News Article | May 10, 2017
Among today's most promising weapons against cancer is the use of therapies that direct the immune system against a tumor. One approach - immune checkpoint blockade - is designed to circumvent the "off switches" that prevent the immune system from attacking healthy tissues but also can shield a tumor from the immune response. These drugs have had remarkable success in some but not all patients, and long-term survival has been achieved in a minority of patients. Now a study from Massachusetts General Hospital (MGH) investigators has identified a surprising mechanism for resistance to immune checkpoint blockade. In their paper published online in Science Translational Medicine, the researchers describe finding that an antibody-based drug designed to block the immunosuppressive molecule PD-1 is removed from its target T cells by macrophages within minutes of administration in several mouse models of cancer. They also identify the molecular mechanism behind this drug capture, which could lead to ways to prevent the process. "Immune checkpoint blockers are very effective in some patients but not others, and our current ability to understand why treatments work or fail is quite limited," says Mikael Pittet, PhD, director of the Cancer Immunology Program in the MGH Center for Systems Biology and senior author of the report. "Using high-resolution molecular imaging to track immune checkpoint drugs in real time, we were able to discover what was happening, devise ways to extend the time the drug binds to its target and improve treatment efficacy in our models." Immune checkpoint molecules like PD-1 are expressed on the surface of CD8 T cells - the immune system's "killer cells" that attack cells that are damaged or diseased, including cancer cells - and act to suppress an inappropriate T cell response. Monoclonal antibodies that block pathways controlled by checkpoint molecules are the basis of current checkpoint blockade drugs. The MGH team used intravital microscopy - which examines biological processes in living animals through tiny implanted windows - to track the activity of an antiPD-1 drug in mouse models of colon cancer. As expected, the labeled antibody was observed to bind to PD-1 molecules on CD8 T cells within a few minutes. But as little as 20 minutes later, the drug had been taken up by macrophages within the tumors. The same process of rapid antibody binding to PD-1 molecules on CD8 T cells, followed by macrophage uptake, was observed in models of melanoma and lung cancer. To determine how the antibodies were being removed from T cells, the researchers first confirmed that the macrophages neither expressed PD-1 molecules nor did they take up antibody not bound to T cells. Experiments in mouse and human tumor cells revealed that antibody removal was accomplished through the interaction of the Fc region - the portion of an antibody that communicates with and directs the action of immune cells - and Fc receptors on the surface of macrophages. Administering an Fc receptor inhibitor prior to anti-PD-1 treatment both extended the binding of the drug to CD8 T cells and led to complete tumor disappearance in a mouse model. Whether a similar strategy could improve the results of immune checkpoint blockade in human patients may be answered by current clinical trials that combine immune checkpoint blockers with drugs targeting macrophages, which have number of detrimental effects in cancer. "Our observations would not have been possible without a method of dynamically imaging drug action on a cellular level," says Pittet, who is an associate professor of Radiology at Harvard Medical School. "Our platform for imaging anti-PD-1 in live animals can easily be adapted to study additional checkpoint blockade agents, so we are building a program to track the cellular interactions that will allow us to decipher drug mechanisms and hopefully leverage knowledge into engineering better therapeutics." The lead authors of the Science Translational Medicine report are Sean Arlauckas, PhD, and Christopher S. Garris, MGH Center for Systems Biology. Additional co-authors are Rainer Kohler, PhD, Michael Cuccarese, PhD, Katherine Yang, PhD, Miles Miller, PhD, Jonathan Carlson, MD, PhD, and Ralph Weissleder, MD, PhD, Center for Systems Biology; Maya Kitaoka and Robert Anthony, PhD, MGH Center for Immunology and Infectious Disease; and Gordon Freeman, PhD, Dana-Farber Cancer Institute. Support for the study includes the Samana Cay MGH Research Scholar Fund, National Institutes of Health grants R01AI084880, R01CA164448, R21CA190344, U54-CA151884, P50CA086355, DP2AR068272-01, and HL084312; Department of Defense grant PC140318, and the David H. Koch-Prostate Cancer Foundation Award in Nanotherapeutics. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
