Unos investigadores de la Universidad de Harvard han inventado un minúsculo robot hecho de material genético que pueden cargar con diferentes moléculas y dirigirlo a células específicas para que depositen esas sustancias, como fármacos, pero también para modificar su comportamiento. Se abre incluso la posibilidad espectacular, dicen, de enviar con esas moléculas de carga órdenes a las células cancerosas para que se autodestruyan. También se abre la perspectiva de programar así la respuesta inmunológica del organismo a varias enfermedades. No se trata de un trabajo teórico: Shawn Douglas y sus colaboradores incluso han hecho un prototipo del nanorobot de ADN y lo han ensayado con éxito en cultivos celulares.
Sus experimentos se han centrado en dos diferentes tipos de células cancerosas, de leucemia y linfoma, enviando instrucciones para activar el interruptor de suicidio celular, es decir, el mecanismo normal que permite la eliminación de las células anormales o envejecidas, explican en un comunicado de Harvard. Para cada caso, las instrucciones transportadas por el nanorobot y codificadas en fragmentos de anticuerpos, han sido diferentes.
No es la primera vez que los científicos abordan el reto de construir un dispositivo así utilizando las herramientas de la biotecnología y de la nanotecnología, aprovechando queel material genético es biodegradable y biocompatible, pero el equipo Douglas ha encontrado soluciones de diseño novedosas y prácticas. Basándose en la técnica denominada de origami de ADN, es decir, en el complejo plegamiento tridimensional de fragmentos de material genético, han dado forma de tonel tonel a su nanorobot , con sus dos mitades unidas por una especie de bisagras y cerrado con unos pestillos moleculares capaces de identificar diferentes células diana. Cuando el dispositivo llega a esas células de abre y deposita su carga, ya sea un fármaco o moléculas capaces de modificar su comportamiento, incluso induciendo el suicidio. El nanorobot es reprogramables porque puede llevar diferentes moléculas de búsqueda y reconocimiento de receptores de la superficie de distintas células. Estos investigadores, que presentan su trabajo en Science, han logrado una estructura eficaz del nanorobot, logrando abrirlo, cerrarlo, reabrirlo para insertar y para llevarla a las células de destino.
**Publicado en "EL PAIS"
17 February 2012
New molecule discovered in fight against allergy
Scientists at The University of Nottingham have discovered a new molecule that could offer the hope of new treatments for people allergic to the house dust mite. The team of immunologists led by Dr Amir Ghaem-Maghami and Professor Farouk Shakib in the University's School of Molecular Medical Sciences have identified the molecule DC-SIGN which appears to play a role in damping down the body's allergic response to the house dust mite.
The molecule can be found on the surface of the immune cells which play a key role in the recognition of a major allergen from house dust mites called Der p 1, a leading cause of asthma in northern Europe. The recognition of the allergen by the immune system is thought to lead to on-going sensitisation and the development of allergic symptoms.
The discovery furthers our understanding of how the body's immune system identifies and reacts to allergens, which could ultimately pave the way for developing new therapies or treatments for preventing allergies.
It's especially good news for the millions of people with asthma whose condition is worsened by their allergy to house dust mite and other environmental allergens. House dust mite droppings contain a whole raft of allergens that trigger a reaction when they become airborne and are inhaled.
Dr Amir Ghaem-Maghami said: "There has been a sharp increase in the prevalence of allergies over the past few decades and allergic asthma among children has reached epidemic proportions in many industrialised countries, including the UK. Despite improvements in patient care, mortality and morbidity of allergic asthma has remained high, and most therapies target symptoms rather than curing the condition.
"Many people with asthma are highly sensitive to airborne allergens such as those from house dust mite -- in fact, many studies have shown that up to 80 per cent of people with asthma are allergic to house dust mite.
"A better understanding of how the interaction between allergens and the immune system triggers allergy is vital if we are to develop more effective and efficient treatments for this debilitating condition."
Allergy is a disorder caused by the body's immune system reacting to harmless substances found in the environment, known as allergens. Believing itself under attack, the immune system produces an antibody called IgE, which eventually leads to the release of further chemicals (including histamine) by certain immune cells, which together cause an inflammatory response and the classic symptoms of allergy -- itchy eyes, sneezing, runny nose and wheezing.
The Nottingham work, published this week in the Journal of Biological Chemistry, has focused on the role of DC-SIGN, a receptor found on the surface of antigen presenting cells. These cells are among the first cells in the immune system that come into contact with allergens.
