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  • richardmitnick 8:13 pm on June 21, 2017 Permalink | Reply
    Tags: Aging-related mutations in blood cells represent major new risk factor for cardiovascular disease, , Broad Institute,   

    From Broad: “Aging-related mutations in blood cells represent major new risk factor for cardiovascular disease” 

    Broad Institute

    Broad Institute

    06.21.17
    No writer credit

    New work points to inflammation as key player in heart disease; suggests future potential for screening to reduce risk.

    1
    Credit : Susanna M. Hamilton, Broad Communications

    Scientists at the Broad Institute of MIT and Harvard have found that a set of genetic mutations in blood cells that arises during aging may be a major new risk factor for cardiovascular disease. In contrast to inherited genetic predispositions and traditional lifestyle risk factors, such as smoking or an unhealthy diet, the new mutations are “somatic mutations” that originate in stem cells in the bone marrow as people age.

    Because the mutations are relatively common in older people (over 10% of people over the age of 70 harbor at least one of these mutations), potential future efforts to screen for the mutations in blood cells, identify people at increased risk for coronary heart disease, and reduce risk in those individuals through lifestyle changes or therapeutic interventions could have a significant clinical impact, according to the researchers.

    “There is more work to be done, but these results demonstrate that pre-malignant mutations in blood cells are a major cause of cardiovascular disease that in the future may be treatable either with standard therapies or new therapeutic strategies based on these findings,” said Benjamin Ebert, a co-senior author of the new study, an institute member at the Broad, a professor of medicine at Harvard Medical School, and a hematologist at Brigham and Women’s Hospital.

    Featured in New England Journal of Medicine, the work also contributes to the broader understanding of pathogenesis in coronary heart disease by supporting the hypothesis that inflammation, in addition to elevated cholesterol levels, plays an important role in this illness and potentially other diseases of aging.

    “A key finding from this study is that somatic mutations are actually modulating risk for a common disease, something we haven’t seen other than in cancer,” said first author Siddhartha Jaiswal, a pathologist at Massachusetts General Hospital and researcher in the Ebert lab. “It opens up interesting questions about other diseases of aging in which acquired mutations, in addition to lifestyle and inherited factors, could modulate disease risk.”

    Previous research led by Ebert and Jaiswal revealed that some somatic mutations that are able to confer a selective advantage to blood stem cells become much more frequent with aging. They named this condition “clonal hematopoiesis of indeterminate potential,” (CHIP), and found that it increases the risk of developing a blood cancer more than 10-fold and it appeared to increase mortality from heart attacks or stroke. In the new study, the researchers analyzed data from four case-control studies on more than 8,000 people and found that having one of the CHIP-related mutations nearly doubled the risk for coronary heart disease, with the mutations conferring an even greater risk in people who have previously had a heart attack before age 50.

    While the human genetics data showed a strong association between CHIP and coronary heart disease, the team hoped to uncover the underlying biology. Using a mouse model prone to developing atherosclerosis, the scientists showed that loss of one of the CHIP-mutated genes, Tet2, in bone marrow cells leads to larger atherosclerotic plaques in blood vessels, evidence that this mutation can accelerate atherosclerosis in mice.

    Atherosclerosis is believed to be a disease of chronic inflammation that can arise in response to excess cholesterol in the vessel wall. To examine this on a cellular level the team turned to the macrophage, an immune cell found in atherosclerotic plaques that can develop from CHIP stem cells and carry the same mutations. Because Tet2 and other CHIP-related mutations are known to be so-called “epigenetic regulators” that can alter the activity of other genes, the team examined gene expression levels in the Tet2-mutated macrophages from mice. They found that the mutated cells appear to be “hyper-inflammatory” with increased expression of inflammatory molecules that contribute to atherosclerosis. In support of this finding, humans with TET2 mutations also had higher levels of one of these molecules, IL-8, in their blood.

    The work demonstrates that CHIP associates with coronary heart disease in humans, that mutation of the CHIP-related gene Tet2 causes atherosclerosis in mice, and that an inflammatory mechanism likely underlies the process. More work is needed to show whether other genes that are mutated in CHIP also lead to increased inflammation. The team is also exploring whether interventions such as cholesterol lowering therapy or anti-inflammatory drugs might have benefit in people with CHIP.

    Inflammation is also thought to modulate several other diseases of aging besides cardiovascular disease, such as autoimmune disorders and neurodegenerative disease. Because CHIP also increases in frequency with age, somatic mutations that alter inflammatory processes could influence several diseases of aging, though more work is needed to test this possibility.

    “By combining genetic analysis on large cohorts with disease model and gene expression studies, we’ve been able to confirm the earlier hints of CHIP’s surprising role in cardiovascular disease,” said co-senior author Sekar Kathiresan, director of the Broad’s Cardiovascular Disease Initiative, associate professor of medicine at Harvard Medical School, and director of the Center for Genomic Medicine at Massachusetts General Hospital. “Beyond the mutations that you inherit from your parents, this work reveals a new genetic mechanism for atherosclerosis — mutations in blood stem cells that arise with aging.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

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    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

    Harvard University

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  • richardmitnick 2:11 pm on May 14, 2017 Permalink | Reply
    Tags: , Broad Institute, , Medscape, , , WCG Outsmart Ebola Together   

    From Medscape via Broad: Women in Stem- “Outbreaks, Evolution, and Rock ‘n’ Roll: Topol Talks to Pardis Sabeti” 

    Broad Institute

    Broad Institute

    1

    Medscape

    May 10, 2017
    Eric J. Topol, MD

    3
    Pardis Sabeti

    Eric J. Topol, MD: Hello. I am Eric Topol, editor-in-chief of Medscape. I have the special privilege of having a conversation with Pardis Sabeti. She is an extraordinary scientist and physician at the Broad Institute at Harvard Medical School and MIT. We are going to talk about the arc of her life and career, beginning when she moved here at age 2 from Tehran.

    Pardis Sabeti, MD, DPhil: Yes. We came to the United States around the time of the Iranian revolution and had refugee status here. Then we moved to Hawaii, New Jersey, Georgia, and Florida, and we settled in Florida.

    Dr Topol: At one point you were not sure whether you were going to own a flower shop, be a novelist, or become a doctor. Is that right?

    Dr Sabeti: That was when I was about 6 years old. I liked flowers a lot, so I thought, “This seems like the life.” As a kid, I liked to write. As an immigrant and as a child of revolution, my dad amused himself by saying, “You can be anything you want to be in the world: a lawyer or a doctor.” My sister became a lawyer and I became a doctor, but neither of us practice.

    Dr Topol: Music has been a big part of your life. When did that become rooted?

    Dr Sabeti: That was not until graduate school. I have liked music my whole life and played a little piano as a kid. I went to concerts all the time. That was how I enjoyed spending my time. When I was in grad school, I had two American friends and we were in England together. They would play “fantasy band” all the time and make up band names and that kind of stuff. One night I said, “Why do you keep fantasy-banding? Why not just start a band?” They said they at least had to have a rhythm section, so the next day I bought a bass and that started my journey.

    Dr Topol: These days, you are a lead singer and writer for a rock band. How often do you get involved with that?

    Dr Sabeti: It wanes and waxes. It’s not very conducive to faculty life. I dropped it for a while and then I had an accident and picked it up again. Music is great, because every once in a while your soul just wants to speak and you have an opportunity to do it. It’s pretty sporadic, but I have been writing some music recently.

    Dr Topol: Somehow or other, you landed at MIT.

    Dr Sabeti: In the 6th grade, the idea of going to MIT got sparked. My math teacher showed us a 270 competition: The MIT mechanical engineering department has a contest in which everyone builds robots that compete against each other. I saw that video as a kid and thought, “I need to be there.” I was locked onto MIT as my dream school since then.

    Dr Topol: You also became a Rhodes Scholar and went to Oxford.

    Dr Sabeti: It was a bizarre experience right after college to be in this wonderland that was Oxford, and a lot of existential crises happened right after college. It was a very informative and great experience.

    Dr Topol: Were you already starting to get into the whole selection, mutation, and evolutionary biology by then?

