The Benefits Of Multiple Mates

New research could explain why females of many species have multiple partners. Published on Friday 21 November 2008 in leading journal Science, the study was carried out by a team from the Universities of Exeter (UK), Okayama (Japan) and Liverpool (UK).



Females of most species, including many mammals, mate with multiple partners. The driving forces for this practice, known as 'polyandry', have been a mystery for evolutionary biologists for decades. This research suggests that polyandry could be the result of females adapting to avoid producing offspring carrying selfish genetic elements that reduce male fertility.



The research team based the study on the fruitfly Drosophila pseudoobscura, which they bred over ten generations. Some males of this species carry a 'selfish gene' on their X chromosome that causes sperm carrying the Y-chromosome to fail. This means that males carrying this gene can only produce daughters, all of which carry the sperm damaging gene.



In this study females evolved to mate with more partners when they were exposed to males carrying this selfish gene. There was no way for the females to tell whether or not a potential mate carried the gene, but they evolved to re-mate more quickly. After ten generations, they re-mated after an average of 2.75 days, compared with 3.25 days among the original population. By mating more frequently, females ensure sperm from different males compete. This competition favours males without the sperm-damaging selfish genes, allowing females to bias paternity against these males.



Corresponding author Dr Nina Wedell of the University of Exeter said: "Multiple mating by females has puzzled biologists for decades. It's more risky and costs precious time and energy for females. Our study suggests that these significant costs are worthwhile because the female increases her chances of producing healthy offspring of both sexes that do not carry the selfish gene."



Selfish genes occur at random as a result of mutations. They spread quickly through populations because they subvert normal patterns of inheritance, increasing their presence in the next generation.



The researchers believe the findings have relevance for a range of species with polyandrous females, including some primates. Dr Nina Wedell explains: "Selfish genetic elements exist in all living organisms and many compromise male fertility. Our study could provide a new explanation for why polyandry is so remarkably widespread."



At this stage the researchers do not know what implications these findings might have for understanding human reproduction. However, it is possible that some types of male fertility disorder are caused by the manipulation of selfish genes.







This study was funded by the Natural Environment Research Council.



Source: Sarah Hoyle


University of Exeter

Commercial Sense And Sensor Abilities From DegraSense Ltd.

A new company, DegraSense Ltd, has been established to develop a point of care dental diagnostic that could improve the treatment of periodontal disease and other inflammatory conditions.



The new Queen Mary spin out aims to commercialise novel protease biosensor technology developed from the research activities of Dr Steffi Krause from the School of Engineering and Materials Science, and Dr Mike Watkinson from the School of Biological and Chemical Sciences.



Drs Krause and Watkinson believe there are potential applications for the biosensor technology in a range of industries including environmental and food testing, but they will initially focus on developing a non-invasive sensor capable of monitoring inflammation and bacterial infection. The initial application will be the diagnosis and treatment of periodontal disease, estimated to cost the NHS ВЈ250 million per year.



There are currently no accurate clinical methods for dentists to distinguish between active and dormant sites in periodontal disease progression. DegraSense plans to develop a low cost, disposable biosensor that will enable a dentist to identify areas of active inflammation immediately prior to treatment. This will enable more efficient targeting of expensive and labour intensive surgical treatment for patients with gum disease.



Dr Krause, who has been appointed founder Director of the new company said: "This is a new and exciting prospect. It brings together a number of years of research and the involvement of industrial partners so we can push forward towards a product that can make a real difference to dental treatment everywhere. The diagnosis of periodontal disease should reduce the incidences of invasive and uncomfortable dental procedures to the patient and at the same time should bring significant savings both to the patient and the health care provider."






Queen Mary, University of London



Queen Mary is one of the leading colleges in the federal University of London, with over 13,000 undergraduate and postgraduate students, and an academic and support staff of around 2,600. Queen Mary is a research university, with over 80 per cent of research staff working in departments where research is of international or national excellence (RAE 2001). It has a strong international reputation, with around 20 per cent of students coming from over 100 countries.



The College has 21 academic departments and institutes organised into three sectors: Science and Engineering; Humanities, Social Sciences and Laws; and the School of Medicine and Dentistry. It has an annual turnover of ВЈ200 million, research income worth ВЈ43 million, and it generates employment and output worth nearly ВЈ400 million to the UK economy each year.



Queen Mary's roots lie in four historic colleges: Queen Mary College, Westfield College, St Bartholomew's Hospital Medical College and the London Hospital Medical College.



Source: Sian Halkyard


Queen Mary, University of London

Biological Clue In Brain Tumour Development

Scientists at The University of Nottingham have uncovered a vital new biological clue that could lead to more effective treatments for a children's brain tumour that currently kills more than 60 per cent of young sufferers.



Clinician-scientists at the University's Children's Brain Tumour Research Centre, working on behalf of the Children's Cancer and Leukaemia Group (CCLG), have studied the role of the WNT biological pathway in central nervous system primitive neuroectodermal tumours (CNS PNET), a type of brain tumour that predominantly occurs in children and presently has a very poor prognosis.



In a paper published in the British Journal of Cancer, they have shown that in over one-third of cases, the pathway is 'activated', suggesting that it plays a role in tumour development. The research also highlighted a link between WNT pathway activation and patient survival - patients who had a CNS PNET tumour that was activated survived for longer than those without pathway activation.



The reason for the link between WNT pathway activation and better patient prognosis is as yet unclear. It could be that these tumours represent a less aggressive subset or that pathway activation itself actually harms the tumour. However, the pathway could represent an important new target for the treatment of more effective drugs, with fewer side effects.



Senior author Professor Richard Grundy, from the Children's Brain Tumour Research Centre, said: "The principal aim of our research is to reduce the morbidity and mortality of children with central nervous system tumours through improved understanding of tumour biology. Following on from this, we need to translate this knowledge into effective new treatments for brain tumours through the development and assessment of accurately targeted treatments that will cause fewer side effects than conventional chemotherapy or radiotherapy and be more effective. The ultimate aim is to develop 'drugs' that target just the abnormal genes in cancer cells, rather than the current norm which involves the indiscriminate destruction of dividing cells which might be healthy or malignant. Overall, this is an important finding in a poorly understood, poor prognosis disease, which we hope, in time, will lead to the development of new treatments for CNS PNETs.



"We hope our findings will lead to a more detailed understanding of CNS PNETS, which is crucial if we are to ensure each child receives the most appropriate treatment for their disease and that we reduce the number of children in which their cancer recurs."



In total, around 450 children and young adults under 18 years are diagnosed with a brain tumour each year in the UK. Overall, 60 per cent of children with the cancer in the UK can be successfully treated, but survival for CNS PNETs is less than 40 per cent.



Notes:



Funding was provided by the Connie and Albert Taylor Trust, The Samantha Dickson Brain Tumour Trust, the Brain Tumour Research Fund Birmingham Children's Hospital Special Trustees.















The paper, An Investigation of WNT Pathway Activation and Association with Survival in Central Nervous System Primitive Neuroectodermal Tumours (CNS PNET) by HA Rogers, S Miller, J Lowe, M-A Brundler, B Coyle and RG Grundy is published in the latest edition of the British Journal of Cancer.



About the Children's Cancer and Leukaemia Group



Cancer Research UK is the major funding provider of the Children's Cancer and Leukaemia Group and funds the UK clinical trials work of the group in 21 paediatric centres throughout the British Isles. The Children's Cancer and Leukaemia Group is the national professional body responsible for the organisation, treatment and management of virtually all children with cancer in the UK. The group is acknowledged as one of the world's leading childhood cancer clinical trial groups who have made a significant contribution to the international success in treating childhood cancer, resulting in improvements in survival.



British Journal of Cancer



The BJC is owned by Cancer Research UK. Its mission is to encourage communication of the very best cancer research from laboratories and clinics in all countries. Broad coverage, its editorial independence and consistent high standards have made BJC one of the world's premier general cancer journals. bjcancer.



The University of Nottingham



The University of Nottingham is ranked in the UK's Top 10 and the World's Top 100 universities by the Shanghai Jiao Tong (SJTU) and Times Higher (THE) World University Rankings.



More than 90 per cent of research at The University of Nottingham is of international quality, according to RAE 2008, with almost 60 per cent of all research defined as 'world-leading' or 'internationally excellent'. Research Fortnight analysis of RAE 2008 ranks the University 7th in the UK by research power. In 27 subject areas, the University features in the UK Top Ten, with 14 of those in the Top Five.



The University provides innovative and top quality teaching, undertakes world-changing research, and attracts talented staff and students from 150 nations. Described by The Times as Britain's 'only truly global university', it has invested continuously in award-winning campuses in the United Kingdom, China and Malaysia. Twice since 2003 its research and teaching academics have won Nobel Prizes. The University has won the Queen's Award for Enterprise in both 2006 (International Trade) and 2007 (Innovation - School of Pharmacy), and was named 'Entrepreneurial University of the Year' at the Times Higher Education Awards 2008.



Nottingham was designated as a Science City in 2005 in recognition of its rich scientific heritage, industrial base and role as a leading research centre. Nottingham has since embarked on a wide range of business, property, knowledge transfer and educational initiatives (science-city) in order to build on its growing reputation as an international centre of scientific excellence. The University of Nottingham is a partner in Nottingham: the Science City.



Source: Emma Thorne


University of Nottingham

The Shapes of Life: NIGMS Project Yields More Than 1,000 Protein Structures

The Protein Structure Initiative (PSI), a national program aimed at determining the three-dimensional shapes of a wide
range of proteins, has now determined more than 1,000 different structures. These structures will shed light on how proteins
function in many life processes and could lead to targets for the development of new medicines.