The team found that DC-SIGN binds to major allergen from house dust mite (Der p 1) and dogs (Can f 1) and seems to play a regulatory role in the allergic response to house dust mite allergens. The binding of allergen to DC-SIGN on antigen presenting cells seems to promote a mechanism that could dampen harmful immune responses to allergens.
This is opposite to the role of another allergen reception -- the mannose receptor -- that has previously been identified by the Nottingham group.
The discovery shows that DC-SIGN could potentially play a beneficial role in regulating immune responses to environmental allergens.
*Source: University of Nottingham
The molecule can be found on the surface of the immune cells which play a key role in the recognition of a major allergen from house dust mites called Der p 1, a leading cause of asthma in northern Europe. The recognition of the allergen by the immune system is thought to lead to on-going sensitisation and the development of allergic symptoms.
The discovery furthers our understanding of how the body's immune system identifies and reacts to allergens, which could ultimately pave the way for developing new therapies or treatments for preventing allergies.
It's especially good news for the millions of people with asthma whose condition is worsened by their allergy to house dust mite and other environmental allergens. House dust mite droppings contain a whole raft of allergens that trigger a reaction when they become airborne and are inhaled.
Dr Amir Ghaem-Maghami said: "There has been a sharp increase in the prevalence of allergies over the past few decades and allergic asthma among children has reached epidemic proportions in many industrialised countries, including the UK. Despite improvements in patient care, mortality and morbidity of allergic asthma has remained high, and most therapies target symptoms rather than curing the condition.
"Many people with asthma are highly sensitive to airborne allergens such as those from house dust mite -- in fact, many studies have shown that up to 80 per cent of people with asthma are allergic to house dust mite.
"A better understanding of how the interaction between allergens and the immune system triggers allergy is vital if we are to develop more effective and efficient treatments for this debilitating condition."
Allergy is a disorder caused by the body's immune system reacting to harmless substances found in the environment, known as allergens. Believing itself under attack, the immune system produces an antibody called IgE, which eventually leads to the release of further chemicals (including histamine) by certain immune cells, which together cause an inflammatory response and the classic symptoms of allergy -- itchy eyes, sneezing, runny nose and wheezing.
The Nottingham work, published this week in the Journal of Biological Chemistry, has focused on the role of DC-SIGN, a receptor found on the surface of antigen presenting cells. These cells are among the first cells in the immune system that come into contact with allergens.
The team found that DC-SIGN binds to major allergen from house dust mite (Der p 1) and dogs (Can f 1) and seems to play a regulatory role in the allergic response to house dust mite allergens. The binding of allergen to DC-SIGN on antigen presenting cells seems to promote a mechanism that could dampen harmful immune responses to allergens.
This is opposite to the role of another allergen reception -- the mannose receptor -- that has previously been identified by the Nottingham group.
The discovery shows that DC-SIGN could potentially play a beneficial role in regulating immune responses to environmental allergens.
*Source: University of Nottingham
Cellular aging increases risk of heart attack and early death
Every cell in the body has chromosomes with so-called telomeres, which are shortened over time and also through lifestyle choices such as smoking and obesity. Researchers have long speculated that the shortening of telomeres increases the risk of heart attack and early death. Now a large-scale population study in Denmark involving nearly 20,000 people shows that there is in fact a direct link, and has also given physicians a future way to test the actual cellular health of a person. In an ongoing study of almost 20,000 Danes, a team of researchers from the University of Copenhagen have isolated each individual's DNA to analyse their specific telomere length -- a measurement of cellular aging.
"The risk of heart attack or early death is present whether your telomeres are shortened due to lifestyle or due to high age," says Clinical Professor of Genetic Epidemiology Borge Nordestgaard from the Faculty of Health and Medical Sciences at the University of Copenhagen. Professor Nordestgaard is also a chief physician at Copenhagen University Hospital, where he and colleagues conduct large scale studies of groups of tens of thousands of Danes over several decades.
Lifestyle can affect cellular aging
The recent "Copenhagen General Population Study" involved almost 20,000 people, some of which were followed during almost 19 years, and the conclusion was clear: If the telomere length was short, the risk of heart attack and early death was increased by 50 and 25 per cent, respectively.
"That smoking and obesity increases the risk of heart disease has been known for a while. We have now shown, as has been speculated, that the increased risk is directly related to the shortening of the protective telomeres -- so you can say that smoking and obesity ages the body on a cellular level, just as surely as the passing of time," says Borge Nordestgaard.