    Dr Sabeti: No. I think that is what made that happen. I had gone to MIT and I loved all the engineering, but I still thought that I was supposed to be a doctor. I had intended to go to medical school, but I got this scholarship on a lark. I was planning to go to medical school when I came back. Along the way, somehow, I ended up getting a PhD. It was an interesting experience there. They had a shorter PhD track. That was when I started doing that work, and it changed the direction of my life.

    In the Middle of an Outbreak

    Dr Topol: And then you went to medical school—a big commitment. When you started your career, did you know that you were going to be leading the charge to do genomic epidemiology of Ebola and Zika?

    Dr Sabeti: Definitely not. Because I never intended to be a scientist, I didn’t have a very specific path for what I wanted to do. I feel like I am on a scavenger hunt; I don’t know exactly where it’s going, but this path has captured my attention for some time.

    Dr Topol: This is quite a hunt. Just what you did with Ebola—you were named a Time “Person of the Year” in 2014 and one of the 100 most influential people in the world. You went to West Africa with folks in your lab, and many other people you work with, to try to get the knowledge that was needed to titrate the horrendous Ebola epidemic. Can you tell us about that?

    Dr Sabeti: Sure. For one thing, I am just a bit player. At the end of the day, the Ebola fighters were recognized for the work that we all did collectively. I was privileged to be one of the people who were named as an example, but it was a collective effort. To us, the seemingly small part that we played was that we naturally come from the genomics world—I cut my teeth on the Human Genome Project—where sharing data and an open feeling about science was just a given.

    This is an outbreak that we found ourselves in the middle of because it came to the site where we were working in Africa. As we were trying to do what we could to help our collaborators and partners there, and to get attention, we started publishing science on this. We started releasing our data to the lab. What was interesting is that we decided we didn’t care about getting recognition; we just wanted to get the data out to the world. Paradoxically, that is what got us attention. It was apparently unusual to share data openly as soon as you generated it. It became a call to the community.

    Dr Topol: You were putting your lives on the line to do this work. What was that like?

    Dr Sabeti: To be honest, as a scientist, that is the risk you take. We were working on Lassa fever for some time. I have been quarantined before. We take risks, but they are very measured, calculated risks. Fundamentally, in all cases, it was the clinicians who became infected. We saw that across the board in the outbreak. As the researchers, we work in a very contained environment and we can isolate things very well. We are really in the service of the clinicians. We take risks, but for us, there was more risk of being in a car crash than being infected with Ebola. We were honored to be there to support them.

    Dr Topol: More recently, you have been involved with the Zika virus story. Where do we stand with that?

    Dr Sabeti: Zika is different. Ebola was a rapidly escalating outbreak. It was one of those viruses that can transmit from human to human with very acute infections and a very high fatality rate. It was a frightening event. Zika is less fatal. It does not transmit as easily. It usually involves mosquitoes. But it is a more challenging virus to battle; it’s more widespread, and mosquitoes are hard to manage. The virus hides itself a little at low concentrations in the blood for short periods of time, so the diagnosis is challenging. But it becomes really important because of the effects it can have on pregnancy and on children born to mothers who have Zika. Zika causes a visceral reaction in all of us because it affects a vulnerable population that we all care about.

    Please Play With Our Data

    Dr Topol: In 2015 you gave a TED Talk on how we are going to deal with the next deadly virus. Can you summarize what you talked about at the time?

    Dr Sabeti: That was in the middle of the Ebola outbreak. I had been asked to give a talk at TEDWomen. I just discussed what was on my mind at the time. I had not really thought out exactly what the message would be, and I did not know, necessarily, that it would be posted online. In fact, I sang during my talk. It was good in the room, but they wanted to cut it out and make it the right length [for TED Talks online]. I just had fun with it. The message was about outbreaks and how frightening they are. But it’s a war that we can win—but that we win by collaboration. It is very different from other types of threats to humanity. That was what I felt—the power of human capacity and love to overcome these kinds of challenges.

    See the full article here .

    You can Help Stamp Out EBOLA.

    This WCG project runs at Scripps Institute

    Scripps

    Outsmart Ebola Together

    Visit World Community Grid (WCG). Download and install the BOINC software on which it runs. Attach to the Outsmart Ebola Together project. This will allow WCG to use your computer’s free CPU cycles to process computational data for the project.

    While you are at WCG and BOINC, check out the other very worthwhile projects running on this software. All project results are “open source”, free for the use of scientists world while to advance health and other issues of mankind.

    YOU CAN HELP FIND A CURE FOR THE ZIKA VIRUS.

    There is a new project at World Community Grid [WCG] called OpenZika.
    Zika
    Zika depiction. Image copyright John Liebler, http://www.ArtoftheCell.com
    Rutgers Open Zika

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the OpenZika project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

    This project is directed by Dr. Alexander Perryman a senior researcher in the Freundlich lab, with extensive training in developing and applying computational methods in drug discovery and in the biochemical mechanisms of multi-drug-resistance in infectious diseases.

    1
    Dr. Alex Perryman, Rutgers New Jersey Medical School

    He is a member of the Center for Emerging & Re-emerging Pathogens, in the Department of Pharmacology, Physiology, and Neuroscience, at the Rutgers University, New Jersey Medical School. Previously, he was a Research Associate in Prof. Arthur J. Olson’s lab at The Scripps Research Institute (TSRI), where he ran the day-to-day operations of the FightAIDS@Home project, the largest computational drug discovery project devoted to HIV/AIDS, which also runs on WCG. While in the Olson lab, he also designed, led, and ran the largest computational drug discovery project ever performed against malaria, the GO Fight Against Malaria project, also on WCG.

    Rutgers smaller

    boincstatsimage-new

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

    Harvard University

    MIT Widget

     
  • richardmitnick 9:37 pm on September 12, 2016 Permalink | Reply
    Tags: , Broad Institute, , T Cells with problems   

    From Broad: “Unraveling tangled transcriptional webs reveals a dysfunction program in T cells” 

    Broad Institute

    Broad Institute

    September 12th, 2016
    Tom Ulrich

    1
    No image caption. No image credit.

    The immune system’s T cells stand as one of the body’s main lines of defense against infection and cancer. But when confronted with an established tumor or a chronic viral infection — situations where they receive many signals for a long time to get out there and do something — T cells often do an odd thing. They just…stop.

    These T cells exist in a unique state of dysfunction. They are neither anergic (unresponsive to all signals to attack) nor senescent (old and quiescent). Rather, they are stuck, unable to turn against the tumor or invading virus and wipe it out on their own. Their brakes are on.

    “These cells look like normal activated T cells in many respects, but they don’t make anything that helps promote the immune response,” said Chao Wang, a postdoctoral fellow working with Broad associate members and Brigham and Women’s Hospital researchers Vijay Kuchroo and Ana Anderson. “They may actually hinder the response by producing suppressive factors.”

    If the brakes could be turned off, however, these cells could be wielded as powerful therapeutic tools. The successful use of checkpoint inhibitors — drugs that interfere with T cell-regulating proteins such as PD-1 and CTLA-4 on dysfunctional T cells — to treat some cancers highlights this approach’s immense promise.

    But not every patient or every tumor responds to these immunotherapy treatments, suggesting that additional circuits play roles in T cell dysfunction.

    “The fact that checkpoint blockade works means that you can boost T cell function without pushing the cells into dangerous overactivity,” said Meromit Singer, a postdoctoral fellow working with Kuchroo and Broad core member and Klarman Cell Observatory director Aviv Regev. “By understanding the profile and the mechanisms underlying this dysfunctional state, we might be able to tweak the cells in a way that allows them to act in our favor.”

    However, when others have looked for gene expression profiles that might tell dysfunctional and healthy, activated T cells apart, they found the profiles to be very similar. It is as though the two states — activation and dysfunction — were coupled.

    Whether they are lies at the heart of a study Singer, Wang, Anderson, Kuchroo, Regev, and colleagues published recently in Cell. Using a mix of bulk and single cell transcriptomics and functional genomics, the group unwound the transcriptional threads of T cell activation and dysfunction in the context of cancer. Their findings not only revealed a distinct dysfunction gene expression program, but identified two of its major drivers, opening a new landscape of potential therapeutic targets that might be used to rouse dysfunctional T cells and get them back in the ring.

