Individual differences in taste perception directly related to genetic variation in taste receptors

Why do brussels sprouts taste bitterly repellent to one person and bland - or even delicious - to the next?



A study published in the February 22 issue of Current Biology confirms the influential role of genetics in determining the wide range of human sensitivity to taste, ultimately impacting how we each perceive the world in a slightly different way.



"Each human carries their own distinctive set of taste receptors which gives them a unique perception of how foods and medicines taste," explains Monell Chemical Senses Center psychophysicist Paul Breslin, PhD, who shares first authorship and is a corresponding contributor for the study. "This paper shows that a single gene codes for multiple forms of a taste receptor, with each form having a differing sensitivity to taste compounds. Further, a person's perceptual sensitivity to these bitter tasting compounds corresponds strikingly well with their genetically-determined receptor sensitivity."



In the paper, researchers at the Monell Center and collaborating institutions related individual perception of the bitter-tasting compounds PTC and PROP to variation in a bitter taste receptor gene known as hTAS2R38.



The researchers cloned two forms (haplotypes) of the hTAS2R38 gene and expressed the corresponding receptors in a cell culture. The two haplotypes, known as PAV and AVI, vary with respect to amino acid substitutions encoded at certain positions on the taste receptor protein.



In the cell culture experiments, small amounts of the bitter compounds activated cells expressing the PAV form of the receptor, whereas cells expressing the AVI form were unresponsive to the same compounds. Cells expressing other haplotypes (eg PVI, AAI or AAV) had intermediate sensitivity to the bitter compounds.



Other experiments examined bitterness perception in human subjects. People with the PAV form of the hTAS2R38 gene were most sensitive to the bitter taste of PROP and PTC. Subjects homozygous for the AVI haplotype were 100 to 1000 times less sensitive to bitter taste of the two compounds, confirming the lack of response in the cell culture experiment. These data implicate the responsive PAV haplotype as a major determinant of sensitivity to the bitter taste of PROP and PTC in humans.



"These data answer a long-standing question about why humans differ in their ability to taste some bitter compounds," explains study co-author Danielle Reed, PhD, a Monell geneticist. "Now we can expand our use of this procedure to understand why people are sensitive to other types or tastes, such as sweet or umami, or other types of bitter compounds. We would then be able to test people for their innate ability or inability to taste a variety of flavors and foods." Such knowledge may someday be used to help patients consume beneficial bitter-tasting compounds, such as pharmaceuticals and health-promoting bitter-tasting plants.



The studies demonstrate that variations in a single bitter receptor gene can code for different taste receptors, each sensitive to distinct bitter taste compounds. Thus, while each human may have 25 or so bitter receptor taste genes, because each gene can code for multiple receptors with differing sensitivities, there may be hundreds of different bitter taste receptors in the human population as a whole, leading to wide individual variation in perception of bitterness.
















The existence of both bitter "tasters" and "non-tasters" has the scientists curious for more answers. Breslin comments, "From a human evolutionary perspective, we want to understand how and why both tasters and non-tasters evolved and were maintained in the gene pool." Reed continues, "Usually when we see a trait like this, there is a biological advantage to maintaining the variation. We're wondering what that could be."



Sharing first authorship of the paper with Breslin is Bernd Bufe from the German Institute of Human Nutrition (DIFE). Also contributing to the studies were Wolfgang Meyerhof and Christina Kuhn at the German Institute of Human Nutrition; Un-Kyung Kim and Dennis Drayna from the National Institute on Deafness and Other Communication Disorders at the National Institutes of Health; Jay P. Slack from the Givuadan Flavors Corporation; and Christopher D. Tharp of Monell.



---------------------



The Monell Chemical Senses Center is a nonprofit basic research institute based in Philadelphia, Pennsylvania. For 35 years, Monell has been the nation's leading research center focused on understanding the senses of smell, taste and chemical irritation: how they function and affect lives from before birth through old age. Using a multidisciplinary approach, scientists collaborate in the areas of: sensation and perception, neuroscience and molecular biology, environmental and occupational health, nutrition and appetite, health and well being, and chemical ecology and communication. For more information about Monell, please visit monell.



Contact: Paul Breslin

breslinmonell

Monell Chemical Senses Center

Nature more than nurture decides how religious we are

A study published in the current issue of Journal of Personality studied adult male monozygotic (MZ) and dizygotic (DZ)
twins to find that difference in religiousness are influenced by both genes and environment. But during the transition from
adolescence to adulthood, genetic factors increase in importance while shared environmental factors decrease. Environmental
factors (i.e. parenting and family life) influence a child's religiousness, but their effects decline with the transition
into adulthood. An analysis of self-reported religiousness showed that MZ twins maintained their religious similarity over
time, while the DZ twins became more dissimilar. "These correlations suggest low genetic and high environmental influences
when the twins were young but a larger genetic influence as the twins age" the authors state.


Participants for this study were 169 MZ and 104 DZ male twin pairs from Minnesota. Religiousness was tested using self-report
of nine items that measured the centrality of religion in their lives. The twins graded the frequency in which they partook
in religious activities such as reading scripture or other religious material and the importance of religious faith in daily
life. They also reported on their mother's, their father's, and their own religiousness when they were growing up. They were
also asked to report on the current and past religiousness of their brother. The factors were divided into subscales--
external aspects of religion, like observing religious holidays, that might be the most susceptible to environmental
influence and internal aspects, like seeking help through prayer, that might be the most susceptible to heritable influence.
The external items were found to be more environmentally and less genetically influenced during childhood, but more
genetically influenced in adulthood. The internal scale showed a similar pattern, but the genetic influences seemed to be
slightly larger in childhood compared to the external scale and so more consistent across the two ages. "Like other
personality traits, adult religiousness is heritable, and though changes in religiousness occur during development, it is
fairly stable," the authors conclude.


This article is published in the latest issue of the Journal of Personality. Media wishing to receive a PDF of this article
please contact journalnewsbos.blackwellpublishing


Journal of Personality publishes scientific investigations in the field of personality. It focuses particularly on
personality and behavior dynamics, personality development, and individual differences in the cognitive, affective, and
interpersonal domains.


Laura B. Koenig, M.A., is a graduate student in the department of Psychology at the University of Minnesota. Her research
includes investigating the environmental influences on religiousness in adoptees and the genetic and environmental
connections between religiousness, antisocial, and prosocial behavior.


Contact: Jill Yablonski

Journalnewsbos.blackwellpublishing

781-388-8448

Blackwell Publishing Ltd.

blackwellpublishing

Spread Of Breast Cancer Driven By A Genetic 'Gang Of 4'

Studies of human tumor cells implanted in mice have shown that the abnormal activation of four genes drives the spread of breast cancer to the lungs. The new studies by Howard Hughes Medical Institute researchers reveal that the aberrant genes work together to promote the growth of primary breast tumors. Cooperation among the four genes also enables cancerous cells to escape into the bloodstream and penetrate through blood vessels into lung tissues.



Although shutting off these genes individually can slow cancer growth and metastasis, the researchers found that turning off all four together had a far more dramatic effect on halting cancer growth and metastasis. Metastasis occurs when cells from a primary tumor break off and invade another organ. It is the deadliest transformation that a cancer can undergo, and therefore researchers have been looking for specific genes that propel metastasis.



In the newly published experiments, the researchers also found that they could reduce the growth and spread of human breast tumors in mice by simultaneously targeting two of the proteins produced by these genes, using drugs already on the market. The researchers are exploring clinical testing of combination therapy with the drugs - cetuximab (trade name Erbitux) and celecoxib (Celebrex) - to treat breast cancer metastasis.



The research team, led by Howard Hughes Medical Institute investigator Joan Massagu?© at the Memorial Sloan-Kettering Cancer Center, published its findings in articles in the journal Nature and in the online early edition of the Proceedings of the National Academy of Sciences.



In an earlier study, Massagu?© and his colleagues had identified 18 genes whose abnormal activity is associated with breast cancer's ability to spread to the lungs. In the new study published in Nature, Massagu?© and his colleagues at Sloan-Kettering, along with researchers from Hospital Clinic de Barcelona and the Institute for Research in Biomedecine in Spain, focused on four of these genes. These genes, which code for proteins called epiregulin, COX2, and matrix metalloproteinases 1 and 2, were already known to help regulate growth and remodeling of blood vessels, said Massagu?©.



"Our understanding of the genes for these four proteins and their behavior in metastasis led us to hypothesize that they might be cooperating with each other in a way that would give an advantage to cells in the primary tumor," said Massagu?©. "These same genes, we believed, might also be used for some related purpose in the target organ, the lung."



To test this idea, the researchers silenced various combinations of the four genes in human breast cancer cells that had metastasized to the lung, and then tested these cells in mice. To silence the four genes, the scientists used a technique called RNA interference, in which RNA molecules are tailored to suppress expression of target genes.
















"We found that depriving aggressive metastatic tumor cells of these genes decreased both their ability to grow large aggressive tumors in the mouse mammary gland and also the ability to release cells from these tumors into the circulation," said Massagu?©. "The remarkable thing was that while silencing these genes individually was effective, silencing the quartet nearly completely eliminated tumor growth and spread."



Microscopic analysis of blood vessel structure in the tumors revealed that knocking down all four genes greatly reduced growth of the tangle of blood vessels typically seen in tumors. Further experiments revealed that the tumor blood vessels that did form allowed fewer cancer cells to escape into circulation.



The researchers next explored how loss of the four abnormal genes affected the metastatic capability of the cells in the lung. They injected cells deficient in the four genes directly into the circulatory system of mice. "When these cells reached the lung capillaries, they just got stuck there," said Massagu?©. "We concluded that metastatic cells use these same genes to loosen up cells in capillaries, so that the cells can penetrate the lung tissue to grow there.



