Several neurodegenerative diseases - including Alzheimer's and ALS (Lou Gehrig's disease) - are caused when the body's own proteins fold incorrectly, recruit and convert healthy proteins to the misfolded form, and aggregate in large clumps that gum up the works of the nervous system. "For Star Trek fans, this is like the Borg, [a fictional race of cyborgs that abduct and assimilate humans and other species]," says Steven Plotkin, a biophysicist at the University of British Columbia in Vancouver who studies the process of protein misfolding.
Plotkin's team has developed an algorithm that can predict which regions of a protein are prone to exposure upon misfolding, and how mutations in the protein and changes in the cellular environment might affect the stability of these vulnerable regions. These predictions help scientists gain a better understanding of protein dynamics, and may one day help in developing treatments to effectively combat currently incurable neurodegenerative diseases. The team will present its findings at the 56th Annual Meeting of the Biophysical Society (BPS), held Feb. 25-29 in San Diego, Calif.
The algorithm developed by Plotkin's group uses the energy equations of thermodynamics to calculate the likelihood that certain stretches of protein will be displayed when the protein misfolds. Since the exposed regions are specific to the misfolded version of the protein, researchers can use these regions as targets for diagnostic and therapeutic treatments. The algorithm can be adapted for different proteins and predicts several potential target regions for each protein. The group has used it to study neurodegenerative disease-causing proteins as well as misfolded proteins that have been implicated in some cancers.
More recently, the research group used computer simulations to manipulate proteins in a virtual environment, testing out how easy it is for mutated proteins to misfold and propagate. Using this tool has helped the team predict the progression of hereditary ALS disease.
"The fact that we can predict the lifetime of an individual diagnosed with hereditary ALS from simulations of a protein's mechanical properties is something that is both satisfying and that gives one pause," says Plotkin. "We hope that such information might give some clues as to how to develop effective therapies for this disease."
Saturday, February 25, 2012
Stem Cell Development Triggers Memory
Researchers at the RIKEN-MIT Center for Neural Circuit Genetics have discovered an answer to the long-standing mystery of how brain cells can both remember new memories while also maintaining older ones.
They found that specific neurons in a brain region called the dentate gyrus serve distinct roles in memory formation depending on whether the neural stem cells that produced them were of old versus young age.
The study will appear in the March 30 issue of Cell and links the cellular basis of memory formation to the birth of new neurons - a finding that could unlock a new class of drug targets to treat memory disorders.
The findings also suggest that an imbalance between young and old neurons in the brain could disrupt normal memory formation during post-traumatic stress disorder (PTSD) and aging. "In animals, traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging," said the study's senior author Susumu Tonegawa, 1987 Nobel Laureate and Director of the RIKEN-MIT Center.
Other authors include Toshiaki Nakashiba and researchers from the RIKEN-MIT Center and Picower Institute at MIT; the laboratory of Michael S. Fanselow at the University of California at Los Angeles; and the laboratory of Chris J. McBain at the National Institute of Child Health and Human Development.
In the study, the authors tested mice in two types of memory processes. Pattern separation is the process by which the brain distinguishes differences between similar events, like remembering two Madeleine cookies with different tastes. In contrast, pattern completion is used to recall detailed content of memories based on limited clues, like recalling who one was with when remembering the taste of the Madeleine cookies.
Pattern separation forms distinct new memories based on differences between experiences; pattern completion retrieves memories by detecting similarities. Individuals with brain injury or trauma may be unable to recall people they see every day. Others with PTSD are unable to forget terrible events. "Impaired pattern separation due to the loss of young neurons may shift the balance in favor of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients," Tonegawa said.
Neuroscientists have long thought these two opposing and potentially competing processes occur in different neural circuits. The dentate gyrus, a structure with remarkable plasticity within the nervous system and its role in conditions from depression to epilepsy to traumatic brain injury - was thought to be engaged in pattern separation and the CA3 region in pattern completion. Instead, the MIT researchers found that dentate gyrus neurons may perform pattern separation or completion depending on the age of their cells.
