Stem cells of any kind are defined by their eternal nature, reproducing themselves and providing a pool of cells from which more differentiated tissues arise.
Now a group of researchers from Baylor College of Medicine in collaboration with researchers in Australia and the United Kingdom, demonstrate that two specific "sister" genes that control transcription play often overlapping roles in maintaining this pool of hematopoietic or blood cell-forming stem cells.
In a report in the current issue of the journal Cell Stem Cell, the scientists show that genes for two transcription factors -- the stem cell leukemia gene (Scl) and the lymphoblastic leukemia gene 1 (Lyl1) - play overlapping or redundant roles in maintaining this pool of hematopoietic (blood-forming cells) stem cells. These are so-called "adult" stem cells because they can differentiate only into tissues of the blood system.
"Both genes are involved in T-cell acute lymphoblastic leukemia," said Dr. Margaret Goodell, director of the Stem Cells and Regenerative Medicine (STaR) Center of Baylor College of Medicine and senior author of the report that appears in the current issue of the journal Cell Stem Cell. "No one knew what role Lyl1 played in hematopoiesis (the formation of blood and related cells). The two of them have a functional redundancy. If one is missing, the cell might be a little 'sick,' but it survives. If both are missing, the cells die pretty quickly."
"Scl has been well studied and is a paradigm for hematopoiesis," she said. "Lyl1 was a lost sister. Only recently have a few groups studied it."
Previous studies had shown that when animals lacked the gene Scl in the embryonic stage, they did not make progenitor cells intrinsic to the formation of the blood cells and had defects in the blood vessel system. When the gene Scl is turned off in adult animals, blood cells are not repopulated in the short term but they do come back over the long term, the researchers noted.
George Souroullas, a graduate student in Goodell's laboratory at BCM and first author of the paper said, "Up to this point, it was believed that Scl was dispensable for maintaining adult hematopoietic stem cell function after development. Our study however, shows that not only is it not dispensable, but it collaborates with Lyl1, and both necessary for cell survival."
When blood-forming stem cells lack Scl and have only one copy of the Lyl1 gene, they can still be used successfully in a stem cell transplant, enabling animals to continue to make blood cells in the long-term. However, if these stem cells lack Lyl1 and Scl, they die rapidly.
This suggests that Scl and Lyl1 are not only important in the formation of these kinds of stem cell but also for their maintenance in adults, the researchers said.
"If these genes work together in stem cells, they might play a similar role in leukemia cells," said Goodell.
While she describes the two as sister genes, Goodell believes they have distinct roles as well.
Souroullas said, "While these genes are very similar and functionally redundant in adult stem cells, some molecular differences in protein structure, supported by other data in our lab, suggest that they may in fact have distinct functions in differentiated blood cell types"
Goodell added that "one may be more important in the embryo while the other in the adult."
Others who took part in this work include; Jessica M. Salmon and David J. Curtis of the University of Melbourne in Australia and Fred Sablitzky of the University of Nottingham in Nottingham, United Kingdom.
Funding for this work came from the National Health & Medical Research Council in Australia and the National Institutes of Health in the United States.
This report is available at cell/cell-stem-cell/home
For more information on basic science research at Baylor College of Medicine, please go to bcm.edu/news.
Source: Glenna Picton
Baylor College of Medicine
вторник, 30 августа 2011 г.
суббота, 27 августа 2011 г.
Missing sequence of the human Y chromosome found
Sequence may contain genes controlling stature and tumor development - Scientists report today in the journal Genome
Research that they have successfully cloned and characterized a previously intractable DNA sequence: a 554-kilobase-pair
genomic segment near the centromere of the human Y chromosome. This sequence contains eight putatively active genes that
could be implicated in sex-associated height differences and gonadal tumor development.
This pericentromeric gap was one of the few holes remaining in the "finished" sequence of the human genome reported last
October by the International Human Genome Sequencing Consortium. This "finished" sequence was the culmination of a 13-year
effort to elucidate the order and orientation of 2.85 billion basepairs that comprise the human genome. The high-quality
sequence spanned more than 99% of the euchromatic (gene-containing) portion of the genome with an accuracy of 99.999%, but
despite this accomplishment, substantial sections of chromosomal sequences were still missing.
The Y chromosome, a sex chromosome that is specific to the human male, has posed a particular challenge to researchers
attempting to decode its sequence. It contains an extraordinary abundance of repetitive elements, including transposons and
tandem arrays of satellite sequences. This highly repetitive, transcriptionally dormant genomic landscape, termed
"heterochromatin," defines approximately two-thirds of the Y chromosome, including a section spanning the centromere. Such
repetitive sequences, although not recalcitrant to cloning, are laborious to assemble, requiring meticulous analysis of
complex repeated sequences.
In this case, the challenge was undertaken by a team of scientists led by Gudrun Rappold, Ph.D., Professor of Human Genetics
at the University of Heidelberg in Germany. Their manuscript describing this work, published online today and in the February
print issue of Genome Research (www.genome), presents the sequencing and analysis of 554 kilobases of previously
uncharacterized sequence from the pericentromeric region of the Y chromosome. This sequence contains a 450-kilobase
"euchromatic island" with eight presumably active genes flanked by repetitive satellite sequences.
To ensure that this 554-kilobase sequence was in fact missing from the "finished" human genome sequence and was not a
structural polymorphism present only in a subset of males in the human population, members of Rappold's laboratory -
including Stefan Kirsch, Ph.D., lead author on the paper - tested 100 men of different ethnic origin for the presence of this
554-kilobase fragment. Indeed, the sequence was present in all 100 individuals tested, but not in any female controls,
confirming that this sequence was a fundamental part of the Y chromosome.
More surprising, however, was Rappold's finding that this "missing" sequence was not unique to the Y chromosome. Rather, this
sequence exhibited between 95-99% homology to sequences on exactly half (11 of 22) of the other chromosomes in the human
genome, including the pericentromeric regions of autosomes (non-sex chromosomes) 1, 2, 3, 4, 9, 10, 11, 14, 15, 16, and 22.
This remarkable similarity can be attributed to segmental duplications, a phenomenon whereby large portions of the genome are
copied during evolution. Segmental duplications, which emerged during the past 30 million years of primate evolution, are
significantly enriched in subtelomeric and pericentromeric sequences, and now comprise approximately 5% of the human genome,
were considered to be one of the biggest obstacles to finishing the human genome sequence. "The identification of these
segmental duplications suggests an underrepresentation of pericentromeric regions of the acrocentric chromosomes in the
current human genome sequence," Rappold pointed out.
The current study was designed as part of a long-term effort to characterize the molecular genetic basis for
Y-chromosome-linked phenotypes. Rappold and colleagues had previously physically mapped the GCY locus, which is thought to be
the genetic determinant of sex-related stature differences in humans and is in close proximity to the Y centromere. In
addition, the GBY, or gonadoblastoma locus, which is responsible for development of tumors associated with the
undifferentiated gonad, has been genetically mapped to the region. Because the "missing" sequence described in this study
contained eight putatively active genes, further functional testing of these genes may reveal insights into the genetic basis
for stature and gonadoblastoma.
About this study:
The article referenced here is published online as a "Genome Research in Advance" paper today and will appear in the February
print issue of Genome Research. The citation for the article is as follows: Kirsch, S., Wei?, B., Miner, T.L., Waterston,
R.H., Clark, R.A., Eichler, E.E., M?nch, C., Schempp, W., and Rappold, G. 2005. Interchromosomal segmental duplications of
the pericentromeric region on the human Y chromosome. Genome Res. 15: 195-204. A copy of the paper is available upon request.
About Genome Research:
Genome Research (genome) is an international, monthly,
peer-reviewed journal published by Cold Spring Harbor Laboratory Press. Launched in 1995, it is one of the five most highly
cited primary research journals in genetics and genomics. The journal publishes novel genome-based studies and cutting-edge
methodologies in comparative and functional genomics, bioinformatics, proteomics, evolutionary and population genetics,
systems biology, epigenetics, and biotechnology.
Cold Spring Harbor Laboratory Press is an internationally renowned publisher of books, journals, and electronic media,
located on Long Island, New York. It is a division of Cold Spring Harbor Laboratory, an innovator in life science research
and the education of scientists, students, and the public. For more information, visit cshlpress.