"These findings provide a beautiful explanation for how the genes that we identified in breast cancer patients as being associated with lung metastasis manipulate blood vessels to give them an advantage both in the primary tumors and in the lung," he said.



Two drugs already on the market act directly on proteins produced by the genes Massagu?©'s group had been studying. Cetuximab is an antibody that blocks the action of epiregulin and is used to treat advanced colorectal cancer. Celecoxib is an inhibitor of COX2 that is used as an anti-inflammatory, and is being tested in clinical trials against many types of cancer. The researchers also tested whether cetuximab and celecoxib would work effectively in concert to reduce metastasis in mice.



"We found that the combination of these two inhibitory drugs was effective, even though the drugs individually were not very effective," said Massagu?©. "This really nailed the case that if we can inactivate these genes in concert, it will affect metastasis," he said.



Massagu?© said that while clinical trials of the drug combination are being discussed, "there are already treatments to diminish the chance of metastasis in breast cancer, so such trials would have to be designed very carefully to understand how and whether the new drug combination would be of additional benefit." In the article published in the Proceedings of the National Academy of Sciences, Massagu?© and his colleagues explored how the entire group of 18 genes, called the 'lung metastasis gene-expression signature' (LMS) influenced both breast tumor growth and spread to the lungs. Co-authors on the paper were from the University of Chicago, The Netherlands Cancer Institute, Veridex L.L.C., The Cleveland Clinic and the Erasmus Medical Center in The Netherlands.



"There has been an undeniable link between tumor size and growth and metastatic risk, but the molecules and mechanisms underlying this link have remained unresolved," said Massagu?©. "The hypothesis we wanted to test was that these signature genes play a role in both primary tumor growth and metastasis to the lung."



After analyzing 738 human breast cancer tumors, the researchers concluded that those in which the LMS genes were abnormally active were, indeed, more likely to develop lung metastases. They also found that the activity of these LMS genes gave cancer cells a growth advantage by allowing tumors to develop a rich network of blood vessels to deliver oxygen and nutrients, said Massagu?©.



Although large tumors are more likely to metastasize, Massagu?© said his group's findings indicated that the activity of the LMS genes was also critical to the metastasis process. "As the tumors grow and become enriched with LMS-positive cells, because the genes give them an advantage, they reach a point where the tumor becomes richly vascularized," said Massagu?©. "Then, they can massively execute the advantage the LMS genes provide them to metastasize to the lung."



Massagu?© said he and his colleagues will explore in more detail the function of other LMS genes, in addition to the four reported in the Nature paper. They plan to investigate whether shutting down other LMS genes will affect metastasis of breast cancer to the lung, and whether the LMS genes influence breast cancer metastasis to other sites, such as the bone and brain. Finally, they will explore whether the LMS genes play a corresponding role in metastasis of other cancers -- such as sarcoma, melanoma and colon cancer -- to the lung, said Massagu?©.






Contact: Jim Keeley


Howard Hughes Medical Institute



View drug information on Erbitux.

Key Nerve Navigation Pathway Identified

Newly launched nerve cells in a growing embryo must chart their course to distant destinations, and many of the means they use to navigate have yet to surface. In a study published in the current issue of the journal Neuron, scientists at the Salk Institute for Biological Studies have recovered a key signal that guides motor neurons -- the nascent cells that extend from the spinal cord and must find their way down the length of limbs such as arms, wings and legs.



The Salk study, led by Samuel Pfaff, Ph.D, a professor in the Gene Expression Laboratory, identifies a mutation they christened Magellan, after the Portuguese mariner whose ship Victoria was first to circumnavigate the globe. The Magellan mutation occurs in a gene that normally pilots motor neurons on the correct course employing a newly discovered mechanism, their results demonstrate.



In the mutants, growing neurons can be seen leaving the spinal cord normally but then appear to lose direction. The elongating cells develop "kinks" and sometimes fold back on themselves or become entwined in a spiral, forming coils outside the spinal cord. "They appear to become lost in a traffic roundabout," described Pfaff, who observed the growing neurons with fluorescent technology.



Understanding how motor neurons reach the appropriate targets is necessary for the implementation of novel therapies, including embryonic stem cell replacement for the treatment of presently incurable disorders such as Lou Gehrig's disease, in which motor neurons undergo irreversible decay.



"Embryonic studies provide useful insights on how to replicate the system in an adult," said Pfaff. And, as he also pointed out, the mechanisms used by motor neurons are likely to be similar to those used in other parts of the central nervous system, such as the brain. The Magellan mutation discovered by Pfaff's group was found in mice, but the affected gene, called Phr1, has also been identified in other model systems, including fruit flies and the worm species C. elegans.



A growing nerve bears at its bow a structure called the growth cone, a region rich in the receptor molecules whose job is to receive cues from the environment, much as ancient mariners who observed the stars and set their course accordingly. During development, the growth cone continuously pushes forward, while the lengthening neuron behind it matures into the part of the cell called the axon. Once the growing cell "lands" at its target in a muscle cell, it is the axon that will relay the messages that allow an animal to control and move its limbs at will.



In Magellan mutants, Pfaff's team discovered that the growth cone becomes disordered. Rather than forming a distinct "cap" on the developing neuron, the cone is dispersed in pieces along both the forward end and the axon extending behind it.
















"The defect is found in the structure of the neuron itself," said Pfaff, noting that the fundamental pieces, such as the receptors capable of reading cues, all seem to be present. Without the correct orientation of receptors, however, signals cannot be read accurately, resulting in growth going off course.



"A precise gradient normally exists across the cone," said Pfaff, "which is disrupted in the Magellan mutants." As a result, cells lose their polarity. They literally do not know the front end from the back end, according to Pfaff. This sense of polarity is a universal feature common to all growing neurons. Therefore, "Phr1 is likely to play a role in most growing neurons to ensure their structure is retained at the same time they are growing larger," he said.



Pfaff and his group identified Magellan using a novel system they had developed, in which individual motor neurons and axons can be visualized fluorescently. They were able to screen more than a quarter of a million mutations, and the mutations of interest were rapidly mapped to known genes as a result of the availability of the sequenced mouse genome -- a byproduct of the effort to sequence entire genomes such as that in the human.



The Magellan mutation is located in a gene known as Phr1, which is also active in other parts of the nervous system, indicating that it most likely functions to steer other types of neurons, such as those that enervate sensory organs or connect different regions of the brain. Studies of Magellan may therefore shed light on how a variety of neurological disorders might be treated with cell replacement strategies.







Lead author on the study is Joseph W. Lewcock, formerly a postdoctoral fellow in Pfaff's laboratory and currently at Genentech, Inc. Additional Salk authors include postdoctoral fellow Nicolas Genoud and senior research assistant Karen Lettieri.



The study, titled "The ubiquitin ligase Phr1 regulates axon outgrowth through modulation of microtubule dynamics," was supported by the National Institute for Neurological Disorders and Stroke.



The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.



Source: Gina Kirchweger


Salk Institute

Genetic Risk Factors Identified For Sudden Cardiac Death

Building on these findings, the Helmholtz scientists and their clinical partners want to obtain further insights into the pathogenesic mechanisms of the disease and gain perspectives for early diagnosis and therapy. The results of the genome-wide study have been published online in the journal Nature Genetics.



Together with scientists of the international research consortium QTSCD (QT Interval and Sudden Cardiac Death), Dr. Arne Pfeufer of the Institute of human Genetics at Helmholtz Zentrum M??nchen has identified 10 gene variants which predispose to an elevated risk for arrhythmias and SCD. In interaction with other, still undiscovered factors, these gene variants influence heart repolarization and raise or lower the risk of cardiac arrhythmias. In their study, the scientists examined the electrocardiograms of more than 15,000 persons from Germany, Italy and the U.S.



"The results of a second science consortium, QTGEN, were nearly identical to our findings," said Pfeufer. This provides assurance for the scientists involved in the study - the Munich research team led by Professor Thomas Meitinger, institute director at Helmholtz Zentrum M??nchen and holder of the chair in human genetics at the Technische Universit?¤t M??nchen (TUM) and Assistant Professor Stefan K?¤?¤b, MD, senior physician at the University Hospital of Munich, Campus Grosshadern, along with their German, Italian and American colleagues - that their approach was correct and that the findings are absolutely reliable.



"For clinicians, an important indicator for increased arrhythmia risk is the QT interval in the ECG," Stefan K?¤?¤b explained. The QT interval describes the time span needed to send the electrical impulse into the heart ventricles and then to recharge. A prolonged QT interval can - depending on the underlying disease - increase the risk of arrhythmias and SCD up to five-fold.



The scientists were not looking for rare variants carried by only a few people. Rather, they were particularly interested in common gene variants, which in each person can influence the length of the QT interval. They do not increase the personal disease risk as single genes, but rather in combination of genetic factors and in context with other risk factors such as medications or ischemia.



"We view this form of genome-wide search for common gene variants associated with widespread diseases as a very promising approach for making discoveries in totally uncharted territory," said Thomas Meitinger, describing the method. "In contrast to the study of single genes, this genome-wide approach offers entirely new starting points for the investigation of common diseases such as sudden cardiac death."



The provision of highly valid population-based data of test persons from the KORA study platform headed by Professor H.-Erich Wichmann, director of the Institute of Epidemiology at Helmholtz Zentrum M??nchen, formed an essential basis for the successful realization of the research project.
