One in four Danes has short telomeres
The study also revealed that one in four Danes has telomeres with such short length that not only will they statistically die before their time, but their risk of heart attack is also increased by almost 50 per cent.
"Future studies will have to reveal the actual molecular mechanism by which the short telomere length causes heart attacks," says Borge Nordestgaard, and asks, "Does one cause the other or is the telomere length and the coronary event both indicative of a third -- yet unknown -- mechanism?"
Another possible prospect of the study is that general practitioners could conduct simple blood tests to reveal a person's telomere length and thereby the cellular wear and age.
"The risk of heart attack or early death is present whether your telomeres are shortened due to lifestyle or due to high age," says Clinical Professor of Genetic Epidemiology Borge Nordestgaard from the Faculty of Health and Medical Sciences at the University of Copenhagen. Professor Nordestgaard is also a chief physician at Copenhagen University Hospital, where he and colleagues conduct large scale studies of groups of tens of thousands of Danes over several decades.
Lifestyle can affect cellular aging
The recent "Copenhagen General Population Study" involved almost 20,000 people, some of which were followed during almost 19 years, and the conclusion was clear: If the telomere length was short, the risk of heart attack and early death was increased by 50 and 25 per cent, respectively.
"That smoking and obesity increases the risk of heart disease has been known for a while. We have now shown, as has been speculated, that the increased risk is directly related to the shortening of the protective telomeres -- so you can say that smoking and obesity ages the body on a cellular level, just as surely as the passing of time," says Borge Nordestgaard.
One in four Danes has short telomeres
The study also revealed that one in four Danes has telomeres with such short length that not only will they statistically die before their time, but their risk of heart attack is also increased by almost 50 per cent.
"Future studies will have to reveal the actual molecular mechanism by which the short telomere length causes heart attacks," says Borge Nordestgaard, and asks, "Does one cause the other or is the telomere length and the coronary event both indicative of a third -- yet unknown -- mechanism?"
Another possible prospect of the study is that general practitioners could conduct simple blood tests to reveal a person's telomere length and thereby the cellular wear and age.
*Source: University of Copenhagen
Protein that functions in normal breast may also contribute to breast cancer metastasis
The trefoil factor 3 (TFF3) protein protects and maintains the integrity of the epithelial surface in the normal breast. New research has found that while TFF3 protein expression is higher in well-differentiated low grade tumors and therefore associated with features of a good prognosis, it has a more sinister role in breast cancer invasion and metastasis. The report is published in the March issue of The American Journal of Pathology. "Our findings suggest that TFF3 is regulated by estrogen and has beneficial properties in breast epithelia," says lead investigator Felicity E.B. May, PhD, of the Northern Institute for Cancer Research and the Department of Pathology at Newcastle University, UK. "We propose that early during breast tumorigenesis, TFF3 retains its association with normal functionality of breast epithelial cells. Subsequently, with the loss of tumor cell differentiation, its function is subverted to promote the development of tumors and infiltration and lymph node metastasis."
To determine the role of TFF3 in breast cancer, researchers measured its level in tissue samples from normal breasts, benign breast lesions, in situ carcinomas, invasive carcinomas, and involved lymph nodes. TFF3 was expressed in the majority of benign and malignant breast lesions studied. Well-differentiated tumor types expressed higher levels of TFF3. There was a positive association between TFF3 protein expression and microvessel density, suggesting that it stimulates angiogenesis in breast tumors.
A striking finding of the study is the strength and consistency of the association between TFF3 expression and a more metastatic phenotype in invasive breast cancer. TFF3 was expressed at higher levels in primary tumors with associated metastasis, and its expression was higher in malignant cells that have metastasized away from those within the primary tumor. There appears to be a switch in the normal polarized secretion of TFF3 in invasive cancer, which allows it to exert invasion-promoting effects.
The study suggests that TFF3 may be one of the genes that mediate the various effects of estrogens in breast cancer. "The paradox remains, however, for both the estrogen receptor and TFF3, that they contribute to the normal physiology of the breast epithelium yet are involved in the progression of cancer," notes Dr. May.