The PSI is a 10-year, approximately $600 million project funded largely by the National Institute of General Medical Sciences
(NIGMS), part of the National Institutes of Health. The first half of this project-a pilot phase that started in 2000-has
centered on developing new tools and processes that enable researchers to quickly, cheaply, and reliably determine the shapes
of many proteins found in nature.



"One thousand protein structures is a significant milestone for the PSI, and it shows an impressive return on the investment
in the technology and methods for rapid structure determination," said Jeremy M. Berg, Ph.D., director of NIGMS. "These
structures are interesting in their own right and provide the basis for modeling many important proteins."



Some of the newly determined structures are of proteins found in plants, mice, yeast, and bacteria, including the pathogenic
types that cause pneumonia, anthrax, and tuberculosis.



The nine PSI pilot centers have transformed protein structure determination from a mostly manual process to a highly
automated one. Robotic instruments rapidly clone, express, purify, crystallize, and analyze many proteins simultaneously,
cutting the time it takes to determine a single protein structure from months to days. For example, a robotic arm drops
protein solution into thousands of tiny wells for crystallization trials, and an imaging system quickly scans the wells
looking for signs of crystal formation-key to capturing protein structures.



"At this large scale, it would be unthinkable to do all these steps by hand," said John Norvell, Ph.D., director of the PSI
at NIGMS and a scientist trained in protein structure determination. He noted that some robotics and automated tools have
been refined and are now marketed by companies for general structural biology applications.



As the PSI pilot centers have put automated structure determination pipelines in place, the number of protein structures they
have solved has increased significantly. In the second, third, and fourth years of the pilot phase, the centers in aggregate
reported 109, 217, and 348 structures, respectively. Now, halfway through the fifth year, they've surpassed a total of 1,000.
Many of these structures are very different from previously known structures, said Norvell.



The findings contribute to the initiative's ultimate goal of providing structural information on 4,000-6,000 unique proteins
that represent the variety found in organisms ranging from bacteria to humans. Researchers can use these structures, which
are determined experimentally, to build computer models of the structures of other proteins with related amino acid
sequences.
















Although the main focus of the second phase of the PSI will be on solving protein structures, Norvell said there will be
continued development of new technology: "As we reach for higher-hanging fruit-protein structures that are more complex and
harder to solve-we will need to develop additional tools and methods."



As part of the PSI effort, all the structures determined by the centers are collected, stored, and made publicly available by
the Protein Data Bank (PDB), rcsb/pdb, a repository of
three-dimensional biological structure data.



"The protein structures solved by the PSI are more than a scientific stamp collection," explained Norvell. "They will help
researchers better understand the function of proteins, predict the shape of unknown proteins, quickly identify targets for
drug development, and compare protein structures from normal and diseased tissues." In general, a broad range of biomedical
researchers will benefit from the PSI's technical advances, experimental data, and availability of new materials, such as
reagents.



"There are a lot of proteins that are incredibly important to understanding human biology and medicine, yet we know very
little about most of them," said Norvell. "The PSI will provide important information about these molecules so vital to
life."



The nine pilot centers participating in the first phase of the PSI are:


-- The Berkeley Structural Genomics Center, strgen


-- The Center for Eukaryotic Structural Genomics, uwstructuralgenomics


-- The Joint Center for Structural Genomics, jcsg


-- The Midwest Center for Structural Genomics, mcsg.anl


-- The New York Structural Genomics Research Consortium, nysgrc


-- The Northeast Structural Genomics Consortium, nesg


-- The Southeast Collaboratory for Structural Genomics, secsg


-- The Structural Genomics of Pathogenic Protozoa Consortium, sgpp


-- The TB Structural Genomics Consortium, doe-mbi.ucla/TB


The pilot phase of the PSI will end in mid-2005. Centers for the second phase will be announced in July 2005.



In addition to NIGMS, the PSI currently receives funding from the National Institute of Allergy and Infectious Diseases, a
component of the National Institutes of Health.



For more information about the PSI, please visit nigms.nih/psi. To schedule an interview with Jeremy M. Berg, Ph.D., or John Norvell,
Ph.D., please contact the NIGMS Office of Communications and Public Liaison at 301-496-7301.



NIGMS is one of the 27 components of NIH, the premier federal agency for biomedical research. The NIGMS mission is to support
basic biomedical research that lays the foundation for advances in disease diagnosis, treatment and prevention.


Emily Carlson - carlsonenigms.nih

NIH/National Institute of General Medical Sciences

Neurons That Control Obesity In Fruit Flies Pinpointed By Caltech Researchers

A team of scientists from the California Institute of Technology (Caltech) have pinpointed two groups of neurons in fruit fly brains that have the ability to sense and manipulate the fly's fat stores in much the same way as do neurons in the mammalian brain. The existence of this sort of control over fat deposition and metabolic rates makes the flies a potentially useful model for the study of human obesity, the researchers note.



Their findings were published in the August 13 issue of the journal Neuron.



By manipulating neural activity in fruit fly brains using transgenic techniques, the researchers found that, "just as in mammals, fly fat-store levels are measured and controlled by specific neurons in the brain," says Caltech postdoctoral scholar Bader Al-Anzi, the Neuron paper's first author. "Silencing these neurons created obese flies, while overactivating them produced lean flies."



Mammalian brains are given information about the body's fat stores by hormones such as leptin and insulin, and respond to that information by inducing changes in food intake and metabolism to maintain a constant body weight. The researchers found that similar behavioral and metabolic changes occurred in the fruit flies, though which changes occurred depended on which of the two sets of newly identified neurons was silenced.



For instance, silencing one group of neurons led to an increase in food intake, a decrease in metabolism, and an increase in the synthesis of fatty acids (the building blocks of fat). Silencing the other group led to a similar decrease in metabolism and increase in fatty-acid synthesis, as well as to a defect in the flies' ability to utilize their fat stores.



Increasing activity in either of the groups of neurons, on the other hand, resulted in depletion of fat stores by increasing the flies' metabolism and decreasing their synthesis of fatty acids.



The next step is to "see exactly how neurons regulate fat storage, and how the two different groups of neurons identified in this study work," says Kai Zinn, professor of biology at Caltech, who led the research group. "They clearly regulate fat storage using different mechanisms."



The paper is the result of research originally led by Caltech biologist Seymour Benzer, a pioneer in the study of genes and behavior. Zinn continued this research after Benzer's death in late 2007.



"The goal was to establish a model system for obesity in humans," Zinn explains. "This could, at some point, eventually define new drug targets."



The search for a model system is critical, adds Al-Anzi. With obesity on the rise - statistics say that more than a third of adults in Western society are overweight - efforts to find its roots in human brains or human genes have similarly increased. Unfortunately, Al-Anzi notes, these efforts "have not been extremely successful."
















In addition, says Al-Anzi, "While mammalian models such as the mouse have provided progress in the field, they tend to be difficult and expensive research subjects."



Thus, he notes, "The obesity research field would benefit greatly if another model organism could be used, one that is accessible for easy, fast, and affordable biomedical research methods. We believe the fruit fly can be such an organism.



"There is a surprising amount of overlap between the simple fruit fly and more complex mammals in many basic biological processes," Al-Anzi adds. "This is why it's an excellent model system for exploring such medically relevant issues as Alzheimer's disease, alcoholism, and addiction. Our results thus far suggest that body-weight regulation will be no different."



Having now established that fruit flies are indeed similar to mammals in the way they control fat deposition via the brain, researchers can begin to test antiobesity dietary or drug treatments on flies whose fat-regulating neurons have been silenced. "Treatments that cause these flies to return to normal body weight could then be retested for their effectiveness in a mammalian obesity model," Al-Anzi notes.



Knowing the neurons involved in the regulation of fat storage could also lead to identifying the genes that allow for the critical communications between the brain and the fat stores. "This can be done by identifying the genes that are selectively expressed only in those neurons," he explains.



In addition, this research should help researchers determine if the mechanisms behind appetite and body-weight regulation in fruit flies have been conserved over evolutionary time and throughout the animal kingdom. "This has been shown to be the case for genes that regulate behavioral phenomena like learning and circadian rhythms," notes Al-Anzi, "and we hope that body-weight and appetite regulation will be no different."



In addition to Al-Anzi, Zinn, and Benzer, other authors on the Neuron paper, "Obesity-blocking neurons in Drosophila," include Caltech research technician Viveca Sapin; Christopher Waters, formerly of Caltech; and biologist Robert Wyman from Yale University.



Their research was supported by a Life Sciences Research Foundation grant provided by Bristol-Myers Squibb to Al-Anzi, and by a National Institutes of Health RO1 grant to Benzer.



Source:
Lori Oliwenstein


California Institute of Technology

Rice, Iowa state biologists search for 'half-fusion'

Every living cell is surrounded by a membrane, a thin barrier that separates the genetic machinery of life from the
non-living world outside. Though barriers, membranes are not impervious. Cells use a complex hierarchy of proteins that work
in concert to allow cell membranes to fuse - with other cells or with membrane-encased packages of proteins and other
chemicals that the cell needs to take in or release.


Though well-studied, the molecular details of membrane fusion remain mysterious. In particular, scientists don't understand
how holes form between two membranes, but a new study by biochemists at Rice University and Iowa State University offers
intriguing new clues about the nature of this process. The study is published in this month's issue of Nature Structural and
Molecular Biology.


"Membrane fusion is one of the most basic processes of life," said James McNew, assistant professor of biochemistry and cell
biology at Rice University. "It begins at fertilization and occurs billions of times a second in our bodies, and if it ever
stops, we die."