The MIT researchers assessed pattern separation in mice who learned to distinguish between two similar but distinct chambers: one safe and the other associated with an unpleasant foot shock. To test their pattern completion abilities, the mice were given limited cues to escape a maze they had previously learned to negotiate. Normal mice were compared with mice lacking either young neurons or old neurons. The mice exhibited defects in pattern completion or separation depending on which set of neurons was removed.
"By studying mice genetically modified to block neuronal communication from old neurons -- or by wiping out their adult-born young neurons - we found that old neurons were dispensable for pattern separation, whereas young neurons were required for it," co-author Toshiaki Nakashiba said. "Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons."
They found that specific neurons in a brain region called the dentate gyrus serve distinct roles in memory formation depending on whether the neural stem cells that produced them were of old versus young age.
The study will appear in the March 30 issue of Cell and links the cellular basis of memory formation to the birth of new neurons - a finding that could unlock a new class of drug targets to treat memory disorders.
The findings also suggest that an imbalance between young and old neurons in the brain could disrupt normal memory formation during post-traumatic stress disorder (PTSD) and aging. "In animals, traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging," said the study's senior author Susumu Tonegawa, 1987 Nobel Laureate and Director of the RIKEN-MIT Center.
Other authors include Toshiaki Nakashiba and researchers from the RIKEN-MIT Center and Picower Institute at MIT; the laboratory of Michael S. Fanselow at the University of California at Los Angeles; and the laboratory of Chris J. McBain at the National Institute of Child Health and Human Development.
In the study, the authors tested mice in two types of memory processes. Pattern separation is the process by which the brain distinguishes differences between similar events, like remembering two Madeleine cookies with different tastes. In contrast, pattern completion is used to recall detailed content of memories based on limited clues, like recalling who one was with when remembering the taste of the Madeleine cookies.
Pattern separation forms distinct new memories based on differences between experiences; pattern completion retrieves memories by detecting similarities. Individuals with brain injury or trauma may be unable to recall people they see every day. Others with PTSD are unable to forget terrible events. "Impaired pattern separation due to the loss of young neurons may shift the balance in favor of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients," Tonegawa said.
Neuroscientists have long thought these two opposing and potentially competing processes occur in different neural circuits. The dentate gyrus, a structure with remarkable plasticity within the nervous system and its role in conditions from depression to epilepsy to traumatic brain injury - was thought to be engaged in pattern separation and the CA3 region in pattern completion. Instead, the MIT researchers found that dentate gyrus neurons may perform pattern separation or completion depending on the age of their cells.
The MIT researchers assessed pattern separation in mice who learned to distinguish between two similar but distinct chambers: one safe and the other associated with an unpleasant foot shock. To test their pattern completion abilities, the mice were given limited cues to escape a maze they had previously learned to negotiate. Normal mice were compared with mice lacking either young neurons or old neurons. The mice exhibited defects in pattern completion or separation depending on which set of neurons was removed.
"By studying mice genetically modified to block neuronal communication from old neurons -- or by wiping out their adult-born young neurons - we found that old neurons were dispensable for pattern separation, whereas young neurons were required for it," co-author Toshiaki Nakashiba said. "Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons."
The Number Of GP Visits Before Cancer Patients Are Referred To Specialists Examined By Study
More than three quarters (77%) of cancerpatients who first present to their family doctors (GPs) with suspicious symptoms are referred to hospital after only one or two consultations, a new study has found. However, the new research also shows a wide variation in the number of times a cancer patient sees their general practitioner before they are referred to a specialist, with the most pre-referral consultations occurring when the cancer was one of the less common types, or when the patient was either female, young, or an older person from an ethnic minority. The research was published 24 February, in the journalThe Lancet Oncology.
The study, led by researchers at the University of Cambridge, found that patients with breast,melanoma, testicular and endometrial cancers are more likely to be referred to a specialist after just one or two consultations. However, patients with some less common cancers such asmultiple myeloma, pancreatic, stomach and ovarian cancer, as well as patients with lung andcolon cancers and lymphomas are more likely to require three or more visits to their family doctor before they are referred to a hospital specialist. Patients with multiple myeloma, a blood cancer that is notoriously difficult to diagnose since it mimics many other conditions, are 18 times more likely to require three or more pre-referral consultations compared with patients withbreast cancer.