Contact: Maria A. Smit
smitcshl.edu
Cold Spring Harbor Laboratory
Research that they have successfully cloned and characterized a previously intractable DNA sequence: a 554-kilobase-pair
genomic segment near the centromere of the human Y chromosome. This sequence contains eight putatively active genes that
could be implicated in sex-associated height differences and gonadal tumor development.
This pericentromeric gap was one of the few holes remaining in the "finished" sequence of the human genome reported last
October by the International Human Genome Sequencing Consortium. This "finished" sequence was the culmination of a 13-year
effort to elucidate the order and orientation of 2.85 billion basepairs that comprise the human genome. The high-quality
sequence spanned more than 99% of the euchromatic (gene-containing) portion of the genome with an accuracy of 99.999%, but
despite this accomplishment, substantial sections of chromosomal sequences were still missing.
The Y chromosome, a sex chromosome that is specific to the human male, has posed a particular challenge to researchers
attempting to decode its sequence. It contains an extraordinary abundance of repetitive elements, including transposons and
tandem arrays of satellite sequences. This highly repetitive, transcriptionally dormant genomic landscape, termed
"heterochromatin," defines approximately two-thirds of the Y chromosome, including a section spanning the centromere. Such
repetitive sequences, although not recalcitrant to cloning, are laborious to assemble, requiring meticulous analysis of
complex repeated sequences.
In this case, the challenge was undertaken by a team of scientists led by Gudrun Rappold, Ph.D., Professor of Human Genetics
at the University of Heidelberg in Germany. Their manuscript describing this work, published online today and in the February
print issue of Genome Research (www.genome), presents the sequencing and analysis of 554 kilobases of previously
uncharacterized sequence from the pericentromeric region of the Y chromosome. This sequence contains a 450-kilobase
"euchromatic island" with eight presumably active genes flanked by repetitive satellite sequences.
To ensure that this 554-kilobase sequence was in fact missing from the "finished" human genome sequence and was not a
structural polymorphism present only in a subset of males in the human population, members of Rappold's laboratory -
including Stefan Kirsch, Ph.D., lead author on the paper - tested 100 men of different ethnic origin for the presence of this
554-kilobase fragment. Indeed, the sequence was present in all 100 individuals tested, but not in any female controls,
confirming that this sequence was a fundamental part of the Y chromosome.
More surprising, however, was Rappold's finding that this "missing" sequence was not unique to the Y chromosome. Rather, this
sequence exhibited between 95-99% homology to sequences on exactly half (11 of 22) of the other chromosomes in the human
genome, including the pericentromeric regions of autosomes (non-sex chromosomes) 1, 2, 3, 4, 9, 10, 11, 14, 15, 16, and 22.
This remarkable similarity can be attributed to segmental duplications, a phenomenon whereby large portions of the genome are
copied during evolution. Segmental duplications, which emerged during the past 30 million years of primate evolution, are
significantly enriched in subtelomeric and pericentromeric sequences, and now comprise approximately 5% of the human genome,
were considered to be one of the biggest obstacles to finishing the human genome sequence. "The identification of these
segmental duplications suggests an underrepresentation of pericentromeric regions of the acrocentric chromosomes in the
current human genome sequence," Rappold pointed out.
The current study was designed as part of a long-term effort to characterize the molecular genetic basis for
Y-chromosome-linked phenotypes. Rappold and colleagues had previously physically mapped the GCY locus, which is thought to be
the genetic determinant of sex-related stature differences in humans and is in close proximity to the Y centromere. In
addition, the GBY, or gonadoblastoma locus, which is responsible for development of tumors associated with the
undifferentiated gonad, has been genetically mapped to the region. Because the "missing" sequence described in this study
contained eight putatively active genes, further functional testing of these genes may reveal insights into the genetic basis
for stature and gonadoblastoma.
About this study:
The article referenced here is published online as a "Genome Research in Advance" paper today and will appear in the February
print issue of Genome Research. The citation for the article is as follows: Kirsch, S., Wei?, B., Miner, T.L., Waterston,
R.H., Clark, R.A., Eichler, E.E., M?nch, C., Schempp, W., and Rappold, G. 2005. Interchromosomal segmental duplications of
the pericentromeric region on the human Y chromosome. Genome Res. 15: 195-204. A copy of the paper is available upon request.
About Genome Research:
Genome Research (genome) is an international, monthly,
peer-reviewed journal published by Cold Spring Harbor Laboratory Press. Launched in 1995, it is one of the five most highly
cited primary research journals in genetics and genomics. The journal publishes novel genome-based studies and cutting-edge
methodologies in comparative and functional genomics, bioinformatics, proteomics, evolutionary and population genetics,
systems biology, epigenetics, and biotechnology.
Cold Spring Harbor Laboratory Press is an internationally renowned publisher of books, journals, and electronic media,
located on Long Island, New York. It is a division of Cold Spring Harbor Laboratory, an innovator in life science research
and the education of scientists, students, and the public. For more information, visit cshlpress.
Contact: Maria A. Smit
smitcshl.edu
Cold Spring Harbor Laboratory
среда, 24 августа 2011 г.
Drug-Radiation Combo Used To Eradicate Lung Cancer In Mouse Model
Researchers at UT Southwestern Medical Center have eliminated non-small cell lung (NSCL) cancer in mice by using an investigative drug called BEZ235 in combination with low-dose radiation.
In a study appearing in the October issue of Cancer Research, UT Southwestern researchers found that if they administered BEZ235 before they damaged the DNA of tumor cells with otherwise nontoxic radiation, the drug blocked the pro-survival actions of a protein called PI3K, which normally springs into action to keep tumor cells alive while they repair DNA damage.
Researchers tested this novel therapeutic strategy in mice transplanted with NSCL cancers obtained from patients.
They found that tumors in the mice treated with BEZ235 alone were significantly smaller than those in mice not given the drug. Although the tumors stopped growing, they did not die.
By contrast, tumors were completely eradicated in mice treated with a combination of BEZ235 and radiation.
"These early results suggest that the drug-radiation combination might be an effective therapy in lung cancer patients," said Dr. Pier Paolo Scaglioni, assistant professor of internal medicine at UT Southwestern and senior author of the study.
NSCL cancer is a leading cause of cancer-related deaths worldwide. The cancer cells often harbor mutations in a gene called K-RAS. Patients with such K-RAS mutations typically are more resistant to treatment with radiation and have a poor prognosis.
K-RAS mutations lead to the activation of networks, or pathways, of several so-called signaling proteins, which in turn play key roles in the regulation of tumor growth. One of these proteins, called PI3K, is activated to keep cells alive that have sustained DNA damage.
Several components of the signaling pathways, including PI3K, have been investigated as possible anti-cancer drug targets. The investigational drug BEZ235 is currently being tested in clinical trials against PI3K and another signaling protein called mTOR.
"To date, no effective targeted therapy exists for NSCL cancer tumors that harbor K-RAS mutations," Dr. Scaglioni said.
Dr. Scaglioni and his team first tested the effectiveness of BEZ235 alone and found that it inhibits the proliferation of both lung cancer cells cultured in vitro and the growth of lung-cancer tumors in mice.
"The results were striking, but we wanted to find a strategy to precipitate cell death of these tumors," said Dr. Georgia Konstantinidou, a postdoctoral researcher at UT Southwestern and the lead author of the study. "We did it with radiation, which is a standard form of treatment for lung cancer."
Dr. Scaglioni's team exposed isolated cancer cells to BEZ235 followed by low doses of radiation, which induced small breaks in the DNA of the cells but otherwise would have no effect on cell survival. When this type of DNA damage occurs, cancer cells rely on the PI3K signaling pathway to survive while they repair their DNA.
"We stressed the cells in such a way that they needed this signaling pathway to survive," Dr. Scaglioni said. "Without the PI3K response, they will die."
When the researchers then treated the cells with BEZ235, which blocks PI3K, the stressed NSCL cancer cells readily underwent programmed cell death.
Dr. Scaglioni said that the next step is to use BEZ235 or similar drugs in clinical trials on NSCL cancer patients as well as other cancers, including pancreatic, colon and thyroid cancers, where the PI3K signaling pathway also plays a role.