Importantly, the investigators also evaluated the potential of TFF3 as a biomarker of lymphovascular invasion and lymph node metastasis. They found that TFF3 had greater predictive power than other markers analyzed, including tumor grade, age, tumor size and type, and estrogen and progesterone receptor status. "Our study reinforces the view that TFF3 expression merits evaluation as a prognostic biomarker and as a predictive marker of response to therapy," concludes Dr. May. "It is probable that its malign effects will be mitigated by adjuvant endocrine therapy in women with hormone-responsive cancers. However, the usefulness of TFF3 as a marker of hormone responsiveness needs to be evaluated."
**Source: Elsevier Health Sciences
To determine the role of TFF3 in breast cancer, researchers measured its level in tissue samples from normal breasts, benign breast lesions, in situ carcinomas, invasive carcinomas, and involved lymph nodes. TFF3 was expressed in the majority of benign and malignant breast lesions studied. Well-differentiated tumor types expressed higher levels of TFF3. There was a positive association between TFF3 protein expression and microvessel density, suggesting that it stimulates angiogenesis in breast tumors.
A striking finding of the study is the strength and consistency of the association between TFF3 expression and a more metastatic phenotype in invasive breast cancer. TFF3 was expressed at higher levels in primary tumors with associated metastasis, and its expression was higher in malignant cells that have metastasized away from those within the primary tumor. There appears to be a switch in the normal polarized secretion of TFF3 in invasive cancer, which allows it to exert invasion-promoting effects.
The study suggests that TFF3 may be one of the genes that mediate the various effects of estrogens in breast cancer. "The paradox remains, however, for both the estrogen receptor and TFF3, that they contribute to the normal physiology of the breast epithelium yet are involved in the progression of cancer," notes Dr. May.
Importantly, the investigators also evaluated the potential of TFF3 as a biomarker of lymphovascular invasion and lymph node metastasis. They found that TFF3 had greater predictive power than other markers analyzed, including tumor grade, age, tumor size and type, and estrogen and progesterone receptor status. "Our study reinforces the view that TFF3 expression merits evaluation as a prognostic biomarker and as a predictive marker of response to therapy," concludes Dr. May. "It is probable that its malign effects will be mitigated by adjuvant endocrine therapy in women with hormone-responsive cancers. However, the usefulness of TFF3 as a marker of hormone responsiveness needs to be evaluated."
**Source: Elsevier Health Sciences
La OMS analiza los límites a la difusión de estudios sobre la gripe aviar
La Organización Mundial de la Salud (OMS) reúne en Ginebra a científicos que están analizando los recientes estudios sobre el virus de la gripe aviar (H5N1) y discuten si es necesario o deseable publicarlos, dado el eventual peligro de que sean utilizados con fines ajenos a la investigación.
En la reunión participan una veintena de científicos de Australia, EEUU, Francia, Gran Bretaña y Holanda, y de países asiáticos como China, Indonesia, Japón y Vietnam, afectados especialmente por ese virus.
A mediados de diciembre del año pasado se supo que 38 científicos de las universidades Erasmo de Rotterdam (Holanda) y Wisconsin (EEUU), liderados por el virólogo holandés Ron Fouchier, habían descubierto cinco mutaciones genéticas que el virus H5N1 puede sufrir para su contagio entre las personas.
El objetivo del estudio holandés, que ha sido financiado por el Instituto Nacional de Salud estadounidense, perseguía conseguir la información necesaria para evitar una posible pandemia originada por esa variante de la gripe. Para ello, estaban intentando crear la vacuna que protegería contra las nuevas cepas.
Los científicos estaban a punto de publicar sus resultados en las revistas especializadas 'Nature' y 'Science', pero fueron presionados para no hacerlo por las autoridades sanitarias de EEUU, que temían que, si compartían públicamente estos conocimientos, podían eventualmente ser usados por terroristas para crear un arma biológica.
Normalmente, el virus H5N1 se transmite entre aves de corral y su contagio a humanos se produce raramente, por lo que la transmisión entre personas podría ser altamente letal.
De hecho, cada vez que se refiere al H5N1, la OMS recuerda que el virus es potencialmente muy peligroso porque si bien normalmente no contamina a las personas, cuando lo hace, mata al 60% de los infectados.
Tras la polémica, el pasado 30 de diciembre la OMS alertó del riesgo potencial de hacer investigaciones sobre el virus de gripe si no se aplican las estrictas normas y recomendaciones aprobadas por este organismo, y más de 20 días después, decidió convocar la reunión que se celebra hoy.