"These findings highlight limitations in current scientific knowledge about these cancers," said lead investigator Dr Georgios Lyratzopoulos, Clinical Senior Research Associate at the University of Cambridge. "Medical research in recent decades has prioritised improving cancer treatments, but knowledge about the 'symptom signature' of common cancers and practical solutions on how best to diagnose them is still emerging. Hopefully, our study will stimulate investment into research, focusing on patients with cancers and characteristics where the potential to improve the experience of diagnosis of cancer is greatest."
The researchers have also found that the diagnosis of cancer is more challenging among young patients, women, and older ethnic minority patients - all of these three groups are known to have a lower risk of developing cancer compared with older, male and white patients in the United Kingdom.
These findings amplify similar patterns first reported by co-author Dr Richard Neal, Senior Lecturer in General Practice at Bangor University, among cancer patients who took part in a similar survey that was carried out in 2000. Dr Neal said: "The fact that the diagnosis of cancer may be more challenging in some patient groups and for some cancers can help us to tailor diagnostic efforts. The findings will also inform the forthcoming update of the NICE Guidelines for Referral of Suspected Cancer, which will have an important impact on policy and practice."
The researchers proposed some explanations as to why some of the patient groups were less likely to receive a prompt referral:
"Whilst doctors may have concerns about the accuracy of patient-reported data, we have good reasons to believe the validity of our findings", said co-author Greg Rubin, Professor of General Practice and Primary Care at Durham University. "This is because they correlate well with data collected by general practitioners who took part in the independent National Audit of Diagnosis of Cancer in Primary Care. We hope further strides towards diagnosing cancer earlier will be made through the use of both patient experience and clinical audit data."
In order to improve the promptness of referrals, the study makes recommendations for both clinicians and policy makers. For clinicians, they highlight the need to be more aware of some of the patient groups and cancers which tended to be diagnosed less promptly and the need to participate in data collection to benchmark their practice. They also suggest that policy makers 'should explore and evaluate physician-level educational interventions, further development of point-of-care decisions aids, risk calculators and diagnostic tests, and system re-design to enable greater appropriate and timely use of specialist diagnostic tests (such as imaging or endoscopy)'.
Although the researchers are based in the UK, they believe their findings have implications for other countries as well, as they reflect the difficulties of diagnosis cancers with non-specific symptoms and signs more generally. Most patients subsequently diagnosed with cancer first see a doctor in the community regardless of where they live.
The study, led by researchers at the University of Cambridge, found that patients with breast,melanoma, testicular and endometrial cancers are more likely to be referred to a specialist after just one or two consultations. However, patients with some less common cancers such asmultiple myeloma, pancreatic, stomach and ovarian cancer, as well as patients with lung andcolon cancers and lymphomas are more likely to require three or more visits to their family doctor before they are referred to a hospital specialist. Patients with multiple myeloma, a blood cancer that is notoriously difficult to diagnose since it mimics many other conditions, are 18 times more likely to require three or more pre-referral consultations compared with patients withbreast cancer.
"These findings highlight limitations in current scientific knowledge about these cancers," said lead investigator Dr Georgios Lyratzopoulos, Clinical Senior Research Associate at the University of Cambridge. "Medical research in recent decades has prioritised improving cancer treatments, but knowledge about the 'symptom signature' of common cancers and practical solutions on how best to diagnose them is still emerging. Hopefully, our study will stimulate investment into research, focusing on patients with cancers and characteristics where the potential to improve the experience of diagnosis of cancer is greatest."
The researchers have also found that the diagnosis of cancer is more challenging among young patients, women, and older ethnic minority patients - all of these three groups are known to have a lower risk of developing cancer compared with older, male and white patients in the United Kingdom.
