Researchers in Singapore are reporting development of a new electronic sensor that shows promise as a faster, less expensive, and more practical alternative than tests now used to detect DNA. Such tests are done for criminal investigation, disease diagnosis, and other purposes. The new lab-on-a-chip test could lead to wider, more convenient use of DNA testing, the researchers say. Their study is scheduled for the Sept. 2 issue of the Journal of the American Chemical Society, a weekly publication.
In the new study, Zhiqiang Gao and colleagues note that current methods for detecting DNA involve the used of the polymerase chain reaction (PCR). This technique "amplifies" or makes multiple copies of trace amounts of DNA, much as a photocopier produces multiple copies of documents, in order to detect the genetic material more easily. The amplification step is one reason why tests involving PCR can be too expensive, cumbersome, and imprecise for wider use.
The researchers describe development of a so-called "nanogap sensor" that appears to overcome those obstacles. The process uses a pair of micro-sized metal electrodes separated by a nanogap, 1/50,000 the width of a human hair, in combination with special chemical probes to capture tiny segments of DNA. The newly formed "circuit" then translates the presence of DNA into an electrical signal so that it can be measured by a computer. In laboratory tests, the sensor showed "excellent" sensitivity at detecting trace amounts of human DNA and may eliminate the need for DNA amplification altogether, the researchers say.
Source
Journal of the American Chemical Society
понедельник, 30 мая 2011 г.
Is Hybridoma Production About To Take A Quantum Leap Forward?
Recently published research* has established the ability of Neowater® to enhance the various processes involved in the production of pure human monoclonal antibodies by refining the standard hybridoma production process.
Biopharmaceutical companies have started to evaluate the use of fully human monoclonal antibodies as a complementary or primary therapeutic agent against a variety of diseases. The most obvious advantage would be to bypass the interference from the patient's immune system that typically characterizes the use of chemerical or humanized antibodies. Due to the growing interest and the potential benefits, the efficient production of human monoclonal antibodies is a high priority. But any attempt to produce these by natural means encounters formidable obstacles, not only from an ethical standpoint but also from the difficulty inherent in generating human antibodies against human tissues.
The capacity to humanize monoclonal antibodies in 1988 through hybridoma cell production methods opened exciting new vistas in R&D and biomed products. If this method could be further refined to produce pure, natural human monoclonal antibodies, research would take a quantum leap forward in the development of new medical and pharmaceutical discoveries for serious and life-threatening conditions that cannot yet be successfully treated with synthesized hybrids.
One proven way to profoundly enhance the media solutions used for cell growth, and particularly membrane proteins, is Radio Frequency (RF) radiation. The RF is absorbed by the aqueous solution and stimulates new membrane formation - a vital stage in hybridoma cell growth. The problem is that the beneficial effect decays once the source of RF is removed, and the new membrane formation does not receive the full benefit. Without this extra "boost", the delicate process of producing viable, fully human monoclonal antibodies faces an insurmountable obstacle.
This obstacle has been effectively removed by Neowater®, a novel nanoparticle-doped (NPD) water created by a unique patented water-based nanotechnology.
Neowater® is a non-toxic form of water that mimics intracellular water, which is found uniquely in the human body and its cells. NPD water is characterized by a shifting in the physical properties of ordinary water, imparting new levels of compatibility with hydrophobic substances. Neowater® also maintains the beneficial effect of RF radiation on water for years after its production, thanks to its extraordinary structural stability.
The researchers performed numerous experiments to test the growth rate of hybridoma cells in NPD-based media. They specifically tested the effect of the NPD environment on the complete process of human monoclonal antibody production, and their results were published recently in the BMC Biotechnology Journal.
To evaluate the hybridoma formation process (utilizing the chemical fusion method), the researchers received samples of human peripheral blood mononuclear cells (PBMC) from several donors; each sample was tested either in a NPD or a DI (de-ionized) environment. In referring to the results, the researchers stated: "We witnessed a statistically significant difference in the yield of hybridoma cells between NPD and DI environments."
In another experiment, the isolation of subclones and autocrine activity of hybridoma cells was tested. The researchers reported: "We observed greater clonal outgrowth of antibody-secreting hybridoma cells in NPD-based media as compared to DI-based media." Moreover, they found that "the cloneability of cells from a semi-stable clone is also enhanced in NPD-based media."
The researchers noted that hybridoma clones grown on NPD-based media secreted more monoclonal antibodies into their environment. However, they also observed that "Some cells grow faster in NPD-based media…This result might not reflect greater secretion per cell, but rather greater proliferation of cells with a similar secretion." After normalization of this biased situation, the researchers calculated that "the secretion of monoclonal antibody in NPD-based media is roughly twice that obtained in DI-based media."
This interesting and unexpected result led the researchers to conduct further tests: To what extent are cell proliferation rates affected by NPD-based media" Growing CHO (Chinese Hamster Ovary) cells in NPD-based and DI-based media, the researchers observed an unmistakable increase in proliferation when cells were incubated in NPD-based media, in comparison to the DI-based media: "an increase by an average of nearly 30%" .
The researchers then tested the proliferation rate of primary human fibroblast cells incubated either in NPD-based or DI-based media. Unlike the CHO cells, these are sensitive to cell density and were grown at two different starting dilutions. Here the NPD-based media had the opposite effect: the CHO cells displayed a slower proliferation rate than that of DI-based media (in both dilutions). The researchers concluded: "As is evident from the curves, primary human fibroblasts proliferated poorly in NPD-based media, compared to DI-based media.... they appear to sense the lower effective cell density."
The above paper demonstrates the remarkable power of Neowater® for enhancing the stabilization, activity and proliferation of cells and antibodies - as well as inhibiting the proliferation of other cells. This is just one example of the wide research potential that Neowater® offers, which will eventually impact the healthcare industry. Imagine the novel and cutting-edge methodologies suddenly available to stem-cell therapeutics, site-specific antibody treatments, and targeted anti-cancer drugs using fully human mAbs.
Many promising biomed and therapeutic concepts that have been shelved, blocked by the basic difference between regular water and intracellular water, can now cross the "molecular water barrier", thanks to the nanoparticle restructuring capability of Neowater®. We can expect a new era in R&D as these concepts are facilitated by Neowater® technology and find realization in therapeutic applications.
* "ENHANCEMENT OF HYBRIDOMA FORMATION, CLONEABILITY AND CELL PROLIFERATION IN A NANOPARTICLE-DOPED AQUEOUS ENVIRONMENT", authored by Natalie Gavrilov-Yusim1, Ekaterina Hahiashvili1, Marina Tashker1, Victoria Yavelsky1, Ohad Karnieli2 and Leslie Lobel1
1Department of Virology and Developmental Genetics, Ben Gurion University of the Negev, Beer-sheva 84105, Israel
2Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel)
Source: Irit Gabbai
Do-Coop Technologies Ltd.
Biopharmaceutical companies have started to evaluate the use of fully human monoclonal antibodies as a complementary or primary therapeutic agent against a variety of diseases. The most obvious advantage would be to bypass the interference from the patient's immune system that typically characterizes the use of chemerical or humanized antibodies. Due to the growing interest and the potential benefits, the efficient production of human monoclonal antibodies is a high priority. But any attempt to produce these by natural means encounters formidable obstacles, not only from an ethical standpoint but also from the difficulty inherent in generating human antibodies against human tissues.
The capacity to humanize monoclonal antibodies in 1988 through hybridoma cell production methods opened exciting new vistas in R&D and biomed products. If this method could be further refined to produce pure, natural human monoclonal antibodies, research would take a quantum leap forward in the development of new medical and pharmaceutical discoveries for serious and life-threatening conditions that cannot yet be successfully treated with synthesized hybrids.
One proven way to profoundly enhance the media solutions used for cell growth, and particularly membrane proteins, is Radio Frequency (RF) radiation. The RF is absorbed by the aqueous solution and stimulates new membrane formation - a vital stage in hybridoma cell growth. The problem is that the beneficial effect decays once the source of RF is removed, and the new membrane formation does not receive the full benefit. Without this extra "boost", the delicate process of producing viable, fully human monoclonal antibodies faces an insurmountable obstacle.
This obstacle has been effectively removed by Neowater®, a novel nanoparticle-doped (NPD) water created by a unique patented water-based nanotechnology.
Neowater® is a non-toxic form of water that mimics intracellular water, which is found uniquely in the human body and its cells. NPD water is characterized by a shifting in the physical properties of ordinary water, imparting new levels of compatibility with hydrophobic substances. Neowater® also maintains the beneficial effect of RF radiation on water for years after its production, thanks to its extraordinary structural stability.
The researchers performed numerous experiments to test the growth rate of hybridoma cells in NPD-based media. They specifically tested the effect of the NPD environment on the complete process of human monoclonal antibody production, and their results were published recently in the BMC Biotechnology Journal.
To evaluate the hybridoma formation process (utilizing the chemical fusion method), the researchers received samples of human peripheral blood mononuclear cells (PBMC) from several donors; each sample was tested either in a NPD or a DI (de-ionized) environment. In referring to the results, the researchers stated: "We witnessed a statistically significant difference in the yield of hybridoma cells between NPD and DI environments."
In another experiment, the isolation of subclones and autocrine activity of hybridoma cells was tested. The researchers reported: "We observed greater clonal outgrowth of antibody-secreting hybridoma cells in NPD-based media as compared to DI-based media." Moreover, they found that "the cloneability of cells from a semi-stable clone is also enhanced in NPD-based media."
The researchers noted that hybridoma clones grown on NPD-based media secreted more monoclonal antibodies into their environment. However, they also observed that "Some cells grow faster in NPD-based media…This result might not reflect greater secretion per cell, but rather greater proliferation of cells with a similar secretion." After normalization of this biased situation, the researchers calculated that "the secretion of monoclonal antibody in NPD-based media is roughly twice that obtained in DI-based media."
This interesting and unexpected result led the researchers to conduct further tests: To what extent are cell proliferation rates affected by NPD-based media" Growing CHO (Chinese Hamster Ovary) cells in NPD-based and DI-based media, the researchers observed an unmistakable increase in proliferation when cells were incubated in NPD-based media, in comparison to the DI-based media: "an increase by an average of nearly 30%" .
The researchers then tested the proliferation rate of primary human fibroblast cells incubated either in NPD-based or DI-based media. Unlike the CHO cells, these are sensitive to cell density and were grown at two different starting dilutions. Here the NPD-based media had the opposite effect: the CHO cells displayed a slower proliferation rate than that of DI-based media (in both dilutions). The researchers concluded: "As is evident from the curves, primary human fibroblasts proliferated poorly in NPD-based media, compared to DI-based media.... they appear to sense the lower effective cell density."
The above paper demonstrates the remarkable power of Neowater® for enhancing the stabilization, activity and proliferation of cells and antibodies - as well as inhibiting the proliferation of other cells. This is just one example of the wide research potential that Neowater® offers, which will eventually impact the healthcare industry. Imagine the novel and cutting-edge methodologies suddenly available to stem-cell therapeutics, site-specific antibody treatments, and targeted anti-cancer drugs using fully human mAbs.
Many promising biomed and therapeutic concepts that have been shelved, blocked by the basic difference between regular water and intracellular water, can now cross the "molecular water barrier", thanks to the nanoparticle restructuring capability of Neowater®. We can expect a new era in R&D as these concepts are facilitated by Neowater® technology and find realization in therapeutic applications.
* "ENHANCEMENT OF HYBRIDOMA FORMATION, CLONEABILITY AND CELL PROLIFERATION IN A NANOPARTICLE-DOPED AQUEOUS ENVIRONMENT", authored by Natalie Gavrilov-Yusim1, Ekaterina Hahiashvili1, Marina Tashker1, Victoria Yavelsky1, Ohad Karnieli2 and Leslie Lobel1
1Department of Virology and Developmental Genetics, Ben Gurion University of the Negev, Beer-sheva 84105, Israel
2Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel)
Source: Irit Gabbai
Do-Coop Technologies Ltd.
Organon And MRC Technology Sign Antibody Development Agreement
Organon, the human
healthcare business unit of Akzo Nobel, together with MRC Technology
(London, UK) announced that they have signed a collaborative
agreement to develop a humanized antibody for the treatment of certain
forms of cancer. The Therapeutic Antibody Group (TAG) at MRCT will use its
proprietary CDR grafting technology to generate a humanized clinical
candidate from a murine antibody discovered at Organon's Research Center
in Cambridge, MA (USA). Organon will pay MRCT research and development
milestones, and royalties based on net sales that may result from the
commercialization of any antibody products. Organon will retain all
development and commercialization rights. Additional financial terms were
not disclosed.
"Organon has been stepping up its efforts to discover and develop novel
biotherapeutics for oncology and auto-immune disorders. The collaboration with
MRCT on its well-validated antibody humanization technology is a further step
towards becoming effective biotherapeutic drug hunters," said David Nicholson,
EVP of R&D at Organon.
TAG has a proven track record of success in antibody humanization which
extends over 18 years and encompasses around 30 successfully humanized
antibodies," said Dr. Tarran Jones, Director of TAG. "Eight of these humanized
antibodies have progressed to the clinic and two, Elan/Biogen Idec's Tysabri® and
Chugai/Roche's Actemra®, have gone on to achieve market approval. We are
looking forward to applying our expertise in collaboration with Organon to
humanize their monoclonal antibody which addresses such an important disease
area."
Antibody humanization
Antibody humanization, also known as CDR-grafting (CDR is a synonym for
complementarity determining region) was first invented at the MRC Laboratory of
Molecular Biology in the UK by Dr. Sir Greg Winter and patented by the MRC in the late
1980's. CDR-grafting involves the genetic transfer of mouse CDRs (which are responsible
for antigen binding) into human frameworks of a variable region. A variable region is one
domain of an immunoglobulin chain, a whole antibody itself comprising of one light and
one heavy immunoglobulin chain. The key to success in antibody humanization is a careful
analysis of the mouse antibody to identify key framework residues important for the
preservation of antibody function in the humanized antibody.
About Organon
Organon creates, manufactures and markets innovative prescription medicines that
improve the health and quality of human life. Through a combination of innovation and
business partnerships, Organon seeks to leverage its position as a leading
biopharmaceutical company in each of its core therapeutic fields: fertility, gynecology and
selected areas of anesthesia. It has extensive expertise in neuroscience and a rich and
focused R&D program. Research areas also include immunology and specific areas of
oncology. Organon products are distributed in over 100 countries worldwide, of which more
than 50 have an Organon subsidiary. Organon is the human healthcare business unit of
Akzo Nobel.
About Medical Research Council Technology (MRCT)
MRCT is the exclusive commercialisation catalyst for the UK Medical Research Council
(MRC), working to translate cutting edge scientific discoveries into commercial products.
MRCT bridges the gap between innovative basic science and making medicine. By
providing both chemical tools and therapeutic antibody candidates, we give pharmaceutical
and biotechnology companies new starting points for drug discovery and development,
based on MRC advances in science.
MRCT's Therapeutic Antibody Group (TAG) scientists have a proven track record of
success in antibody humanisation which extends over 18 years and has produced 8
clinical candidates and two regulatory approved humanised antibodies. TAG collaborates
with MRC scientists to translate innovative antibody-based drug targets into potent and
selective therapeutic antibody candidates which can then be partnered with industry. In
addition, MRCT provides the pharmaceutical and biotechnology industry access to the
world-class antibody humanisation and expression expertise of TAG.
Safe Harbor Statement Organon*
This press release may contain statements which address such key issues as growth strategy, future
financial results, market positions, product development, pharmaceutical products in the pipeline, and
product approvals of Organon. Such statements should be carefully considered, and it should be
understood that many factors could cause forecasted and actual results to differ from these statements.
These factors include, but are not limited to, price fluctuations, currency fluctuations, progress of drug
development, clinical testing and regulatory approval, developments in raw material and personnel costs,
pensions, physical and environmental risks, legal issues, and legislative, fiscal, and other regulatory
measures. Stated competitive positions are based on management estimates supported by information
provided by specialized external agencies. For a more comprehensive discussion of the risk factors
affecting our business please see our Annual Report on Form 20-F filed with the United States Securities
and Exchange Commission, a copy of which can be found on the company's corporate website
akzonobel.
* Pursuant to the U.S. Private Securities Litigation Reform Act 1995.
View drug information on Actemra; Tysabri.
healthcare business unit of Akzo Nobel, together with MRC Technology
(London, UK) announced that they have signed a collaborative
agreement to develop a humanized antibody for the treatment of certain
forms of cancer. The Therapeutic Antibody Group (TAG) at MRCT will use its
proprietary CDR grafting technology to generate a humanized clinical
candidate from a murine antibody discovered at Organon's Research Center
in Cambridge, MA (USA). Organon will pay MRCT research and development
milestones, and royalties based on net sales that may result from the
commercialization of any antibody products. Organon will retain all
development and commercialization rights. Additional financial terms were
not disclosed.
"Organon has been stepping up its efforts to discover and develop novel
biotherapeutics for oncology and auto-immune disorders. The collaboration with
MRCT on its well-validated antibody humanization technology is a further step
towards becoming effective biotherapeutic drug hunters," said David Nicholson,
EVP of R&D at Organon.
TAG has a proven track record of success in antibody humanization which
extends over 18 years and encompasses around 30 successfully humanized
antibodies," said Dr. Tarran Jones, Director of TAG. "Eight of these humanized
antibodies have progressed to the clinic and two, Elan/Biogen Idec's Tysabri® and
Chugai/Roche's Actemra®, have gone on to achieve market approval. We are
looking forward to applying our expertise in collaboration with Organon to
humanize their monoclonal antibody which addresses such an important disease
area."