The QTSCD study arose from long-standing close collaboration between human geneticists, cardiologists, epidemiologists and informaticians of Helmholtz Zentrum M??nchen, the university hospital Klinikum rechts der Isar of the Technische Universit?¤t M??nchen and the university hospital of Ludwig Maximilian University (LMU), Campus Grosshadern. Other partners of Helmholtz Zentrum M??nchen in the QTSCD consortium were the scientists of the Heinz Nixdorf RECALL Study in Essen and the research center Life & Brain of the University of Bonn. Professor Aravinda Chakravarti of John Hopkins University in Baltimore was director of the project.



In a next step, follow-up studies shall confirm the connection between the new gene variants and sudden cardiac death. "We want to collect and evaluate further data on the respective individual genetic risk for arrhythmias in a large number of patients," Dr. K?¤?¤b said. The common objective of the Helmholtz scientists and their clinical partners through these studies is to gain further insights into pathogenetic mechanisms and thus gain perspectives for improved risk prediction and more successful therapy.



Notes:



In Germany the research project was funded by Germany's Federal Ministry for Education and Research (BMBF) within the framework of the National Genome Research Network (NGFN). Funds were also provided by the Excellence Initiative of Ludwig Maximilian University Munich and the French Fondation Leducq to combat cardiovascular disease.



The Institute of Human Genetics at Helmholtz Zentrum M??nchen (Director: Professor Thomas Meitinger, PhD) is concerned with the identification of disease genes and the characterization of their functions. The focus of the research projects is on genome-wide DNA and RNA studies to elucidate the genetic causes of complex diseases, particularly in the fields of neurology and cardiology. Another focus is the systemic analysis of the interaction of genetic variance and environmental factors, using proteomic methods.



The Institute of Epidemiology at Helmholtz Zentrum M??nchen (Director: Professor H.-Erich Wichmann, MD, PhD) is concerned with methodological problems of quantifying small risks, with the effect of particles and airborne pollutants on the lung and the cardiovascular system as well as the regional distribution and development of respiratory diseases and allergies. A new focus of the Institute is the molecular analysis of complex diseases (e.g. asthma, type 2 diabetes, myocardial infarction). The central objective is to investigate the role of environmental influences and genetic disposition on human health, using epidemiological methods.



KORA (Cooperative Health Research in the Region of Augsburg) is an investigation platform for population-based health research in the fields of epidemiology, health economics, and health care. KORA is a network of surveys representative for the population and follow-up studies building on these. The unique feature of this platform is the broad participation of external partners in the planning, implementation and financing of individual projects.



Helmholtz Zentrum M??nchen is the German Research Center for Environmental Health. As leading center oriented toward Environmental Health, it focuses on chronic and complex diseases which develop from the interaction of environmental factors and individual genetic disposition. Helmholtz Zentrum M??nchen has around 1680 staff members. The head office of the center is located in Neuherberg to the north of Munich on a 50-hectare research campus. Helmholtz Zentrum M??nchen belongs to the Helmholtz Association, Germany's largest research organization, a community of 15 scientific-technical and medical-biological research centers with a total of 26,500 staff members.



Original Publications:



QTCSD

Pfeufer, A. et al: Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nature Genetics online - Publication March 22, 2009 (DOI 10.1038/ng.362)



QTGEN

Newton-Cheh, C. et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. Advance online publication March 22, 2009 (DOI: 10.1038/ng.361



Source: Sven Winkler


Helmholtz Zentrum M??nchen - German Research Center for Environmental Health

Study In Mice Shows Direct Link Between Disrupted Protein Folding And Abnormal Fat Metabolism In The Liver

A University of Iowa researcher and colleagues at the University of Michigan have discovered a direct link between disruption of a critical cellular housekeeping process and fatty liver disease, a condition that causes fat to accumulate in the liver.



The findings, published in the Dec. 9 issue of the journal Developmental Cell, might open new avenues for understanding and perhaps treating fatty liver disease, which is the most common form of liver disease in the Western world and may affect as many as one in three American adults. Although fatty liver itself does not necessarily cause illness, it is associated with serious conditions like diabetes, metabolic syndrome, cirrhosis of the liver and liver failure.



The study, led by Tom Rutkowski, Ph.D., assistant professor of anatomy and cell biology at the UI Roy J. and Lucille A. Carver College of Medicine, and Randal Kaufman, Ph.D., professor of biological chemistry and internal medicine at the University of Michigan Medical School, shows that disrupted protein folding causes fatty liver in mice. The finding is the first to demonstrate a direct link between this form of cellular stress and abnormal fat metabolism.



Protein folding, which occurs in a cellular compartment called the endoplasmic reticulum (ER), is a vital cellular process because proteins must be correctly folded into defined three-dimensional shapes in order to function. Unfolded or misfolded proteins are a sign of cellular stress and can cause serious problems -- misfolded proteins cause amyloid plaques found in Alzheimer's disease. Cells rely on a very sensitive system known as the unfolded protein response (UPR) to guard against the cellular stress caused by protein folding problems.



To investigate how cells adapt to stress, the researchers created mice that were missing one component of the UPR. Under normal conditions, mice with the genetic mutation looked and behaved normally. However, the mutated mice were much less able to cope with cellular stress caused by disrupted protein folding than wild-type mice. In addition, the team found that protein misfolding caused fatty liver in mice with the mutation.



"We did not set out to understand fatty liver disease," said Rutkowski, who was a postdoctoral researcher in Kaufman's University of Michigan lab when the study was done. "We were really trying to understand the basic biology of how cells respond to stress, and through our approach to that fundamental question we were able to identify a connection to a condition that is of enormous importance to human health.



"When we realized that our experiments to investigate protein folding abnormalities were producing fatty liver disease as a consequence, it tied in with previous circumstantial evidence suggesting that ER stress might be involved in the liver's role in fat metabolism," he added.
















The researchers followed up on the result and found that mice also developed fatty liver if their ability to fold proteins in the ER was genetically impaired, even when the UPR was functionally intact. This result suggested that the UPR is able to protect the liver against ER stress to a certain degree, but that fatty liver will result when the stress is too severe.



Further analysis of the mice models identified some of the genes that connect prolonged ER stress with faulty fat metabolism in the liver. In particular, the team found that unresolved ER stress leads to persistent expression of a gene called CHOP and that leads to changes in expression of fat metabolism genes. Mice with no CHOP were partially protected from fatty liver.



The results suggest that it is not disruption of a specific protein that caused fatty liver, but rather anything that perturbs the ER's ability to fold proteins correctly that is important. If this finding holds true for fatty liver disease in humans, therapies aimed at improving protein folding in the ER, or inhibiting CHOP, could help treat the condition.



"Our study does prove that perturbing protein folding can lead to fatty liver," Rutkowski said. "The next step is to investigate whether real physiological stresses like chronic alcohol consumption, obesity and viral infection also lead to fatty liver disease through protein folding problems in the ER."







In addition to Rutkowski and Kaufman, who also is a Howard Hughes Medical Institute investigator, key members of the research team included Jun Wu, Ph.D., who was a graduate student at University of Michigan Medical Center, and Mahmood Hussain, Ph.D., at State University of New York Downstate Medical Center. Researchers from the University of Michigan Medical Center; the University of Washington, Seattle, Wash.; and Wayne State University, Detroit, Mich., also were involved in the study.



The study was funded in part by the National Institutes of Health



Source: Jennifer Brown


University of Iowa

DNA-based molecular nano-wires

An international consortium of 7 universities and research centres are seeking an alternative to silicon-based microelectronics in using molecules of DNA, which could enable a reduction in size of the current systems by a thousand times. The University of the Basque Country (UPV/EHU) is participating in this project through the research group led by Professor ?ngel Rubio Secades of the Department of Materials Physics.


The really innovative nature of this project lies, on the one hand, in the use of all the recognition and self-assembly potential of biological systems, more specifically, using derivatives of DNA such as G4-DNA, M-DNA and PC-DNA with a greater electronic potential than DNA itself (which is by itself an insulator).


On the other, it lies in carrying out studies in surface chemistry combined with scanning probe microscopy (SPM) and spectroscopy, the measurement of electrical transport, sophisticated nano-manufacture and theoretical studies of the computational simulation of the stability and properties of synthesised devices and/or motivating new structures that might have a greater potential. In this way the manner of designing nano-wires using these molecular derivatives is being developed.


As is the way of controlling the interaction between the molecular electrode and the molecular substrate, seeking a deep understanding of the energy conduction mechanisms of these nano-wires and being able to produce models of nanomolecular devices based on these DNA derivatives.


This release is also available in Spanish.


Garazi Andonegi

garazielhuyar

34-943-363-040

Elhuyar Fundazioa

basqueresearch

Genetic map of human diversity completed, hope for cure of many diseases

We all share 99.9% of each other's genes, the remaining 0.1% is what makes some of us more susceptible to diseases such as Alzheimer's, Cancer, Diabetes, Heart Disease and a vast array of other conditions.


A couple of hundred scientists from various countries have spent the last few years working away at trying to identify the genetic differences between people. They have been trying to break down the human genome.


269 volunteers were involved in this fete. Some of them came from the Yoruba tribe, Nigeria, others were citizens of Tokyo, Japan, from Beijing, China and European Americans from Utah, USA. The geneticists analysed these people's DNA and built up a map of their genetic diversity (a map showing their genetic differences). The map is based on haplotypes. Haplotypes are large chunks of DNA that contain a unique battery of single mutations - these mutations are inherited together in identical blocks.


The map is called a HapMap (Hap is taken from the word Haplotypes). The scientists have managed to identify and map over one million single mutations to their haplotypes.