News Article | April 20, 2017
A Massachusetts General Hospital (MGH)-led research team has identified a surprising new role for macrophages, the white blood cells primarily known for removing pathogens, cellular debris and other unwanted materials. In their paper published in Cell the investigators describe discovering that macrophages are also essential to the healthy functioning of the heart, helping conduct the electric signals that coordinate the heartbeat. "Our finding that a new cell type is involved in cardiac conduction may lead to better understanding of normal heart function. What really surprised me was that macrophages can depolarize -- change their electric charge -- when coupled to a myocyte. Down the line, this work on the role of macrophages in conduction may lead to new treatments for cardiac arrhythmias," says corresponding author Matthias Nahrendorf, MD, PhD, of the MGH Center for Systems Biology. Best known for their immune system activity of engulfing and digesting microbes, damaged cells and foreign substances, macrophages are found in tissues throughout the body and have recently been shown to have additional functions related to the tissues where they reside. While macrophages are required for healing damaged tissues in the heart, their presence within healthy heart muscle suggests a role in normal heart function. Nahrendorf's study was designed to investigate their potential role in transmitting and coordinating the electrical signals that stimulate heart muscle contraction. Initial experiments in mice revealed that cardiac macrophages are more abundant in the atrioventicular (AV) node -- a key structure connecting the atria (upper chambers) to the ventricles (lower chambers) -- which coordinates contraction timing for the upper and lower chambers. Similarly high concentrations of macrophages were found in AV nodes from human autopsy samples. Subsequent animal experiments found that macrophages connect to heart muscle cells via gap junctions -- pore-like structures known to coordinate heart muscle contractions -- and that the shifts in electric charge that carry the conduction signal are synchronized between macrophages and adjacent heart muscle cells called myocytes. Mice lacking a key gap junction protein showed an abnormal slowing of signal conduction through the AV node, and a complete depletion of tissue macrophages led to the development of AV block -- a delay in conduction between the atria and ventricles that, in human patients, requires pacemaker implantation. Overall, the findings suggest that cardiac macrophages are essential participants in the cardiac conduction system and that changes in their numbers or properties may contribute to heart rhythm abnormalities. Nahrendorf and his colleagues are continuing to explore the role of macrophages in both the healthy heart and in common disorders of signal conduction. He adds that the cells' natural propensity to surround and take up materials for disposal could be used to induce macrophages to ingest drugs carried on nanoparticles. The co-lead authors of the Cell paper are Maarten Hulsmans, PhD, of the MGH Center for Systems Biology and Sebastian Clauss, MD, and Ling Xiao, PhD, of the MGH Cardiovascular Research Center. Additional co-authors include David Milan, MD, and Patrick Ellinor, MD, PhD, of the CVRC. Support for the study includes National Institutes of Health grants NS084863, HL128264, HL114477, HL117829, HL092577, HL105780, and HL096576. The MGH has filed a patent application covering the work described in this paper. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
Vazquez A.,Center for Systems Biology |
Bertino J.R.,University of New Brunswick
Cancer Research | Year: 2013
Previous studies have documented the roles of transport via the reduced folate carrier, retention via polyglutamylation, and increased levels of the target enzyme, dihydrofolate reductase in sensitivity to methotrexate. Recent studies have shown that the mitochondrial enzymes in the cellular metabolism of serine, folate, and glycine are overexpressed in a subset of human cancers and that their expression is required for tumor maintenance. In this Perspective article, we propose that the expression of mitochondrial enzymes in the metabolism of serine and glycine, in addition to those involved in folate metabolism, are determinants of the response to methotrexate. Furthermore, we show that myc activation in tumors is associated with upregulation of these enzymes.Wepropose that patients whose tumors show this phenotype will be sensitive to folate antagonists targeting thymidylate or purine biosynthesis. © 2012 AACR.