Antibody humanization
Antibody humanization, also known as CDR-grafting (CDR is a synonym for
complementarity determining region) was first invented at the MRC Laboratory of
Molecular Biology in the UK by Dr. Sir Greg Winter and patented by the MRC in the late
1980's. CDR-grafting involves the genetic transfer of mouse CDRs (which are responsible
for antigen binding) into human frameworks of a variable region. A variable region is one
domain of an immunoglobulin chain, a whole antibody itself comprising of one light and
one heavy immunoglobulin chain. The key to success in antibody humanization is a careful
analysis of the mouse antibody to identify key framework residues important for the
preservation of antibody function in the humanized antibody.
About Organon
Organon creates, manufactures and markets innovative prescription medicines that
improve the health and quality of human life. Through a combination of innovation and
business partnerships, Organon seeks to leverage its position as a leading
biopharmaceutical company in each of its core therapeutic fields: fertility, gynecology and
selected areas of anesthesia. It has extensive expertise in neuroscience and a rich and
focused R&D program. Research areas also include immunology and specific areas of
oncology. Organon products are distributed in over 100 countries worldwide, of which more
than 50 have an Organon subsidiary. Organon is the human healthcare business unit of
Akzo Nobel.
About Medical Research Council Technology (MRCT)
MRCT is the exclusive commercialisation catalyst for the UK Medical Research Council
(MRC), working to translate cutting edge scientific discoveries into commercial products.
MRCT bridges the gap between innovative basic science and making medicine. By
providing both chemical tools and therapeutic antibody candidates, we give pharmaceutical
and biotechnology companies new starting points for drug discovery and development,
based on MRC advances in science.
MRCT's Therapeutic Antibody Group (TAG) scientists have a proven track record of
success in antibody humanisation which extends over 18 years and has produced 8
clinical candidates and two regulatory approved humanised antibodies. TAG collaborates
with MRC scientists to translate innovative antibody-based drug targets into potent and
selective therapeutic antibody candidates which can then be partnered with industry. In
addition, MRCT provides the pharmaceutical and biotechnology industry access to the
world-class antibody humanisation and expression expertise of TAG.
Safe Harbor Statement Organon*
This press release may contain statements which address such key issues as growth strategy, future
financial results, market positions, product development, pharmaceutical products in the pipeline, and
product approvals of Organon. Such statements should be carefully considered, and it should be
understood that many factors could cause forecasted and actual results to differ from these statements.
These factors include, but are not limited to, price fluctuations, currency fluctuations, progress of drug
development, clinical testing and regulatory approval, developments in raw material and personnel costs,
pensions, physical and environmental risks, legal issues, and legislative, fiscal, and other regulatory
measures. Stated competitive positions are based on management estimates supported by information
provided by specialized external agencies. For a more comprehensive discussion of the risk factors
affecting our business please see our Annual Report on Form 20-F filed with the United States Securities
and Exchange Commission, a copy of which can be found on the company's corporate website
akzonobel.
* Pursuant to the U.S. Private Securities Litigation Reform Act 1995.
View drug information on Actemra; Tysabri.
Sequencing Of Wasp Genome May Help Fight Human Diseases Spread By Insects
About 100 million years ago, the bacterium Wolbachia came up with a trick that has made it one of the most successful parasites in the animal kingdom: It evolved the ability to manipulate the sex lives of its hosts.
"When it developed this capability, Wolbachia spread rapidly among the world's populations of insects, mites, spiders and nematodes, producing the greatest pandemic in the history of life," says Seth Bordenstein, assistant professor of biological sciences at Vanderbilt, who is studying the relationship between this parasitic bacteria and Nasonia, a genus of small wasps that prey on various species of flies, including houseflies, blowflies and flesh flies.
Bordenstein is a member of the Nasonia Genome Working Group, a collaboration of scientists who published the complete genomes of three species of Nasonia in the January 15 issue of the journal Science. In the paper the group identifies several genes that the wasps appear to have picked up from the bacteria.
This new genetic information has allowed Bordenstein to identify one of the key tools in the bacteria's bag of tricks. It causes a gene in the wasp's immune system to produce less of the protein responsible for detecting bacterial intruders and issuing the chemical alarm signal that activates the wasp's various defense mechanisms. This hijacking of the immune system allows the bacteria to invade the bodies of its hosts with relative impunity, he proposes.
Exactly how the bacteria alters its hosts' reproductive systems to its advantage remains a matter for future study. But scientists have identified the bacteria's basic strategies. Depending on its host, the bacteria either:
Kills infected males;
Feminizes infected males so they develop as females or infertile pseudo-females;
Induces parthenogenesis: the reproduction of infected females without males;
Makes the sperm of infected males incompatible with the eggs of uninfected females or females infected with a different Wolbachia strain.
Wolbachia favors female over male offspring because they are present in mature eggs, but not in mature sperm. As a result, only infected females pass the infection on to their offspring.
"This makes them the ultimate feminist weapon," Bordenstein quips.
Although the bacteria's parasitism is limited to arthropods - animals with exoskeletons instead of backbones like insects, spiders and crustaceans - its prevalence means that it has a major impact on the biosphere. According to one study, more than 16 percent of the insect species in South and Central America, Mexico, the Caribbean Islands and southern Florida are infected and as many as 70 percent of all insect species are potential hosts.
Recognition of Wolbachia's capabilities has made it a promising candidate for genetic engineers looking for more effective ways to fight human diseases spread by insects. "Once we understand how Wolbachia works, we should be able to add some genes that allow us to control insects that vector human diseases like malaria and dengue fever," says Bordenstein. "There is already a number of research projects supported by the Gates Foundation and the National Institutes of Health pursuing this idea."
Although the ubiquitous bacteria cannot trick the human immune system, it does have an adverse impact on human health. For example, it infects many species of nematodes, including the filarial nematodes that infect more than 200 million people worldwide, causing debilitating inflammatory diseases, such as river blindness and elephantiasis.
In the last 10 years scientists have realized that it is actually the bacteria, not the nematode, that is responsible for most of the symptoms produced by these illnesses. Although Wolbachia can only survive about three days in the human body, the parasitic nematodes act as a continuing source of the bacteria that cause most of the damage. This surprising insight into the disease pathology has improved the treatment of these illnesses: They are now treated with an antibiotic that kills the bacteria and is less toxic than anti-nematode medications.
Bordenstein's research was supported by a grant from the National Institutes of Health and the genome sequencing was funded by the National Human Genome Research Institute. Additional details about the research conducted in the Bordenstein lab is available at bordensteinlab.vanderbilt.
Source: David F. Salisbury
Vanderbilt University
"When it developed this capability, Wolbachia spread rapidly among the world's populations of insects, mites, spiders and nematodes, producing the greatest pandemic in the history of life," says Seth Bordenstein, assistant professor of biological sciences at Vanderbilt, who is studying the relationship between this parasitic bacteria and Nasonia, a genus of small wasps that prey on various species of flies, including houseflies, blowflies and flesh flies.
Bordenstein is a member of the Nasonia Genome Working Group, a collaboration of scientists who published the complete genomes of three species of Nasonia in the January 15 issue of the journal Science. In the paper the group identifies several genes that the wasps appear to have picked up from the bacteria.
This new genetic information has allowed Bordenstein to identify one of the key tools in the bacteria's bag of tricks. It causes a gene in the wasp's immune system to produce less of the protein responsible for detecting bacterial intruders and issuing the chemical alarm signal that activates the wasp's various defense mechanisms. This hijacking of the immune system allows the bacteria to invade the bodies of its hosts with relative impunity, he proposes.
Exactly how the bacteria alters its hosts' reproductive systems to its advantage remains a matter for future study. But scientists have identified the bacteria's basic strategies. Depending on its host, the bacteria either:
Kills infected males;
Feminizes infected males so they develop as females or infertile pseudo-females;
Induces parthenogenesis: the reproduction of infected females without males;
Makes the sperm of infected males incompatible with the eggs of uninfected females or females infected with a different Wolbachia strain.
Wolbachia favors female over male offspring because they are present in mature eggs, but not in mature sperm. As a result, only infected females pass the infection on to their offspring.
"This makes them the ultimate feminist weapon," Bordenstein quips.
Although the bacteria's parasitism is limited to arthropods - animals with exoskeletons instead of backbones like insects, spiders and crustaceans - its prevalence means that it has a major impact on the biosphere. According to one study, more than 16 percent of the insect species in South and Central America, Mexico, the Caribbean Islands and southern Florida are infected and as many as 70 percent of all insect species are potential hosts.
Recognition of Wolbachia's capabilities has made it a promising candidate for genetic engineers looking for more effective ways to fight human diseases spread by insects. "Once we understand how Wolbachia works, we should be able to add some genes that allow us to control insects that vector human diseases like malaria and dengue fever," says Bordenstein. "There is already a number of research projects supported by the Gates Foundation and the National Institutes of Health pursuing this idea."
Although the ubiquitous bacteria cannot trick the human immune system, it does have an adverse impact on human health. For example, it infects many species of nematodes, including the filarial nematodes that infect more than 200 million people worldwide, causing debilitating inflammatory diseases, such as river blindness and elephantiasis.
In the last 10 years scientists have realized that it is actually the bacteria, not the nematode, that is responsible for most of the symptoms produced by these illnesses. Although Wolbachia can only survive about three days in the human body, the parasitic nematodes act as a continuing source of the bacteria that cause most of the damage. This surprising insight into the disease pathology has improved the treatment of these illnesses: They are now treated with an antibiotic that kills the bacteria and is less toxic than anti-nematode medications.
Bordenstein's research was supported by a grant from the National Institutes of Health and the genome sequencing was funded by the National Human Genome Research Institute. Additional details about the research conducted in the Bordenstein lab is available at bordensteinlab.vanderbilt.
Source: David F. Salisbury
Vanderbilt University
AGES Selects BrukerВґs MALDI Biotyper System For Mass Spectrometry-based Molecular Microbial Identification
At the 32rd OEGHMP annual meeting opening here today, Bruker announces that its MALDI Biotyper workflow for microbial identification in clinical microbiology has been selected by the Austrian Agency for Health and Food Safety (AGES) for MALDI-TOF based analyses of microorganisms.
AGES is responsible for several tasks in regard to public health and food safety for the Austrian government. The organization researches, analyzes and performs inspections according to the policy guidelines of Austrian Food Laws. The agency requires veterinary inspections and dedicates itself to the prevention and control of infectious diseases in the population. Just recently, scientists of the AGES discovered the source of a listeriosis outbreak in Austria and Germany that caused eight deaths due to contaminated cheese products. In order to provide always state of the art microbiological analyses AGES is the first organization in Austria using the IVD-CE marked IVD MALDI Biotyper system that is in accordance with the European Union In Vitro Diagnostic Directive 98/79/EC.
University Professor Dr. med. Franz Allerberger, Head of the Human Medicine Division, AGES commented: "Microbial analyses based on MALDI-TOF mass spectrometry as a molecular identification tool provide premium information in order to describe and differentiate microorganisms very reliably. With advantages in speed, accuracy and cost per sample over phenotypic standard tests, the MALDI Biotyper has the potential to become a new clinical standard for microbial identification. In particular, for fastidious microorganisms like anaerobic and non-fermenting bacteria the superior discrimination power of the MALDI Biotyper has been proven in several publications. In order to substantiate the MALDI Biotyper benefit especially for difficult species in the daily clinical routine AGES will be the leading organization for quality assurance and standardization for the analysis after Legionella infections. In this context we will also perform a respective round robin test comprising labs from all over the world."
Dr. Guido Mix, Bruker Daltonics Director for Microbiology Business Development, concluded: "The MALDI Biotyper is already a very suitable and reliable tool for daily microbiological routine analysis. Globally more than 100 clinical diagnostic labs, as well as further microbiology departments at industrial and academic sites operate this protein fingerprinting-based approach. We are very pleased to collaborate with an organization like the AGES in order to explore the MALDI Biotyper capabilities beyond current standardized operational species identification procedures, and towards strain typing or clone tracking."
About the Bruker MALDI Biotyper
Bruker's dedicated MALDI Biotyper solution enables identification, taxonomical classification or dereplication of microorganisms like bacteria, yeasts and fungi. Classification and identification of microorganisms is achieved reliably and fast using high-throughput MALDI-TOF mass spectrometry. Applications include clinical routine microbial identification (in EU only - for research use only elsewhere), environmental and pharmaceutical analysis, taxonomical research, food and consumer product processing and quality control, as well as in marine microbiology. Bruker's robust MALDI Biotyper method requires minimal sample preparation efforts and offers low cost per sample. For more information, please visit maldibiotyper.
Source
Bruker Corporation
AGES is responsible for several tasks in regard to public health and food safety for the Austrian government. The organization researches, analyzes and performs inspections according to the policy guidelines of Austrian Food Laws. The agency requires veterinary inspections and dedicates itself to the prevention and control of infectious diseases in the population. Just recently, scientists of the AGES discovered the source of a listeriosis outbreak in Austria and Germany that caused eight deaths due to contaminated cheese products. In order to provide always state of the art microbiological analyses AGES is the first organization in Austria using the IVD-CE marked IVD MALDI Biotyper system that is in accordance with the European Union In Vitro Diagnostic Directive 98/79/EC.
University Professor Dr. med. Franz Allerberger, Head of the Human Medicine Division, AGES commented: "Microbial analyses based on MALDI-TOF mass spectrometry as a molecular identification tool provide premium information in order to describe and differentiate microorganisms very reliably. With advantages in speed, accuracy and cost per sample over phenotypic standard tests, the MALDI Biotyper has the potential to become a new clinical standard for microbial identification. In particular, for fastidious microorganisms like anaerobic and non-fermenting bacteria the superior discrimination power of the MALDI Biotyper has been proven in several publications. In order to substantiate the MALDI Biotyper benefit especially for difficult species in the daily clinical routine AGES will be the leading organization for quality assurance and standardization for the analysis after Legionella infections. In this context we will also perform a respective round robin test comprising labs from all over the world."
Dr. Guido Mix, Bruker Daltonics Director for Microbiology Business Development, concluded: "The MALDI Biotyper is already a very suitable and reliable tool for daily microbiological routine analysis. Globally more than 100 clinical diagnostic labs, as well as further microbiology departments at industrial and academic sites operate this protein fingerprinting-based approach. We are very pleased to collaborate with an organization like the AGES in order to explore the MALDI Biotyper capabilities beyond current standardized operational species identification procedures, and towards strain typing or clone tracking."
About the Bruker MALDI Biotyper
Bruker's dedicated MALDI Biotyper solution enables identification, taxonomical classification or dereplication of microorganisms like bacteria, yeasts and fungi. Classification and identification of microorganisms is achieved reliably and fast using high-throughput MALDI-TOF mass spectrometry. Applications include clinical routine microbial identification (in EU only - for research use only elsewhere), environmental and pharmaceutical analysis, taxonomical research, food and consumer product processing and quality control, as well as in marine microbiology. Bruker's robust MALDI Biotyper method requires minimal sample preparation efforts and offers low cost per sample. For more information, please visit maldibiotyper.
Source
Bruker Corporation
Improved Technique Determines Structure In Membrane Proteins
Understanding the form and function of certain proteins in the human body is becoming faster and easier, thanks to the work of researchers at the University of Illinois.
By combining custom-built spectrometers, novel probe designs and faster pulse sequences, a team led by Illinois chemistry professor Chad Rienstra has developed unique capabilities for probing protein chemistry and structure through the use of solid-state nuclear magnetic resonance spectroscopy.
The researchers' recent results represent significant progress toward atomic-scale resolution of protein structure by solid-state NMR spectroscopy. The technique can be applied to a large range of membrane proteins and fibrils, which, because they are not water-soluble, are often not amenable to more conventional solution NMR spectroscopy or X-ray crystallography.
"In our experiments, we explore couplings between atoms in proteins," Rienstra said. "Our goal is to translate genomic information into high-resolution structural information, and thereby be able to better understand the function of the proteins."
Solid-state NMR spectroscopy relaxes the need for solubility of the sample. In solution NMR spectroscopy, molecules are allowed to tumble randomly in the magnetic field. In solid-state NMR spectroscopy, molecules are immobilized within a small cylinder called a rotor. The rotor is then spun at high speed in the magnetic field.
"With increased speed and sensitivity, we can obtain very high resolution spectra," Rienstra said. "And, because we can resolve thousands of signals at a time - one for each atom in the sample - we can determine the structure of the entire protein."
To improve sensitivity and accelerate data collection, Rienstra's group is developing smaller rotors that can be spun at rates exceeding 25,000 rotations per second. The faster rotation rate and smaller sample size allows the researchers to obtain more data in less time, and solve structure with just a few milligrams of protein.
The determination of protein structure benefits not only from improvements in technology, but also from the researchers' novel approach to refining geometrical parameters.
Structure determination is normally based upon distances between atoms. Rienstra discovered a way of measuring both the distance between atoms and their relative orientations with very high precision.
"Using this technique, we can more precisely define the fragments of the molecule, and how they are oriented," Rienstra said. "That allows us to define protein features and determine structure at the atomic scale."
Rienstra will describe his group's latest findings and techniques at the national meeting of the American Chemical Society, to be held in Philadelphia, Aug. 17-21. Rienstra and his collaborators described their work - creating the highest resolution protein structure solved by solid-state NMR - in the March 25 issue of the Proceedings of the National Academy of Sciences.
The work was funded by the National Science Foundation and the National Institutes of Health.
Source: James E. Kloeppel
University of Illinois at Urbana-Champaign
By combining custom-built spectrometers, novel probe designs and faster pulse sequences, a team led by Illinois chemistry professor Chad Rienstra has developed unique capabilities for probing protein chemistry and structure through the use of solid-state nuclear magnetic resonance spectroscopy.