    A signature revealed

    The research team started out by comparing gene expression in three T cell populations from a mouse cancer model: 1) severely dysfunctional cells displaying two immune system checkpoint receptors, Tim-3 and PD-1; 2) semi-functional cells carrying PD-1 alone; and 3) fully functional cells with neither marker.

    Two genes in particular jumped out in the expression data: metallothionein 1 (MT1), a zinc metabolism gene, and its relative MT2. When the team disabled (or “knocked out”) both in a mouse model, it slowed tumor growth but also had a surprising effect on the T cells themselves: The three marker-based cell populations remained, but all three behaved like normal, healthy T cells, even those carrying both dysfunction markers.

    This gave the researchers an opening. “This was a beautiful result, because it meant we could compare cells that were generally similar but functionally different,” Singer said. “Genes expressed differently between the normal and MT knockout cells might direct the dysfunction phenotype.”

    And indeed, when the team compared expression profiles across the three cell populations in both normal and MT knockout cells, several genes — many known to be T cell regulators — clustered into a distinct dysfunction-associated signature.

    Unmixing the smoothie

    To this point, the team had used bulk batches of T cells as their source material, raising one key question: Was the signature real? “Maybe there was a coupling between activation and dysfunction,” Singer said, “but maybe the issue was that we were looking at a smoothie, that we’d been mushing healthy and dysfunctional subpopulations together like you’d mix a mango and a banana.”

    Reassuringly, however, the team found the same dysfunction signature both in individual T cells analyzed at the single cell level and, importantly, in data from a study of human melanoma patients’ T cells.

    “We found two subpopulations in our single cell data,” Singer said, “one expressing a dysfunction program and the other an activation program. It’s as though individual cells are deciding which program they’re going to express.”

    Why might this be? “It may be that all T cells go through the activation stage in the tumor environment, where they’re under chronic stimulation,” Wang mused. “And something about the activation program allows the cell to turn on the dysfunction program.

    “There are self-regulatory programs that in acute stimulation settings trigger cell death when a T cell’s job is done,” she continued. “We might be seeing an analogous autoregulatory response related to chronic stimulation.”

    Finding a driver

    Key to almost any gene expression program are the transcription factors important for driving its execution. When the team sifted through their data, the factor GATA3 stood out as a possible top driver of their dysfunction program.

    To test the possibility that GATA3 was an important driver, the team, with Regev lab postdoctoral fellow Le Cong, used CRISPR-Cas9 gene editing to knock the GATA3 gene out in freshly collected T cells and injected the modified cells into a mouse melanoma model. The result: reduced tumor growth, and markedly improved T cell function.

    “It means that when these tumor-invading T cells lack GATA3, they stay active and well,” Singer said.

    Opportunity knocking?

    The team’s results suggest new questions about how these T cell populations evolve from functional to dysfunctional over time, something that time-course experiments could reveal.

    Then there is the curious role of zinc. GATA3 is a zinc-finger transcription factor; it needs zinc to do its job. The MT genes encode proteins that help process zinc. And the dysfunctional T cells in the team’s models had markedly increased levels of free zinc in the cytoplasm, while MT knockout T cells contained roughly normal zinc levels.

    “A third of our genome depends on zinc for proper function,” Wang noted. “When and where you have zinc in the cell really matters. The fact that the MT genes showed up prominently in our data suggests zinc dysregulation at the cellular level.”

    The data also highlight opportunities for developing new immunotherapy treatments and prognostic tools.

    “Now that we’ve homed in on GATA3, we can start to study its network in a focused way and look for potentially druggable targets,” Wang said. Singer agreed, adding, “We’re also interested in finding out whether screening for these populations clinically might help predict how a given patient’s tumor might respond to immunotherapy.”

    “This study gives us a level of resolution into the T cell states present within tumors that we’ve never had before,” Anderson said. “Now that we better understand what’s going on in these cells and how it relates to dysfunction, we have a better sense of where to focus our search for new diagnostic and therapeutic targets.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

    Harvard University

    MIT Widget

     
  • richardmitnick 6:56 am on August 23, 2016 Permalink | Reply
    Tags: , Broad Institute, , Largest collection of human exome sequence   

    From Broad: “Largest collection of human exome sequence data yields unprecedented tool for diagnosing rare disease” 

    Broad Institute

    Broad Institute

    August 17th, 2016
    Paul Goldsmith
    617-714-8600
    paulg@broadinstitute.org

    Deep genetic catalog powers studies of disease and DNA variation

    Based on the largest resource of its kind, members of the Exome Aggregation Consortium (ExAC) led by scientists at the Broad Institute of MIT and Harvard report scientific findings from data on the exome sequences (protein-coding portions of the genome) from 60,706 people from diverse ethnic backgrounds. Containing over 10 million DNA variants – many very rare and most identified for the first time – the ExAC dataset is a freely available, high-resolution catalog of human genetic variation that has already made a major impact on clinical research and diagnosis of rare genetic diseases.

    Featured in the August 18 issue of Nature, analysis of the data reveals properties of genetic variation undetectable in smaller data sets, for example, the first direct observation of mutations that arose multiple times independently among the samples – so-called “mutational recurrence.” The work also uncovers a class of genes that harbor less variation than expected, representing likely disease-causing DNA variants that are rare or absent in the population because they are so detrimental to human health. With immediate utility for clinical applications, the study further shows that the ExAC database improves the ability to evaluate candidate pathogenic variants in rare disease.

    “The success of ExAC was made possible by the willingness of our colleagues in many large, disease-focused consortia to openly share sequencing data,” said Daniel MacArthur, senior author of the study, co-director of the Program in Medical and Population Genetics at the Broad Institute, and an assistant professor at Massachusetts General Hospital and Harvard Medical School. Previous resources contained far fewer exomes without much ancestral diversity, so they were inadequate for studies of rare disease variants. “The scale and diversity of the ExAC resource is invaluable,” MacArthur added. “It gives us the ability to discover extremely rare variants and offers an unparalleled window into the roots of rare genetic diseases.”

    After collecting the raw data from tens of thousands of human exomes from research collaborators around the globe, the consortium relied upon the analytical and computational capabilities of the Broad Institute’s Genomics Platform and Data Sciences and Data Engineering group to produce a catalog of human genetic variation of unprecedented resolution – roughly one variant every eight bases, or letters, of DNA. Many of these variants had never been reported and most are very rare, occurring in less than 1 in 10,000 people.

    With a patient’s genome sequence in hand, a clinician can compare any rare mutations found in his or her genome with those in the ExAC database, shedding light on the genes and proteins that may underlie a patient’s disorder. A variant found in a patient’s DNA sequence that is extremely rare in ExAC, especially one that is predicted to disrupt the function of the resulting protein, then becomes a key suspect in causing the rare disease. Since its release to the scientific community in October 2014 the ExAC resource has had more than five million page views online, and has allowed clinicians to provide more accurate genetic diagnoses for thousands of rare disease patients.

    “The ExAC resource gives us incredible insight when evaluating a patient’s genome sequence in the clinic,” said Heidi Rehm, medical director of the Broad’s Clinical Research Sequencing Platform and chief laboratory director of the Laboratory for Molecular Medicine at Partners Personalized Medicine. In clinical sequencing, many DNA variants are rare or understudied, so it is unclear if they have any effect on disease risk and whether they should be taken into consideration when diagnosing and treating patients. By looking at the frequencies of a patient’s variants in the ExAC database, Rehm and her team can rule out those that are relatively common, allowing them to more quickly home in on the true disease-causing variants and avoid costly follow-up on benign ones.

    The resource has also been used by researchers to identify dozens of new rare genetic disorders. “In our own research, using the ExAC resource has allowed us to apply novel statistical methods to identify several new severe developmental disorders,” said Matthew Hurles, a researcher at the Wellcome Trust Sanger Institute and frequent user of the ExAC database. “Resources such as ExAC exemplify the benefits that can be achieved for families coping with rare genetic diseases, as a result of the mass altruism of many research participants who allow their data to be aggregated and shared.”

