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  • richardmitnick 1:35 pm on July 17, 2017 Permalink | Reply
    Tags: , HMS, ,   

    From HMS: “Resistance Fighters” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    July 17, 2017
    EKATERINA PESHEVA

    1
    Pulmonary medicine physician Maha Farhat and mathematician and evolutionary biologist Michael Baym join forces in the Department of Biomedical Informatics to stem the rising tide of drug resistance. Image: HMS. Rick Groleau.

    A mathematician and a pulmonologist walk into a bar…

    As tales of unlikely convergences go, this one is about the improbable intersection of big data and clinical efforts to combat bacterial drug resistance. Except in this case, the paths of mathematician Michael Baym and pulmonologist Maha Farhat crossed in the Department of Biomedical Informatics at Harvard Medical School.

    Farhat and Baym are the newest faculty members of a young but rapidly growing department aspiring to improve diagnoses and catalyze treatments by translating information into practical clinical knowledge.

    Farhat and Baym are on a quest to do just that.

    “We met very recently and, as it turns out, we have a lot of common threads in our work,” Farhat said.

    For one, they share a passion for unraveling the evolutionary mysteries of microbial drug resistance and curbing its spread. They also each harbor a belief that the most promising pathway to solving drug resistance lies in using large-scale genomic data and computation.

    “We ended up basically identifying the same problem taking a very similar angle on a solution, despite coming from completely different backgrounds and skill sets,” Baym said.

    The TB warrior

    As an idealistic first-year medical student at Montreal’s McGill University, Farhat set out to find her professional raison d’être among the diseases that cause the greatest morbidity and mortality.

    “I was shocked to find out that TB was still one of the top five causes of death and the number one infectious disease killer globally,” Farhat said.

    One of Farhat’s formative experiences was her collaboration with pulmonologist Dick Menzies, of the Montreal Chest Institute. He spent his mornings researching diagnostic tests for TB and his afternoons taking care of patients and doing procedures.

    Smitten by such intellectual dexterity, Farhat decided she too wanted to pursue life as a physician-scientist. Farhat helped Menzies design a clinical calculator to help physicians interpret results of the tuberculin skin test—the most commonly used screen for exposure to TB. The test requires injecting a small amount of TB protein in a person’s forearm and observing the skin reaction to determine past exposure to the germ. This test, however, is by itself a notoriously unreliable predictor of actual infection.

    The TB calculator that Menzies and Farhat developed used an algorithm that, in addition to factoring in the size of the skin welt, also included a range of patient characteristics to drive a more accurate interpretation. This experience was Farhat’s first encounter with the notion that computation could aid the design of clinical tools.

    “It really got me interested in how one could take information and data and collate them in a user-friendly format to maximize their clinical use,” Farhat says.

    These days, Fahrat uses decidedly more sophisticated methods. She is working to define the diversity of the TB genome as a way to understand genetic differences across TB strains and how such differences predict variations in response to treatment. Even so, her current work is very much philosophically aligned with her earlier experiences as a student.

    “The premise is the same as the work we did with the TB calculator—developing the right methods, but, perhaps more importantly, putting them in a context that clinicians can use easily,” Farhat says. “This is where I see myself.”

    Individualized medicine meets computation

    Very quickly, Baym realized, that in order to harness evolution in any practical way, scientists had to define the genetic characteristics of an organism not merely on the level of the species but within the individual organism. In the context of bacterial infections, this means genetically analyzing strains in individual patients and tracking how the bacterium evolves to survive drug therapies.

    Scaled-up, the approach could lead to valuable insights about the ways in which bacteria mutate to adapt to the combined pressures of drugs and the immune system.

    In TB, such scaling up would first require cataloguing hundreds of thousands of TB genomes—a point the scientific community is rapidly approaching, Farhat said.

    “We expect that in the next few years, we’ll have more than 100,000 different TB genomes sequenced,” Farhat said. “Currently, there are about 20,000 TB genomes in the public domain.”

    Insights gleaned from such an array of data could lead to the development of therapies that avert or interrupt microbial mutations.

    Such level of analysis could also help scientists profile and predict the behavior of a bacterial strain beyond its ability to mutate and survive drugs. For example, the data could yield clues about virulence or infectivity, such as whether a particular strain of TB is more likely to cause infection of the brain—TB meningitis—or the more commonly seen infection of the lungs.

    Large-scale genomic data could also spark the design of point-of-care tests that detect the precise genetic subtype, including resistance-fueling mutations, within mere hours. By contrast, the current approach takes up to two months and involves collecting sputum from a patient, sending it to a lab and performing an antibiotic screen to determine which medication the bacterium responds to.

    This means that for up to two months, patients are treated with drugs based on an imperfect guesstimate of their likelihood of carrying a resistant strain rather than actual evidence.

    “This cuts to the core of the problem,” Baym said. “Clinicians don’t have access to enough data fast enough to make proper decisions about treatments.”

    One of Farhat’s formative experiences was her collaboration with pulmonologist Dick Menzies, of the Montreal Chest Institute. He spent his mornings researching diagnostic tests for TB and his afternoons taking care of patients and doing procedures.

    Smitten by such intellectual dexterity, Farhat decided she too wanted to pursue life as a physician-scientist. Farhat helped Menzies design a clinical calculator to help physicians interpret results of the tuberculin skin test—the most commonly used screen for exposure to TB. The test requires injecting a small amount of TB protein in a person’s forearm and observing the skin reaction to determine past exposure to the germ. This test, however, is by itself a notoriously unreliable predictor of actual infection.

    The TB calculator that Menzies and Farhat developed used an algorithm that, in addition to factoring in the size of the skin welt, also included a range of patient characteristics to drive a more accurate interpretation. This experience was Farhat’s first encounter with the notion that computation could aid the design of clinical tools.

    “It really got me interested in how one could take information and data and collate them in a user-friendly format to maximize their clinical use,” Farhat says.

    These days, Fahrat uses decidedly more sophisticated methods. She is working to define the diversity of the TB genome as a way to understand genetic differences across TB strains and how such differences predict variations in response to treatment. Even so, her current work is very much philosophically aligned with her earlier experiences as a student.

    “The premise is the same as the work we did with the TB calculator—developing the right methods, but, perhaps more importantly, putting them in a context that clinicians can use easily,” Farhat says. “This is where I see myself.”

    The recovering mathematician

    Baym has been always fascinated by evolution’s elegant simplicity—a set of basic rules and patterns creating life’s astounding complexity over a period of time.

    While working on his doctorate in computational biology at MIT, he attended a talk on antibiotic resistance. It was a eureka moment for him. Drug resistance, Baym realized, was at its core an evolutionary phenomenon—bacteria adapting to and surviving an environmental challenge.

    “I realized that a very basic understanding of evolution could really make a difference in how we tackle antibiotic resistance, and at the same time it was a very basic problem to test our understanding of evolution against.”

    Baym started to talk to evolutionary biologists everywhere. During these conversations, one name kept popping up: Roy Kishony, then a professor of systems biology at Harvard Medical School. His work involved experiments in evolutionary manipulation. Baym cold-called Kishony. One thing led to another and Baym ended up as a post-doc in Kishony’s lab.