For example, inside the cells in our brains, spines and nerves, membranes are used to seal up and transport tiny packets of
signaling chemicals from the center of the cell to the outer cell membrane. These packets, or vesicles, wait just inside the
cell membrane for the appropriate signal, and once they receive it, they fuse with the membrane and eject their contents into
the surrounding tissue, causing an immediate chain reaction that keeps our hearts beating and allows us to move our muscles.
Membrane fusion is also used to initiate disease.


"Some invading organisms like enveloped viruses use the fusion process to infect the cell," McNew said.


To understand membrane fusion, it helps to envision the basic structure of membranes. Just five billionths of meter across,
membranes are bilayers, meaning they contain two separate layers, or sheets of fatty acids. Each of these sheets has a one
side that is strongly attracted to water and one side that strongly repels it. The water-hating sides of the sheets stick
tightly to one another, sealing out water on either side of the bilayer.


Additionally, all biological membranes are dotted with proteins, and some of these are called transmembrane proteins, meaning
parts of them penetrate through the membrane like a needle through cloth. A large body of evidence suggests that a class of
transmembrane proteins called SNAREs are responsible for driving membrane fusion during normal cellular activity. Exactly how
they do this is unknown, but previous studies have suggested two possibilities.


One model proposes that the portion of the SNARE protein that crosses the membrane forms a pore-like connection that mixes
both layers of the membrane in one step. The other theory suggests that the SNARE proteins mix the two separate layers of a
membrane one at a time, generating an intermediate stated called "hemifusion" or half-fusion. During hemifusion, the outer,
water-loving sides of two membranes become connected, and the inner water-loving layers do not. In this state, the combining
cells or vesicles could transfer proteins and other material stuck to their outside layers, but they do not exchange any
material that's locked inside. Hemifusion has been observed in non-biological membranes containing no proteins, but has been
difficult to detect with SNARE proteins.


McNew and his Iowa State colleagues, Yeon-Kyun Shin, Zengliu Su, Fan Zhang and Yibin Xu, developed an ingenious method of
tagging both inner and outer portions of the synthetic membranes with fluorescent dyes so they could use fluorescence
spectroscopy to assay mixing of the inner and outer layers.


McNew and colleagues sought to find out if hemifusion was an intermediate fusion state in biological systems, so they created
a test system that contained a lipid bilayer studed with SNARE proteins taken from bakers yeast. Using both normal SNAREs and
a mutant variety, they were able to show that membrane fusion catalyzed by the SNARE machinery mixes the outer layer of the
membrane separately from the inner layer -- a hallmark of hemifusion -- suggesting that a hemifusion intermediate can exist
in biological systems and may well be the mechanism that all living cells utilize.


Preliminary data from follow-up studies indicate that these results are also generalizable to SNARE proteins from animals.



The research was funded by the National Science Foundation, the Welch Foundation and the National Institutes of Health.



CONTACTS: Jade Boyd

jadeboydrice

713-348-6778

Rice University

Mike Krapfl

mkrapfliastate

515-294-4917

Iowa State University

iastate

Molecular Memories Mark Males From Females

Medical Research Council scientists have found that males and females have different ways of remembering things.



In a test, male mice learned to avoid a dangerous situation better than females. In other tasks, there was no difference in learning performance, but there were different molecules in the brain being used to form the memories.



The work will help scientists to understand memory-related diseases, which affect the sexes to different extents.



"There's clear evidence now from our studies that at the molecular level there is a sex difference," said Professor Peter Giese, who led the study. "Our science would suggest that males and females simply use different memory processes."



Professor Giese describes his research in an MRC podcast. This work at the Institute of Psychiatry, King's College London, was supported by the MRC.



In the task, the team placed mice in a chamber and attempted to train them to avoid a potentially dangerous situation. They subjected the animals to a mild electric shock to their feet while playing them an audio signal.



Compared with females, a higher proportion of males learned to physically freeze when they were returned to the chamber and then exposed to the sound signal, associating this environment and the tone with danger. This ability to learn was absent in genetically-engineered male mice - but not female mice - which lacked a certain brain protein involved in the regulation of memory genes.



"We think that we have a window into understanding the molecular basis of sex differences in memory formation," said Professor Giese.



The protein, called CaMKK, may function abnormally in some brain diseases and cognitive disorders. This finding could help to understand why some brain diseases affect different proportions of women and men, such as Alzheimer's disease, schizophrenia and learning disabilities.



The protein CaMKK has a role in the process believed to underlie what happens in the brain when a memory is laid down and stored. This model of learning, established in 1973 by MRC-funded researcher Dr Tim Bliss at the National Institute for Medical Research (NIMR), is called long-term potentiation.



Dr Bliss said: "If long-term potentiation is the basis of memory, then one might predict that in animal models of Alzheimer's disease there should be an impairment of long-term potentiation. In many cases there is."



MRC scientists have found that mice with Down's syndrome - a symptom of which in humans is impaired learning ability - have deficits in long-term potentiation and memory. In 2005, a team at NIMR created a model of a Down's syndrome by engineering a mouse which contains an extra chromosome, the cause of the syndrome in humans, press release.



Dr Bliss said: "In most mouse models of Alzheimer's disease, there is an impairment in long-term potentiation. This is also true in models of neurodegenerative and other sorts of diseases in which memory is affected, including Down's syndrome as we recently showed."


Background


Professor Giese published his findings in the following papers:


Calcium/calmodulin kinase kinases ОІ has a male-specific role in memory formation.
Mizuno et al. (2007).
Neuroscience, 145, 393.



Sex-dependent up-regulation of two splicing factors, Psf and Srp20, during hippocampal memory formation.
Antunes-Martins et al. (2007).
Learn. Mem. 14, 693.



Ca2+/calmodulin kinase kinase О± is dispensable for brain development but is required for distinct memories in male, though not in female, mice.
Mol. Cell. Biol. 26, 9094.



The Medical Research Council funds excellent science with the aim of improving human health. Its work ranges from science at the molecular level to public health research carried out in universities, hospitals and a network of units and institutes. The MRC works closely with the Health Departments, the National Health Service and industry to take account of the public's needs. The results have led to some of the most significant discoveries in medical science and benefited millions of people in the UK and around the world.

Medical Research Council

Stealth Armour For Slow Release Microscopic Drug Vesicles, Created By Chemists, Inspired By Plankton

The ability of some forms of plankton and bacteria to build an extra natural layer of nanoparticle-like armour has inspired chemists at the University of Warwick to devise a startlingly simple way to give drug bearing polymer vesicles (microscopic polymer based sacs of liquid) their own armoured protection.



The Warwick researchers have been able to decorate these hollow structures with a variety of nanoparticles opening a new strategy in the design of vehicles for drug release, for example by giving the vesicle "stealth" capabilities which can avoid the body's defences while releasing the drug.



Advances in polymerisation have led to a surge in the creation of vesicles made from polymer molecules. Such vesicles have interesting chemical and physical properties which makes these hollow structures potential drug delivery vehicles.



The University of Warwick team were convinced that even more strength, and interesting tailored properties, could be given to the vesicles if they could add an additional layer of colloidal armour made from a variety of nanoparticles.



Lead researcher on the University of Warwick team Associate Professor Stefan Bon said:



"We took our inspiration from nature, in how it adds protection and mechanical strength in certain classes of cells and organisms. In addition to the mechanical strength provided by the cytoskeleton of the cell, plants, fungi, and certain bacteria have an additional cell wall as outermost boundary. Organisms that particularly attracted our interest were those with a cell wall composed of an armour of colloidal objects - for instance bacteria coated with S-layer proteins, or phytoplankton, such as the coccolithophorids, which have their own CaCO3-based nano-patterned colloidal armour"



The Warwick researchers hit on a surprisingly simple and highly effective method of adding a range of different types of additional armour to the polymer based vesicles. One of those armour types was a highly regular packed layer of microscopic polystyrene balls. This configuration meant the researchers could design a vesicle which had an additional and precise permeable reinforced barrier for drug release, as a result of the crystalline-like ordered structure of the polystyrene balls.



The researchers also succeeded in using the same technique to add a gelatine-like polymer to provide a "stealth" armour to shield vesicles from unwanted attention from the body's immune system while it slowly released its drug treatment. This particular coating (a poly((ethyl acrylate)-co-(methacrylic acid)) hydrogel) absorbs so much surrounding water into its outer structure that it may be able to fool the body's defence mechanism into believing it is in fact just water.



The Warwick researchers had the idea of simply giving their chosen colloidal particles, or latex, based armour the opposite charge to that of the polymer vesicles, to bind them together. This turned out to be even more effective and easy to manipulate and tailor than they even they had hoped for. However the researchers needed a new way of actually observing the vesicles to see if their plan had worked. Previous observational methods required researchers to dry out the vesicles before examining then under an electron microscope - but this seriously deformed the vesicles and thus provide little useful data. However the University of Warwick had recently acquired a cryo electron microscope thanks to funding from the Science City programme. This allowed the research team to quickly freeze the vesicles to -150oc preserving the vesicles shape before observation by the electron microscope. This revealed that the researchers' simple charge based method had worked exactly as planned.


Notes:


The research has just been published in a paper entitled Polymer Vesicles with a Colloidal Armor of Nanoparticles by Rong Chen, Daniel J. G. Pearce, Sara Fortuna, David L. Cheung, and Stefan A. F. Bon* Department of Chemistry, University of Warwick in the current Journal of the American Chemical Society.



Source:

Dr.Stefan A. F. Bon


University of Warwick

Discovering new regulators of the immune system

Contact: Gemma Bradley

pressbiomedcentral

44-207-323-0323

BioMed Central


London, U.K. and South San Francisco, CA. In an attempt to find new regulators of the immune system, a team of researchers at Rigel Pharmaceuticals, Inc. have created a successful method for discovering molecules that are involved in signalling pathways.