News Article | November 13, 2015
University of Oregon scientists have found that strength in numbers doesn't hold true for microbes in the intestines. A minority population of the right type might hold the key to regulating good health. The discovery, based on research using zebrafish raised completely germ free, is reported in a paper published in the Nov. 11 issue of Cell Host & Microbe. The findings provide a path to study the function of each bacterial species in the gut and to eventually, perhaps, predict and prevent disease, says lead author Annah S. Rolig, a postdoctoral researcher in the UO's Institute of Molecular Biology. In the project, researchers watched for immune response as isolates of species of bacteria, normally associated with healthy zebrafish, were introduced one at a time and in combination into previously germ-free intestines of the fish. In a telling sequence, one bacterial species, Vibrio, drew numerous neutrophils, which indicated a rapid inflammatory response in one fish. Another species, Shewanella, inserted into a separate germ-free fish barely attracted an immune response. In a third germ-free fish, both species were introduced together and assembled with a ratio of 90- percent Vibrio to 10-percent Shewanella. The inflammatory response in the third fish was completely controlled by the low-abundance species. "Until now, we've only been able to capture proportional information, like you'd see displayed in a pie graph, of the makeup of various microbiota, in percentages of their abundance," Rolig said. "Biologists in this field have typically assumed an equal contribution based on that makeup." Low counts of a bacterial species generally have been discounted in importance, but slight shifts in the ratios of abundant microbe populations have been thought to have roles in obesity, diabetes and inflammatory bowel diseases such as Crohn's disease. That thinking is now changing, Rolig said. "The contribution of each bacterium is not equal. There is a per-capita effect that needs to be considered." The keystone - an important participant that functions to regulate a healthy microbiota - may reside in low-abundant bacterial species. The research team found through additional scrutiny that these species secreted molecules - for now unidentified - that allowed them to dampen the immune response to the whole community. "Now we've shown that these minor members can have a major impact. If we can identify these keystone species, and find that in a disease state one species may be missing, we might be able to go in with a specific probiotic to restore healthy functioning," said Rolig, who also is a scientist in the National Institutes of Health-funded Microbial Ecology and Theory of Animals Center for Systems Biology, known as the META Center, at the UO. To develop a model to capture per-capita contributions of microbes in a population, Rolig and her co-authors -- biology graduate student Adam R. Burns, microbiologist Brendan Bohannan of the Institute of Ecology and Evolution and biologist Karen Guillemin, director of the META Center -- turned to UO physicist Raghuveer Parthasarathy. His math-driven model, detailed in the paper, provides formulas that predict collective inflammatory responses of combinations of bacteria. "I'm really proud of this paper because it exemplifies an achievement of one of the major goals of the META Center for Systems Biology, namely to provide a predictive model of how host-microbe systems function," Guillemin said. "This experimental and modeling framework could be readily generalized to more complex systems such as humans, for example to predict disease severity in individuals with inflammatory bowel disease based on the pro-inflammatory capacity of their gut microbes as assayed in cell culture."
News Article | December 13, 2016
The findings, which could someday lead to new diabetes treatments, highlight the important role of resident microbes in development of the pancreas EUGENE, Ore. -- Dec. 13, 2016 -- A newly discovered bacterial protein produced in the zebrafish gut triggers insulin-producing beta cells of the pancreas to multiply during early larval development, say University of Oregon researchers. The research potentially has human health implications. Beta cells are the only cells that produce insulin, a hormone that regulates sugar metabolism. A lack of insulin production is associated with Type 1 diabetes, an autoimmune disease that affects some 1.5 million people in the U.S. The research appeared in a paper published online on Dec. 13 in the open-access journal eLife. The research demonstrates the developmental role of teeming communities of bacteria and other microbes -- the microbiota -- in the bodies of animals, said UO biologist Karen Guillemin, a co-author. Understanding how the microbiota affects the development of beta cells, which are lost in patients with Type 1 diabetes, eventually could lead to new diagnostic, preventative and therapeutic approaches for this disease, she said. "We're realizing that the microbiome is a rich source for discovering new biomolecules that have enormous potential for manipulating and promoting our health," said Guillemin, a professor in the UO Department of Biology and Institute of Molecular Biology. She also is director of the UO's META Center for Systems Biology. Using germ-free zebrafish as a model, lead author and doctoral student Jennifer Hampton Hill explored the possibility that certain gut bacteria are necessary for the pancreas to populate itself with a robust number of beta cells during development. She found that, during the first week of life, germ-free fish