Other UT Southwestern researchers involved in the study included Dr. Erik Bey, assistant instructor at the Harold C. Simmons Comprehensive Cancer Center, Dr. Andrea Rabellino, postdoctoral researcher in internal medicine, Dr. Katja Schuster, postdoctoral researcher in internal medicine, Dr. Adi Gazdar, professor of pathology in UT Southwestern's Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research, and Dr. David Boothman, professor in the Simmons Comprehensive Cancer Center and of pharmacology and radiation oncology. Researchers from the University of Camerino in Italy and Novartis Pharma in Switzerland also participated.
The work was supported by the National Institutes of Health, American Cancer Society, Concern Foundation, Gibson Foundation, Leukemia of Texas, U.S. Department of Energy and the American Italian Cancer Foundation.
Source: Connie Piloto
UT Southwestern Medical Center
In a study appearing in the October issue of Cancer Research, UT Southwestern researchers found that if they administered BEZ235 before they damaged the DNA of tumor cells with otherwise nontoxic radiation, the drug blocked the pro-survival actions of a protein called PI3K, which normally springs into action to keep tumor cells alive while they repair DNA damage.
Researchers tested this novel therapeutic strategy in mice transplanted with NSCL cancers obtained from patients.
They found that tumors in the mice treated with BEZ235 alone were significantly smaller than those in mice not given the drug. Although the tumors stopped growing, they did not die.
By contrast, tumors were completely eradicated in mice treated with a combination of BEZ235 and radiation.
"These early results suggest that the drug-radiation combination might be an effective therapy in lung cancer patients," said Dr. Pier Paolo Scaglioni, assistant professor of internal medicine at UT Southwestern and senior author of the study.
NSCL cancer is a leading cause of cancer-related deaths worldwide. The cancer cells often harbor mutations in a gene called K-RAS. Patients with such K-RAS mutations typically are more resistant to treatment with radiation and have a poor prognosis.
K-RAS mutations lead to the activation of networks, or pathways, of several so-called signaling proteins, which in turn play key roles in the regulation of tumor growth. One of these proteins, called PI3K, is activated to keep cells alive that have sustained DNA damage.
Several components of the signaling pathways, including PI3K, have been investigated as possible anti-cancer drug targets. The investigational drug BEZ235 is currently being tested in clinical trials against PI3K and another signaling protein called mTOR.
"To date, no effective targeted therapy exists for NSCL cancer tumors that harbor K-RAS mutations," Dr. Scaglioni said.
Dr. Scaglioni and his team first tested the effectiveness of BEZ235 alone and found that it inhibits the proliferation of both lung cancer cells cultured in vitro and the growth of lung-cancer tumors in mice.
"The results were striking, but we wanted to find a strategy to precipitate cell death of these tumors," said Dr. Georgia Konstantinidou, a postdoctoral researcher at UT Southwestern and the lead author of the study. "We did it with radiation, which is a standard form of treatment for lung cancer."
Dr. Scaglioni's team exposed isolated cancer cells to BEZ235 followed by low doses of radiation, which induced small breaks in the DNA of the cells but otherwise would have no effect on cell survival. When this type of DNA damage occurs, cancer cells rely on the PI3K signaling pathway to survive while they repair their DNA.
"We stressed the cells in such a way that they needed this signaling pathway to survive," Dr. Scaglioni said. "Without the PI3K response, they will die."
When the researchers then treated the cells with BEZ235, which blocks PI3K, the stressed NSCL cancer cells readily underwent programmed cell death.
Dr. Scaglioni said that the next step is to use BEZ235 or similar drugs in clinical trials on NSCL cancer patients as well as other cancers, including pancreatic, colon and thyroid cancers, where the PI3K signaling pathway also plays a role.
Other UT Southwestern researchers involved in the study included Dr. Erik Bey, assistant instructor at the Harold C. Simmons Comprehensive Cancer Center, Dr. Andrea Rabellino, postdoctoral researcher in internal medicine, Dr. Katja Schuster, postdoctoral researcher in internal medicine, Dr. Adi Gazdar, professor of pathology in UT Southwestern's Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research, and Dr. David Boothman, professor in the Simmons Comprehensive Cancer Center and of pharmacology and radiation oncology. Researchers from the University of Camerino in Italy and Novartis Pharma in Switzerland also participated.
The work was supported by the National Institutes of Health, American Cancer Society, Concern Foundation, Gibson Foundation, Leukemia of Texas, U.S. Department of Energy and the American Italian Cancer Foundation.
Source: Connie Piloto
UT Southwestern Medical Center
воскресенье, 21 августа 2011 г.
Homosexuality Is Biological But Not Hard-Wired In Fruit Flies
While the biological basis for homosexuality remains a mystery, a team of neurobiologists reports they may have closed in on an answer -- by a nose.
The team led by University of Illinois at Chicago researcher David Featherstone has discovered that sexual orientation in fruit flies is controlled by a previously unknown regulator of synapse strength. Armed with this knowledge, the researchers found they were able to use either genetic manipulation or drugs to turn the flies' homosexual behavior on and off within hours.
Featherstone, associate professor of biological sciences at UIC, and his coworkers discovered a gene in fruit flies they called "genderblind," or GB. A mutation in GB turns flies bisexual.
Featherstone found the gene interesting initially because it has the unusual ability to transport the neurotransmitter glutamate out of glial cells -- cells that support and nourish nerve cells but do not fire like neurons do. Previous work from his laboratory showed that changing the amount of glutamate outside cells can change the strength of nerve cell junctions, or synapses, which play a key role in human and animal behavior.
But the GB gene became even more interesting when post-doctoral researcher Yael Grosjean noticed that all the GB mutant male flies were courting other males.
"It was very dramatic," said Featherstone. "The GB mutant males treated other males exactly the same way normal male flies would treat a female. They even attempted copulation."
Other genes that alter sexual orientation have been described, but most just control whether the brain develops as genetically male or female. It's still unknown why a male brain chooses to do male things and a female brain does female things. The discovery of GB provided an opportunity to understand why males choose to mate with females.
"Based on our previous work, we reasoned that GB mutants might show homosexual behavior because their glutamatergic synapses were altered in some way," said Featherstone. Specifically, the GB mutant synapses might be stronger.
"Homosexual courtship might be sort of an 'overreaction' to sexual stimuli," he explained.
To test this, he and his colleagues genetically altered synapse strength independent of GB, and also fed the flies drugs that can alter synapse strength. As predicted, they were able to turn fly homosexuality on and off -- and within hours.
"It was amazing. I never thought we'd be able to do that sort of thing, because sexual orientation is supposed to be hard-wired," he said. "This fundamentally changes how we think about this behavior."
Featherstone and his colleagues reasoned that adult fly brains have dual-track sensory circuits, one that triggers heterosexual behavior, the other homosexual. When GB suppresses glutamatergic synapses, the homosexual circuit is blocked.
Further work showed precisely how this happens -- without GB to suppress synapse strength, the flies no longer interpreted smells the same way.
"Pheromones are powerful sexual stimuli," Featherstone said. "As it turns out, the GB mutant flies were perceiving pheromones differently. Specifically, the GB mutant males were no longer recognizing male pheromones as a repulsive stimulus."
Featherstone says it may someday be possible to domesticate insects such as fruit flies and manipulate their sense of smell to turn them into useful pollinators rather than costly pests.
The research appeared on line today in Nature Neuroscience, and is scheduled for print in the January issue.
Grosjean, now with the Center of Integrative Genomics in Lausanne, Switzerland, is the paper's first author. Along with Featherstone, authors include Hrvoje Augustin of UIC and Micheline Grillet and Jean-Francois Ferveur of the Universit?© de Bourgogne in Dijon, France.
Source: Paul Francuch
University of Illinois at Chicago
The team led by University of Illinois at Chicago researcher David Featherstone has discovered that sexual orientation in fruit flies is controlled by a previously unknown regulator of synapse strength. Armed with this knowledge, the researchers found they were able to use either genetic manipulation or drugs to turn the flies' homosexual behavior on and off within hours.
Featherstone, associate professor of biological sciences at UIC, and his coworkers discovered a gene in fruit flies they called "genderblind," or GB. A mutation in GB turns flies bisexual.
Featherstone found the gene interesting initially because it has the unusual ability to transport the neurotransmitter glutamate out of glial cells -- cells that support and nourish nerve cells but do not fire like neurons do. Previous work from his laboratory showed that changing the amount of glutamate outside cells can change the strength of nerve cell junctions, or synapses, which play a key role in human and animal behavior.