These findings amplify similar patterns first reported by co-author Dr Richard Neal, Senior Lecturer in General Practice at Bangor University, among cancer patients who took part in a similar survey that was carried out in 2000. Dr Neal said: "The fact that the diagnosis of cancer may be more challenging in some patient groups and for some cancers can help us to tailor diagnostic efforts. The findings will also inform the forthcoming update of the NICE Guidelines for Referral of Suspected Cancer, which will have an important impact on policy and practice."
The researchers proposed some explanations as to why some of the patient groups were less likely to receive a prompt referral:
- As differences in ethnic minorities were only apparent for older patients, they indicate that communication difficulties may be responsible.
- For bladder cancer, women were more than twice as likely as men to have required three or more consultations with their doctor before a decision to refer to hospital was made. In women, there may be difficulties in discriminating symptoms and signs of bladder cancer from those of benign gynaecological conditions or bladder infection.
- As young people have a lower rate of cancer, the researchers believe GPs are less likely to consider cancer as a possibility.
"Whilst doctors may have concerns about the accuracy of patient-reported data, we have good reasons to believe the validity of our findings", said co-author Greg Rubin, Professor of General Practice and Primary Care at Durham University. "This is because they correlate well with data collected by general practitioners who took part in the independent National Audit of Diagnosis of Cancer in Primary Care. We hope further strides towards diagnosing cancer earlier will be made through the use of both patient experience and clinical audit data."
In order to improve the promptness of referrals, the study makes recommendations for both clinicians and policy makers. For clinicians, they highlight the need to be more aware of some of the patient groups and cancers which tended to be diagnosed less promptly and the need to participate in data collection to benchmark their practice. They also suggest that policy makers 'should explore and evaluate physician-level educational interventions, further development of point-of-care decisions aids, risk calculators and diagnostic tests, and system re-design to enable greater appropriate and timely use of specialist diagnostic tests (such as imaging or endoscopy)'.
Although the researchers are based in the UK, they believe their findings have implications for other countries as well, as they reflect the difficulties of diagnosis cancers with non-specific symptoms and signs more generally. Most patients subsequently diagnosed with cancer first see a doctor in the community regardless of where they live.
Exploiting A Weakness In Cancer's Defense System
Researchers at the EPFL have identified an important mechanism that could lead to the design of more effective cancer vaccines. Their discovery of a new-found role of the lymphatic system in tumour growth shows how tumours evade detection by using a patient's own immune system.
Tumour cells present antigens or protein markers on their surfaces which make them identifiable to the host immune system. In the last decade, cancer vaccines have been designed that work by exposing the patient's immune cells to tumour-associated antigens and so priming them to kill cells that present those antigens. These have caused much excitement, not least because by acting so specifically on cancer cells, they could potentially eliminate the unpleasant side effects of chemo- and radiotherapy.
Like soldiers protecting a fort
However, clinical trials of such vaccines have had a very low success rate to date, mainly because tumours have various mechanisms for evading detection by immune cells, even when those immune cells - called T cells - have been primed to seek them out. Those mechanisms are, in general, poorly understood. But in a paper to be published this week in Cell Reports, the laboratories of Melody Swartz at EPFL and Stéphanie Hugues at UNIGE provide a key insight into one of them. They describe for the first time how, like soldiers protecting a fort, lymph vessels surrounding a tumour ward off T cell attack.
Plenty of research has shown that tumours can induce the growth of lymph vessels in their vicinity, and that this growth is correlated with metastasis and poor prognosis. It was assumed that these lymph vessels simply provided an escape route for cancer cells, transporting them to distant sites. In the new study, led by postdoc Amanda Lund, the researchers show that lymph vessels actually suppress the immune response, deleting the attacking T cells or leaving them "functionally exhausted" by the time they reach the tumour.
They studied a type of tumour that expresses large amounts of VEGF-C, a molecule that is naturally expressed in humans and that stimulates lymphatic growth. Having engineered the tumour cells to express a foreign antigen, they compared the efficacy of a vaccine designed to prime T cells to kill cells carrying that antigen, either when VEGF-C was present or when its activity was blocked . With VEGF-C suppressed, the vaccine's efficacy increased and tumour growth slowed fourfold.