    Individualized medicine meets computation

    Very quickly, Baym realized, that in order to harness evolution in any practical way, scientists had to define the genetic characteristics of an organism not merely on the level of the species but within the individual organism. In the context of bacterial infections, this means genetically analyzing strains in individual patients and tracking how the bacterium evolves to survive drug therapies.

    Scaled-up, the approach could lead to valuable insights about the ways in which bacteria mutate to adapt to the combined pressures of drugs and the immune system.

    In TB, such scaling up would first require cataloguing hundreds of thousands of TB genomes—a point the scientific community is rapidly approaching, Farhat said.

    “We expect that in the next few years, we’ll have more than 100,000 different TB genomes sequenced,” Farhat said. “Currently, there are about 20,000 TB genomes in the public domain.”

    Insights gleaned from such an array of data could lead to the development of therapies that avert or interrupt microbial mutations.

    Such level of analysis could also help scientists profile and predict the behavior of a bacterial strain beyond its ability to mutate and survive drugs. For example, the data could yield clues about virulence or infectivity, such as whether a particular strain of TB is more likely to cause infection of the brain—TB meningitis—or the more commonly seen infection of the lungs.

    Large-scale genomic data could also spark the design of point-of-care tests that detect the precise genetic subtype, including resistance-fueling mutations, within mere hours. By contrast, the current approach takes up to two months and involves collecting sputum from a patient, sending it to a lab and performing an antibiotic screen to determine which medication the bacterium responds to.

    This means that for up to two months, patients are treated with drugs based on an imperfect guesstimate of their likelihood of carrying a resistant strain rather than actual evidence.

    “This cuts to the core of the problem,” Baym said. “Clinicians don’t have access to enough data fast enough to make proper decisions about treatments.”

    A newly developed molecular TB test—now gaining wider use—can detect resistance within a few hours to the drug rifampin—a first-line therapy. Rifampin, however, is only one of an arsenal of TB drugs that clinicians use routinely.

    Developing new and more exquisitely sensitive point-of-care TB tests demands the sampling of hundreds of thousands of patients with a given infection to define the circulating strains. The strains then would have to be analyzed genetically so that the tests can be calibrated to detect a wide range of mutations.

    Point-of-care testing could be particularly transformative for TB care outside the United States, where the greatest disease burden is. In the United States, all patients diagnosed with TB are automatically tested for resistant forms of the infection. Elsewhere, the vast majority of patients are given the standard treatment, and resistance testing is only performed if a patient shows poor response to the drug therapy after two months of treatment.

    But having large amounts of genomic data won’t, by itself, be enough to solve the problem, Farhat said.

    “In order for us to be able to make the leap to using whole genome sequencing in point-of-care diagnostics we really have to understand the basic biology of each organism and the genetic markers of resistance.”

    Driving evolution to a breaking point

    When it comes to mutation and survival, every organism adapts and mutates up until it reaches a breaking point. That breaking point varies from organism to organism but generally results from a several pressures, such as drugs or the immune system, beyond which the organism can no longer adapt. Figuring out the breaking point for each bacterial strain and devising therapies that deliver that lethal punch would be the holy grail on the quest to curb microbial resistance.

    In the case of TB, this may mean devising precision-targeted therapies or a combination of therapies that disarm the specific mutation that enables survival.

    “You can treat an infection with a certain combination of therapies that will either work or fail in one of a handful of ways. If we can understand and predict these in advance, we can respond accordingly,” Baym said. “That’s the broad idea.”

    This approach would precipitate a shift away from broad-spectrum treatments that target all possible mutations and strains toward ultra-narrow spectrum drugs that precision-target specific mutants within the pool of bacterial cells affecting individual patients.

    “That’s the frontier we’re chasing,” Baym said.

    The difference between where the standard of treatment is now and where Farhat and Baym aim to get would be akin to the recent shift in cancer care: away from carpet-bombing therapies to using a tumor’s genomic profile to individualize treatment.

    “We would no longer just classify infectious diseases as TB or E.coli but subtype to the level of particular mutations within each person,” Farhat said.

    Upping the price of a microbe’s survival

    For germs, resistance doesn’t come cheap. The process of adapting to a pressure alters the microbe’s cellular machinery. It taxes it. Even though the changes allow the pathogen to become resistant, they harm the cellular apparatus in different ways. This, Farhat said, is the “fitness cost” an organism pays for its survival. As a result, the mutant cell starts to grow more slowly. Over time, as the cell tries to outcompete others, it will eventually accumulate a second set of mutations that compensate for the loss of cellular fitness. This second set of mutations—so-called compensatory mutations—could represent another therapeutic target.

    Drugs that allow scientists to halt compensatory mutations could eradicate mutant strains before they proliferate and cause serious disease. Another option would be devising treatments that target the weakened mutant before it even acquires a compensatory mutation.

    “Once you open the door to respond predictively to evolution, there’s a whole range of treatment strategies,” Baym said. “There’s a large but not infinite way to get resistance. We know we need more data than we have right now but we think that if we collect enough, we can define all of the ways that bacteria use to become resistant.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

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  • richardmitnick 12:02 pm on July 10, 2017 Permalink | Reply
    Tags: Allen Discovery Center for Human Brain Evolution at Boston Children’s Hospital and Harvard Medical School, , HMS   

    From HMS: “Decoding Brain Evolution” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    July 6, 2017
    NANCY FLIESLER

    1
    Image: monsitj/Getty Images

    How did our distinctive brains evolve? What genetic changes, coupled with natural selection, gave us language? What allowed modern humans to form complex societies, pursue science, create art?

    While we have some understanding of the genes that differentiate us from other primates, that knowledge cannot fully explain human brain evolution. But with a $10 million grant to some of Boston’s most highly evolved minds in genetics, genomics, neuroscience and human evolution, some answers may emerge in the coming years.

    The Seattle-based Paul G. Allen Frontiers Group has announced the creation of an Allen Discovery Center for Human Brain Evolution at Boston Children’s Hospital and Harvard Medical School. It will be led by Christopher A. Walsh, the Bullard Professor of Pediatrics and Neurology at HMS and chief of the Division of Genetics and Genomics at Boston Children’s. Michael Greenberg, the Nathan Marsh Pusey Professor of Neurobiology and head of the Department of Neurobiology at HMS, and David Reich, professor of genetics at HMS, will co-lead the center.

    “Unraveling the mysteries of the human brain will propel our understanding of brain development, brain evolution and human behavior,” said George Q. Daley, dean of HMS. “It also will help us understand what makes us unique as a species.

    “The research conducted by these three remarkable scientists spans the gamut from molecule to organism to system and underscores the cross-pollination among basic, translational and clinical discovery as well as across neurobiology, genetics, evolutionary biology and neurology,” Daley said.

    The center’s agenda is a bold one: to catalogue the key genes required for human brain evolution, to analyze their roles in human behavior and cognition and to study their functions to discover evolutionary mechanisms.

    “To understand when and how our modern brains evolved, we need to take a multi-pronged approach that will reflect how evolution works in nature and identify how experience and environment affect the genes that gave rise to modern human behavior,” Walsh said.