did not undergo the same expansion of beta cells as conventionally reared fish. Exposing the germ-free fish to specific bacteria, however, restored the beta cell mass to normal levels. This restoration became the basis for her search and ultimate discovery of a novel bacterial protein that on its own could stimulate the growth of insulin-producing cells. "The research suggests that animals rely on the cues and signals from the microbial communities that inhabit their bodies and that they are important for very intricate parts of development," Hampton Hill said. "It's exciting to think that bacteria could play such an important role in a process that is so essential for homeostasis, for the ability to regulate glucose metabolism." "This is a new idea that the microbiome could be a source for signals for the development of the pancreas," Guillemin said. "This is the first time that anyone has made a connection between the microbiome and the development of beta cells." Scientists have been increasing their understanding of how host-associated microbes influence the development of the gut and immune system, but the formative role of microbes in other digestive organs such as the pancreas remains an underexplored area, the researchers said. The UO has been a leader in zebrafish research since the 1960s when biologist George Streisinger pioneered a new method for the study of vertebrate development and genetics with the introduction of the small fish as a model organism. Over the past 15 years, Guillemin and colleagues have developed methods for growing germ-free zebrafish, allowing them to ask what happens when the animals develop in the absence of microbes. The use of germ-free zebrafish allowed Hampton Hill to methodically screen for gut bacteria that could stimulate beta cell proliferation. She then focused on one bacterium from this group and investigated its secreted proteins for beta cell-expanding activity. Those efforts led to a list of 163 prospective proteins. She next turned to the genome sequences of the previously screened bacteria and asked which of the prospective proteins were shared by the beta cell-expanding bacteria and absent from inert bacteria. Her criteria returned only a single protein candidate that had never been studied. When she made a purified version of it and added it to her germ-free fish, the beta cell population expanded -- earning the protein its name of Beta Cell Expansion Factor A, or BefA. Knowing the molecular identity of BefA allowed the researchers to search for its sequence in other bacterial genomes. They found it to be present in several common human-gut associated bacteria. When Hampton Hill purified two of these related proteins from human bacteria, they proved to be equally potent at stimulating beta cell expansion in zebrafish. "We had spent many years collecting and characterizing zebrafish gut bacteria, and it was gratifying that we could harness all of this knowledge in the discovery of BefA," Guillemin said. The finding that specific gut bacteria produce proteins that stimulate beta cell development sheds new light on epidemiological data connecting low-diversity childhood microbiomes with increased Type 1 diabetes risk. It may be, Guillemin and Hampton Hill said, that low-diversity microbiomes are less capable of stimulating beta cell expansion early in life, leaving children with little buffer if their immune systems go on the attack. An implication of the study, Guillemin said, is the importance of promoting healthy microbiome development in children -- for example, by promoting breast feeding and avoiding excessive use of antibiotics. Additional research is needed to identify the mechanism by which BefA proteins affect beta cell development and whether the proteins have the same effect in other animals, including humans, she said. "Ultimately we'd like to team up with researchers studying Type 1 diabetes to look at developing BefA-related molecules as potential therapeutics." p>Additional co-authors on the study were Eric A. Franzosa and Curtis Huttenhower, both of Harvard University's T. H. Chan School of Public Health in Boston and the Broad Institute in Cambridge, Massachusetts. Co-author Guillemin also is affiliated with the Humans and the Microbiome Program at the Canadian Institute for Advanced Research in Toronto. The National Institutes of Health supported the research through grants P50GM098911, T32GM007413 and P01HD22486. Note: The UO is equipped with an on-campus television studio with a point-of-origin Vyvx connection, which provides broadcast-quality video to networks worldwide via fiber optic network. There also is video access to satellite uplink and audio access to an ISDN codec for broadcast-quality radio interviews.
News Article | February 16, 2017
Research using mutant zebrafish that model human disease zeroes in on how changes in the abundance of certain resident bacteria determines disease fate EUGENE, Ore. -- Feb. 16, 2017 -- Numerous human diseases, including inflammatory bowel disease, diabetes and autism spectrum disorders have been linked to abnormal gut microbial communities, or microbiomes, but an open question is whether these altered microbiomes are drivers of disease. A new study at the University of Oregon, led by postdoctoral fellow Annah Rolig, took aim at that question with experiments in zebrafish to dissect whether changes in the abundance of certain gut bacteria can cause intestinal inflammation. The study, published Feb. 16 in PLOS Biology, made use of a mutant zebrafish strain that models human Hirschsprung disease, which is caused by loss of the gut neurons that coordinate gut