The researchers' recent results represent significant progress toward atomic-scale resolution of protein structure by solid-state NMR spectroscopy. The technique can be applied to a large range of membrane proteins and fibrils, which, because they are not water-soluble, are often not amenable to more conventional solution NMR spectroscopy or X-ray crystallography.
"In our experiments, we explore couplings between atoms in proteins," Rienstra said. "Our goal is to translate genomic information into high-resolution structural information, and thereby be able to better understand the function of the proteins."
Solid-state NMR spectroscopy relaxes the need for solubility of the sample. In solution NMR spectroscopy, molecules are allowed to tumble randomly in the magnetic field. In solid-state NMR spectroscopy, molecules are immobilized within a small cylinder called a rotor. The rotor is then spun at high speed in the magnetic field.
"With increased speed and sensitivity, we can obtain very high resolution spectra," Rienstra said. "And, because we can resolve thousands of signals at a time - one for each atom in the sample - we can determine the structure of the entire protein."
To improve sensitivity and accelerate data collection, Rienstra's group is developing smaller rotors that can be spun at rates exceeding 25,000 rotations per second. The faster rotation rate and smaller sample size allows the researchers to obtain more data in less time, and solve structure with just a few milligrams of protein.
The determination of protein structure benefits not only from improvements in technology, but also from the researchers' novel approach to refining geometrical parameters.
Structure determination is normally based upon distances between atoms. Rienstra discovered a way of measuring both the distance between atoms and their relative orientations with very high precision.
"Using this technique, we can more precisely define the fragments of the molecule, and how they are oriented," Rienstra said. "That allows us to define protein features and determine structure at the atomic scale."
Rienstra will describe his group's latest findings and techniques at the national meeting of the American Chemical Society, to be held in Philadelphia, Aug. 17-21. Rienstra and his collaborators described their work - creating the highest resolution protein structure solved by solid-state NMR - in the March 25 issue of the Proceedings of the National Academy of Sciences.
The work was funded by the National Science Foundation and the National Institutes of Health.
Source: James E. Kloeppel
University of Illinois at Urbana-Champaign
Super-Thin Membrane Design Opens Possibility For Better Dialysis, Fuel Cells, Neuro-Stem Cell Cultivation
A newly designed porous membrane, so thin it's invisible edge-on, may revolutionize the way doctors and scientists manipulate objects as small as a molecule.
The 50-atom thick filter can withstand surprisingly high pressures and may be a key to better separation of blood proteins for dialysis patients, speeding ion exchange in fuel cells, creating a new environment for growing neurological stem cells, and purifying air and water in hospitals and clean-rooms at the nanoscopic level.
At more than 4,000 times thinner than a human hair, the new barely-there membrane is thousands of times thinner than similar filters in use today.
Details on the membrane, developed at the University of Rochester, appear in today's issue of the journal Nature. "It's amazing, we have a material as thin as some of the molecules it's sorting, and even riddled with holes, but can withstand enough pressure to make real-world nano-filtering a practical reality," says research associate Christopher Striemer, co-creator of the membrane. "That ultra-thinness means much higher efficiency and lower sample loss, so we can do things that can't normally be done with current materials."
The membrane is a 15-nanometer-thick slice of the same silicon that's used every day in computer-chip manufacturing. In the lab of Philippe Fauchet, professor of electrical and computer engineering at the University, Striemer discovered the membrane as he was looking for a way to better understand how silicon crystallizes when heated.
He used such a thin piece of silicon - only about 50 atoms thick - because it would allow him to use an electron microscope to see the crystal structure in his samples, formed with different heat treatments.
Striemer found that as parts of the silicon contracted into crystals, holes opened up in their wakes. Imagine a party of people spread out evenly throughout a room, but as the evening progresses and people huddle into cliques, scattered areas of empty floor open up.
In talks with Striemer and Fauchet, James L. McGrath, assistant professor of biomedical engineering, and his graduate student, Tom Gaborski, realized that since the membrane's holes were only nanometers in size, it might be possible to separate objects as small as proteins much more effectively than is being done now.
Current molecular-level filters use a polymer-based design that is a jumble of varying holes and tunnels. The sizes of holes in the polymer model vary greatly, and since its "holes" are really convoluted tunnels through the material, they require much more time for proteins to pass through, and they are prone to clogging.
Recently, researchers had tried to design an ideal filter by drilling holes into a thin slice of another silicon-based material with an ion beam. While the effort did result in a filter with regular holes, the process was too laborious to be cost effective, and its membrane was so brittle that it required an elaborate support structure to prevent it from shattering.
While McGrath knew he might have the exact filter researchers have been searching for, he needed to test if the predictions held up. "When you build something at this scale, you're closing in on the quantum world and you never know what the properties are going to be," he says.
When Striemer tested his design, he found that the same 50-atom thickness could hold back an astonishing 15 pounds per square inch of pressure.
To test the membrane, Gaborski placed a solution of two blood proteins, albumin and IgG, behind the membrane and forced it gently through the nanoscopic holes. In just over six minutes, the albumin had passed through, but the larger IgG protein was stopped.
And as if filtering by nanoscale size weren't enough, the Rochester team has found a way for the nano-filter to carry a fixed charge, effectively making the hole "smaller" for molecules of a certain charge than for others. In a single filter it's now possible to quickly and easily separate molecules by their size and their chargeвЂ"a serious boon for fuel cell researchers, who wish to move only certain ions from one part of a fuel cell to another.
Separating molecules by size and charge efficiently is also the goal of kidney dialysis researchers. Johnson & Johnson recently gave the Rochester team a $100,000 grant to pursue developing the membrane's use in separating blood proteins with the hope of creating a more efficient method of dialysis.
"Kidneys do a much better job than dialysis machines of filtering blood proteins and keeping the ones you need, like albumin, and getting rid of toxins, which in some cases are smaller proteins," says McGrath. "They use a type of cellulose or plastic membrane with relatively poor discrimination. We think we can engineer these membranes to provide superior discrimination of proteins, which may make the process of dialysis faster and more effective than it is today."
The Rochester group sees many more applications for the membrane in the future. One of the most intriguing ideas is that it may play a role in growing neurons from stem cells.
Steve Goldman, Glenn-Zutes Chair in Biology of the Aging Brain and professor of neurology at the University of Rochester, discussed the technology with McGrath and colleagues and was impressed. "It's a spectacularly interesting technology, that opens a realm of new possibilities in fields as diverse as organ reconstitution, proteomics and microfluidics," says Goldman. "Its potential applications to neuroscience, cell biology and medical research may be profound."
Recent evidence suggests that neurological stem cells may grow better when in the immediate vicinity of certain "helper" cells. A problem arises after the new neurons are grown, when scientists need to separate the neurons from these helper cells. McGrath suggests that the neurological stem cells can be adhered to one side of the membrane, and the helper cells on the other.
The silicon membrane is about the thickness of the cell's own membranes, meaning the two groups of cells can actually touch each other through the membrane's pores without passing through themselves. The chemical communication between the helper and stem cells can continue as if the two sets of cells were in direct contact, but after the neurons are fully formed, they can easily be separated from the helper cells.
The Rochester team is working to realize the potential of the membrane by refining its fabrication. Striemer found he could "tune" the size of the filter holes depending on the temperature to which the silicon is heated, but the process is not yet accurate enough for engineers to simply select any pore size and fabricate it.
The researchers have just founded a company, SiMPore, to commercialize the numerous applications of the nanomembrane. Many of the University's laboratories will be involved in testing and developing the membrane, and the founders have already been approached by semiconductor giants such as Intel to see if the filter could remove nanoparticles from solutions used in microchip-manufacturing.
The team is currently testing the membranes to see how they stand up to regular wear and tear, and how resistant they are to clogging, which is a chief problem with conventional filters.
Contact: Jonathan Sherwood
University of Rochester
The 50-atom thick filter can withstand surprisingly high pressures and may be a key to better separation of blood proteins for dialysis patients, speeding ion exchange in fuel cells, creating a new environment for growing neurological stem cells, and purifying air and water in hospitals and clean-rooms at the nanoscopic level.
At more than 4,000 times thinner than a human hair, the new barely-there membrane is thousands of times thinner than similar filters in use today.
Details on the membrane, developed at the University of Rochester, appear in today's issue of the journal Nature. "It's amazing, we have a material as thin as some of the molecules it's sorting, and even riddled with holes, but can withstand enough pressure to make real-world nano-filtering a practical reality," says research associate Christopher Striemer, co-creator of the membrane. "That ultra-thinness means much higher efficiency and lower sample loss, so we can do things that can't normally be done with current materials."
The membrane is a 15-nanometer-thick slice of the same silicon that's used every day in computer-chip manufacturing. In the lab of Philippe Fauchet, professor of electrical and computer engineering at the University, Striemer discovered the membrane as he was looking for a way to better understand how silicon crystallizes when heated.
He used such a thin piece of silicon - only about 50 atoms thick - because it would allow him to use an electron microscope to see the crystal structure in his samples, formed with different heat treatments.
Striemer found that as parts of the silicon contracted into crystals, holes opened up in their wakes. Imagine a party of people spread out evenly throughout a room, but as the evening progresses and people huddle into cliques, scattered areas of empty floor open up.
In talks with Striemer and Fauchet, James L. McGrath, assistant professor of biomedical engineering, and his graduate student, Tom Gaborski, realized that since the membrane's holes were only nanometers in size, it might be possible to separate objects as small as proteins much more effectively than is being done now.
Current molecular-level filters use a polymer-based design that is a jumble of varying holes and tunnels. The sizes of holes in the polymer model vary greatly, and since its "holes" are really convoluted tunnels through the material, they require much more time for proteins to pass through, and they are prone to clogging.
Recently, researchers had tried to design an ideal filter by drilling holes into a thin slice of another silicon-based material with an ion beam. While the effort did result in a filter with regular holes, the process was too laborious to be cost effective, and its membrane was so brittle that it required an elaborate support structure to prevent it from shattering.
While McGrath knew he might have the exact filter researchers have been searching for, he needed to test if the predictions held up. "When you build something at this scale, you're closing in on the quantum world and you never know what the properties are going to be," he says.
When Striemer tested his design, he found that the same 50-atom thickness could hold back an astonishing 15 pounds per square inch of pressure.
To test the membrane, Gaborski placed a solution of two blood proteins, albumin and IgG, behind the membrane and forced it gently through the nanoscopic holes. In just over six minutes, the albumin had passed through, but the larger IgG protein was stopped.
And as if filtering by nanoscale size weren't enough, the Rochester team has found a way for the nano-filter to carry a fixed charge, effectively making the hole "smaller" for molecules of a certain charge than for others. In a single filter it's now possible to quickly and easily separate molecules by their size and their chargeвЂ"a serious boon for fuel cell researchers, who wish to move only certain ions from one part of a fuel cell to another.
Separating molecules by size and charge efficiently is also the goal of kidney dialysis researchers. Johnson & Johnson recently gave the Rochester team a $100,000 grant to pursue developing the membrane's use in separating blood proteins with the hope of creating a more efficient method of dialysis.
"Kidneys do a much better job than dialysis machines of filtering blood proteins and keeping the ones you need, like albumin, and getting rid of toxins, which in some cases are smaller proteins," says McGrath. "They use a type of cellulose or plastic membrane with relatively poor discrimination. We think we can engineer these membranes to provide superior discrimination of proteins, which may make the process of dialysis faster and more effective than it is today."
The Rochester group sees many more applications for the membrane in the future. One of the most intriguing ideas is that it may play a role in growing neurons from stem cells.
Steve Goldman, Glenn-Zutes Chair in Biology of the Aging Brain and professor of neurology at the University of Rochester, discussed the technology with McGrath and colleagues and was impressed. "It's a spectacularly interesting technology, that opens a realm of new possibilities in fields as diverse as organ reconstitution, proteomics and microfluidics," says Goldman. "Its potential applications to neuroscience, cell biology and medical research may be profound."
Recent evidence suggests that neurological stem cells may grow better when in the immediate vicinity of certain "helper" cells. A problem arises after the new neurons are grown, when scientists need to separate the neurons from these helper cells. McGrath suggests that the neurological stem cells can be adhered to one side of the membrane, and the helper cells on the other.
The silicon membrane is about the thickness of the cell's own membranes, meaning the two groups of cells can actually touch each other through the membrane's pores without passing through themselves. The chemical communication between the helper and stem cells can continue as if the two sets of cells were in direct contact, but after the neurons are fully formed, they can easily be separated from the helper cells.
The Rochester team is working to realize the potential of the membrane by refining its fabrication. Striemer found he could "tune" the size of the filter holes depending on the temperature to which the silicon is heated, but the process is not yet accurate enough for engineers to simply select any pore size and fabricate it.
The researchers have just founded a company, SiMPore, to commercialize the numerous applications of the nanomembrane. Many of the University's laboratories will be involved in testing and developing the membrane, and the founders have already been approached by semiconductor giants such as Intel to see if the filter could remove nanoparticles from solutions used in microchip-manufacturing.
The team is currently testing the membranes to see how they stand up to regular wear and tear, and how resistant they are to clogging, which is a chief problem with conventional filters.
Contact: Jonathan Sherwood
University of Rochester
New Pathway Identified In Parkinson's Through Brain Imaging
A new study led by researchers at Columbia University Medical Center has identified a novel molecular pathway underlying Parkinson's disease and points to existing drugs which may be able to slow progression of the disease.
The pathway involved proteins known as polyamines that were found to be responsible for the increase in build-up of other toxic proteins in neurons, which causes the neurons to malfunction and, eventually, die. Though high levels of polyamines have been found previously in patients with Parkinson's, the new study which appeared in an early online edition of Proceedings of the National Academy of Sciences is the first to identify a mechanism for why polyamines are elevated in the first place and how polyamines mediate the disease.
The researchers also demonstrated in a mouse model of Parkinson's disease that polyamine-lowering drugs had a protective effect.
"The most exciting thing about the finding is that it opens up the possibility of using a whole class of drugs that is already available," says Scott A. Small, MD, the senior author of the study and Herbert Irving Associate Professor of Neurology in the Sergievsky Center and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center. "Additionally, since polyamines can be found in blood and spinal fluid, this may lead to a test that could be used for early detection of Parkinson's."
Currently, treatments for Parkinson's can help alleviate some of the disease's symptoms, but they cannot prevent the build-up of toxic proteins and the death of neurons caused by the disease. When polyamines were scrutinized decades ago as a potential therapy against cancer, polyamine-lowering drugs were tested and have completed the Phase 1 and 2 safety stages of clinical trials. However, whether the drugs can pass through the blood-brain barrier remains to be determined and further testing will be needed. If the drugs can reduce the level of polyamines in the brain, they may pave the way for a Parkinson's treatment that can slow the disease's progression.
"This research has the potential to progress quickly," says James Beck, PhD, director of research programs at the Parkinson's Disease Foundation, which helped support the research. "Equally exciting are the new avenues of research this study opens, hopefully leading to better treatments for Parkinson's Disease down the road."
Though many cellular defects have been found to cause rare, inherited forms of Parkinson's disease, most cases of Parkinson's are caused by unknown changes inside the brain's neurons.
The researchers used a wide variety of scientific techniques to search for still unidentified defects in the brain. The suite of techniques which started with high resolution brain imaging has been used to reveal previously unknown molecules in the brain that worsen Alzheimer's disease.
Imaging Reveals Brainstem Defect in Parkinson's Patients
#
The success of the technique depends on identifying regions of the brain affected by the disease and comparing them to unaffected regions.
Using high resolution functional magnetic resonance imaging (fMRI), Nicole Lewandowski, PhD, who is currently a post-doctoral research scientist in Dr. Small's lab, identified such regions in the brainstem of patients with Parkinson's. The scans showed that one region of the brainstem was consistently less active in these patients than in healthy control subjects. Also revealed in the scans was a neighboring region that was unaffected by the disease.
Next, using brain tissue from deceased patients with Parkinson's, the researchers looked for proteins that could potentially explain the brainstem imaging differences.
"One such protein we found, called SAT1, stood out," said Dr. Small. "Because SAT1 is known as an enzyme that helps break down polyamines, and previous research had shown that Parkinson's patients have high levels of polyamines in their brains, we hypothesized that SAT1 and polyamines are involved in the development of Parkinson's disease."
Three Experiments Confirm Polyamines Are Pathogenic
To validate the finding, three separate studies in yeast, mice, and people were performed.
The yeast studies revealed that polyamines promote the accumulation of a toxic Parkinson's-causing protein in living cells, and not just in test tubes, as was known from previous research. Conducted by Gregory Petsko, PhD, the Gyula and Katica Tauber Professor of Biochemistry and Chemistry and Chair of Biochemistry at Brandeis University and Dagmar Ringe, PhD, the Harold and Bernice Davis Professor of Aging and Neurodegenerative Disease Research at Brandeis, the new studies found that yeast cells, engineered to produce the toxic Parkinson's protein, die more quickly in the presence of increasing polyamine levels. Furthermore, in a screen conducted for mediators of Parkinson's toxins in the lab of Susan Linquist, PhD, professor of biology in the Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute at MIT, other genes related to polyamine transport were identified.
In the mice studies, a link was established among SAT1, polyamines, and Parkinson's toxins in a mammalian brain. These experiments also revealed that drugs that target SAT1 may be able to slow down the progression of Parkinson's disease. Using drugs that increase SAT1 activity and therefore lower polyamine levels, researchers in the lab of Eliezer Masliah, MD, professor of neurosciences and pathology at the UC San Diego School of Medicine, found a decrease in Parkinson's toxins and the damage which they cause within brain regions affected by the disease.