As published this week in the Journal of Biology, the team conducted a functional genome-wide screen and discovered novel modulators of T-cell receptor signalling that could aid in the development of drugs that target the immune response.


T cells are an integral part of the immune response. Helper T cells encourage antibody-producing B cells to replicate and secrete antibodies, and play a role in the inflammatory response. Cytotoxic T cells identify and kill cells that have been infected with viruses.


As all these functions are initiated by T-cell receptors, each response must be determined by the particular set of downstream signalling components that are activated. Until now, identifying novel components of these pathways has been slow.

As the article notes, the researchers believe that this study demonstrates, 'a successful approach for discovering and validating, in a functionally relevant context, important immune regulators on a genome-wide scale.'



The research team, led by Dr. Charlene Liao, as part of a collaboration with Novartis, used retroviruses to carry into cells lymphoid genes that regulate T-cell receptor signalling when expressed.

Normally, a cell surface marker called CD69 is up regulated when T-cell receptors are activated. However, the researchers selected cells that, when given a new gene to express, failed to up regulate this protein.


They then checked that this repression was caused by the introduced gene and was not a side effect of the procedure. After three rounds of selection, 33 individual genes were cloned. Some of these were already known to play a role in the immune response, some already had unrelated functions assigned to them, and others were completely novel.



The Rigel team carried out additional experiments on three of the genes that were identified in the screen to verify their functional relevance.

These experiments confirmed that the genes EDG1, PAK2, and the previously unidentified TRAC-1 were normally expressed in the lymphoid system and that truncated versions of the proteins they produce could repress T-cell receptor signalling in T-cells.



The authors write: 'This approach provides a tool for functional cloning of regulators in numerous signal transduction pathways. […] Importantly, the outlined strategy, which requires no prior sequence information of the players involved, does not bias the search to previously known signalling molecules, molecules flagged by DNA-array technologies or signalling molecules discovered in other contexts.'



Once published, this article will be freely available online, in keeping with BioMed Central's policy of open access to research articles:
















Systematic Identification of Regulator Proteins Critical for T Cell activation
Peter Chu, Jorge Pardo, Haoran Zhao, Connie C Li, Erlina Pali, Mary M Shen, Kunbin Qu, Simon X Yu, Betty C B Huang, Peiwen Yu, Esteban S Masuda, Frank Kolbinger, Gregorio Aversa, Jan de Vries, Donald G Payan and X Charlene Liao.

Journal of Biology 2:21

jbiol/content/2/3/21

Published 15th September 2003


Please publish the URL in any news report so that your readers will be able to read the original paper.



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Journal of Biology (jbiol) is published by BioMed Central (biomedcentral), an independent online publishing house committed to providing immediate free access to peer-reviewed biological and medical research. This commitment is based on the view that open access to research is essential to the rapid and efficient communication of science. In addition to open-access original research, BioMed Central also publishes reviews and other subscription-based content.



About Rigel Pharmaceuticals, Inc. (rigel)

Rigel's mission is to become a source of novel, small-molecule drugs to meet large, unmet medical needs. Rigel has identified three lead product development programs: mast cell inhibition to treat immunologic diseases such as asthma/allergy and autoimmune disorders, antiviral agents to treat hepatitis C, and ligases, a new class of cancer drug targets. Rigel has begun clinical testing of its first product candidate, R112, for allergic rhinitis, and plans to begin clinical trials of three additional drug candidates, for the treatment of hepatitis C, rheumatoid arthritis, and asthma by the end of 2004.



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City Planners Could Learn A Lesson Or Two From Tiny Cells On How To Maximize Traffic Flow

Researchers at the University of Illinois at Chicago have found that intra-cellular trafficking is tightly coordinated for maximum flow through cellular compartments -- much as vehicles on a crowded road are allowed to pass quickly through a succession of green traffic lights.



The molecular mechanism that underlies this coordination is reported by lead researcher Nava Segev, UIC professor of biological sciences, in the November issue of Nature Cell Biology.



While the finding was made using yeast cells, intra-cellular mechanisms discovered in yeast almost invariably correspond to processes in mammalian cells, including humans, and the mechanism Segev described may find applicability in the biomedical field.



"Every system in our body depends on intra-cellular trafficking, because anything that goes from the inside of a cell to the outside, or from outside to inside, uses this process," Segev said. "Malfunctioning of this pathway can cause a variety of human diseases. For example, problems in insulin secretion or presentation of insulin-receptors on the cell membrane result in diabetes. Defects in growth factor secretion and presentation of their receptors on cells result in cancer. Defects in neurotransmitter release or internalization result in brain disorders."



A special set of proteins is responsible for the coordination. Molecular switches that go by the letters Ypt allow membrane-enclosed vesicles to pass in and out of cellular compartments. Activator proteins flip the switches on. One activator protein, called TRAPP, coordinates two Ypt switches for quick entrance and subsequent exit from a central cellular compartment known as the Golgi apparatus.



"The Golgi is a central station in all cells, through which all intra-cellular traffic passes," Segev explained.



Specific subunits of TRAPP previously identified by the UIC researchers were found to be the key to coordinated switching and traffic flow through the Golgi. They have now shown that components of TRAPP act in sequence to direct the flow. One form of TRAPP turns on the first Ypt for entry into the Golgi, while at the other end of the Golgi, two subunits join TRAPP to activate the Ypt required for exit from the Golgi, Segev said.



Segev said the mechanism that her lab identified must now be shown to exist in mammalian cells. Her earlier discovery of the Ypt molecular switches in yeast and the subsequent finding of their homologues in mammalian cells, together with the fact that TRAPP is conserved in evolution from yeast to man, lead her to believe the entire coordinated switching mechanism is universal.







Principal co-authors of the paper are Nadya Morozova and Yongheng Liang, both post-doctoral researchers at UIC. Some key reagents were provided by colleagues in the department of cellular and molecular medicine at the University of California, San Diego.



Contact: Paul Francuch


University of Illinois at Chicago

Finding New Ways To Disarm Deadly South American Hemorrhagic Fever Viruses

New World hemorrhagic fevers are emerging infectious diseases found in South America that can cause terrible, Ebola-like symptoms. Current treatments are expensive and only partially effective.



Now, Howard Hughes Medical Institute (HHMI) researchers have discovered exactly how one type of New World hemorrhagic fever virus latches onto and infects human cells, offering a much-needed lead toward new treatments.



"New World hemorrhagic fevers are nasty, serious, and often fatal diseases," says Stephen C. Harrison, an HHMI investigator at Harvard Medical School and senior author of the report, published March 7, 2010, in Nature Structural & Molecular Biology. "The need for new interventions is high."



Arenaviruses, the infectious agents that cause New World hemorrhagic fevers, circulate naturally in rodents and can infect people who are in close contact with the animals. Symptoms include severe inflammation and bleeding from the mouth, nose, eyes, and other orifices. Most outbreaks occur in rural regions of Bolivia, Venezuela, Argentina, and Brazil. "The outbreaks of New World hemorrhagic fever tend to be brief and brutal, with mortality rates of 20 to 30 percent," says Jonathan Abraham, an M.D./Ph.D. candidate at Harvard University and first author of the paper. "These viruses aren't a huge public health issue yet, but you could say the New World hemorrhagic fevers are an emerging disease threat."



Researchers have known about these viruses since the 1960s, but the molecular basis of the disease has only been tackled recently, says Abraham, whose graduate studies are funded by HHMI through a Gilliam Fellowship for Advanced Study. The Gilliam Fellowships program currently supports the doctoral education of 30 exceptional students from disadvantaged backgrounds.



In 2007, Abraham was working with Boston Children's Hospital virologist Hyeryun Choe when he was co-first author on a report in Nature identifying the human cell surface receptor that the Machupo virus, an arenavirus, grabs to gain access to the human cell it is infecting. The receptor, called transferrin receptor 1, offers a handhold for Machupo virus as it invades cells in the body. Nearly every human cell displays the transferrin receptor, which ferries iron into cells.



Abraham then brought the project to Harrison, who had mentored the young scientist in 2004 as part of HHMI's Exceptional Research Opportunities Program (EXROP), which places undergraduate students from disadvantaged backgrounds in the laboratories of HHMI investigators and HHMI professors. The pairing was fortuitous. In Choe's laboratory, Abraham had developed methods to produce the Machupo virus surface protein, which links to the human transferrin receptor. Meanwhile, Harrison had stocks of purified transferrin receptor because he had previously worked to image the molecule and understood its molecular structure.
















Together, the pair made batches of the Machupo surface protein bound to the transferrin receptor and then set about creating an image showing how the two molecules connected. They used x-ray crystallography, a technique in which protein crystals are bombarded with x-ray beams. As the x-rays pass through and bounce off of atoms in the crystal, they produce a diffraction pattern, which can then be analyzed to determine the three-dimensional shape of the protein. After a data collection trip to the powerful x-ray beam at Argonne National Laboratory in Illinois, Abraham and Harrison were able to examine the atomic structure of the Machupo surface protein attached to the transferrin receptor.



The images show that the Machupo surface protein binds to the transferrin receptor in a surprising way - using a loop called the apical domain. The biological function of this loop in humans is unknown, Harrison says. Other segments of the receptor bind iron-bearing transferrin, but the apical domain appears to be uninvolved in that process. "We don't know the normal function of the apical domain. Obviously it didn't evolve just to give Machupo virus a way to infect humans, but that's what the virus has evolved to latch onto," he says.



Because the apical domain is not involved in the critical task of moving iron into cells, Harrison says it presents an attractive target for drugs. In theory, an antibody designed to attach to the apical domain would prevent the Machupo virus from attaching to cells, blocking infection. One possible treatment strategy, then, would be to infuse patients with such an antibody during the early stages of infection, which might slow the infection enough to let patients recover.



