Water, Water, Everywhere... But Is It Safe To Drink?

"Over the last couple of generations, there has been a huge amount of groundwater pollution worldwide, and this has had a negative impact on our drinking water supply," says Barbara Sherwood Lollar, Canada Research Chair in Isotope Geochemistry of the Earth and the Environment at the University of Toronto.



Sherwood Lollar took part in the THINK CANADA Press Breakfast at AAAS. Her research examines society's efforts to reverse and stop groundwater pollution, and the effectiveness of bioremediation technologies - using microbes to clean up organic contaminants such as petroleum hydrocarbons (oil, gasoline or diesel) or chemicals used in the electronics or transportation industries.



While the disposal of these organic contaminants tends to be well regulated today, this has not always been the case. Lax regulations and enforcement during the period immediately after the Second World War has left Europe and North America with a legacy of past contamination.



"This contamination has had a pervasive impact on the environment," says Sherwood Lollar. "It is still out there, and it needs to be dealt with."



Over the past decade, many techniques used to clean up groundwater contamination have harnessed the power of microbiology and the work of geochemists like Sherwood Lollar. "We are not genetically engineering microbes," she explains. "In many settings, naturally occurring microbes feed off the organic contaminants and, in the process, convert them to non-toxic end products."



Until now, the real difficulty has been in proving that the process exists and that the microbes are actually cleaning up the contaminants. Sherwood Lollar has developed techniques that show where the clean-up is happening and, just as importantly, where it is not.



"Elements like carbon have different stable isotopes: Carbon-12 and Carbon-13. One is slightly heavier than the other, and the microbes tend to feed mostly on the lighter one. When the microbes have been working for some time, the ratio of heavy-to-light carbon will change. It is this change - referred to as an isotopic signature - that lets us know the water is being cleaned up," says Sherwood Lollar.



By cleaning up contaminated groundwater, it is possible to recuperate what would otherwise be a lost resource. The technique is starting to be used by regulators, and Sherwood Lollar is working with an international group of scientists to put together a guidance document for the United States Environmental Protection Agency (EPA).



This will provide a set of recommendations about use in the field for practitioners, which will be a first step towards mainstreaming the technique.



"It's a common misconception that water - and especially our supply of groundwater - is a renewable resource," says Sherwood Lollar. "But it isn't. So, it is particularly important that we manage it well and that we do whatever we can to conserve, protect and remediate what we have."



Source:

Michael Adams

Natural Sciences and Engineering Research Council

Regenerative Activity In The Peripheral Nervous System Could Mean Regeneration For The Central Nervous System

Researchers at the Peninsula Medical School in the South West of England, University College London, the San Raffaele Scientific Institute in Milan and Cancer Research UK, have for the first time identified a protein that is key to the regeneration of damage in the peripheral nervous system and which could with further research lead to understanding diseases of our peripheral nervous systems and provide clues to methods of repairing damage in the central nervous system, according to a paper published this week in the Journal of Cell Biology.



The team looked at a protein called c-Jun, a transcription factor that regulates the expression of other genes. They found that the c-Jun protein plays a vital role in the regulating the plasticity of Schwann cells which is vital for the way in which the peripheral nervous system regenerates and repairs itself after injury.



Schwann cells produce the sheaths that surround and insulate neurons. When there is damage to the peripheral nervous system Schwann cells unwrap themselves from the degenerating axon. During this process of repair, Schwann cells then provide the correct environment for the neurons to re-grow and complete the process of repair.



By identifying this transcription factor, the research team believes that there is scope to produce eventual cures for damage and diseases of the peripheral nervous system, such as the inherited condition Charcot-Marie-Tooth disease and the autoimmune disorder Guillain-Barre disease.



Unlike the peripheral nervous system, the central nervous system does not regenerate when damaged. With further research, the team hopes to work towards identifying ways in which Schwann cells and c-Jun could be used to repair the spinal cord, leading to possible cures and relief for millions of people around the world suffering from damage of the central nervous system.



Further research could also identify whether abnormal activation of the c-Jun protein may be involved in causing Schwann cell tumours, for instance in the condition of neurofibromatosis type 2, leading to a better understanding of this condition and the development of therapies for this condition.



Dr. David Parkinson from the Peninsula Medical School, who was lead researcher on the paper, commented: "This is a very exciting first step towards understanding how the peripheral nervous system repairs itself, how that process could be used to produce cures for diseases of and damage to the peripheral nervous system, and how it could ultimately encourage the central nervous system to behave like the peripheral nervous system and repair itself."



He added: "We knew that Schwann cells, unlike other cells in the body, are constantly able to rejuvenate themselves. We now have a better understanding of how this happens, and that understanding could be used to create treatments and therapies for a wide range of degenerative diseases."







The Peninsula Medical School is a joint entity of the University of Exeter, the University of Plymouth and the NHS in the South West of England, and a partner of the Combined Universities in Cornwall. The Peninsula Medical School has created for itself an excellent national and international reputation for groundbreaking research in the areas of diabetes and obesity, neurological disease, child development and ageing, clinical education and health technology assessment.



Source: Andrew Gould


The Peninsula College of Medicine and Dentistry

$3M From NIDA To Support Effective Prevention, Treatment And Service Strategies For Drug Abusing Youth And Adults

The Center for Proteomics and Bioinformatics and the Case Center for AIDS Research at Case Western Reserve University School of Medicine have a received a $989,108 grant from the National Institute of Drug Abuse (NIDA) at the National Institute of Health (NIH), with the ability to receive a total of $3,007,946 by 2011. The grant will allow the Center for Proteomics and Bioinformatics to expand its activities in the HIV/AIDS area, which already represents approximately 30 percent of its projects, while providing the Center for AIDS Research an opportunity to introduce advanced proteomic technology into its research portfolio. Together, the centers will study the effects of drug use on the biology of HIV/AIDS.



The new grant, over three years of funding (2009: $989,108; 2010: $1,004,415; 2011: $1,014,423), will allow the development of reliable proteomic and epigenetic biomarkers (certain proteins that can be measured as an indicator of or to better understand the progression of a disease) for chronic immune activation during HIV disease and it will help the Centers better understand the effects of current or prior drug use and Hepatitis C-co infection (HCV) on disease progression and therapy. The grant also will provide funding for technology development in proteomics and systems biology research tools, further cementing existing collaborative relationships between CFAR investigators at the School of Medicine, the Dental school, the Louis Stokes VA hospital and investigators at the Center for Proteomics and Bioinformatics.



"There is a pressing need to obtain objective measurements of how HIV disease progresses and to investigate whether drug abuse alters the course of HIV disease," said Jonathan Karn, chair of the Department of Molecular Biology & Microbiology, director of the Case Center for AIDS Research (CFAR), and co-PI on the study. "Currently patients under HAART (anti-viral) therapy show a wide range of clinical outcomes, but physicians lack reliable indicators of how HIV disease progresses."



The AIDS Clinical Trials Unit, through the School of Medicine and University, provides both centers ample access to specimens needed to conduct this study.



"We will develop several pilot projects in collaboration with the CFAR investigator team to explore the proteomes of patients who have HIV or HCV, who may be on anti-retroviral therapy, and who may be drug users or in drug treatment programs," said Mark Chance, director, Center for Proteomics and Bioinformatics and lead PI of the study. "At the same time, specific changes in genes or epigenetic changes will also be explored. A Proteomics and Bioinformatics core will support these pilot projects with study design and biostatistical expertise, proteomics services, and systems biology data analysis."
















During the pilot phase, the Center will fund and coordinate a set of inter-related projects designed to provide a better understanding of the impact on immune function and activity in HIV-infected individuals who are also exposed to addictive drugs, and the importance of viral HCV. In each of these projects there will be a direct examination of the proteomic responses in either cells lining the digestive tract or immune cells and parallel examination of plasma readouts from affected patients.



The data will be rationalized using techniques to identify specific inflammatory pathways that are activated. Technologies for analyzing epigenetic changes in the immune system will be developed, with a goal of being able to correlate changes in the genome with those in the proteome. The ultimate goal of these projects will be the development of informative biomarkers and methods that can be used in large-scale population studies to further evaluate the impact of drug use on HIV disease.



"We are delighted to be able to initiate new research in this area and welcome the innovative leadership that NIDA is providing to study of the molecular basis of the interactions between drug use and HIV disease," said Chance. "This grant is important from an institutional perspective as well because it will introduce Case's advanced proteomics and systems biology capacities to NIDA, and provide investigators who are currently studying HIV/AIDS with an excellent opportunity to identify and study their drug abuse cohorts."



Needle sharing and/or impaired decision-making resulting from intoxication that can lead to risky sexual behaviors, often lead drug users to contract HIV/AIDS; the number of HIV patients who use or have used drugs is 10-30 percent. Better approaches to understanding their HIV/AIDS progression and developing treatments specific to their conditions is a specific goal of the research.



Source:
Christina DeAngelis


Case Western Reserve University

Biophysical Society Selects 2009 Distinguished Service, Emily M. Gray And Society Fellow Recipients

The Biophysical Society is pleased to announce the recipients of its 2009 Distinguished Service Award and the Emily M. Gray Award, as well as the Society's 2009 Fellows. All of the award winners and Fellows will be recognized at the Awards Ceremony during the Biophysical Society's 53rd Annual Meeting on Monday March 2, 2009 at the Boston Convention and Exhibition Center in Boston, Massachusetts.



Jeremy M. Berg of the National Institute of General Medical Sciences, NIH, will receive the Distinguished Service Award for his active and continuous support for biomedical research in general, and biophysics in particular, and the successful and creative leadership he has demonstrated in these activities. His longstanding support stems from his deep knowledge in the sciences basic to medicine and health, anchored in his own research career and the important contributions he has made to understanding the structural and functional roles of proteins in key physiological functions. The Distinguished Service Award, established by the Biophysical Society, honors service in the field of biophysics and for contributions beyond achievements in research.



