hess, et al. Metagenomic Discovery of Biomass-Degrading Genes and Genomes From Cow Rumen. Science, 28 January 2011: 463-467 DOI: 10.1126/science.1200387

Courtesy: ScienceDaily

Genetic Code for Form of Pancreatic Cancer Cracked

Scientists at Johns Hopkins have deciphered the genetic code for a type of pancreatic cancer, called neuroendocrine or islet cell tumors. The work, described online in the Jan. 20 issue of Science Express, shows that patients whose tumors have certain coding "mistakes" live twice as long as those without them.

"One of the most significant things we learned is that each patient with this kind of rare cancer has a unique genetic code that predicts how aggressive the disease is and how sensitive it is to specific treatments," says Nickolas Papadopoulos, Ph.D., associate professor at the Johns Hopkins Kimmel Cancer Center and director of translational genetics at Hopkins' Ludwig Center. "What this tells us is that it may be more useful to classify cancers by gene type rather than only by organ or cell type."

Pancreatic neuroendocrine cancers account for about five percent of all pancreatic cancers. Some of these tumors produce hormones that have noticeable effects on the body, including variations in blood sugar levels, weight gain, and skin rashes while others have no such hormone "signal."

In contrast, hormone-free tumors grow silently in the pancreas, and "many are difficult to distinguish from other pancreatic cancer types," according to Ralph Hruban, M.D., professor of pathology and oncology, and director of the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins.

For the new study, the team investigated non-hormonal pancreatic neuroendocrine tumors in 68 men and women. Patients whose tumors had mutations in three genes -- MEN-1, DAXX and ATRX -- lived at least 10 years after diagnosis, while more than 60 percent of patients whose tumors lacked these mutations died within five years of diagnosis.

The Johns Hopkins team, which previously mapped six other cancer types, used automated tools to create a genetic "map" that provides clues to how tumors develop, grow and spread.

Within the code are individual chemicals called nucleotides, which pair together in a pre-programmed fashion to build DNA and, in turn, a genome. Combinations of these nucleotide letters form genes, which provide instructions that guide cell activity. Changes in the nucleotide pairs, called mutations, can create coding errors that transform a normal cell into a cancerous one.

In the first set of experiments, the Johns Hopkins scientists sequenced nearly all protein-encoding genes in 10 of the 68 samples of pancreatic neuroendocrine tumors and compared these sequences with normal DNA from each patient to identify tumor-specific changes or mutations.

In another set of experiments, the investigators searched through the remaining 58 pancreatic neuroendocrine tumors to determine how often these mutated genes appeared.

The most prevalent mutation, in the MEN-1 gene, occurred in more than 44 percent of all 68 tumors. MEN-1, which has been previously linked to many cancers, creates proteins that regulate how long strands of DNA are twisted and shaped into dense packets that open and close depending on when genes need to be activated. Such a process is regulated by proteins and chemicals that operate outside of genes, termed "epigenetic" by scientists.

Two other commonly mutated genes, DAXX and ATRX, which had not previously been linked to cancer, also have epigenetic effects on how DNA is read. Of the samples studied, mutations in DAXX and ATRX were found in 25 percent and 17.6 percent, respectively. The proteins made by these two genes interact with specific portions of DNA to alter how its chemical letters are read.

"To effectively detect and kill cancers, it may be important to develop new diagnostics and therapeutics that take aim at both epigenetic and genetic processes," says Kenneth Kinzler, Ph.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center and co-director of the Ludwig Center at Johns Hopkins.

The Johns Hopkins team also found that 14 percent of the samples studied contained mutations in a gene family called mTOR, which regulates cell signaling processes. Papadopoulos says that patients with tumors containing such alterations in the mTOR pathway could be candidates for treatment with mTOR inhibitor drugs.

"This is a great example of the potential for personalized cancer therapy," says Hruban. "Patients who are most likely to benefit from a drug can be identified and treated, while patients whose tumors lack changes in the mTOR pathway could be spared the side effects of drugs that may not be effective in their tumors."

Papadopoulos, Kinzler, and co-authors Bert Vogelstein, Luis Diaz, and Victor Velculescu are co-founders and members of the scientific advisory board of Inostics, a company that is developing technologies for the molecular diagnosis of cancer. They own Inostics stock, which is subject to certain restrictions under the Johns Hopkins University's conflict of interest policy. Kinzler, Vogelstein and Velculescu are entitled to shares of any royalties received by the University on sales of products related to genes described in this manuscript.

Major funding for the study was provided by the Caring for Carcinoid Foundation, a nonprofit foundation which funds research on carcinoid cancer, pancreatic neuroendocrine cancer, and related neuroendocrine cancers. Additional funding was from the Lustgarten Foundation for Pancreatic Cancer Research, the Sol Goldman Pancreatic Cancer Research Center, the Joseph Rabinowitz Fund for Pancreatic Cancer Research, the Virginia and D.K. Ludwig Fund for Cancer Research, the Raymond and Beverly Sackler Research Foundation, the AACR Stand Up to Cancer's Dream Team Translational Cancer Research Grant and the National Institutes of Health.

Journal Reference:

1. Y. Jiao, C. Shi, B. H. Edil, R. F. de Wilde, D. S. Klimstra, A. Maitra, R. D. Schulick, L. H. Tang, C. L. Wolfgang, M. A. Choti, V. E. Velculescu, L. A. Diaz, B. Vogelstein, K. W. Kinzler, R. H. Hruban, N. Papadopoulos. DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors. Science, 2011; DOI: 10.1126/science.1200609

Courtesy: ScienceDaily

Defense Mechanism Against Bacteria and Fungi Deciphered

To defend microbial attacks, the human body naturally produces a group of antibiotics, called defensins. An interdisciplinary team of biochemists and medical scientists has now deciphered the mechanism of action of a defensin, hitherto looked upon as exhibiting only minor activity. Their results might be useful in future drug development for inflammatory and infectious diseases. Nature now presents their findings online ahead of the print publication.

Under standard laboratory conditions, the human beta-defensin 1 (hBD-1), a human antibiotic naturally produced in the body, had always shown only little activity against microbes. Nevertheless the human body produces it in remarkable quantities. The solution to the puzzle was the investigation process itself, as the research group led by Dr. Jan Wehkamp at the Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology of the Stuttgart-based Robert Bosch Hospital found out.

Before the research group took a new approach to this research, defensins were usually tested in the presence of oxygen, although little oxygen is present, for example, in the human intestine. Starting out from the discovery that a special antibiotic-activating protein of the human body is diminished in patients with inflammatory bowel diseases, Crohn's Disease and Ulcerative Colitis, the working group investigated how defensins act under low-oxygen conditions. During their investigations the scientists found out that under these conditions hBD-1 unfolds a strong antibiotic activity against lactic acid bacteria and yeast.

Furthermore the researchers discovered that another human protein, thioredoxin, is able to activate beta-defensin 1 even in the presence of oxygen. Moritz Marcinowski and Professor Johannes Buchner from the Department of Chemistry at the Technical University of Munich, used circular dichroism spectroscopy to elucidate the differences between the folded inactive and the unfolded active form of the protein.