Mientras, los científicos no sólo no publicaron los resultados, sino que se impuso una moratoria de 60 días, en los que no continuarán con las investigaciones, a la espera de que la comunidad científica se ponga de acuerdo sobre cómo proceder en el futuro.
**AGENCIAS
En la reunión participan una veintena de científicos de Australia, EEUU, Francia, Gran Bretaña y Holanda, y de países asiáticos como China, Indonesia, Japón y Vietnam, afectados especialmente por ese virus.
A mediados de diciembre del año pasado se supo que 38 científicos de las universidades Erasmo de Rotterdam (Holanda) y Wisconsin (EEUU), liderados por el virólogo holandés Ron Fouchier, habían descubierto cinco mutaciones genéticas que el virus H5N1 puede sufrir para su contagio entre las personas.
El objetivo del estudio holandés, que ha sido financiado por el Instituto Nacional de Salud estadounidense, perseguía conseguir la información necesaria para evitar una posible pandemia originada por esa variante de la gripe. Para ello, estaban intentando crear la vacuna que protegería contra las nuevas cepas.
Los científicos estaban a punto de publicar sus resultados en las revistas especializadas 'Nature' y 'Science', pero fueron presionados para no hacerlo por las autoridades sanitarias de EEUU, que temían que, si compartían públicamente estos conocimientos, podían eventualmente ser usados por terroristas para crear un arma biológica.
Normalmente, el virus H5N1 se transmite entre aves de corral y su contagio a humanos se produce raramente, por lo que la transmisión entre personas podría ser altamente letal.
De hecho, cada vez que se refiere al H5N1, la OMS recuerda que el virus es potencialmente muy peligroso porque si bien normalmente no contamina a las personas, cuando lo hace, mata al 60% de los infectados.
Tras la polémica, el pasado 30 de diciembre la OMS alertó del riesgo potencial de hacer investigaciones sobre el virus de gripe si no se aplican las estrictas normas y recomendaciones aprobadas por este organismo, y más de 20 días después, decidió convocar la reunión que se celebra hoy.
Mientras, los científicos no sólo no publicaron los resultados, sino que se impuso una moratoria de 60 días, en los que no continuarán con las investigaciones, a la espera de que la comunidad científica se ponga de acuerdo sobre cómo proceder en el futuro.
**AGENCIAS
Common flame retardant linked to social, behavioral and learning deficits
Mice genetically engineered to be susceptible to autism-like behaviors that were exposed to a common flame retardant were less fertile and their offspring were smaller, less sociable and demonstrated marked deficits in learning and long-term memory when compared with the offspring of normal unexposed mice, a study by researchers at UC Davis has found. The researchers said the study is the first to link genetics and epigenetics with exposure to a flame retardant chemical. The research was published online February 16 in the journal Human Molecular Genetics. It will be presented during a symposium on Feb. 18, at the annual meeting of the American Association for the Advancement of Science (AAAS) by Janine LaSalle, a professor in the Department of Medical Microbiology and Immunology in the UC Davis School of Medicine and the UC Davis Genome Center.
"This study highlights the interaction between epigenetics and the effects of early exposure to flame retardants," said Janine LaSalle, the study's senior author and a researcher affiliated with the UC Davis MIND Institute. "Our experiments with wild-type and mutant mice indicate that exposure to flame retardants presents an independent risk of neurodevelopmental deficits associated with reduced sociability and learning."
Epigenetics describes the heritable changes in gene expression caused by mechanisms other than those in the DNA sequence. One such mechanism is DNA methylation, in which genes are silenced when their activation no longer is required. DNA methylation is essential for normal development. The researchers chose a mouse that was genetically and epigenetically susceptible to social behavioral deficits in order to understand the potential effect of this environmental pollutant on genetically susceptible humans.
LaSalle and her colleagues examined the effects of the chemical BDE-47 (Tetrabromodiphenl ether), a member of the class of flame retardants called polybrominated diphenylethers, or PBDEs. PBDEs have been used in a wide range of products, including electronics, bedding, carpeting and furniture. They have been shown to persist in the environment and accumulate in living organisms, and toxicological testing has found that they may cause liver toxicity, thyroid toxicity and neurodevelopmental toxicity, according to the U.S. Environmental Protection Agency. BDE-47 is the PBDE found at highest concentrations in human blood and breast milk, raising concerns about its potential neurotoxic effects during pregnancy and neonatal development.
The research was conducted in the offspring of mice genetically engineered for the autism phenotype found in Rett syndrome, a disorder that occurs primarily in females and causes regression in expressive language, motor skills and social reciprocity in late infancy. The condition affects about 1 in 10,000 children.