Philip C. Nelson, University of Pennsylvania, will receive the Emily M. Gray Award for his far reaching and significant contributions to the teaching of biophysics, developing innovative educational materials, and fostering an environment exceptionally conducive to education in Biological Physics. The Award is given for significant contributions to education in biophysics whether by teaching, developing novel educational methods or materials, promoting scientific outreach efforts to the public or to youth, generating a track record of attracting new students to the field of biophysics, or by otherwise fostering an environment exceptionally conducive to education in biophysics.



Five Biophysical Society members have been named to the 2009 class of Society Fellows. This award is designed to honor the Society's distinguished members who have demonstrated excellence in science and to the expansion of the field of biophysics. The Fellows are:

Donald M. Bers, University of California, Davis, for his contributions to the field of cellular and molecular biology of excitation contraction and coupling in the heart;



Betty Gaffney, Florida State University, for being in the investigative forefront of spin labeling technology and electron paramagnetic resonance, the structure and dynamics of biological membranes, and the mechanisms of lipoxygenase function;



Robert Jernigan, Baker Center for Bioinformatics & Computational Biology Plant Sciences Institute, Iowa State University, for his distinguished research and leadership in coarse-grained studies of proteins and their interactions;



Mark T. Nelson, University of Vermont, for his important contributions to explaining complex physiological processes in smooth muscle function; and



Diane Papazian, David Geffen School of Medicine, UCLA, for her contributions to the physiology and biophysics of ion channels and how mutation in such channels are linked to diseases.





The Biophysical Society, founded in 1956, is a professional, scientific society established to encourage development and dissemination of knowledge in biophysics. The Society promotes growth in this expanding field through its annual meeting, monthly journal, and committee and outreach activities. Its 8200 members are located throughout the U.S. and the world, where they teach and conduct research in colleges, universities, laboratories, government agencies, and industry. For more information on the society or the 2009 annual meeting, visit biophysics/.



Source: Ellen R. Weiss


Biophysical Society

Space Versus Phylogeny: Disentangling Phylogenetic And Spatial Signals In Comparative Data

Variation in traits across species or populations is the outcome of both environmental and historical factors.


Trait variation is therefore a function of both the phylogenetic and spatial context of species. Here we introduce a method that within a single framework estimates the relative roles of spatial and phylogenetic variation in comparative data.


The approach requires traits measured across phylogenetic units, e.g. species, the spatial occurrences of those units and a phylogeny connecting them.


Proceedings of the Royal Society B: Biological Sciences


Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.


Proceedings of the Royal Society B: Biological Sciences

New Way To Assemble Artificial Tissues Created By Tissue Engineers

Tissue engineering has long held promise for building new organs to replace damaged livers, blood vessels and other body parts. However, one major obstacle is getting cells grown in a lab dish to form 3-D shapes instead of flat layers.



Researchers at the MIT-Harvard Division of Health Sciences and Technology (HST) have come up with a new way to overcome that challenge, by encapsulating living cells in cubes and arranging them into 3-D structures, just as a child would construct buildings out of blocks.



The new technique, dubbed "micromasonry," employs a gel-like material that acts like concrete, binding the cell "bricks" together as it hardens. Ali Khademhosseini, assistant professor of HST, and former HST postdoctoral associate Javier Gomez Fernandez describe the work in a paper published online in the journal Advanced Materials.



The tiny cell bricks hold potential for building artificial tissue or other types of medical devices, says Jennifer Elisseeff, associate professor of biomedical engineering at Johns Hopkins University, who was not involved in the research. "They're very elegant and have a lot of flexibility in how you grow them," she says. "It's very creative."



To obtain single cells for tissue engineering, researchers have to first break tissue apart, using enzymes that digest the extracellular material that normally holds cells together. However, once the cells are free, it's difficult to assemble them into structures that mimic natural tissue microarchitecture.



Some scientists have successfully built simple tissues such as skin, cartilage or bladder on biodegradable foam scaffolds. "That works, but it often lacks a controlled microarchitecture," says Khademhosseini, who is also an assistant professor at Brigham and Women's Hospital. "You don't get tissues with the same complexity as normal tissues."



The HST researchers built their "biological Legos" by encapsulating cells within a polymer called polyethylene glycol (PEG), which has many medical uses. Their version of the polymer is a liquid that becomes a gel when illuminated, so when the PEG-coated cells are exposed to light, the polymer hardens and encases the cells in cubes with side lengths ranging from 100 to 500 millionths of a meter.



Once the cells are in cube form, they can be arranged in specific shapes using templates made of PDMS, a silicon-based polymer used in many medical devices. Both template and cell cubes are coated again with the PEG polymer, which acts as a glue that holds the cubes together as they pack themselves tightly onto the scaffold surface.



After the cubes are arranged properly, they are illuminated again, and the liquid holding the cubes together solidifies. When the template is removed, the cubes hold their new structure.



Gomez Fernandez and Khademhosseini used this method to build tubes that could function as capillaries, potentially helping to overcome one of the most persistent problems with engineered organs - lack of an immediate blood supply. "If you build an organ, but you can't provide nutrients, it is going to die," says Gomez Fernandez, now a postdoctoral fellow at Harvard. They hope their work could also lead to a new way to make artificial liver or cardiac tissue.



Other researchers have developed a technique called organ printing to create complex 3-D tissues, but that process requires a robotic machine that is not in widespread use. The new technique does not require any special equipment. "You can reproduce this in any lab," says Gomez Fernandez. "It's very simple."



To get to the point where these engineered tissues could become clinically useful, "the short-term next step is really looking at different cell types and the viability of tissue growth," says Elisseeff. The researchers are now doing that, and they are also exploring the use of different polymers that could replace PEG and offer more control over cell placement.



Source:

Jennifer Hirsch

Massachusetts Institute of Technology

Protein's Role In Cancer Spread Pinpointed By Study

Edinburgh scientists have identified the way a specific cell protein can trigger the spread of cancer. The study by researchers in the Cell Signalling Unit, University of Edinburgh Cancer Research Centre could pave the way for new drugs which limit the protein's ability to turn a normal cell cancerous.



The protein, MDM2, normally functions to control the activity of a key cancer preventing protein called p53. In some of the body's cells, the biochemical ratio between MDM2 and p53 can become unbalanced causing MDM2 to act as a cancer-promoting agent.



The project's lead investigator, Dr Kathryn Ball, a researcher at the University, explains: "One way in which MDM2 controls the p53 protein is by activating its destruction and we are interested in understanding how this happens at a biochemical level.



"In the current study, funded by Cancer Research UK, we have identified protein fragments which can bind to MDM2, inhibiting its activity. These fragments could be a good template for drugs designed to hinder the role of MDM2 in the p53 destruction pathway. We hope our findings may lead to improved treatments for a broad range of cancer types."



Welcoming the findings, Professor John Toy, medical director at Cancer Research UK, said: "p53 is a crucial protein that acts as a guardian of the normal cell. Its failure to do its job properly is associated with many types of cancer. If p53 is being destroyed by another protein in a cancer cell, then it offers an excellent target when designing new anti-cancer drugs. This research suggests MDM2 is just such a target."







The study is published in the current edition of Molecular Cell.



Contact: Linda Menzies


University of Edinburgh

New Targets For Modification Enzymes Uncovered By Epigenetic Research

Enzymes regulating genetic expression can be just as important as the genome itself, increasing evidence shows. The expanding field of epigenetics focuses on the multiple influences on DNA and surrounding molecules that determine whether genes are turned on or off during development and disease processes.



A consortium of scientists, led by Albert Jeltsch at Jacobs University, Breman, Germany, Yoichi Shinkai at Kyoto University, Japan, and Xiaodong Cheng at Emory University, has now discovered new non-histone targets for one enzyme previously believed to modify only histones--the group of proteins that creates tightly bundled packages of DNA strands. The research is reported online in the journal Nature Chemical Biology.



These modification enzymes, called protein methyltransferases, add methyl groups to lysine amino acids within the histones and change their influence on gene expression. The newly identified non-histone targets add yet another influence on gene expression in addition to the already-known DNA methylation and histone modifications in the epigenome.



The international research team has found that a histone methyltransferase called G9a adds methyl groups to other proteins in addition to histones and changes the behavior of those proteins. The researchers used a peptide array technology called SPOT to identify the new enzyme targets.



"This discovery broadens our view of methyltransferases and tells us that epigenetic regulation in cells is even more complicated than we thought," says principal investigator Xiaodong Cheng, PhD, professor of biochemistry at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar.



"We have known for some time that we had a great deal more to discover about methyltransferases. This is an important piece of the puzzle, and additional research will continue to help us unwind the multiple mechanisms involved in epigenetic gene regulation."







The research was partly supported by the National Institute of General Medical Sciences of the National Institutes of Health.



Source: Holly Korschun


Emory University

The Secret Of Life May Be As Simple As What Happens Between The Sheets--Mica Sheets

That age-old question, "where did life on Earth start?" now has a new answer. If the life between the mica sheets hypothesis is correct, life would have originated between sheets of mica that were layered like the pages in a book.



The so-called "life between the sheets" mica hypothesis was developed by Helen Hansma of the University of California, Santa Barbara, with funding from the National Science Foundation (NSF). This hypothesis was originally introduced by Hansma at the 2007 annual meeting of the American Society for Cell Biology, and is now fully described by Hansma in the September 7, 2010 issue of Journal of Theoretical Biology.



According to the "life between the sheets" mica hypothesis, structured compartments that commonly form between layers of mica--a common mineral that cleaves into smooth sheets--may have sheltered molecules that were the progenitors to cells. Provided with the right physical and chemical environment in the structured compartments to survive and evolve, the molecules eventually reorganized into cells, while still sheltered between mica sheets.