contractions. Just like Hirschsprung disease patients, who sometimes develop an inflammatory condition called Hirschsprung-associated enterocolitis, a subset of the fish developed intestinal inflammation. The researchers successfully tracked how gut bacterial abundances influenced inflammation. Fish with intestinal inflammation had a larger abundance of a subset of bacteria that appeared to be pro-inflammatory, which they confirmed by dosing the fish with one of these bacteria and finding that it increased the severity of disease symptoms. They also found a subset of bacteria that was depleted in the inflamed intestines, but present in the mutant fish that remained disease-free. Dosing the fish with a strain of these depleted bacteria ameliorated the disease. Finally, they showed that they could cure the inflammation by transplanting gut neurons from healthy fish into the diseased fish. These studies demonstrate that inflammatory intestinal pathologies, such as Hirschsprung-associated enterocolitis or inflammatory bowel disease, can be explained as an overgrowth of certain pro-inflammatory groups of bacteria or a loss of anti-inflammatory bacteria, said Judith Eisen, a professor of biology and an expert on gut neurons in zebrafish. The study stems from a long-term collaboration between Eisen and Karen Guillemin, who studies gut bacteria and inflammation. "When we started this work, very few people were thinking about how the nervous system and gut bacteria interact," said Eisen, who is a member of the UO's Institute of Neuroscience. "Our studies demonstrate how important it is to consider all the interacting cells of an organ, including the microbial cells." "Human microbiomes can be overwhelmingly variable due to differences between people's environments, diets and genetics," said Guillemin, a biologist and member of the UO's Institute of Molecular Biology. "The zebrafish model allowed us to control those variables and see how bacterial strains tracked with inflammation. From these patterns, we could show that the drivers of disease can be a very few members of a complex microbial community." Identifying the bacteria that drive and protect against disease is the first step toward developing microbial interventions and therapies, said Rolig, a postdoctoral researcher in the UO's Institute of Molecular Biology. "The fact that we could alleviate inflammation by adding back a single key bacterial strain, suggests that it could be useful as a probiotic for inflammatory diseases," said Rolig, who, along with Eisen, is a scientist in the National Institutes of Health-funded Microbial Ecology and Theory of Animals Center for Systems Biology, known as the META Center, which Guillemin heads. The next steps for the research group are to use what they have learned from this zebrafish model of gut inflammation to design better probiotics to treat intestinal inflammation. Co-authors with Rolig, Eisen and Guillemin were: Erika K. Mittge, Josh V. Troll, Travis J. Wiles and W. Zak Stephens of the UO's Institute of Molecular Biology; and Julia Ganz, Kristin Alligood and Ellie Melancon of the UO Institute of Neuroscience. The National Institutes of Health supported the research. Sources: Judith Eisen, professor of biology, 541-346-4524, email@example.com; Karen Guillemin, professor of biology, 541-346-5360, firstname.lastname@example.org; and Annah Rolig, postdoctoral fellow, 541-346-5999, email@example.com Note: The UO is equipped with an on-campus television studio with a point-of-origin Vyvx connection, which provides broadcast-quality video to networks worldwide via fiber optic network. There also is video access to satellite uplink and audio access to an ISDN codec for broadcast-quality radio interviews.
New method developed to predict response to nanotherapeutics Taking a precision medicine approach to nanomedicine, researchers use MR imaging with magnetic nanoparticles to predict which tumors may be more responsive to therapeutic nanoparticles
News Article | November 19, 2015
Home > Press > New method developed to predict response to nanotherapeutics: Taking a precision medicine approach to nanomedicine, researchers use MR imaging with magnetic nanoparticles to predict which tumors may be more responsive to therapeutic nanoparticles Abstract: Many nanotherapeutics are currently being tested in clinical trials and several have already been clinically approved to treat cancers. But the ability to predict which patients will be most responsive to these treatments has remained elusive. Now, a collaboration between investigators at Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH) has led to a new approach that uses an FDA-approved, magnetic nanoparticle and magnetic resonance imaging (MRI) to identify tumors most likely to respond to drugs delivered via nanoparticles. The team's preclinical results are published in Science Translational Medicine November 18. "Just as genetics is used in some cases to predict an individual's response to a drug, we wanted to develop a companion diagnostic that can predict response based on physiological differences," said Miles Miller, PhD, a postdoctoral fellow at the MGH Center for Systems Biology. "We hypothesized that ferumoxytol - a product that has been approved for the treatment of anemia - could be used to identify tumors that are more likely to respond to a nanomedicine." "Our goal is to develop new nanotherapeutics that can be safely and effectively delivered to cancer patients," said Omid Farokhzad, MD, director of the Laboratory of Nanomedicine and Biomaterials at BWH. "One of the key translational challenges has been to better match