Genetic studies in patients with Parkinson's provided further evidence that polyamines may help drive Parkinson's disease in people. After examining the SAT1 gene in nearly 100 patients with Parkinson's and additional genotyping in a further ~800 subjects (389 PD patients and 408 controls), enrolled in the Genetic Epidemiology of Parkinson's disease study at CUMC, Columbia geneticist Lorraine Clark, PhD, assistant professor of clinical pathology and cell biology, together with Karen Marder, MD, MPH, who is the Sally Kerlin Professor of Neurology in the Sergievsky Center and in the Taub Institute, uncovered a novel genetic variant that was found exclusively in the study's patients with Parkinson's but not in controls.
"Even though the variant was rare in patients with Parkinson's, finding it was surprising and further strengthens the possibility that defects in the polyamine pathway help to trigger the disease," said Dr. Small.
Dr. Small is now testing current polyamine-lowering drugs to see if the compounds can pass through the blood-brain barrier, or if they can be altered to do so. Drugs that pass through the blood-brain barrier can be administered more easily (e.g., they can be taken by mouth) instead of directly infusing them into the brain.
This work was supported in part by the National Institute of Neurological Disorders and Stroke, the Parkinson's Disease Foundation and Columbia's Irving Institute for Clinical and Translational Research (CTSA).
Authors of the paper are:
Nicole M. Lewandowskia,b, Shulin Juc, Miguel Verbitskya,d, Barbara Rossa, Melissa L. Geddiee, Edward Rockensteinf,g, Anthony Adamef, Alim Muhammada, Jean Paul Vonsattela,h, Dagmar Ringec, Lucien Cotea,i, Susan Lindquiste, Eliezer Masliahf,g, Gregory A. Petskoc, Karen Mardera,i,j, Lorraine N. Clarka,d,h, and Scott A. Smalla,i
Source: Columbia University Medical Center
The pathway involved proteins known as polyamines that were found to be responsible for the increase in build-up of other toxic proteins in neurons, which causes the neurons to malfunction and, eventually, die. Though high levels of polyamines have been found previously in patients with Parkinson's, the new study which appeared in an early online edition of Proceedings of the National Academy of Sciences is the first to identify a mechanism for why polyamines are elevated in the first place and how polyamines mediate the disease.
The researchers also demonstrated in a mouse model of Parkinson's disease that polyamine-lowering drugs had a protective effect.
"The most exciting thing about the finding is that it opens up the possibility of using a whole class of drugs that is already available," says Scott A. Small, MD, the senior author of the study and Herbert Irving Associate Professor of Neurology in the Sergievsky Center and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center. "Additionally, since polyamines can be found in blood and spinal fluid, this may lead to a test that could be used for early detection of Parkinson's."
Currently, treatments for Parkinson's can help alleviate some of the disease's symptoms, but they cannot prevent the build-up of toxic proteins and the death of neurons caused by the disease. When polyamines were scrutinized decades ago as a potential therapy against cancer, polyamine-lowering drugs were tested and have completed the Phase 1 and 2 safety stages of clinical trials. However, whether the drugs can pass through the blood-brain barrier remains to be determined and further testing will be needed. If the drugs can reduce the level of polyamines in the brain, they may pave the way for a Parkinson's treatment that can slow the disease's progression.
"This research has the potential to progress quickly," says James Beck, PhD, director of research programs at the Parkinson's Disease Foundation, which helped support the research. "Equally exciting are the new avenues of research this study opens, hopefully leading to better treatments for Parkinson's Disease down the road."
Though many cellular defects have been found to cause rare, inherited forms of Parkinson's disease, most cases of Parkinson's are caused by unknown changes inside the brain's neurons.
The researchers used a wide variety of scientific techniques to search for still unidentified defects in the brain. The suite of techniques which started with high resolution brain imaging has been used to reveal previously unknown molecules in the brain that worsen Alzheimer's disease.
Imaging Reveals Brainstem Defect in Parkinson's Patients
#
The success of the technique depends on identifying regions of the brain affected by the disease and comparing them to unaffected regions.
Using high resolution functional magnetic resonance imaging (fMRI), Nicole Lewandowski, PhD, who is currently a post-doctoral research scientist in Dr. Small's lab, identified such regions in the brainstem of patients with Parkinson's. The scans showed that one region of the brainstem was consistently less active in these patients than in healthy control subjects. Also revealed in the scans was a neighboring region that was unaffected by the disease.
Next, using brain tissue from deceased patients with Parkinson's, the researchers looked for proteins that could potentially explain the brainstem imaging differences.
"One such protein we found, called SAT1, stood out," said Dr. Small. "Because SAT1 is known as an enzyme that helps break down polyamines, and previous research had shown that Parkinson's patients have high levels of polyamines in their brains, we hypothesized that SAT1 and polyamines are involved in the development of Parkinson's disease."
Three Experiments Confirm Polyamines Are Pathogenic
To validate the finding, three separate studies in yeast, mice, and people were performed.
The yeast studies revealed that polyamines promote the accumulation of a toxic Parkinson's-causing protein in living cells, and not just in test tubes, as was known from previous research. Conducted by Gregory Petsko, PhD, the Gyula and Katica Tauber Professor of Biochemistry and Chemistry and Chair of Biochemistry at Brandeis University and Dagmar Ringe, PhD, the Harold and Bernice Davis Professor of Aging and Neurodegenerative Disease Research at Brandeis, the new studies found that yeast cells, engineered to produce the toxic Parkinson's protein, die more quickly in the presence of increasing polyamine levels. Furthermore, in a screen conducted for mediators of Parkinson's toxins in the lab of Susan Linquist, PhD, professor of biology in the Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute at MIT, other genes related to polyamine transport were identified.
In the mice studies, a link was established among SAT1, polyamines, and Parkinson's toxins in a mammalian brain. These experiments also revealed that drugs that target SAT1 may be able to slow down the progression of Parkinson's disease. Using drugs that increase SAT1 activity and therefore lower polyamine levels, researchers in the lab of Eliezer Masliah, MD, professor of neurosciences and pathology at the UC San Diego School of Medicine, found a decrease in Parkinson's toxins and the damage which they cause within brain regions affected by the disease.
Genetic studies in patients with Parkinson's provided further evidence that polyamines may help drive Parkinson's disease in people. After examining the SAT1 gene in nearly 100 patients with Parkinson's and additional genotyping in a further ~800 subjects (389 PD patients and 408 controls), enrolled in the Genetic Epidemiology of Parkinson's disease study at CUMC, Columbia geneticist Lorraine Clark, PhD, assistant professor of clinical pathology and cell biology, together with Karen Marder, MD, MPH, who is the Sally Kerlin Professor of Neurology in the Sergievsky Center and in the Taub Institute, uncovered a novel genetic variant that was found exclusively in the study's patients with Parkinson's but not in controls.
"Even though the variant was rare in patients with Parkinson's, finding it was surprising and further strengthens the possibility that defects in the polyamine pathway help to trigger the disease," said Dr. Small.
Dr. Small is now testing current polyamine-lowering drugs to see if the compounds can pass through the blood-brain barrier, or if they can be altered to do so. Drugs that pass through the blood-brain barrier can be administered more easily (e.g., they can be taken by mouth) instead of directly infusing them into the brain.
This work was supported in part by the National Institute of Neurological Disorders and Stroke, the Parkinson's Disease Foundation and Columbia's Irving Institute for Clinical and Translational Research (CTSA).
Authors of the paper are:
Nicole M. Lewandowskia,b, Shulin Juc, Miguel Verbitskya,d, Barbara Rossa, Melissa L. Geddiee, Edward Rockensteinf,g, Anthony Adamef, Alim Muhammada, Jean Paul Vonsattela,h, Dagmar Ringec, Lucien Cotea,i, Susan Lindquiste, Eliezer Masliahf,g, Gregory A. Petskoc, Karen Mardera,i,j, Lorraine N. Clarka,d,h, and Scott A. Smalla,i
Source: Columbia University Medical Center
Antibacterial Effects Of Healing Clays Tested By ASU Researchers
Clay is most commonly associated with the sublime experience of the European spa where visitors have been masked, soaked and basted with this touted curative since the Romans ruled. If ASU geochemist Lynda Williams and microbiologist Shelley Haydel's research on the antibacterial properties of clays realizes its full potential, smectite clay could one day rise above cosmetic use to take its place comfortably with antibacterial behemoths like penicillin.
"We use maggots and leeches in hospitals, so why not clay?" Haydel poses. "I had a professor in graduate school say, 'Maybe perhaps once in your life, in your scientific career, you'll come across something that can change the world.' Sometimes I think: Is this it? Will this help some people?"
Theirs is an unusual research pairing. They are female scientists, each in the College of Liberal Arts and Sciences, yet pursuing different lines of scientific discovery. Williams is an associate research professor in the School of Earth and Science Exploration and studies clay mineralogy. Haydel is an assistant professor and expert in tuberculosis in the School of Life Sciences and with the Center for Infectious Disease and Vaccinology in the Biodesign Institute at Arizona State University.
"People are interested in natural cures and I think that there is a lot of nature that we don't understand yet," Williams says. "What if we discover a mechanism for controlling microbes that had never been discovered before? It is these avenues, at the boundaries of scientific discovery, at the edges of my field and knowledge (and Shelley's), where such discoveries are made."
National Institutes of Health (NIH) program directors agreed. They awarded a $438,970 grant over two years to Williams and Haydel for the study of clay mineral alternative treatment for Buruli ulcer. What makes this award even more interesting is the rarity for a geochemist to net a NIH grant.
National Center encourages alternative studies
The National Center for Complementary and Alternative Medicine at NIH was established in 1998 for just this kind of study. One of the 27 Institutes making up NIH, the Center funds scientific research and technologies that examine herbal remedies, such as dandelion, green tea, valerian, and horse chestnut, and practices like acupuncture, Tai Chi, and Reiki that fall outside conventional medicines.
The ASU duo will examine the mechanisms that allow two clays mined in France to heal Buruli ulcer, a flesh-eating bacterial disease found primarily in central and western Africa. Buruli ulcer has been declared to be "an emerging public health threat" by the World Health Organization (WHO). Related to leprosy and tuberculosis, the Mycobacterium ulcerans produces a toxin, lesions, and destroys the fatty tissues under the skin.
"The toxin is immunosuppressant; the patients feel no pain and the body mounts no response to infection. It leads to disfigurement, isolation, not unlike that seen in leprosy," Haydel explains. "Traditional antibiotics can only make a difference at the very earliest stages of the disease, so treatments have, in the past, been largely confined to amputations or surgical excision of the infected sites."
This means if the clays are antibacterial in nature and the locus for that activity can be isolated, they may represent a new form of treatment, one that goes beyond the capacity of existing antibiotics. "And they could be produced and distributed cheaply," Williams notes.
Humanitarians answer Internet challenge
So how did a clay mineralogist whose background is in low temperature geochemistry become involved with a health care project centered in the Ivory Coast? The scientific equivalent of an online dating or matchmaking service: "I answered a posting on the Clay Mineral Society's list serve placed by Thierry Brunet de Courssou. He was asking to have someone take high resolution scanning electron micrographs of the clays," Williams explains. "I confess that we all ignored him initially."
According to the Brunet de Courssou Web site, the family has been operating health clinics on the Ivory Coast and in New Guinea. For a decade, Madame Line Brunet de Courssou, Thierry's mother, had been importing two French clays to treat people with Buruli ulcer and was getting startling results, while her use of native clays had no effect. Williams reviewed the mother's work and notes that "Line Brunet de Courssou was a careful observer." However, Madame Brunet de Courssou was not a scientist. The mother, who is now deceased, approached the WHO in 2002 at its fifth advisory group meeting on Buruli ulcer, having documented more than 50 cases of successful healing with the clay treatments. WHO documents indicate that the organization was receptive, calling her results "impressive," yet, Williams notes, funding was denied for lack of scientific study.
Williams, from a family of physicians, says that it was really the second message that finally drew her to the project. "He said, 'I guess that no American scientists are interested in helping poor people in Africa.'"
He guessed wrong. Armed with 100 grams of green powder (clay high in reduced iron), Williams not only took the micrographs of the minerals, she went a step further and examined their crystal structure and chemical compositions. She recruited Haydel to the project before the microbiologist arrived at ASU in 2005. Haydel brought more than 13 years of experience with pathogenic bacteria, in particular tuberculosis, to the project. Within two months of Haydel's arrival, they submitted the grant proposal to the NIH.
"I approached this work from the viewpoint of a clinical microbiologist," Haydel says. "I ordered bacterial strains that pharmaceutical companies use to test their antimicrobials."
Haydel and Williams tested both of the French clays that Brunet de Courssou had been importing. One completely inhibited pathogenic Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa (often a problem as an opportunistic infection in burn wards) and Mycobacterium marinum (related to Mycobacterium ulcerans, which causes Buruli ulcer disease). The clay was also found to partially inhibit the growth of pathogenic Staphylococcus aureus, including a multi-drug resistant variety. "The other clay actually helps the bacteria to grow," Haydel adds.
What makes one clay kill bacteria, and the other promote growth? And why do most clays tested have no effect? Research like that being done by Williams and Haydel can answer such questions. "Clay can be as variable as the bacteria we are studying. There is a lot to be learned yet," Williams notes.
Clay's properties fuel interest
Williams' career fascination with clay started when she was a mineral exploration geologist looking for ore deposits. She worked with 'the father of clay mineralogy,' Bob Reynolds, at Dartmouth College. Later, as a research associate at Louisiana State University, a colleague was studying geophasia - eating clay, a behavior seen in animals and people, since the time of the aborigines.
"In the South Appalachian Mountains, poor women would eat the local clay to help soothe nausea and stomach ailments, particularly during pregnancy. The clay was rich in kaolinite. (Kaolinite is the major ingredient in the over the counter remedy Kaopectate). But one day, they ran out of clay and moved over to another mountain and people began dying. We wanted to know why."
The key to clay's variable nature seems to be its structure. "Clay is a mineral; it has a crystalline structure that is both flexible and fluid," Williams says. She likens them to very thin, two-nanometer-thick slices of bread in a "peanut butter and jelly sandwich." The "bread" is composed of three regions, two silicate layers with tetrahedral rings bounding an octahedral core. The "peanut butter" is the charged cations, for example, potassium, that stick to the negatively charged tetrahedral ring surface. And the jelly? Organic compounds or other species of any or no charge are possible. This interlayer, as the peanut butter and jelly are termed, can vary in width and composition depending on the kinds of waters and elements present when it was formed. It is this interlayer where much of the elemental variability between clays can be found. And the interlayer surface area is huge (greater than 100 square meters per gram of clay - bigger than a football field). As a result, surface chemical reactions from these sites have an enormous impact on the geochemistry of the local environment.
Williams is passionate about her subject: "Clays are as individual in character as people are in personality. They can be as old as Precambrian time (probably older, since meteorites contain clay minerals from other celestial bodies) or as young as I can make them in my lab in a few hours. They form when the chemistry, temperature and pressure conditions are right. In the case of the two French clays we are testing, their chemical structures are almost identical, but the different trace element chemistry of the interlayer records an older geologic condition, from a time when the antimicrobial property was likely inherited."
Crystal structure, the interlayer, the way other materials, metals, ions bind to clays, the absorptive characteristics of clays, all could potentially play a role in the antibacterial activity they find in the one French clay. And, while preliminary results suggest that the antibacterial activity is associated with the interlayer, crystal size and structure also seem to play a role.
It is a mystery that engages both research partners: "It's fascinating," Haydel says. "Here we are bridging geology, microbiology, cell biology - transdisciplinary sciences, exactly what (ASU President) Michael Crow has been promoting. A year ago, I'd look at the clay and say, 'well that's dirt.' Now I know a little something about clay structure; Lynda knows a little bit about microbiology. Alone, we each would have had to study for years; together we are partnering these disciplines with synergy that really works."
SOURCES:
Lynda Williams
Shelley Haydel
Contact: Carol Hughes
Arizona State University
"We use maggots and leeches in hospitals, so why not clay?" Haydel poses. "I had a professor in graduate school say, 'Maybe perhaps once in your life, in your scientific career, you'll come across something that can change the world.' Sometimes I think: Is this it? Will this help some people?"
Theirs is an unusual research pairing. They are female scientists, each in the College of Liberal Arts and Sciences, yet pursuing different lines of scientific discovery. Williams is an associate research professor in the School of Earth and Science Exploration and studies clay mineralogy. Haydel is an assistant professor and expert in tuberculosis in the School of Life Sciences and with the Center for Infectious Disease and Vaccinology in the Biodesign Institute at Arizona State University.
"People are interested in natural cures and I think that there is a lot of nature that we don't understand yet," Williams says. "What if we discover a mechanism for controlling microbes that had never been discovered before? It is these avenues, at the boundaries of scientific discovery, at the edges of my field and knowledge (and Shelley's), where such discoveries are made."
National Institutes of Health (NIH) program directors agreed. They awarded a $438,970 grant over two years to Williams and Haydel for the study of clay mineral alternative treatment for Buruli ulcer. What makes this award even more interesting is the rarity for a geochemist to net a NIH grant.
National Center encourages alternative studies
The National Center for Complementary and Alternative Medicine at NIH was established in 1998 for just this kind of study. One of the 27 Institutes making up NIH, the Center funds scientific research and technologies that examine herbal remedies, such as dandelion, green tea, valerian, and horse chestnut, and practices like acupuncture, Tai Chi, and Reiki that fall outside conventional medicines.
The ASU duo will examine the mechanisms that allow two clays mined in France to heal Buruli ulcer, a flesh-eating bacterial disease found primarily in central and western Africa. Buruli ulcer has been declared to be "an emerging public health threat" by the World Health Organization (WHO). Related to leprosy and tuberculosis, the Mycobacterium ulcerans produces a toxin, lesions, and destroys the fatty tissues under the skin.
