Snapshot of Science is a monthly digest of publication summaries, press releases and blog posts featuring researchers from Massachusetts General Hospital.

Welcome to the August 2018 edition of Snapshot of Science. Here's a quick look at some recent publications, press releases and stories about the Mass General research community.

In this issue we highlight:

  • 24 new studies published in high impact journals, along with 16 summaries submitted by the research teams
  • 12 new research-related press releases from the Mass General Public Affairs office
  • 9 posts from the Mass General Research Institute blog

Publications

*Author-submitted summaries available when indicated

RARE CELL TYPE LINKED TO CYSTIC FIBROSIS
A Revised Airway Epithelial Hierarchy Includes CFTR-expressing Ionocytes
Montoro DT, Haber AL, Biton M, Vinarsky V, Lin B, Birket SE [et al.], Rajagopal J.
Published in Nature on August 1, 2018 *Summary available | See press release


AN INTRAOPERATIVE DIAGNOSTIC ASSAY TO IDENTIFY IDH MUTATIONS
Genotype-targeted Local Therapy of Glioma
Shankar GM, Kirtane AR, Miller JJ, Mazdiyasni H, Rogner J, Tai T [et al.], Cahill DP.
Published in Proc Natl Acad Sci USA on August 6, 2018 *Summary available | See press release


INSIGHTS INTO THE ROLE OF THE UNIPORTER IN MANGANESE TOXICITY
MICU1 Imparts the Mitochondrial Uniporter with the Ability to Discriminate Between Ca(2+) and Mn(2)
Kamer KJ, Sancak Y, Fomina Y, Meisel JD, Chaudhuri D, Grabarek Z, Mootha VK.
Published in Proc Natl Acad Sci USA on August 6, 2018 *Summary available


INSIGHTS INTO MODIFIERS OF HUNTINGTON DISEASE
Genetic Modification of Huntington Disease Acts Early in the Prediagnosis Phase
Long JD, Lee JM, Aylward EH, Gillis T, Mysore JS, Abu Elneel K [et al.], Gusella JF.
Published in Am J Hum Genet on August 7, 2018 *Summary available


CREATING KNOCK-IN MICE FOR VACCINATION MODELS
One-step CRISPR/Cas9 Method for the Rapid Generation of Human Antibody Heavy Chain Knock-in Mice
Lin YC, Pecetta S, Steichen JM, Kratochvil S, Melzi E, Arnold J [et al.], Batista FD.
Published in EMBO J on August 7, 2018  *Summary available


INSIGHTS TO IMPROVE VACCINE DESIGN FOR EBOLA VIRUS
A Role for Fc Function in Therapeutic Monoclonal Antibody-mediated Protection Against Ebola Virus
Gunn BM, Yu WH, Karim MM, Brannan JM, Herbert AS, Wec AZ [et al.], Alter G.
Published in Cell Host Microbe on August 8, 2018


CIRCULATING RNAs AS A BIOMARKER FOR HEART DISEASE
Associations of Circulating Extracellular RNAs with Myocardial Remodeling and Heart Failure
Shah RV, Rong J, Larson MG, Yeri A, Ziegler O, Tanriverdi K [et al.], Freedman JE.
Published in JAMA Cardiology on August 8, 2018 *Summary available


EEG SCANS IDENTIFY A DISTINCT BRAIN STATE PRIOR TO ANESTHESIA EMERGENCE
A Transient Cortical State with Sleep-like Sensory Responses Precedes Emergence from General Anesthesia in Humans
Lewis LD, Piantoni G, Peterfreund RA, Eskandar EN, Harrell PG, Akeju O [et al.], Purdon PL.
Published in Elife on August 10, 2018


A NEW METHOD TO SUPERCOOL WATER WITHOUT FREEZING
Long-term Deep-supercooling of Large-volume Water and Red Cell Suspensions Via Surface Sealing with Immiscible Liquids
Huang H, Yarmush ML, Usta OB.
Published in Nat Commun on August 10, 2018 *Summary available | See press release


LONG-TERM PROTECTION OF CHOLERA VACCINE BY DOSE
Long-term Effectiveness of One and Two Doses of a Killed, Bivalent, Whole-cell Oral Cholera Vaccine in Haiti: An Extended Case-control Study
Franke MF, Ternier R, Jerome JG, Matias WR, Harris JB, Ivers LC.
Published in Lancet Global Health on August 10, 2018 | *Summary available


A NEW GENETIC RISK FACTOR FOR HEART ATTACK
Genome-wide Polygenic Scores for Common Diseases Identify Individuals with Risk Equivalent to Monogenic Mutations
Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH [et al.], Kathiresan S.
Published in Nat Genet on August 13, 2018 *Summary available | See press release


A DISTINCT MOLECULAR ORIGIN FOR HÜRTHLE CELL CARCINOMA
Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma
Gopal RK, Kübler K, Calvo SE, Polak P, Livitz D, Rosebrock D [et al.], McFadden DG.
Published in Cancer Cell on August 13, 2018 *Summary available