Now, the scientists can make comparisons between groups of people who are susceptible to certain diseases and those that are not. They do this by using the HapMap. We will be able to find the genes that cause certain diseases to happen much more quickly as a result of this work, say the scientists - 20 times more quickly, they say.


You can read all about this in the coming issue of Nature, October 27th, 2005.


: Christian

Editor: blog

Blocking Cancer-Causing Gene Improves Radiation Effectiveness, Jefferson Researchers Find

Inhibiting a particular cancer-causing gene can enhance the cell-killing effects of radiation, a team of radiation oncologists and cancer biologists at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia has found.



Adam Dicker, M.D., Ph.D., professor of radiation oncology at Jefferson Medical College and his co-workers used an increasingly common animal model, the zebrafish, and antisense technology to show that the drug flavopiridol works by blocking the activity of the gene, cyclin D1, which is made in excessive amounts in about half of all breast cancers. Using similar techniques in the future, the scientists say, may enable researchers to better gauge the effects of drugs.



According to Dr. Dicker, flavopiridol was found to inhibit cyclins, a family of genes vital to cell functioning. When it was initially tested in clinical trials, it was found to be toxic in humans. But in the laboratory, it added to the cell-killing effects of ionizing radiation, which is used to treat cancer. No one was sure why.



To find out, Dr. Dicker and his group turned to zebrafish. If they understood how the drug was causing toxicity, they or someone else could potentially design molecular copycat drugs that worked just as well, but were less toxic.



"Zebrafish enabled us to add a vertebrate system to examine both efficacy and toxicity issues," he notes. They reported their findings November 7, 2006 at the annual meeting of the American Society for Therapeutic Radiology and Oncology in Philadelphia.



In the work, Dr. Dicker and his co-workers first showed that flavopiridol-treated zebrafish embryos were much more sensitive than normal zebrafish to the effects of radiation. Then, believing that this effect stemmed from the drug's ability to block cyclin D, they used antisense technology to "knock down" - reduce the expression of - several cyclin genes, including cyclin D1.



Antisense DNA drugs work by binding to RNA messages from a target gene. The genetic code in the RNA cannot be read, essentially turning off the gene.



"We think that the radiosensitization is primarily due to cyclin D1," Dr. Dicker says. "We were able to genetically reduce the amount of cyclin D1 through the antisense technology, and when compared to embryos treated with radiation and flavopiridol, we saw that the effects were essentially identical. This shows the power of the system. Flavopiridol hits five or six cyclins and this allows us to find which cyclins are responsible for the radiosensitive effects.



"Theoretically, if we had a drug that inhibited several cyclins, we could understand the effect of inhibiting each cyclin by knocking it down with antisense," he says. "The technique helps explain drug function."






Contact: Steve Benowitz


Thomas Jefferson University

BRIT1 Allows DNA Repair Teams Access To Damaged Sites

Like a mechanic popping the hood of a car to get at a faulty engine, a tumor-suppressing protein allows cellular repair mechanisms to pounce on damaged DNA by overcoming a barrier to DNA access.


Reporting online at Nature Cell Biology this week, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center shows that BRIT1 connects with another protein complex to relax DNA's tight packaging at the site of the damage.


"Relaxing this barrier allows two different DNA repair pathways greater access to the damage, preventing flawed DNA from being passed on as the cell divides, which causes genomic instability leading to cancer," said senior author Shiaw-Yih Lin, Ph.D., assistant professor in M. D. Anderson's Department of Systems Biology.


BRIT1 is under-expressed in human ovarian, breast and prostate cancer cell lines. Lin and colleagues previously showed that the protein plays a key role in early detection of DNA damage.


Chromosomes are made of DNA that is tightly intertwined with proteins called histones to form chromatin. Chromatin is a very condensed structure that forms a natural barrier inhibiting access to genes, said first author Guang Peng, Ph.D., a post-doctoral fellow in Systems Biology. ATP-dependent chromatin remodeling is a fundamental mechanism used by cells to relax chromatin in DNA repair, but the detailed molecular mechanism by which it is recruited to DNA lesions in response to damage signaling has been largely unknown.


BRIT1 summons help


"Our studies demonstrate a novel mechanism by which BRIT1 recruits chromatin remodeling factors to DNA lesions to facilitate chromatin relaxation and DNA repair," Peng said.


A series of lab experiments showed that BRIT1 accomplishes this by enhanced binding to a known chromatin remodeling complex called SWI-SNF when a specific site on the complex is phosphorylated. BRIT1 also maintains the relaxation factor at the damage site.


The team showed that normal BRIT1 aids repair of double-stranded DNA breaks by allowing access to two repair pathways: homologous recombination (HR) and non-homologous end-joining (NHEC).


DNA repair efficiency dropped by between 40 and 60 percent in cells with BRIT1 knocked down that were then exposed to ionizing radiation, allowing many damaged cells to divide and pass on their genetic defects.


Potential for cancer treatment


Having shown that BRIT1 deficiency impairs HR repair, Peng said one solution the team is examining is to treat cancer cells lacking BRIT1 with PARP inhibitors, drugs that specifically kill HR-deficient cancer cells.


BRIT1 mutations are known to cause a neurological condition called primary microcephaly, in which the brain develops to only one third of normal size. The team showed that in experiments using cells derived from primary microcephaly patients that BRIT1 dysfunction may specifically contribute to development of the neurological disease by failing to bind to SWI-SNF to relax chromatin.


The research was funded by grants from the National Cancer Institute and an American Cancer Society Research Scholar Award.


Co-authors with Lin and Peng are: Eon-Kyoung Yim, Hui Dai, Mei-Ren Pan, Ph.D., Ruozhen Hu, all of M. D. Anderson's Department of Systems Biology; Hu is also a student in the University of Texas Graduate School of Biomedical Sciences; Andrew Jackson, Ph.D., of MRC Human Genetics Unit, Western General Hospital in Edinburgh; Ineke van der Burgt, Ph.D., Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, Netherlands; Kaiyi Li, Ph.D., Department of Surgery, Baylor College of Medicine.


About M. D. Anderson


The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For four of the past six years, including 2008, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.


Source: University of Texas M. D. Anderson Cancer Center

NYT Examines Challenges To Improving 'Personalized Medicine' For Breast Cancer, Other Diseases

The New York Times on Tuesday examined how improvements in genetic testing could affect "personalized medicine" for the treatment of breast cancer and other diseases in the future. Personalized medicine uses genetic screening and other tests to provide physicians with more information to tailor patients' treatments, the Times reports. Experts believe that most drugs currently on the market work for only about half of patients who take them, meaning that "much of the nation's approximately $300 billion annual drug spending [is] wasted," and "countless patients are being exposed unnecessarily to side effects," according to the Times. The Times reports that personalized medicine would "go beyond" the "one-size-fits-all" approach of conventional research studies -- in which the "winning treatment [is] recommended for everybody" -- by determining the best treatments for individual patients, rather than treating all patients the same "in hopes of benefiting the fortunate few." However, there is no universally recognized method for evaluating genetic tests, and many can be marketed without FDA approval.

The Times reports that the breast cancer treatment tamoxifen -- a generic drug used to prevent the recurrence of tumors -- "illustrates the promise and current limitations of genetic testing." A 2003 study led by the Indiana University School of Medicine's David Flockhart demonstrated that tamoxifen is converted through the CYP2D6 enzyme -- also known as 2D6 -- into another substance called endoxifen, which is what actually exerts the cancer-fighting effect. However, the enzyme has different levels of activity in different people because of variations in individuals' 2D6 genes, according to Flockhart. He said that up to 7% of people have an inactive enzyme, depending on their ethnicity, and an additional 20% to 40% have a modestly active enzyme. For these individuals, tamoxifen would offer little or no protection against tumors because the patients' bodies could not convert the drug into endoxifen. Currently, most US patients are treated with aromatase inhibitors -- a more expensive, newer class of drugs that cost about $18,000 over five years, compared with $500 for tamoxifen. Aromatase inhibitors performed better than tamoxifen in clinical trials conducted "before the role of 2D6 was generally understood," the Times reports. However, those trials might have found that tamoxifen worked as well or better than the newer drugs if only women with active 2D6 were included, according to researchers at the Dana-Faber Cancer Institute.

The Times reports that "proving these suppositions and having them incorporated into medical practice have not been easy." Tests are available to detect the 2D6 genes of individual patients for about $300, but many experts are hesitant to use the tests because of conflicting study results examining the relationship between tamoxifen and the genes. In addition, there are dozens of variants of the 2D6 gene, and laboratories can differ in how they interpret test results. There also are no clear guidelines for how doctors should act upon the information provided by the test. Drug maker Genentech has petitioned FDA to regulate the tests, and the agency in a meeting last month said that clinical trials would be the best way to validate the tests. However, developers of the tests say that new trials would be too expensive and time-consuming, "so many tests are validated by reanalyzing patient data from old trials," the Times reports. For example, a 2005 study by Matthew Goetz and colleagues at the Mayo Clinic analyzed stored tumor samples from an old trial of breast cancer patients to test the 2D6 genes of each patient. The study found that 32% of women with inactive 2D6 enzymes had relapsed or died within two years, compared with only 2% of women with active enzymes.














Experts also point to other "formidable obstacles on the path to the promised land of personalized medicine," according to the Times. The ability of test developers to prove that their tests are accurate and useful is one major obstacle. Other obstacles include the reluctance of drugmakers to encourage or develop tests that could limit the use of their drugs and the possibility that insurers might not pay for the tests. However, drugmakers are "starting to realize that their medicines might not be approved for paid or without better evidence that they work," according to the Times (Pollack, New York Times, 12/30/08).