Surprisingly, while almost all proteins are active only in their folded form, in the case of the small defensin the opposite is true. To activate the beta-defensin 1 the thioredoxin opens the three disulphide bridges that hold the molecule together. The molecule then opens up into the active state. Using this mechanism the body has the opportunity to selectively activate the defensin.

So far the cause of inflammatory bowel disease is unclear. Genetic as well as environmental factors seem to play a role, finally leading to a weakening of the antimicrobial barrier, which is mainly mediated by defensins. Accordingly the identified mechanism might contribute to the development of new therapies to treat affected patients.

The presented work is the result of a cooperation project with six participating centers, led by Emmy Noether junior research group leader Dr. Jan Wehkamp. In addition to five researchers from Stuttgart (Dr. Margarete Fischer-Bosch-Institute for Clinical Pharmacology and the Robert Bosch-Hospital (Bjoern Schroeder, Sabine Nuding, Julia Beisner, Eduard Stange and Jan Wehkamp) the Department of Dermatology at University of Tübingen (Martin Schaller), the Max-Planck-Institute for Developmental Biology in Tübingen (Sandra Groscurth), the Department of Dermatology at University of Kiel (Zhihong Wu), as well as the Department of Chemistry at the Technische Universitaet Muenchen (Moritz Marcinowski and Johannes Buchner) were involved. The work was funded by the Deutsche Forschungsgemeinschaft (Emmy Noether-Program for young researchers, Cluster of Excellence Center for Integrated Protein Science Munich) and by the Robert- Bosch-Foundation.

Journal Reference:

1. Bjoern O. Schroeder, Zhihong Wu, Sabine Nuding, Sandra Groscurth, Moritz Marcinowski, Julia Beisner, Johannes Buchner, Martin Schaller, Eduard F. Stange, Jan Wehkamp. Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1. Nature, 2011; 469 (7330): 419 DOI: 10.1038/nature09674

Courtesy: ScienceDaily

Mindfulness Meditation Training Changes Brain Structure in Eight Weeks

Participating in an 8-week mindfulness meditation program appears to make measurable changes in brain regions associated with memory, sense of self, empathy and stress. In a study that will appear in the January 30 issue of Psychiatry Research: Neuroimaging, a team led by Massachusetts General Hospital (MGH) researchers report the results of their study, the first to document meditation-produced changes over time in the brain's grey matter.

"Although the practice of meditation is associated with a sense of peacefulness and physical relaxation, practitioners have long claimed that meditation also provides cognitive and psychological benefits that persist throughout the day," says Sara Lazar, PhD, of the MGH Psychiatric Neuroimaging Research Program, the study's senior author. "This study demonstrates that changes in brain structure may underlie some of these reported improvements and that people are not just feeling better because they are spending time relaxing."

Previous studies from Lazar's group and others found structural differences between the brains of experienced mediation practitioners and individuals with no history of meditation, observing thickening of the cerebral cortex in areas associated with attention and emotional integration. But those investigations could not document that those differences were actually produced by meditation.

For the current study, MR images were take of the brain structure of 16 study participants two weeks before and after they took part in the 8-week Mindfulness-Based Stress Reduction (MBSR) Program at the University of Massachusetts Center for Mindfulness. In addition to weekly meetings that included practice of mindfulness meditation -- which focuses on nonjudgmental awareness of sensations, feelings and state of mind -- participants received audio recordings for guided meditation practice and were asked to keep track of how much time they practiced each day. A set of MR brain images were also taken of a control group of non-meditators over a similar time interval.

Meditation group participants reported spending an average of 27 minutes each day practicing mindfulness exercises, and their responses to a mindfulness questionnaire indicated significant improvements compared with pre-participation responses. The analysis of MR images, which focused on areas where meditation-associated differences were seen in earlier studies, found increased grey-matter density in the hippocampus, known to be important for learning and memory, and in structures associated with self-awareness, compassion and introspection. Participant-reported reductions in stress also were correlated with decreased grey-matter density in the amygdala, which is known to play an important role in anxiety and stress. Although no change was seen in a self-awareness-associated structure called the insula, which had been identified in earlier studies, the authors suggest that longer-term meditation practice might be needed to produce changes in that area. None of these changes were seen in the control group, indicating that they had not resulted merely from the passage of time.

"It is fascinating to see the brain's plasticity and that, by practicing meditation, we can play an active role in changing the brain and can increase our well-being and quality of life." says Britta Hölzel, PhD, first author of the paper and a research fellow at MGH and Giessen University in Germany. "Other studies in different patient populations have shown that meditation can make significant improvements in a variety of symptoms, and we are now investigating the underlying mechanisms in the brain that facilitate this change."

Amishi Jha, PhD, a University of Miami neuroscientist who investigates mindfulness-training's effects on individuals in high-stress situations, says, "These results shed light on the mechanisms of action of mindfulness-based training. They demonstrate that the first-person experience of stress can not only be reduced with an 8-week mindfulness training program but that this experiential change corresponds with structural changes in the amygdala, a finding that opens doors to many possibilities for further research on MBSR's potential to protect against stress-related disorders, such as post-traumatic stress disorder." Jha was not one of the study investigators.

James Carmody, PhD, of the Center for Mindfulness at University of Massachusetts Medical School, is one of co-authors of the study, which was supported by the National Institutes of Health, the British Broadcasting Company, and the Mind and Life Institute.

Journal Reference:

1. Britta K. Hölzel, James Carmody, Mark Vangel, Christina Congleton, Sita M. Yerramsetti, Tim Gard, Sara W. Lazar. Mindfulness practice leads to increases in regional brain gray matter density. Psychiatry Research: Neuroimaging, 2011; 191 (1): 36 DOI: 10.1016/j.pscychresns.2010.08.006

Courtesy: ScienceDaily

New Therapies for Prevention and Treatment of Alzheimer's Disease Identified

A Blanchette Rockefeller Neurosciences Institute (BRNI) study published in the Journal of Neuroscience reveals underlying causes for the degeneration of synapses in Alzheimer's Disease and identifies promising pharmaceutical solutions for the devastating condition that affects more than 5 million people in the United States. The BRNI study is the first to achieve fundamental molecular understanding of how synapses are lost in Alzheimer's Disease before the plaques and tangles develop. At the same time, it is the first study to demonstrate the comprehensive benefits of synaptogenic compounds in treating Alzheimer's Disease.

The BRNI study marks an important shift in our understanding of how Alzheimer's Disease is caused and should be treated. Previous autopsy-based studies have shown the critical role of synaptic loss in producing dementia (though, not the reason behind the degeneration), yet for decades scientists and pharmaceutical companies have focused on ways to target the amyloid plaques and neurofibrillary tangles thought to play a role in causing Alzheimer's Disease. By preventing the loss of synapses, BRNI's new therapeutics prevent the progressive symptoms of Alzheimer's Disease.

"Alzheimer's Disease is not primarily a disease of plaques and tangles as many had previously concluded, it is most importantly a disease of synapses," said Dr. Daniel Alkon, the scientific director of BRNI and co-author of the study, "This study found that treatments that target the loss of synapses in the Alzheimer's brain, can virtually eliminate all other elements of the disease -- elevation of the toxic protein, A Beta, the loss of neurons, the appearance of plaques, and loss of cognitive function; the animals' brains were normalized."