    The ExAC database is also being used by researchers exploring the more fundamental effects of genetic variation, for example, looking at variation in transcription factor proteins and its impact on protein-protein interaction networks.

    Interestingly, variation that was expected, but not found, in the data offered new insight. Some genes were found to have less than the expected number of missense mutations, which change the protein sequence, or “loss-of-function” mutations, which obliterate protein function. With such a large sample size, the researchers were able to quantify the deficit of these types of mutation per gene, identifying a few thousand “highly constrained” genes for which natural selection has weeded out these mutations because their effects are so detrimental. With no knowledge about the diseases they cause and often no actual instances of these mutations in the ExAC database, the “missing variation” indicates that these highly constrained genes are likely to cause severe disease. If clinical or research sequencing reveals a loss-of-function or missense mutation in one of these genes in a patient’s genome, it becomes a strong candidate for causing his or her rare disease.

    The ExAC data also revealed more than 100 previously reported disease-causing mutations to actually be benign, reducing the number of these false positive findings in databases widely used by clinical labs. This finding demonstrates the value of the ExAC database in assessing claims that specific mutations cause disease.

    “With its large sample size and high resolution across many populations, the ExAC database provides much greater power to interpret rare disease-causing variants than ever before, even for common diseases,” said Jose Florez, an institute member at the Broad, chief of the Diabetes Unit at the Massachusetts General Hospital, and an associate professor at Harvard Medical School.

    About the Exome Aggregation Consortium

    The ExAC project was funded by institutional support from the Broad Institute of MIT and Harvard, along with grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of General Medical Sciences (NIGMS). A complete list of the scientific groups that have contributed to the ExAC database is available at http://exac.broadinstitute.org/about.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

    Harvard University

    MIT Widget

     
  • richardmitnick 1:55 pm on August 9, 2016 Permalink | Reply
    Tags: , Better off without it, Broad Institute, , Ulcerative colitis   

    From Broad- “Better off without it: Broken gene may help protect against ulcerative colitis” 

    Broad Institute

    Broad Institute

    August 9th, 2016
    Veronica Meade-Kelly

    1
    Researchers have uncovered a protective genetic mutation that is specific to ulcerative colitis. Image by Lauren Solomon, Broad Communications.

    We often think of the body as a machine, with every part—right down to each single gene—working with optimal efficiency to keep us healthy and disease-free. Take a single bolt out of that machine and something could go wrong—a part ceases to move at the proper speed perhaps, or worse, an entire system fails.

    But what if you removed that hypothetical bolt and the “machine” actually worked better? What if missing that one part, for instance, helped the body burn fuel more efficiently, or prevented a glitch that would otherwise cause the machine to fall into disrepair? Were that the case, then perhaps studying that part and its function within the larger machine might reveal more about how the machine works—or might even suggest ways to fix things if the machine broke down.

    Scientists have found that something akin to that in human genetics, where research has uncovered a handful of so-called “loss-of-function” (LoF) mutations that appear to help protect individuals from certain diseases. These mutations are slight variations in an individual’s genetic code that essentially “break” a gene, causing the gene to produce an incomplete (or “truncated”) protein that doesn’t function in the body the way it normally would.

    In 2006, scientists found that such LoF mutations in the gene PCSK9, which produces a protein involved in cholesterol regulation, were associated with lower LDL cholesterol and a lower risk of heart attack. Subsequently, an LoF mutation in the gene CARD9 was found to confer protection against ulcerative colitis (UC) and Crohn’s disease, two debilitating inflammatory bowel diseases (IBDs). Such findings are promising because they point to a specific part of the genome that may be involved in inhibiting disease, suggesting potential therapeutic targets.

    “The hypothesis is that if you inhibit that gene, you will mimic the effect of the mutation, which is to protect the individual from disease. This makes these loss-of-function mutations an attractive lead for drug developers,” explains Manuel Rivas, a computational scientist in the Broad Institute’s Medical and Population Genetics (MPG) Program.

    Rivas and others are now conducting searches for other LoF mutations and, this week in Nature Communications, Rivas was first author of a paper that announced the discovery of such a protective mutation specific to UC, a chronic disease of the large intestine that affects roughly 700,000 people in the U.S. alone.

    To track down the mutation, Rivas and colleagues, including senior author Mark Daly, who is co-director of Broad’s MPG Program, sequenced genes in regions of the genome that had been previously linked to IBD. Samples that they sequenced came from over 3,000 individuals—some with UC or Crohn’s disease, and others who were healthy controls. The team looked at the sequencing data for evidence of mutations that resulted in “broken” genes that did not produce functional proteins. The search produced a short list of LoF mutations that they then studied more closely, comparing the prevalence of these mutations in IBD sufferers versus healthy individuals.

    “The assumption is that if you see many more copies of the LoF mutation in healthy controls compared to individuals who suffer from the disease, then that suggests a protective effect,” Rivas says.

    The process led them to a single mutation in RNF186, a gene that’s biological function is just starting to be deciphered. Individuals with UC were unlikely to carry this mutation, while it was much more common in the healthy controls. Since those with the “broken” gene tended not to get UC, the findings suggest that the gene and the protein it produces might somehow play a role in the development of the disease. That makes RNF186 and its protein a promising focus for follow-up studies to determine whether they, or related biological pathways, might make effective targets for therapeutics.

    “The nice thing about these protective alleles that disrupt or knockout the function of a gene is they get us closer to understanding the biological role of the gene—what it does in health and disease,” says Daly, who is also founding chief of the Analytic and Translational Genetics Unit at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School. “That’s why there is great enthusiasm for this approach of looking for mutations that break genes; these insights can directly inform the development of new therapies that will have genetic evidence suggesting their safety and efficacy.”

    One of the keys to finding such mutations, the researchers say, is access to large collections of genetic samples. Since these LoF mutations may be rare, they may only appear—and so may only be detectable—in large studies. For this study, the researchers benefited from the availability of large sample collections and the willingness of scientists at several institutions and in many countries to share data. Access to the deCODE database turned out to be particularly helpful. deCODE houses and analyzes vast amounts of data from genetic samples taken from Iceland. Since the Icelandic population is relatively isolated, specific rare mutations may be passed on and retained among the people who live on the island, and can therefore appear with greater frequency than in other populations. For instance, the mutation found in RNF186 was four times more common in the population represented in the deCODE data than in other data sets.

    “We are incredibly grateful to our colleagues around the globe who were willing to openly share their data. It was that spirit of collaboration that enabled this discovery to be confirmed so rapidly,” Daly says.

    Now that the mutation has been identified, the next steps are to explore the function of the RNF186 protein more in depth and to determine what role it may play in UC. The goal is to elucidate the biology underlying the disease enough that drug developers can explore potential treatments that may mimic the effects of the mutation. That path has worked thus far for PCSK9, where the LoF mutation was shown to help protect against heart attack. That discovery has inspired treatments currently in clinical trials.

    The researchers are also looking to follow up this study with others seeking LoF mutations.

    “For me as a statistical geneticist, I’m interested in taking this approach to a broader set of traits and diseases and integrating many other data types. Focusing on these ‘broken’ genes has proven to be a valuable approach; it helps us efficiently home in on relevant biology,” Rivas says.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

    Harvard University

    MIT Widget

     
  • richardmitnick 12:11 pm on July 29, 2016 Permalink | Reply
    Tags: , Broad Institute,   

    From Broad: “Taking aim at rare cancer variants” 

    Broad Institute

    Broad Institute

    July 28th, 2016
    Leah Eisenstadt

    1
    Not all cancer mutations are drivers; Target Accelerator takes aim at identifying the ones most important to human disease. Image courtesy of Lauren Solomon, Broad Communications

    If you walked into a cancer clinic ten years ago as a newly diagnosed patient, you’d likely get “standard of care” treatment based on the location of the cancer in your body and its stage. Make that same visit today and your physician may instead begin with a close look at your tumor’s DNA.