Reprinted with kind permission from nationalpartnership. You can view the entire Daily Women's Health Policy Report, search the archives, or sign up for email delivery here. The Daily Women's Health Policy Report is a free service of the National Partnership for Women & Families, published by The Advisory Board Company.


© 2008 The Advisory Board Company. All rights reserved.

Link Between Mutations In Gene And Ciliopathies

An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, have discovered a connection between mutations in the INPP5E gene and ciliopathies. Their findings, which may lead to new therapies for these diseases, appear in the online edition of Nature Genetics.



Ciliopathies are a newly emerging group of diseases caused by defects in the function or structure of cellular primary cilia, which are small, cellular appendages of previously unknown function. Examples of ciliopathies include mental retardation, retinal blindness, obesity, polycystic kidney disease, liver fibrosis, ataxia, and some forms of cancer.



Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego and a Howard Hughes Medical Institute investigator, and his colleagues showed that when two copies of mutated INPP5E are present in an individual, the result is Joubert syndrome, a condition marked by mental retardation and impaired balance. They linked the function of the protein that is encoded by this gene to enzymatic conversion of one of the most important signaling molecules in the body, phosphatylinositol, currently one of the main targets of the pharmaceutical industry to treat a host of diseases, including cancer.



The Gleeson team, led by UC San Diego scientists Stephanie Bielas, PhD, and Jennifer Silhavey, MS, discovered that the enzyme goes to a cellular structure known as the cilium, a long-forgotten organelle without clear function until recently. However, in the past five years, the field of cilia biology has exploded due to the recognition that many of our basic bodily functions are regulated and "fine-tuned" by the cilium.



Because all of the genetic mutations led to an alteration in the enzyme activity, it suggests that the phosphatylinositol pathway could be modulated using drugs already in the pharmaceutical pipeline in order to target a host of cilia-related diseases, to re-establish the normal pathway function and improve the diverse symptoms of ciliopathies.



"Many patients show symptoms that worsen over time," said Gleeson. "It is possible that if effective treatments were available, they could stop or possibly reverse the course of the disease, and prenatal testing could be made available for patients at risk for these conditions."



Currently, existing treatments for ciliopathies are only to ease symptoms. However, according to Gleeson there is recent evidence that one new drug, roscovitine, could arrest polycystic kidney disease, which suggests that similar therapeutical approaches may be helpful in treating other ciliopathies.



One of the most exciting aspects of cilia disease is the connection with obesity. It is possible that modulation of these pathways could represent new avenues to explore for weight control, according to Gleeson.
















Notes:

Contributors to the discovery include co-first authors Stephanie L. Bielas and Jennifer L. Silhavy of UC San Diego; Francesco Brancati of the Casa Sollievo della Sofferenza-Mendel Institute and G. d'Annunzio University Foundation, Italy; Marina V. Kisseleva of the Washington University School of Medicine; Lihadh Al-Gazali of the United Arab Emirates University, United Arab Emirates; Laszlo Sztriha of the University of Szeged, Hungary; Riad A. Bayoumi of Sultan Qaboos University, Sultanate of Oman; Maha S. Zaki of the National Research Centre, Egypt; Alice Abdel-Aleem of the National Research Centre, Egypt; Ozgur Rosti of Istanbul University, Turkey; Hulya Kayserili of Istanbul University, Turkey; Dominika Swistun, Lesley Scott and Seth J. Field of UC San Diego; Enrico Bertini of the Bambino Gesu Children's Research Hospital, Italy; Eugen Boltshauser of the University Children's Hospital of Zurich, Switzerland; Elisa Fazzi of the Instituto di Ricovero e Cura a Carattere Scientifico C. Mondino Institute of Neurology, Italy; Lorena Travaglini of the Casa Sollievo della Sofferenza-Mendel Institute, Italy; Stephanie Gayral, Monique Jacoby and Stephane Schurmans of the Universite Libre de Bruxelles, Belgium; Bruno Dallapiccola of the Casa Sollievo della Sofferenza-Mendel Institute and Sapienza University, Italy; Philip W. Majerus of the Washington University School of Medicine; and Enza Maria Valente of the Casa Sollievo della Sofferenza-Mendel Institute and University of Messina, Italy.


The research was supported in part by grants from the National Institutes of Health, the Italian Ministry of Health, the Telethon Foundation Italy, the American Heart Association, the National Institute of Neurological Disorder and Stroke, the Burroughs Wellcome Fund, the March of Dimes and the Howard Hughes Medical Institute.



Source:
Debra Kain


University of California - San Diego

New Reporting Guidelines For Genetic Risk Prediction Studies: GRIPS Statement

This week PLoS Medicine publishes the Genetic RIsk Prediction Studies (GRIPS) Statement, a checklist and guidance to help strengthen the reporting of genetic risk prediction studies.


Because progress in gene discovery for complex diseases is fuelling interest in the application of genetic risk models for clinical and public health practice, the number of studies assessing predictive ability is steadily increasing, but the quality and completeness of reporting varies. The GRIPS Statement (and accompanying explanation document) provides guidance to enhance the transparency of study reporting, thereby improving the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis.


In order to encourage dissemination, PLoS Medicine is co-publishing this article with Annals of Internal Medicine, BMJ, Circulation: Cardiovascular Genetics, European Journal of Clinical Investigation, European Journal of Epidemiology, European Journal of Human Genetics, Genetics in Medicine, Genome Medicine, and Journal of Clinical Epidemiology.


Funding:

The workshop was sponsored by the US Centers for Disease Control and Prevention on behalf of the Human Genome Epidemiology Network (HuGENet). A. Cecile J.W. Janssens is financially supported by grants from the Erasmus University Medical Center Rotterdam, the Center for Medical Systems Biology in the framework of the Netherlands Genomics Initiative (NGI) and the VIDI grant of the Netherlands Organisation for Scientific Research (NWO). John P.A. Ioannidis: Tufts CTSI is supported by the National Institutes of Health/ National Center for Research Resources (UL1 RR025752). Opinions in this paper are those of the authors and do not necessarily represent the official position or policies of the Tufts CTSI. Julian Little holds a Canada Research Chair in Human Genome Epidemiology. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.


Competing Interests: John P. A. Ioannidis is a member of the PLoS Medicine Editorial Board.



Citation:


"Strengthening the Reporting of Genetic Risk Prediction Studies: The GRIPS Statement"

Janssens ACJW, Ioannidis JPA, van Duijn CM, Little J, Khoury MJ, et al. (2011)

PLoS Med 8(3): e1000420. doi:10.1371/journal.pmed.1000420

18 Honoured By National Academy Of Sciences For Major Contributions To Science

The National Academy of Sciences (NAS) will honor 18 individuals in 2009 with awards recognizing extraordinary scientific achievements in the areas of biology, chemistry, geology, astronomy, social sciences, psychology, and application of science for the public good.



The recipients for 2009 are:
GRAHAM ALLISON, Douglas Dillon Professor of Government and director of the Belfer Center for Science and International Affairs at Harvard's John F. Kennedy School of Government, is the recipient of the NAS AWARD FOR BEHAVIORAL RESEARCH RELEVANT TO THE PREVENTION OF NUCLEAR WAR. Allison is being honored for illuminating alternative ways of thinking about political decision making with special relevance to crises, including nuclear crises, as demonstrated in his groundbreaking ESSENCE OF DECISION and subsequent works. The award, established by the gift of William and Katherine Estes, comes with a $20,000 prize and recognizes basic research in any field of cognitive or behavioral science that uses rigorous formal and empirical methods to advance our understanding of issues relating to the risk of nuclear war.


CORNELIA I. BARGMANN, Howard Hughes Medical Institute investigator and Torsten N. Wiesel Professor at Rockefeller University, is the recipient of the RICHARD LOUNSBERY AWARD. Bargmann is being honored for her extraordinarily inventive and successful use of molecular and classical genetics to probe the individual nerve cell basis of behavior in C. ELEGANS. The Lounsbery Award -- consisting of a medal and a prize of $50,000 -- is awarded to French and American scientists in alternate years for extraordinary scientific achievement in biology and medicine. The award is supported by the Richard Lounsbery Foundation.


JONATHAN BECKWITH, American Cancer Society Professor in the department of microbiology and molecular genetics at Harvard University, will receive the SELMAN A. WAKSMAN AWARD IN MICROBIOLOGY. Beckwith is being honored for fundamental contributions to gene regulation, protein targeting and secretion, and disulfide biochemistry, and also for the development of gene fusions as an experimental tool. This award, established by the Foundation for Microbiology, recognizes excellence in the field of microbiology and comes with a prize of $5,000.


STEPHEN P. BELL, Howard Hughes Medical Institute investigator and professor of biology at the Massachusetts Institute of Technology, is the recipient of the NAS AWARD FOR MOLECULAR BIOLOGY. Bell is being honored for groundbreaking studies illuminating the mechanisms of DNA replication in eukaryotic cells. The award consists of a medal and a prize of $25,000, and is sponsored by Pfizer Inc.


CHARLES L. BENNETT, professor of physics and astronomy at Johns Hopkins University, is the recipient of the COMSTOCK PRIZE IN PHYSICS. Bennett is being honored for his mapping of the cosmic microwave background and determining the universe's age, mass-energy content, geometry, expansion rate, and reionization epoch with unprecedented precision. This prize of $20,000 is awarded for a recent innovative discovery or investigation in electricity, magnetism, or radiant energy.