    “The launch of this center is a wonderful opportunity for three laboratories that have been working independently to come together and study the genetic, molecular and evolutionary forces that have given rise to the spectacular capacities of the human brain,” said Greenberg.

    The funding “will allow us to use ancient DNA analysis to track changes in the frequency of genetic mutations over time, which will in turn illuminate our understanding of the nature of human adaptation,” added Reich.

    An evolving understanding

    We already know some basics of human brain evolution. First came the enlargement of the primate brain, culminating perhaps 2 million years ago with the emergence of our genus, Homo, and the use of crude stone tools and fire. Next came a tripling of brain size during the 500,000 years before Homo sapiens arose. Finally, just over 50,000 years ago, there was a great leap forward in human behavior, with archaeological evidence of more efficient manufacturing of stone tools and a rich aesthetic and spiritual life.

    What transpired genetically? Prior research has taken a piecemeal approach to occasional genes that have different structures in humans versus non-humans. For example, Walsh’s lab has identified several genes that regulate cerebral cortical size and patterning, some of them through the study of brain abnormalities. The lab recently found a gene involved in brain folding—thanks to a brain malformation called polymicrogyria—that may have enhanced our language ability.

    But such findings only scratch the surface of the cognitive, behavioral and cultural strides humans have made over the past 50,000 years. That’s a blink of the eye in evolutionary terms. What enabled us to invent money, develop agriculture, build factories, write symphonies, tell jokes?

    Rosetta Stone(s) to decode brain evolution

    The researchers think not one but multiple mechanisms of evolution helped form the modern human brain. Such mechanisms include:

    Gene addition, duplication or deletion
    Alteration in the protein-coding sequence of genes to create new or modified biochemical functions
    Changes in noncoding DNA sequences altering patterns of gene expression, allowing an existing gene to be “re-purposed”
    Polygenic changes (changes in many genes working together)

    Accordingly, the center’s research methods will include, in varying combinations:

    Sequencing of ancient DNA recovered from bones and teeth
    Genomic studies of large populations to identify regions that correlate with human traits
    Genetic studies to test functional effects of mutations in the evolutionarily important genomic sequences
    Functional studies in neurons to determine the roles of these evolutionarily important sequences in the brain

    No genetic stone unturned

    All these approaches will be supported by powerful computational data analysis—reaching across genomes, across populations, across hundreds of thousands of years.

    The project leaders summed it up: “This group will provide the most rigorous possible examination of how, when and where the unique features of the amazing human brain came about.”

    The $10 million grant will be distributed over four years, with the potential for $30 million over eight years.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 5:19 am on May 23, 2017 Permalink | Reply
    Tags: , , HMS, , Unlocking the barrier   

    From HMS: “Unlocking the barrier” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    May 3, 2017 [Another disciple of timely social media.]
    KEVIN JIANG

    Disrupting an omega-3 fatty acid transporter could open blood-brain barrier for drug delivery.

    1
    Normal brain blood vessels completely contain a fluorescent dye (left). Vessels without the lipid transport protein Mfsd2a exhibit a leaky blood-brain barrier (right). Image: Gu lab

    Already extolled for their health benefits as a food compound, omega-3 fatty acids now appear to also play a critical role in preserving the integrity of the blood-brain barrier, which protects the central nervous system from blood-borne bacteria, toxins and other pathogens, according to new research from Harvard Medical School.

    Reporting in the May 3 issue of Neuron, a team led by Chenghua Gu, associate professor of neurobiology at HMS, describes the first molecular explanation for how the barrier remains closed by suppressing transcytosis—a process for transporting molecules across cells in vesicles, or small bubbles.

    They found that the formation of these vesicles is inhibited by the lipid composition of blood vessel cells in the central nervous system, which involves a balance between omega-3 fatty acids and other lipids maintained by the lipid transport protein Mfsd2a.

    While the blood-brain barrier is a critical evolutionary mechanism that protects the central nervous system from harm, it also represents a major hurdle for delivering therapeutic compounds into the brain.

    Blocking the activity of Mfsd2a may be a strategy for getting drugs across the barrier and into the brain to treat a range of disorders such as brain cancer, stroke and Alzheimer’s.

    “This study presents the first clear molecular mechanism for how low rates of transcytosis are achieved in central nervous system blood vessels to ensure the impermeable nature of the blood-brain barrier,” Gu said. “There is still a lot we do not know about how the barrier is regulated. A better understanding of the mechanisms will allow us to begin to manipulate it, with the goal of getting therapeutics into the brain safely and effectively.”

    The blood-brain barrier is composed of a network of endothelial cells that line blood vessels in the central nervous system. These cells are connected by tight junctions that prevent most molecules from passing between them, including many drugs that target brain diseases. In a 2014 study published in Nature, Gu and colleagues discovered that a gene and the protein it encodes, Mfsd2a, inhibits transcytosis and is critical for maintaining the blood-brain barrier. Mice that lacked Mfsd2a, which is found only in endothelial cells in the central nervous system, had higher rates of vesicle formation and leaky barriers, despite having normal tight junctions.

    Unfavorable conditions

    In the current study, Gu, Benjamin Andreone, an HMS neurobiology student and their colleagues examined how Mfsd2a maintains the blood-brain barrier.

    Mfsd2a is a transporter protein that moves lipids containing DHA, an omega-3 fatty acid found in fish oil and nuts, into the cell membrane. To test the importance of this function to the barrier, the team created mice with a mutated form of Mfsd2a, in which a single amino acid substitution shut down its ability to transport DHA. They injected these mice with a fluorescent dye and observed leaky blood-brain barriers and higher rates of vesicle formation and transcytosis—mirroring mice that completely lacked Mfsd2a.

    A comparison of the lipid composition of endothelial cells in brain capillaries against those in lung capillaries—which do not have barrier properties and do not express Mfsd2a—revealed that brain endothelial cells had around two- to five-fold higher levels of DHA-containing lipids.

    Additional experiments revealed that Mfsd2a suppresses transcytosis by inhibiting the formation of caveolae—a type of vesicle that forms when a small segment of the cell membrane pinches in on itself. As expected, mice with normal Cav-1, a protein required for caveolae formation, and that lacked Mfsd2a exhibited higher transcytosis and leaky barriers. Mice that lacked both Mfsd2a and Cav-1, however, had low transcytosis and impermeable blood-brain barriers.

    2
    Endothelial cells without Mfsd2a (top) have higher rates of caveolae vesicle formation, compared to cells with Mfsd2a (bottom). No image credit.

    “We think that by incorporating DHA into the membrane, Mfsd2a is fundamentally changing the composition of the membrane and making it unfavorable for the formation of these specific type of caveolae,” Andreone said. “Even though we observed low rates of vesicle formation and transcytosis in blood-brain barrier cells decades ago, this is the first time that a cellular mechanism can explain this phenomenon.”

    By revealing the role of Mfsd2a and how it controls transcytosis in the central nervous system, Gu and her colleagues hope to shed light on new strategies to open the barrier and allow drugs to enter and remain in the brain. They are currently testing the efficacy of an antibody that potentially can temporarily block the function of Msfd2a, and whether caveolae-mediated transcytosis can be leveraged to shuttle therapeutics across the barrier.