The study utilized mice genetically engineered to express the symptoms and pathology of human Alzheimer's Disease in two different strains. BRNI used a difficult training regimen for the mice in order to reveal that significant cognitive deficits occurred five months before plaques were detected in their brains, providing evidence that plaques and tangles are not at the root of the disease.

Treatments of Bryostatin and similar compounds synthesized at BRNI that target the enzyme PKCε, which controls the creation of synapses at the molecular level, were administered for twelve weeks during the study. While the compounds promoted the growth of new synapses and preservation of existing synapses, they also stopped the decrease of PKCε and the increase of soluble β amyloid, meaning that the treatments could be used to prevent the familiar hallmarks of Alzheimer's Disease, the plaques and tangles. BRNI has received approval to move forward with Phase II clinical testing for Bryostatin to treat Alzheimer's Disease, which is set to begin within the next several months.

The synaptogenic BRNI drugs have also shown potential for the treatment of traumatic brain injury (TBI), as recently reported in the journal Neurobiology of Disease, and stroke described in the Proceedings of the National Academy of Science in 2008 and 2009.

The target of the synaptogenic compounds is the same molecule identified as a biomarker for early diagnosis of Alzheimer's Disease in clinical trials conducted by BRNI and published in Neurobiology of Aging in 2010. As a result of that study, researchers at the Institute are now working to develop a skin test for identifying Alzheimer's Disease in its early stages before significant progression.

Journal Reference:

1. Jarin Hongpaisan, Miao-Kun Sun, and Daniel L. Alkon. PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice. Journal of Neuroscience, 2011; 31: 630-643 DOI: 10.1523/JNEUROSCI.5209-10.2011

Courtesy: ScienceDaily

Genetically Modified Chickens That Don't Transmit Bird Flu Developed; Breakthrough Could Prevent Future Bird Flu Epidemics

Chickens genetically modified to prevent them spreading bird flu have been produced by researchers at the Universities of Cambridge and Edinburgh.

The scientists have successfully developed genetically modified (transgenic) chickens that do not transmit avian influenza virus to other chickens with which they are in contact. This genetic modification has the potential to stop bird flu outbreaks spreading within poultry flocks. This would not only protect the health of domestic poultry but could also reduce the risk of bird flu epidemics leading to new flu virus epidemics in the human population.

The study, funded by the Biotechnology and Biological Sciences Research Council (BBSRC), is published in the journal Science.

Dr Laurence Tiley, Senior Lecturer in Molecular Virology from the University of Cambridge, Department of Veterinary Medicine, said: "Chickens are potential bridging hosts that can enable new strains of flu to be transmitted to humans. Preventing virus transmission in chickens should reduce the economic impact of the disease and reduce the risk posed to people exposed to the infected birds. The genetic modification we describe is a significant first step along the path to developing chickens that are completely resistant to avian flu. These particular birds are only intended for research purposes, not for consumption."

Professor Helen Sang, from The Roslin Institute at the University of Edinburgh, said, "The results achieved in this study are very encouraging. Using genetic modification to introduce genetic changes that cannot be achieved by animal breeding demonstrates the potential of GM to improve animal welfare in the poultry industry. This work could also form the basis for improving economic and food security in many regions of the world where bird flu is a significant problem."

To produce these chickens, the Cambridge and Edinburgh scientists introduced a new gene that manufactures a small "decoy" molecule that mimics an important control element of the bird flu virus. The replication machinery of the virus is tricked into recognising the decoy molecule instead of the viral genome and this interferes with the replication cycle of the virus.

When the transgenic chickens were infected with avian flu, they became sick but did not transmit the infection on to other chickens kept in the same pen with them. This was the case even if the other chickens were normal (non-transgenic) birds.

Dr Tiley continued, "The decoy mimics an essential part of the flu virus genome that is identical for all strains of influenza A. We expect the decoy to work against all strains of avian influenza and that the virus will find it difficult to evolve to escape the effects of the decoy. This is quite different from conventional flu vaccines, which need to be updated in the face of virus evolution as they tend only to protect against closely matching strains of virus and do not always prevent spread within a flock."

Professor Douglas Kell, BBSRC Chief Executive, said: "Infectious diseases of livestock represent a significant threat to global food security and the potential of pathogens, such as bird flu, to jump to humans and become pandemic has been identified by the Government as a top level national security risk. The BBSRC funds world-class research to help to protect the UK from such eventualities and the present approach provides a very exciting example of novel approaches to producing disease-resistant poultry."

Journal Reference:

1. Jon Lyall, Richard M. Irvine, Adrian Sherman, Trevelyan J. Mckinley, Alejandro Núñez, Auriol Purdie, Linzy Outtrim, Ian H. Brown, Genevieve Rolleston-Smith, Helen Sang, and Laurence Tiley. Suppression of Avian Influenza Transmission in Genetically Modified Chickens. Science, 2011; 331 (6014): 223-226 DOI: 10.1126/science.1198020

Courtesy: ScienceDaily

Early Development of Anti-HIV Neutralizing Antibodies

New findings are bringing scientists closer to an effective HIV vaccine. Researchers from Seattle Biomedical Research Institute (Seattle BioMed), Vanderbilt University and the Ragon Institute of MGH, MIT and Harvard report findings showing new evidence about broadly-reactive neutralizing antibodies, which block HIV infection. Details are published January 13 in the open-access journal PLoS Pathogens.

According to author Leo Stamatatos, Ph.D., director of the Viral Vaccines Program at Seattle BioMed and a major stumbling block in the development of an effective vaccine against HIV is the inability to elicit, by immunization, broadly reactive neutralizing antibodies (NAbs). These antibodies bind to the surface of HIV and prevent it from attaching itself to a cell and infecting it. However, a fraction of people infected with HIV develop broadly neutralizing antibodies (bNAbs) capable of preventing cell-infection by diverse HIV isolates, which are the type of antibodies researchers wish to elicit by vaccination.

"We've found that the people who develop broadly-reactive neutralizing antibodies -- which are about 30% of those infected -- tend to have a healthier immune system that differs from others who don't develop those antibodies," Stamatatos explained, saying that these antibodies target only a few regions of HIV which is good from the standpoint of vaccine development. "It gives us less to target," he said.

In addition, the new findings show that these antibodies are generated much sooner than previously thought, in some cases as soon as a year after infection.

"These studies provide a strong rationale to begin teasing out the early immunological signals that allow some individuals, but not others, to mount broadly reactive neutralizing antibody responses," adds co-author Galit Alter, Ph.D.

"Now we know that these broadly-reactive neutralizing antibodies don't develop simply by chance and we can work to understand what makes this 30% of the HIV-infected population different," Stamatatos explained. By understanding that, we can hopefully use that information to design new immunogens and immunization protocols that can mimic the early events that lead to the development of such antibodies during natural infection."

This study was funded by NIH grants R01 AI081625 (LS), U01 A1078407 (SK), P01 AI78063 (SK). We would also like to acknowledge support by the M. J. Murdock Charitable Trust and the J. B. Pendleton Charitable Trust.