patients to new nanotherapeutics based on patients' physiology. Our work takes a precision medicine approach to nanotherapeutics: using this technique, we can predict how well drug-loaded nanoparticles will accumulate in a particular tumor." Farokhzad -- who has founded three companies, all of which have nanomedicines in the clinic or fast-approaching clinical trials -- teamed up with Ralph Weissleder, MD, PhD, Director of the MGH Center for Systems Biology and an expert in high-resolution in vivo imaging. The researchers hypothesized that the accumulation of nanoparticles may vary from patient to patient based on an individual's unique physiology. For instance, some patients may harbor tumors with more "leaky" vasculature or other physiological conditions that allow nanoparticles to accumulate faster at tumor sites. This accumulation of nanoparticles within tumors is known as the enhanced permeability and retention (EPR) effect. To determine if it would be possible to predict which tumors have high or low EPR, the investigators used ferumoxytol in mouse models of solid tumor cancers. Because it is magnetic, ferumoxytol can be imaged using MRI. "Clinical impact is the ultimate goal of our work. Therefore, we tested an imaging technology, MRI, commonly used in the clinic and a diagnostic nanoparticle, ferumoxytol, that is already FDA-approved for other indications," said Weissleder, who is also an Attending Clinician in Interventional Radiology at MGH. In addition to using MRI, the team labeled the magnetic nanoparticles with a fluorescent dye, allowing them to see the accumulation of particles on a single-cell level by microscopy.They categorized each tumor as having "low," "medium" or "high" EPR and then treated each tumor with a chemotherapeutic drug delivered via nanoparticles. The researchers report that in preclinical models, their MR imaging strategy accurately predicted how much drug would reach the tumors (with more drug being delivered to tumors with higher EPR) and therefore how well the tumors would respond to the drug-loaded nanoparticles. "This work represents a major stepping stone toward translating new discoveries of nanotherapeutics into clinical impact and selecting patients for nanotherapeutic trials," said Farokhzad. To continue moving this work closer to clinical validation, the team intends to perform similar studies in patients. Studies of different forms of cancer may also help the team to identify which cancer types will be most responsive to nanotherapeutics. ### This work was supported in part by the NIH (R01CA164448, U54-CA151884, 5P50CA086355, and HL084312, T32 CA79443) and the David H. Koch-Prostate Cancer Foundation Award in Nanotherapeutics. Farokhzad discloses his financial interest in BIND Therapeutics, Selecta Biosciences and Blend Therapeutics, which develop nanoparticle medical technologies but did not support this study. About Brigham and Women's Hospital Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 4.2 million annual patient visits, nearly 46,000 inpatient stays and employs nearly 16,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $600 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation's first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials groups. For more information, resources and to follow us on social media, please visit BWH's online newsroom. About Massachusetts General Hospital Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $800 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2015, MGH returned into the number one spot on the 2015-16 U.S. News & World Report list of "America's Best Hospitals." For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.
News Article | January 20, 2016
Scientists hunting for academic jobs got a rare glimpse into the mysterious tenure-track hiring process. A blog post written by computational genomicist Sean Eddy at Harvard University in Cambridge, Massachusetts, outlined the steps that he and his colleagues have taken since November to evaluate nearly 200 applicants for a Harvard faculty position. Interviews for six candidates begin this week. A tweet by Eddy on 9 January attracted fresh attention to the blog post, with commenters applauding his efforts to lift the veil on the selection process. Holly Bik, a genomics and bioinformatics researcher at New York University who is applying for jobs, tweeted: Eddy is a co-chair of the hiring committee for the faculty position at Harvard’s FAS Center for Systems Biology, and only joined the faculty there in July 2015. He says that he wrote the blog post to clarify the hiring process, adding that he is not commenting on Harvard’s recruitment policy. “People don’t get a lot of information about what happens in one of these searches and what the selection criteria are,” he says. “I’m worried about people not applying because they think we’re not going to hire minorities or women or people who don’t have Harvard degrees.” Eddy described the first step as triage, in which three faculty members (including the two hiring committee chairs) review every application, spending about ten minutes on each one. He wrote that he is looking for a clear research question in the research proposal, and looks through the publication history and attached publications — not to scrutinize journal impact factors or citation counts, but to assess the quality, creativity and trajectory of a candidate’s scientific contributions. “I think a lot of the angsty gnashing of teeth about needing Nature/Science/Cell papers is self-inflicted by the candidates,” Eddy writes. Honours, grants and letters of recommendation count at this stage, too. Successful