    “Many of the drugs that could be effective against diseases of the brain have a hard time crossing the blood-brain barrier,” Gu said. “Suppressing Mfsd2a may be an additional strategy that allows us to increase transcytosis, and deliver cargo such as antibodies against beta-amyloid or compounds that selectively attack tumor cells. If we can find a way across the barrier, the impact would be enormous.”

    This work was supported by The National Institutes of Health (grants F31NS090669, NS092473), the Mahoney postdoctoral fellowship, the Howard Hughes Medical Institute, the Kaneb Fellowship, Fidelity Biosciences Research Initiative and the Harvard Blavatnik Biomedical Accelerator.

    Additional authors include Brian Wai Chow, Aleksandra Tata, Baptiste Lacoste, Ayal Ben-Zvi, Kevin Bullock, Amy A. Deik, David D. Ginty and Clary B. Clish.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 12:39 pm on January 23, 2017 Permalink | Reply
    Tags: , , Harvard Cryo-Electron Microscopy Center for Structural Biology, HMS,   

    From HMS: “The Future of Molecular Visualization” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    January 18, 2017
    No writer credit found

    New cryo-electron microscopy center to transform biomedical imaging

    1
    Cryo-EM images can reveal new insights into how the molecular machines of a cell operate. Image: Maofu Liao.

    Seeing a molecule in a microscope was once the stuff of science fiction. No longer.

    With the creation of the Harvard Cryo-Electron Microscopy Center for Structural Biology in the Longwood Medical Area, Harvard University today launched a pivotal initiative in molecular visualization, which promises remarkable advances in scientists’ ability to see molecules directly.

    Visualizing molecules at the level of atoms enables in-depth understanding of molecular mechanisms in both normal and disease states. Seeing subtle molecular details will fuel the development of next-generation precision therapeutics.

    The new center emerged from a bold and visionary collaboration among partners from Harvard Medical School, the University’s Office of the Provost, Boston Children’s Hospital and Dana-Farber Cancer Institute.

    “This new center demonstrates how Harvard and its affiliated institutions can partner to establish leading-edge facilities and resources that accelerate biomedical discoveries,” said Alan Garber, provost of Harvard University.

    Stephen Blacklow, the Gustavus Adolphus Pfeiffer Professor and chair of the Department of Biological Chemistry and Molecular Pharmacology at HMS, remarked, “The cooperation and resolve shown by all participants in pursuit of this effort has been truly impressive and foreshadows an outstanding future for molecular visualization at Harvard.”

    George Q. Daley, dean of HMS, said, “We now have a microscope that allows us to see single molecules at the atomic level. This innovation will energize science in the hospitals and on the Quad, catalyzing translational research to see where it can bear on disease.”

    “Cryo-electron microscopy is an important tool to reveal the structures of many building blocks essential to our understanding of human biology and the alterations that affect health and disease states,” added Barbara J. McNeil, former acting dean of HMS.

    “We are extremely excited about the new HMS center and look forward over the coming years to an explosion in our understanding of cellular machines,” said Wade Harper, the Bert and Natalie Vallee Professor of Molecular Pathology and chair of the Department of Cell Biology at HMS.

    Cryo-electron microscopy (cryo-EM) represents the latest frontier in imaging deployed by structural biologists.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 10:34 am on January 11, 2017 Permalink | Reply
    Tags: A healthy lifestyle may help you sidestep Alzheimer’s, , , HMS,   

    From HMS: “A healthy lifestyle may help you sidestep Alzheimer’s” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    January 09, 2017
    Heidi Godman

    1
    No image caption. No image credit

    January is an inspiring time to make resolutions about eating a healthy diet and exercising more, maybe because you want to look or feel better. Personally, those reasons aren’t always enough to keep me from skipping a workout if I have too much on my schedule. I guess I’m a typical mom, putting my family and my job first.

    But this year, I have plenty of renewed inspiration to put my health first, and it’s the kind that will keep me up at night if I don’t stick to it: evidence suggests that adopting healthier lifestyle habits may help you thwart or even prevent the development of Alzheimer’s disease. Dementia runs in my family.

    About Alzheimer’s

    Alzheimer’s disease, the most common form of dementia, is characterized by the accumulation of two types of protein in the brain: tangles (tau) and plaques (amyloid-beta). Eventually, Alzheimer’s kills brain cells and takes people’s lives.

    What causes Alzheimer’s? We still aren’t sure. “For 1% of all cases, there are three genes that determine definitively whether you will have Alzheimer’s, and all three relate to amyloid-beta production, which in these cases is likely the cause of Alzheimer’s,” says Dr. Gad Marshall, associate medical director of clinical trials at the Center for Alzheimer Research and Treatment at Harvard-affiliated Brigham and Women’s Hospital. “For the other 99%, amyloid and tau are closely associated with Alzheimer’s, but many things may contribute to the development of symptoms, such as inflammation in the brain, vascular risk factors, and lifestyle.”

    Promising evidence

    So far, evidence suggests that several healthy habits may help ward off Alzheimer’s. Consider the following steps.

    Exercise. “The most convincing evidence is that physical exercise helps prevent the development of Alzheimer’s or slow the progression in people who have symptoms,” says Dr. Marshall. “The recommendation is 30 minutes of moderately vigorous aerobic exercise, three to four days per week.”

    Eat a Mediterranean diet. “This has been shown to help thwart Alzheimer’s or slow its progression. A recent study showed that even partial adherence to such a diet is better than nothing, which is relevant to people who may find it difficult to fully adhere to a new diet,” says Dr. Marshall. The diet includes fresh vegetables and fruits; whole grains; olive oil; nuts; legumes; fish; moderate amounts of poultry, eggs, and dairy; moderate amounts of red wine; and red meat only sparingly.

    Get enough sleep. “Growing evidence suggests that improved sleep can help prevent Alzheimer’s and is linked to greater amyloid clearance from the brain,” says Dr. Marshall. Aim for seven to eight hours per night.

    Not as certain

    We have some — but not enough — evidence that the following lifestyle choices help prevent Alzheimer’s.

    Learn new things. “We think that cognitively stimulating activities may be helpful in preventing Alzheimer’s, but the evidence for their benefit is often limited to improvement in a learned task, such as a thinking skills test, that does not generalize to overall improvement in thinking skills and activities of daily living,” says Dr. Marshall.

    Connect socially. “We think that greater social contact helps prevent Alzheimer’s,” explains Dr. Marshall, but so far, “there is only information from observational studies.”

    Drink — but just a little. There is conflicting evidence about the benefit of moderate alcohol intake (one drink per day for women, one or two for men) and reduced risk of Alzheimer’s. “It is thought that wine in particular, and not other forms of alcohol, may be helpful, but this has not been proved,” says Dr. Marshall.