Mica chunks embedded in rocks could have provided the right physical and chemical environment for pre-life molecules and developing cells because:
Mica compartments could have held, protected and sheltered molecules, and thereby promoted their survival. Also, mica could have provided enough isolation for molecules to evolve without being disturbed and still allow molecules to migrate towards one another and eventually bond together to form large organic molecules. And mica compartments may have provided something akin to a template for the production of a life form composed of compartments, which are now known as cells.
Mica sheets are held together by potassium. If high levels of potassium were donated by mica sheets to developing cells, the high levels of potassium found in mica sheets could account for the high levels of potassium currently found in human cells.
Mica chunks embedded in rocks that were sitting in an early ocean would have received an endless supply of energy from waves, the sun, and the occasional sloshing of water into the spaces between the mica sheets. This energy could have pushed the mica sheets into up-and-down motions that could have pushed together molecules sitting between mica sheets, thereby enabling them to bond together.

Because mica surfaces are hospitable to living cells and to all the major classes of large biological molecules, including proteins, nucleic acids, carbohydrates and fats, the "between the sheets" mica hypothesis is consistent with other well-known hypotheses that propose that life originated as RNA, fatty vesicles or primitive metabolisms. Hansma says a "mica world" might have sheltered all the ancient metabolic and fat-vesicle and RNA "worlds."



Hansma also says that mica would provide a better substrate for developing cells than other minerals that have been considered for that role. Why? Because most other minerals would probably have tended to intermittently become either too wet or too dry to support life. By contrast, the spaces between mica sheets would probably have undergone more limited wet/dry cycles that would support life without reaching killing extremes. In addition, many clays that have been considered as potential surfaces for life's origins respond to exposure to water by swelling. By contrast, mica resists swelling and would therefore provide a relatively stable environment for developing cells and biological molecules, even when it did get wet.
















Hansma sums up her hypothesis by observing that "mica would provide enough structure and shelter for molecules to evolve but also accommodate the dynamic, ever-changing nature of life."



What's more, Hansma says that "mica is old." Some micas are estimated to be over 4 billion years old. And micas such as biotite have been found in regions containing evidence of the earliest life-forms, which are believed to have existed about 3.8 million years ago.



Hansma's passion for mica evolved gradually--starting when she began conducting pioneering, NSF-funded research in former husband Paul K. Hansma's AFM lab to develop techniques for imaging DNA and other biological molecules in the atomic force microscope (AFM)--a high-resolution imaging technique that allows researchers to observe and manipulate molecular and atomic level features.



Says Helen Hansma, "Mica sheets are atomically flat, so we can see DNA molecules on the mica surface without having to cover the DNA with something that makes it look bigger and easier to see. Sometimes we can even see DNA molecules swimming on the surface of mica, under water, in the AFM. Mica sheets are so thin (one nanometer) that there are a million of them in a millimeter-thick piece of mica."



Hansma's "life between the sheets" hypothesis first struck her a few years ago, after she and family members had collected some mica from a Connecticut mine. When she put water on a piece of the mica under her dissecting microscope, she noticed a greenish organic 'crud' at some step edges in the mica. "It occurred to me that this might be a good place for the origins of life--sheltered within these stacks of sheets that can move up and down in response to flowing water, which could have provided the mechanical energy for making and breaking chemical bonds," says Hansma.



Hansma says that recent advancements in imaging techniques, including the AFM, made possible her recent research, leading to her "between mica sheets" hypothesis. She adds that direct support for her hypothesis might be obtained from additional studies involving mica sheets in an AFM, being subjected its push-and-pull forces while sitting in liquids resembling an early ocean.



Source:

Lily Whiteman

National Science Foundation

A Method That Captures Cell Growth And Activity Highlighted By Cold Spring Harbor Protocols

This month's issue of Cold Spring Harbor Protocols/ features a cutting-edge method that provides a snapshot of growth and activity patterns in mixed populations of cells. Click here to view the protocol which is freely accessible online.



Written by Ingrid Schmid, a scientist at UCLA (cyto.mednet.ucla/), the protocol involves taking a population of cells and labeling their nucleic acids (DNA and RNA) and cell-surface proteins with specific dyes. Then, using a technique called flow cytometry, scientists can determine the DNA and RNA content of the cells. This allows them to identify the cell-cycle stage of each cell, which provides insight into patterns of cell growth and activity in the population. For example, they can identify which sub-populations of cells are actively dividing and which are not.



Schmid and her colleagues have used the procedure to characterize specific sub-populations of cells in human blood that are involved in the immune response.



This month's issue of Cold Spring Harbor Protocols also includes the related classic technique for the quantification of DNA and RNA in solutions. This essential and routine procedure is used in virtually every laboratory. Click here to view the protocol which is also freely accessible online.







About Cold Spring Harbor Protocols: Cold Spring Harbor Protocols (cshprotocols/) is an online resource of methods used in a wide range of biology laboratories. It is structured to be highly interactive, with each protocol cross-linked to related methods, descriptive information panels, and illustrative material to maximize the total information available to investigators. Each protocol is clearly presented and designed for easy use at the bench -- complete with reagents, equipment, and recipe lists. Life science researchers can access the entire collection via institutional site licenses, and can add their suggestions and comments to further refine the techniques.



About Cold Spring Harbor Laboratory Press: Cold Spring Harbor Laboratory Press is an internationally renowned publisher of books, journals, and electronic media, located on Long Island, New York. Since 1933, it has furthered the advance and spread of scientific knowledge in all areas of genetics and molecular biology, including cancer biology, plant science, bioinformatics, and neurobiology. It is a division of Cold Spring Harbor Laboratory, an innovator in life science research and the education of scientists, students, and the public. For more information, visit cshlpress/.



Source: Maria Smit


Cold Spring Harbor Laboratory

Graphene Could Hold The Key To Speeding Up DNA Sequencing

In a paper published as the cover story of the September 9, 2010 Nature, researchers from Harvard University and MIT have demonstrated that graphene, a surprisingly robust planar sheet of carbon just one-atom thick, can act as an artificial membrane separating two liquid reservoirs.



By drilling a tiny pore just a few-nanometers in diameter, called a nanopore, in the graphene membrane, they were able to measure exchange of ions through the pore and demonstrated that a long DNA molecule can be pulled through the graphene nanopore just as a thread is pulled through the eye of a needle.



"By measuring the flow of ions passing through a nanopore drilled in graphene we have demonstrated that the thickness of graphene immersed in liquid is less then 1 nm thick, or many times thinner than the very thin membrane which separates a single animal or human cell from its surrounding environment," says lead author Slaven Garaj, a Research Associate in the Department of Physics at Harvard. "This makes graphene the thinnest membrane able to separate two liquid compartments from each other. The thickness of the membrane was determined by its interaction with water molecules and ions."



Graphene, the strongest material known, has other advantages. Most importantly, it is electrically conductive.



"Although the membrane prevents ions and water from flowing through it, the graphene membrane can attract different ions and other chemicals to its two atomically close surfaces. This affects graphene's electrical conductivity and could be used for chemical sensing," says co-author Jene Golovchenko, Rumford Professor of Physics and Gordon McKay Professor of Applied Physics at Harvard, whose pioneering work started the field of artificial nanopores in solid-state membranes.



"I believe the atomic thickness of the graphene makes it a novel electrical device that will offer new insights into the physics of surface processes and lead to a wide range of practical application, including chemical sensing and detection of single molecules."



In recent years graphene has astonished the scientific community with its many unique properties and potential applications, ranging from electronics and solar energy research to medical applications.



Jing Kong, also a co-author on the paper, and her colleagues at MIT first developed a method for the large-scale growth of graphene films that was used in the work.



The graphene was stretched over a silicon-based frame, and inserted between two separate liquid reservoirs. An electrical voltage applied between the reservoirs pushed the ions towards graphene membrane. When a nanopore was drilled through the membrane, this voltage channeled the flow of ions through the pore and registered as an electrical current signal.



When the researchers added long DNA chains in the liquid, they were electrically pulled one by one through the graphene nanopore. As the DNA molecule threads the nanopore, it blocks the flow of ions, resulting in a characteristic electrical signal that reflects the size and conformation of the DNA molecule.



Co-author Daniel Branton, Higgins Professor of Biology, Emeritus at Harvard, is one of the researches who, more than a decade ago, initiated the use of nanopores in artificial membranes to detect and characterize single molecules of DNA.



Together with his colleague David Deamer at the University of California, Branton suggested that nanopores might be used to quickly read the genetic code, much as one reads the data from a ticker-tape machine.



As a DNA chain passes through the nanopore, the nucleobases, which are the letters of the genetic code, can be identified. But a nanopore in graphene is the first nanopore short enough to distinguish between two closely neighboring nucleobases.



Several challenges still remain to be overcome before a nanopore can do such reading, including controlling the speed with which DNA threads through the nanopore.



When achieved, nanopore sequencing could lead to very inexpensive and rapid DNA sequencing and has potential to advance personalized health care.



"We were the first to demonstrate DNA translocation through a truly atomically thin membrane. The unique thickness of the graphene might bring the dream of truly inexpensive sequencing closer to reality. The research to come will be very exciting," concludes Branton.



Garaj, Golovchenko, Kong, and Branton's other co-authors on the Nature paper were W. Hubbard in the Harvard School of Engineering and Applied Sciences and A. Reina in the Department of Materials Science and Engineering, MIT. The work was funded by the National Human Genome Research Institute, National Institutes of Health.



Source:

Michael Patrick Rutter

Harvard University

Researchers Pinpoint Neural Nanoblockers In Carbon Nanotubes

Carbon nanotubes hold many exciting possibilities, some of them in the realm of the human nervous system. Recent research has shown that carbon nanotubes may help regrow nerve tissue or ferry drugs used to repair damaged neurons associated with disorders such as epilepsy, Parkinson's disease and perhaps even paralysis.



Yet some studies have shown that carbon nanotubes appear to interfere with a critical signaling transaction in neurons, throwing doubt on the tubes' value in treating neurological disorders. No one knew why the tubes were causing a problem.