Journal Reference:

1. Iliyana Mikell, D. Noah Sather, Spyros A. Kalams, Marcus Altfeld, Galit Alter, Leonidas Stamatatos. Characteristics of the Earliest Cross-Neutralizing Antibody Response to HIV-1. PLoS Pathogens, 2011; 7 (1): e1001251 DOI: 10.1371/journal.ppat.1001251

Courtesy: ScienceDaily

Living Cells Used to Create 'Biotic' Video Games

The digital revolution has triggered a wild proliferation of video games, but what of the revolution in biotechnology? Does it have the potential to spawn its own brood of games? Stanford physicist Ingmar Riedel-Kruse has begun developing "biotic games" involving paramecia and other living organisms. He hopes the games lead to advances in education and crowd-sourcing of laboratory research while helping to raise the level of public discourse on bio-related issues.

Using living organisms, the group created three games that mimic some classic video games.

Video game designers are always striving to make games more lifelike, but they'll have a hard time topping what Stanford researcher Ingmar Riedel-Kruse is up to. He's introducing life itself into games.

Riedel-Kruse and his lab group have developed the first video games in which a player's actions influence the behavior of living microorganisms in real time -- while the game is being played.

These "biotic games" involve a variety of basic biological processes and some simple single-celled organisms (such as paramecia) in combination with biotechnology.

The goal is for players to have fun interacting with biological processes, without dealing with the rigor of conducting a formal experiment, said Riedel-Kruse, an assistant professor of bioengineering.

"We hope that by playing games involving biology of a scale too small to see with the naked eye, people will realize how amazing these processes are and they'll get curious and want to know more," he said.

"The applications we can envision so far are on the one hand educational, for people to learn about biology, but we are also thinking perhaps we could have people running real experiments as they play these games.

"That is something to figure out for the future, what are good research problems which a lay person could really be involved in and make substantial contributions. This approach is often referred to as crowd-sourcing."

Applying their lab equipment and knowledge to game development, Riedel-Kruse's group came up with eight games falling broadly into three classes, depending on whether players directly interact with biological processes on the scale of molecules, single cells or colonies of single cells.

The results of their design efforts are presented in a paper published in the 10^th anniversary issue of Lab on a Chip (the first issue of 2011), published by the Royal Society of Chemistry. The paper is available online now.

Initially, Riedel-Kruse said, the researchers just wanted to see whether they could design such biotic games at all, so this first round of development produced fairly simple games.

"We tried to mimic some classic video games," he said. For example, one game in which players guide paramecia to "gobble up" little balls, a la PacMan, was christened PAC-mecium. Then there is Biotic Pinball, POND PONG and Ciliaball. The latter game is named for the tiny hairs, called cilia, that paramecia use in a flipper-like fashion to swim around -- and in the game enables kicking a virtual soccer ball.

The basic design of the games involving paramecia -- the single-celled organisms used in countless biology experiments from grade school classes to university research labs -- consists of a small fluid chamber within which the paramecia can roam freely. A camera sends live images to a video screen, with the "game board" superimposed on the image of the paramecia. A microprocessor tracks the movements of the paramecia and keeps score.

The player attempts to control the paramecia using a controller that is much like a typical video game controller. In some games, such as PAC-mecium, the player controls the polarity of a mild electrical field applied across the fluid chamber, which influences the direction the paramecia move. In Biotic Pinball, the player injects occasional whiffs of a chemical into the fluid, causing the paramecia to swim one direction or another.

Riedel-Kruse emphasized that paramecia, being single-celled organisms, lack a brain and the capacity to feel pain. "We are talking about microbiology with these games, very primitive life forms. We do not use any higher-level organisms," he said. "Since multiple test players raised the question of exactly where one should draw this line, these games could be a good tool to stimulate discussions in schools on bioethical issues."

The game on the molecular level involves a common laboratory technique called polymerase chain reaction, or PCR, an automated process that lets researchers make millions of copies of an organism's DNA in as little as two hours.

In this game, called PolymerRace, the player is linked to the output of a PCR machine that is running different reactions simultaneously. While the reactions are running, the players can bet on which reactions will be run the fastest.

"The game PolymerRace is inspired by horse races, where you have different jockeys riding different horses," Riedel-Kruse said. "There is a little bit of bio-molecular logic involved and a little bit of chance."

The third game uses colonies of yeast cells that players have to distinguish based on their bread-vinegar like smell -- olfactory stimuli anyone can experience just by walking into a bakery.

"The idea is that while we as humans play the game, we interact with real biological processes or material," he said. His research group thinks that aspect of the games could help motivate children and even adults to learn more about biology, which is increasingly important to society.

"We would argue that modern biotechnology will influence our life at an accelerating pace, most prominently in the personal biomedical choices that we will be faced with more and more often," Riedel-Kruse said. "Therefore everyone should have sufficient knowledge about the basics of biomedicine and biotechnology. Biotic games could promote that."

Riedel-Kruse wants to maximize the educational potential of these games to enable lay people to contribute to biomedical research. The team hopes that by publishing his group's initial efforts, other researchers in the life sciences will be prompted to explore how their own research could be adapted to "biotic" video games.

Other researchers have developed biologically relevant Internet-based video games such as Fold-It, which lets players try different approaches to folding proteins, and EteRNA, developed in a collaboration between Stanford and Carnegie Mellon University, which lets players propose new molecular structures for ribonucleic acids (RNA).

Fold-It and EteRNA were developed to address specific research questions. Fold-It was strictly a simulation; and although EteRNA will actually test some proposed structures in the laboratory, the players themselves do not have direct interaction with biological processes in real time as in Riedel-Kruse's biotic games.

Part of Riedel-Kruse's continuing work will include close collaborations with Rhiju Das, an assistant professor of biochemistry at Stanford and one of the developers of EteRNA, and Daniel Schwartz, professor in the School of Education at Stanford. The three co-founded the "Bio-X.Game Center" to develop and apply biotic games to education and research.

Journal Reference:

1. Ingmar H. Riedel-Kruse, Alice M. Chung, Burak Dura, Andrea L. Hamilton, Byung C. Lee. Design, engineering and utility of biotic games. Lab on a Chip, 2011; 11 (1): 14 DOI: 10.1039/C0LC00399A

Courtesy: ScienceDaily

New System for Analyzing Information on WikiLeaks, Social Media

The Data Management Group of the Universitat Politècnica de Catalunya (DAMA-UPC) has designed a system for exploring information on networks or graphs that can complement internet search engines and is of particular interest in areas related to social media, the internet, biomedicine, fraud detection, education and advanced bibliographic searches.

According to Josep Lluís Larriba, director of DAMA-UPC, the technology can be used to extract information from WikiLeaks from two perspectives: one, to obtain generic indicators that provide information on whether the data network has the features of a social network and whether communities of data are created that can provide relevant information; and two, to use the documents hosted on the website to analyze how a topic evolves over time, how a person or a group relates to different topics and how the documents themselves interrelate.

High-speed complex queries

The new DEX technology patented by the UPC can be used to explore large volumes of networked data. The system offers high-speed processing, configurable data entry from multiple sources, and the management of networks with billions of nodes and connections from a desktop PC.

Users can quickly and easily identify interrelated records by formulating queries based on simple values such as names and keywords. Until now, this was possible to a certain extent using database technology, but DEX extracts new information from interrelated data and improves the speed and the capacity to perform complex queries in large data networks.