A weakness in cancer's defense system exploited
The researchers went on to show that the endothelial cells which line lymph vessels "scavenge" tumour-specific antigens and present them to the tumour-specific T cells in a suppressive manner. This, in turn, promotes the local deletion of those T cells. According to Prof Swartz, that means that first targeting the lymph vessels associated with a tumour could, in theory, significantly increase the efficacy of existing cancer vaccines. "It would be like removing the soldiers from around the fort before sending in your opposing army," she says. "If you disable the lymph vessels' suppressive functions, our data suggest that tumour-killing T cells would do their job a lot more effectively." Future clinical trials are needed to put that theory to the test.
Tumour cells present antigens or protein markers on their surfaces which make them identifiable to the host immune system. In the last decade, cancer vaccines have been designed that work by exposing the patient's immune cells to tumour-associated antigens and so priming them to kill cells that present those antigens. These have caused much excitement, not least because by acting so specifically on cancer cells, they could potentially eliminate the unpleasant side effects of chemo- and radiotherapy.
Like soldiers protecting a fort
However, clinical trials of such vaccines have had a very low success rate to date, mainly because tumours have various mechanisms for evading detection by immune cells, even when those immune cells - called T cells - have been primed to seek them out. Those mechanisms are, in general, poorly understood. But in a paper to be published this week in Cell Reports, the laboratories of Melody Swartz at EPFL and Stéphanie Hugues at UNIGE provide a key insight into one of them. They describe for the first time how, like soldiers protecting a fort, lymph vessels surrounding a tumour ward off T cell attack.
Plenty of research has shown that tumours can induce the growth of lymph vessels in their vicinity, and that this growth is correlated with metastasis and poor prognosis. It was assumed that these lymph vessels simply provided an escape route for cancer cells, transporting them to distant sites. In the new study, led by postdoc Amanda Lund, the researchers show that lymph vessels actually suppress the immune response, deleting the attacking T cells or leaving them "functionally exhausted" by the time they reach the tumour.
They studied a type of tumour that expresses large amounts of VEGF-C, a molecule that is naturally expressed in humans and that stimulates lymphatic growth. Having engineered the tumour cells to express a foreign antigen, they compared the efficacy of a vaccine designed to prime T cells to kill cells carrying that antigen, either when VEGF-C was present or when its activity was blocked . With VEGF-C suppressed, the vaccine's efficacy increased and tumour growth slowed fourfold.
A weakness in cancer's defense system exploited
The researchers went on to show that the endothelial cells which line lymph vessels "scavenge" tumour-specific antigens and present them to the tumour-specific T cells in a suppressive manner. This, in turn, promotes the local deletion of those T cells. According to Prof Swartz, that means that first targeting the lymph vessels associated with a tumour could, in theory, significantly increase the efficacy of existing cancer vaccines. "It would be like removing the soldiers from around the fort before sending in your opposing army," she says. "If you disable the lymph vessels' suppressive functions, our data suggest that tumour-killing T cells would do their job a lot more effectively." Future clinical trials are needed to put that theory to the test.
Discovery Of Genetic Risk For Elevated Arsenic Toxicity
One of the first large-scale genomic studies conducted in a developing country has discovered genetic variants that elevate the risk for skin lesions in people chronically exposed to arsenic. Genetic changes found near the enzyme for metabolizing the chemical into a less toxic form can significantly increase an individual's risk for developing arsenic-related disease.
The discovery could point the way to new screening and intervention options for people who are exposed to groundwater with high levels of arsenic, said scientists at the University of Chicago Medicine, Columbia University, and in Bangladesh in a study published in PLoS Genetics.
"These results add clarity to the genetic architecture that is playing a role in arsenic toxicity and its underlying biology," said senior author Habibul Ahsan, MD, MMedSc, Louis Block Professor of health studies, medicine and human genetics at the University of Chicago Medicine. "It's a rare type of study for a major problem affecting millions of people around the world, and it opens up opportunities for genetic studies of other major public health problems in developing countries."