Harrison says the finding might also help virologists predict which of the 22 known arenaviruses might be capable of infecting humans. Only five are known to infect humans now - and all of those bind to the human transferrin receptor. Presumably the other 17 viruses produce surface proteins that are unable to bind to the human transferrin receptor, Harrison says.



For Abraham, the idea of finding a treatment for these New World hemorrhagic fevers is close to his heart. His family hails from Haiti, where there is a "huge burden of infectious diseases. I'd like to dedicate my career to studying pathogens in underserved parts of the world," he says.



Source:

Andrea Widener

Howard Hughes Medical Institute

Gene regulates major immune response in plants

Researchers at Yale have identified a gene that regulates the major immune response in plants, programmed cell death
(PCD), according to a recent report in the journal Cell.


To protect themselves from viruses, plants create a zone of dead cells around an infection site that prevents the infection
from spreading. Savithramma Dinesh-Kumar, associate professor of Molecular, Cellular and Developmental Biology at Yale and
his colleagues discovered how the plants keep from killing themselves after they turn on the cell-suicide PCD process.



Dinesh-Kumar first developed a technique for silencing or inactivating plant genes -- a technique that is now used by several
research groups. His group studies the interaction between plants and viruses using tobacco as a model system.


They identified and silenced a "pro-survival" gene, BECLIN-1, that is important in the PCD response. When BECLIN-1 is active,
infection is localized to a small number of cells that later die and form discrete brown lesions on the leaves. When the gene
is inactivated, the plant can no longer regulate PCD, leading to cell death throughout the leaf and plant.


PCD has been described in virtually all cell types, both plant and animal. It is an important aspect of many biological
processes including immune system function, embryonic development and elimination of defective cells. Failure of PCD can
result in devastating diseases such as cancer, Alzheimer's and AIDS.


"This work gives us a better understanding of how plants fend off microbial attacks through carefully controlled destruction
of infected cells," said James Anderson, of the Division of Genetics and Developmental Biology at the National Institute of
General Medical Sciences (NIGMS). "Like other studies carried out in model organisms, these findings shed light on similar
processes that occur in mammals, and may eventually be used to better human health."


Collaborators in the research include Yule Liu and Michael Schiff at Yale, Kirk Czymmek at Delaware Biotechnology Institute,
Zsolt Tallуczy at Columbia University and Beth Levine at Texas Southwestern.The work was supported by grants from the
National Institutes of Health (NIGMS / NIAID) and a NSF Plant Genome grant.


Citation: Cell 121: 567-577, (May 20, 2005).


Janet Rettig Emanuel

janet.emanuelyale

Yale University

yale

Physics Research With Atomic Force Microscope Could Lead To Better Health Care

Where biology, chemistry and physics intersect, a Kansas State University professor expects to find applications to improve human health.



Robert Szoszkiewicz, an assistant professor of physics at K-State, is continuing research on molecules both singularly and as a group. His study of proteins as a single molecule shows promise to help scientists understand the causes of diseases like some cancers. Meanwhile, his research on bunched molecules could lead to a more efficient way to identify antibodies in blood.



Szoszkiewicz's research on proteins began at Columbia University and some of it was published in June in Nature Chemistry magazine. He and his former colleagues looked at the unexpected complexity in the dynamics of stretching and breaking of a single chemical bond between two atoms embedded in a protein. A cleavage of that particular bond has been precisely signaled by unfolding and elongation of a part of a protein.



"There is lots of potential for this research to really address issues of major importance in biology because this will be related to particular pathways through which some kinds of diseases, cancers and biological processes develop," he said. "And, we can study that on the very molecular level by studying the single proteins involved and stretching them and seeing how this contributes to the overall picture."



The research uses an atomic force microscope, a tool involving a cantilever with a sharp tip that under certain circumstances becomes attached to the protein molecule. The researchers stretch the molecules and measure precisely their tiny displacements.



"Any work that we do on the ground level of stretching any kind of chemical bonds is fundamentally important because it's the kind of knowledge no one has ever measured on this scale," he said. "Proteins constantly fold and unfold. A folded protein is the one that's biologically active and performing a function. So any problems during its folding and unfolding translate to some potential diseases like cancers."



Szoszkiewicz received a grant from K-State's Terry C. Johnson Center for Basic Cancer Research to use these techniques to stretch some proteins that are significant in breast cancer. He is collaborating with Anna Zolkiewska and Michal Zolkiewski, both K-State associate professors of biochemistry.



Another area of Szoszkiewicz's research began while at the Georgia Institute of Technology. It involves changing the properties of a surface at the very local scale by using an atomic force microscope in which the sharp cantilever tip can be heated up to between 500 degrees and 600 degrees Celsius.



When this heated tip is scraped across a surface, Szoszkiewicz said, the heat can -- under certain circumstances -- initiate a chemical reaction on that very surface. He and his colleagues have created patches of chemically changed surface only 10 to 15 nanometers across, but Szoszkiewicz thinks he will be able to change the surface just bunch of molecules at a time. This ability to pattern the surface, he said, could improve personalized medicine by allowing scientists to create tiny chips on which many tests can be run simultaneously.
















"You could take a small sample of blood and screen it for any possible drug that could work for you," he said. "Ordinarily to do such a screening would require a humongous amount of testing material and antibodies. If you could prepare a surface that will selectively bind only one or two molecules of a kind and then see if you have bound or not, then you would need only a few milliliters of blood, and you could test it against millions of molecules. Of course, there are other factors involved and the particular interactions between single blood molecules and their antibodies might not be that simple. But this still remains to be seen."



Szoszkiewicz said that if scientists can pattern the surface in the way they like, another application might be tiny electric circuits and lenses that guide, respectively, electrons and photons. Also, using an atomic force microscope in this way, he said, physicists can not only change the chemical properties of the surface but they also can change the topography of a surface -- in other words, how the surface looks.



For example, Szoszkiewicz and colleagues have created and investigated the nature of nanoscale ripples created on polymers, or the "polymer dunes" at a nanoscale level. Using custom-made polymers, the researchers scratched them with the hot tip while using enough heat to indent within the polymer during scratching but not to destroy the polymer sample. Such research investigated how these tiny dunes created on polymers change with the application of heat. In this case, heat functions like wind would on real sand dunes. The researchers investigated under which conditions the dune gets pushed in the way they wanted it and forms a desired shape.



"This way you can prepare structures that can serve to sort materials at the nanoscale," he said. "Later on you virtually throw some other molecules on the surface, and maybe some of it will go into the grooves, depending on the chemistry."



The researchers were able to prepare several types of nanoscopic ripples -- these so-called tiny dunes -- with the most common type being the one in which the ripples organize in a roughly linear fashion. However, they also explored circular geometry. Their work has been published in the June issue of the journal Physical Review B.



"What we have proven in this paper is that, under certain conditions, by scanning continuously along these circles, you can make the ripples along your circular scanning path, and under certain circumstances to move them collectively and continuously," Szoszkiewicz said. "Measuring the collective velocities, we found that they would approach the velocities of shifting a big sand dune, just scaled down."



Szoszkiewicz's continuation of these projects in his lab at K-State include several other researchers: Heidi Martin, sophomore in physics from Junction City; Ashim Dey, doctoral student in physics, Manhattan; Neelam Khan, May 2009 doctoral graduate in physics; and Vera Okuneva, research assistant in biology.



Source:
Robert Szoszkiewicz


Kansas State University

Ever-Sharp Urchin Teeth May Yield Tools That Never Need Honing

To survive in a tumultuous environment, sea urchins literally eat through stone, using their teeth to carve out nooks where the spiny creatures hide from predators and protect themselves from the crashing surf on the rocky shores and tide pools where they live.



The rock-boring behavior is astonishing, scientists agree, but what is truly remarkable is that, despite constant grinding and scraping on stone, urchin teeth never, ever get dull. The secret of their ever-sharp qualities has puzzled scientists for decades, but now a new report by scientists from the University of Wisconsin-Madison and their colleagues has peeled back the toothy mystery.



Writing in the journal Advanced Functional Materials, a team led by UW-Madison professor of physics Pupa Gilbert describes the self-sharpening mechanism used by the California purple sea urchin to keep a razor-sharp edge on its choppers.



The urchin's self-sharpening trick, notes Gilbert, is something that could be mimicked by humans to make tools that never need honing.



"The sea urchin tooth is complicated in its design. It is one of the very few structures in nature that self-sharpen," says Gilbert, explaining that the sea urchin tooth, which is always growing, is a biomineral mosaic composed of calcite crystals with two forms - plates and fibers - arranged crosswise and cemented together with super-hard calcite nanocement. Between the crystals are layers of organic materials that are not as sturdy as the calcite crystals.



"The organic layers are the weak links in the chain," Gilbert explains. "There are breaking points at predetermined locations built into the teeth. It is a concept similar to perforated paper in the sense that the material breaks at these predetermined weak spots."



The crystalline nature of sea urchin dentition is, on the surface, different from other crystals found in nature. It lacks the obvious facets characteristic of familiar crystals, but at the very deepest levels the properties of crystals are evident in the orderly arrangement of the atoms that make up the biomineral mosaic teeth of the sea urchin.



To delve into the fundamental nature of the crystals that form sea urchin teeth, Gilbert and her colleagues used a variety of techniques from the materials scientist's toolbox. These include microscopy methods that depend on X-rays to illuminate how nanocrystals are arranged in teeth to make the sea urchins capable of grinding rock. Gilbert and her colleagues used these techniques to deduce how the crystals are organized and melded into a tough and durable biomineral.