"The toxin is immunosuppressant; the patients feel no pain and the body mounts no response to infection. It leads to disfigurement, isolation, not unlike that seen in leprosy," Haydel explains. "Traditional antibiotics can only make a difference at the very earliest stages of the disease, so treatments have, in the past, been largely confined to amputations or surgical excision of the infected sites."
This means if the clays are antibacterial in nature and the locus for that activity can be isolated, they may represent a new form of treatment, one that goes beyond the capacity of existing antibiotics. "And they could be produced and distributed cheaply," Williams notes.
Humanitarians answer Internet challenge
So how did a clay mineralogist whose background is in low temperature geochemistry become involved with a health care project centered in the Ivory Coast? The scientific equivalent of an online dating or matchmaking service: "I answered a posting on the Clay Mineral Society's list serve placed by Thierry Brunet de Courssou. He was asking to have someone take high resolution scanning electron micrographs of the clays," Williams explains. "I confess that we all ignored him initially."
According to the Brunet de Courssou Web site, the family has been operating health clinics on the Ivory Coast and in New Guinea. For a decade, Madame Line Brunet de Courssou, Thierry's mother, had been importing two French clays to treat people with Buruli ulcer and was getting startling results, while her use of native clays had no effect. Williams reviewed the mother's work and notes that "Line Brunet de Courssou was a careful observer." However, Madame Brunet de Courssou was not a scientist. The mother, who is now deceased, approached the WHO in 2002 at its fifth advisory group meeting on Buruli ulcer, having documented more than 50 cases of successful healing with the clay treatments. WHO documents indicate that the organization was receptive, calling her results "impressive," yet, Williams notes, funding was denied for lack of scientific study.
Williams, from a family of physicians, says that it was really the second message that finally drew her to the project. "He said, 'I guess that no American scientists are interested in helping poor people in Africa.'"
He guessed wrong. Armed with 100 grams of green powder (clay high in reduced iron), Williams not only took the micrographs of the minerals, she went a step further and examined their crystal structure and chemical compositions. She recruited Haydel to the project before the microbiologist arrived at ASU in 2005. Haydel brought more than 13 years of experience with pathogenic bacteria, in particular tuberculosis, to the project. Within two months of Haydel's arrival, they submitted the grant proposal to the NIH.
"I approached this work from the viewpoint of a clinical microbiologist," Haydel says. "I ordered bacterial strains that pharmaceutical companies use to test their antimicrobials."
Haydel and Williams tested both of the French clays that Brunet de Courssou had been importing. One completely inhibited pathogenic Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa (often a problem as an opportunistic infection in burn wards) and Mycobacterium marinum (related to Mycobacterium ulcerans, which causes Buruli ulcer disease). The clay was also found to partially inhibit the growth of pathogenic Staphylococcus aureus, including a multi-drug resistant variety. "The other clay actually helps the bacteria to grow," Haydel adds.
What makes one clay kill bacteria, and the other promote growth? And why do most clays tested have no effect? Research like that being done by Williams and Haydel can answer such questions. "Clay can be as variable as the bacteria we are studying. There is a lot to be learned yet," Williams notes.
Clay's properties fuel interest
Williams' career fascination with clay started when she was a mineral exploration geologist looking for ore deposits. She worked with 'the father of clay mineralogy,' Bob Reynolds, at Dartmouth College. Later, as a research associate at Louisiana State University, a colleague was studying geophasia - eating clay, a behavior seen in animals and people, since the time of the aborigines.
"In the South Appalachian Mountains, poor women would eat the local clay to help soothe nausea and stomach ailments, particularly during pregnancy. The clay was rich in kaolinite. (Kaolinite is the major ingredient in the over the counter remedy Kaopectate). But one day, they ran out of clay and moved over to another mountain and people began dying. We wanted to know why."
The key to clay's variable nature seems to be its structure. "Clay is a mineral; it has a crystalline structure that is both flexible and fluid," Williams says. She likens them to very thin, two-nanometer-thick slices of bread in a "peanut butter and jelly sandwich." The "bread" is composed of three regions, two silicate layers with tetrahedral rings bounding an octahedral core. The "peanut butter" is the charged cations, for example, potassium, that stick to the negatively charged tetrahedral ring surface. And the jelly? Organic compounds or other species of any or no charge are possible. This interlayer, as the peanut butter and jelly are termed, can vary in width and composition depending on the kinds of waters and elements present when it was formed. It is this interlayer where much of the elemental variability between clays can be found. And the interlayer surface area is huge (greater than 100 square meters per gram of clay - bigger than a football field). As a result, surface chemical reactions from these sites have an enormous impact on the geochemistry of the local environment.
Williams is passionate about her subject: "Clays are as individual in character as people are in personality. They can be as old as Precambrian time (probably older, since meteorites contain clay minerals from other celestial bodies) or as young as I can make them in my lab in a few hours. They form when the chemistry, temperature and pressure conditions are right. In the case of the two French clays we are testing, their chemical structures are almost identical, but the different trace element chemistry of the interlayer records an older geologic condition, from a time when the antimicrobial property was likely inherited."
Crystal structure, the interlayer, the way other materials, metals, ions bind to clays, the absorptive characteristics of clays, all could potentially play a role in the antibacterial activity they find in the one French clay. And, while preliminary results suggest that the antibacterial activity is associated with the interlayer, crystal size and structure also seem to play a role.
It is a mystery that engages both research partners: "It's fascinating," Haydel says. "Here we are bridging geology, microbiology, cell biology - transdisciplinary sciences, exactly what (ASU President) Michael Crow has been promoting. A year ago, I'd look at the clay and say, 'well that's dirt.' Now I know a little something about clay structure; Lynda knows a little bit about microbiology. Alone, we each would have had to study for years; together we are partnering these disciplines with synergy that really works."
SOURCES:
Lynda Williams
Shelley Haydel
Contact: Carol Hughes
Arizona State University
Int'l human genome sequencing consortium describes finished human genome sequence
Researchers trim count of human genes to 20,000-25,000 -
The International Human Genome Sequencing Consortium, led in the United States by the National Human Genome Research
Institute (NHGRI) and the Department of Energy (DOE), today published its scientific description of the finished human genome
sequence, reducing the estimated number of human protein-coding genes from 35,000 to only 20,000-25,000, a surprisingly low
number for our species.
The paper appears in the Oct. 21 issue of the journal Nature. In the paper, researchers describe the final product of the
Human Genome Project, which was the 13-year effort to read the information encoded in the human chromosomes that reached its
culmination in 2003. The Nature publication provides rigorous scientific evidence that the genome sequence produced by the
Human Genome Project has both the high coverage and accuracy needed to perform sensitive analyses, such as focusing on the
number of genes, the segmental duplications involved in disease and the "birth" and "death" of genes over the course of
evolution.
"Only a decade ago, most scientists thought humans had about 100,000 genes. When we analyzed the working draft of the human
genome sequence three years ago, we estimated there were about 30,000 to 35,000 genes, which surprised many. This new
analysis reduces that number even further and provides us with the clearest picture yet of our genome," said NHGRI Director
Francis S. Collins, M.D., Ph.D. "The availability of the highly accurate human genome sequence in free public databases
enables researchers around the world to conduct even more precise studies of our genetic instruction book and how it
influences health and disease."
One of the central goals of the effort to analyze the human genome is the identification of all genes, which are generally
defined as stretches of DNA that code for particular proteins. According to the new findings, researchers have confirmed the
existence of 19,599 protein-coding genes in the human genome and identified another 2,188 DNA segments that are predicted to
be protein-coding genes.
"The analysis found that some of the earlier gene models were erroneous due to defects in the unfinished, draft sequence of
the human genome," said Jane Rogers, Ph.D., head of sequencing at the Wellcome Trust Sanger Institute in Hinxton, England.
"The task of identifying genes remains challenging, but has been greatly assisted by the finished human genome sequence, as
well as by the availability of genome sequences from other organisms, better computational models and other improved
resources."
The Nature paper also provides the scientific community with a peer-reviewed description of the finishing process, and an
assessment of the quality of the finished human genome sequence, which was deposited into public databases in April 2003. The
assessment confirms that the finished sequence now covers more than 99 percent of the euchromatic (or gene-containing)
portion of the human genome and was sequenced to an accuracy of 99.999 percent, which translates to an error rate of only 1
base per 100,000 base pairs - 10 times more accurate than the original goal.
The contiguity of the sequence is also massively improved. The average DNA letter now sits on a stretch of 38.5 million base
pairs of uninterrupted, high-quality sequence - about 475 times longer than the 81,500 base-pair stretch that was available
in the working draft. Access to uninterrupted stretches of sequenced DNA can greatly assist researchers hunting for genes and
the neighboring DNA sequences that may regulate their activity, dramatically cutting the effort and expense required to find
regions of the human genome that may contain small and often rare variants involved in disease.
"Finished" doesn't mean that the human genome sequence is perfect. There still remain 341 gaps in the finished human genome
sequence, in contrast to the 150,000 gaps in the working draft announced in June 2000. The technology now available cannot
readily close these recalcitrant gaps in the human genome sequence. Closing those gaps will require more research and new
technologies, rather than industrial-scale efforts like those employed by the Human Genome Project.
"The human genome sequence far exceeds our expectations in terms of accuracy, completeness and continuity. It reflects the
dedication of hundreds of scientists working together toward a common goal - creating a solid foundation for biomedicine in
the 21st century," said Eric Lander, Ph.D., director of the Broad Institute of MIT and Harvard in Cambridge, Mass.
In addition to reducing the count of human genes, scientists reported that the improved quality of the finished human genome
sequence, compared with earlier drafts, provides a much clearer picture of certain phenomena such as duplication of DNA
segments and the birth and death of genes.
Segmental duplications are large, almost identical copies of DNA, which are present in at least two locations in the human
genome. A number of human diseases are known to be associated with mutations in segmentally duplicated regions, including
Williams syndrome, Charcot-Marie-Tooth and DiGeorge syndrome. "Segmental duplications were almost impossible to study in the
draft sequence. Now, through the unstinting efforts of groups around the world, this important and rapidly evolving part of
our genome is open for scientific exploration," said Robert H. Waterston, M.D., Ph.D., former director of the Genome
Sequencing Center at Washington University in St. Louis and now chair of the Department of Genome Sciences at the University
of Washington in Seattle.
Segmental duplications cover 5.3 percent of the human genome, significantly more than in the rat genome, which has about 3
percent, or the mouse genome, which has between 1 and 2 percent. Segmental duplications provide a window into understanding
how our genome evolved and is still changing. The high proportion of segmental duplication in the human genome shows our
genetic material has undergone rapid functional innovation and structural change during the last 40 million years, presumably
contributing to unique characteristics that separate us from our non-human primate ancestors.
The consortium's analysis found the distribution of segmental duplications varies widely across human chromosomes. The Y
chromosome is the most extreme case, with segmental duplications occurring along more than 25 percent of its length. Some
segmental duplications tend to be clustered near the middle (centromeres) and ends (telomeres) of each chromosome, where,
researchers postulate, they may be used by the genome as an evolutionary laboratory for creating genes with new functions.
The accuracy of the finished human genome sequence produced by the Human Genome Project has also given scientists some
initial insights into the birth and death of genes in the human genome. Scientists have identified more than 1,000 new genes
that arose in the human genome after our divergence with rodents some 75 million years ago. Most of these arose through
recent gene duplications and are involved with immune, olfactory and reproductive functions. For example, there are two
families of genes recently duplicated in the human genome that encode sets of proteins (pregnancy-specific beta-1
glycoprotein and choriogonadotropin beta proteins) that may be involved in the extended period of pregnancy unique to humans.
Additionally, researchers used the finished human genome to identify and characterize 33 nearly intact genes that have
recently acquired one or more mutations, causing them to stop functioning, or "die." Scientists pinpointed these
non-functioning genes, referred to as pseudogenes, in the human genome by aligning them with the mouse and rat genomes, in
which the corresponding genes have maintained their functionality. Interestingly, researchers determined that 10 of these
pseudogenes in the human genome sequence appear to have coded for proteins involved in olfactory reception, which helps to
explain why humans have fewer functional olfactory receptors and, consequently, a poorer sense of smell than rodents. The
molecular biology of the sense of smell was just recognized by the awarding of a Nobel Prize in Physiology or Medicine to
Richard Axel and Linda B. Buck.
Next, the researchers aligned the 33 pseudogenes with the draft sequence of the chimpanzee genome to determine whether they
were still functional before Homo sapiens' divergence from great apes about 5 million years ago. The analysis revealed that
27 of the pseudogenes were non-functional in both humans and chimps. However, five of the genes that were inactive in humans
were found to be still functional in chimpanzees. "The identification of these pseudogenes and their functional counterparts
in chimpanzee provides fertile ground for future research projects," said Richard Gibbs, Ph.D., director of Baylor College of
Medicine's Human Genome Sequencing Center in Houston, which currently is sequencing the genome of another non-human primate,
the rhesus macaque (Macaca mulatta).
More than 2,800 researchers who took part in the International Human Genome Sequencing Consortium share authorship on today's
Nature paper, which expands upon the group's initial analysis published in Feb. 2001. Even more detailed annotations and
analyses have already been published for chromosomes 5, 6, 7, 9, 10, 13, 14, 19, 20, 21, 22 and Y. Publications describing
the remaining 12 chromosomes are forthcoming.
The finished human genome sequence and its annotations can be accessed through the following public genome browsers: GenBank
(ncbi.nih/Genbank) at NIH's National Center for
Biotechnology Information (NCBI); the UCSC Genome Browser (genome.ucsc) at the University of California at Santa Cruz; the Ensembl Genome Browser (ensembl) at the Wellcome Trust Sanger Institute and the
EMBL-European Bioinformatics Institute; the DNA Data Bank of Japan (ddbj.nih.ac.jp); and EMBL-Bank (ebi.ac.uk/embl/index.html) at the European Molecular Biology Laboratory's Nucleotide Sequence
Database.
The International Human Genome Sequencing Consortium includes scientists at 20 institutions located in France, Germany,
Japan, China, Great Britain and the United States. The five largest sequencing centers are located at: Baylor College of
Medicine; the Broad Institute of MIT and Harvard; DOE's Joint Genome Institute, Walnut Creek, Calif.; Washington University
School of Medicine; and the Wellcome Trust Sanger Institute.
NHGRI is one of 27 institutes and centers at the National Institutes of Health, an agency of the Department of Health and
Human Services. Additional information about NHGRI can be found at its Web site, genome.
Contact: Geoff Spencer
spencergmail.nih
301-402-0911
NIH/National Human Genome Research Institute
The International Human Genome Sequencing Consortium, led in the United States by the National Human Genome Research
Institute (NHGRI) and the Department of Energy (DOE), today published its scientific description of the finished human genome
sequence, reducing the estimated number of human protein-coding genes from 35,000 to only 20,000-25,000, a surprisingly low
number for our species.
The paper appears in the Oct. 21 issue of the journal Nature. In the paper, researchers describe the final product of the
Human Genome Project, which was the 13-year effort to read the information encoded in the human chromosomes that reached its
culmination in 2003. The Nature publication provides rigorous scientific evidence that the genome sequence produced by the
Human Genome Project has both the high coverage and accuracy needed to perform sensitive analyses, such as focusing on the
number of genes, the segmental duplications involved in disease and the "birth" and "death" of genes over the course of
evolution.
"Only a decade ago, most scientists thought humans had about 100,000 genes. When we analyzed the working draft of the human
genome sequence three years ago, we estimated there were about 30,000 to 35,000 genes, which surprised many. This new
analysis reduces that number even further and provides us with the clearest picture yet of our genome," said NHGRI Director
Francis S. Collins, M.D., Ph.D. "The availability of the highly accurate human genome sequence in free public databases
enables researchers around the world to conduct even more precise studies of our genetic instruction book and how it
influences health and disease."
One of the central goals of the effort to analyze the human genome is the identification of all genes, which are generally
defined as stretches of DNA that code for particular proteins. According to the new findings, researchers have confirmed the
existence of 19,599 protein-coding genes in the human genome and identified another 2,188 DNA segments that are predicted to
be protein-coding genes.
"The analysis found that some of the earlier gene models were erroneous due to defects in the unfinished, draft sequence of
the human genome," said Jane Rogers, Ph.D., head of sequencing at the Wellcome Trust Sanger Institute in Hinxton, England.
"The task of identifying genes remains challenging, but has been greatly assisted by the finished human genome sequence, as
well as by the availability of genome sequences from other organisms, better computational models and other improved
resources."
The Nature paper also provides the scientific community with a peer-reviewed description of the finishing process, and an
assessment of the quality of the finished human genome sequence, which was deposited into public databases in April 2003. The
assessment confirms that the finished sequence now covers more than 99 percent of the euchromatic (or gene-containing)
portion of the human genome and was sequenced to an accuracy of 99.999 percent, which translates to an error rate of only 1
base per 100,000 base pairs - 10 times more accurate than the original goal.
The contiguity of the sequence is also massively improved. The average DNA letter now sits on a stretch of 38.5 million base
pairs of uninterrupted, high-quality sequence - about 475 times longer than the 81,500 base-pair stretch that was available
in the working draft. Access to uninterrupted stretches of sequenced DNA can greatly assist researchers hunting for genes and
the neighboring DNA sequences that may regulate their activity, dramatically cutting the effort and expense required to find
regions of the human genome that may contain small and often rare variants involved in disease.
"Finished" doesn't mean that the human genome sequence is perfect. There still remain 341 gaps in the finished human genome
sequence, in contrast to the 150,000 gaps in the working draft announced in June 2000. The technology now available cannot
readily close these recalcitrant gaps in the human genome sequence. Closing those gaps will require more research and new
technologies, rather than industrial-scale efforts like those employed by the Human Genome Project.