applications are then re-read by three faculty members randomly chosen from the entire eight-member committee. They take a more thorough look at the research aims and the publications. In the end, however, Eddy admits: “A lot of it comes down to intangibles, like whether people in the department get excited about a candidate’s research question,” he writes. Eddy noted that the applicant group was made up of only 21% female candidates and 5% from underrepresented minorities. Many — Eddy didn’t count the exact number — had done at least some of their training at Harvard. Bik responded to the blog post, noting that she avoided applying for Harvard positions because of the sheer volume of other jobs that she was also applying for. She decided to place her bets on positions where she thought she had the best chance of success. “I said: ‘I’m not going to apply for this one because I have other applications that I really need to focus more of my time on’,” she said in an interview. On Twitter, Eddy asked Bik’s advice on how to avoid applicants taking themselves out of the running so that employers can recruit from a broader pool of applicants: Bik also suggested in her blog comment that crowd-sourced job wikis — on which job applicants anonymously compile information about available faculty positions — would be good places for schools to encourage applications from people who might need a nudge. In his post, Eddy also wrote that he tries to consider his own implicit biases — such as those against women and minorities in science — during the shortlisting process. One way to measure these biases is with an online test designed by Harvard social ethicist Mahzarin Banaji and her colleagues. Eddy says that he has taken this test a few times — after starting at Harvard and again after reading the hiring committee’s guidelines. “I used to think that I don’t have such biases. … Now I know I have implicit biases,” he wrote in the blog post. To counteract them, he said he initially evaluated applications from women and minority candidates separately from those from men, and then combined the shortlists — but not to create quotas, he added. “It’s one of the few concrete things I can think of to do in a process like this, to force people including myself to have a conscious, slow, second look at their decisions,” Eddy said. “It’s a work in progress. These are tough issues.” Bioengineer Ian Holmes, an associate professor at the University of California, Berkeley, who has worked with Eddy in the past, commended him in a tweet: Holmes acknowledged his own bias in subsequent tweets, adding in an interview: “I find it regrettable that I am biased, but I think there is more shame in not acknowledging one’s bias than in having the bias.” Eddy’s post resonated with other faculty members who have been involved in recruitment. Joan Strassmann, an evolutionary biologist and professor at Washington University in St. Louis, tweeted: Strassmann has written for years about the challenges of hiring faculty members on her Sociobiology blog. “I don’t want anyone to not go into [academia] because it seems like a club with secret rules,” she said in an interview. In November, she wrote how the process is inherently unfair. “Our job is to hire an excellent scientist, colleague, and teacher,” she wrote. “There are likely to be others even better in the pool, but not discoverable by our imperfect techniques.” Bik says that increased transparency in hiring is good for applicants. Whereas some might have insider information about a position because of well-connected mentors, others may have to rely only on what they can find online. “I think that transparency and availability of information are extremely valuable to evening out the playing field.”
News Article | October 23, 2015
In the battle against cancer, which kills nearly 8 million people worldwide each year, doctors have in their arsenal many powerful weapons, including various forms of chemotherapy and radiation. What they lack, however, is good reconnaissance — a reliable way to obtain real-time data about how well a particular therapy is working for any given patient. Magnetic resonance imaging and other scanning technologies can indicate the size of a tumor, while the most detailed information about how well a treatment is working comes from pathologists’ examinations of tissue taken in biopsies. Yet these methods offer only snapshots of tumor response, and the invasive nature of biopsies makes them a risky procedure that clinicians try to minimize. Now, researchers at MIT’s Koch Institute for Integrative Cancer Research are closing that information gap by developing a tiny biochemical sensor that can be implanted in cancerous tissue during the initial biopsy. The sensor then wirelessly sends data about telltale biomarkers to an external “reader” device, allowing doctors to better monitor a patient’s progress and adjust dosages or switch therapies accordingly. Making cancer treatments more targeted and precise would boost their efficacy while reducing patients’ exposure to serious side effects. “We wanted to make a device that would give us a chemical signal about what’s happening in the tumor,” says Michael Cima, the David H. Koch (1962) Professor in Engineering in the Department of Materials Science and Engineering and a Koch Institute investigator who oversaw the sensor’s development. “Rather than waiting months to see if the tumor is shrinking, you could get an early read to see if you’re moving in the right direction.” Two MIT doctoral students in Cima’s lab worked with him on the sensor project: Vincent Liu, now a postdoc at MIT, and