Autism spectrum disorders are a group of neurodevelopmental disabilities that can cause significant social, communication and behavioral deficits. The U.S. Centers for Disease Control and Prevention estimates that an average of 1 in 110 children born in the United States today will be diagnosed with an autism spectrum disorder.
Rett syndrome is causally linked to defects in the methyl-CpG-binding protein 2 gene MECP2 situated on the X chromosome. Mutations in MECP2 result in a nonfunctional MeCP2 protein, which is required for normal brain development. The researchers evaluated the effects of exposure to BDE-47 on mice genetically engineered to have mutations in MECP2 and their offspring, or pups. The genetically engineered Mecp2 mother mice, or dams, were bred with non-mutant wild-type males. The dams were monitored for 10 weeks -- for four weeks prior to conception, three weeks during gestation and three weeks of lactation. They were then compared with a control group of normal, unexposed dams and pups over several generations and hundreds of mice.
The study found that that the weights of the pups of the lactating BDE-47-exposed dams were diminished when compared with the controls, as were their survival rates. To assess the effects of the flame retardant exposure on the pups and their genotypes, the researchers placed them through more than 10 cognitive, social and physical tests.
Female offspring of dams exposed with BDE-47 spent half as much time interacting with another mouse in a 10-minute sociability test compared to controls. The reduced sociability in BDE-47 exposed females corresponded to reduced DNA methylation in females regardless of genotype. In addition, genetic and environmental interaction effects in this study were specifically observed in females.
In a short-term memory test of social novelty, although all mice showed the expected preference for interacting with a novel over a familiar mouse, BDE-47-exposed mutant female mice spent about half as much time interacting with the familiar mouse than their non-mutant littermates. In a long-term memory test of swimming to reach a hidden platform in a cloudy pool, female mice who were both mutant and BDE-47 exposed did not learn to reach the platform faster after fourdays of training. These behavioral changes in social and cognitive learning specifically in the interaction group corresponded to changes in a known epigenetic regulator of DNA methylation in brain, DNA methyltransferase 3a (Dnmt3a).
LaSalle said that the study results are important because better understanding of the epigenetic pathways implicated in social behavior and cognition may lead to improved treatments for autism spectrum disorders.
"While the obvious preventative step is to limit the use and accumulation of PBDEs in our environment, this would likely be a long-term solution," LaSalle said. "These pollutants are going to be hard to get rid of tomorrow. However, one important preventative that all women could do tomorrow is to start taking prenatal vitamins before becoming pregnant, as these may counteract the toxins in our environment through DNA methylation," she said.
**Source: University of California - Davis Health System
"This study highlights the interaction between epigenetics and the effects of early exposure to flame retardants," said Janine LaSalle, the study's senior author and a researcher affiliated with the UC Davis MIND Institute. "Our experiments with wild-type and mutant mice indicate that exposure to flame retardants presents an independent risk of neurodevelopmental deficits associated with reduced sociability and learning."
Epigenetics describes the heritable changes in gene expression caused by mechanisms other than those in the DNA sequence. One such mechanism is DNA methylation, in which genes are silenced when their activation no longer is required. DNA methylation is essential for normal development. The researchers chose a mouse that was genetically and epigenetically susceptible to social behavioral deficits in order to understand the potential effect of this environmental pollutant on genetically susceptible humans.
LaSalle and her colleagues examined the effects of the chemical BDE-47 (Tetrabromodiphenl ether), a member of the class of flame retardants called polybrominated diphenylethers, or PBDEs. PBDEs have been used in a wide range of products, including electronics, bedding, carpeting and furniture. They have been shown to persist in the environment and accumulate in living organisms, and toxicological testing has found that they may cause liver toxicity, thyroid toxicity and neurodevelopmental toxicity, according to the U.S. Environmental Protection Agency. BDE-47 is the PBDE found at highest concentrations in human blood and breast milk, raising concerns about its potential neurotoxic effects during pregnancy and neonatal development.
The research was conducted in the offspring of mice genetically engineered for the autism phenotype found in Rett syndrome, a disorder that occurs primarily in females and causes regression in expressive language, motor skills and social reciprocity in late infancy. The condition affects about 1 in 10,000 children.