The DAMA-UPC group, which sees huge potential for the technology in the field of social media and the internet, proposes using the DEX system to analyze data on WikiLeaks, the international media organization that publishes anonymous reports and leaked documents on its website.

From fraud detection to the evolution of cancer

In what was the first major application of DEX, the Notary Certification Agency (ANCERT) used the technology to detect fraud in real estate transactions and the Catalan Institute of Oncology is using it to study the evolution of cancer in Catalonia. The DAMA-UPC group is now looking into how DEX technology can be applied to pharmaceutical data analysis to explore developments in the use of medicines.

The group is also conducting research into how information spreads across the internet and at what speed, and why some news spreads faster than others. The project is developed in the framework of the Social Media project, a strategic industrial research project funded by the National Strategic Consortia for Technical Research (CENIT) program.

In the field of e-learning, the team is working on a project under the RecerCaixa grant program aimed at recommending and exploring audiovisual content for primary and secondary schools.

Exploring scientific information

In addition to the fields of health, fraud detection, education and the internet, the technology created by the DAMA-UPC group also offers benefits to the scientific world.

The group has designed BIBEX (www.dama.upc.edu/bibex), a unique prototype for the Spanish Ministry of Science and Innovation aimed at exploring scientific publications and relating specific literature published worldwide. BIBEX also offers other advantages: scientists can recommend scientific articles and find reviewers to evaluate scientific publications. In the future, BIBEX will offer a tool for businesses to find research groups that are working in common areas of interest.

Technology transfer

Sparsity Technologies (www.sparsity-technologies.com) is a spin-off that was created in 2010 with the participation of the UPC to promote and market the technologies developed by the DAMA-UPC group.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Universitat Politècnica de Catalunya, via AlphaGalileo.

Courtesy: ScienceDaily

Scientists Construct Synthetic Proteins That Sustain Life

In a groundbreaking achievement that could help scientists "build" new biological systems, Princeton University scientists have constructed for the first time artificial proteins that enable the growth of living cells.

The team of researchers created genetic sequences never before seen in nature, and the scientists showed that they can produce substances that sustain life in cells almost as readily as proteins produced by nature's own toolkit.

"What we have here are molecular machines that function quite well within a living organism even though they were designed from scratch and expressed from artificial genes," said Michael Hecht, a professor of chemistry at Princeton, who led the research. "This tells us that the molecular parts kit for life need not be limited to parts -- genes and proteins -- that already exist in nature."

The work, Hecht said, represents a significant advance in synthetic biology, an emerging area of research in which scientists work to design and fabricate biological components and systems that do not already exist in the natural world. One of the field's goals is to develop an entirely artificial genome composed of unique patterns of chemicals.

"Our work suggests," Hecht said, "that the construction of artificial genomes capable of sustaining cell life may be within reach."

Nearly all previous work in synthetic biology has focused on reorganizing parts drawn from natural organisms. In contrast, Hecht said, the results described by the team show that biological functions can be provided by macromolecules that were not borrowed from nature, but designed in the laboratory.

Although scientists have shown previously that proteins can be designed to fold and, in some cases, catalyze reactions, the Princeton team's work represents a new frontier in creating these synthetic proteins.

The research, which Hecht conducted with three former Princeton students and a former postdoctoral fellow, is described in the online journal PLoS ONE, published by the Public Library of Science.

Hecht and the students in his lab study the relationship between biological processes on the molecular scale and processes at work on a larger magnitude. For example, he is studying how the errant folding of proteins in the brain can lead to Alzheimer's disease, and is involved in a search for compounds to thwart that process. In work that relates to the new paper, Hecht and his students also are interested in learning what processes drive the routine folding of proteins on a basic level -- as proteins need to fold in order to function -- and why certain key sequences have evolved to be central to existence.

Proteins are the workhorses of organisms, produced from instructions encoded into cellular DNA. The identity of any given protein is dictated by a unique sequence of 20 chemicals known as amino acids. If the different amino acids can be viewed as letters of an alphabet, each protein sequence constitutes its own unique "sentence."

And, if a protein is 100 amino acids long (most proteins are even longer), there are an astronomically large number of possibilities of different protein sequences, Hecht said. At the heart of his team's research was to question how there are only about 100,000 different proteins produced in the human body, when there is a potential for so many more. They wondered, are these particular proteins somehow special? Or might others work equally well, even though evolution has not yet had a chance to sample them?

Hecht and his research group set about to create artificial proteins encoded by genetic sequences not seen in nature. They produced about 1 million amino acid sequences that were designed to fold into stable three-dimensional structures.

"What I believe is most intriguing about our work is that the information encoded in these artificial genes is completely novel -- it does not come from, nor is it significantly related to, information encoded by natural genes, and yet the end result is a living, functional microbe," said Michael Fisher, a co-author of the paper who earned his Ph.D. at Princeton in 2010 and is now a postdoctoral fellow at the University of California-Berkeley. "It is perhaps analogous to taking a sentence, coming up with brand new words, testing if any of our new words can take the place of any of the original words in the sentence, and finding that in some cases, the sentence retains virtually the same meaning while incorporating brand new words."

Once the team had created this new library of artificial proteins, they inserted those proteins into various mutant strains of bacteria in which certain natural genes previously had been deleted. The deleted natural genes are required for survival under a given set of conditions, including a limited food supply. Under these harsh conditions, the mutant strains of bacteria died -- unless they acquired a life-sustaining novel protein from Hecht's collection. This was significant because formation of a bacterial colony under these selective conditions could occur only if a protein in the collection had the capacity to sustain the growth of living cells.

In a series of experiments exploring the role of differing proteins, the scientists showed that several different strains of bacteria that should have died were rescued by novel proteins designed in the laboratory. "These artificial proteins bear no relation to any known biological sequences, yet they sustained life," Hecht said.

Added Kara McKinley, also a co-author and a 2010 Princeton graduate who is now a Ph.D. student at the Massachusetts Institute of Technology: "This is an exciting result, because it shows that unnatural proteins can sustain a natural system, and that such proteins can be found at relatively high frequency in a library designed only for structure."

In addition to Hecht, Fisher and McKinley, other authors on the paper include Luke Bradley, a former postdoctoral fellow in Hecht's lab who is now an assistant professor at the University of Kentucky, and Sara Viola, a 2008 Princeton graduate who is now a medical student at Columbia University.

Journal Reference:

1. Mark Isalan, Michael A. Fisher, Kara L. McKinley, Luke H. Bradley, Sara R. Viola, Michael H. Hecht. De Novo Designed Proteins from a Library of Artificial Sequences Function in Escherichia Coli and Enable Cell Growth. PLoS ONE, 2011; 6 (1): e15364 DOI: 10.1371/journal.pone.0015364

Courtesy: ScienceDaily

Origin of Life on Earth: 'Natural' Asymmetry of Biological Molecules May Have Come from Space

Certain molecules do exist in two forms which are symmetrical mirror images of each other: they are known as chiral molecules. On Earth, the chiral molecules of life, especially amino acids and sugars, exist in only one form, either left-handed or right-handed. Why is it that life has initially chosen one form over the other?