But the GB gene became even more interesting when post-doctoral researcher Yael Grosjean noticed that all the GB mutant male flies were courting other males.
"It was very dramatic," said Featherstone. "The GB mutant males treated other males exactly the same way normal male flies would treat a female. They even attempted copulation."
Other genes that alter sexual orientation have been described, but most just control whether the brain develops as genetically male or female. It's still unknown why a male brain chooses to do male things and a female brain does female things. The discovery of GB provided an opportunity to understand why males choose to mate with females.
"Based on our previous work, we reasoned that GB mutants might show homosexual behavior because their glutamatergic synapses were altered in some way," said Featherstone. Specifically, the GB mutant synapses might be stronger.
"Homosexual courtship might be sort of an 'overreaction' to sexual stimuli," he explained.
To test this, he and his colleagues genetically altered synapse strength independent of GB, and also fed the flies drugs that can alter synapse strength. As predicted, they were able to turn fly homosexuality on and off -- and within hours.
"It was amazing. I never thought we'd be able to do that sort of thing, because sexual orientation is supposed to be hard-wired," he said. "This fundamentally changes how we think about this behavior."
Featherstone and his colleagues reasoned that adult fly brains have dual-track sensory circuits, one that triggers heterosexual behavior, the other homosexual. When GB suppresses glutamatergic synapses, the homosexual circuit is blocked.
Further work showed precisely how this happens -- without GB to suppress synapse strength, the flies no longer interpreted smells the same way.
"Pheromones are powerful sexual stimuli," Featherstone said. "As it turns out, the GB mutant flies were perceiving pheromones differently. Specifically, the GB mutant males were no longer recognizing male pheromones as a repulsive stimulus."
Featherstone says it may someday be possible to domesticate insects such as fruit flies and manipulate their sense of smell to turn them into useful pollinators rather than costly pests.
The research appeared on line today in Nature Neuroscience, and is scheduled for print in the January issue.
Grosjean, now with the Center of Integrative Genomics in Lausanne, Switzerland, is the paper's first author. Along with Featherstone, authors include Hrvoje Augustin of UIC and Micheline Grillet and Jean-Francois Ferveur of the Universit?© de Bourgogne in Dijon, France.
Source: Paul Francuch
University of Illinois at Chicago
четверг, 18 августа 2011 г.
'Personalized Medicine' Leaves The Public Confused
Ordinary people worry about the extra, and often burdensome, responsibilities which could come with scientists' promises of 'personalised medicine', according to evidence being presented at a major two-day showcase of groundbreaking social science research into the whole field of genomics, funded by the Economic and Social Research Council (ESRC).
The event -- 'Genomics and Society: Today's Answers, Tomorrow's Questions' -- is taking place in London Thursday 25 through Friday 26 October 2007. This landmark gathering brings together policymakers, researchers and natural scientists with what is becoming the world's largest concentration of social scientific research in this field -- the ESRC Genomics Network (EGN).
Topics as diverse as plant and animal genetics, embryonic stem cell research, genetic databases, and the potential for huge advances in medicine, physical health and psychiatry are on the agenda. Regulation and ethics are also key focuses of attention, including research highlighting challenges faced by policymakers seeking to balance animal welfare against scientific productivity. And a study of four of the top ten Indian pharmaceutical firms reveals that many of the scientists who left for technologically more advanced regions of the world are now returning, bringing with them new skills and expertise from the west.
Peoples' views on the use of genetic testing to prescribe and develop drugs, which has been seen as a technology that will accentuate the move towards 'individualisation' of healthcare, were the focus of work led by Professor Brian Wynne, associate director of Cesagen - one of three research centres in the Network, and based at the universities of Lancaster and Cardiff.
Professor Wynne and Elisa Pieri used focus groups to get the opinions of 'hard-to-reach' sections of the public, such as senior citizens, young people and parents of young children, as well as members of some ethnic communities in the north-west of England.
They found strong concerns about the increased, and often burdensome, levels of responsibility for people that would come from the being able to discover that they were susceptible to, or had early signs of, particular diseases, and about the necessary genetic testing it entails.
Professor Wynne said: "Contrary to much of what is written and said about personalised medicine, members of the public highlighted how such promised options would impact and place strains on their families and relatives, as well as potentially lead to stigmatisation.
"They were worried that it would limit their access to key services, such as insurance, mortgages, some medical coverage, and potentially even impact on their employment opportunities."
People also felt that individuals' social and financial status would play a role in whether certain changes in lifestyles and treatments, suggested as a result of testing, could really be achieved. As Professor Wynne underlined: "It is the credibility of the promises which drive such prospective innovations, and the real social conditions of their enactment, that are questions which government, industry and science need to take seriously as public policy issues."
Professor Steve Yearley, director of the Network's Genomics Policy and Research Forum said: "This landmark event, marking the Network's transition to a new five-year phase of funding, gives the opportunity for a cross-fertilisation of ideas and healthy debate on the past, present and future roles of genomics in society."
1. 'Today's Answers, Tomorrow's Questions' -- Thursday 25 and Friday 26, October at One Great George Street, London SW1P 3AA. There is a dedicated conference website giving detailed programme information at: genomicsandsociety/
2. Launched in 2002 to examine the social and economic consequences surrounding the development and use of genomics, the Economic and Social Research Council (ESRC) Genomics Network is one of the ESRC's largest social science investments. The Networknsists of Cesagen (Centre for Economic and Social Aspects of Genomics) a Cardiff-Lancaster collaboration led by Professor Ruth Chadwick; Egenis (ESRC Centre for Genomics in Society) headed by Professor John Dupr?© at Exeter; and Innogen (ESRC Centre for Social and Economic Research on Innovation in Genomics) -- collaboration between the University of Edinburgh and the Open University, directed by Professor David Wield; and the ESRC Genomics Policy and Research Forum, led by Professor Steve Yearley, Professor of Sociology of Scientific Knowledge at Edinburgh University. The ESRC recently announced continued funding totalling ??17 million between now and 2012 for the three research centres -- Cesagen, Egenis and Innogen.
3. Methodology: For the Cesagen qualitative study 'Public Engagement and Personalised Medicine', 14 focus groups were conducted. Data was analysed using a Grounded Theory approach, and the constant comparative method. Analysis was aided by Atlas.ti software.
4. The Economic and Social Research Council (ESRC) is the UK's largest funding agency for research and postgraduate training relating to social and economic issues. It supports independent, high quality research relevant to business, the public sector and voluntary organisations. The ESRC's planned total expenditure in 2007 - 08 is ??181 million. At any one time the ESRC supports over 4,000 researchers and postgraduate students in academic institutions and research policy institutes. More at esrcsocietytoday.ac/
5. ESRC Society Today offers free access to a broad range of social science research and presents it in a way that makes it easy to navigate and saves users valuable time. As well as bringing together all ESRC-funded research and key online resources such as the Social Science Information Gateway and the UK Data Archive, non-ESRC resources are included, for example the Office for National Statistics. The portal provides access to early findings and research summaries, as well as full texts and original datasets through integrated search facilities. More at esrcsocietytoday.ac/
Source: Danielle Moore
Economic & Social Research Council
The event -- 'Genomics and Society: Today's Answers, Tomorrow's Questions' -- is taking place in London Thursday 25 through Friday 26 October 2007. This landmark gathering brings together policymakers, researchers and natural scientists with what is becoming the world's largest concentration of social scientific research in this field -- the ESRC Genomics Network (EGN).
Topics as diverse as plant and animal genetics, embryonic stem cell research, genetic databases, and the potential for huge advances in medicine, physical health and psychiatry are on the agenda. Regulation and ethics are also key focuses of attention, including research highlighting challenges faced by policymakers seeking to balance animal welfare against scientific productivity. And a study of four of the top ten Indian pharmaceutical firms reveals that many of the scientists who left for technologically more advanced regions of the world are now returning, bringing with them new skills and expertise from the west.
Peoples' views on the use of genetic testing to prescribe and develop drugs, which has been seen as a technology that will accentuate the move towards 'individualisation' of healthcare, were the focus of work led by Professor Brian Wynne, associate director of Cesagen - one of three research centres in the Network, and based at the universities of Lancaster and Cardiff.