Now a team of Brown University researchers has found that it's not the tubes that are to blame. Writing in the journal Biomaterials, the scientists report that the metal catalysts used to form the tubes are the culprits, and that minute amounts of one metal - yttrium - could impede neuronal activity. The findings mean that carbon nanotubes without metal catalysts may be able to treat human neurological disorders, although other possible biological effects still need to be studied.



"We can purify the nanotubes by removing the metals," said Lorin Jakubek, a Ph.D. candidate in biomedical engineering and lead author of the paper, "so, it's a problem we can fix."



Jakubek took single-walled carbon nanotubes to the laboratory of Diane Lipscombe, a Brown neuroscientist. The researchers zeroed in on ion channels located at the end of neurons' axons. These channels are gateways of sorts, driven by changes in the voltage across neurons' membranes. When an electrical signal, known as an action potential, is triggered in neurons, these ion channels "open," each designed to take in a certain ion. One such ion channel passes only calcium, a protein that is critical for transmitter release and thus for neurons to communicate with each other.



In experiments using cloned calcium ion channels in embryonic kidney cells, the scientists discovered that nickel and yttrium, two metal catalysts used to form the single-walled carbon nanotubes, were interfering with the ion channel's ability to absorb the calcium.



Because its ionic radius is nearly identical to calcium's, yttrium in particular "gets stuck and prevents calcium from entering and passing through. It's an ion pore blocker," said Lipscombe, who specializes in neuronal ion channels and is a corresponding author on the paper.



The experiments showed that yttrium in trace amounts - less than 1 microgram per milliliter of water - may disrupt normal calcium signaling in neurons and other electrically active cells, an amount far lower than what had been thought to be safe levels. With nickel, the amount needed to impede calcium signaling was 300 times higher.



"Yttrium is so potent that ... a very low nanotube dose" would be needed to affect neuronal activity, said Robert Hurt, professor of engineering and a corresponding author on the paper.



Jakubek said she was surprised that the metals turned out to be the cause. "Based on the literature, I thought it would be the nanotubes themselves," she said.



Spiro Marangoudakis, Jessica Raingo and Xinyuan Liu contributed to the paper. The National Institutes of Health, the National Science Foundation and the U.S. Environmental Protection Agency funded the research.



Source:
Richard Lewis


Brown University

How Brain Cells Deal With Mathematical Rules

Intelligent behavior requires strategic processing of numbers and abstract quantity information in accordance with internally maintained goals. For instance, we typically adopt a "less than" strategy when shopping for a product to pay the smallest amount of money. When searching for a job, on the other hand, our plan of action is "greater than", and we strive to earn the largest sum of money. In such pragmatic situations, our decisions on quantities are guided by mathematical rules applied to them. They constitute the foundation of mathematical operations and are thus taught to first-graders. Neurobiologists in the laboratory of Andreas Nieder at the University of TГјbingen now showed for the first time how brain cells process simple mathematical rules. The study is published online in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) (January 18.-24. 2010).


Humans are unrivalled in their understanding of numbers and rules, but the foundations of such high-level skills can already be found in the animal kingdom. To get a glimpse of where and how brain cells master such complex tasks, scientists at the Institute of Neurobiology in TГјbingen trained rhesus monkeys to compare set sizes (numerosities) and to switch flexibly between two abstract mathematical rules. The "greater than" rule required the monkeys to release a lever if the first test display showed more dots than the sample display, whereas the "less than" rule required a lever release if the number of items in the test display was smaller compared to the first test display. The monkeys learned the quantitative "greater than/less than"-rule and were able to choose the smaller or greater set size relative to the sample numerosity, independently of the absolute numerosity of the displays. While the animals were performing this task, neurons recorded in the prefrontal cortex of the frontal lobe exhibited interesting activity. Irrespective of the absolute magnitude of the dot sets, the brain cells exclusively represented the mathematical rule at hand. Approximately one half of these neurons were only active whenever the animal followed the "greater than"-rule, whereas the other half preferred the "less than"-rule.


This new study provides valuable insight into the neurobiological foundations of highly abstract thinking that is necessary for mathematical operations. "First of all we want to understand how neurons process mathematical operations" Andreas Nieder explains. "At the same time, our investigations of the number sense are meaningful for assessing the very complex thinking processes that are necessary, for instance, when dealing with numbers." It is the cerebral cortex at the frontal pole of the brain that constitutes the brain's highest cognitive control center. This region of the brain also gives rise to mental activities that build personality. Damage to the frontal lobe (e.g. after injuries or stroke) disturb goal-directed logical thinking and reasoning. The new study provides important clues to how the healthy brain obeys abstract mathematical rules, which in turn will help to elucidate and treat related mental illnesses.


Source: Universitaet Tuebingen

Roche's XCELLigence System Designed To Reduce Animal Testing In Pharmaceutical Development

BOTOX® is an important medicine that over the last 15 years of clinical use has helped millions of patients with serious medical conditions worldwide. Pharmaceutical manufacturers using Clostridium botulinum toxin (BOTOX®) in drugs are required by the Food and Drug Administration (FDA) in the United States and by other worldwide health regulatory agencies to protect patients and consumers by assuring product safety and efficacy through animal testing and other methods.

In a recent study (Biochemica 4/2008, in print), James O'Connell et.al. from ACEA Biosciences in San Diego have used the label-free, real time xCELLigence cell analyzer system to test biological effects of botulinum toxin on live cells. Currently, there is no in vitro assay approved by the USFDA and other international regulatory bodies for the release of Botulinum Toxin A. The preliminary results indicated that the xCELLigence System was able to detect specific biological effects on two CNS-derived cell lines - A172 glioblastoma cell line and SH-SY5Y neuroblastoma cell line. Additional cell lines are currently being evaluated.


According to Dr. O'Connell, the xCELLigence System was also used to identify closely related Clostidrium difficile toxins A and B directly from stool samples using cell culture and specific toxin neutralization with highly specific toxin A and B antibodies. "The test as performed with the xCELLigence System is extremely sensitive and is highly specific. Our preliminary results with botulinum toxin indicate the possibility of replacing the animal test for BOTOX® with a highly sensitive and specific real time, label free cell-based assay on xCELLigence."


"We believe that the combination of the xCELLligence System with other high information content systems such as the 454 and Roche NimbleGen Systems will bring a new level of accuracy and information to in vitro testing that will significantly reduce the number of animal tests required in pharmaceutical development," comments James O'Connell.


In the U.S., BOTOX® (botulinum toxin type A, Allergan, Inc.) is approved for the treatment of four debilitating conditions, including two eye disorders that can lead to functional blindness, cervical dystonia which is a painful movement disorder affecting the head and neck, and excessive underarm sweating. Worldwide, it is approved for twenty different indications in more than seventy-five countries, and the therapeutic use of BOTOX® accounts for the majority of all BOTOX® use.


The safety and efficacy of BOTOX® currently is assessed by using the LD50 Test (Lethal Dose 50%). The LD50 Test involves injecting groups of animals with different doses of a chemical to estimate the dose that kills 50% of them. In the case of BOTOX®, mice are injected with the active ingredient-a form of the same toxin that causes Botulism food poisoning-and the mice experience differing levels of muscular paralysis.


For more information on the technology, please visit xCELLigence.roche.


About Roche


Headquartered in Basel, Switzerland, Roche is one of the world's leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As the world's biggest biotech company and an innovator of products and services for the early detection, prevention, diagnosis and treatment of diseases, the Group contributes on a broad range of fronts to improving people's health and quality of life. Roche is the world leader in in-vitro diagnostics and drugs for cancer and transplantation, and is a market leader in virology. It is also active in other major therapeutic areas such as autoimmune diseases, inflammatory and metabolic disorders and diseases of the central nervous system. In 2007 sales by the Pharmaceuticals Division totalled 36.8 billion Swiss francs, and the Diagnostics Division posted sales of 9.3 billion francs. Roche has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai, and invested over 8 billion Swiss francs in R&D in 2007. Worldwide, the Group employs about 80,000 people. Additional information is available on the Internet at roche.


NIMBLEGEN and XCELLIGENCE are trademarks of Roche.


454 is a trademark of 454 Life Sciences Corporation, Branford, CT, USA, a Roche company.


BOTOX is a trademark of Allergan Inc.


All other brands and product names are trademarks of their respective holders.

roche


View drug information on Botox Cosmetic.

Molecular Hula Hoop

Humans have long been trying to make the dream of nanoscopic robots come true. The dream is, in fact, taking on some aspects of reality. Nanoscience has produced components for molecular-scale machines. One such device is a rotor, a movable component that rotates around an axis. Trying to observe such rotational motion on the molecular scale is an extremely difficult undertaking. Japanese researchers at the Universities of Osaka and Kyoto have now met this challenge. As Akira Harada and his team report in the journal Angewandte Chemie, they were able to get "snapshots" of individual molecular rotors caught in motion.



As the subject of their study the researchers chose a rotaxane. This is a two-part molecular system: A rod-shaped molecule is threaded by a second, ring-shaped molecule like a cuff while a stopper at the end of the rod prevents the ring from coming off. The researchers attached one end of the rod to a glass support. To observe the rotational motions of the cuff around the sleeve, the scientists attached a fluorescing side chain to the cuff as a probe.



To observe the rotation of the ring around the rod, the researchers used a microscopic technique called defocused wide-field total internal reflection fluorescence microscopy. This gave snapshots of individual rotaxane molecules in the form of emission patterns. In simplified terms, if the cuff is motionless, the patterns make it possible to calculate the direction in which the probe emits its fluorescent light. This makes it possible to calculate the orientation of the cuff, which remains constant for every snapshot. However, if the cuff is rotating, the emission pattern does not reveal the spatial orientation of the probe.



The researchers showed that the cuff of the rotaxane does not rotate if the sample is dry. However, when it is wet they can see very rapid rotational and vibrational motion. The cuff rotates faster than the time required to snap a picture: the rotational speed is thus over 360° in 300 milliseconds.