Autism spectrum disorders are a group of neurodevelopmental disabilities that can cause significant social, communication and behavioral deficits. The U.S. Centers for Disease Control and Prevention estimates that an average of 1 in 110 children born in the United States today will be diagnosed with an autism spectrum disorder.
Rett syndrome is causally linked to defects in the methyl-CpG-binding protein 2 gene MECP2 situated on the X chromosome. Mutations in MECP2 result in a nonfunctional MeCP2 protein, which is required for normal brain development. The researchers evaluated the effects of exposure to BDE-47 on mice genetically engineered to have mutations in MECP2 and their offspring, or pups. The genetically engineered Mecp2 mother mice, or dams, were bred with non-mutant wild-type males. The dams were monitored for 10 weeks -- for four weeks prior to conception, three weeks during gestation and three weeks of lactation. They were then compared with a control group of normal, unexposed dams and pups over several generations and hundreds of mice.
The study found that that the weights of the pups of the lactating BDE-47-exposed dams were diminished when compared with the controls, as were their survival rates. To assess the effects of the flame retardant exposure on the pups and their genotypes, the researchers placed them through more than 10 cognitive, social and physical tests.
Female offspring of dams exposed with BDE-47 spent half as much time interacting with another mouse in a 10-minute sociability test compared to controls. The reduced sociability in BDE-47 exposed females corresponded to reduced DNA methylation in females regardless of genotype. In addition, genetic and environmental interaction effects in this study were specifically observed in females.
In a short-term memory test of social novelty, although all mice showed the expected preference for interacting with a novel over a familiar mouse, BDE-47-exposed mutant female mice spent about half as much time interacting with the familiar mouse than their non-mutant littermates. In a long-term memory test of swimming to reach a hidden platform in a cloudy pool, female mice who were both mutant and BDE-47 exposed did not learn to reach the platform faster after fourdays of training. These behavioral changes in social and cognitive learning specifically in the interaction group corresponded to changes in a known epigenetic regulator of DNA methylation in brain, DNA methyltransferase 3a (Dnmt3a).
LaSalle said that the study results are important because better understanding of the epigenetic pathways implicated in social behavior and cognition may lead to improved treatments for autism spectrum disorders.
"While the obvious preventative step is to limit the use and accumulation of PBDEs in our environment, this would likely be a long-term solution," LaSalle said. "These pollutants are going to be hard to get rid of tomorrow. However, one important preventative that all women could do tomorrow is to start taking prenatal vitamins before becoming pregnant, as these may counteract the toxins in our environment through DNA methylation," she said.
**Source: University of California - Davis Health System
Successful human tests for first wirelessly controlled drug-delivery chip
About 15 years ago, MIT professors Robert Langer and Michael Cima had the idea to develop a programmable, wirelessly controlled microchip that would deliver drugs after implantation in a patient's body. This week, the MIT researchers and scientists from MicroCHIPS Inc. reported that they have successfully used such a chip to administer daily doses of an osteoporosis drug normally given by injection. The results, published in the Feb. 16 online edition of Science Translational Medicine, represent the first successful test of such a device and could help usher in a new era of telemedicine -- delivering health care over a distance, Langer says.
"You could literally have a pharmacy on a chip," says Langer, the David H. Koch Institute Professor at MIT. "You can do remote control delivery, you can do pulsatile drug delivery, and you can deliver multiple drugs."
In the new study, funded and overseen by MicroCHIPS, scientists used the programmable implants to deliver an osteoporosis drug called teriparatide to seven women aged 65 to 70. The study found that the device delivered dosages comparable to injections, and there were no adverse side effects.
These programmable chips could dramatically change treatment not only for osteoporosis, but also for many other diseases, including cancer and multiple sclerosis. "Patients with chronic diseases, regular pain-management needs or other conditions that require frequent or daily injections could benefit from this technology," says Robert Farra, president and chief operating officer at MicroCHIPS and lead author of the paper.
"Compliance is very important in a lot of drug regimens, and it can be very difficult to get patients to accept a drug regimen where they have to give themselves injections," says Cima, the David H. Koch Professor of Engineering at MIT. "This avoids the compliance issue completely, and points to a future where you have fully automated drug regimens."
Achieving precision
The MIT research team started working on the implantable chip in the mid-1990s. John Santini, then a University of Michigan undergraduate visiting MIT, took it on as a summer project under the direction of Cima and Langer. Santini, who later returned to MIT as a graduate student to continue the project, is also an author of the new paper.