Professor Wynne and Elisa Pieri used focus groups to get the opinions of 'hard-to-reach' sections of the public, such as senior citizens, young people and parents of young children, as well as members of some ethnic communities in the north-west of England.
They found strong concerns about the increased, and often burdensome, levels of responsibility for people that would come from the being able to discover that they were susceptible to, or had early signs of, particular diseases, and about the necessary genetic testing it entails.
Professor Wynne said: "Contrary to much of what is written and said about personalised medicine, members of the public highlighted how such promised options would impact and place strains on their families and relatives, as well as potentially lead to stigmatisation.
"They were worried that it would limit their access to key services, such as insurance, mortgages, some medical coverage, and potentially even impact on their employment opportunities."
People also felt that individuals' social and financial status would play a role in whether certain changes in lifestyles and treatments, suggested as a result of testing, could really be achieved. As Professor Wynne underlined: "It is the credibility of the promises which drive such prospective innovations, and the real social conditions of their enactment, that are questions which government, industry and science need to take seriously as public policy issues."
Professor Steve Yearley, director of the Network's Genomics Policy and Research Forum said: "This landmark event, marking the Network's transition to a new five-year phase of funding, gives the opportunity for a cross-fertilisation of ideas and healthy debate on the past, present and future roles of genomics in society."
1. 'Today's Answers, Tomorrow's Questions' -- Thursday 25 and Friday 26, October at One Great George Street, London SW1P 3AA. There is a dedicated conference website giving detailed programme information at: genomicsandsociety/
2. Launched in 2002 to examine the social and economic consequences surrounding the development and use of genomics, the Economic and Social Research Council (ESRC) Genomics Network is one of the ESRC's largest social science investments. The Networknsists of Cesagen (Centre for Economic and Social Aspects of Genomics) a Cardiff-Lancaster collaboration led by Professor Ruth Chadwick; Egenis (ESRC Centre for Genomics in Society) headed by Professor John Dupr?© at Exeter; and Innogen (ESRC Centre for Social and Economic Research on Innovation in Genomics) -- collaboration between the University of Edinburgh and the Open University, directed by Professor David Wield; and the ESRC Genomics Policy and Research Forum, led by Professor Steve Yearley, Professor of Sociology of Scientific Knowledge at Edinburgh University. The ESRC recently announced continued funding totalling ??17 million between now and 2012 for the three research centres -- Cesagen, Egenis and Innogen.
3. Methodology: For the Cesagen qualitative study 'Public Engagement and Personalised Medicine', 14 focus groups were conducted. Data was analysed using a Grounded Theory approach, and the constant comparative method. Analysis was aided by Atlas.ti software.
4. The Economic and Social Research Council (ESRC) is the UK's largest funding agency for research and postgraduate training relating to social and economic issues. It supports independent, high quality research relevant to business, the public sector and voluntary organisations. The ESRC's planned total expenditure in 2007 - 08 is ??181 million. At any one time the ESRC supports over 4,000 researchers and postgraduate students in academic institutions and research policy institutes. More at esrcsocietytoday.ac/
5. ESRC Society Today offers free access to a broad range of social science research and presents it in a way that makes it easy to navigate and saves users valuable time. As well as bringing together all ESRC-funded research and key online resources such as the Social Science Information Gateway and the UK Data Archive, non-ESRC resources are included, for example the Office for National Statistics. The portal provides access to early findings and research summaries, as well as full texts and original datasets through integrated search facilities. More at esrcsocietytoday.ac/
Source: Danielle Moore
Economic & Social Research Council
понедельник, 15 августа 2011 г.
How To Construct A 'Firefly' Worm
Research describing a new modified luminescent worm that allows, for the first time, to measure, in real time, the metabolism of an entire living organism has just been published in the journal BMC Physiology1. The key behind this capacity relies in the fact that the luminescence is produced using the animal's available energy, which reflects its metabolism that, as such, can be extrapolated from measuring the emitted light. The new altered Caenorhabditis elegans (C.elegans) - which is widely used to study human genes - by detecting metabolic changes in the exact moment these occur, will help to understand the cause behind these changes and contribute to understand C. elegans (and human) genes, as well as the mechanisms behind disease and health. In fact, Alzheimer's, Parkinson's disease and different types of stress - such as starvation and oxygen deprivation - are just some of the phenomena characterised by visible metabolic changes that can now be further investigated using this new animal model.
C.elegans is a animal model used to study human genes and their function due to the fact that part of its genome has been conserved throughout evolution, and is shared by humans. But although much research has been done on the worm's genes, much still needs to be learned specially among the genes behind physiology, which - contrary to those linked to vital functions or body shape - can be difficult to identify, since abnormalities in them not always result in visible alterations.
Adenosine triphosphate (or ATP) is a high-energy molecule used as source of energy by the body cells, where its levels are directly linked to the organism's metabolism. This means that alterations in the body ATP can help to reveal metabolic problems and, in fact, ATP changes are associated with a series of problems including neurodegenerative diseases and stress.
It was this link between ATP, metabolism and disease that led Cristina Lagido, Jonathan Pettitt, Aileen Flett and L. Anne Glover from the Institute of Medical Sciences at the University of Aberdeen, UK to hypothesise that ATP levels could be used as a physiological parameter in C. elegans to complement the genetic data and help to further understand its (as well as the human) genome.
With this aim in mind the researchers went to create a modified luminescent C. elegans expressing the protein firefly luciferase that, as the name indicates, comes from fireflies where it produces light by using ATP to transform a pigment called luciferin. This new worm was constructed by inserting the luciferase gene into the DNA of a virus that was then injected into the C. elegans reproductive glands. During viral infection the virus will insert its DNA (with the luciferase gene) into the worm genome, leading to production of luciferase throughout all the animal life.
The idea was, that, when luciferin (that does not exist in the animal) was supplied in excess, the animal's luminescence would be directly related to the amount of ATP existent in the worm. And, since C. elegans is transparent, the luminescence could then be measured allowing the researchers to calculated ATP levels and, consequently, follow the animal's metabolism in real time.
But first, to confirm that the worm's luminescence was indeed related to its ATP levels, the animals were put in conditions known to affect this molecule quantity - whether by exposing them to the toxic compound sodium azide (which is a known agent of stress) or by directly inhibiting their ATP production - and their luminescence was measured. In both cases, luminescence was significantly reduced as expected and with azide, increased levels of this compound resulted in reduced luminescent further supporting the link ATP-luminescence. Furthermore, because the effects of non-lethal doses of sodium azide - like the ones used in these experiments - are known to be reversible, after the measurements with azide the animals were washed and their luminescence measured again to be found that the emitted light was back to normal levels. Final support to the link ATP levels-luminescence came from the fact that ATP variations found in the azide experiments, agreed with measurements done by others studying similar conditions, but using different methods.
These results confirmed that Lagido, Glover and colleagues' modified C. elegans was, in fact, a reliable model to follow the worm's metabolism in real time. This was the first time that it was shown that luminescence could be used to assess ATP levels in a living multicellular organism.
What is most interesting about Lagido, Glover and colleagues' modified C.elegans is how, despite its apparently simplicity, this new worm is a potentially incredible research tool to understand better the many genetic pathways involved in C. elegans physiology, including those participating in metabolism, ageing, disease and stress response. Cristina Lagido - a Portuguese researcher - and colleagues' work has created a unique tool to link physiology and genetics in an organism which - most importantly- shares many of its genes with us humans.
Notes:
1 BMC Physiology 2008, 8:7
"Bridging the phenotypic gap: real-time assessment of mitochondrial function and metabolism of the nematode Caenorhabditis elegans"
Contacts for the authors of the original paper:
Cristina Lagido - c.lagido (at) abdn.ac
L. Anne Glover l.a.glover (at) abdn.ac
Link to the original paper - biomedcentral/content/pdf/1472-6793-8-7.pdf (PDF)
Piece researched and :
Catarina Amorim
catarina.amorim (at) linacre.ox.ac
C.elegans is a animal model used to study human genes and their function due to the fact that part of its genome has been conserved throughout evolution, and is shared by humans. But although much research has been done on the worm's genes, much still needs to be learned specially among the genes behind physiology, which - contrary to those linked to vital functions or body shape - can be difficult to identify, since abnormalities in them not always result in visible alterations.