"The human genome sequence far exceeds our expectations in terms of accuracy, completeness and continuity. It reflects the
dedication of hundreds of scientists working together toward a common goal - creating a solid foundation for biomedicine in
the 21st century," said Eric Lander, Ph.D., director of the Broad Institute of MIT and Harvard in Cambridge, Mass.
In addition to reducing the count of human genes, scientists reported that the improved quality of the finished human genome
sequence, compared with earlier drafts, provides a much clearer picture of certain phenomena such as duplication of DNA
segments and the birth and death of genes.
Segmental duplications are large, almost identical copies of DNA, which are present in at least two locations in the human
genome. A number of human diseases are known to be associated with mutations in segmentally duplicated regions, including
Williams syndrome, Charcot-Marie-Tooth and DiGeorge syndrome. "Segmental duplications were almost impossible to study in the
draft sequence. Now, through the unstinting efforts of groups around the world, this important and rapidly evolving part of
our genome is open for scientific exploration," said Robert H. Waterston, M.D., Ph.D., former director of the Genome
Sequencing Center at Washington University in St. Louis and now chair of the Department of Genome Sciences at the University
of Washington in Seattle.
Segmental duplications cover 5.3 percent of the human genome, significantly more than in the rat genome, which has about 3
percent, or the mouse genome, which has between 1 and 2 percent. Segmental duplications provide a window into understanding
how our genome evolved and is still changing. The high proportion of segmental duplication in the human genome shows our
genetic material has undergone rapid functional innovation and structural change during the last 40 million years, presumably
contributing to unique characteristics that separate us from our non-human primate ancestors.
The consortium's analysis found the distribution of segmental duplications varies widely across human chromosomes. The Y
chromosome is the most extreme case, with segmental duplications occurring along more than 25 percent of its length. Some
segmental duplications tend to be clustered near the middle (centromeres) and ends (telomeres) of each chromosome, where,
researchers postulate, they may be used by the genome as an evolutionary laboratory for creating genes with new functions.
The accuracy of the finished human genome sequence produced by the Human Genome Project has also given scientists some
initial insights into the birth and death of genes in the human genome. Scientists have identified more than 1,000 new genes
that arose in the human genome after our divergence with rodents some 75 million years ago. Most of these arose through
recent gene duplications and are involved with immune, olfactory and reproductive functions. For example, there are two
families of genes recently duplicated in the human genome that encode sets of proteins (pregnancy-specific beta-1
glycoprotein and choriogonadotropin beta proteins) that may be involved in the extended period of pregnancy unique to humans.
Additionally, researchers used the finished human genome to identify and characterize 33 nearly intact genes that have
recently acquired one or more mutations, causing them to stop functioning, or "die." Scientists pinpointed these
non-functioning genes, referred to as pseudogenes, in the human genome by aligning them with the mouse and rat genomes, in
which the corresponding genes have maintained their functionality. Interestingly, researchers determined that 10 of these
pseudogenes in the human genome sequence appear to have coded for proteins involved in olfactory reception, which helps to
explain why humans have fewer functional olfactory receptors and, consequently, a poorer sense of smell than rodents. The
molecular biology of the sense of smell was just recognized by the awarding of a Nobel Prize in Physiology or Medicine to
Richard Axel and Linda B. Buck.
Next, the researchers aligned the 33 pseudogenes with the draft sequence of the chimpanzee genome to determine whether they
were still functional before Homo sapiens' divergence from great apes about 5 million years ago. The analysis revealed that
27 of the pseudogenes were non-functional in both humans and chimps. However, five of the genes that were inactive in humans
were found to be still functional in chimpanzees. "The identification of these pseudogenes and their functional counterparts
in chimpanzee provides fertile ground for future research projects," said Richard Gibbs, Ph.D., director of Baylor College of
Medicine's Human Genome Sequencing Center in Houston, which currently is sequencing the genome of another non-human primate,
the rhesus macaque (Macaca mulatta).
More than 2,800 researchers who took part in the International Human Genome Sequencing Consortium share authorship on today's
Nature paper, which expands upon the group's initial analysis published in Feb. 2001. Even more detailed annotations and
analyses have already been published for chromosomes 5, 6, 7, 9, 10, 13, 14, 19, 20, 21, 22 and Y. Publications describing
the remaining 12 chromosomes are forthcoming.
The finished human genome sequence and its annotations can be accessed through the following public genome browsers: GenBank
(ncbi.nih/Genbank) at NIH's National Center for
Biotechnology Information (NCBI); the UCSC Genome Browser (genome.ucsc) at the University of California at Santa Cruz; the Ensembl Genome Browser (ensembl) at the Wellcome Trust Sanger Institute and the
EMBL-European Bioinformatics Institute; the DNA Data Bank of Japan (ddbj.nih.ac.jp); and EMBL-Bank (ebi.ac.uk/embl/index.html) at the European Molecular Biology Laboratory's Nucleotide Sequence
Database.
The International Human Genome Sequencing Consortium includes scientists at 20 institutions located in France, Germany,
Japan, China, Great Britain and the United States. The five largest sequencing centers are located at: Baylor College of
Medicine; the Broad Institute of MIT and Harvard; DOE's Joint Genome Institute, Walnut Creek, Calif.; Washington University
School of Medicine; and the Wellcome Trust Sanger Institute.
NHGRI is one of 27 institutes and centers at the National Institutes of Health, an agency of the Department of Health and
Human Services. Additional information about NHGRI can be found at its Web site, genome.
Contact: Geoff Spencer
spencergmail.nih
301-402-0911
NIH/National Human Genome Research Institute
New Gene Mutation Identified In Common Type Of Dementia
Researchers have identified a new gene mutation linked to frontotemporal dementia, according to a study published in the July 10, 2007, issue of Neurology®, the medical journal of the American Academy of Neurology.
Frontotemporal dementia, one form of which is known as Pick's disease, involves progressive shrinking of the areas of the brain that control behavior and language. Symptoms include language problems and personality changes, often with inappropriate social behavior. Unlike Alzheimer's disease dementia, the disease does not affect memory in the early stages. The genetic form of the disease is rare; most cases occur randomly.
"We are hopeful that this finding will help us better understand how this disease works and eventually help us develop new therapies for the disease," said study author Amalia Bruni, MD, of the Regional Neurogenetic Centre in Lamezia Terme, Italy.
The researchers discovered a new mutation in the gene named progranulin in an extended family in southern Italy. The genealogy of this family has been reconstructed for 15 generations, going back to the 16th century; 36 family members have had frontotemporal dementia. For this study, DNA tests were conducted on 70 family members, including 13 people with the disease. "This is an important result that we pursued for more than 10 years," said study co-author Ekaterina Rogaeva, PhD, with the Centre for Research in Neurodegenerative Diseases at the University of Toronto.
The mutation identified in this study is in a gene on chromosome 17. The mutation leads to a loss of progranulin, a protein growth factor that helps brain cells survive. The mutation causes only half of the protein to be produced, because only one copy of the gene is active. Production of too much progranulin has been associated with cancer.
The new gene mutation was found in nine of those family members with the disease and 10 people who are currently too young to have the symptoms of the disease. But four people with the disease did not have the gene mutation. Bruni noted that these four people belong to a branch of the family with the disease in at least three generations. "These results are intriguing, since the family has two genetically distinct diseases that appear almost identical," said Bruni.
The Italian family had no cases with two copies of the mutated gene. "We would have expected to see cases with two copies of the mutated gene, especially since this family shares much of the same genetic material, as there have been at least five marriages between first cousins over the years," Bruni said. "It's possible that loss of both copies of the progranulin gene leads to the death of embryos, and that's why there were no cases with two copies of the mutated gene."
"Another intriguing aspect in this Italian family is the variable age at onset, which ranged from 35 to 87 years in the family members who inherited the same mutation. Our future research will try to identify the modifying factors responsible for the severity of the disorder," said Rogaeva.
Rogaeva says their studies will also try to identify the second gene responsible for dementia in this family.
The study was supported by grants from the Canadian Institutes of Health Research, Howard Hughes Medical Institute, Canada Foundation for Innovation, Japan-Canada and Canadian Institutes of Health Research Joint Health Research Program, Parkinson Society of Canada, W. Garfield Weston Fellows, Japanese Society for the Promotion of Science, National Institute on Aging Intramural Program, Italian Ministry of Health, and the Calabria Regional Health Department.
The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer's disease, epilepsy, Parkinson's disease, and multiple sclerosis.
For more information about the American Academy of Neurology, visit aan.
American Academy of Neurology (AAN)
1080 Montreal Ave.
St. Paul, MN 55116
United States
neurology
Frontotemporal dementia, one form of which is known as Pick's disease, involves progressive shrinking of the areas of the brain that control behavior and language. Symptoms include language problems and personality changes, often with inappropriate social behavior. Unlike Alzheimer's disease dementia, the disease does not affect memory in the early stages. The genetic form of the disease is rare; most cases occur randomly.
"We are hopeful that this finding will help us better understand how this disease works and eventually help us develop new therapies for the disease," said study author Amalia Bruni, MD, of the Regional Neurogenetic Centre in Lamezia Terme, Italy.
The researchers discovered a new mutation in the gene named progranulin in an extended family in southern Italy. The genealogy of this family has been reconstructed for 15 generations, going back to the 16th century; 36 family members have had frontotemporal dementia. For this study, DNA tests were conducted on 70 family members, including 13 people with the disease. "This is an important result that we pursued for more than 10 years," said study co-author Ekaterina Rogaeva, PhD, with the Centre for Research in Neurodegenerative Diseases at the University of Toronto.
The mutation identified in this study is in a gene on chromosome 17. The mutation leads to a loss of progranulin, a protein growth factor that helps brain cells survive. The mutation causes only half of the protein to be produced, because only one copy of the gene is active. Production of too much progranulin has been associated with cancer.
The new gene mutation was found in nine of those family members with the disease and 10 people who are currently too young to have the symptoms of the disease. But four people with the disease did not have the gene mutation. Bruni noted that these four people belong to a branch of the family with the disease in at least three generations. "These results are intriguing, since the family has two genetically distinct diseases that appear almost identical," said Bruni.
The Italian family had no cases with two copies of the mutated gene. "We would have expected to see cases with two copies of the mutated gene, especially since this family shares much of the same genetic material, as there have been at least five marriages between first cousins over the years," Bruni said. "It's possible that loss of both copies of the progranulin gene leads to the death of embryos, and that's why there were no cases with two copies of the mutated gene."
"Another intriguing aspect in this Italian family is the variable age at onset, which ranged from 35 to 87 years in the family members who inherited the same mutation. Our future research will try to identify the modifying factors responsible for the severity of the disorder," said Rogaeva.
Rogaeva says their studies will also try to identify the second gene responsible for dementia in this family.
The study was supported by grants from the Canadian Institutes of Health Research, Howard Hughes Medical Institute, Canada Foundation for Innovation, Japan-Canada and Canadian Institutes of Health Research Joint Health Research Program, Parkinson Society of Canada, W. Garfield Weston Fellows, Japanese Society for the Promotion of Science, National Institute on Aging Intramural Program, Italian Ministry of Health, and the Calabria Regional Health Department.
The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer's disease, epilepsy, Parkinson's disease, and multiple sclerosis.
For more information about the American Academy of Neurology, visit aan.
American Academy of Neurology (AAN)
1080 Montreal Ave.
St. Paul, MN 55116
United States
neurology
Potential Parkinson's Treatments Could Follow Identification Of Dopamine 'Mother Cells'
'Mother cells' which produce the neurons affected by Parkinson's disease have been identified by scientists, according to new research published in the journal Glia.
The new discovery could pave the way for future treatments for the disease, including the possibility of growing new neurons, and the cells which support them, in the lab. Scientists hope these could then be transplanted into patients to counteract the damage caused by Parkinson's.
The new study focuses on dopaminergic neurons - brain cells which produce and use the chemical dopamine to communicate with surrounding neurons. The researchers found that these important neurons are created when a particular type of cell in the embryonic brain divides during the early stages of brain development in the womb.
If a person suffers from Parkinson's disease, it is the depletion of these dopaminergic neurons and the associated lack of dopamine in the body which causes chronic and progressive symptoms including tremors, stiff muscles and slow movement.
The international research team used mouse models in the laboratory to examine the early stages of brain formation. They discovered that dopaminergic neurons are formed by precursor cells identified as 'radial glia-like cells' by the scientists because of their similarity to radial glia cells which are already known to build other parts of the brain.
The scientists hope that this discovery could, in the future, lead to new therapies which would use these radial glia-like cells derived from patients' own stem cells to grow replacement neurons in the lab, which could then be transplanted into the brain to replace the neurons they have lost.
One of the authors of the paper, Dr Anita Hall from Imperial College London's Department of Life Sciences, explains the potential of the team's findings: "You could call these radial glia-like cells the stem cells of this part of the brain - they contain all the information needed to create and support the young dopamine-producing neurons which are essential for important human functions including motor activity, cognition and some behaviours.
"Now that we understand how these neurons are produced, we hope that this knowledge can be used to develop novel therapies including techniques to create replacement neurons for people with Parkinson's which could be implanted into the brain to bolster their vital supplies of dopamine."
Dr Hall adds, however, that more research is needed to work out how exactly these glia-like cells could be used: "Using these mother cells to grow new neurons in the lab which are fit to be transplanted into humans will be complicated, and extensive further research is needed before this becomes a clinical reality. For example, we're not yet sure whether the mother cells themselves would need to be transplanted too, in order to facilitate successful dopamine production in the brain of a Parkinson's patient," she said.
In the UK, one in every 500 people - approximately 120,000 individuals - has Parkinson's disease. Around 10,000 people are diagnosed with the disease every year. The symptoms of Parkinson's disease usually appear when about 80% of the brain's dopamine has been lost. The level of dopamine in the brain then continues to fall slowly over many years. The reasons why the loss of dopamine occurs in the brains of people with Parkinson's is currently unknown.
The study was led by Professor Ernest Arenas at the Karolinska Institute in Sweden.
Source: Danielle Reeves
Imperial College London
The new discovery could pave the way for future treatments for the disease, including the possibility of growing new neurons, and the cells which support them, in the lab. Scientists hope these could then be transplanted into patients to counteract the damage caused by Parkinson's.
The new study focuses on dopaminergic neurons - brain cells which produce and use the chemical dopamine to communicate with surrounding neurons. The researchers found that these important neurons are created when a particular type of cell in the embryonic brain divides during the early stages of brain development in the womb.
If a person suffers from Parkinson's disease, it is the depletion of these dopaminergic neurons and the associated lack of dopamine in the body which causes chronic and progressive symptoms including tremors, stiff muscles and slow movement.
The international research team used mouse models in the laboratory to examine the early stages of brain formation. They discovered that dopaminergic neurons are formed by precursor cells identified as 'radial glia-like cells' by the scientists because of their similarity to radial glia cells which are already known to build other parts of the brain.
The scientists hope that this discovery could, in the future, lead to new therapies which would use these radial glia-like cells derived from patients' own stem cells to grow replacement neurons in the lab, which could then be transplanted into the brain to replace the neurons they have lost.
One of the authors of the paper, Dr Anita Hall from Imperial College London's Department of Life Sciences, explains the potential of the team's findings: "You could call these radial glia-like cells the stem cells of this part of the brain - they contain all the information needed to create and support the young dopamine-producing neurons which are essential for important human functions including motor activity, cognition and some behaviours.
"Now that we understand how these neurons are produced, we hope that this knowledge can be used to develop novel therapies including techniques to create replacement neurons for people with Parkinson's which could be implanted into the brain to bolster their vital supplies of dopamine."
Dr Hall adds, however, that more research is needed to work out how exactly these glia-like cells could be used: "Using these mother cells to grow new neurons in the lab which are fit to be transplanted into humans will be complicated, and extensive further research is needed before this becomes a clinical reality. For example, we're not yet sure whether the mother cells themselves would need to be transplanted too, in order to facilitate successful dopamine production in the brain of a Parkinson's patient," she said.
In the UK, one in every 500 people - approximately 120,000 individuals - has Parkinson's disease. Around 10,000 people are diagnosed with the disease every year. The symptoms of Parkinson's disease usually appear when about 80% of the brain's dopamine has been lost. The level of dopamine in the brain then continues to fall slowly over many years. The reasons why the loss of dopamine occurs in the brains of people with Parkinson's is currently unknown.
The study was led by Professor Ernest Arenas at the Karolinska Institute in Sweden.
Source: Danielle Reeves
Imperial College London
Discovery Of Anthrax Cellular Entry Point Is A Milestone In The Ongoing Efforts To Protect Humans From Bioterrorism And Bio-Warfare
The long-sought-after biological "gateway" that anthrax uses to enter healthy cells has been uncovered by microbiologists at the University of Alabama at Birmingham (UAB).
Anthrax spores enter the cell through something called Mac-1, a receptor that sits on the surface of certain cells.
This is the first study to uncover exactly how the bacteria get inside cells to begin with, the UAB researchers said. Previous studies have shown what happens after anthrax spores enter the body and wreak havoc.
Unraveling the anthrax-Mac-1 gateway is a milestone in the ongoing efforts to protect humans from bioterrorism and biological warfare, the UAB microbiologists said. Such a discovery will speed the development of new drugs and vaccines to fight or prevent anthrax infection, and advance the understanding of bacterial infection.
The findings are published in the online version of the journal Proceedings of the National Academy of Sciences and will soon appear in a print edition.
"We know anthrax infection can occur in wild and domestic animals, but in humans this disease is extremely rare and very dangerous. It is a bioweapon," said John Kearney, Ph.D., a professor in the UAB Department of Microbiology and co-author on the study. "This study reveals the biological paradigm that makes the anthrax spore clever enough to target the Mac-1 receptor, and use this entry point to boost its lethality."