Knowing the secret of the ever-sharp sea urchin tooth, says Gilbert, could one day have practical applications for human toolmakers. "Now that we know how it works, the knowledge could be used to develop methods to fabricate tools that could actually sharpen themselves with use," notes Gilbert. "The mechanism used by the urchin is the key. By shaping the object appropriately and using the same strategy the urchin employs, a tool with a self-sharpening edge could, in theory, be created."


Notes:


The new research was supported by grants from the U.S. Department of Energy and the National Science Foundation. In addition to Gilbert, researchers from the University of California, Berkeley; Argonne National Laboratory; the Weizmann Institute of Science; and the Lawrence Berkeley National Laboratory contributed to the report.



Source:

Pupa Gilbert

University of Wisconsin-Madison

Aging Could Be A Case Of Specific Genetic Instructions Rather Than Rust - Implying Halting Or Reversing Aging Process May Be Possible One Day

Age may not be rust after all. Specific genetic instructions drive aging in worms, report researchers at the Stanford University School of Medicine. Their discovery contradicts the prevailing theory that aging is a buildup of tissue damage akin to rust, and implies science might eventually halt or even reverse the ravages of age.


"We were really surprised," said Stuart Kim, PhD, professor of developmental biology and of genetics, who is the senior author of the research.


Kim's lab examined the regulation of aging in C. elegans, a millimeter-long nematode worm whose simple body and small number of genes make it a useful tool for biologists. The worms age rapidly: their maximum life span is about two weeks.


Comparing young worms to old worms, Kim's team discovered age-related shifts in levels of three transcription factors, the molecular switches that turn genes on and off. These shifts trigger genetic pathways that transform young worms into geezers. The findings will appear in the July 24 issue of the journal Cell.


The question of what causes aging has spawned competing schools of thought. One side says inborn genetic programs make organisms grow old. This theory has had trouble gaining traction because it implies that aging evolved, that natural selection pushed older organisms down a path of deterioration. However, natural selection works by favoring genes that help organisms produce lots of offspring. After reproduction ends, genes are beyond natural selection's reach, so scientists argued that aging couldn't be genetically programmed.


The alternate theory holds that aging is an inevitable consequence of accumulated wear and tear: Toxins, free-radical molecules, DNA-damaging radiation, disease and stress ravage the body to the point it can't rebound. So far, this theory has dominated aging research.


But the Stanford team's findings told a different story. "Our data just didn't fit the current model of damage accumulation, and so we had to consider the alternative model of developmental drift," Kim said.


The scientists used microarrays - silicon chips that detect changes in gene expression - to hunt for genes that were turned on differently in young and old worms. They found hundreds of age-regulated genes switched on and off by a single transcription factor called elt-3, which becomes more abundant with age. Two other transcription factors that regulate elt-3 also changed with age.


To see whether these signal molecules were part of a wear-and-tear aging mechanism, the researchers exposed worms to stresses thought to cause aging, such as heat (a known stressor for nematode worms), free-radical oxidation, radiation and disease. But none of the stressors affected the genes that make the worms get old.


So it looked as though worm aging wasn't a storm of chemical damage. Instead, Kim said, key regulatory pathways optimized for youth have drifted off track in older animals. Natural selection can't fix problems that arise late in the animals' life spans, so the genetic pathways for aging become entrenched by mistake. Kim's team refers to this slide as "developmental drift."















"We found a normal developmental program that works in young animals, but becomes unbalanced as the worm gets older," he said. "It accounts for the lion's share of molecular differences between young and old worms."


Kim can't say for sure whether the same process of drift happens in humans, but said scientists can begin searching for this new aging mechanism now that it has been discovered in a model organism. And he said developmental drift makes a lot of sense as a reason why creatures get old.


"Everyone has assumed we age by rust," Kim said. "But then how do you explain animals that don't age?"
Some tortoises lay eggs at the age of 100, he points out. There are whales that live to be 200, and clams that make it past 400. Those species use the same building blocks for their DNA, proteins and fats as humans, mice and nematode worms. The chemistry of the wear-and-tear process, including damage from oxygen free-radicals, should be the same in all cells, which makes it hard to explain why species have dramatically different life spans.


"A free radical doesn't care if it's in a human cell or a worm cell," Kim said.


If aging is not a cost of unavoidable chemistry but is instead driven by changes in regulatory genes, the aging process may not be inevitable. It is at least theoretically possible to slow down or stop developmental drift.


"The take-home message is that aging can be slowed and managed by manipulating signaling circuits within cells," said Marc Tatar, PhD, a professor of biology and medicine at Brown University who was not involved in the research. "This is a new and potentially powerful circuit that has just been discovered for doing that."


Kim added, "It's a new way to think about how to slow the aging process."


Stanford co-authors on the study included postdoctoral scholar Yelena Budovskaya, PhD; doctoral student Lucinda Southworth; Kendall Wu, PhD, a former Stanford postdoctoral scholar now working at Affymetrix Inc., and Min Jiang, a former Stanford lab technician. The Stanford team collaborated with Patricia Tedesco and Thomas Johnson of the University of Colorado-Boulder.


The research was supported by grants from the National Institutes of Health, the Ellison Medical Foundation and the Larry L. Hillblom Foundation.


Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford.

Alzheimer's Vaccine Clears Plaque But Has Little Effect On Learning And Memory Impairment

A promising vaccine being tested for Alzheimer's disease does what it is designed to do - clear beta-amyloid plaques from the brain - but it does not seem to help restore lost learning and memory abilities, according to a University of California, Irvine study.



The findings suggest that treating the predominant pathology of Alzheimer's disease - beta-amyloid plaques - by itself may have only limited clinical benefit if started after there is significant plaque growth. However, a combination of vaccination with therapies that also target related neuron damage and cognitive decline may provide the best treatment opportunity for people with this neurodegenerative disease. Study results appear in the April 2 issue of the Journal of Neuroscience.



"We've found that reducing plaques is only part of the puzzle to treat Alzheimer disease," said study leader, UC Irvine neurobiologist Elizabeth Head. "Vaccines such as this one are a good first step for effective Alzheimer's treatment, but complimentary treatments must be developed to address the complexity of the disease."



Head and colleagues studied for a two-year period in aging canines the effect of a vaccine that is currently under clinical development for treating patients with Alzheimer's disease. The vaccine contains the beta-amyloid 1-42 protein and stimulates the immune system to produce antibodies against this same protein that is in the brain plaques. Dogs are used for such studies because beta-amyloid plaques grow naturally in their brains and they exhibit cognitive declines similar to those seen in humans.



After the aged dogs with beta-amyloid-plaque growth were immunized (which is similar to starting a treatment in patients with Alzheimer's disease), the researchers found, in comparison with non-treated aged dogs, little difference in the results of behavioral tests that measure cognitive loss. Later, brain autopsies showed that although plaques had been cleared from multiple brain regions - including the entorhinal cortex, a region of the brain involved with learning and memory and primarily affected by Alzheimer's - damaged neurons remained.



Head said this discovery helps explain why there was little difference in the behavioral test results between immunized and nonimmunized dogs. In addition, she added, it implies that after clearing beta-amyloid plaques from the brain, the next step is to repair these neurons. This approach will be critical for treating and reversing the effects of the Alzheimer's disease.



Currently, Head and her colleagues are developing approaches to repair these damaged neurons and hope to test them clinically.





Head is a researcher with the UC Irvine Institute for Brain Aging and Dementia. Viorela Pop, Vitaly Vasilevko, Mary Ann Hill, Tommy Saing, Floyd Sarsoza, Michaela Nistor, Lori-Ann Christie, Saskia Milton, Charles Glabe and David Cribbs of UC Irvine; and Edward Barrett of the Lovelace Respiratory Research Institute in Albuquerque, N.M., assisted with the study. The National Institutes of Health supported the study, and the Lovelace Institute provided the canine study subjects.



About the University of California, Irvine: The University of California, Irvine is a top-ranked university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 27,000 undergraduate and graduate students and nearly 2,000 faculty members. The third-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3.6 billion.



Source: Tom Vasich


University of California - Irvine

Recovery Of Wartime Limb Injuries May Be Improved By Myostatin Inhibitors

Inhibiting a growth factor that keeps muscles from getting too big may optimize recovery of injured soldiers, researchers say.



They are studying two myostatin inhibitors in mice with limb injuries, first to see which works best and then to identify the best delivery mechanism, says Dr. Mark Hamrick, bone biologist in the Medical College of Georgia Schools of Graduate Studies and Medicine.



"Fifty to 60 percent of the injuries occurring in Iraq are to the limbs, and the average injury requires five surgeries," Dr. Hamrick says. "Myostatin inhibitors are known to improve muscle regeneration and we have evidence that they also increase bone formation. We believe these inhibitors will result in a stronger, more rapid recovery for these soldiers and other victims of traumatic limb injuries."



A $1.2 million grant from the Office of Naval Research to Dr. Hamrick is enabling laboratory studies of two experimental myostatin inhibitors: a decoy receptor and a binding protein, both developed by MetaMorphix, Inc. of Beltsville, Md. Both inhibitors have been shown effective in muscle regeneration, but this is the first trial that looks at their impact on bone.



Two delivery mechanisms also will be studied. "Is the best approach a single injection bolus that circulates everywhere or just localized delivery?" Dr. Hamrick says.



Study collaborators include Dr. Li Liang of the life sciences company MetaMorphix, who will oversee development of the inhibitors; Dr. Xuejun Wen, bioengineer at Clemson University in Clemson, S.C.; and David Immel, radiographic imaging expert at Savannah River National Laboratory in Aiken, S.C., who will provide three-dimensional, high-resolution computerized tomography scans of injured limbs before and after treatment.