A consortium bringing together several French teams led by Louis d'Hendecourt (1), CNRS senior researcher at the Institut d'astrophysique spatiale (Université Paris-Sud 11 / CNRS), has for the first time obtained an excess of left-handed molecules (and then an excess of right-handedones) under conditions that reproduce those found in interstellar space. This result therefore supports the hypothesis that the asymmetry of biological molecules on Earth has a cosmic origin. The researchers also suggest that the solar nebula formed in a region of massive stars.

This work has just been published online on the web site of The Astrophysical Journal Letters. The experiment was carried out at the SOLEIL synchrotron facility in collaboration with the Laboratoire de chimie des molécules bioactives et des arômes (Université de Nice/CNRS) and with the support of CNES.

Chiral molecules are molecules that can exist in two forms (enantiomers) which are symmetrical mirror images of each other, one left-handed and the other right-handed. For instance, our hands are chiral since they come in two forms, the left hand and the right hand, that are symmetrical with their mirror image but not super imposable on it. Biological molecules are mostly chiral, with some forms being favored over others. For instance, the amino acids that make up proteins only exist in one of their two enantiomeric forms, the left-handed (L) form. On the other hand, the sugars present in the DNA of living organisms are solely right-handed (D). This property that organic molecules have of existing in living organisms in only one of their two structural forms is called homochirality.

What is the origin of such asymmetry in biological material? There are two competing hypotheses. One postulates that life originated from a mixture containing 50% of one enantiomer and 50% of the other (known as a racemic mixture), and that homochirality progressively emerged during the course of evolution. The other hypothesis suggests that asymmetry leading to homochirality preceded the appearance of life and was of cosmic origin. This is supported by the detection of L excesses in certain amino acids extracted from primitive meteorites. According to this scenario, these amino acids were synthesized non-racemically in interstellar space and delivered to Earth by cometary grains and meteorites.

To lend more weight to this hypothesis, the researchers first reproduced analogs of interstellar and cometary ices in the laboratory (2). The novel aspect of their experiment was that, using the DESIRS beamline at the SOLEIL synchrotron facility, the ices were subjected to circularly polarized ultraviolet radiation (UV-CPL) (3), which is supposed to mimic the conditions encountered in some space environments. When the ices were warmed up, an organic residue was produced. A detailed analysis of this mixture revealed that it contained a significant enantiomeric excess in one chiral amino acid, alanine. The excess, which was over 1.3%, is comparable to that measured in primitive meteorites. The researchers thus succeeded in producing, under interstellar conditions, asymmetrical molecules of life from a mixture that did not contain chiral substances. This is the first time that a scenario that explains the origin of this asymmetry has been demonstrated using an experiment that reproduces an entirely natural synthesis.

This result reinforces the hypothesis that the origin of homochirality is prebiotic and cosmic, in other words genuinely interstellar. According to this scenario, the delivery of extraterrestrial organic material containing an enantiomeric excess synthesized by an asymmetrical astrophysical process (in this case, UV-CPL radiation) is the cause of the asymmetry of life's molecules on Earth. This material may even have formed outside the solar system. Finally, the solar nebula may have formed in regions of massive star formation. In such regions, infrared radiation circularly polarized in the same direction has been observed.

These findings imply that the selection of a single enantiomer for the molecules of life observed on Earth is not the result of chance but rather of a deterministic physical mechanism.

Notes:

(1) 2003 CNRS Silver Medal

(2) In the 1980s, Louis d'Hendecourt developed a technique to generate interstellar ice analogs in the laboratory.

(3) The Orion nebula produces circularly polarized light at levels of 17% in the infrared. It is calculated that it also radiates in the ultraviolet, radiation which is able to break the (strong) covalent bonds betweens the atoms of ice molecules.

Journal Reference:

1. Pierre de Marcellus, Cornelia Meinert, Michel Nuevo, Jean-Jacques Filippi, Grégoire Danger, Dominique Deboffle, Laurent Nahon, Louis Le Sergeant d'Hendecourt, Uwe J. Meierhenrich. Non-racemic amino acid production by ultraviolet irradiation of achiral interstellar ice analogs with circularly polarized light. The Astrophysical Journal, 2011; 727 (2): L27 DOI: 10.1088/2041-8205/727/2/L27

Courtesy: ScienceDaily

What Triggers Mass Extinctions? Study Shows How Invasive Species Stop New Life

An influx of invasive species can stop the dominant natural process of new species formation and trigger mass extinction events, according to research results published December 29 in the journal PLoS ONE. The study of the collapse of Earth's marine life 378 to 375 million years ago suggests that the planet's current ecosystems, which are struggling with biodiversity loss, could meet a similar fate.

Although Earth has experienced five major mass extinction events, the environmental crash during the Late Devonian was unlike any other in the planet's history. The actual number of extinctions wasn't higher than the natural rate of species loss, but very few new species arose.

"We refer to the Late Devonian as a mass extinction, but it was actually a biodiversity crisis," said Alycia Stigall, a scientist at Ohio University and author of the PLoS ONE paper.

"This research significantly contributes to our understanding of species invasions from a deep-time perspective," said Lisa Boush, program director in the National Science Foundation (NSF)'s Division of Earth Sciences, which funded the research.

"The knowledge is critical to determining the cause and extent of mass extinctions through time, especially the five biggest biodiversity crises in the history of life on Earth. It provides an important perspective on our current biodiversity crises."

The research suggests that the typical method by which new species originate--vicariance--was absent during this ancient phase of Earth's history, and could be to blame for the mass extinction.

Vicariance occurs when a population becomes geographically divided by a natural, long-term event, such as the formation of a mountain range or a new river channel, and evolves into different species. New species also can originate through dispersal, which occurs when a subset of a population moves to a new location.

In a departure from previous studies, Stigall used phylogenetic analysis, which draws on an understanding of the tree of evolutionary relationships to examine how individual speciation events occurred.

She focused on one bivalve, Leptodesma (Leiopteria), and two brachiopods, Floweria and Schizophoria (Schizophoria), as well as a predatory crustacean, Archaeostraca. These small, shelled marine animals were some of the most common inhabitants of the Late Devonian oceans, which had the most extensive reef system in Earth's history.

The seas teemed with huge predatory fish such as Dunkleosteus, and smaller life forms such as trilobites and crinoids (sea lilies). The first forests and terrestrial ecosystems appeared during this time; amphibians began to walk on land. As sea levels rose and the continents closed in to form connected land masses, however, some species gained access to environments they hadn't inhabited before.

The hardiest of these invasive species that could thrive on a variety of food sources and in new climates became dominant, wiping out more locally adapted species. The invasive species were so prolific at this time that it became difficult for many new species to arise.

"The main mode of speciation that occurs in the geological record is shut down during the Devonian," said Stigall. "It just stops in its tracks."

Of the species Stigall studied, most lost substantial diversity during the Late Devonian, and one, Floweria, became extinct. The entire marine ecosystem suffered a major collapse. Reef-forming corals were decimated and reefs did not appear on Earth again for 100 million years. The giant fishes, trilobites, sponges and brachiopods also declined dramatically, while organisms on land had much higher survival rates.

The study is relevant for the current biodiversity crisis, Stigall said, as human activity has introduced a high number of invasive species into new ecosystems.