Adenosine triphosphate (or ATP) is a high-energy molecule used as source of energy by the body cells, where its levels are directly linked to the organism's metabolism. This means that alterations in the body ATP can help to reveal metabolic problems and, in fact, ATP changes are associated with a series of problems including neurodegenerative diseases and stress.
It was this link between ATP, metabolism and disease that led Cristina Lagido, Jonathan Pettitt, Aileen Flett and L. Anne Glover from the Institute of Medical Sciences at the University of Aberdeen, UK to hypothesise that ATP levels could be used as a physiological parameter in C. elegans to complement the genetic data and help to further understand its (as well as the human) genome.
With this aim in mind the researchers went to create a modified luminescent C. elegans expressing the protein firefly luciferase that, as the name indicates, comes from fireflies where it produces light by using ATP to transform a pigment called luciferin. This new worm was constructed by inserting the luciferase gene into the DNA of a virus that was then injected into the C. elegans reproductive glands. During viral infection the virus will insert its DNA (with the luciferase gene) into the worm genome, leading to production of luciferase throughout all the animal life.
The idea was, that, when luciferin (that does not exist in the animal) was supplied in excess, the animal's luminescence would be directly related to the amount of ATP existent in the worm. And, since C. elegans is transparent, the luminescence could then be measured allowing the researchers to calculated ATP levels and, consequently, follow the animal's metabolism in real time.
But first, to confirm that the worm's luminescence was indeed related to its ATP levels, the animals were put in conditions known to affect this molecule quantity - whether by exposing them to the toxic compound sodium azide (which is a known agent of stress) or by directly inhibiting their ATP production - and their luminescence was measured. In both cases, luminescence was significantly reduced as expected and with azide, increased levels of this compound resulted in reduced luminescent further supporting the link ATP-luminescence. Furthermore, because the effects of non-lethal doses of sodium azide - like the ones used in these experiments - are known to be reversible, after the measurements with azide the animals were washed and their luminescence measured again to be found that the emitted light was back to normal levels. Final support to the link ATP levels-luminescence came from the fact that ATP variations found in the azide experiments, agreed with measurements done by others studying similar conditions, but using different methods.
These results confirmed that Lagido, Glover and colleagues' modified C. elegans was, in fact, a reliable model to follow the worm's metabolism in real time. This was the first time that it was shown that luminescence could be used to assess ATP levels in a living multicellular organism.
What is most interesting about Lagido, Glover and colleagues' modified C.elegans is how, despite its apparently simplicity, this new worm is a potentially incredible research tool to understand better the many genetic pathways involved in C. elegans physiology, including those participating in metabolism, ageing, disease and stress response. Cristina Lagido - a Portuguese researcher - and colleagues' work has created a unique tool to link physiology and genetics in an organism which - most importantly- shares many of its genes with us humans.
Notes:
1 BMC Physiology 2008, 8:7
"Bridging the phenotypic gap: real-time assessment of mitochondrial function and metabolism of the nematode Caenorhabditis elegans"
Contacts for the authors of the original paper:
Cristina Lagido - c.lagido (at) abdn.ac
L. Anne Glover l.a.glover (at) abdn.ac
Link to the original paper - biomedcentral/content/pdf/1472-6793-8-7.pdf (PDF)
Piece researched and :
Catarina Amorim
catarina.amorim (at) linacre.ox.ac
пятница, 12 августа 2011 г.
Research On First Genetic Model Of Obesity In A Fish Should Facilitate New Obesity Treatments
Everyone knows that eating lean fish helps slim waistlines, but researchers from the Center for the Study of Weight Regulation and Associated Disorders at Oregon Health and Science University in Portland, OR, have found a new way fish can help eliminate obesity. In a study to be published in the July 2007 print issue of The FASEB Journal, researchers describe the first genetic model of obesity in a fish. Having this model should greatly accelerate the development of new drugs to help people lose weight and keep it off.
According to corresponding author Roger Cone, "Being able to model human disorders like obesity in zebrafish allows scientists to understand the molecular basis of disease. This may ultimately increase the efficiency and power of the drug discovery process, thus bringing new medicines to the market faster and cheaper."
In the study, researchers caused obesity in zebrafish by introducing the same type of genetic mutation that causes severe obesity in humans. The genetic change blocks the activity of a receptor, the melanocortin-4 receptor, which is at the heart of a "device" in our brains called the "adipostat." The adipostat regulates body weight homeostatically, like the thermostat in a house, and works to keep long-term energy stores - a.k.a. body fat - constant. The adipostat is what makes it difficult for people to lose weight and keep it off.
"Americans - even children - are getting fat at an alarming rate," said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal, "and with this model, we are a step closer to temporarily turning off or diminishing the fat-storing mechanisms that were once crucial to the survival of our species. The zebrafish has become a model animal for the study of many diseases because it has a backbone and because its genetics have been well described. This is one more example of how basic experimental biology - zoology physiology and genetics in this case - can be brought to bear on human problems."
According the U.S. Centers for Disease Control and Prevention, the prevalence of overweight and obesity have risen steadily over the past 30 years. Among adults aged 20-74 years the prevalence of obesity increased from 15.0% (1976-1980) to 32.9% (2003-2004). For children aged 2-5 years, the prevalence of overweight increased from 5.0% to 13.9%; for those aged 6-11 years, prevalence increased from 6.5% to 18.8%; and for those aged 12-19 years, prevalence increased from 5.0% to 17.4%. Being overweight or obese increases the risk of many diseases and health conditions, including, but not limited to: hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory problems, and some types of cancer.
A fact sheet on this article, as well as high and low resolution images of zebrafish and zebrafish embryos are available at The FASEB Journal's Press Room. Visit www.fasebj and click "Press Room" in the left column. The FASEB Journal is published by the Federation of American Societies for Experimental Biology (FASEB) and is consistently ranked among the top three biology journals worldwide by the Institute for Scientific Information. FASEB comprises 21 nonprofit societies with more than 80,000 members, making it the largest coalition of biomedical research associations in the United States. FASEB advances biological science through collaborative advocacy for research policies that promote scientific progress and education and lead to improvements in human health.
Contact: Cody Mooneyhan
Federation of American Societies for Experimental Biology
According to corresponding author Roger Cone, "Being able to model human disorders like obesity in zebrafish allows scientists to understand the molecular basis of disease. This may ultimately increase the efficiency and power of the drug discovery process, thus bringing new medicines to the market faster and cheaper."
In the study, researchers caused obesity in zebrafish by introducing the same type of genetic mutation that causes severe obesity in humans. The genetic change blocks the activity of a receptor, the melanocortin-4 receptor, which is at the heart of a "device" in our brains called the "adipostat." The adipostat regulates body weight homeostatically, like the thermostat in a house, and works to keep long-term energy stores - a.k.a. body fat - constant. The adipostat is what makes it difficult for people to lose weight and keep it off.
"Americans - even children - are getting fat at an alarming rate," said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal, "and with this model, we are a step closer to temporarily turning off or diminishing the fat-storing mechanisms that were once crucial to the survival of our species. The zebrafish has become a model animal for the study of many diseases because it has a backbone and because its genetics have been well described. This is one more example of how basic experimental biology - zoology physiology and genetics in this case - can be brought to bear on human problems."
According the U.S. Centers for Disease Control and Prevention, the prevalence of overweight and obesity have risen steadily over the past 30 years. Among adults aged 20-74 years the prevalence of obesity increased from 15.0% (1976-1980) to 32.9% (2003-2004). For children aged 2-5 years, the prevalence of overweight increased from 5.0% to 13.9%; for those aged 6-11 years, prevalence increased from 6.5% to 18.8%; and for those aged 12-19 years, prevalence increased from 5.0% to 17.4%. Being overweight or obese increases the risk of many diseases and health conditions, including, but not limited to: hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory problems, and some types of cancer.
A fact sheet on this article, as well as high and low resolution images of zebrafish and zebrafish embryos are available at The FASEB Journal's Press Room. Visit www.fasebj and click "Press Room" in the left column. The FASEB Journal is published by the Federation of American Societies for Experimental Biology (FASEB) and is consistently ranked among the top three biology journals worldwide by the Institute for Scientific Information. FASEB comprises 21 nonprofit societies with more than 80,000 members, making it the largest coalition of biomedical research associations in the United States. FASEB advances biological science through collaborative advocacy for research policies that promote scientific progress and education and lead to improvements in human health.