This press release is available in German.



Author: Akira Harada, Osaka University (Japan),
chem.sci.osaka-u.ac.jp/lab/harada/Eng/mem/Lab-m11e.htm

Title: Single-Molecule Imaging of Rotaxanes Immobilized on Glass Substrates: Observation of Rotary Movement

Angewandte Chemie International Edition 2008, 47, No. 32, 6077?, doi: 10.1002/anie.200801431



Source: Akira Harada


Wiley-Blackwell

News From The Journal Of Neuroscience

1. Two RIM1 Isoforms Are Present in Active Zones


Pascal S. Kaeser, Hyung-Bae Kwon, Chiayu Q. Chiu, Lunbin Deng, Pablo E. Castillo, and Thomas C. SГјdhof



Presynaptic active zones comprise many proteins that help to ensure rapid neurotransmitter release near postsynaptic receptors, and modification of some of these proteins produces long-term potentiation or depression. Although most active-zone proteins have been assigned to a specific step in the release process (e.g., vesicle docking, priming, or fusion), the molecular mechanisms involved remain unknown, and additional proteins continue to be discovered. This week, Kaeser et al. report that the gene encoding an active-zone scaffolding protein, RIM1О±, encodes a previously undiscovered second isoform, RIM1ОІ. RIM1О± has several protein-interaction domains that enable it to bind several other active-zone proteins. RIM1ОІ lacks the N-terminal protein interaction domain of RIM1О±, but is otherwise identical. RIM1О± and RIM1ОІ have largely overlapping expression patterns and functions. For example, both molecules appear to influence vesicle release probability at both excitatory and inhibitory synapses. But only RIM1О± appears to be involved in protein-kinase-A-dependent presynaptic long-term plasticity.



2. Crk and CrkL Mediate Reelin Signaling


Tae-Ju Park and Tom Curran



Crk and CrkL are widely expressed adaptor proteins whose function is to bring together tyrosine-phosphorylated proteins and their downstream effectors. Crk and CrkL interact with many proteins and are involved in diverse biological process throughout the body. Park and Curran now suggest that Crk and CrkL are important components of the Reelin signaling cascade in neurons. Deletion of both Crk and CrkL specifically in developing neurons produced a phenotype nearly identical to that of reelin mutations. For example, layer formation, neuronal migration, and dendrite development were severely disrupted in the cerebellum, hippocampus, and cerebral cortex. Reelin, an extracellular secreted protein, binds to lipoprotein receptors, resulting in activation of tyrosine kinases that phosphorylate the protein Disabled-1. Disabled-1 then promotes phosphorylation of the kinase Akt. In Crk/CrkL double-knock-out mice, levels of phosphorylated Disabled-1 were comparable to wild-type, but Akt phosphorylation was reduced, placing Crk/CrkL between Disabled-1 and Akt in the Reelin signaling pathway.



3. Estradiol Decreases Cortical Functional Lateralization


Susanne Weis, Markus Hausmann, Barbara Stoffers, RenГ© Vohn, Thilo Kellermann, and Walter Sturm



The cerebral hemispheres are functionally specialized: the left hemisphere is generally dominant in verbal tasks, whereas the right hemisphere dominates in spatial tasks. This asymmetry is thought to depend on inhibition of the nondominant hemisphere by the dominant hemisphere. The degree of functional lateralization varies across individuals, and females tend to exhibit less asymmetry than males. Furthermore, functional cerebral asymmetries vary in women throughout menstrual cycles, and asymmetries in postmenopausal women are comparable to those in men, suggesting that sex hormones alter interhemispheric inhibition. To test this hypothesis, Weis et al. measured brain activity during a verbal task using functional magnetic resonance imaging in men and in women at two points of the menstrual cycle when estradiol levels differed. As predicted, active regions of the left hemisphere inhibited homotypic areas in the right hemisphere in men and in women when their estradiol levels were low, but the inhibition disappeared when estradiol levels were high.
















4. Near-Infrared Light Protects Retinas from Mitochondrial Damage



Julio C. Rojas, Jung Lee, Joseph M. John, and F. Gonzalez-Lima



Near-infrared light therapy (NILT) increases survival of cultured neurons exposed to various stressors, improves behavioral recovery from stroke in rabbits, and speeds wound healing in humans. These effects are thought to be mediated by upregulation of mitochondrial proteins, endogenous antioxidants, and antiapoptotic proteins such as heat-shock proteins and Bcl-2. This week, Rojas et al. report that NILT greatly reduced retinal damage and associated behavioral deficits produced in rats by the mitochondrial toxin rotenone. NILT prevented rotenone-induced decreases in light sensitivity and greatly reduced thinning of the retinal layers. Interestingly, NILT increased activity of the mitochondrial respiratory protein cytochrome oxidase and of the antioxidant superoxide dismutase throughout the brain, suggesting that the infrared light can penetrate the skull (at least in rats) and induce neuroprotective effects in the brain. Because many neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, involve mitochondrial dysfunction similar to that produced by rotenone, NILT may prove effective in treating these diseases as well.







Please click here for the current table of contents.



Source: Sara Harris


Society for Neuroscience



View drug information on Estradiol Transdermal System.

Scientists Discover Crucial Molecule In Cancer Rejection

Researchers at the Centenary Institute in Sydney have discovered a molecule on the surface of immune cells which plays a critical role in cancer rejection.



Using advanced multi-photon microscopy, the scientists have tracked the migration of immune cells called T cells within tumours in experimental models, and found that the surface molecule (CD44) directly impacts whether a tumour progresses or is rejected by T cells.



Professor Wolfgang Weninger, Head of the Immune Imaging program at Centenary, says this discovery advances our knowledge of the immune processes at play in cancer.



"The immune system and cancer were first linked in the 1900s but it wasn't until the 1980s that interactions between the immune system and cancer cells became a focus for medical researchers," says Professor Weninger.



"We know that migration of T cells within tumours is very important for rejection but we didn't know about how it worked. We found that this particular molecule regulates the navigation of T cells in tumours. In its absence, T cells are inhibited in migration and show a defect in their ability to reject a tumour."



Understanding how tumours avoid the natural processes of the immune system is one of the biggest questions in cancer. Finding the answer could significantly improve cancer treatment.



Professor Weninger explains: "By understanding how the immune system fights tumours, we may be able to optimise cancer therapies in the future. It may provide the opportunity to design treatments that mimic certain aspects of immune responses and cellular processes, making cancer treatments less hit and miss and reducing the toll on patients."



Centenary Institute Executive Director, Professor Mathew Vadas, points out this discovery has been made possible by recent advances in research technology - in particular multi-photon microscopy.



"Previously, cancer researchers could only build assumptions by linking series' of still images of the immune system at work," Professor Vadas says. "Multi-photon microscopy allows us to make real time movies showing exactly how the immune cells interact and is opening up new frontiers for medical research."



Professor Weninger, a world leader in this form of imaging, is driving this research revolution using one of Australia's first multi-photon microscopes at the Centenary Institute in Sydney.



This discovery firmly places Professor Weninger and his team's focus on the next piece of the puzzle - how does the actual process of tumour rejection work?



"This next stage of our research is very exciting. What are the physical interactions of T cells and tumours and how do the T cells actually defeat a tumour?" says Professor Weninger. "If we can get to the bottom of these immune system interplays, the benefits for cancer patients around the world could be truly enormous."







About the Centenary Institute



The Centenary Institute is an independent medical research institute, affiliated with Royal Prince Alfred Hospital and the University of Sydney. Our unique blend of highly skilled staff and state-of-the art equipment and facilities has allowed us to become world leaders in three critical areas of medical research - cancer, cardiovascular disease and infectious diseases. For further information about the Centenary Institute, visit centenary.au/.



Publication reference



Mrass P, Kinjyo I, Ng LG, Reiner SL, PurГ© E, Weninger W. CD44 mediates successful interstitial navigation by killer T cells and enables efficient antitumor immunity. Immunity. 2008 Dec;29(6):971-85.



Source: Erin Sharp


Research Australia

Metallic Nanostructures Enable The Manufacture Of New Security And Medical Sensor Devices

Scientists have designed tiny new sensor structures that could be used in novel security devices to detect poisons and explosives, or in highly sensitive medical sensors, according to research published tomorrow in Nano Letters.



The new 'nanosensors', which are based on a fundamental science discovery in UK, Belgian and US research groups, could be tailor-made to instantly detect the presence of particular molecules, for example poisons or explosives in transport screening situations, or proteins in patients' blood samples, with high sensitivity.



The researchers were led by Imperial College London physicists funded by the Engineering and Physical Sciences Research Council. The team showed that by putting together two specific 'nanostructures' made of gold or silver, they can make an early prototype device which, once optimised, should exhibit a highly sensitive ability to detect particular chemicals in the immediate surroundings.



The nanostructures are each about 500 times smaller than the width of a human hair. One is shaped like a flat circular disk while the other looks like a doughnut with a hole in the middle. When brought together they interact with light very differently to the way they behave on their own. The scientists have observed that when they are paired up they scatter some specific colours within white light much less, leading to an increased amount of light passing through the structure undisturbed. This is distinctly different to how both structures scatter light separately. This decrease in the interaction with light is in turn affected by the composition of molecules in close proximity to the structures. The researchers hope that this effect can be harnessed to produce sensor devices.



Lead researcher on the project Professor Stefan Maier from Imperial's Department of Physics, and an Associate of Imperial's Institute for Security Science and Technology, said:



"Pairing up these structures has a unique effect on the way they scatter light - an effect which could be very useful if, as our computer simulations suggest, it is extremely sensitive to changes in surrounding environment. With further testing we hope to show that it is possible to harness this property to make a highly sensitive nanosensor."



Metal nanostructures have been used as sensors before, as they interact very strongly with light due to so-called localised plasmon resonances. But this is the first time a pair with such a carefully tailored interaction with light has been created.