Myostatin is primarily produced by muscle cells. Females tend to produce more myostatin receptors, which helps explain why men tend to have greater muscle mass. Dr. Hamrick's lab also has found the receptor on bone-derived stem cells - needed to help repair an injury - and others have found it in healing fractures. "When you take it away, the healed callus that forms at the fracture site has more bone in it," says Dr. Hamrick. "Myostatin also increases fibrosis and scarring within tissue so part of what you are doing is blocking that."



Bone and muscle healing typically go hand in hand. Muscle provides blood, growth factors and potentially stem cells for a healing callus. It's not yet known how well bones reciprocate. "If you can improve muscle healing, you can improve bone healing," Dr. Hamrick says. "Young people have a tremendous potential to heal that can be improved with better approaches to preventing infection and to healing soft tissue and bone in an integrated manner."



Researchers hope to move to clinical trials in two to three years, Dr. Hamrick says. "If we find the primary role of myostatin is very early in the healing process and see a big jump in expression early in a fracture callus, it may be that a single injection bolus immediately after injury is the best time for treatment rather than continued treatment over a period of time."



Myostatin is most highly expressed during development, but adults have some as well, so blocking it still facilitates muscle growth and development, primarily in response to exercise. Myostatin expression also tends to rise following an injury, apparently to control proliferation of new and regenerating cells, Dr. Hamrick says. Although there is no FDA-approved myostatin inhibitor, body builders often take supplements that claim to reduce myostatin function and help build muscle.



A whole spectrum of naturally occurring genetic variations likely result in minor alterations in myostatin signaling that could help explain why some people are more muscular than others, Dr. Hamrick notes. In a separate study funded by the National Institutes of Health, he is using a genetically engineered 'mighty mouse,' which is missing the myostatin gene, to find the best way to optimize bone growth and help young people avoid osteoporosis. German researchers reported in 2004 in the New England Journal of Medicine the case of a child whose muscles already were bulging as a newborn apparently because of a dysfunctional myostatin gene.






Source: Toni Baker


Medical College of Georgia

Proteins That Help Bacteria Put Up A Fight Identified By Scientists

Scientists have identified the role of two proteins that contribute to disease-causing bacteria cells' versatility in resisting certain classes of antibiotics.



The finding is a step toward development of drug therapies that could target bacterial resistance at its cellular source. Before researchers can design such drugs, they must understand all of the activities at play in the conflict between bacteria and the agents that kill them.



This finding by Ohio State University microbiologists extends the understanding of how bacteria cells resist antibiotics through the activities of two genetically distinct forms of what are called MprFs, or multiple peptide resistance factors. The proteins they studied are MprF1 and MprF2.



These proteins were found to be key to the mechanism allowing bacteria cells to change the electrical charge of their membrane, which is how the cells develop their resistance to certain antimicrobial agents and, more generally, how they adapt their membrane to new environmental conditions, such as those provided by their host organism.



"Both of these proteins are potentially very good drug targets because in theory, if you can target them and inhibit their action, you can make bacteria strains more susceptible to existing antibiotics," said Michael Ibba, associate professor of microbiology at Ohio State and a coauthor of the study.



The findings are described online in this week's issue of Proceedings of the National Academy of Sciences.



Scientists have already observed that the cell membranes of many disease-causing bacteria develop resistance by changing their electrical charge from negative to positive. Many antibiotics work because they carry a positive charge that attracts them to negatively charged bacteria cells. The opposite charges allow antibiotics to penetrate and kill bacteria. But by changing their naturally occurring negative charge to positive, some bacteria cells establish a protective "coat" that repels the antibiotic.



A common example of antibiotic resistance is Methicillin-resistant Staphylococcus aureus (MRSA), the strain of bacteria responsible for thousands of difficult-to-treat infections reported in humans each year.



"There is a dispute that remains unresolved as to whether or not this pathway we're investigating is involved in MRSA. It's very unclear. By understanding the mechanism, we might be able to find out if this is involved in MRSA or not," Ibba said.



Ibba and HervГ© Roy, a postdoctoral researcher at Ohio State and lead author of the study, concentrated on exploring the activities of these specific MprF proteins, which are just two of dozens of forms of a class of genes associated with the development of resistance in about 200 bacteria species. They investigated the activity of two forms of MprF from the pathogen Clostridium perfringens, one of the most common sources of food poisoning in the United States.
















MprF proteins affect the membrane's charge by using an adapter molecule, called transfer RNA (tRNA), to transfer amino acids to the lipids that make up the cell membrane. This action leads to modification of the membrane and the change in its charge.



Ibba and Roy found that both MprF1 and MprF2 perform this same function, but they use different amino acids that lead to the modification. The amino acid lysine has already been identified as a player in this modification, and is used by MprF2. Ibba and Roy found that MprF1, however, uses the amino acid alanine instead. This amino acid also contributes to cell membrane modification and seems to have additional functions that remain unknown.



"This is a new function that we discovered, that MprF1 uses alanine, which then allows the cell to fine tune the properties of the membrane," Roy said. "Earlier studies found these effects on the membrane, but no one knew what protein caused it."



What makes these proteins even more potent in the resistance effort is that they can use the adapter molecule in a variety of forms to achieve membrane modification. When the researchers manipulated the tRNA's structure and properties to match differences in the molecule that would occur in different species of bacteria, the proteins could still recognize the molecule and put it to use to perform the amino acid transfer that changes the cell membrane.



"This means that there is no species barrier for the spread of this virulence factor among other bacteria because this protein can recognize tRNA in any species, no matter what it looks like," Roy said.



Ibba and Roy describe their findings as only the beginning of investigating the role of the MprF family of proteins in bacteria. They believe other amino acids could also be used that would modify bacteria cell membranes, and are investigating additional pathways within the cells that lead to remodeled membranes.



"We know the change to the membrane is key to resistance," Ibba said. "We now know there is not just one way that can happen. We have just found a second way an organism can do this, and it is able to make the change to the membrane in two different ways. From our findings there are almost certainly even more ways that the membrane can be modified, and that's what we're looking for next."







This research was supported by the National Institute of General Medical Sciences.



Written by Emily Caldwell



Source: Michael Ibba


Ohio State University

Fast Forensic Test Can Match Suspects' DNA With Crime Samples In Four Hours

A newly developed test could make checking DNA from people arrested for crimes with DNA samples from crime scenes stored in forensic databases almost as easy as matching fingerprints. With the test, police could check on whether a person's DNA matches that found at past crime scenes while suspects are still being processed and before a decision on whether to release them on bail. A report on the fast forensic test appears in the ACS' Analytical Chemistry, a semi-monthly journal.


Andrew Hopwood, Frederic Zenhausern, and colleagues explain that some criminals are arrested, spend less than a day in jail, and then commit crimes while they are out on bail. If police could quickly test the suspects' DNA, to see if their genetic material matches entries in crime databases, they may be able to keep the most dangerous people locked up. But currently, most genetic tests take 24-72 hours, and by the time that the results are back, the suspects often have been released.


To increase the speed of forensic DNA testing, the scientists built a chip that can copy and analyze DNA samples taken from a cotton swab. Forensic technicians can collect DNA from suspects by swabbing their mouth, mixing the sample with a few chemicals, and warming it up. The DNA-testing-lab-on-a-chip does the rest. The entire process takes only four hours at present. Hopwood and Zenhausern teams are already optimizing it and reducing the cycle time down to two hours. Once that is done, police could even double-check their DNA evidence before releasing a suspect.


"Integrated Microfluidic System for Rapid Forensic DNA Analysis: Sample Collection to DNA Profile"

Andrew J. Hopwood, Cedric Hurth, Jianing Yang, Zhi Cai, Nina Moran, John G. Lee-Edghill, Alan Nordquist, Ralf Lenigk, Matthew D. Estes, John P. Haley, Colin R. McAlister, Xiaojia Chen, Carla Brooks, Stan Smith, Keith Elliott, Pieris Koumi, Frederic Zenhausern and Gillian Tully

Anal. Chem.

DOI: 10.1021/ac101355r Publication Date (Web): July 15, 2010

Glutamate & Dopamine, Biological Predictors Of The Transition To Psychosis?

There is growing evidence that two neurotransmitters dopamine and glutamate are abnormal in people with psychotic illness, including schizophrenia. Among many other things, these chemicals play a role in cognitive functions, such as memory, learning, and problem-solving.


A new study in Biological Psychiatry is now the first to examine the relationship between these two brain chemicals by measuring both in the same individuals.


Dr. James Stone and colleagues studied people with sub-threshold psychotic symptoms, who were at very high risk of undergoing transition to full-blown psychotic illness, using two brain imaging techniques - magnetic resonance spectroscopy, which allows measurement of glutamate in the brain, and [18F]DOPA positron emission tomography, which gives a measure of dopamine neuron activity.


"By combining neuroimaging approaches, we may get new insights into the disturbances in brain circuits that contribute to the emergence of psychosis and the full schizophrenia syndrome from the less developed symptoms of the at-risk state," commented Dr. John Krystal, Editor of Biological Psychiatry.


They found that in these individuals, lower glutamate in hippocampus, a major structure in the brain involved in memory, was associated with increased dopamine activity. This was in keeping with earlier animal models, and with clinical studies of hippocampal and striatal function in psychosis.


According to Dr. Stone, "the findings support the hypothesis of an abnormal relationship between the dopamine and glutamate neurotransmitter systems in individuals with psychosis, and suggest that the development of drugs targeting glutamatergic transmission may be useful in the early treatment of psychosis."


The findings also suggest that this abnormal glutamate-dopamine relationship may be a risk marker for later transition to a psychotic disorder.


Sources: Elsevier, AlphaGalileo Foundation.