Contact: Cody Mooneyhan
Federation of American Societies for Experimental Biology
вторник, 9 августа 2011 г.
Genetics And Metastasis Studied In Colorectal Cancer
Colorectal cancer is one of the most prevalent cancers in the Western world. The tumor starts off as a polyp but then turns into an invasive and violent cancer, which often spreads to the liver. In an article recently published in the journal Cancer Research, Prof. Avri Ben-Ze'ev and Dr. Nancy Gavert of the Weizmann Institute's Molecular Cell Biology Department reveal mechanisms that help this cancer metastasize.
In a majority of cases, colorectal cancer is initiated by changes in a key protein -- beta-catenin. One of the roles of this protein is to enter the cell nucleus and activate gene expression. But in colorectal and other cancers, beta-catenin over-accumulates in the cell and inappropriately activates genes, leading to cancer.
Surprisingly, one of the genes activated by beta-catenin, which had been previously detected in colorectal cancer cells by Ben-Ze'ev's group, codes for a receptor called L1-CAM. This receptor is a protein usually found on nerve cells, where it plays a role in nerve cell recognition and motility. What is this receptor doing in cancer cells" Ben-Ze'ev's previous research had shown that L1-CAM is only expressed on certain cells located at the invasive front of the tumor tissue, hinting that it could be an important player in metastasis.
In this study, the scientists found that colorectal cancer cells engineered to express the L1-CAM gene indeed spread to the liver, while those cells lacking L1-CAM did not.
In collaboration with Prof. Eytan Domany and research student Michal Sheffer of the Insitute's Physics of Complex Systems Department, Ben-Ze'ev then compared the expression of genes induced by L1-CAM in cultured colon cancer cells to those in 170 samples of colorectal cancer tissue removed from patients, and in 40 samples of normal colon tissue. Out of some 160 genes induced by L1-CAM, about 60 were highly expressed in the cancerous tissue, but not in normal colon tissue. Ben-Ze'ev plans to conduct further research into the role of these genes, to uncover L1-CAM's function in metastasis.
Prof. Avri Ben-Ze'ev's research is supported by the Jean-Jacques Brunschwig Fund for the Molecular Genetics of Cancer; Curie-Weizmann; and the Eugene and Delores Zemsky Charitable Foundation Inc. Prof. Ben-Ze'ev is the incumbent of the Samuel Lunenfeld-Reuben Kunin Chair of Genetics.
The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
Source: Yivsam Azgad
Weizmann Institute of Science
In a majority of cases, colorectal cancer is initiated by changes in a key protein -- beta-catenin. One of the roles of this protein is to enter the cell nucleus and activate gene expression. But in colorectal and other cancers, beta-catenin over-accumulates in the cell and inappropriately activates genes, leading to cancer.
Surprisingly, one of the genes activated by beta-catenin, which had been previously detected in colorectal cancer cells by Ben-Ze'ev's group, codes for a receptor called L1-CAM. This receptor is a protein usually found on nerve cells, where it plays a role in nerve cell recognition and motility. What is this receptor doing in cancer cells" Ben-Ze'ev's previous research had shown that L1-CAM is only expressed on certain cells located at the invasive front of the tumor tissue, hinting that it could be an important player in metastasis.
In this study, the scientists found that colorectal cancer cells engineered to express the L1-CAM gene indeed spread to the liver, while those cells lacking L1-CAM did not.
In collaboration with Prof. Eytan Domany and research student Michal Sheffer of the Insitute's Physics of Complex Systems Department, Ben-Ze'ev then compared the expression of genes induced by L1-CAM in cultured colon cancer cells to those in 170 samples of colorectal cancer tissue removed from patients, and in 40 samples of normal colon tissue. Out of some 160 genes induced by L1-CAM, about 60 were highly expressed in the cancerous tissue, but not in normal colon tissue. Ben-Ze'ev plans to conduct further research into the role of these genes, to uncover L1-CAM's function in metastasis.
Prof. Avri Ben-Ze'ev's research is supported by the Jean-Jacques Brunschwig Fund for the Molecular Genetics of Cancer; Curie-Weizmann; and the Eugene and Delores Zemsky Charitable Foundation Inc. Prof. Ben-Ze'ev is the incumbent of the Samuel Lunenfeld-Reuben Kunin Chair of Genetics.
The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
Source: Yivsam Azgad
Weizmann Institute of Science
суббота, 6 августа 2011 г.
Marsupials And Humans Shared Same Genetic Imprinting 150 Million Years Ago
Research published in Nature Genetics by a team of international scientists including the University of Melbourne, Department of Zoology, has established an identical mechanism of genetic imprinting, a process involved in marsupial and human fetal development, which evolved 150 million years ago.
"This paper shows that we share a common genetic imprinting mechanism which has been active for about 150 million years despite the differences in reproductive strategies between marsupials and humans," said Professor Geoffrey Shaw of the Department of Zoology at the University of Melbourne, a coauthor on the paper.
Professor Marilyn Renfree who lead the University of Melbourne research team says marsupials give birth to very small young that develop mainly within the pouch while humans have more developed young at birth that undergo a large period of growth in the uterus.
"Our team provided vital samples and genetic resources from marsupials to enable this study and contributed our world-leading expertise on marsupial biology and genomics to the interpretation of the results," Professor Renfree said.
Genomic imprinting is a mechanism that regulates gene expression in the developing fetus and plays a major role in regulating its growth.
"We all carry two copies of every gene in our DNA, one inherited from our mother and one from our father. So for each gene we have a 'back-up'. Normally, both copies of the gene are used for development, but in some special cases the gene from either our mother or father is switched off, so we only have one active copy. This phenomenon is known as genomic imprinting," explained Dr Andrew Pask also from the Department of Zoology.
"Because there is no back up copy, when errors occur in this process, it results in many human genetic diseases mainly affecting growth and brain function."
Pask explains that a key gene regulating fetal growth is the Insulin-like-growth-factor-2 or IGF2 which is an imprinted gene.
"We inherit a single working copy of this gene from our fathers, while the copy we inherit from our mothers is switched off. The switch for this gene is controlled by another gene known as H19. The H19 gene is unusual gene that makes a microRNA and not a protein."
"MicroRNA genes have been sought in marsupials for years, and now for the first time one has been discovered," Dr Pask said.
Pask explains that the microRNA structure is virtually identical to that of mice and humans, but there was no evidence of this gene or a similar microRNA in the more distantly related platypus.
The study was a large team effort involving researchers in the UK, from the Babraham Institute, the Sanger Institute and the University of Cambridge, in Australia, from the University of Melbourne, and the USA, from the University of Texas at San Antonio (all part of the Sequence Analysis of Vertebrate Orthologous Imprinted Regions 'SAVOIR' consortium).
"Understanding how genetic imprinting evolved is important," said Dr Shaw, "It helps us to determine how the mechanism works and what we can do to avoid the development of a number of human diseases."
Contacts:
Dr Andrew Pask
Department of Zoology, University of Melbourne, Australia
Associate Professor Geoff Shaw
Department of Zoology, University of Melbourne, Australia
Source: Rebecca Scott
University of Melbourne
"This paper shows that we share a common genetic imprinting mechanism which has been active for about 150 million years despite the differences in reproductive strategies between marsupials and humans," said Professor Geoffrey Shaw of the Department of Zoology at the University of Melbourne, a coauthor on the paper.
Professor Marilyn Renfree who lead the University of Melbourne research team says marsupials give birth to very small young that develop mainly within the pouch while humans have more developed young at birth that undergo a large period of growth in the uterus.
"Our team provided vital samples and genetic resources from marsupials to enable this study and contributed our world-leading expertise on marsupial biology and genomics to the interpretation of the results," Professor Renfree said.
Genomic imprinting is a mechanism that regulates gene expression in the developing fetus and plays a major role in regulating its growth.
"We all carry two copies of every gene in our DNA, one inherited from our mother and one from our father. So for each gene we have a 'back-up'. Normally, both copies of the gene are used for development, but in some special cases the gene from either our mother or father is switched off, so we only have one active copy. This phenomenon is known as genomic imprinting," explained Dr Andrew Pask also from the Department of Zoology.
"Because there is no back up copy, when errors occur in this process, it results in many human genetic diseases mainly affecting growth and brain function."
Pask explains that a key gene regulating fetal growth is the Insulin-like-growth-factor-2 or IGF2 which is an imprinted gene.