The device could be tailored to detect different chemicals by decorating the nanostructure surface with specific 'molecular traps' that bind the chosen target molecules. Once bound, the target molecules would change the colours that the device absorbs and scatters, alerting the sensor to their presence. The team's next step is to test whether the pair of nanostructures can detect chosen substances in lab experiments.



Professor Maier concludes: "This study is a beautiful example of how concepts from different areas of physics fertilise each other - in essence our nanosensor system is a classical analogue of electromagnetically induced transparency, a famous phenomenon from quantum mechanics."


Notes:


The research was conducted by the team at Imperial College London in collaboration with IMEC and the Catholic University in Leuven, Belgium, and Rice University in Houston, Texas.



Source:
Danielle Reeves


Imperial College London

Cells' Grouping Tactic Points To New Cancer Treatments

The study, which used embryonic cells, points to a new way of treating cancer where therapy is targeted at the process of cancer cells grouping together. The aim is to stop cancer cells from spreading and causing secondary tumours.



In order for cells to migrate they form protrusions - much like oars of a boat - in the direction that they want to travel. However, if a single cell is isolated it produces these oars in all directions and ends up rowing in circles. To move around effectively cells must stick together before attempting to travel.



The study, published today in the journal Developmental Cell, explains how this process works. Scientists have discovered that when cells group together the contact with other cells inhibits the formation of protrusions or 'oars'. This means that protrusions only form on the cells that are on the outside edges of the group, causing the group to move in specific direction as the group is pushed by the outermost 'leader' cells.



Dr Roberto Mayor, UCL Department of Cell and Developmental Biology and lead author of the research, said, "Being able to form a group with neighbour cells is advantageous for migration of embryonic cells as well as cancer cells during tumour metastasis - they have strength in unity.



"The findings suggest an alternative way in which cancer treatments might work in the future if therapies can be targeted at the process of group formation to stop cancer cells from spreading and causing secondary tumours."



The experiments were carried out using neural crest cells, which are found next to the developing central nervous system in embryos. These cells can develop into a huge variety of different kind of cells including heart, face, skin and muscle cells. Scientists blocked surface molecules, proteins called N-cadherin, on the neural crest cells that are involved in forming contacts between cells. When they did this the power of the cells to group together was lost, along with any ability to migrate.



It is expected that inhibition of N-cadherin would have the same the effect in cancer cells, which also move in groups during metastasis.



The work was funded by the Medical Research Council, the Biotechnology and Biological Sciences Research Council and the Wellcome Trust.



Source:

Clare Ryan


University College London

Genes That Confirm A Connection Between Caloric Restriction And Longevity

For nearly 70 years scientists have known that caloric restriction prolongs life. In everything from yeast to primates, a significant decrease in calories can extend lifespan by as much as one-third. But getting under the hood of the molecular machinery that drives this longevity has remained elusive.



Now, reporting in the journal Cell, researchers from Harvard Medical School, in collaboration with scientists from Cornell Medical School and the National Institutes of Health, have discovered two genes in mammalian cells that act as gatekeepers for cellular longevity. When cells experience certain kinds of stress, such as caloric restriction, these genes rev up and help protect cells from diseases of aging.



"We've reason to believe now that these two genes may be potential drug targets for diseases associated with aging," says David Sinclair, associate professor of pathology at Harvard Medical School and senior author on the paper.



The new genes that Sinclair's group have discovered, in collaboration with Anthony Sauve of Cornell Medical School and Rafael de Cabo of NIH, are called SIRT3 and SIRT4. They are members of a larger class of genes called sirtuins. (Another gene belonging to this family, SIRT1, was shown last year to also have a powerful impact on longevity when stimulated by the red-wine molecule resveratrol.)



In this paper, the newly discovered role of SIRT3 and SIRT4 drives home something scientists have suspected for a long time: mitochondria are vital for sustaining the health and longevity of a cell.



Mitochondria, a kind of cellular organ that lives in the cytoplasm, are often considered to be the cell's battery packs. When mitochondria stability starts to wane, energy is drained out of the cell, and its days are numbered. In this paper, Sinclair and his collaborators discovered that SIRT3 and SIRT4 play a vital role in a longevity network that maintains the vitality of mitochondria and keeps cells healthy when they would otherwise die.



When cells undergo caloric restriction, signals sent in through the membrane activate a gene called NAMPT. As levels of NAMPT ramp up, a small molecule called NAD begins to amass in the mitochondria. This, in turn, causes the activity of enzymes created by the SIRT3 and SIRT4 genes--enzymes that live in the mitochondria--to increase as well. As a result, the mitochondria grow stronger, energy-output increases, and the cell's aging process slows down significantly. (Interestingly, this same process is also activated by exercise.)



"We're not sure yet what particular mechanism is activated by these increased levels of NAD, and as a result SIRT3 and SIRT4," says Sinclair, "but we do see that normal cell-suicide programs are noticeably attenuated. This is the first time ever that SIRT3 and SIRT4 have been linked to cell survival."



In fact, the mitochondria appear to be so essential to the cell's life that when all other energy sources inside the cell--including the nucleus--are wiped out, yet the mitochondria are kept intact and functional, the cell remains alive.
















"Mitochondria are the guardians of cell survival," says Sinclair. "If we can keep boosting levels of NAD in the mitochondria, which in turn stimulates buckets more of SIRT3 and SIRT4, then for a period of time the cell really needs nothing else."



Sinclair and his colleagues have coined a phrase for this observation: the Mitochondrial Oasis Hypothesis.



SIRT3 and SIRT4 may now also be potential drug targets for diseases associated with aging. For example, in recent years scientists have become increasingly aware of the importance of mitochondrial function in treating diseases such as cancer, diabetes, and neurodegeneration.



"Theoretically, we can envision a small molecule that can increase levels of NAD, or SIRT3 and SIRT4 directly, in the mitochondria," says Sinclair. "Such a molecule could be used for many age-related diseases."



According to Suave of Cornell, "This study also highlights how advanced technological methods can help resolve fundamental biological questions in ways that were hard to achieve as recently as a few years ago."







This study is supported by the National Institutes of Health and the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging. Sinclair and Suave are consultants to Sirtris Pharmaceuticals, a company aiming to treat diseases by modulating sirtuins. Sinclair is also a cofounder of Sirtris Pharmaceuticals and sits on their advisory board and board of directors.



Full Citation:

Cell, Volume 130, Issue 5, September 21, 2007

"Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival"

Hongying Yang(1,6), Tianle Yang(2), Joseph A. Baur(1), Evelyn Perez(3), Takashi Matsui(5), Juan J. Carmona(1), Dudley W. Lamming(1), Nadja C. Souza-Pinto(4), Vilhelm A. Bohr(4), Anthony Rosenzweig(5), Rafael de Cabo(3), Anthony A. Sauve(2), and David A. Sinclair(1)



1-Department of Pathology, Paul F. Glenn Laboratories, Harvard Medical School, Boston, MA

2-Department of Pharmacology, Weill Medical College of Cornell University, New York, NY

3-Laboratory of Experimental Gerontology

4-Laboratory of Molecular Gerontology, National Institute on Aging, Institutes of Health, Baltimore, MD

5-Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA

6-Present address: Sirtris Pharmaceuticals, Cambridge, MA



Harvard Medical School (hms.harvard) has more than 7,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, The CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.



Source: Davic Cameron


Harvard Medical School

Study Suggests Antioxidants Are Unlikely To Prevent Aging

Diets and beauty products which claim to have anti-oxidant properties are unlikely to prevent ageing, according to research funded by the Wellcome Trust. Researchers at the Institute of Healthy Ageing at UCL (University College London) say this is because a key fifty year old theory about the causes of ageing is wrong.



"Superoxide" free radicals - oxygen molecules that have an imbalance of electrons to protons - are generated in the body through natural processes such as metabolism. These free radicals can cause oxidation in the body, analogous to rust when iron is exposed to oxygen. Biological systems, such as the human body, are usually able to restrict or repair this damage.



In 1956, Denham Harman proposed the theory that ageing is caused by an accumulation of molecular damage caused by "oxidative stress", the action of reactive forms of oxygen, such as superoxide, on cells. This theory has dominated the field of ageing research for over fifty years. But now, a study published online today in the journal Genes & Development suggests that this theory is probably incorrect and that superoxide is not a major cause of ageing.



"The fact is that we don't understand much about the fundamental mechanisms of ageing," says Dr David Gems from UCL. "The free radical theory of ageing has filled a knowledge vacuum for over fifty years now, but it just doesn't stand up to the evidence."



Dr Gems and colleagues at the Institute of Healthy Ageing studied the action of key genes involved in removing superoxide from the bodies of the nematode worm C. elegans, a commonly-used model for research into ageing. By manipulating these genes, they were able to control the worm's ability to "mop up" surplus superoxide and limit potential damage caused by oxidation.



Contrary to the result predicted by the free radical theory of ageing, the researchers found that the lifespan of the worm was relatively unaffected by its ability to tackle the surplus superoxide. The findings, combined with similar recent findings from the University of Texas using mice, imply that this theory is incorrect.



"One of the hallmarks of ageing is the accumulation of molecular damage, but what causes this damage?" says Dr Gems. "It's clear that if superoxide is involved, it only plays a small part in the story. Oxidative damage is clearly not a universal, major driver of the ageing process. Other factors, such as chemical reactions involving sugars in our body, clearly play a role."



Dr Gems believes the study suggests that anti-ageing products which claim to have anti-oxidant properties are unlikely to have any effect.



"A healthy, balanced diet is very important for reducing the risk of developing many diseases associated with old age, such as cancer, diabetes and osteoporosis," he says. "But there is no clear evidence that dietary antioxidants can slow or prevent ageing. There is even less evidence to support the claims of most anti-ageing products."



The research was welcomed by Dr Alan Schafer, Head of Molecular and Physiological Sciences at the Wellcome Trust.