ROBERT N. CLAYTON, Enrico Fermi Distinguished Service Professor Emeritus at the University of Chicago, will receive the J. LAWRENCE SMITH MEDAL. He is being honored for pioneering the study of oxygen isotopes to unravel the nature and origin of meteorites, showing that meteorites were assembled from components with distinct nuclear origins. The medal and a prize of $25,000 are awarded for recent original and meritorious investigations of meteoric bodies.


JOSEPH FELSENSTEIN, professor in the departments of genome sciences and biology at the University of Washington, is awarded the JOHN J. CARTY AWARD FOR THE ADVANCEMENT OF SCIENCE. Felsenstein is being honored for revolutionizing population genetics, phylogenetic biology, and systematics by developing a sophisticated computational framework to deduce evolutionary relationships of genes and species from molecular data. The Carty Award -- a medal and a prize of $25,000 awarded annually for noteworthy and distinguished accomplishment in any field of science -- is being presented in the area of evolution in 2009.


ALFRED G. FISCHER, professor emeritus in the department of geological sciences at the University of Southern California, is the recipient of the MARY CLARK THOMPSON MEDAL. He is being honored for leadership and research in the discovery of the cyclical and period nature of the sedimentary record in the geologic past and its connections with earth-system change, including biodiversity. This medal, with a prize of $15,000, is awarded to recognize important contributions to geology and paleontology.


JOANNA S. FOWLER, senior chemist in the department of medicine at Brookhaven National Laboratory, is awarded the NAS AWARD IN CHEMICAL SCIENCES. Fowler is being honored for exceptional accomplishments in the synthesis of positron-emitting chemical probes, and for their implementation in biomedical imaging and studies of IN VIVO biochemistry, which have had a major impact on human health worldwide. The medal and prize of $15,000 are given for innovative research in the chemical sciences that contributes to the better understanding of the natural sciences and to the benefit of humanity, and is supported by the Merck Company Foundation.


NEIL GEHRELS is the recipient of the HENRY DRAPER MEDAL. Gehrels, chief of the Astroparticle Physics Laboratory at the NASA/Goddard Space Flight Center, is being honored for his pioneering contributions to gamma ray astronomy. His leadership of the Compton Gamma Ray Observatory and the Swift Mission has led to new insights into the extreme physics of active galactic nuclei and gamma ray bursts. The Henry Draper Medal and a prize of $15,000 are awarded for an original investigation in astronomical physics.


ARTHUR R. GROSSMAN of the Carnegie Institution for Science is the recipient of the GILBERT MORGAN SMITH MEDAL. Grossman is being honored for pioneering creative and comprehensive research on algae and cyanobacteria, elucidating molecular mechanisms by which they adapt to changes in light color and to nutrient stress. The Gilbert Morgan Smith Medal and prize of $20,000 are awarded for excellence in published research on marine or freshwater algae.


ROGER W. HENDRIX of the University of Pittsburgh is awarded the NAS AWARD FOR SCIENTIFIC REVIEWING. Hendrix's reviews, overviews, and minireviews have focused research in the areas of structure, assembly, and genomics of bacteriophages and include numerous original and provocative ideas. The prize of $10,000 -- given in 2009 in the field of genetics -- acknowledges excellence in scientific reviewing within the past 10 years. The award is supported by ANNUAL REVIEWS, the Institute for Scientific Information, and THE SCIENTIST in honor of J. Murray Luck.


ALI JAVEY, assistant professor of electrical engineering and computer sciences at the University of California, Berkeley, is the recipient of the NAS AWARD FOR INITIATIVES IN RESEARCH. Javey is being recognized for seminal advances in carbon nanoelectronics, utilizing and synthesizing concepts from chemistry, physics, and engineering. The prize of $15,000 is awarded to recognize innovative young scientists and to encourage research likely to lead toward new capabilities for human benefit. The award -- established by AT&T Bell Laboratories in honor of William O. Baker and supported by Alcatel-Lucent -- is being presented in 2009 in the field of nanoscience.


TIRIN MOORE, assistant professor in the department of neurobiology at Stanford University School of Medicine, and ANDREW J. OXENHAM, assistant professor in the department of psychology at the University of Minnesota, will each receive a TROLAND RESEARCH AWARD. Moore is being honored for fundamental and insightful contributions to our understanding of the neuronal mechanisms that control directed visual attention. Oxenham is being honored for profound and rigorous contributions to our understanding of the relationship between auditory perception and its underlying physiological mechanisms. The Troland Research Awards are two research awards of $50,000 given annually to young investigators to recognize unusual achievement and to further their research within the broad spectrum of experimental psychology.


JOHN D. ROBERTS, Institute Professor of Chemistry Emeritus at the California Institute of Technology, is awarded the NAS AWARD FOR CHEMISTRY IN SERVICE TO SOCIETY. Roberts is being honored for seminal contributions in physical organic chemistry, in particular the introduction of NMR spectroscopy to the chemistry community. The award, consisting of a prize of $20,000, was established by E.I. du Pont de Nemours & Co.


KEITH W. TANTLINGER of Tantlinger Engineering is awarded the GIBBS BROTHERS MEDAL. Tantlinger is being honored for his visionary and innovative design of the cellular container ship and supporting systems that transformed the world's shipping fleet and facilitated the rapid expansion of global trade. The medal and prize of $20,000 are given for outstanding contributions in the field of naval architecture and marine engineering.

Also to be honored at the April 26 awards ceremony, which will take place during the Academy's 146th annual meeting, is NEAL F. LANE, Malcolm Gillis University Professor and senior fellow of the James A. Baker III Institute for Public Policy at Rice University, who was chosen to receive the PUBLIC WELFARE MEDAL. Lane, who served as assistant to the president for science and technology and director of the Office of Science and Technology Policy from 1998 to 2001, and as director of the National Science Foundation from 1993 to 1998, is honored for serving the scientific community in many executive and leadership roles and for his continuing efforts to advance and promote science and technology in the United States. The medal was established to recognize distinguished contributions in the application of science to the public welfare and has been presented since 1914.







The National Academy of Sciences is a private, nonprofit honorific society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Since 1863, the National Academy of Sciences has served to "investigate, examine, experiment, and report upon any subject of science or art" whenever called upon to do so by any department of the government.



[ This news release is available at NATIONAL-ACADEMIES ]



Source: Maureen O'Leary


National Academy of Sciences

Scripps Research Scientists Win $65 Million In New Grants To Reveal Form And Function Of Proteins

Scripps Research Institute scientists have been awarded approximately $65 million in four five-year grants as part of the National Institutes of Health's (NIH) latest round of structural biology funding. The projects will focus on determining the shapes and functions of proteins and protein complexes that are important in biology and medicine.



"The grants are an acknowledgement of The Scripps Research Institute's leadership in the field of structural studies," said Scripps Research President Richard A. Lerner, M.D. "We're looking forward to many more important advances from our scientists thanks to this latest round of support from the NIH."



The four Scripps Research grants are part of the NIH Protein Structure Initiative (PSI), an effort that started in 2000 with the main goal of developing highly efficient methods for solving the structures of many different proteins. The new grants mark the beginning of the effort's third phase, called "PSI:Biology." A key aim of this phase is to apply the high-throughput methods developed during the initiative's first decade to challenging biological problems and systems.



"These awards to Scripps Research represent the key elements of the Protein Structure Initiative - from generating structures and new structure determination methods for particularly challenging proteins to harnessing the power of high-throughput to address important biological problems," said Ward Smith, Ph.D., director of the PSI. "Together, these approaches can significantly advance our understanding of the role proteins play in health and disease."



The Scripps Research grants are:
$37.6 million to a consortium led by Ian A. Wilson, D.Phil., Hansen Professor of Structural Biology and member of the Skaggs Institute for Chemical Biology at Scripps Research.
$5.8 million to a group led by Jamie Williamson, Ph.D., professor, dean of the graduate school, and member of the Skaggs Institute, and Daniel R. Salomon, M.D., associate professor and Medical Director of the Scripps Center for Organ and Cell Transplantation
$16.8 million to a center led by Raymond Stevens, Ph.D., professor in the Departments of Molecular Biology and Chemistry, together with Scripps Research investigators Assistant Professor Vadim Cherezov, Associate Professor Peter Kuhn, Professor Hugh Rosen, and Professor Kurt W??thrich
$5 million to the Scripps Research portion of a collaboration led by Geoffrey Chang, Ph.D., associate professor and member of the Skaggs Institute, in conjunction with Doug Rees, Howard Hughes Medical Institute investigator and Professor at the California Institute of Technology, and Michael Stowell, associate professor at the University of Colorado. The total for this grant is $11.5 million.

Large-Scale Structure Determination



Building on a decade of success and the solution of more than 1,000 structures, Wilson will continue to lead one of four, long-standing, large-scale PSI centers.
















The consortium - called the Joint Center for Structural Genomics (JCSG) and comprising scientists at the University of California, San Diego; Genomics Institute of the Novartis Research Foundation (GNF); Sanford-Burnham Medical Research Institute; and Stanford Synchrotron Radiation Lightsource (SSRL), Stanford University - will continue to operate its pipeline for high-throughput structure determination. Structures that the group plans to tackle over the next five years include challenging targets, such as eukaryotic proteins, as well as protein-protein, protein-RNA, protein-DNA, and other complexes.



One theme of the center's research will be the human "microbiome," the totality of microbes in a defined environment, such as the human digestive tract.



"Interactions of bacteria with the human body are profound and have a significant impact on maintenance of general human health," said Wilson. "In addition, they are associated with obesity, inflammatory diseases, diabetes, and certain cancers, to name but a few disorders."



The center will focus on solving these structures by continuing to hone their highly efficient methods and by conducting collaborative research, including with scientists outside the PSI network.