Bacillus anthracis infection occurs in three forms: cutaneous (skin), inhalation and through swallowing spores. The skin infection is the most common type and can be treated with antibiotics if diagnosed rapidly.
The more serious form is inhalation anthrax, which was diagnosed in a few adults during the anthrax scare after the Sept. 11, 2001, terror attacks against the United States.
In the UAB study, researchers worked under strict bio-safe conditions to infect cultures of cells and laboratory-bred mice with a strain of anthrax often used in research.
Infection rates and other observations were significant enough to convince the microbiologists anthrax relies on Mac-1 to do its damage inside healthy cells.
"By showing how anthrax spores recognize Mac-1 receptors, this discovery points toward a precise entry point which B. anthracis uses to proliferate and trigger lethal consequences," said Claudia Oliva, Ph.D., and Melissa Swiecki, Ph.D., both researchers in the UAB Department of Microbiology and co-lead authors on the study.
Funding support for the study came from the National Institutes of Health.
Source: Troy Goodman
University of Alabama at Birmingham
Anthrax spores enter the cell through something called Mac-1, a receptor that sits on the surface of certain cells.
This is the first study to uncover exactly how the bacteria get inside cells to begin with, the UAB researchers said. Previous studies have shown what happens after anthrax spores enter the body and wreak havoc.
Unraveling the anthrax-Mac-1 gateway is a milestone in the ongoing efforts to protect humans from bioterrorism and biological warfare, the UAB microbiologists said. Such a discovery will speed the development of new drugs and vaccines to fight or prevent anthrax infection, and advance the understanding of bacterial infection.
The findings are published in the online version of the journal Proceedings of the National Academy of Sciences and will soon appear in a print edition.
"We know anthrax infection can occur in wild and domestic animals, but in humans this disease is extremely rare and very dangerous. It is a bioweapon," said John Kearney, Ph.D., a professor in the UAB Department of Microbiology and co-author on the study. "This study reveals the biological paradigm that makes the anthrax spore clever enough to target the Mac-1 receptor, and use this entry point to boost its lethality."
Bacillus anthracis infection occurs in three forms: cutaneous (skin), inhalation and through swallowing spores. The skin infection is the most common type and can be treated with antibiotics if diagnosed rapidly.
The more serious form is inhalation anthrax, which was diagnosed in a few adults during the anthrax scare after the Sept. 11, 2001, terror attacks against the United States.
In the UAB study, researchers worked under strict bio-safe conditions to infect cultures of cells and laboratory-bred mice with a strain of anthrax often used in research.
Infection rates and other observations were significant enough to convince the microbiologists anthrax relies on Mac-1 to do its damage inside healthy cells.
"By showing how anthrax spores recognize Mac-1 receptors, this discovery points toward a precise entry point which B. anthracis uses to proliferate and trigger lethal consequences," said Claudia Oliva, Ph.D., and Melissa Swiecki, Ph.D., both researchers in the UAB Department of Microbiology and co-lead authors on the study.
Funding support for the study came from the National Institutes of Health.
Source: Troy Goodman
University of Alabama at Birmingham
Regulating Energy Supply To The Brain During Fasting
If the current financial climate has taught us anything, it's that a system where over-borrowing goes unchecked eventually ends in disaster. It turns out this rule applies as much to our bodies as it does to economics. Instead of cash, our body deals in energy borrowed from muscle and given to the brain.
Unlike freewheeling financial markets, the lending process in the body is under strict regulation to ensure that more isn't lent than can be afforded. New research by scientists at the Salk Institute for Biological Studies reveals just how this process is implemented.
"We have all seen the sub-prime mortgage crisis," says Marc Montminy, M.D., Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology who led the current study. "If you take out a loan, sooner or later you've got to pay your debt, and the same is true in fasting metabolism."
The Salk researchers' findings, which are published ahead of print in the Oct. 5 edition of the journal Nature, may pave the way for novel therapies for sufferers of metabolic diseases in whom such regulation can spiral out of control.
Most tissues in our bodies respond to fasting by switching from their usual high-octane energy source - glucose - to burning a low-octane, cheaper alternative-fat. For our brains, however, only the high-performance fuel will do. If no food-derived glucose is available, the body must manufacture its own supply to maintain the brain in the manner to which it is accustomed. It does so by taking energy from muscle in the form of protein and converting it to glucose in the liver, a process known as gluconeogenesis. The sugar is then shipped via the bloodstream to the brain to keep it running smoothly.
Gluconeogenesis needs to be turned on rapidly in response to fasting, but shutting it off again is just as crucial. "You don't want gluconeogenesis to be prolonged," says postdoctoral researcher and co-first author Yi Liu, Ph.D. "Because it uses muscle as a protein source, it will eventually lead to muscle wastage." Adds Montminy, "The question has always been how is the production of glucose turned on, and how is shut off again?"
Previous work by the Montminy lab and others has shown that two key proteins, CRTC2 and FOXO1, are needed to turn on glucose-making genes during fasting. CRTC2 is activated by glucagon, a hormone whose levels go up when we stop eating. FOXO1, on the other hand, is activated when levels of the food-stimulated hormone insulin drop below a certain threshold. CRTC2's and FOXO1's activity needs to be tightly regulated, since producing too much glucose would result in over-borrowing of energy from muscle tissue.
To uncover the mechanism that ensures that this doesn't happen, the Salk researchers created mice containing the gene for luciferase, a light-emitting enzyme usually found in fireflies, engineered in such a way that it was only turned on when CRTC2 was active. Using imaging equipment, they could then detect CRTC2 activity in the livers of live mice simply by measuring how much they glowed.
When the mice were fasted, CRTC2 was rapidly activated, and the livers lit up, but to the scientists' surprise, after six hours the light went out. Experimentally decreasing the levels of CRTC2 or FOXO1 confirmed there was a two-stage fasting-response. Lowering CRTC2 reduced gluconeogenesis only early on, while less FOXO1 only affected late glucose production. As in a relay race, during fasting the baton for glucose production appeared to be passed from CRTC2 in stage one to FOXO1 in stage two.
The crucial switch from CRTC2 to FOXO1 comes in the form of SIRT1, a nutrient sensor that accumulates in the late fasting stage. Yi discovered that SIRT1 has opposite effects on CRTC2 and FOXO1: it sends the former to the recycling bin, while it activates the latter, and thus the baton is safely transferred from CRTC2 to the FOXO1.
Why does the body want to change between these two regulators of glucose production? Again, it comes down to body economics. CRTC2 acts as a rapid response unit to quickly produce high levels of glucose when it detects glucagon. Switching to FOXO1 later on slows down this production to more sustainable levels, while at the same time helping to produce ketone bodies, an alternative fuel the brain can use that does not require taking protein from muscle. "It is just like paying your loan back," says Montminy. "Later on you produce blood sugar at a different rate than you did at the beginning."
Knowledge of how this nutrient switch is working may help design new drugs to regulate sugar levels in diabetes patients. In, particular, chemical activators of the SIRT1 switch may be key. "This way we could provide control for patients with insulin resistance," says Montminy, "as typically their blood sugars are elevated after overnight fasting because the switches that regulate the glucose-producing enzymes are too active." Perhaps, then, a pharmacological rescue package for patients whose lending systems have been left unregulated may be on the horizon.
Other researchers contributing to this study were the co-first authors Renaud Dentin, Ph.D., at the Salk Institute and Danica Chen, Ph.D., at the Massachusetts Institute of Technology, Cambridge, along with Susan Hedrick and Kim Ravnskjaer in Montminy's laboratory; Simon Schenk and Jerrold Olefsky at the University of California, San Diego; Jill Milne at Sirtris Pharmaceuticals, Inc., Baltimore; David J. Meyers and Phil Cole at the Johns Hopkins University School of Medicine; John Yates III at The Scripps Research Institute; and Leonard Guarente at MIT.
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
View drug information on Glucagon.
Unlike freewheeling financial markets, the lending process in the body is under strict regulation to ensure that more isn't lent than can be afforded. New research by scientists at the Salk Institute for Biological Studies reveals just how this process is implemented.
"We have all seen the sub-prime mortgage crisis," says Marc Montminy, M.D., Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology who led the current study. "If you take out a loan, sooner or later you've got to pay your debt, and the same is true in fasting metabolism."
The Salk researchers' findings, which are published ahead of print in the Oct. 5 edition of the journal Nature, may pave the way for novel therapies for sufferers of metabolic diseases in whom such regulation can spiral out of control.
Most tissues in our bodies respond to fasting by switching from their usual high-octane energy source - glucose - to burning a low-octane, cheaper alternative-fat. For our brains, however, only the high-performance fuel will do. If no food-derived glucose is available, the body must manufacture its own supply to maintain the brain in the manner to which it is accustomed. It does so by taking energy from muscle in the form of protein and converting it to glucose in the liver, a process known as gluconeogenesis. The sugar is then shipped via the bloodstream to the brain to keep it running smoothly.
Gluconeogenesis needs to be turned on rapidly in response to fasting, but shutting it off again is just as crucial. "You don't want gluconeogenesis to be prolonged," says postdoctoral researcher and co-first author Yi Liu, Ph.D. "Because it uses muscle as a protein source, it will eventually lead to muscle wastage." Adds Montminy, "The question has always been how is the production of glucose turned on, and how is shut off again?"
Previous work by the Montminy lab and others has shown that two key proteins, CRTC2 and FOXO1, are needed to turn on glucose-making genes during fasting. CRTC2 is activated by glucagon, a hormone whose levels go up when we stop eating. FOXO1, on the other hand, is activated when levels of the food-stimulated hormone insulin drop below a certain threshold. CRTC2's and FOXO1's activity needs to be tightly regulated, since producing too much glucose would result in over-borrowing of energy from muscle tissue.
To uncover the mechanism that ensures that this doesn't happen, the Salk researchers created mice containing the gene for luciferase, a light-emitting enzyme usually found in fireflies, engineered in such a way that it was only turned on when CRTC2 was active. Using imaging equipment, they could then detect CRTC2 activity in the livers of live mice simply by measuring how much they glowed.
When the mice were fasted, CRTC2 was rapidly activated, and the livers lit up, but to the scientists' surprise, after six hours the light went out. Experimentally decreasing the levels of CRTC2 or FOXO1 confirmed there was a two-stage fasting-response. Lowering CRTC2 reduced gluconeogenesis only early on, while less FOXO1 only affected late glucose production. As in a relay race, during fasting the baton for glucose production appeared to be passed from CRTC2 in stage one to FOXO1 in stage two.
The crucial switch from CRTC2 to FOXO1 comes in the form of SIRT1, a nutrient sensor that accumulates in the late fasting stage. Yi discovered that SIRT1 has opposite effects on CRTC2 and FOXO1: it sends the former to the recycling bin, while it activates the latter, and thus the baton is safely transferred from CRTC2 to the FOXO1.
Why does the body want to change between these two regulators of glucose production? Again, it comes down to body economics. CRTC2 acts as a rapid response unit to quickly produce high levels of glucose when it detects glucagon. Switching to FOXO1 later on slows down this production to more sustainable levels, while at the same time helping to produce ketone bodies, an alternative fuel the brain can use that does not require taking protein from muscle. "It is just like paying your loan back," says Montminy. "Later on you produce blood sugar at a different rate than you did at the beginning."
Knowledge of how this nutrient switch is working may help design new drugs to regulate sugar levels in diabetes patients. In, particular, chemical activators of the SIRT1 switch may be key. "This way we could provide control for patients with insulin resistance," says Montminy, "as typically their blood sugars are elevated after overnight fasting because the switches that regulate the glucose-producing enzymes are too active." Perhaps, then, a pharmacological rescue package for patients whose lending systems have been left unregulated may be on the horizon.
Other researchers contributing to this study were the co-first authors Renaud Dentin, Ph.D., at the Salk Institute and Danica Chen, Ph.D., at the Massachusetts Institute of Technology, Cambridge, along with Susan Hedrick and Kim Ravnskjaer in Montminy's laboratory; Simon Schenk and Jerrold Olefsky at the University of California, San Diego; Jill Milne at Sirtris Pharmaceuticals, Inc., Baltimore; David J. Meyers and Phil Cole at the Johns Hopkins University School of Medicine; John Yates III at The Scripps Research Institute; and Leonard Guarente at MIT.
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
View drug information on Glucagon.
Overcoming The Limits Of Resolution
The STED (stimulated emission depletion) microscope invented by Hell is the first optical microscope to show details in resolutions far below the light wavelength using conventional lenses. This technique opens up new possibilities in the life sciences because it allows non-invasive imaging of the inside of cells. The prestigious award from the scientific publisher Springer will be awarded for the tenth time this year and carries prize money of US $5,000. Stefan Hell will receive the prize during a plenary session at the trade show Laser.World of Photonics 2007 in Munich on 19 June.
Stefan Hell has been a researcher at the Max Planck Institute for Biophysical Chemistry in Göttingen since 1997. This is where he and his colleagues conducted the first basic experiments to overcome the limit of resolution. Ever since the work carried out by Ernst Abbe in 1873, half the light's wavelength has been considered a practically unsurpassable limit in light microscopes that use focused visible light. In an STED microscope, the effective focal spot of fluorescence emission on the focal plane of the lens is radically decreased, allowing nanoscale imaging. Resolutions 10 -12 times higher than the diffraction limit have been obtained so far. In principle, however, STED microscopes can achieve molecular resolutions, because the effective focal spot can be reduced indefinitely due to the almost exponential depletion of the fluorescent state.
Hell's pioneering research has attracted attention from throughout the world and has been published in a number of scientific journals in this field. He is a scientific member of the Max Planck Society, adjunct professor of physics at the University of Heidelberg, honorary professor of experimental physics at the University of Göttingen and a member of the Göttingen Academy of Sciences. He has received numerous research prizes in Germany and abroad, including the Prize of the International Commission for Optics (2000), the Carl Zeiss Research Award (2002) and last year's German Innovation Award presented by the German President.
The Julius Springer Prize for Applied Physics recognizes researchers who have made an outstanding and innovative contribution to the field of applied physics. It has been awarded annually since 1998 by the editors-in-chief of the Springer journals Applied Physics A - Materials Science & Processing and Applied Physics B - Lasers and Optics.
Springer (springer/) is one of the world's leading publishers in the science, technology and medicine (STM) sector. It is part of Springer Science+Business Media, a leading supplier of scientific and specialist literature.
The prize will be presented on Tuesday, 19 June 2007, following the Plenary 2 at 10:30 -12:00 am | ICM, Room 1 | 18.th International Congress on Photonics in Europe | Munich
Contact: Renate Bayaz
Springer
Stefan Hell has been a researcher at the Max Planck Institute for Biophysical Chemistry in Göttingen since 1997. This is where he and his colleagues conducted the first basic experiments to overcome the limit of resolution. Ever since the work carried out by Ernst Abbe in 1873, half the light's wavelength has been considered a practically unsurpassable limit in light microscopes that use focused visible light. In an STED microscope, the effective focal spot of fluorescence emission on the focal plane of the lens is radically decreased, allowing nanoscale imaging. Resolutions 10 -12 times higher than the diffraction limit have been obtained so far. In principle, however, STED microscopes can achieve molecular resolutions, because the effective focal spot can be reduced indefinitely due to the almost exponential depletion of the fluorescent state.
Hell's pioneering research has attracted attention from throughout the world and has been published in a number of scientific journals in this field. He is a scientific member of the Max Planck Society, adjunct professor of physics at the University of Heidelberg, honorary professor of experimental physics at the University of Göttingen and a member of the Göttingen Academy of Sciences. He has received numerous research prizes in Germany and abroad, including the Prize of the International Commission for Optics (2000), the Carl Zeiss Research Award (2002) and last year's German Innovation Award presented by the German President.
The Julius Springer Prize for Applied Physics recognizes researchers who have made an outstanding and innovative contribution to the field of applied physics. It has been awarded annually since 1998 by the editors-in-chief of the Springer journals Applied Physics A - Materials Science & Processing and Applied Physics B - Lasers and Optics.
Springer (springer/) is one of the world's leading publishers in the science, technology and medicine (STM) sector. It is part of Springer Science+Business Media, a leading supplier of scientific and specialist literature.
The prize will be presented on Tuesday, 19 June 2007, following the Plenary 2 at 10:30 -12:00 am | ICM, Room 1 | 18.th International Congress on Photonics in Europe | Munich
Contact: Renate Bayaz
Springer
New Treatment Yields Complete Regression Of A Human Cancer In Mice
A simple modification in an anti-cancer treatment currently in clinical trials substantially improves the drug's effectiveness and reduces side effects in experiments with laboratory mice, researchers are reporting in an article scheduled for the May 16 edition of ACS' Bioconjugate Chemistry, a bi-monthly journal. Enzon Pharmaceuticals' David Filpula and colleagues at the National Cancer Institute worked on SS1P, a so-called immunotoxin that targets and destroys cells producing the surface protein mesothelin.
Ovarian, pancreatic and malignant mesothelioma cells all produce abnormally large amounts of mesothelin and thus are targets for SS1P. In the new study, researchers modified SS1P with PEGylation, which involves attaching chains of polyethylene glycol (also known as PEG) to the molecule. PEGylation is a well-established process that is used in at least six protein-based pharmaceutical products currently on the market.
PEGylated SS1Ps had fewer side effects and were more effective in mice bearing human tumors than standard SS1P, the report states. A single dose of the modified SS1P resulted in complete regression of the mouse tumors, the first time that such an effect had been observed, the researchers said. PEGylation of SS1P and other immunotoxins may hold promise for use in cancer patients, as well, they added.