In addition, the modern extinction rate exceeds the rate of ancient extinction events, including the event that wiped out the dinosaurs 65 million years ago.

"Even if you can stop habitat loss, the fact that we've moved all these invasive species around the planet will take a long time to recover from because the high level of invasions has suppressed the speciation rate substantially," Stigall said.

Maintaining Earth's ecosystems, she suggests, would be helped by focusing efforts and resources on protection of new species generation. "The more we know about this process," Stigall said, "the more we will understand how to best preserve biodiversity."

Journal Reference:

1. Anna Stepanova, Alycia L. Stigall. Invasive Species and Biodiversity Crises: Testing the Link in the Late Devonian. PLoS ONE, 2010; 5 (12): e15584 DOI: 10.1371/journal.pone.0015584

Courtesy: ScienceDaily

Key Protein Discovered That Allows Nerve Cells to Repair Themselves

A team of scientists led by Melissa Rolls, an assistant professor of biochemistry and molecular biology at Penn State University, has peered inside neurons to discover an unexpected process that is required for regeneration after severe neuron injury. The process was discovered during Rolls's studies aimed at deciphering the inner workings of dendrites -- the part of the neuron that receives information from other cells and from the outside world.

The research will be published in the print edition of the scientific journal Current Biology on 21 December 2010.

"We already know a lot about axons -- the part of the nerve cell that is responsible for sending signals," Rolls said. "However, dendrites -- the receiving end of nerve cells -- have always been quite mysterious." Unlike axons, which form large, easily recognizable bundles, dendrites are highly branched and often buried deep in the nervous system, so they have always been harder to visualize and to study. However, Rolls and her team were able to get around these difficulties. They looked inside dendrites in vivo by using a simple model organism -- the fruit fly -- whose nerve cells are similar to human nerve cells. One of the first mysteries they tackled was the layout of what Rolls referred to as intracellular "highways" -- or microtubules.

"Imagine the nerve cell with two branches -- or arms -- splayed out from it on opposite sides," Rolls explained. "Both arms have highways -- microtubules -- that run along their length and allow all the raw building materials made in the cell body to be carried to the far reaches of the cell. But the highways point in opposite directions. In axons, the growing ends -- or plus ends -- of the microtubules point away from the cell body. In contrast, in the dendrites the plus ends point towards the cell body. No one understands how a single cell can set up two different highway systems."

Unlike many other cells in our bodies, most neurons must last a lifetime. They rely on their key infrastructure -- microtubules -- to be extremely well organized, but also to be flexible so that they can be rebuilt in response to injury. Part of that flexibility comes microtubules' ability to grow constantly. Rolls and her team visualized this growth and realized that there must be a set of proteins controlling just how the highways are laid down at key intersections -- or branch points -- to keep all the microtubules pointing the same way. They identified the proteins, which include the motor protein kinesin-2, and found that when these proteins were missing the microtubules no longer pointed the same way in dendrites; that is, their polarity became disorganized.

After identifying the set of proteins required to maintain an orderly microtubule infrastructure in dendrites, the team tested whether these proteins play a role in the ability of neurons to respond to injury. Most neurons are irreplaceable, and yet they have an incredible ability to regenerate their missing parts. In earlier studies, Rolls and her team had found that, after an axon is cut off and the nerve cell no longer is able to send signals, a new axon grows from the other side of the cell; that is, from a dendrite. As part of this process, the microtubules must flip polarity. In other words, the dendrite highways must be completely rebuilt in the axonal direction. "When we disabled the flies' ability to produce the kinesin-2 protein, we found that the highways could not be rebuilt correctly, and nerve regeneration failed," Rolls explained. "Apparently, kinesin-2 is a crucial protein for polarity maintenance and for the ability to set up a new highway system when neurons need to regenerate."

Rolls also explained that visualizing how nerves maintain their intracellular highways is important for understanding neurodegenerative disease as well as response to nerve injury, which often occurs after accidents and other trauma. If the proteins that control the layout of microtubules, or carry cargo along them, do not function properly, they can become culprits in neurodegenerative diseases such as hereditary spastic paraplegia. "We hope that by showing how microtubules are built in healthy neurons and rebuilt in response to injury, our study might provide insights for future researchers who are developing drug therapies for patients with nerve disease or damage," Rolls said.

This work was funded by an American Heart Association Scientist Development Grant, a March of Dimes Basil O'Connor Starter Scholar Award, the National Institutes of Health, and a Pew Scholar in the Biomedical Sciences award to Melissa Rolls.

Journal Reference:

1. Floyd J. Mattie, Megan M. Stackpole, Michelle C. Stone, Jessie R. Clippard, David A. Rudnick, Yijun Qiu, Juan Tao, Dana L. Allender, Manpreet Parmar, and Melissa M. Rolls. Directed Microtubule Growth, TIPs, and Kinesin-2 Are Required for Uniform Microtubule Polarity in Dendrites. Current Biology, Online December 9, 2010 DOI: 10.1016/j.cub.2010.11.050

Courtesy: ScienceDaily

Scientists Peer Into the Future of Stem Cell Biology

Remarkable progress in understanding how stem cell biology works has been reported by a team of leading scientists, directed by experts at UC Santa Barbara. Their research has been published in the journal Cell Stem Cell.

Stem cell biology is making waves around the world with great hope for the eventual repair of parts of the body. While many scientists see these breakthroughs as viable, there are hurdles that must be overcome, including the worrisome potential for introducing cancer when making a repair to an organ.

Significant interdisciplinary research in stem cells is being performed at UC Santa Barbara, by a team of neurobiologists and physicists, with assistance from scientists at Harvard Medical School, UCLA's Geffen School of Medicine, and the Yale Stem Cell Center.

The paper is a collaboration between biology, physics, and engineering. The two first authors are Pierre Neveu, of the Neuroscience Research Institute (NRI) and UCSB's Kavli Institute of Theoretical Physics (KITP); and Min Jeong Kye, of the NRI, MCDB, UCSB's Center for Stem Cell Biology and Engineering.

An important concept in this research is pluripotency -- the ability of the human embryonic stem cell to differentiate or become almost any cell in the body, explained senior author Kenneth S. Kosik, professor in the Department of Molecular, Cellular & Developmental Biology (MCDB). Kosik is also the Harriman Chair in Neuroscience Research and co-director of the NRI. And, Kosik is a practicing physician specializing in Alzheimer's Disease.

"The beauty and elegance of stem cells is that they have these dual properties," said Kosik. "On the one hand, they can proliferate -- they can divide and renew. On the other hand, they can also transform themselves into any tissue in the body, any type of cell in the body."

Kosik said that scientists have learned that many cells in the body have the potential to become pluripotent cells. "The big engines of change are the transcription factors," said Kosik. "They drive the laboratory procedure by which we can reverse the progression during development from stem cell to differentiated cell and use differentiated cells from our skin to make stem cells."

With human embryonic stem cells, Kosik explained that for some time he and his team have been studying a set of control genes called microRNAs. "To really understand microRNAs, the first step is to remember the central dogma of biology --DNA is the template for RNA, and RNA is translated to protein. But microRNAs stop at the RNA step and never go on to make a protein."