"With increasing lifespan comes greater exposure and vulnerability to the ageing process," comments Dr Schafer. "Research such as this points to how much we have to learn about ageing, and the importance of understanding the mechanisms behind this process. This new study will encourage researchers to explore new avenues in ageing research."







Source: Craig Brierley


Wellcome Trust

Scientists Discover Trigger That Deploys Geckos' Amazing Grip

Geckos are very adept at climbing through difficult terrain using an intricate adhesive system. Until now it has not been known when and how they switch on their unique system of traction.



Scientists at the University of Calgary and Clemson University in South Carolina have discovered that the geckos' amazing grip is triggered by gravity.



This latest development in gecko adhesive research will be published Aug. 5 by Anthony Russell of the U of C and Tim Higham of Clemson in the online edition of the Proceedings of the Royal Society B.



"Geckos use microscopic, hair-like filaments to attach to surfaces. Only at certain angles do they switch on their traction system, however," says Russell, a biological sciences professor at the U of C. "We are trying to understand this process, which will help in mimicking it for application to robotics."



Geckos have long been known for their remarkable abilities to move on smooth surfaces such as glass. This study adds a new angle to previous research: geckos must be on an incline in order to trigger the deployment of their adhesive system.



"Much has been learned in recent years about the mechanism by which clinging takes place, but little is known about how geckos determine when to use this ability," says Higham, a former U of C student and now an assistant professor of biological sciences at Clemson. "We show that perception of body orientation determines when the adhesive system is switched on."



The scientists discovered that the tipping point which turns on the gecko's adhesive system is 10 degrees. Three of the six geckos studied applied their adhesive system on a 10 degree slope. At 30 degrees all six applied the system. The three that applied the traction at 10 degrees slowed down, the three that didn't were much quicker.



"There are costs, in terms of speed, and benefits, in terms of traction, associated with this switch just as there are for Formula 1 cars when rain tires are employed instead of slicks when circumstances place a premium on grip over outright speed," says Russell.



In the case of the geckos, the intricate way that the toes are used in order to achieve the grip necessary to climb is responsible for slowing them.



Russell and Higham are both evolutionary biologists and study animals in their natural environment as well as in the lab. Insights gained through basic research assist them in designing experiments through an appreciation of how evolution has crafted its own solutions to complex problems.



The goal of Russell's research is to try to understand this complex traction system and to apply this knowledge to the development of commercial applications.



The results could be used in such areas as space exploration, medical procedures, military applications such as bomb disposal, and purposes as simple as hanging pictures on walls.



Source:
Leanne Yohemas


University of Calgary

How Ubiquitin Chains Are Added To Cell-Cycle Proteins Could Lead To The Development Of Targeted Cancer Therapies

Researchers from the California Institute of Technology (Caltech) have been able to view in detail, and for the first time, the previously mysterious process by which long chains of a protein called ubiquitin are added by enzymes called ubiquitin ligases to proteins that control the cell cycle. Ubiquitin chains tag target proteins for destruction by protein-degrading complexes in the cell.



"We found that ubiquitin ligases build ubiquitin chains very rapidly by transferring ubiquitins one at a time," says Raymond Deshaies, professor of biology at Caltech and Howard Hughes Medical Institute investigator.



Their findings, and the innovative process by which they were obtained, are described in this week's issue of the journal Nature.



Ubiquitin is one of nature's most unusual proteins. Unlike most of its protein brethren, ubiquitin has to be physically attached to other proteins to do its job.



"As its name implies, ubiquitin is found in essentially every kind of eukaryotic cell," says Caltech graduate student Nathan Pierce, the Nature paper's lead author.



In their Nature paper, the Caltech team looked at the process of ubiquitylation, the method by which ubiquitin and ubiquitin chains are added to target proteins. The target proteins used in the study, cyclin E and ОІ-Catenin, are both involved in controlling the cell cycle.



It was already known, Pierce explains, that the addition of a chain of four or more ubiquitins to a target protein marks that protein for annihilation. The destruction of cyclin E is critical for the accurate replication of DNA, while the degradation of ОІ-Catenin keeps cells from dividing during development at the wrong time. If ОІ-Catenin is not degraded, cells proliferate excessively and become predisposed to tumorigenesis. Meanwhile, cells that don't degrade cyclin E accumulate DNA damage and mutations, which can help fuel the unchecked growth of a tumor.



It was also already known that ubiquitin chains are added to the protein using three different enzymes, dubbed E1, E2, and E3. Simply put, E1 activates ubiquitin for transfer, then passes it over to E2. E3 then gets into the act. A form of E3 called a RING ligase (RING stands for "really interesting new gene") plays a key role in the tagging of cyclin E and ОІ-Catenin; according to Pierce, the RING ligase "simultaneously binds to E2 and the target protein (like cyclin E), and then causes E2 to transfer the ubiquitin to the target protein."



Despite all of this knowledge, one question has remained: is the chain transferred to the protein in an already assembled form, or are the ubiquitins moved over one at a time?



"The process is so complicated and so fast," Pierce notes, "that we weren't able to see how the chain is actually built."



To address that issue, Pierce created a sort of biological stop-motion animation that allowed the Caltech team to watch every step in the transfer of ubiquitin from E2 onto the cyclin E protein substrate.
















"We devised methods to take snapshots of ubiquitin ligase reactions at a rate of up to 100 'pictures' every second," says Deshaies. "This enables us to see things that would normally evade detection. "



Previous studies had looked at the reaction on the scale of seconds or minutes, Pierce adds. But through an innovative use of a laboratory tool called a quench-flow machine - a machine that allows for extreme precision in the stopping, or "quenching," of a reaction - the team was able to look at what was going on over intervals of just 10 milliseconds in both yeast and human proteins.



"Prior methods did not have sufficient time resolution to see what was going on," says Deshaies. "It's as if you gave an ice-cream cone to a kid and took pictures every minute. You would see the ice cream disappear from the first photo to the next, but since the pictures are too far apart in time, you would have no idea whether the child ate the ice cream one bite at a time, or swallowed the entire scoop in one gulp."



The new method revealed the biological equivalent of small, single bites of ice cream. "Using our approach," Deshaies says, "we could see that our ubiquitin ligase builds ubiquitin chains one ubiquitin at a time."



"Once we knew what the steps were, we calculated the rates at which they occur," adds Pierce. "And from those rates, we were able to really describe the biology of how this system works."



The quest doesn't stop there, of course. "One thing we have to understand now is, how do ubiquitin ligases achieve the speeds that they do?" asks Deshaies. "What special mechanisms do they have to enable them to build chains rapidly? And the flip side of the coin: What sets the speed limit? Why can't our ubiquitin ligase work even faster?"



A recent paper published in the journal Cell by Gary Kleiger, a postdoctoral scholar in the Deshaies lab, answered some of these speed-related questions. By measuring the rates at which E2 and E3 interacted with one another, Kleiger was able to demonstrate their unusually fast association - faster than predicted for normal proteins. E2 and E3 use oppositely-charged surfaces to attract each other, thereby speeding up the formation of a functional complex of the two proteins. This helps explain how the rapid sequential additions of ubiquitin described in the Nature paper are possible.



Gaining these kinds of insights into the ubiquitin system is important, Deshaies says, because ubiquitin ligases play a critical role in a number of human diseases, including cancer, due to their role in the regulation of the cell cycle.



"Once we understand these aspects of how ubiquitin ligases work, and what limits their speed, we will be in an excellent position to think about how we might develop drugs that attack the ligase's Achilles' heel, to make its slowest step even slower," he says. "If we can slow down ubiquitin ligases enough, they may become too slow to get their job done - to build chains - in the time available to them to do so. Being able to develop drugs to block their function would open up a new frontier in medicine."



"We were able to invent HIV therapeutics because we understand how reverse transcriptase works," adds Pierce. "The same applies here. We need to understand how these enzymes work if we're ever going to be able to target them with therapeutics."



In addition to Pierce and Deshaies, other researchers involved in the study included Kleiger and Shu-ou Shan, assistant professor of chemistry at Caltech.



The work described in the Nature paper, "Detection of Sequential Polyubiquitylation on a Millisecond Time-Scale," was funded by a Gordon Ross Fellowship, National Institutes of Health training and research grants, and the Howard Hughes Medical Institute.



Source: Lori Oliwenstein


California Institute of Technology

Study Reveals A Reprogrammed Role For The Androgen Receptor In Adndrogen-independent Prostate Cancer

The androgen receptor a protein ignition switch for prostate cancer cell growth and division is a master of adaptability. When drug therapy deprives the receptor of androgen hormones, thereby halting cell proliferation, the receptor manages to find an alternate growth route. A new study by Dana-Farber Cancer Institute and Ohio State University scientists demonstrates how.


The shift from androgen-dependent to androgen-independent cell growth occurs, in part, because the androgen receptor switches on an entirely different set of genes in the latter group than in the former, the researchers report in the July 24 issue of Cell. In contrast to androgen-dependent prostate tumors, androgen-independent ones experience an uptick in the activity of genes that control cell division, or mitosis. One such gene, called UBE2C, which causes cells to ignore a natural pause in the division process, becomes especially active, the researchers report. This pause, or "checkpoint," ensures that cell division progresses normally; without it, daughter cells may grow even more aggressively and be harder to stop.


"The evolution of prostate cancer from an androgen-dependent state to an androgen-independent one is a key step in its progression," says study senior author Myles Brown, MD, of Dana-Farber. "The discovery that the androgen receptor directs a distinct gene pathway in androgen-independent prostate cancers may lead to the identification of genes in that pathway that can be targeted by future therapies."


Prostate cancers whose growth is fed by androgen are commonly treated with androgen-blocking drugs. Such medications can hold the disease in check for a period of time that varies from patient to patient, but the tumor almost invariably gains the ability to grow without external androgen.


One of the ways such cells re-start their growth is by producing their own androgen, scientists have discovered. Another way involves the androgen receptor itself the "keyhole" in the cell nucleus that androgen molecules fit into but the actual mechanism by which it operates hasn't been known.