"Releasable PEGylation of Mesothelin Targeted Immunotoxin SS1P Achieves Single Dosage Complete Regression of a Human Carcinoma in Mice"
CONTACT:
David Filpula, Ph.D.
Enzon Pharmaceuticals, Inc.
Piscataway, New Jersey
ACS News Service Weekly PressPac -- April 18, 2007
The American Chemical Society - the world's largest scientific society - is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.
Contact: Michael Woods
American Chemical Society
Ovarian, pancreatic and malignant mesothelioma cells all produce abnormally large amounts of mesothelin and thus are targets for SS1P. In the new study, researchers modified SS1P with PEGylation, which involves attaching chains of polyethylene glycol (also known as PEG) to the molecule. PEGylation is a well-established process that is used in at least six protein-based pharmaceutical products currently on the market.
PEGylated SS1Ps had fewer side effects and were more effective in mice bearing human tumors than standard SS1P, the report states. A single dose of the modified SS1P resulted in complete regression of the mouse tumors, the first time that such an effect had been observed, the researchers said. PEGylation of SS1P and other immunotoxins may hold promise for use in cancer patients, as well, they added.
"Releasable PEGylation of Mesothelin Targeted Immunotoxin SS1P Achieves Single Dosage Complete Regression of a Human Carcinoma in Mice"
CONTACT:
David Filpula, Ph.D.
Enzon Pharmaceuticals, Inc.
Piscataway, New Jersey
ACS News Service Weekly PressPac -- April 18, 2007
The American Chemical Society - the world's largest scientific society - is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.
Contact: Michael Woods
American Chemical Society
Study Identifies Pathway Required For Normal Reproductive Development
Massachusetts General Hospital (MGH) clinical researchers, in collaboration with basic scientists from the University of California, Irvine (UC Irvine) have identified a new molecular pathway required for normal development of the reproductive, olfactory and circadian systems in both humans and mice. In their report to appear in the Proceedings of the National Academy of Sciences, the team describes defects in a gene called PROK2 (prokineticin 2) in human siblings with two different forms of infertility. The UC Irvine team had previously reported that mice lacking PROK2 had abnormal olfactory structures and disrupted circadian rhythm. The paper is receiving early online release.
"We have demonstrated that PROK2 signaling is a novel pathway that is critical to the development of neurons that control the reproductive system, findings that should enable better understanding of human reproduction," says lead author Nelly Pitteloud, MD, of the Reproductive Endocrine Unit in the MGH Department of Medicine.
The current study is the latest in a series of investigations by the MGH group into the genetic basis of idiopathic hypogonadotropic hypogonadism (IHH), a rare condition in which puberty does not take place naturally. IHH occurs when a structure in the brain called the hypothalamus fails to develop neurons that secrete gonadotropin-releasing hormone (GnRH), a major controller of the reproductive system. Several genes involved in IHH have been discovered by the MGH investigators and others throughout the world; however, only 30 percent of IHH cases can currently be attributed to a known gene defect.
The investigation focused on PROK2, a protein known to regulate the development of the olfactory bulbs, the portion of the brain involved in the sense of smell, and to have a critical role in circadian rhythm in the mice. A form of IHH called Kallmann syndrome involves lack of both reproductive development and a sense of smell. PROK2's involvement in these systems led the researchers to investigate the protein's potential role in GnRH deficiency in human and mice.
The MGH team analyzed the PROK2 genes of 100 study participants: 50 with Kallmann syndrome and 50 with IHH and a normal sense of smell. Three members from the same family in Portugal -- two brothers and a sister -- had identical defects in both copies of the PROK2 gene. Further study of this family revealed another brother with the mutation in only one PROK2 copy and a normal reproductive history. Five siblings of these individuals -- now in their 70s -- had died in infancy; similar early deaths have been seen in the PROK2-deficient mice. Interestingly, while the two affected brothers both had Kallmann syndrome, their affected sister had a normal sense of smell but did not experience normal puberty.
"Until recently, IHH with a normal sense of smell and Kallmann syndrome with no sense of smell had been considered two distinct clinical entities," says Pitteloud, an assistant professor of Medicine at Harvard Medical School. "We now have described several kindreds in which different family members exhibit both syndromes yet harbor the identical mutation. So, it looks like additional gene defects or environmental cues modify how these syndromes develop in affected families."
The collaborative UC Irvine team was led by Qun-Yong Zhou, PhD, a professor of Pharmacology in its School of Medicine. His group has made fundamental contributions to the understanding of the neurobiological functions of prokineticin and its receptors. Their analysis of the reproductive status of mice lacking functional copies of Prok2 gene revealed that the animals' reproductive defect is due to the abnormal migration of neurons that secrete GnRH.
"Many recessive human genetic disorders, particularly the ones that have associated infertility symptom, are very difficult or almost infeasible to investigate using genetic analysis. The current study provides an elegant example how mouse studies can pinpoint the underlying genetic cause for human IHH disorders." says Zhou.
Zhou and William Crowley Jr, MD, chief of the MGH Reproductive Endocrine Unit and director of the Harvard Reproductive Endocrine Sciences Center, are senior authors of the PNAS paper. Other co-authors are Taneli Raivio, Lindsay Cole, Lacey Plummer, and Elka Jacobson-Dickman, of MGH; Cheng Kang Zhang and Jia-Da Li, UC Irvine; Duarte Pignatelli, University of Porto, Portugal; and Patricia Mellon, University of California at San Diego. The study was supported by grants from the National Institutes of Health.
Massachusetts General Hospital (massgeneral/), established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.
The University of California, Irvine (today.uci/) is a top-ranked university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 25,000 undergraduate and graduate students and about 1,800 faculty members. The second-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3.7 billion.
Source: Sue McGreevey
Massachusetts General Hospital
"We have demonstrated that PROK2 signaling is a novel pathway that is critical to the development of neurons that control the reproductive system, findings that should enable better understanding of human reproduction," says lead author Nelly Pitteloud, MD, of the Reproductive Endocrine Unit in the MGH Department of Medicine.
The current study is the latest in a series of investigations by the MGH group into the genetic basis of idiopathic hypogonadotropic hypogonadism (IHH), a rare condition in which puberty does not take place naturally. IHH occurs when a structure in the brain called the hypothalamus fails to develop neurons that secrete gonadotropin-releasing hormone (GnRH), a major controller of the reproductive system. Several genes involved in IHH have been discovered by the MGH investigators and others throughout the world; however, only 30 percent of IHH cases can currently be attributed to a known gene defect.
The investigation focused on PROK2, a protein known to regulate the development of the olfactory bulbs, the portion of the brain involved in the sense of smell, and to have a critical role in circadian rhythm in the mice. A form of IHH called Kallmann syndrome involves lack of both reproductive development and a sense of smell. PROK2's involvement in these systems led the researchers to investigate the protein's potential role in GnRH deficiency in human and mice.
The MGH team analyzed the PROK2 genes of 100 study participants: 50 with Kallmann syndrome and 50 with IHH and a normal sense of smell. Three members from the same family in Portugal -- two brothers and a sister -- had identical defects in both copies of the PROK2 gene. Further study of this family revealed another brother with the mutation in only one PROK2 copy and a normal reproductive history. Five siblings of these individuals -- now in their 70s -- had died in infancy; similar early deaths have been seen in the PROK2-deficient mice. Interestingly, while the two affected brothers both had Kallmann syndrome, their affected sister had a normal sense of smell but did not experience normal puberty.
"Until recently, IHH with a normal sense of smell and Kallmann syndrome with no sense of smell had been considered two distinct clinical entities," says Pitteloud, an assistant professor of Medicine at Harvard Medical School. "We now have described several kindreds in which different family members exhibit both syndromes yet harbor the identical mutation. So, it looks like additional gene defects or environmental cues modify how these syndromes develop in affected families."
The collaborative UC Irvine team was led by Qun-Yong Zhou, PhD, a professor of Pharmacology in its School of Medicine. His group has made fundamental contributions to the understanding of the neurobiological functions of prokineticin and its receptors. Their analysis of the reproductive status of mice lacking functional copies of Prok2 gene revealed that the animals' reproductive defect is due to the abnormal migration of neurons that secrete GnRH.
"Many recessive human genetic disorders, particularly the ones that have associated infertility symptom, are very difficult or almost infeasible to investigate using genetic analysis. The current study provides an elegant example how mouse studies can pinpoint the underlying genetic cause for human IHH disorders." says Zhou.
Zhou and William Crowley Jr, MD, chief of the MGH Reproductive Endocrine Unit and director of the Harvard Reproductive Endocrine Sciences Center, are senior authors of the PNAS paper. Other co-authors are Taneli Raivio, Lindsay Cole, Lacey Plummer, and Elka Jacobson-Dickman, of MGH; Cheng Kang Zhang and Jia-Da Li, UC Irvine; Duarte Pignatelli, University of Porto, Portugal; and Patricia Mellon, University of California at San Diego. The study was supported by grants from the National Institutes of Health.
Massachusetts General Hospital (massgeneral/), established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.
The University of California, Irvine (today.uci/) is a top-ranked university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 25,000 undergraduate and graduate students and about 1,800 faculty members. The second-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3.7 billion.
Source: Sue McGreevey
Massachusetts General Hospital
Secrets Of Chromosome Movement Yielded By St. Jude Study
Investigators at St. Jude Children's Research Hospital have used the lowly yeast to gain insights into how a dividing human cell ensures that an identical set of chromosomes gets passed on to each new daughter cell. Errors in this critical part of cell division can cause one daughter cell to get extra copies of some chromosomes that should have moved into the other daughter cell, or no copies of other chromosomes - a problem that is prevalent in cancer and can cause miscarriages or disease, such as Down syndrome.
St. Jude researchers made their discovery by tracking the activity of a small army of molecules with exotic names like argonaute (Ago1) and dicer; these molecules help maintain a specialized, tightly packaged form of DNA called heterochromatin at the part of the chromosome called the centromere. The investigators also showed the order in which certain critical events occur in setting up and maintaining this heterochromatin. The work is important because it gives scientists insight into how each daughter cell receives the normal number of chromosomes; and it offers important clues to understanding the genetic cause of certain catastrophic diseases. A report on this work appeared in "Molecular Cell."
All of the cell's DNA is wrapped around a series of structures, called histone octamers, to generate chromatin - much like thread wound around a spool. This chromatin is then further compacted to form the characteristic, thick structures commonly recognized in illustrations and photographs as chromosomes. At the centromere, DNA is packaged into an even more compact and specialized form of chromatin called centromeric heterochromatin.
The centromere is the last point at which the two identical chromosomes are joined before the cell divides. Centromeric heterochromatin helps to yoke together the "sister chromatids" of each chromosome pair as they line up in the center of the dividing cell before separating and moving into their respective daughter cells. When the cell has ensured that it is safe to continue dividing, each sister chromatid moves in opposite directions toward the two new daughter cells that are forming.
"The cell must establish and then maintain centromeric heterochromatin to ensure that each chromosome pair is stable and securely linked together until it's time to separate," said Janet Partridge, Ph.D., assistant member of the St. Jude Department of Biochemistry. "Otherwise, the chromosome pairs would drift apart and leave daughter cells with too many or too few chromosomes." Partridge is the report's senior author.
The St. Jude team studied combinations of molecules in yeast called the RITS and RDRC complexes, which together with an enzyme called Clr4 (Suv39 in humans), establish and maintain centromeric heterochromatin in the yeast cell during a carefully choreographed series of steps.
RITS is composed of the proteins Ago1, Tas3 and Chp1 and works closely with RDRC. RDRC produces a type of genetic material called double-stranded RNA, which an enzyme, called dicer, then chops into smaller pieces called small interfering RNA (siRNA). siRNA is bound by RITS, and in turn, helps RITS to reinforce the centromeric heterochromatin and keep it stable.
In addition, the Clr4 enzyme puts chemical tags onto the histone "spool" in a process called methylation. Methylation attracts a protein called Swi6 (HP1 in humans) to the chromosome to reinforce heterochromatin.
Previously, scientists - including Partridge's team - showed that cells lacking any component of RITS, RDRC or the Clr4 complex fail to assemble intact centromeric heterochromatin and suffer loss of chromosomes. However, researchers did not know whether the same components of these complexes are needed to support both establishment and the maintenance of centromeric heterochromatin. Therefore, Partridge's team developed specially modified yeast cells that allowed them to study these events individually.
By separating the Ago1 component of the RITS complex away from the Chp1-Tas3 components, rather than completely removing Ago1 from the cell, the researchers were able to generate yeast that could still maintain heterochromatin it had already established. These yeast cells had normal chromosome movement during cell division.
The investigators then showed that the same yeast cells also require the continuous presence of Clr4 to initially assemble normal centromeric heterochromatin. Specifically, the researchers used these yeast cells to show that the establishment of centromeric heterochromatin requires Clr4 to methylate histones at the centromere. The methylated centromere then attracts the RITS complex to this site. The St. Jude researchers' work also suggests that the siRNA is not so important for this first step, but does play an important role in propagating and maintaining centromeric heterochromatin.
"Until we did this study, it was virtually impossible to figure out which molecular events were specifically required for the two different processes of establishing and maintaining centromeric heterochromatin," Partridge said. "Now we have the tools to ask what is required for the cell to perform each task. This has important implications not just for understanding how centromeric heterochromatin assembles, but also for learning how heterochromatin forms elsewhere on the chromosome, a process that is often disturbed in cancer."
Other authors of this report include Jennifer DeBeauchamp, Aaron Kosinski, Dagny Ulrich, Michael Hadler and Victoria Noffsinger (St. Jude).
This work was supported in part by a Cancer Center (CORE) support grant and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit stjude/.
Contact: Summer Freeman
St. Jude Children's Research Hospital
St. Jude researchers made their discovery by tracking the activity of a small army of molecules with exotic names like argonaute (Ago1) and dicer; these molecules help maintain a specialized, tightly packaged form of DNA called heterochromatin at the part of the chromosome called the centromere. The investigators also showed the order in which certain critical events occur in setting up and maintaining this heterochromatin. The work is important because it gives scientists insight into how each daughter cell receives the normal number of chromosomes; and it offers important clues to understanding the genetic cause of certain catastrophic diseases. A report on this work appeared in "Molecular Cell."
All of the cell's DNA is wrapped around a series of structures, called histone octamers, to generate chromatin - much like thread wound around a spool. This chromatin is then further compacted to form the characteristic, thick structures commonly recognized in illustrations and photographs as chromosomes. At the centromere, DNA is packaged into an even more compact and specialized form of chromatin called centromeric heterochromatin.
The centromere is the last point at which the two identical chromosomes are joined before the cell divides. Centromeric heterochromatin helps to yoke together the "sister chromatids" of each chromosome pair as they line up in the center of the dividing cell before separating and moving into their respective daughter cells. When the cell has ensured that it is safe to continue dividing, each sister chromatid moves in opposite directions toward the two new daughter cells that are forming.
"The cell must establish and then maintain centromeric heterochromatin to ensure that each chromosome pair is stable and securely linked together until it's time to separate," said Janet Partridge, Ph.D., assistant member of the St. Jude Department of Biochemistry. "Otherwise, the chromosome pairs would drift apart and leave daughter cells with too many or too few chromosomes." Partridge is the report's senior author.
The St. Jude team studied combinations of molecules in yeast called the RITS and RDRC complexes, which together with an enzyme called Clr4 (Suv39 in humans), establish and maintain centromeric heterochromatin in the yeast cell during a carefully choreographed series of steps.
RITS is composed of the proteins Ago1, Tas3 and Chp1 and works closely with RDRC. RDRC produces a type of genetic material called double-stranded RNA, which an enzyme, called dicer, then chops into smaller pieces called small interfering RNA (siRNA). siRNA is bound by RITS, and in turn, helps RITS to reinforce the centromeric heterochromatin and keep it stable.
In addition, the Clr4 enzyme puts chemical tags onto the histone "spool" in a process called methylation. Methylation attracts a protein called Swi6 (HP1 in humans) to the chromosome to reinforce heterochromatin.
Previously, scientists - including Partridge's team - showed that cells lacking any component of RITS, RDRC or the Clr4 complex fail to assemble intact centromeric heterochromatin and suffer loss of chromosomes. However, researchers did not know whether the same components of these complexes are needed to support both establishment and the maintenance of centromeric heterochromatin. Therefore, Partridge's team developed specially modified yeast cells that allowed them to study these events individually.
By separating the Ago1 component of the RITS complex away from the Chp1-Tas3 components, rather than completely removing Ago1 from the cell, the researchers were able to generate yeast that could still maintain heterochromatin it had already established. These yeast cells had normal chromosome movement during cell division.
The investigators then showed that the same yeast cells also require the continuous presence of Clr4 to initially assemble normal centromeric heterochromatin. Specifically, the researchers used these yeast cells to show that the establishment of centromeric heterochromatin requires Clr4 to methylate histones at the centromere. The methylated centromere then attracts the RITS complex to this site. The St. Jude researchers' work also suggests that the siRNA is not so important for this first step, but does play an important role in propagating and maintaining centromeric heterochromatin.
"Until we did this study, it was virtually impossible to figure out which molecular events were specifically required for the two different processes of establishing and maintaining centromeric heterochromatin," Partridge said. "Now we have the tools to ask what is required for the cell to perform each task. This has important implications not just for understanding how centromeric heterochromatin assembles, but also for learning how heterochromatin forms elsewhere on the chromosome, a process that is often disturbed in cancer."
Other authors of this report include Jennifer DeBeauchamp, Aaron Kosinski, Dagny Ulrich, Michael Hadler and Victoria Noffsinger (St. Jude).
This work was supported in part by a Cancer Center (CORE) support grant and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit stjude/.
Contact: Summer Freeman
St. Jude Children's Research Hospital
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