    The emerging focus on precision medicine urges a tailored approach to therapy that aims to give the right medicine to the right patient at the right time. Several cancer drugs are now available that attack tumors harboring specific mutations in well-known oncogenes, and patients with those tumors can benefit now from the early advances in precision medicine.

    Imagine, however, that you’re one of the many cancer patients whose molecular testing ends in frustration. Your physician returns with good news and bad news: your tumor has six mutations in well-known cancer genes, but unfortunately yours are not the usual suspects. The specific genetic misspellings in your tumor have never been seen before and cannot be interpreted. In scientific parlance, they are “variants of unknown significance.” Your tumor’s mutations could be driving your cancer, making it amenable to a therapy that targets those genes, or they could be completely benign genetic changes, known as passenger mutations because they are simply along for the ride, so treating you with a targeted therapy could do more harm than good. Despite having your tumor’s unique genetic information in hand, your physician has no way to interpret the rare variants and can’t use your results to make treatment decisions.

    In oncology today, there are relatively few tumor mutations that are well enough understood to impact clinical care. Part of the problem is that most of the genetic variants found in tumors are rare, with some variants found in only a single patient in the world, and the roles of these unstudied variants remain a mystery. In addition, the traditional model of studying the function of a mutated gene involves many years of resource-intensive experimental work, an approach that has not kept pace with the recent discovery of scores of cancer mutations through efforts like The Cancer Genome Atlas project.

    Several years ago, researchers in the Cancer Program at the Broad Institute of MIT and Harvard recognized the need to generate large-scale functional maps of the cancer genome to better understand the disease, inform clinical decision making, and aid the search for new cancer medicines. The researchers initiated an effort known as “Target Accelerator” to develop new ways of assessing the function of disease variants in a high-throughput way. With the broad goal of improving genome interpretation in cancer, the effort is now starting to bear fruit with two new scientific papers that illustrate the potential of this approach, especially in elucidating cancer’s uncommon mutations.

    “A core challenge for researchers around the globe is to learn how to interpret the biological meaning of the many rare genetic variants found in cancer and other illnesses,” said Jesse Boehm, associate director of the Cancer Program. “We thought it might be possible to study the function of disease variants in a systematic way, but proof-of-principle experiments were lacking. So we took on the challenge.”

    A first study of function at scale

    In the first findings to come out of the Target Accelerator effort, a team led by Cancer Program researchers William Hahn, Jesse Boehm, and Gaddy Getz developed a scalable, systematic approach to study the function of genetic variants associated with an array of cancers. They analyzed existing DNA sequence data from more than 5,000 tumors from 27 different types of cancer, choosing 474 mutations to investigate further. With the help of the Broad’s Genetic Perturbation Platform (GPP), they generated cells in which the activity of these mutant genes was turned up, or “overexpressed.” They used model systems originally developed by Hahn and Boehm that contain some, but not all, of the mutations required to turn normal cells into cancer cells. The team then overexpressed the 474 mutant genes to determine which ones finished the job, causing tumors to grow in mice. By pooling cells that each overexpressed a different mutation and tracking their relative abundance, the researchers were able to test the tumor-forming potential of many mutated genes at once. In a complementary set of experiments, the team turned to changes in gene activity, also known as gene expression, to interpret the function of mutations.

    “This is the first experiment of this scale to differentiate the functional consequences of tumor mutations, shedding important light on the myriad rare mutations that are uncovered through clinical and research sequencing,” said Hahn, senior author on the paper and institute member of the Broad who is also a medical oncologist and a professor at the Dana–Farber Cancer Institute and Harvard Medical School.

    Appearing in Cancer Discovery, the results revealed a dozen new functional mutations that appear to underlie cancer (many found only once in the set of 5,338 tumors), including rare variants in the well-studied cancer gene KRAS that had previously been overlooked and several mutations in genes that are just now being linked to cancer: POT1 and PIK3CB.

    “We’ve shown that as physicians, we can’t dismiss the rare mutations just because they’ve never been seen or studied before,” said Eejung Kim, a first author on the paper and physician/scientist-in-training in Hahn’s lab.

    A closer look at lung cancer

    A second study to come from the Target Accelerator effort and appearing in Cancer Cell focused on lung cancer and was led by Boehm and Broad institute member Matthew Meyerson.

    “Lung adenocarcinoma has one of the highest rates of mutation among cancers, so it’s critical that we take a systematic approach to differentiating driver mutations from passengers if we want to one day target these rare variants therapeutically,” said Meyerson, also a professor of pathology at Dana-Farber Cancer Institute and Harvard Medical School.

    Many of the mutations in lung tumors are rare and unstudied. Even for patients with alterations in the frequently mutated gene EGFR, which can be targeted with the drug gefitinib (Iressa), roughly one-third of those mutations are variants of unknown significance, so the drug cannot be prescribed.

    The researchers selected nearly 200 mutations in 53 genes from patient data to functionally profile through three complementary assays. The first relied upon a gene expression-based method that built upon earlier work from the Broad’s Connectivity Map (CMap) team to determine which mutations impact gene function. Using the L1000 assay, an inexpensive, bead-based gene expression monitoring system developed by the CMap team, they could generate a molecular fingerprint of expression changes due to each mutant gene and its normal counterpart.

    The team developed a novel algorithm to analyze the data termed eVIP (expression-based Variant Impact Phenotyping), pioneered by co-first author Angela Brooks, now an assistant professor of biomolecular engineering at University of California, Santa Cruz. The algorithm analyzes expression signatures generated using the L1000 assay in lung cancer cells in which mutant genes are overexpressed (again, with the help of Broad’s GPP). With eVIP, the strength of changes in each mutation’s expression fingerprint indicates whether the variants are passengers, gain-of-function mutations, or loss-of-function mutations.

    “The approach is exciting because for the first time in a single assay, we can profile the function of any mutation in a set, regardless of each gene’s particular function,” said Alice Berger, co-first author on the paper, postdoctoral researcher at the Broad, and instructor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, who will soon be an assistant member at Fred Hutchinson Cancer Research Center. “We’re using the expression profile as a universal sensor of function, so we can characterize many, many genes at one time.”

    The team used two additional assays to determine which mutations promoted tumor formation and which mutations conferred resistance to cellular EGFR inhibition.

    As expected, many of the mutations they tested appeared to be passengers. However, among the driver mutations they uncovered in the EGFR/RAS pathway were not only famous oncogenes, but also many rare ones (some only seen in one patient, ever) that seem to have the same function as the common mutations. The results provide more evidence that rare mutations can be clinically important.

    The eVIP method is powerful because it can also identify loss-of-function mutations in tumor suppressor genes. Lung tumor sequencing has uncovered many missense mutations – those that change a single amino acid in the protein – in tumor suppressor genes. These tiny spelling changes were not strongly suspected to alter the protein’s function or drive cancer. This study found the opposite to be true in the case of two frequently mutated tumor suppressor genes, KEAP1 and STK11. They discovered that most of the missense variants in those genes reduce protein function, indicating that missense mutations in tumor suppressors could hold clinical importance.

    An engine of genome interpretation

    These studies and others from the Target Accelerator effort represent an engine of genome interpretation that cuts across the entire Broad community to leverage many parts of the institution, including the Genetic Perturbation Platform, the Connectivity Map team, the Proteomics Platform, the Imaging Platform, and the Genomics Platform.

    “These are uniquely Broad projects because they build a web of people, technologies, and ideas that existed, but that needed to be assembled and applied to a particular disease output,” said Boehm. “The success of these efforts will help us plan Target Accelerator’s next phase, in which we’ll incorporate other forms of genetic perturbation, new bioassays, and single-cell sequencing in a systematic way.”

    The broad goal is to improve precision medicine going forward, which will rely on more experimental data and improved computational methods to predict the impact of mutations. “I hope that by the time I’m treating cancer patients, we have a more comprehensive functional survey of cancer mutations,” said Kim. “Giving patients meaningful information on their tumor’s particular genetic makeup holds the potential to transform the way we treat and diagnose this devastating illness.”