    What you should do

    Even though we don’t have enough evidence that all healthy lifestyle choices prevent Alzheimer’s, we do know they can prevent other chronic problems. For example, limiting alcohol intake can help reduce the risk for certain cancers, such as breast cancer. So it’s wise to make as many healthy lifestyle choices as you can. “They’re all beneficial, and if they wind up helping you avoid Alzheimer’s, all the better,” says Dr. Marshall.

    But don’t feel like you need to rush into a ramped-up routine of living a healthier lifestyle. All it takes if one small change at a time, such as:

    exercising an extra day per week.
    getting rid of one unhealthy food from your diet.
    going to bed half an hour earlier, or shutting off electronic gadgets half an hour earlier than normal, to help you wind down.
    listening to a new kind of music, or listening to a podcast about a topic you’re unfamiliar with.
    or having lunch with a friend you haven’t seen in a while.

    Once you make one small change, try making another. Over time, they will add up. My change is that I’m going to add 15 more minutes to my exercise routine; that way, I’ll rack up more exercise minutes per week, and I won’t feel bad if I have to skip a workout now and then. By putting my health first, I’ll be in better shape for my family and my job, and hopefully, I’ll be better off in older age.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

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    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 7:56 am on August 23, 2016 Permalink | Reply
    Tags: , HMS, Hypertrophic cardiomyopathy (HCM) – in black Americans, Imprecise Diagnoses,   

    From HMS: “Imprecise Diagnoses” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    August 17, 2016
    EKATERINA PESHEVA

    1
    No image caption. No image credit.

    Genetic tests for potentially fatal heart anomaly can misdiagnose condition in black Americans

    Genetic testing has greatly improved physicians’ ability to detect potentially lethal heart anomalies among asymptomatic family members of people who suffer cardiac arrest or sudden cardiac death.

    But a study from Harvard Medical School published in the Aug. 18 issue of The New England Journal of Medicine shows that over the last decade these lifesaving tools may have disproportionately misdiagnosed one cardiac condition — hypertrophic cardiomyopathy (HCM) – in black Americans.

    HCM, which affects one in 500 people, is an often-asymptomatic thickening of the heart muscle that can spark fatal arrhythmias in seemingly healthy young adults.

    The notion that genetic tests could misread benign genetic alterations as disease-causing mutations is not entirely new, but this study is believed to be the first one to trace the root of the problem to racially biased methodologies in early studies that defined certain common genetic variants as causes of HCM.

    Indeed, the analysis reveals that in the case of HCM, the false positive diagnoses stemmed from inadequately designed clinical studies that used predominantly white populations as control groups.

    White Americans harbor far fewer benign mutations on several genes implicated in HCM than black Americans. The higher rate of benign alterations in the latter group can cause test results to be misread as abnormal, the researchers say.

    Using statistical simulations, the HMS team demonstrated that including even small numbers of black participants in the original studies would have improved test accuracy and, consequently, helped avert some of the false-positive diagnoses.

    The findings, the researchers say, highlight the importance of interpreting genetic test results against diverse control populations to ensure that normal variations of genetic markers common in one racial or ethnic group do not get misclassified as disease-causing in another.

    The team says their findings point to a pressing need to reevaluate decades-old genetic studies by using new racially diverse sequencing data.

    “We believe that what we’re seeing in the case of hypertrophic cardiomyopathy may be the tip of the iceberg of a larger problem that transcends a single genetic disease,” said study first author Arjun Manrai, a research fellow in the Department of Biomedical Informatics at Harvard Medical School. “We hope our study motivates a systematic review of this issue across other genetic conditions.

    Aside from the emotional toll that a genetic misdiagnosis can take on individuals and families, the researchers say their findings represent a cautionary tale with a broad relevance to geneticists, clinicians and policy-makers alike.

    “Our study powerfully illustrates the importance of racial and ethnic diversity in research,” says Zak Kohane, senior investigator on the study and chair of the Department of Biomedical Informatics at Harvard Medical School. “Racial and ethnical inclusiveness improves the validity and accuracy of clinical trials and, in doing so, can better guide clinical decision-making and choice of optimal therapy. This is the essence of precision medicine.”

    In the current study, the team analyzed more than 8,000 DNA samples stored in three national databases — the National Institutes of Health’s Mendelian Exome Sequencing Project, the 1000 Genomes Project and the Human Genome Diversity Project.

    Five genetic variants — each of them benign — accounted for 75 percent of all genetic variation across populations. However, the team found, these five mutations occurred disproportionately in black Americans.

    Between 2.9 and 27 percent of black Americans harbored one or more such variants, compared with 0.02 to 2.9 percent of white Americans.

    Next, researchers examined records of more than 2,000 patients and family members tested at a leading genetic laboratory between 2004 and 2014. Seven patients received reports indicating they harbored disease-causing mutations that were subsequently reclassified as benign. Five of the seven patients were black, and two were of unspecified ancestry.

    Researchers say it remains unclear how many of the seven patients had been re-contacted to communicate the change in test results.
    The investigators caution that test results from a single genetic lab are not necessarily representative of the scope of the problem nationally, but say their findings likely point to a discrepancy that goes beyond a single laboratory and a single condition.

    To trace the root of the misclassifications, researchers reviewed the five original studies that shaped early understanding of genetic variants and their role in the development of hypertrophic cardiomyopathy. All of them, the researchers found, analyzed small population sizes and none indicated that black people were included in the control groups.

    But, the investigators add, even small studies can avert misclassification of genetic variants as long they include racially diverse populations.

    Using statistical simulation, the team showed that a sample of 200 people that included 20 black participants would have only 50 percent chance of correctly ruling out a harmful mutation. The same sample would have more than an 80 percent accuracy if a third of patients were black and more than 90 percent accuracy if half of them were black.

    Investigators say the newly created Exome Aggregation Consortium — a compilation of data from various large-scale sequencing projects that includes DNA from more than 60,000 individuals — is well-powered to discern between harmful and benign mutations even for relatively rare genetic variants and should help in the reanalysis of decades-old data.

    The latest clinical guidelines urge physicians to interpret genetic test results by cross-referencing them against racially matched controls. However, with expanding efforts to sequence DNA from various ethnic and racial groups, researchers say more genetic variants will be reclassified in the next decade. Interpreting the meaning of test results within the context of such rapidly evolving knowledge will pose a serious challenge for clinicians.

    One way to address the problem, the HMS team says, could be the use of point-of-care risk calculators to help clinicians and genetic counselors more precisely gauge the significance of a given genetic variant. Such risk calculators would use algorithms that incorporate statistical probability, race, ethnicity and family history to help sift variant noise from truly pathogenic mutations.

    “Ensuring that genomic medicine benefits all people and all populations equally is nothing short of a moral imperative, not only for scientists and clinicians but for political and health policy powers that be,” Kohane said.

    The work was funded by the National Human Genome Research Institute under grant 5T32HG002295-9, by the National Institute of Mental Health under grant P50MH094267 and by the National Centers for Biomedical Computing under grant 5U54-LM-008748.

    Other investigators on the research included Birgit Funke, Ph.D., Heidi Rehm, Ph.D., Morten Olesen, Ph.D., Bradley Maron, M.D., Peter Szolovits, Ph.D., 
David Margulies, M.D., Joseph Loscalzo, M.D., Ph.D.