To find that mechanism, Brown's team, including co-lead authors Qianben Wang, PhD, now of Ohio State, and Wei Li, PhD, now of Baylor College of Medicine, charted the activity levels, or expression, of genes controlled by the androgen receptor in androgen-dependent and androgen-independent prostate cancer cells. In the androgen-independent cells, they found a group of genes with epigenetic markings tiny attachments to DNA that switchs genes on and off that caused them to be especially active. The genes form a completely separate pathway from the one active in androgen-dependent cells.


It's not known what causes those epigenetic changes to occur, but "we are profiling the genome-wide epigenetic landscape of androgen-dependent and -independent cancers, trying both experimental and computational methods to identify additional regulators," says study co-senior author X. Shirley Liu, PhD, of Dana-Farber.


"The androgen receptor clearly works by an entirely different program in androgen-dependent and -independent cancers," says Wang. "Having discovered that program, we'll be in a better position to understand how it operates and how gene-targeted therapies may shut it down."


The study was supported by grants from the National Institutes of Health, the U.S. Department of Defense, and the Prostate Cancer Foundation.


Co-authors of the study include Yong Zhang, PhD, Kexin Xu, PhD, Mathieu Lupien, Meredith Regan, ScD, Clifford Meyer, PhD, Arjun Kumn Manrai, Michelangelo Fiorentino, MD, PhD, Christopher Fiore, Massimo Loda, MD, and Philip Kantoff, MD, Dana-Farber; Rameen Beroukhim, MD, PhD, Dana-Farber and the Broad Institute of Harvard and MIT; Zhong Chen, PhD, Ohio State; Xin Yuan, MD, PhD, Hongyun Wang, PhD, and Steven Balk, MD, PhD, Beth Israel Deaconess Medical Center, Boston; Jindan Yu, PhD, Rohit Mehra, MD, Bo Han, and Arul Chinnaiyan, MD, PhD, University of Michigan; Tao Wu, PhD, Harvard Medical School; Jason Carroll, PhD, Cambridge Research Institute in the United Kingdom; Olli Janne, MD, PhD, University of Helsinki; Mark Rubin, MD, Weill Cornell Medical College; and Lawrence True, MD, University of Washington.


Source: Dana-Farber Cancer Institute

Methods To Screen Genomes And Analyze Evolution Featured In Cold Spring Harbor Protocols

Identifying genes that are important in specific tissues or processes in the mouse used to be a monumental task. New technologies and strategies have simplified this search, making it effective for even the smallest laboratories. This month's issue of Cold Spring Harbor Protocols (cshprotocols/TOCs/toc4_08.dtl) highlights a method for screening the mouse genome using ENU mutagenesis. The method, "Mouse Mutagenesis Using N-ethyl-N-nitrosourea (ENU)," was submitted by Monica Justice and colleagues from the Baylor College of Medicine (bcm/db/db_fac-justice.html). In her laboratory, Justice uses this "forward genetics" method to identify genes that may play a role in human disease. In particular, Justice's lab focuses on the process of hematopoiesis, the development of blood cells. Mutations in these genes can lead to leukemias or lymphomas. The method is freely accessible on the website for Cold Spring Harbor Protocols (cshprotocols/cgi/content/full/2008/5/pdb.prot4985).



The second featured protocol for April is a guide for selecting the proper method for analyzing evolutionary relationships between genes. In "Choosing a Method for Phylogenetic Prediction," David Mount from the University of Arizona (bmcb.biology.arizona/mount.html) provides a step by step process to determine which of the major methods one should use for predicting "phylogeny", the relatedness among gene sequences. The method is freely accessible on the website for Cold Spring Harbor Protocols (cshprotocols/cgi/content/full/2008/5/pdb.ip49).







About Cold Spring Harbor Protocols: Cold Spring Harbor Protocols (cshprotocols/) is a monthly peer-reviewed journal of methods used in a wide range of biology laboratories. It is structured to be highly interactive, with each protocol cross-linked to related methods, descriptive information panels, and illustrative material to maximize the total information available to investigators. Each protocol is clearly presented and designed for easy use at the bench - complete with reagents, equipment, and recipe lists. Life science researchers can access the entire collection via institutional site licenses, and can add their suggestions and comments to further refine the techniques.



About Cold Spring Harbor Laboratory Press: Cold Spring Harbor Laboratory Press is an internationally renowned publisher of books, journals, and electronic media, located on Long Island, New York. Since 1933, it has furthered the advance and spread of scientific knowledge in all areas of genetics and molecular biology, including cancer biology, plant science, bioinformatics, and neurobiology. It is a division of Cold Spring Harbor Laboratory, an innovator in life science research and the education of scientists, students, and the public. For more information, visit cshl/.



Source: David Crotty


Cold Spring Harbor Laboratory

Government Takes Further Action On Substances As Part Of World-Leading Chemicals Management Plan

The Honourable Tony Clement, Minister of Health, and the Honourable John Baird, Minister of the Environment, released preliminary findings for 19 chemical substances identified as high priorities for action under Batch 3 of the Chemicals Management Plan.


"The goal of our world-leading Chemicals Management Plan is to protect the health of Canadians from potentially harmful substances," said Minister Clement. "By identifying four substances that are potentially 'toxic' to human health in this latest batch of substances, the Government is continuing to deliver results for Canadians and meet the commitments we established when the Chemicals Management Plan was launched in 2006."


"Canadians are increasingly concerned about their environmental legacy," said Minister Baird. "This is another example of how our Government, through the Chemicals Management Plan, is taking real action to reduce the presence of harmful chemicals in our environment and protecting it for future generations."


Out of the 19 substances assessed, four are proposed "toxic" to human health. In addition, the Government is also proposing to create a provision for four other substances so that any proposed new use of these substances (which are no longer used or are used in extremely low quantities in Canada) would be subject to notification of the federal government. With this provision the government would be able to set conditions or prohibit the use of these substances if their use would increase exposure to Canadians or environmental organisms.


Following the extensive assessment, the 11 remaining substances are proposed "not toxic."


The notices containing summaries of draft screening assessment reports for all Batch 3 substances will be published in Canada Gazette, Part I on August 23.


Public summaries, which contain information about how all Batch 3 substances are used in Canada are available on the new Chemicals At A Glance Web page. The draft screening assessments as well as risk management scope documents for Batch 3 substances proposed "toxic" can be found on the Chemicals Management Plan Web site. Interested parties can submit comments on these documents until October 23, 2008. Final screening assessments for Batch 3 substances will be published on or before February 21, 2009.


Health Canada

Human Derived Stem Cells Can Repair Rat Hearts Damaged By Heart Attack

When human heart muscle cells derived from embryonic stem cells are implanted into a rat after a heart attack, they can help rebuild the animal's heart muscle and improve function of the organ, scientists report in the September issue of Nature Biotechnology. The researchers also developed a new process that greatly improves how stem cells are turned into heart muscle cells and then survive after being implanted in the damaged rat heart. The findings suggest that stem-cell-based treatments might one day help people suffering from heart disease, the leading cause of death in most of the world.


The study was conducted by researchers at the University of Washington School of Medicine in Seattle and at Geron Corp. in Menlo Park, Calif. The scientists set out to tackle two of the main challenges to treating damaged hearts with stem cells: the creation of cardiac cells from embryonic stem cells, and the survival of those cells once they are implanted in a damaged heart.


"Past attempts at treating infarcted hearts with stem cells have shown promise, but they have really been hampered by these challenges," explained Dr. Chuck Murry, director of the Center for Cardiovascular Biology in the UW Institute for Stem Cell and Regenerative Medicine, and corresponding author on the study. "This method we developed goes a long way towards solving both of those problems. We got stem cells to differentiate into mostly cardiac muscle cells, and then got those cardiac cells to survive and thrive in the damaged rat heart."


Embryonic stem cells can differentiate, or turn into, any type of cell found in the body. But researchers had struggled to get stem cells to differentiate into just cardiomyocytes, or heart muscle cells -- most previous efforts resulted in cell preparations in which only a fraction of 1 percent of the differentiated cells were cardiac muscle cells. By treating the stem cells with two growth factors, or growth-encouraging proteins, and then purifying the cells, they were able to turn about 90 percent of stem cells into cardiomyocytes.


The researchers dealt with the other big challenge of stem cell death by implanting the cells along with a cocktail of compounds aimed at helping them grow. The cocktail included a growth "matrix"-- a sort of scaffolding for the cells to latch on to as they grow -- and drugs that block processes related to cell death. When using the pro-growth cocktail, the success rate of heart muscle grafts improved drastically: 100 percent of rat hearts showed successful tissue grafts, compared to only 18 percent in grafts without the cocktail.


"The problem of cell death is pretty common in stem-cell treatments," Murry explained. "When we try to regenerate with liquid tissues, like blood or bone marrow, we're pretty good at it, but we haven't been very successful with solid tissues like skeletal muscle, brain tissue, or heart muscle. This is one of the most successful attempts so far using cells to repair solid tissues -- every one of the treated hearts had a well-developed tissue graft."


When the researchers followed up on the stem-cell treatment by taking images of the rat hearts, they found that the grafts helped thicken the walls that normally stretch out after a heart attack and cause the heart to weaken. The thickened walls were also associated with more vigorous contraction.


"We found that the grafts didn't just survive in the rat hearts -- they also helped improve the function of the damaged heart," said Dr. Michael Laflamme, UW assistant professor of pathology and the lead author of the study. "That's very important, because one of the major problems for people suffering a myocardial infarction is that the heart is damaged and doesn't pump blood nearly as well. This sort of treatment could help the heart rebound from an infarction and retain more of its function afterwards."


The next step in studying stem-cell treatments for the heart is to conduct similar experiments in large animals, like pigs or sheep, while further refining the treatment in rats. Early human clinical trials could begin in about two years, Murry said.


University of Washington