    Other Broad Institute researchers on the Cancer Discovery paper include co-first authors Nina Ilic, Yashaswi Shrestha, Lihua Zou, and Atanas Kamburov, in addition to co-authors Cong Zhu, Xiaoping Yang, Rakela Lubonja, Nancy Tran, Cindy Nguyen, Michael Lawrence, Federica Piccioni, Mukta Bagul, John Doench, Candace Chouinard, Xiaoyun Wu, Larson Hogstrom, Ted Natoli, Pablo Tamayo, Heiko Horn, Steven Corsello, Kasper Lage, David Root, Aravind Subramanian, Todd Golub, and Gad Getz.

    Other Broad Institute researchers on the Cancer Cell paper include co-first author Xiaoyun Wu, Yashaswi Shrestha, Candace Chouinard, Federica Piccioni, Mukta Bagul, Atanas Kamburov, Marcin Imielinski, Larson Hogstrom, Cong Zhu, Xiaoping Yang, Sasha Pantel, Jacqueline Watson, Joshua D. Campbell, Shantanu Singh, David E. Root, Rajiv Narayan, Ted Natoli, David Lahr, Itay Tirosh, Pablo Tamayo, Gad Getz, Bang Wong, John Doench, Aravind Subramanian, and Todd R. Golub.

    Paper(s) cited:

    Kim E, et al. Systematic functional interrogation of rare cancer variants identifies oncogenic alleles. Cancer Discovery. 2016 Jul;6(7):714-26. doi: 10.1158/2159-8290.

    Berger A, et al. High-throughput phenotyping of lung cancer somatic mutations. Cancer Cell. Online July 28, 2016.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

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  • richardmitnick 10:46 am on July 28, 2016 Permalink | Reply
    Tags: Antibiotic research, , BARDA, Broad Institute, CARB-X, ,   

    From Washington Post via Broad Institute: “Major global partnership to speed antibiotic development launched” 

    Broad Institute

    Broad Institute

    1

    Washington Post

    July 28, 2016
    Lena H. Sun

    2
    Carbapenem-resistant Enterobacteriaceae, or CRE, is considered “nightmare bacteria” because of its resistance to many antibiotics. (Reuters)

    U.S. and British officials announced an ambitious collaboration Thursday designed to accelerate the discovery and development of new antibiotics in the fight against one of the modern era’s greatest health threats: antibiotic resistance.

    CARB-X, for Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator, will create one of the world’s largest public-private partnerships focused on preclinical discovery and development of new antimicrobial products.

    The undertaking includes two agencies within the U.S. Health and Human Services Department that focus on biomedical research and Britain’s Wellcome Trust, a London-based global biomedical research charity. It also includes academic, industry and other nongovernmental organizations.

    [The superbug that doctors have been dreading just reached the U.S.]

    The partnership is committed to providing $44 million in funding in the first year and up to $350 million in new funds over five years to increase the number of antibiotics in the drug-development pipeline. The ultimate goal, officials said, is to move promising antibiotic candidates through the critical early stages so they can attract enough private or public investment for advanced development and win approval by U.S. and British regulatory agencies.

    Biomedical innovations often take place in small companies and academic labs that don’t have the resources and expertise to move products to clinical development. CARB-X aims to provide necessary funding for research and development and technical assistance to move products from proof of concept through preclinical development.

    Only 37 antibiotics are currently in clinical development in the United States, according to The Pew Charitable Trusts. Historically, only about 1 in 5 infectious-disease drugs that enter Phase 1 trials will receive approval from the Food and Drug Administration. There have been no new classes of antibiotics discovered since 1984, according to Pew’s antibiotic resistance project.

    “The establishment of CARB-X is a watershed moment,” Nicole Lurie, a top HHS official in charge of preparedness and response, said during a press briefing Thursday.

    These life-saving drugs are fundamental to modern medicine. They are essential for treating everything from routine skin infections to strep throat and for protecting vulnerable patients receiving chemotherapy or those hospitalized in intensive care units. But the speedy rise of antibiotic-resistant bacteria, which experts say is a result of decades of overuse in animal agriculture and human medicine combined with lagging drug development and innovation, has put people everywhere on the brink of what many public health leaders say is a “post-antibiotic” world. In such a world, even the most simple surgical procedure could have fatal consequences.

    Overseeing the project on the U.S. side is the Biomedical Advanced Research and Development Authority, or BARDA. The HHS agency works on national preparedness for chemical and biological threats. It will be joined by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

    On the British side, oversight will be led by the Wellcome Trust and the AMR Centre, a public-private initiative formed in February to spur development of new antibiotics and diagnostics.

    “Today the world can be a little more optimistic that we can together tackle this challenge,” said Stephen Caddick, director of innovation for the Wellcome Trust.

    Public health leaders said the project has tremendous potential to jump-start drug development.

    “There are a lot of companies that have potential new antibiotics or other therapies, but it’s a very tough environment to raise funds in,” said Allan Coukell, one of Pew’s top antibiotic experts. “The market for these products are generally small. Creating an economic incentive where they can tap into capital to get these products developed and also access some expertise has the potential to have a real impact.”

    CARB-X will be headquartered at Boston University’s School of Law, where the project’s executive team will be led by Kevin Outterson, a leading health law researcher who will serve as principal investigator on the cooperative agreement.

    Outterson said the initial focus will be on superbugs and other pathogens that the Centers for Disease Control and Prevention has deemed to be serious or urgent threats to public health. They include a particularly dangerous family of bacteria known as CRE, or carbapenem-resistant Enterobacteriaceae, which health officials have dubbed “nightmare bacteria.”

    4

    Two U.S. nonprofit life-science accelerators will provide support for early-stage antibiotic development projects: Massachusetts Biotechnology Council in Cambridge, Mass., and the California Life Sciences Institute of South San Francisco.

    BARDA is already working directly with drug companies to support nine new antibiotics that could move into the market in the next one to three years, said Joe Larsen, acting deputy director at BARDA. The goal for CARB-X is to work on about 20 different drug candidates at any given time. “Our target is that at a minimum, two products make it to human testing in five years,” he said.

    During the planning process, Larsen said industry and venture capital executives identified preclinical development as the largest need. Securing funding to conduct studies in animals is particularly challenging, and many trials fail in that phase.

    NIAID Director Anthony Fauci said his institute would be able to provide the in-kind research and support services, such as animal models, for that crucial preclinical investigation.

    Here is what each organization is committing:

    •BARDA will provide $30 million during the first year and up to $250 million during the five-year project.

    •The AMR Centre aims to provide $14 million in the first year and up to $100 million over five years.

    •The Wellcome Trust will contribute additional funding from its existing resources and expertise in overseeing projects of this kind.

    •NIAID, which leads the U.S. government in biomedical research on infectious diseases, will provide in-kind research support and technical support related to early-stage antibiotic drug discovery and product development.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

    Harvard University

    MIT Widget

     
  • richardmitnick 6:45 pm on June 2, 2016 Permalink | Reply
    Tags: A massive approach to finding what's "real" in genome-wide association data, , Broad Institute,   

    From Broad Institute: “A massive approach to finding what’s “real” in genome-wide association data” 

    Broad Institute

    Broad Institute

    June 2nd, 2016
    Tom Ulrich

    What could we learn if we probed the subtle effects of thousands of DNA variations on gene expression, all at once? Two recent Cell papers hint at how an assay called MPRA could help us get there.

    1
    MPRA could help reveal DNA variants’ subtle influences on diseases and traits. Image: Sigrid Knemeyer.

    Genome-wide association studies (GWAS) have been a boon for geneticists by revealing thousands of genetic variants associated with human disease. At the same time, GWAS are the bane of geneticists because they reveal thousands of genetic variants associated with human disease. Which variants are the drivers, the ones that truly cause or contribute to disease development and progression?

    “With GWAS, you get a set of signals, which can tell you which regions of the genome are associated with a particular disease or trait,” said Vijay Sankaran, a Broad associate member and a pediatric hematologist/oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center who studies blood cell disorders. “But it’s hard to know which hits are causal hits, and which are just going along for the ride.”