"We inherit a single working copy of this gene from our fathers, while the copy we inherit from our mothers is switched off. The switch for this gene is controlled by another gene known as H19. The H19 gene is unusual gene that makes a microRNA and not a protein."
"MicroRNA genes have been sought in marsupials for years, and now for the first time one has been discovered," Dr Pask said.
Pask explains that the microRNA structure is virtually identical to that of mice and humans, but there was no evidence of this gene or a similar microRNA in the more distantly related platypus.
The study was a large team effort involving researchers in the UK, from the Babraham Institute, the Sanger Institute and the University of Cambridge, in Australia, from the University of Melbourne, and the USA, from the University of Texas at San Antonio (all part of the Sequence Analysis of Vertebrate Orthologous Imprinted Regions 'SAVOIR' consortium).
"Understanding how genetic imprinting evolved is important," said Dr Shaw, "It helps us to determine how the mechanism works and what we can do to avoid the development of a number of human diseases."
Contacts:
Dr Andrew Pask
Department of Zoology, University of Melbourne, Australia
Associate Professor Geoff Shaw
Department of Zoology, University of Melbourne, Australia
Source: Rebecca Scott
University of Melbourne
среда, 3 августа 2011 г.
New Molecular Imaging Techniques May Lead To Advances In Disease Treatment
A promising new technique has been developed that will enable more accurate non-invasive positron emission tomography (PET) imaging of new cells injected into the body, according to researchers at SNM's 55th Annual Meeting. The new technique, which involves engineering antibody fragments to act as reporter genes - or markers that signal cells of interest for PET imaging purposes - could significantly advance the study of genetically engineered cells to treat diseases.
"Genetic cell engineering is the focus of intense research in almost all areas of medicine and shows great promise for treatment of common illnesses such as heart disease, diabetes, and Parkinson's disease and other neurodegenerative disorders," said Wolfgang Weber, lead researcher of the study, Cell Surface Expression of an Engineered Antibody as a PET Reporter Gene for In Vivo PET Imaging, which was performed at the Department of Molecular and Medical Pharmacology at UCLA in collaboration with the Department of Chemistry at UC Davis.
However, despite intense efforts, researchers have few solid, noninvasive methods for accurately tracking the location, function and viability of small numbers of transplanted cells. "Our research shows that using antibodies as reporter genes in PET imaging provides these capabilities and could contribute to improved treatment of a number of potentially devastating diseases," added Weber, now professor of nuclear medicine at the University of Freiburg, Germany.
To improve PET imaging in this area, researchers have been studying the use of reporter gene-probe combinations. With this technique, cells are created to synthesize a protein that binds to or metabolizes radioactive reporter probes that are injected into the body and detected with PET imaging technology. However, most available reporter gene combinations are not aptly sensitive or specific and have significant limitations in terms of tracking the cells of interest to researchers.
In this new research, Weber and his team explored using cell surface-bound antibody fragments as reporter genes. These engineered antibody fragments, developed by the group of Claude Meares at Davis, bind irreversibly to low-molecular-weight antigens, which act as reporter probes. Cell culture and animal studies demonstrated intense and highly specific uptake of the probes in cells expressing the antibody fragment on the cell surface. These data indicate that antibody-based reporter genes represent a promising new platform for the development of new reporter gene and probe combinations.
Antibody-based reporter genes have several potential advantages over other combinations. For example, the pharmacokinetics of the reporter probe can easily be optimized, and probes can identify antibodies with much higher specificity, thus improving the accuracy of PET imaging. In addition, the number of antibodies that can be used as reporter genes is virtually unlimited compared with available viral or mammalian reporter genes. Antibody-based reporter genes have low immunogenicity and are better suited for imaging the expression of several genes.
Weber and his team were presented with the SNM Molecular Imaging Center of Excellence (MICoE) Abstract Award for their work. The award was presented during SNM's 55th Annual Meeting by MICoE president Martin Pomper.
Scientific Paper 102: L.H. Wei, C. Radu, I.J. Hildebrandt, T. Olafson, M.E. Phelps, A. Wu, J. Czernin, W. Weber, Pharmacology, University of California Los Angeles, Los Angeles, CA; M. McCoy, C. Meares, Chemistry, UC Davis, Davis, CA; "Cell Surface Expression of an Engineered Antibody as a PET Reporter Gene for In Vivo PET Imaging," SNM 55th Annual Meeting, June 14-18, 2008.
About SNM - Advancing Molecular Imaging and Therapy
SNM is an international scientific and medical organization dedicated to increasing understanding and sound practice of molecular imaging throughout the medical community and with the public. Due to the work of SNM members, molecular imaging is a vital element of today's medical practice, adding an additional dimension to diagnosis that can change the way common and devastating diseases are understood and treated.
Our more than 16,000 members set the standard for molecular imaging practice by creating procedure guidelines, sharing information through our Journal and meetings, and leading advocacy on key issues that affect imaging research and practice. For more information visit snm/.
Source: Amy Shaw
Society of Nuclear Medicine
"Genetic cell engineering is the focus of intense research in almost all areas of medicine and shows great promise for treatment of common illnesses such as heart disease, diabetes, and Parkinson's disease and other neurodegenerative disorders," said Wolfgang Weber, lead researcher of the study, Cell Surface Expression of an Engineered Antibody as a PET Reporter Gene for In Vivo PET Imaging, which was performed at the Department of Molecular and Medical Pharmacology at UCLA in collaboration with the Department of Chemistry at UC Davis.
However, despite intense efforts, researchers have few solid, noninvasive methods for accurately tracking the location, function and viability of small numbers of transplanted cells. "Our research shows that using antibodies as reporter genes in PET imaging provides these capabilities and could contribute to improved treatment of a number of potentially devastating diseases," added Weber, now professor of nuclear medicine at the University of Freiburg, Germany.
To improve PET imaging in this area, researchers have been studying the use of reporter gene-probe combinations. With this technique, cells are created to synthesize a protein that binds to or metabolizes radioactive reporter probes that are injected into the body and detected with PET imaging technology. However, most available reporter gene combinations are not aptly sensitive or specific and have significant limitations in terms of tracking the cells of interest to researchers.
In this new research, Weber and his team explored using cell surface-bound antibody fragments as reporter genes. These engineered antibody fragments, developed by the group of Claude Meares at Davis, bind irreversibly to low-molecular-weight antigens, which act as reporter probes. Cell culture and animal studies demonstrated intense and highly specific uptake of the probes in cells expressing the antibody fragment on the cell surface. These data indicate that antibody-based reporter genes represent a promising new platform for the development of new reporter gene and probe combinations.
Antibody-based reporter genes have several potential advantages over other combinations. For example, the pharmacokinetics of the reporter probe can easily be optimized, and probes can identify antibodies with much higher specificity, thus improving the accuracy of PET imaging. In addition, the number of antibodies that can be used as reporter genes is virtually unlimited compared with available viral or mammalian reporter genes. Antibody-based reporter genes have low immunogenicity and are better suited for imaging the expression of several genes.
Weber and his team were presented with the SNM Molecular Imaging Center of Excellence (MICoE) Abstract Award for their work. The award was presented during SNM's 55th Annual Meeting by MICoE president Martin Pomper.
Scientific Paper 102: L.H. Wei, C. Radu, I.J. Hildebrandt, T. Olafson, M.E. Phelps, A. Wu, J. Czernin, W. Weber, Pharmacology, University of California Los Angeles, Los Angeles, CA; M. McCoy, C. Meares, Chemistry, UC Davis, Davis, CA; "Cell Surface Expression of an Engineered Antibody as a PET Reporter Gene for In Vivo PET Imaging," SNM 55th Annual Meeting, June 14-18, 2008.
About SNM - Advancing Molecular Imaging and Therapy
SNM is an international scientific and medical organization dedicated to increasing understanding and sound practice of molecular imaging throughout the medical community and with the public. Due to the work of SNM members, molecular imaging is a vital element of today's medical practice, adding an additional dimension to diagnosis that can change the way common and devastating diseases are understood and treated.
Our more than 16,000 members set the standard for molecular imaging practice by creating procedure guidelines, sharing information through our Journal and meetings, and leading advocacy on key issues that affect imaging research and practice. For more information visit snm/.
Source: Amy Shaw
Society of Nuclear Medicine
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