    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 7:07 am on August 23, 2016 Permalink | Reply
    Tags: , HMS, ,   

    From HMS: “A Neuron’s Hardy Bunch” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    August 17, 2016
    EKATERINA PESHEVA

    1
    A normal mouse neuron with intact docking stations (in green). Docking stations, critical parts of a neuron’s communication machinery, house neurotransmitter-packed bubbles (in red) that stand ready to launch when a trigger arrives. A new HMS study reveals that even when these docking stations are dismantled, neurons retain some of their ability to communicate with each other. No image credit.

    Neuroscientists have long known that brain cells communicate with each other through the release of tiny bubbles packed with neurotransmitters—a fleet of vessels docked along neuronal ends ready to launch when a trigger arrives.

    Now, a study conducted in mice by neurobiologists at Harvard Medical School reveals that dismantling the docking stations that house these signal-carrying vessels does not fully disrupt signal transmission between cells.

    The team’s experiments, described Aug. 17 in the journal Neuron, suggest the presence of mechanisms that help maintain partial communication despite serious structural aberrations.

    “Our results not only address one of the most fundamental questions about neuronal activity and the way cells in the brain communicate with each other but uncover a few surprises too,” said Pascal Kaeser, senior author on the study and assistant professor of neurobiology at HMS.

    “Our findings point to a fascinating underlying resilience in the nervous system.”

    Ultrafast signal transmission between neurons is vital for normal neurologic and cognitive function. In the brain, cell-to-cell communication occurs at the junction that connects two neurons—a structure known as a synapse.

    At any given moment, neurotransmitter-carrying vesicles are on standby at designated docking stations, called active zones, each awaiting a trigger to release its load across the synaptic cleft and deliver it to the next neuron.

    Signal strength and speed are determined by the number of vesicles ready and capable of releasing their cargo to the next neuron.

    Neuroscientists have thus far surmised that destroying the docking stations that house neurotransmitter-loaded bubbles would cause all cell-to-cell communication to cease. The HMS team’s findings suggest otherwise.

    To examine the relationship between docking stations and signal transmission, researchers analyzed brain cells from mice genetically altered to lack two key building proteins, the absence of which led to the dismantling of the entire docking station.

    When researchers measured signal strength in neurons with missing docking stations, they observed that those cells emitted much weaker signals when demand to transmit information was low. However, when stronger triggers were present, these cells transmitted remarkably robust signals, the researchers noticed.

    “We would have guessed that signal transmission would cease altogether but it didn’t,” said Shan Shan Wang, a neuroscience graduate student in Kaeser’s lab and a co-first author of the study. “Neurons appear to retain some residual communication even with a key piece of their communication apparatus missing.”

    Elimination of one active zone building block, a protein called RIM, led to a three-quarter reduction in the pool of vesicles ready for release. Disruption of another key structural protein, ELKS, resulted in one-third fewer ready-to-deploy vesicles. When both proteins were missing, however, the total reduction in the number of releasable vesicles was far less than expected. More than 40 percent of a neuron’s vesicles remained in a “ready to launch” state even with the entire docking station broken down and vesicles failing to dock.

    The finding suggests that not all launch-ready vesicles need to be docked in the active zone when a trigger arrives. Neurons, the researchers say, appear to form a remote critical reserve of vesicles that can be quickly marshaled in times of high demand.

    “In the absence of a docking sites, we observed that vesicles could be quickly recruited from afar when the need arises,” said Richard Held, an HMS graduate student in neuroscience and co-first author on the paper.

    The team cautions that any clinical implications remain far off, but say that their observations may help explain how defects in genes responsible for making neuronal docking stations may be implicated in a range of neurodevelopmental disorders.

    The work was funded by grants from the National Science Foundation (DGE1144152) and the National Institutes of Health (F31NS089077; RO1NS083898); and by the Nancy Lurie Marks Foundation, the Brain Research Foundation, the Harvard Brain Initiative and the Lefler Foundation.

    Co-investigators included Man Yan Wong, Changliang Liu and Aziz Karakhanyan, all of Harvard Medical School.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

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    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 11:40 am on August 15, 2016 Permalink | Reply
    Tags: , Bacteria cell walls, Cracking the Wall, HMS,   

    From HMS: “Cracking the Wall” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    August 15, 2016
    ELIZABETH COONEY

    1
    Lines in this colorized image of Bacillus subtilis reflect the movement of a newly identified polyermase complex (including the SEDS protein) as it synthesizes hoops of bacterial cell wall material. Image: Rudner lab

    Harvard Medical School scientists have identified a new family of proteins that virtually all bacteria use to build and maintain their cell walls.

    The discovery of a second set of cell wall synthesizers can help pave the way for much-needed therapies that target the cell wall as a way to kill harmful bacteria, said study leaders David Rudner and Thomas Bernhardt.

    Findings of the research are published Aug. 15 in Nature.

    “We know these proteins are a great target because they are enzymes we can inhibit from the outside of the cell,” said Rudner, senior author of the paper and HMS professor of microbiology and immunobiology.

    “Now we have a better handle on what these proteins do and how a potential drug might affect their activity,” said Bernhardt, the paper’s co-author and HMS professor of microbiology and immunobiology.

    The cell wall plays a critical role in maintaining a bacterium’s structural integrity, dictating its shape and warding off external assaults from toxins, drugs and viruses. The cell wall is made of chains of sugars linked together by short peptides.

    For half a century, penicillin-binding proteins—molecules named for the drug that disables them—were thought to be the major, perhaps only, cell wall synthesizers.

    Penicillin was discovered in 1928 and first used to treat bacterial infections in 1942, but it wasn’t until 1957 that scientists understood how penicillin blocked the proteins that build the cell walls of bacteria. Research in the 1970s and 1980s on the bacterium Escherichia coli fleshed out the mechanism by which penicillin-binding proteins build the cell wall.

    Clues that other players may be involved in cell wall biogenesis emerged later. A crucial discovery, made in 2003, was overlooked by many in the field: The bacterium Bacillus subtilis was capable of growing and synthesizing its cell wall even in the absence of penicillin-binding proteins. Some researchers were tantalized by the “missing polymerase,” sometimes called the “moonlighting enzyme.”

    Tsuyoshi Uehara, former HMS research fellow in the Bernhardt lab and co-author of the paper, was one of those scientists. He thought a family of proteins responsible for a cell’s shape, elongation, division and spore formation, or SEDS proteins in scientific shorthand, might be prime suspects for the missing enzyme. SEDS proteins move around the circumference of the bacterial cell in a manner suggesting they might be involved in synthesizing the wall, and, if inactivated, perturb cell wall synthesis.

    To test the hypothesis that SEDS proteins may be involved in cell wall synthesis, Alexander Meeske, HMS graduate student in the Rudner lab and the paper’s first author, deleted all the known penicillin-binding proteins involved in polymerizing the cell wall. Yet, SEDS proteins continued to move in much the same way as they always had. The observation made SEDS proteins look like the missing enzymes and more like major players than mere moonlighters.