The group's genome-wide association study, or GWAS, was conducted in nearly 3,000 individuals exposed to arsenic for decades in Bangladesh. Since the widespread installation of hand-pumped wells to tap groundwater sources in the 1970s, as many as 77 million people - about half the population of Bangladesh - have been accidentally exposed to dangerous levels of arsenic. The World Health Organization calls the exposure "the largest mass poisoning of a population in history."
For more than a decade, Ahsan and colleagues have studied the epidemiology of arsenic-related disease, such as skin lesions, diabetes, and respiratory illnesses, in this population, as well as the effectiveness of interventions to prevent toxicity. In the new study, funded by the National Institute of Environmental Health Sciences and the National Cancer Institute, the researchers sought genetic answers for why some individuals appear to be at higher risk for developing disease after arsenic exposure.
"Whatever the source of exposure, different individuals vary with respect to their susceptibility to the toxicity of arsenic," Ahsan said. "Even if they consume or are exposed to arsenic at the same dose and duration, some individuals will manifest toxicity phenotypes and others won't."
Researchers genotyped thousands of arsenic-exposed individuals from the group's main studies for single nucleotide polymorphisms (SNPs) throughout the genome, and looked for associations with arsenic metabolite levels and risk of skin lesions.
After ingestion, the body metabolizes inorganic arsenic into first monomethylarsonic acid (MMA) and then dimethylarsinic acid (DMA). MMA is considered to be more toxic, while DMA is water-soluble and more easily excreted. Higher levels of DMA or lower levels of MMA measured from an individual's urine are associated with lower toxicity.
A research team led by Ahsan and Brandon Pierce, PhD, an assistant professor of epidemiology at the University of Chicago Medicine, then used GWAS to search for SNPs associated with DMA and MMA levels. They found several significant genetic variants in the region of a likely candidate gene: arsenite methyltransferase (As3MT), an enzyme critical for arsenic metabolism. A second GWAS looking for SNPs associated with the development of skin lesions after arsenic exposure, pointed to many of the same variants. In a further study of gene expression levels, those same SNPs were associated with reduced expression of the arsenic metabolizing enzyme.
"This makes perfect sense," Ahsan said. "It gives us a very coherent story that we can now investigate in relation to other arsenic pathologies and in relation to a wide range of arsenic doses in this population."
"Now that we understand the molecular basis of some of this disease risk, it is conceivable to now think of incorporating this information into testing, evaluating, or potentially coming up with successful biomedical interventions," Ahsan continued. "By exploiting these metabolic pathways for a subgroup of individuals who will really be at higher risk for getting those diseases, we may be able to reduce fatal outcomes in this population."
The genetic findings provide strong evidence that efficient metabolism of arsenic through methylation protects against the toxin. Compounds that boost methylation, such as folic acid, could reduce arsenic toxicity - a strategy currently being tested by co-author Mary Gamble, PhD, associate professor of Environmental Health Sciences at Columbia University.
"If we could somehow find a way to do that in Bangladesh, it would make individuals much better methylators of arsenic, and as this current study shows if you're a better methylator you're at a lower risk for disease," said co-author Joseph Graziano, PhD, Professor of Environmental Health Sciences and Director of Superfund Research Program at the Mailman School of Public Health of Columbia University.
Risk variants may also help assess the potential toxicity of cancer chemotherapies which use arsenic or related compounds. SNPs associated with elevated sensitivity to arsenic toxicity could steer oncologists toward lower doses or alternative treatments in certain cancer patients, Ahsan said.
Beyond the clinical applications, the current study demonstrates that large-scale genomic studies are possible in a largely rural population of a developing country. The study offers a rare example of a GWAS result with clear, immediate potential for translational impact.
"Many genomic signals that we see are not robust enough or do not pertain to a large population," Ahsan said. "But in this study, that is not the case. The finding is robust, and the impact is massive."
The discovery could point the way to new screening and intervention options for people who are exposed to groundwater with high levels of arsenic, said scientists at the University of Chicago Medicine, Columbia University, and in Bangladesh in a study published in PLoS Genetics.