Brain Networks Strengthened By Closing Ion Channels

Yale School of
Medicine and University of Crete School of Medicine researchers report in
Cell April 20 the first evidence of a molecular mechanism that dynamically
alters the strength of higher brain network connections.


This discovery may help the development of drug therapies for the
cognitive deficits of normal aging, and for cognitive changes in
schizophrenia, bipolar disorder, or attention deficit hyperactivity
disorder (ADHD).



"Our data reveal how the brain's arousal systems influence the
cognitive networks that subserve working memory-which plays a key role in
abstract thinking, planning, and organizing, as well as suppressing
attention to distracting stimuli," said Amy Arnsten, lead author and
neurobiology professor at Yale.



The brain's prefrontal cortex (PFC) normally is responsible for
so-called executive functions. The ability of the PFC to maintain such
memory-based functions declines with normal aging, is weakened in people
with ADHD, and is severely disrupted in disorders such as schizophrenia and
bipolar disorder.



The current study found that brain cells in PFC contain ion channels
called hyperpolarization-activated cyclic nucleotide-gated channels (HCN),
that reside on dendritic spines, the tiny protrusions on neurons that are
specialized for receiving information. These channels can open when they
are exposed to cAMP (cyclic adenosine monophosphate). When open, the
information can no longer flow into the cell, and thus the network is
effectively disconnected. Arnsten said inhibiting cAMP closes the channels
and allows the network to reconnect.



The study also found alpha-2A adrenergic receptors near the channels
that inhibit the production of cAMP and allow the information to pass
through into the cell, connecting the network. These receptors are
stimulated by a natural brain chemical- norepinephrine- or by medications
like guanfacine.



"Guanfacine can strengthen the connectivity of these networks by
keeping these channels closed, thus improving working memory and reducing
distractibility," she said. "This is the first time we have observed the
mechanism of action of a psychotropic medication in such depth, at the
level of ion channels."



Arnsten said the excessive opening of HCN channels may underlie many
lapses in higher cognitive function. Stress, for example, appears to flood
PFC neurons with cAMP, which opens HCN channels, temporarily disconnects
networks, and impairs higher cognitive abilities.



There is also evidence that this pathway may not be properly regulated
with advancing age, resulting in destruction of cAMP. The dysregulation of
the pathway may contribute to increased forgetfulness and susceptibility to
distraction as we grow older.
















The research is also relevant to common disorders such as ADHD, which
is associated with weaker regulation of attention and behavior. ADHD is
highly heritable, and some patients with ADHD may have genetic changes in
molecules that weaken the production of norepinephrine. Treatments for ADHD
all enhance stimulation of the norepinephrine receptors.



These new data also have important implications for the researchers'
studies of more severe mental illnesses like schizophrenia and bipolar
disorder, which can involve mutations of a molecule called DISC1 (Disrupted
in Schizophrenia) that normally regulates cAMP. Loss of function of DISC1
in patients with schizophrenia or bipolar disorder would increase
vulnerability to cortical network disconnection and profound PFC deficits.
This may be especially problematic during exposure to even mild stress,
which may explain the frequent worsening of symptoms following stress
exposure. "We find it remarkable to relate a genetic mutation in patients
to the regulation by an ion channel of PFC neuronal networks," said
Arnsten.



Co-authors include Min Wang, Brian Ramos, Yousheng Shu, Arthur Simen,
Alvaro Duqye, Avis Brennan, Susheel Vijayraghavan, Anne Dudley, Eric Nou,
David McCormick, James Mazer and Constantinos Paspalas, who also has an
appointment at the University of Crete School of Medicine in Heraklion,
Greece.



The work was supported by research grants from the National Institute
on Aging and the National Institute of Mental Health, as well as from Shire
Pharmaceuticals Group plc and an award from the Kavli Institute of
Neuroscience at Yale.



Arnsten and Yale have a license agreement with Shire Pharmaceuticals
for the development of guanfacine for the treatment of patients with ADHD.
Yale has submitted a patent application on the use of HCN blockers for the
treatment of PFC cognitive deficits based on the data reported in the Cell
paper.


Yale University School of Medicine

med.yale/ysm

Promise Of Big Benefits For Cancer Patients Following New Advances In Science Of The Ultra-Small

A $145-million Federal Government effort to harness the power of nanotechnology to improve the diagnosis, treatment, and prevention of cancer is producing innovations that will radically improve care for the disease. That's the conclusion of an update on the status of the program, called the National Cancer Institute Alliance for Nanotechnology in Cancer. It appears in ACS Nano, a monthly journal published by the American Chemical Society.



Piotr Grodzinski and colleagues note in the article that the alliance, launched in 2004, funds and coordinates research specifically intended to move knowledge about the small science out of laboratories and into hospitals and doctors offices in a big way. It builds on more than 50 years of advances in cancer care that although substantial, still leave cancer as the No. 1 cause of death in the United States and globally.



The article describes a range of advances, including some showing significant promise in clinical trials that are poised to make a big impact on cancer. They promise earlier disease diagnosis, highly targeted treatments that kill cancer cells but leave normal cells alone, fewer side effects, and improved survival, the article indicates.



Article: "Recent Advances from the National Cancer Institute Alliance for Nanotechnology in Cancer"



Source:

Michael Bernstein


American Chemical Society

Genes Help Decide When To Look For New Food

For worms, choosing when to search for a new dinner spot depends on many factors, both internal and external: how hungry they are, for example, how much oxygen is in the air, and how many other worms are around. A new study demonstrates this all-important decision is also influenced by the worm's genetic make-up.



In the simple Caenorhabditis elegans nematode, the researchers found that natural variations in several genes influence how quickly a worm will leave a lawn of bacteria on which it's feeding. One of the genes, called tyra-3, produces a receptor activated by adrenaline - a chemical messenger involved in the 'fight-or-flight' response. The findings appeared online March 16, 2011, in the journal Nature.



"What's encouraging to us about this story is that molecules related to adrenaline are implicated in arousal systems and in decision-making across a lot of different animals, including humans," says Howard Hughes Medical Institute investigator Cornelia Bargmann of Rockefeller University in New York, who mentored the work of graduate student Andres Bendesky. These parallels between diverse species suggest that aspects of our decision-making abilities have ancient evolutionary roots.



Six worms on a small lawn of bacterial food (circle). Occasionally, a worm leaves the food to explore the surrounding environment. Video: Bendesky et al. Nature



C. elegans thrive in agricultural settings, such as orchards and crop lands, feeding on bacteria from rotting fruits and vegetables. But eating in this environment is tricky: the worms encounter many bacterial species that are difficult to digest or even toxic. "The worms need to somehow evaluate a whole spectrum of conditions to decide whether they want to try this food source or go out and look for a better one," Bargmann says.



The great scientific advantage of using C. elegans to study complicated behavioral processes such as decision-making is that the worms have only 302 neurons, and the connections between all those neurons have all been precisely mapped. In contrast, the human brain has billions of neurons. What's more, most of the worm's 20,000 genes have equivalents in the human genome. "Behavior includes the action of genes, their function in neurons, and the neurons' assembly into circuits," Bargmann says. "Studying C. elegans gives you an exceptional ability to make connections between those levels."



Over the past decade, her lab has probed several of these levels. In 2004, they reported that C. elegans sense precise oxygen concentrations in soil, which helps steer them toward their favorite meal: oxygen-consuming bacteria. Three years later, they investigated what neurons do with chemosensory information, finding that odor-sensing neurons can switch on other cells that control crawling and turning behaviors.



In the new study, Bendesky and Bargmann went one level deeper, investigating how genetic tweaks can change a worm's behavior in particular circumstances. To do their experiments, the researchers placed hundreds of different strains of C. C. elegans onto Petri dishes lined with a circular "lawn" of bacteria and calculated the rate at which worms left the lawn. "Lawn-leaving is something that occurs abruptly, in an all-or-none way. It's very striking," Bargmann says.
















To find the genes that affect the behavior, they collaborated with HHMI investigator Leonid Kruglyak and his postdoc Matt Rockman to use a technique called quantitative trait locus analysis, they then analyzed the precise genetic make-up of each strain and correlated it with how frequently each strain left its lawn. In the end, the researchers could pinpoint particular genetic blips associated with moving away from a food source.



One of those blips crops up in a gene called npr-1, which had already been associated with foraging behaviors and immunity in the worm. The npr-1 variant is a special case, however, because it evolved in laboratory strains of C. elegans and is not known to exist in the wild.



In a more exciting development, the researchers also found a natural genetic variation in tyra-3 that is associated with lawn-leaving. This gene encodes a receptor protein that responds to tyramine, an adrenaline-like hormones derived from the amino acid tyrosine. Like adrenaline, tyramine is an internal signal that regulates the function of neurons expressing its various receptors.



To find out where in the brain the tyra-3 gene is turned on, the researchers engineered strains of worms in which they could observe production of tyra-3. By attaching a fluorescent green marker to the tyra-3 protein, they could easily observe whenever the protein was made. They then traced where the green fluorescence appeared inside the worms and discovered that the tyra-3 receptor is produced in a place that makes intuitive sense: sensory neurons. In these neurons, external cues, such as oxygen levels, can be integrated with internal states, such as hunger. "It's the result you would have gotten if you made it up," Bargmann says, laughing.



The findings show that particular genetic variants lead to specific behaviors in the real world - but how, exactly, they do this is still mysterious. "We don't have a fix on when tyramine is being made, where it's released, and how it's working to change behavior," Bargmann says.



Figuring that out is the obvious next step. The trouble is, the tools for tracking the brain's chemical messengers in real time don't exist yet. "We'll just have to put our heads down and develop some," she says.



Source:

Jim Keeley

Howard Hughes Medical Institute