    The picture gets particularly complicated when talking about variants in non-coding DNA, including the vast stretches of DNA containing sequences that control gene expression. By some estimates, between 85 and 90 percent of the variants picked up by GWAS lie in such regions.

    Many scientists are trying to figure out how to connect the dots between non-coding GWAS variants and human biology, health, and ultimately, disease. Three Broad teams, led by Sankaran, Pardis Sabeti, and Broad alum Tarjei Mikkelsen (now with the biotechnology company 10X Genomics), respectively, have focused their efforts on scaling up a staple of the genomics toolkit — the reporter assay — to create a massively parallel reporter assay (MPRA).

    “We want to move from understanding the component pieces of the genome to understanding what changes in those components do,” said Sabeti, an institute member and Harvard computational geneticist and evolutionary biologist, whose lab probes the role genetic variation writ large plays in human and microbial evolution. “We need very sensitive technology to be able to identify these functional changes, particularly if they’re subtle.”


    Access mp4 video here .

    Going massive

    The reporter assay helps scientists sift through GWAS data to find variants that truly affect gene expression or function. A researcher takes a DNA fragment from what may be an enhancer, couples it within a plasmid to a “reporter” gene that provides a readout (e.g., the luciferase gene), and inserts the plasmid into cells. If the readout materializes (e.g., if the cells glow), the enhancer sequence drove expression of the reporter. By running the assay with different variations of the same fragment, a pattern can emerge suggesting whether certain variants affect expression.

    Such classic reporter assays, however, have one major disadvantage: They don’t scale to the level needed to investigate the thousands to tens of thousands of variants that might turn up in a GWAS.

    Mikkelsen and Broad research scientist Alexandre Melnikov worked out the principles of one flavor of MPRA while working in the lab of Broad founding director and president Eric Lander. In a 2012 Nature Biotechnology paper*, they noted that tagging each plasmid with a short, unique DNA barcode provided a second readout. By sequencing and counting the mRNAs produced from each plasmid, they could easily identify the variant(s) with the greatest influence on gene expression and quantify the magnitude of that influence.

    And because each barcode was unique to each plasmid, Mikkelsen and Melnikov’s team could pool and assay thousands of variants simultaneously.

    Homing in on blood cell traits

    Sankaran’s lab is the latest to make use of Mikkelsen and Melnikov’s MPRA system, harnessing it to scrutinize more than 2,750 non-coding variants in 75 GWAS hits linked to red blood cell traits. And as he, Mikkelsen, and co-first authors Jacob Ulirsch and Satish Nandakumar reported** in Cell, MPRA data pointed to 32 hits that actually had some impact on gene expression. They then used additional computational and functional assays to further probe the effects of a subset of these variants on red blood cell traits, as a result revealing that several known genes may have heretofore-unrecognized roles in blood cell development.

    “One of the unexpected lessons we learned was that many of the variants tweaked a master blood development regulator, GATA1,” said Ulirsch, a staff scientist in Sankaran’s lab. “There was a common pattern. Going one by one, variant by variant, we would never have been able to see this.”

    3
    Clockwise from top left: Pardis Sabeti, Vijay Sankaran, Satish
    Nandakumar, Ryan Tewhey, Jacob Ulirsch. Photo: Megan Purdum

    Building MPRA 2.0

    While Mikkelsen and Melnikov’s original method is quite powerful, Sabeti’s lab wanted to see if they could make it even more robust.

    “The original version of MPRA is limited in how many variants you can test,” said Ryan Tewhey, a postdoctoral fellow in Sabeti’s lab. “We wanted to know, can you expand this technology out? Can you test tens of thousands of variants at once? And can you make it more sensitive?”

    Tewhey, Sabeti, and their team doubled the length of each DNA barcode and upped the number of barcodes to as many as 350 per variant. They then used their enhanced assay to study more than 32,000 possible B cell regulatory variants identified by the 1000 Genomes Project, deeply characterizing one associated with risk of ankylosing spondylitis (an autoimmune disease). They also highlighted another 842 candidate variants, including 53 particularly promising ones associated with human traits and diseases.

    As they discussed in their own Cell paper***, the added barcodes reduced the noise in their data and increased the assay’s overall sensitivity.

    “With more barcodes you can start to detect more subtle changes in expression, including changes that might arise from differences between alleles,” Tewhey added.
    Another view into regulation

    MPRA isn’t the only approach for pulling causal needles out of GWAS haystacks, and Tewhey is realistic that it won’t be a panacea for studying all of the cell’s mechanisms for regulating expression.

    “For promoters and enhancers, we know it works well,” he said. “For things related to long distance connectivity or the genome’s shape, we’re not as confident. ”

    Sankaran points out that MPRA really shines in its ability to find themes in genetic variation that researchers can marry to other genetic, structural, or functional data.

    “When you start to get all these independent pieces together, you get a real fine view of what’s important,” he said.

    Papers cited:

    Melnikov A, Murugan A, et al. Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay. Nature Biotechnology. February 26, 2012. DOI: 10.1038/nbt.2137

    Ulirsch JC, Nandakumar SK, et al. Systematic functional dissection of common genetic variation affecting red blood cell traits. Cell. June 2, 2016. DOI: 10:1016/j.Cell.2016.04.048

    Tewhey R, Kotliar D, et al. Direct identification of hundreds of expression-modulating variants using a multiplexed reporter assay. Cell. June 2, 2016. DOI: 10:1016/j.cell.2016.04.027

    *Science paper:
    Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay

    **Science paper:
    Systematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits
    ***Science paper:
    Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

    Harvard University

    MIT Widget

     
  • richardmitnick 5:23 pm on June 2, 2016 Permalink | Reply
    Tags: , Broad Institute, , Researchers unlock new CRISPR system for targeting RNA   

    From Broad Institute: “Researchers unlock new CRISPR system for targeting RNA” 

    Broad Institute

    Broad Institute

    June 2nd, 2016
    Broad Institute of MIT and Harvard
    Paul Goldsmith
    617-714-8600
    paulg@broadinstitute.org

    Discovered in bacteria as viral defense mechanism, researchers program C2c2 to manipulate cellular RNA using CRISPR

    Researchers from the Broad Institute of MIT and Harvard, Massachusetts Institute of Technology, the National Institutes of Health, Rutgers University-New Brunswick and the Skolkovo Institute of Science and Technology have characterized a new CRISPR system that targets RNA, rather than DNA.

    The new approach has the potential to open a powerful avenue in cellular manipulation. Whereas DNA editing makes permanent changes to the genome of a cell, the CRISPR-based RNA-targeting approach may allow researchers to make temporary changes that can be adjusted up or down, and with greater specificity and functionality than existing methods for RNA interference.

    1
    A team led by Feng Zhang of the Broad and MIT and Eugene Koonin of the NIH has revealed that C2c2 helps protect bacteria against viral
    infection by targeting RNA. Photo composite by Lauren Solomon, Broad communications. Images courtesy of Broad communications and NIH.

    In a study* published today in Science, Feng Zhang and colleagues at the Broad Institute and the McGovern Institute for Brain Research at MIT, along with co-authors Eugene Koonin and his colleagues at the NIH, and Konstantin Severinov of Rutgers University-New Brunswick and Skoltech, report the identification and functional characterization of C2c2, an RNA-guided enzyme capable of targeting and degrading RNA.

    The findings reveal that C2c2—the first naturally-occurring CRISPR system that targets only RNA to have been identified, discovered by this collaborative group in October 2015—helps protect bacteria against viral infection. They demonstrate that C2c2 can be programmed to cleave particular RNA sequences in bacterial cells, which would make it an important addition to the molecular biology toolbox.

    The RNA-focused action of C2c2 complements the CRISPR-Cas9 system, which targets DNA, the genomic blueprint for cellular identity and function. The ability to target only RNA, which helps carry out the genomic instructions, offers the ability to specifically manipulate RNA in a high-throughput manner—and manipulate gene function more broadly. This has the potential to accelerate progress to understand, treat and prevent disease.