Christophoros Vassiliou, now a postdoc at the University of California at Berkeley. Their research is featured in a paper in the journal Lab on a Chip that has been published online. The sensors developed by Cima’s team provide real-time, on-demand data concerning two biomarkers linked to a tumor’s response to treatment: pH and dissolved oxygen. As Cima explains, when cancerous tissue is under assault from chemotherapy agents, it becomes more acidic. “Many times, you can see the response chemically before you see a tumor actually shrink,” Cima says. In fact, some therapies will trigger an immune system reaction, and the inflammation will make the tumor appear to be growing, even while the therapy is effective. Oxygen levels, meanwhile, can help doctors gauge the proper dose of a therapy such as radiation, since tumors thrive in low-oxygen (hypoxic) conditions. “It turns out that the more hypoxic the tumor is, the more radiation you need,” Cima says. “So, these sensors, read over time, could let you see how hypoxia was changing in the tumor, so you could adjust the radiation accordingly.” The sensor housing, made of a biocompatible plastic, is small enough to fit into the tip of a biopsy needle. It contains 10 microliters of chemical contrast agents typically used for magnetic resonance imaging (MRI) and an on-board circuit to communicate with the external reader device. Devising a power source for these sensors was critical, Cima explains. Four years ago, his team built a similar implantable sensor that could be read by an MRI scanner. “MRI scans are expensive and not easy to make part of routine care,” he says. “We wanted to take the next step and put some electronics on the device so we could take these measurements without an MRI.” For power, these new sensors rely on the reader. Specifically, there’s a metal coil inside the reader and a much smaller coil in the sensor itself. An electric current magnetizes the coil inside the reader, and that magnetic field creates a voltage in the sensor’s coil when the two coils are close together — a process called mutual inductance. The reader sends out a series of pulses, and the sensor “rings back,” as Cima puts it. The variation in this return signal over time is interpreted by a computer to which the reader is wired, revealing changes in the targeted biomarkers. “With these devices, it’s like taking blood pressure. It’s a simple measurement. You get the readout and move on,” says Ralph Weissleder, a radiologist and director of the Center for Systems Biology lab at Massachusetts General Hospital who is familiar with the research. “Whatever you can do right then and there without any complicated testing, the better it is. Cima’s team successfully tested the sensors in lab experiments, including implanting them in rodents. While the sensors were only implanted for a few weeks, Cima believes they could be used to monitor a person’s health over many years. “There are thousands of people alive today, because they have implantable electronics, like pacemakers and defibrillators,” he says. “We’re making these sensors out of materials that are in these kinds of long-term implants, and given that they’re so small, I don’t think there will be a problem.” These initial experiments showed that the sensors could quickly, reliably, and accurately detect pH and oxygen concentration in tissue. The researchers next want to see how well the sensors do measuring changes in pH over an extended period of time. “I want to push these probes so we can use them to monitor tumor response,” Cima says. “We did a little bit of that in these experiments, but we need to make that really robust.” While the primary application of these sensors would be cancer care, Cima is also eager to collaborate with researchers in other fields, such as environmental science. “For example, you could use these to measure dissolved oxygen or pH from a lot of different sites all over a pond or a lake,” Cima says. “I’m excited about using these sensors to bring big data to environmental monitoring.”
Babitt J.L.,Center for Systems Biology |
Lin H.Y.,Center for Systems Biology
American Journal of Kidney Diseases | Year: 2010
Anemia is prevalent in patients with chronic kidney disease (CKD) and is associated with lower quality of life and higher risk of adverse outcomes, including cardiovascular disease and death. Anemia management in patients with CKD currently revolves around the use of erythropoiesis-stimulating agents and supplemental iron. However, many patients do not respond adequately and/or require high doses of these medications. Furthermore, recent clinical trials have shown that targeting higher hemoglobin levels with conventional therapies leads to increased cardiovascular morbidity and mortality, particularly when higher doses of erythropoiesis-stimulating agents are used and in patients who are poorly responsive to therapy. One explanation for the poor response to conventional therapies in some patients is that these treatments do not fully address the underlying cause of the anemia. In many patients with CKD, as with patients with other chronic inflammatory diseases, poor absorption of dietary iron and the inability to use the body's iron stores contribute to the anemia. Recent research suggests that these abnormalities in iron balance may be caused by increased levels of the key iron regulatory hormone hepcidin. This article reviews the pathogenesis of anemia in CKD, the role and regulation of hepcidin in systemic iron homeostasis and the anemia of CKD, and the potential diagnostic and therapeutic implications of these findings. © 2010 National Kidney Foundation, Inc.