According to Kosik, it doesn't matter how scientists make or obtain stem cells for research. They can be bona fide human embryonic stem cells (HESC) or induced pluripotent stem cells (IPSC) induced from a skin cell. The microRNA patterns don't "respect" how the cells were made, Kosik said. The team found that all pluripotent stem cells are not identical, but did not differ by how they originated. The scientists found two groups of stem cells, irrespective of origin. MicroRNA profiles proved this.

When looking at microRNA, the overall profile is an extraordinarily good predictor -- maybe the best predictor -- of what type of cell you have. "You could be looking through the microscope at a tumor, and you may not be sure about that tumor," said Kosik. "Maybe the tumor is in the brain, but you don't know whether it is a brain tumor, or a metastasis from somewhere else. You can't always tell exactly what type of cells they are.

"The microRNAs will tell you," said Kosik. "Those profiles can tell you the different types of cancer; they can tell you the different types of cells; they can distinguish stem cells from other cells; and they can distinguish skin cells from brain cells. Those profiles, when you look at them in their totality, offer a unique signature that can inform you as to what type of cell you have. So that's a very important property of these microRNAs."

The scientists looked at 400 different microRNAs in both embryonic and induced pluripotent cells. Humans have approximately 1,000 microRNAs.

Pluripotent stem cells have some similarity to cancer cells. They are immortal. They self-renew. Tumors keep dividing. So do pluripotent stem cells. "That's their property, self-renewal, proliferation," said Kosik. "And that's what cancer does. How can it be that pluripotent stem cells can self-renew and are not cancer, but cancer cells self-renew and are cancer? Cancer lacks any control over itself. What's the difference?"

The scientists included studies of 40 types of differentiated body cells, in the microRNA testing. They found that the microRNA was very different in the cancer cells and the differentiated cells. This was not a surprise.

The surprise was that when looking at pluripotent cells, some are more more similar to cancer and others are less similar.

"One of the big problems that people worry about in the use of stem cells for the repair of body parts, is whether or not you are going to be creating cancer," said Kosik. "That's a big worry ¬¬-- one of the major worries. So if we have a way here, and this we don't know yet, but if these microRNA profiles that look like cancer indicate a propensity toward cancer, then that would be very nice to know. But we don't know that yet."

He explained two possibilities: If doctors are going to use stem cells for body repairs, they don't want them to be cancerous, but they do want them to have enough growth potential that they will really make a difference. "So maybe they should look a little bit like cancer," said Kosik. "On the other hand, you don't want them to become a tumor. So maybe you want them to look a little less like cancer. At this point you could make either argument. We just don't know."

Scientists at UCSB will be working on the answers.

Additional authors are Shuping Qi and Harley I. Kornblum, David Geffen School of Medicine, UCLA; David E. Buchholz and Dennis Clegg, UCSB's NRI, MCDB, and Center for Stem Cell Biology and Engineering; Mustafa Sahin, Harvard Medical School; In-Hyun Park, Harvard Stem Cell Institute and Yale Stem Cell Center; Kwang-Soo Kim, Harvard Medical School; George Q. Daley, Harvard Stem Cell Institute; and Boris I. Shraiman, UCSB Department of Physics and KITP.

Journal Reference:

1. Pierre Neveu, Min Jeong Kye, Shuping Qi, David E. Buchholz, Dennis O. Clegg, Mustafa Sahin, In-Hyun Park, Kwang-Soo Kim, George Q. Daley, Harley I. Kornblum. MicroRNA Profiling Reveals Two Distinct p53-Related Human Pluripotent Stem Cell States. Cell Stem Cell, 2010; 7 (6): 671 DOI: 10.1016/j.stem.2010.11.012

Courtesy: ScienceDaily

Bacteria Provide Example of One of Nature's First Immune Systems, Research Shows

Studying how bacteria incorporate foreign DNA from invading viruses into their own regulatory processes, Thomas Wood, professor in the Artie McFerrin Department of Chemical Engineering at Texas A&M University, is uncovering the secrets of one of nature's most primitive immune systems.

His findings, which appear in Nature Communications, a multidisciplinary publication dedicated to research in all areas of the biological, physical and chemical sciences, shed light on how bacteria have throughout the course of millions of years developed resistance to antibiotics by co-opting the DNA of their natural enemies -- viruses.

The battle between bacteria and bacteria-eating viruses, Wood explains, has been going on for millions of years, with viruses attempting to replicate themselves by -- in one approach -- invading bacteria cells and integrating themselves into the chromosomes of the bacteria. When this happens a bacterium makes a copy of its chromosome, which includes the virus particle. The virus then can choose at a later time to replicate itself, killing the bacterium -- similar to a ticking time bomb, Wood says.

However, things can go radically wrong for the virus because of random but abundant mutations that occur within the chromosome of the bacterium. Having already integrated itself into the bacterium's chromosome, the virus is subject to mutation as well, and some of these mutations, Wood explains, render the virus unable to replicate and kill the bacterium.

With this new diverse blend of genetic material, Wood says, a bacterium not only overcomes the virus' lethal intentions but also flourishes at a greater rate than similar bacteria that have not incorporated viral DNA.

"Over millions of years, this virus becomes a normal part of the bacterium," Wood says. "It brings in new tricks, new genes, new proteins, new enzymes, new things that it can do. The bacterium learns how to do things from this.

"What we have found is that with this new viral DNA that has been trapped over millions of years in the chromosome, the cell has created a new immune system," Wood notes. "It has developed new proteins that have enabled it to resists antibiotics and other harmful things that attempt to oxidize cells, such as hydrogen peroxide. These cells that have the new viral set of tricks don't die or don't die as rapidly."

Understanding the significance of viral DNA to bacteria required Wood's research team to delete all of the viral DNA on the chromosome of a bacterium, in this case bacteria from a strain of E. coli. Wood's team, led by postdoctoral researcher Xiaoxue Wang, used what in a sense could be described as "enzymatic scissors" to "cut out" the nine viral patches, which amounted to precisely removing 166,000 nucleotides. Once the viral patches were successfully removed, the team examined how the bacterium cell changed. What they found was a dramatically increased sensitivity to antibiotics by the bacterium.

While Wood studied this effect in E. coli bacteria, he says similar processes have taken place on a massive, widespread scale, noting that viral DNA can be found in nearly all bacteria, with some strains possessing as much as 20 percent viral DNA within their chromosome.

"To put this into perspective, for some bacteria, one-fifth of their chromosome came from their enemy, and until our study, people had largely neglected to study that 20 percent of the chromosome," Wood says. "This viral DNA had been believed to be silent and unimportant, not having much impact on the cell.

"Our study is the first to show that we need to look at all bacteria and look at their old viral particles to see how they are affecting the bacteria's current ability to withstand things like antibiotics. If we can figure out how the cells are more resistant to antibiotics because of this additional DNA, we can perhaps make new, effective antibiotics."

Journal Reference:

1. Xiaoxue Wang, Younghoon Kim, Qun Ma, Seok Hoon Hong, Karina Pokusaeva, Joseph M. Sturino, Thomas K. Wood. Cryptic prophages help bacteria cope with adverse environments. Nature Communications, 2010; 1 (9): 147 DOI: 10.1038/ncomms1146

Courtesy: ScienceDaily