    “C2c2 opens the door to an entirely new frontier of powerful CRISPR tools,” said Feng Zhang, senior author, and Core Institute Member of the Broad Institute. “There are an immense number of possibilities for C2c2 and we are excited to develop it into a platform for life science research and medicine.”

    “The study of C2c2 uncovers a fundamentally novel biological mechanism that bacteria seem to use in their defense against viruses,” said Eugene Koonin, senior author, and leader of the Evolutionary Genomics Group at the NIH’s National Center for Biotechnology Information. “Applications of this strategy could be quite striking.”

    Currently, the most common technique for performing gene knockdown is small interfering RNA (siRNA). According to the researchers, C2c2 RNA-editing methods suggest greater specificity and hold the potential for a wider range of applications, such as:

    Adding modules to specific RNA sequences to alter their function—how they are translated into proteins—which would make them valuable tools for large-scale screens and constructing synthetic regulatory networks, and
    Harnessing C2c2 to fluorescently tag RNAs as a means to study their trafficking and subcellular localization.

    In this work, the team was able to precisely target and remove specific RNA sequences using C2c2 – lowering the expression level of the corresponding protein. This suggests C2c2 could represent an alternate approach to siRNA, complementing the specificity and simplicity of CRISPR-based DNA editing and offering researchers adjustable gene “knockdown” capability using RNA.

    C2c2 has advantages that make it suitable for tool development:

    C2c2 is a two-component system, requiring only a single guide RNA to function, and
    C2c2 is genetically encodable—meaning the necessary components can be synthesized as DNA for delivery into tissue and cells.

    “C2c2’s greatest impact may be made on our understanding the role of RNA in disease and cellular function,” said co-first author Omar Abudayyeh, a graduate student in the Zhang Lab.

    *Science paper:
    C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

    Harvard University

    MIT Widget

     
  • richardmitnick 4:50 pm on January 22, 2016 Permalink | Reply
    Tags: , Broad Institute, ,   

    From Broad Institute: “The beauty of imbalance” 

    Broad Institute

    Broad Institute

    January 21st, 2016
    Angela Page

    Temp 1
    Broad researchers have found that asymmetrical mutational patterns on the two strands of the double helix could be implicated in cancer. Image by Madeleine Price Ball/Lauren Solomon

    Every day, every cell in the body picks up one or two genetic mutations. Luckily, cells have a whole battery of strategies for fixing these errors. But most of the time, even if a mutation doesn’t get fixed — or doesn’t get fixed properly — there are no obvious functional implications. That is, the mutation isn’t known to impair the function of the cell. Some mutations, however — called “driver” mutations — do impair the cell, leading to cancer, aging, or other types of diseases.

    Identifying new driver mutations (a few hundred genes that carry driver mutations are known so far) is a huge focus for most labs that study cancer, including that of Broad Cancer Genome Computational Analysis group director Gad Getz. But in new research recently published in Cell, Getz and computational biology group leader Michael Lawrence wanted to look at all those other mutations: the “passengers” that may or may not cause cancer. Doing so, they surmised, would not only help them understand the fundamental biology of cells, but may also point them toward new mechanisms for causing mutations associated with cancer.

    And that’s exactly what happened. The new work reveals the mechanism behind cancers associated with a family of enzymes called APOBEC, which had been rather enigmatic until now. The original purpose of APOBEC enzymes, according to Lawrence, was probably to fight viruses. But recent studies from Getz’s lab and others have shown that many cancers are enriched for genetic mutations caused by these enzymes.

    “Something that most cervical and bladder cancers, some breast cancers, many head and neck cancers, and a scattering of many other tumor types, all have in common is over-activity of APOBEC enzymes,” Lawrence said. People had been studying APOBEC cancers for years, trying to figure out what exactly was going wrong, but they had so far met with little success.

    One thing that had interested Lawrence and Getz about APOBEC was that while it introduces dozens of mutations all across the genome, it always affects the cytosine bases — the “Cs” in the famous DNA alphabet which also contains As, Ts, and Gs. This was interesting because it played right into a hypothesis about asymmetry that Getz and Lawrence had already begun to explore.

    “Every cell has two DNA strands that wrap around each other in a double helix. Both carry the same information, so each double helix has two copies of the information,” Lawrence said. “When damage happens to the DNA it might happen on just one strand.” Identifying the strand on which the damage originally occurred could give researchers clues about the mechanisms behind cancer mutations.

    “But because the cell so carefully maintains the matching of the two strands, a misplaced base on one strand quickly leads to a complementary misplaced base on the other,” said Nicholas Haradhvala, co-first author on the paper together with Paz Polak, both associated scientists at Broad and members of Getz’s lab at MGH. “By the time DNA sequencing is performed, it is impossible to tell which strand originally was damaged.”

    In order to identify the strand originally damaged, Haradhvala and his colleagues looked at asymmetrical processes such as DNA transcription and replication. DNA transcription is the first step in gene expression, whereby the genetic blueprints contained in the gene are read and translated into proteins. DNA replication is the process by which DNA is copied when cells divide. In transcription, a variety of cellular apparatuses unzip the two DNA strands and then make a mirror image copy of one of them. The other strand hangs out like a vulnerable flag in the wind, waiting for the process to complete, potentially getting blown over with mutations in the meantime. The strand that is being read is further protected from mutation because the process includes a step in which another apparatus comes in with the specific job of repairing any damage it finds. The non-transcribed strand — that vulnerable flag — doesn’t benefit from such a perk.

    After analyzing the mutational patterns of 590 tumors across 14 different cancer types, the team discovered that liver cancers seem to be riddled with mutations that stem from transcription-coupled damage. That is, mutations tend to pile up on the non-transcribed strand more frequently in liver tumors than expected. This is a novel phenomenon that is first described in this work.

    In replication, both strands are copied simultaneously, but since the machinery that does so only works in one direction, copying the strand with the opposite orientation is a bit of a stilted process. The copying apparatus, a protein called a polymerase, takes a step forward, copies everything behind it, and then moves another step forward and copies backwards again. The other strand is just happily copied in a continuous, (literally) straightforward manner. And since the backwards strand is so often hanging out alone, it is more vulnerable to damage just like the non-transcribed strand described above.

    So in both transcription and replication, cellular processes treat the two strands of DNA in an asymmetrical fashion. This asymmetry is what allowed Getz, Lawrence, and their colleagues to figure out the mechanism behind APOBEC cancers. It turns out, according to the team’s painstaking analysis of millions of data points, that the APOBEC enzyme most often introduces mutations to the lagging (or “backward”) strand during DNA replication.

    Both the liver and APOBEC findings are big news. After all, it’s not every day that a new mechanism for generating mutations comes along. But more importantly, they also offer insight into how DNA transcription and replication work from the perspective of mutations — findings that could have implications in understanding even more cancer types in the future.
    “It’s like having a computational microscope,” said Getz. “It allows us to see what’s going on inside the cell, where the action is happening while the DNA is being transcribed or replicated. That’s the beauty of this work.”

    Going forward, Getz, Lawrence, and their colleagues have big plans for their asymmetry work. They are already in the process of collaborating with dozens of labs around the globe to collect and analyze whole genome sequences of 2,800 tumors. Part of that work will include asymmetry analyses like those described here, to try to understand whether these processes have mechanistic implications for other cancer types as well. In the meantime, they are also collaborating with their benchtop biologist colleagues to carry out functional studies as follow up to the computational work done for this study, trying to recreate in a live setting what they saw in that computational microscope.

    Other Broad Researchers:

    Julian Hess, Esther Rheinbay, Jaegil Kim, Yosef Maruvka, Lior Braunstein, Atanas Kamburov, and Amnon Koren.

    Papers cited:

    Burns, et al. Evidence for APOBEC3B mutagenesis in multiple human cancers Nature Genetics. Online July 14, 2013. DOI: 10.1038/ng.2701

    Haradhvala, et al. Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair. Cell. Online January 21, 2016. DOI: 10.1016/j.cell.2015.12.050

    Roberts, et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nature Genetics. January 28, 2013. DOI: 10.1038/ng.2702

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

    Harvard University

    MIT Widget

     
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