    Later experiments, both genetic and biochemical, confirmed that SEDS proteins are indeed a completely new family of cell wall synthesizers.

    The scientists also showed that the two families of cell wall synthesizers could work in tandem: While SEDS proteins circumnavigate the cell wall making hoop-like structures, penicillin-binding proteins move diffusely, making smaller strands that, together with the hoop-like strands, build the cell wall.

    Earlier studies showing that bacteria died when the penicillin-binding proteins were blocked obscured the importance of SEDS proteins, the researchers said.

    In the current paper, the scientists found that SEDS proteins are more common in bacteria than are the penicillin-binding proteins, raising hopes that a potential antibiotic targeting SEDS proteins could be effective against a broad spectrum of bacteria.

    “For a long time in the field, it was thought that one set of enzymes worked in one set of complexes to build a wall. Now we have two sets of enzymes appearing to work in different systems,” Bernhardt said. “Somehow they have to coordinate to build this netlike structure that maintains integrity and expands as the cells grow and divide.”

    How the two families of proteins work together is just one of many questions raised by the new work.

    “Even though the history goes all the way back to the 1920s with penicillin, there’s plenty to learn,” Bernhardt said.

    “That’s what makes this so exciting,” Rudner said. “In this modern era of sequenced genomes, we’re still discovering new enzymes that work in this pathway.”

    This work was supported by the National Institutes of Health grants GM073831, RC2 GM092616, AI083365 and AI099144; and CETR grant U19AI109764.

    Co-investigators included Eammon Riley, William Robins, John Mekalanos, Daniel Kahne, Suzanne Walker and Andrew Kruse. All six Harvard labs are participants in a Centers of Excellence for Translational Research (CETR) grant.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

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    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 8:27 am on August 15, 2016 Permalink | Reply
    Tags: Alchohol use and abuse, , , HMS,   

    From HMS: “Perspective on alcohol use and cancer risk” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    August 12, 2016
    Steven J. Atlas, MD

    1
    No image credit

    As a primary care doctor who gets to know and follow patients over many years, I like to think of myself as a trusted health advisor. When it comes to advice about lifestyle issues that affect health, I rarely think in terms that are black or white. There are exceptions — it is hard to argue against the benefits of regular physical activity and nothing good can come from cigarette smoking. However, for most other things, including use of alcohol, things aren’t so straightforward. Now if I was a specialist who mainly saw the negative effects of alcohol misuse — such as liver specialists who care for people with acute and chronic liver injury or trauma surgeons who see the outcomes of drinking and driving — maybe it would be simpler. But for most of my patients, alcohol is a normal part of life, and has both good and bad attributes.

    This is the background from which I view a new study on the relationship between alcohol and cancer. In case you don’t have time to read to the end, here is the bottom line: This study isn’t going to become part of my discussion about the pros and cons of alcohol consumption. For those who have the time, here’s why:

    First, it isn’t because some of the cancers attributed to alcohol use aren’t serious––they are.

    Anyone who has had a loved one with cancer of the esophagus (swallowing pipe) knows this to be true. The problem is in the context in which I counsel about the role of alcohol in my patient’s lives. For a few, alcohol is nothing but bad news, and this study doesn’t add to what we already know. For these individuals, the challenge is that I don’t have especially effective tools to help these patients remain alcohol free.

    For others, the problem isn’t chronic abuse but bad judgment when they do drink.

    So called binge drinkers can function very well day-to-day, but whether they drink once a week, once a month, or once a year, when they do drink they may not realize their impairment as they get in their car to drive home. For these patients, I assess their risk (for example, are they drinking more than they say they are) and spend a lot of time making them aware of the potential risk and discussing specific strategies to put in place well before the first drink is consumed.

    For most of my patients in whom alcohol isn’t misused, the question is how to frame the health effects.

    I’ll admit to an occasional glass of wine after a long day at work. Then, there is the so-called J-shaped curve of heart disease-related death saying that the lowest risk is in patients with moderate use, that is 1-2 beers (12 oz.), glasses of wine (5 oz.) or 1.5 oz. mixed drink a day. People who abstain entirely have somewhat higher risk, but that is overshadowed by much higher risk in heavy drinkers. I also caution that alcohol can be a source of unneeded calories and for many of my patients it is a simple way to eliminate some.

    Though this new study doesn’t create any new data, it uses existing studies to argue that there is sufficient information to support a role for alcohol in causing cancer despite the problem that were not sure how because alcohol itself (unlike cigarettes) isn’t a known carcinogen. There is also the problem, as noted previously that some alcohol use may decrease risk of heart disease. Finally, if alcohol was causing cancer, wouldn’t we see correlations between population level alcohol consumption and cancer death rates? I’m not aware that such data exists. Without more information about the level of risk for those who drink in moderation and separating that risk from other behaviors that can go along with drinking, such as cigarette use, I don’t find this new evidence to be compelling me to change the discussion I have with patients.

    How I’ll talk to my patients about patterns of alcohol use

    Instead, I will continue categorize my patients based upon their pattern of alcohol use. Even if moderate alcohol use has some finite risk, there is also the question of how much of a risk it is—and how does that risk compare to other things they do or don’t do in their lives. I see this as a key role for primary care physicians. We want to frame personal choices — not enough activity, safe driving habits, unhealthy eating, and yes, alcohol use — in a way that provides perspective and hopefully motivation. My role is to advise about the things each of us can do to improve the quality and quantity of our lives. We all can do better, but I don’t think that scaring patients with the C word is the way to do it.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

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    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 7:39 am on August 4, 2016 Permalink | Reply
    Tags: , HMS, , Poor health care around the globe, Probe and Suture   

    From HMS: “Probe and Suture” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    8.4.16
    Jake Miller

    1

    It doesn’t take long to break a leg. It can happen in an instant and in many different ways: a traffic accident, a workplace misstep, or a slip on the way home from school. But what happens afterward differs greatly depending on where you are.

    In most parts of the United States, the injured leg would be repaired surgically using well-established orthopedic procedures that have been developed to help restore the limb’s normal functioning, and medications would be administered to stave off the risk of infection from either the injury or the surgery.

    For any of the five billion people globally who don’t have access to safe, affordable surgical care, the story could have a different ending: disability, impoverishment, or even death from infection.

    Although surgery is an integral part of health care in industrialized countries, research from a report by the Lancet Commission on Global Surgery, an international group that seeks to improve the quality of and access to surgical care around the world, reveals that nine out of ten people living in many low- and lower-middle-income countries simply do not have access to surgical care. In addition, the report estimates that the worldwide human and economic costs of poor to no access to surgical care could reach slightly more than U.S. $12 trillion in the next five years.

    This situation, say many in the global health community, may result from the fact that for too long surgical care has been considered too costly to be on the list of must-do improvements to the delivery of health care.

    HMS students win innovation challenge with their safe, collapsible, aseptic surgery device

    There is, however, a growing chorus calling for change. New collaborative working models are finding unexpected ways to deliver care, while the work of entities such as the Lancet Commission are providing data to help propel that change. And many of the individuals leading the drive for study and change are surgeons and researchers from HMS.