Biological Problems



The JCSG and other large-scale centers will partner with eight groups of biologists, including one based at Scripps Research, that require the determination of many protein and protein-RNA structures to understand biological processes or a molecule's function.



The Scripps Research center, led by Williamson and Salomon, will focus on better understanding the workings of part of our immune system, which protects us against disease by fending off pathogens such as bacteria, viruses, and tumor cells. The immune system is also a critical determinant of the success or failure of kidney, heart, liver, and bone marrow cell transplants. In particular, the scientists aim to better understand the role of ribonucleoproteins (complexes of RNA and protein involved in a wide range of cellular processes, including protein synthesis) in regulating the activation of T-cells, a type of white blood cell.



"This work should provide significant new insights into the structure of ribonucleoprotein complexes in general," said Williamson. "In addition, we hope to gain new insights into how these complexes are involved in posttranscriptional gene regulation."



"Understanding how T cells draw from all the information embedded in the human genome to determine how to respond to an immune challenge like a virus, tumor cell, or transplant is an opportunity to study the mechanisms of health and disease," added Salomon, "and to do this at the level of protein structures in this new collaboration with the JCSG is a remarkable opportunity to advance translation biology and medicine."



The scientists will use genomic, biochemical, and functional research in combination with structural studies to forge new inroads in the field.



Membrane Protein Structures



The new grants also support nine centers - two of which are based at The Scripps Research Institute - for determining membrane protein structures. Membrane proteins, which are embedded in the membranes of our cells, are important because they enable our nerves, muscles, and even hormones to do their jobs. Currently, however, scientists can't easily visualize their three-dimensional shapes to understand how these proteins function.



The Scripps Research Institute center led by Stevens, Cherezov, Kuhn, Rosen, and W??thrich will focus on a special class of human membrane proteins called G protein-coupled receptors (GPCRs), signaling molecules that span the membranes of cells, "sensing" chemical messages outside the cells and converting them into action within the cell. GPCRs are the largest family of proteins in the human genome.



"Our fundamental understanding of GPCR molecular recognition and signaling is still in the early stages," said Stevens. "Through the creation of the GPCR Network center, we will work directly with the GPCR community on improving our basic understanding of receptor structure and function using a variety of biophysical techniques including NMR, HDX, and X-ray crystallography, as well as computational and chemical screening techniques. Only a few GPCR structures in their inactive state have been solved to date and the basic understanding of this key membrane protein class will change drastically in the next five years with the NIH funding."



In a separate group, Chang, Rees, and Stowell will focus on a class of proteins called transporters - a type of large protein that resides in the cell membrane and moves other molecules in and out. Transporters are vital to the biology of all cells and a variety of diseases occur when these processes are perturbed or disrupted, as in several genetic disorders. In addition, cancer cells resist chemotherapy by using these transporters, and bacterial cells use them to resist antibiotics.



"We actually have very good drugs to fight cancer and to kill bacteria," said Chang. "[But] they can't always get into the cells to work."



This new center, dubbed TransportPDB, aims to develop a comprehensive and efficient approach for pursuing the high-resolution x-ray crystal structures of several transporters that PSI scientists have selected as important in biomedicine.



Source:

Mika Ono

Scripps Research Institute

Restless Legs Syndrome Has Complex Genetic Involvement

A new study confirmed that a gene associated with restless legs syndrome (RLS) susceptibility is located on chromosome
12q and and also suggests that at least one other gene may be involved in restless leg syndrome, according to an article in
the April issue of the Archives of Neurology, one of the JAMA/Archives journals.


Restless legs syndrome is one of the leading causes of insomnia, affecting more than five to 10 percent of the white
population, according to background information in the article. Genetic contributions to restless legs syndrome have been
consistently supported by population, family and twin studies. To identify genetic risk factors, the current study used
information from French Canadian families, where, according to the researchers, prevalence of restless legs syndrome is
higher than in other populations.


Alex Desautels, Ph.D., of the University of Montreal, and colleagues examined the DNA of 19 multigenerational French Canadian
families with four to nine individuals who were affected (or possibly affected) by restless legs syndrome. The researchers
used statistical analysis of the genetic information to determine whether restless legs syndrome in each family was linked
with markers on the same location on chromosome 12q that had previously been associated with restless legs syndrome.


Two-hundred-seventy-six individuals were included in the study, including 146 affected individuals, 39 possibly affected
individuals and 91 unaffected family members. The researchers confirmed that the syndrome was consistent with linkage to
chromosome 12q within five families. Linkage to that location was formally excluded for six other families. The researchers
compared clinical features of the syndrome in affected individuals from the different families to see if those differences
correlated with the differences in linkage. They found that one feature, periodic leg movements during sleep, was
significantly greater for affected individuals from the linked families than for affected individuals from the unlinked
families.


"These results further support the involvement of an RLS-susceptibility locus [gene location] on chromosome 12q in the FC
[French Canadian] population and also provide evidence that there must be other loci involved in this common sleep disorder,"
the authors conclude. "Furthermore, our findings illustrate that extensive characterization of subclinical differences
represents a major tool in the identification of susceptibility loci for complex diseases ??? Although the background of RLS is
most likely complex, this finding may offer a new starting point for further dissecting the genetic cause of RLS."
(Arch Neurol. 2005;62:591-596.
Available post-embargo at archneurol)


This study was supported in part by research grants from the Canadian Institutes of Health Research (CIHR), Ottawa and from
the National Institutes of Health, Bethesda, Md. Dr. Desautels is a recipient of the CIHR studentship.


JAMA/Archives news release

Embryos Part-animal And Part-human Created

Embryos that are part-human and part-animal have been created by scientists at Newcastle University, UK. The scientists, who are researching into a range of illnesses, said the embryos survived for up to three days.


While religious leaders describe this development as monstrous, scientists and medical professionals hail the event as one step closer to understanding illnesses such as Alzheimer's and Parkinson's better, and ultimately being able to treat them. Members of the Catholic Church say these experiments are akin to those of Frankenstein.


Team leader, Dr. Lyle Armstrong, was granted a licence by HFEA (Human Fertilisation and Embryology Authority) to use animal eggs in research aimed at understanding how cells develop. Dr. Armstrong and team have been working on this project since the licence was granted and have made some very preliminary findings.


The hybrid embryos were created by injecting human skin cell DNA into eggs which were extracted from the ovaries of cows - the ovaries had had all their genetic material removed. According to the scientists, they used eggs from cow ovaries because eggs donated from humans are scarce.


Dr Armstrong is part of the North East England Stem Cell Institute (NESCI) and is based at the International Centre for Life in Newcastle.


The scientists stress that the hybrid embryos would never be allowed to survive beyond their 14th day. Their aim is to extract stem cells for research into a range of diseases, and eventually find ways of treating them.


"This is licensed work which has been carefully evaluated. This is a process in a dish, and we are dealing with a clump of cells which would never go on to develop. It's a laboratory process and these embryos would never be implanted into anyone. We now have preliminary data which looks promising but this is very much work in progress and the next step is to get the embryos to survive to around six days when we can hopefully derive stem cells from them," said Professor John Burn, Head of the Institute of Human Genetics, Newcastle University.


Legislation related to the creation of hybrid embryos


A bill which covers new legislation regarding the creation of hybrid embryos will be debated in parliament (UK) in May in the House of Commons. Prime Minister, Gordon Brown, had to give in to demands for a free vote (by parliamentarians) on this issue.


-- Hybrid Embryos - FAQs

-- Institute of Human Genetics

Altered DNA Allows Salmonella To Survive Better In Stomach

Since 1995 there has been a considerable increase in the number of infections with a specific type of Salmonella bacteria transmitted via food. This type, Salmonella serovar Typhimurium DT104, is resistant to at least five different antibiotics. Dutch researcher Armand Hermans found new genetic information in DNA of DT104 that might be involved in its survival and infection mechanism. This genetic information might also be involved in the increase in the number of infections caused by this pathogen.



By comparing the DNA of Salmonella serovar Typhimurium DT104 with the known DNA code of another Salmonella strain, Hermans found new DNA fragments in DT104. These pieces of DNA were found to contain genetic information that might play a role in the survival and infectiousness of this pathogen. The presence of such extra genetic characteristics can make the pathogen stronger and more infectious.



To examine how DT104 behaves to survive various "extreme" conditions, the switching on and off of 500 genetic characteristics was studied. This happened under different conditions such as in a hot, acid or oxygen-free environment. Almost all of the survival characteristics were found to be active under all conditions, whereas the pathogenic characteristics were only active under a few of the conditions. Therefore this pathogen always does everything it can to survive under all conditions, for example, during food conservation or in gastric acid. The pathogenic characteristics of DT104 on the other hand are only active in the intestines where the infection takes place.



Evolution of the pathogen



The DNA of the pathogen says something about how it survives and is transmitted. When a pathogen reproduces, the DNA can change a bit and this can lead to changes in the genetic characteristics. This can, for example, lead to antibiotic resistance but also heat or acid resistance. The pathogens with the best genetic characteristics can spread and survive better and are therefore more infectious: the evolution of a pathogen. Examining which genetic characteristics are present in an infectious Salmonella (in this case the DT104 type) can reveal how this pathogen has become stronger and caused more outbreaks. This information can also be used to make a less dangerous variant of this infectious Salmonella. Such a harmless variant can be used as a vaccine.



Salmonella serovar Typhimurium DT104 is an antibiotic-resistant pathogen that is transmitted via food and is considered to be dangerous for humans. In recent decades the number of infections with this variant has increased in many parts of the world. This research was funded by NWO and contributes to knowledge about the characteristics and behaviour of this dangerous Salmonella.