In 1999, the MIT team published its initial findings in Nature, and MicroCHIPS was founded and licensed the microchip technology from MIT. The company refined the chips, including adding a hermetic seal and a release system that works reliably in living tissue. Teriparatide is a polypeptide and therefore much less chemically stable than small-molecule drugs, so sealing it hermetically to preserve it was an important achievement, Langer says.
The human clinical trial began in Denmark in January 2011. Chips were implanted during a 30-minute procedure at a doctor's office using local anesthetic, and remained in the patients for four months. The implants proved safe, and patients reported they often forgot they even had the implant, Cima says.
Chips used in the study stored 20 doses of teriparatide, individually sealed in tiny reservoirs about the size of a pinprick. The reservoirs are capped with a thin layer of platinum and titanium that melts when a small electrical current is applied, releasing the drug inside. MicroCHIPS is now working on developing implants that can carry hundreds of drug doses per chip.
Because the chips are programmable, dosages can be scheduled in advance or triggered remotely by radio communication over a special frequency called Medical Implant Communication Service (MICS). Current versions work over a distance of a few inches, but researchers plan to extend that range.
Consistent results
In the Science Translational Medicine study, the researchers measured bone formation in osteoporosis patients with the implants, and found that it was similar to that seen in patients receiving daily injections of teriparatide. Another notable result is that the dosages given by implant had less variation than those given by injection.
Henry Brem, professor of neurosurgery, ophthalmology, oncology and biological engineering at Johns Hopkins University School of Medicine, called the results "stunning."
**Source: Massachusetts Institute of Technology
"You could literally have a pharmacy on a chip," says Langer, the David H. Koch Institute Professor at MIT. "You can do remote control delivery, you can do pulsatile drug delivery, and you can deliver multiple drugs."
In the new study, funded and overseen by MicroCHIPS, scientists used the programmable implants to deliver an osteoporosis drug called teriparatide to seven women aged 65 to 70. The study found that the device delivered dosages comparable to injections, and there were no adverse side effects.
These programmable chips could dramatically change treatment not only for osteoporosis, but also for many other diseases, including cancer and multiple sclerosis. "Patients with chronic diseases, regular pain-management needs or other conditions that require frequent or daily injections could benefit from this technology," says Robert Farra, president and chief operating officer at MicroCHIPS and lead author of the paper.
"Compliance is very important in a lot of drug regimens, and it can be very difficult to get patients to accept a drug regimen where they have to give themselves injections," says Cima, the David H. Koch Professor of Engineering at MIT. "This avoids the compliance issue completely, and points to a future where you have fully automated drug regimens."
Achieving precision
The MIT research team started working on the implantable chip in the mid-1990s. John Santini, then a University of Michigan undergraduate visiting MIT, took it on as a summer project under the direction of Cima and Langer. Santini, who later returned to MIT as a graduate student to continue the project, is also an author of the new paper.
In 1999, the MIT team published its initial findings in Nature, and MicroCHIPS was founded and licensed the microchip technology from MIT. The company refined the chips, including adding a hermetic seal and a release system that works reliably in living tissue. Teriparatide is a polypeptide and therefore much less chemically stable than small-molecule drugs, so sealing it hermetically to preserve it was an important achievement, Langer says.
The human clinical trial began in Denmark in January 2011. Chips were implanted during a 30-minute procedure at a doctor's office using local anesthetic, and remained in the patients for four months. The implants proved safe, and patients reported they often forgot they even had the implant, Cima says.
Chips used in the study stored 20 doses of teriparatide, individually sealed in tiny reservoirs about the size of a pinprick. The reservoirs are capped with a thin layer of platinum and titanium that melts when a small electrical current is applied, releasing the drug inside. MicroCHIPS is now working on developing implants that can carry hundreds of drug doses per chip.
Because the chips are programmable, dosages can be scheduled in advance or triggered remotely by radio communication over a special frequency called Medical Implant Communication Service (MICS). Current versions work over a distance of a few inches, but researchers plan to extend that range.
Consistent results
In the Science Translational Medicine study, the researchers measured bone formation in osteoporosis patients with the implants, and found that it was similar to that seen in patients receiving daily injections of teriparatide. Another notable result is that the dosages given by implant had less variation than those given by injection.
Henry Brem, professor of neurosurgery, ophthalmology, oncology and biological engineering at Johns Hopkins University School of Medicine, called the results "stunning."
**Source: Massachusetts Institute of Technology
Subscribe to:
Posts (Atom)