    Tundra to Tropics

    The Gundrum family from Wisconsin anticipated difficulties even before their son Dominic was born. Ultrasounds revealed a rare, severe facial cleft and, from his forehead, an encephalocele, a protrusion of the brain and its membrane. Searching for ways to help their son, they came across the story of a Haitian boy named Dumanel born with a similar condition. Dumanel, they learned, had received help from HMS surgeon, and co-chair of the Lancet Commission, John Meara.

    Dominic also became a patient of Meara’s, and, like Dumanel’s, his facial cleft and encephalocele were repaired. Meara, the Steven C. and Carmella R. Kletjian Professor of Global Health and Social Medicine in the field of Global Surgery at HMS and plastic surgeon-in-chief at Boston Children’s Hospital, has spent years treating patients wherever he finds them, working on the cleft palates and craniofacial anomalies of patients in southeast Asia, Australia, the Caribbean, and the United States. He says he doesn’t think of his work at Boston Children’s and his global surgery work as separate practices.

    “Human beings have the same problems and diseases regardless of whether they’re in Boston or Bangkok,” Meara says. “They should have the same care, wherever they are.”

    In Sync

    Ron Alterman would more than agree with Meara on the need to improve surgical care and access to such care throughout the world. His work in Chile sets inequities in surgical care and facilities in sharp relief.

    In 2014, Alterman, an HMS professor of neurosurgery and the head of neurosurgery at Beth Israel Deaconess Medical Center, traveled to Santiago to perform the first deep-brain stimulation procedure undertaken in Chile’s public hospital system. He was invited by David Aguirre-Padilla, a Chilean neurosurgeon who had spent time in Boston working with Alterman on various neurosurgical techniques, particularly those involving deep-brain stimulation. Aguirre-Padilla hoped to use deep-brain stimulation to treat a young patient who suffered from generalized dystonia, a neurological disorder in which out-of-sync firing of neurons in the brain cause the muscles of the body to contract involuntarily.

    Deep-brain stimulation works like a pacemaker for the brain, sending synchronized electrical signals into specific regions of the brain where electrodes have been implanted. The electrical pulses help regulate the firing of neurons and thus calm the involuntary contractions. To make sure the electrodes are properly placed, a surgeon takes a reading of the patient’s brain activity while the wires are being implanted. Conditions must be controlled within the operating room to ensure clean readings: if, for example, there are electrical wires that aren’t properly shielded, background noise can perturb the readings from the implanted electrodes.

    Alterman has performed this surgery more than a thousand times in operating rooms in New York City and Boston, so the complexity of the procedure did not trouble him. What did present a challenge that day, he says, was the fact that the hospital’s CT scanner broke, stymieing efforts to visually check the placement of the electrodes. To get a visual read on their placement, he and his patient had to take an ambulance across town to a hospital with a functioning MRI.

    Although the patient came through the surgery well, Alterman points out that the lack of suitable support equipment made a complex procedure more challenging than necessary—and could have the same effect on routine procedures. Reliable equipment, a consistent supply of electricity, and clean water can be hard to maintain in some countries, Alterman says, adding that it is a problem that will need to be addressed as Chile and other nations develop their surgical capacity.

    Those who question whether surgery should be considered part of global health development often cite this need for across-the-board modernization and standardization as reasons for keeping surgery out of these development discussions. The costs are said to be too steep with the feeling being that focus should instead be placed on efforts such as eradicating a single communicable disease or providing anti-malarial bed nets, which offer quicker and more obvious returns on investment. By contrast, those who want to keep surgery on the table during global health development discussions point out that the basic infrastructure improvements being advocated for surgical care are also needed for effective nonsurgical care.

    Light Duties

    The need for better surgical equipment and training in her native Vietnam prompted Thanh-Nga Tran ’05 to establish and maintain a center that offers continuing medical education and modern tools to Vietnamese dermatologists.

    When Tran returned to Vietnam during her residency with the Harvard Dermatology Program, she saw many children with disfiguring birthmarks. She was also startled to see some who had been burned and scarred by radioactive phosphorus, an outdated technique for treating vascular anomalies. Tran realized that the scars she saw on her young patients weren’t from a disease or accident, but from a misguided treatment.

    “The cure shouldn’t be worse than the disease itself,” says Tran, an HMS instructor in dermatology at Massachusetts General Hospital and cofounder of the Vietnam Vascular Anomalies Center, now part of the Ho Chi Minh City University of Medicine and Pharmacy.

    During her training at HMS and MIT, Tran had learned about using lasers to treat hemangiomas, the rubbery nodules of extra blood vessels in the skin sometimes known as strawberry birthmarks. With the help of her mentor, Richard Anderson ’84, an HMS professor of dermatology at Mass General, she obtained a donated laser and set out to find a way to get better treatment to the people who needed it.

    Tran knew that one laser and a team of volunteer doctors in a rented room would not reach enough patients or make the systemic changes needed, so she developed partnerships with local doctors and institutions. The center now offers continuing medical education training to Vietnamese dermatologists and has launched a public education campaign on the dangers of using radioactive phosphorus as a dermatologic treatment. Center personnel also have convinced the main cancer hospitals and practitioners in Ho Chi Minh City to end their use of radioactive phosphorus.

    Throughout the HMS community, the individual humanitarian efforts of professionals like Alterman, Meara, and Tran are being augmented by large-scale projects aimed at addressing the lack of surgical infrastructure around the world. In 2012, the Dana Farber–Brigham and Women’s Cancer Center, for example, collaborated with Partners In Health and the Rwanda Ministry of Health to open the first comprehensive cancer referral facility in rural East Africa, while surgeons from Mass General have been developing surgical education programs in Liberia and Bangladesh since 2002. Yet the question of how to fit all these pieces together to solve the puzzle of improving surgery worldwide remains.

    Weights and Measures

    From the beginning, Meara says, the goal of the Lancet Commission wasn’t just to quantify the lack of global surgical capacity; it was to create a base of knowledge and measurable indicators that could be used to build that capacity in a coherent, focused way.

    When the commission was established in 2013, Meara adds, no one knew what was going on with surgery around the world. There were no comprehensive assessments of how many surgeons worked in different countries, few records of how many or what kinds of surgical procedures were being done in a given country each year, and no reliable estimate of what percentage of a population lived within two hours of a hospital that offered essential surgical procedures.

    Even the most basic safety index—how many people survived surgery—has often gone unknown, almost completely absent from international development databases and national health care planning reports.

    According to Meara, the commission has been able to derive rough estimates of various measures in many countries, but detailed measures remain elusive. Since the commission published its report in April 2015, Meara has had the growing corps of surgeons working in the Paul Farmer Global Surgery Fellowship in the HMS Department of Global Surgery and Social Change focus on collecting key indicators of surgical capacity from more than one hundred countries and on developing better, more detailed analyses of the data that are available.

    The important thing, according to those involved in assessing surgery worldwide, is to know that surgery is not a separate entity that competes with all the other changes needed in health care systems. It’s not just about broken legs—it’s about obstructed labor, cancer, infectious disease, and every other condition you can name.

    See the full article herePlease help promote STEM in your local schools.

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    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

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    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
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