For further information please contact:
* Dr Armand Hermans



* The doctoral thesis was defended on 16 January 2007 at Wageningen University and Research Centre

* Supervisors Prof. T. Abee and Prof. M.H. Zwietering
* associate supervisor Dr H.J.M. Aarts



Contact: Dr Armand Hermans


Netherlands Organization for Scientific Research

New Drug Strategy Against Fragile X Syndrome

Researchers at Emory University School of Medicine have identified a potential new strategy for treating fragile X syndrome, the most common inherited cause of intellectual disability.



The researchers have found that a class of drugs called phosphoinositide-3 (PI3) kinase inhibitors can correct defects in the anatomy of neurons seen in a mouse model of fragile X syndrome. In experiments with cultured neurons from the hippocampus, a brain region involved in learning and memory, the drugs could restore normal appearance and levels of protein production at synapses, the junctions between cells where chemical communication occurs. The results, published online this week in the Journal of Neuroscience, suggest that PI3 kinase inhibitors could help improve learning and cognition in individuals with fragile X syndrome.



"This is an important first step toward having a new therapeutic strategy for fragile X syndrome that treats the underlying molecular defect, and it may be more broadly applicable to other forms of autism," says senior author Gary Bassell, professor of cell biology and neurology at Emory University School of Medicine. He adds that his group has recently begun experiments in the mouse model to assess PI3 kinase inhibitors' effects on behaviors associated with fragile X syndrome.



The first author of the paper is postdoctoral fellow Christina Gross. Collaborators included Keqiang Ye, PhD, associate professor of pathology and laboratory medicine, and Stephen Warren, PhD, professor and chairman of human genetics.



In the United States, fragile X syndrome is the most common known one-gene cause of autism, accounting for between two and five percent of cases. Mutations in the PTEN gene and tuberous sclerosis genes, which in humans can lead to autism, also perturb the signaling of the PI3 kinase pathway, Bassell says. This connection suggests that PI3 kinase inhibition might be a viable strategy for treating individuals with mutations affecting this pathway.



While clinical trials in humans testing the effectiveness of another class of drugs, metabotropic glutamate receptor antagonists, against fragile X are well underway, Bassell says "the new approach may offer a different way to calm the overactive signaling, and also restore the glutamate receptor sensitivity that is lost in fragile X."



The genetic mutation responsible for fragile X prevents production of an RNA binding protein, FMRP, which regulates the production of many other proteins at synapses of brain cells. FMRP's absence leads to overactive signaling and protein production at synapses.



"The focus in the field has been on glutamate receptor antagonists," Bassell says. "The effects on glutamate receptor signaling are a big piece of fragile X, but they're not the only piece."



At their synapses, fragile X neurons produce proteins indiscriminately compared to unaffected neurons, he says. The "overexuberant" protein production leads to structural changes at their synapses, including a hyperabundance of dendritic spines. These spines are small protrusions that transmit electrical signals to adjacent neurons, and contribute to the communication between individual neurons in the brain.
















Gross and Bassell discovered that in cells from mice where the FMRP gene has been deleted, the PI3 kinase enzyme is three times more active. PI3 kinase regulates protein synthesis in response to the electrochemical signals neurons send each other. The authors showed that tamping down PI3 kinase activity in fragile X neurons can restore normal levels of both protein synthesis and dendritic spine density.



PI3 kinase inhibitors are already under investigation for their anti-cancer properties, and some drugs of this type, such as wortmannin, can be toxic to normal cells. Bassell notes that this type of drugs would need to be used at low doses to only dampen excess signaling of protein production caused by fragile x. The drugs his team tested were effective in correcting fragile X molecular defects at levels five times lower than those usually employed, and did not reduce protein production in normal cells.



Bassell anticipates that drugs that preferentially inhibit the subtype of PI3 kinase present only in neurons hold greater promise as a novel therapeutic strategy.



"A few of these subtype-specific drugs are already available for researchers, and we are involved in efforts to test these more specific drugs in the fragile x mouse model," he says.



"This is a really exciting time for fragile x research because progress is occurring at a fast pace," Gross says. "I look forward to testing our theory of this mechanistic link between fragile x and autism, which suggests that a specific drug treatment could be broadly applicable."



The research was supported by the National Institutes of Health and the National Fragile X Foundation.



Reference:
C. Gross, M. Nakamoto, X. Yao, C.B. Chan, S.Y. Yim, K. Ye, S.T. Warren and G.J. Bassell. Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J. Neurosci. 30: page #s (2010).



Source:

Jennifer Johnson

Emory University

Method By Which A Protein That Determines Cell Polarity Prevents Breast Cancer

In breast tissue, cells lining the breast's ducts have a certain shape that is required to maintain both organ structure and function. All breast cancers display a loss of this characteristic organization, but very little is known about the molecules and pathways that regulate tissue structure and the role they play during cancer.



A team of scientists at Cold Spring Harbor Laboratory (CSHL) has now discovered that a protein called Scribble, originally discovered as a cell-shape regulator in fruit flies and worms, is an important regulator of breast cancer. They report that normal function of Scribble protein allows breast epithelial cells to form duct-like structures and resist cancer formation. When Scribble stops functioning, the tissue loses its shape and cancers ensue.



A new approach to understanding how cancer begins



The discovery identifies "a new paradigm for understanding how cancer initiates," according to CSHL Professor Senthil Muthuswamy, Ph.D., who headed the team that conducted the research, published in Cell on Nov. 26. The results also constitute first steps toward identifying an entirely new class of molecules and pathways that can be targeted by anti-cancer therapies to prevent pre-cancerous lesions from turning into malignant tumors.



"Thinking about cancer as a disease that results only due to an increase in cell numbers is too simplistic," according to Muthuswamy. He points out that proteins that control cell number and regulate cell structure are both critical in cancer development. He therefore proposes that carcinomas--cancers derived from epithelial cells in organs such as breast, ovary, prostate, lung and pancreas--should be approached as a problem of "deregulated morphogenic processes and not just as a disease of increased cell number."



Seeing cells in three dimensions



Many studies aimed at unraveling cancer's molecular mechanisms use cells cultured on plastic dishes as an experimental platform. "Such models have been quite satisfactory in allowing scientists to analyze mechanisms involved in cell growth" says Muthuswamy. But they don't allow scientists to capture the three-dimensional organization of cells seen in tissue, including their polarity. A major enabler for Muthuswamy's current work is an experimental model system that enables him to grow breast cells in three-dimensional cultures to allow them to form structures similar to those seen in breast ducts and lobules.



On Muthuswamy's novel test bed, cells undergo morphogenesis -- a growth/death cycle that expands and shapes tissue. Such cells give rise to what looks like a hollow ball of cells. The polarity protein Scribble lines the sides of each cell, lending to each a specific orientation.



What happens when Scribble is missing?



In breast epithelial cells grown in this new experimental culture system, when the Scribble protein is missing, cells were observed by Muthuswamy's team to radically change their character and behavior. They lost their orientation -- an effect one might have predicted since Scribble regulates polarity -- and started to fill the hollow ball.. The team hypothesized that the filling-in of the "ball" was akin to the process, in living creatures, by which a breast epithelial tumor would form.
















To test this notion, the experiment was moved from a cell-culture dish to living animals. Mouse breasts were generated using genetically engineered cells that had stopped producing the Scribble protein. In such mice, the researchers found that breast ducts were deformed and tumors typically developed after about one year's time. This dramatic result pointed to Scribble, a cell shape regulator, as a tumor suppressor in breast epithelial cells.



The targets of tumor suppressors are usually cancer-causing genes, or oncogenes, such as Myc, which past research has shown to be overexpressed, i.e., present in abnormal quantity, in human breast cancer. Myc is known to activate pathways of both growth and death in breast epithelial cells. In fact, the only way that cancer can occur when Myc is overexpressed is if some other mechanism blocks its propensity to induce abnormal cells to commit suicide, a process called apoptosis. Muthuswamy and colleagues now identify this "other mechanism" as the loss of the Scribble protein, which thus is revealed to be a tumor suppressor protein.



Cells engineered by the CSHL team to lack Scribble and overexpress Myc not only stayed alive, but also went into a growth overdrive. The combined effect of polarity loss and Myc overactivation was the formation of unusually large and fast-growing breast epithelial tumors.



The CSHL team worked out the molecular players and specific intracellular pathway controlled by Scribble to initiate cell death. This revealed that Scribble only works as a cancer deflector when it finds itself in the right location--within the junctions between cells. Cellular disorientation occurs when mutations in the gene that orders Scribble to be produced in a cell either prevents its expression or causes it to be expressed in the wrong location within the cell. In either case, the same severe consequence ensues: cancer progression.



How Scribble gets deregulated in cancer remains a mystery. The CSHL team is now addressing the question of how the deregulated Scribble pathway can be targeted for diagnosis and treatment.







"Deregulation of Scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma" appears in the November 2008 issue of Cell. The full citation is: Lixing Zhan, Avi Rosenberg, Kenneth C. Bergami, Min Yu, Zhenyu Xuan, Aron B. Jaffe, Craig Allred, and Senthil K. Muthuswamy. The paper appears online at cell/ on Nov 26th 2008.



Cold Spring Harbor Laboratory (CSHL) is a private, not-for-profit research and education institution at the forefront of efforts in molecular biology and genetics to generate knowledge that will yield better diagnostics and treatments for cancer, neurological diseases and other major causes of human suffering.



For more information please visit cshl.edu/.



Source: Hema Bashyam


Cold Spring Harbor Laboratory