"These results add clarity to the genetic architecture that is playing a role in arsenic toxicity and its underlying biology," said senior author Habibul Ahsan, MD, MMedSc, Louis Block Professor of health studies, medicine and human genetics at the University of Chicago Medicine. "It's a rare type of study for a major problem affecting millions of people around the world, and it opens up opportunities for genetic studies of other major public health problems in developing countries."
The group's genome-wide association study, or GWAS, was conducted in nearly 3,000 individuals exposed to arsenic for decades in Bangladesh. Since the widespread installation of hand-pumped wells to tap groundwater sources in the 1970s, as many as 77 million people - about half the population of Bangladesh - have been accidentally exposed to dangerous levels of arsenic. The World Health Organization calls the exposure "the largest mass poisoning of a population in history."
For more than a decade, Ahsan and colleagues have studied the epidemiology of arsenic-related disease, such as skin lesions, diabetes, and respiratory illnesses, in this population, as well as the effectiveness of interventions to prevent toxicity. In the new study, funded by the National Institute of Environmental Health Sciences and the National Cancer Institute, the researchers sought genetic answers for why some individuals appear to be at higher risk for developing disease after arsenic exposure.
"Whatever the source of exposure, different individuals vary with respect to their susceptibility to the toxicity of arsenic," Ahsan said. "Even if they consume or are exposed to arsenic at the same dose and duration, some individuals will manifest toxicity phenotypes and others won't."
Researchers genotyped thousands of arsenic-exposed individuals from the group's main studies for single nucleotide polymorphisms (SNPs) throughout the genome, and looked for associations with arsenic metabolite levels and risk of skin lesions.
After ingestion, the body metabolizes inorganic arsenic into first monomethylarsonic acid (MMA) and then dimethylarsinic acid (DMA). MMA is considered to be more toxic, while DMA is water-soluble and more easily excreted. Higher levels of DMA or lower levels of MMA measured from an individual's urine are associated with lower toxicity.
A research team led by Ahsan and Brandon Pierce, PhD, an assistant professor of epidemiology at the University of Chicago Medicine, then used GWAS to search for SNPs associated with DMA and MMA levels. They found several significant genetic variants in the region of a likely candidate gene: arsenite methyltransferase (As3MT), an enzyme critical for arsenic metabolism. A second GWAS looking for SNPs associated with the development of skin lesions after arsenic exposure, pointed to many of the same variants. In a further study of gene expression levels, those same SNPs were associated with reduced expression of the arsenic metabolizing enzyme.
"This makes perfect sense," Ahsan said. "It gives us a very coherent story that we can now investigate in relation to other arsenic pathologies and in relation to a wide range of arsenic doses in this population."
"Now that we understand the molecular basis of some of this disease risk, it is conceivable to now think of incorporating this information into testing, evaluating, or potentially coming up with successful biomedical interventions," Ahsan continued. "By exploiting these metabolic pathways for a subgroup of individuals who will really be at higher risk for getting those diseases, we may be able to reduce fatal outcomes in this population."
The genetic findings provide strong evidence that efficient metabolism of arsenic through methylation protects against the toxin. Compounds that boost methylation, such as folic acid, could reduce arsenic toxicity - a strategy currently being tested by co-author Mary Gamble, PhD, associate professor of Environmental Health Sciences at Columbia University.
"If we could somehow find a way to do that in Bangladesh, it would make individuals much better methylators of arsenic, and as this current study shows if you're a better methylator you're at a lower risk for disease," said co-author Joseph Graziano, PhD, Professor of Environmental Health Sciences and Director of Superfund Research Program at the Mailman School of Public Health of Columbia University.
Risk variants may also help assess the potential toxicity of cancer chemotherapies which use arsenic or related compounds. SNPs associated with elevated sensitivity to arsenic toxicity could steer oncologists toward lower doses or alternative treatments in certain cancer patients, Ahsan said.
Beyond the clinical applications, the current study demonstrates that large-scale genomic studies are possible in a largely rural population of a developing country. The study offers a rare example of a GWAS result with clear, immediate potential for translational impact.
"Many genomic signals that we see are not robust enough or do not pertain to a large population," Ahsan said. "But in this study, that is not the case. The finding is robust, and the impact is massive."
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