GROWTH IN BRAIN STRUCTURES RELATED TO LANGUAGE BASED ON ADULT-CHILD CONVERSATIONS
Language Exposure Relates to Structural Neural Connectivity in Childhood
Romeo RR, Segaran J, Leonard JA, Robinson ST, West MR, Mackey AP, Yendiki A, Rowe ML, Gabrieli JDE.
Published in Journal of Neuroscience on August 13, 2018


IMPLICATIONS OF REVAMPING MEDICARE PAYMENTS FOR OFFICE VISITS
The CMS Proposal to Reform Office-Visit Payments
Song Z, Goodson JD.
Published in New England Journal of Medicine on August 15, 2018 *Summary available | See press release


ANXIETY AND ONSET OF ALZHEIMER'S DISEASE
Association of Anxiety with Subcortical Amyloidosis in Cognitively Normal Older Adults
Hanseeuw BJ, Jonas V, Jackson J, Betensky RA, Rentz DM, Johnson KA, Sperling RA, Donovan NJ.
Published in Molecular Psychiatry on August 16, 2018 *Summary available


MODIFIED METHOD TO REDUCE GENOMIC INSTABILITY IN NAIVE HESCS
Reduced MEK Inhibition Preserves Genomic Stability in Naive Human Embryonic Stem Cells
Di Stefano B, Ueda M, Sabri S, Brumbaugh J, Huebner AJ, Sahakyan A [et al.], Hochedlinger K.
Published in Nat Methods on August 20, 2018 *Summary available


ROLE OF AUTO-FATTY ACYLATION IN THE REGULATION OF CILIOGENESIS
Auto-fatty Acylation of Transcription Factor RFX3 Regulates Ciliogenesis
Chen B, Niu J, Kreuzer J, Zheng B, Jarugumilli GK, Haas W, Wu X.
Published in Proc Natl Acad Sci USA on August 20, 2018 *Summary available


IMPROVED CHARACTERIZATION OF THE GENETIC CONTRIBUTION TO PLASMA LIPIDS
Deep-coverage Whole Genome Sequences and Blood Lipids Among 16,324 Individuals
Natarajan P, Peloso GM, Zekavat SM, Montasser M, Ganna A, Chaffin M, Khera AV [et al.], Kathiresan S.
Published in Nat Commun on August 23, 2018 *Summary available


NF-2 GENE MUTATIONS MAKE CELLS HYPER-RESPONSIVE TO GROWTH FACTOR SIGNALING
Merlin/ERM Proteins Regulate Growth Factor-induced Macropinocytosis and Receptor Recycling by Organizing the Plasma Membrane:Cytoskeleton Interface
Chiasson-MacKenzie C, Morris ZS, Liu CH, Bradford WB, Koorman T, McClatchey AI.
Published in Genes Dev on August 24, 2018 *Summary available | See press release


UNDERSTANDING THE MIGRATION OF MATURE DENDRITIC CELLS
The Chemokine Receptor CCR8 Promotes the Migration of Dendritic Cells into the Lymph Node Parenchyma to Initiate the Allergic Immune Response
Sokol CL, Camire RB, Jones MC, Luster AD.
Published in Immunity on August 24, 2018 *Summary available


ULTRASOUND REVEALS MECHANISMS FOR IMPROVED DELIVERY ACROSS THE BBB
Mechanisms of Enhanced Drug Delivery in Brain Metastases with Focused Ultrasound-induced Blood-Tumor Barrier Disruption
Arvanitis CD, Askoxylakis V, Guo Y, Datta M, Kloepper J, Ferraro GB [et al.], Jain RK.
Published in PNAS on August 27, 2018 *Summary available | See press release


IMMUNE CELLS TRAVEL THROUGH SKULL BONE MARROW TO BRAIN SURFACE
Direct Vascular Channels Connect Skull Bone Marrow and the Brain Surface Enabling Myeloid Cell Migration
Herisson F, Frodermann V, Courties G, Rohde D, Sun Y, Vandoorne K [et al.], Nahrendorf M.
Published in Nat Neurosci on August 27, 2018 *See press release


IMPROVING ADHERENCE TO AAP GUIDELINES FOR DOWN SYNDROME PATIENTS
Use of Electronic Health Record Integration for Down Syndrome Guidelines
Santoro SL, Bartman T, Cua CL, Lemle S, Skotko BG.
Published in Pediatrics on August 27, 2018 *Summary available


RESULTS FROM PHASE 2 PROGRESSIVE MUTIPLE SCLEROSIS TRIAL
Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis
Fox RJ, Coffey CS, Conwit R, Cudkowicz ME, Gleason T, Goodman A [et al.], Zabeti A.
Published in New England Journal of Medicine on August 30, 2018

Publication Summaries

RARE CELL TYPE LINKED TO CYSTIC FIBROSIS
A Revised Airway Epithelial Hierarchy Includes CFTR-expressing Ionocytes
Montoro DT, Haber AL, Biton M, Vinarsky V, Lin B, Birket SE [et al.], Rajagopal J
Published in Nature on August 1, 2018

Our team from Mass General and the Broad Institute has found a new cell type in the lung that appears to be specialized in the pathways that cause cystic fibrosis. Using a new sequencing technology, we made an organ map of specialized cell types. Surprisingly, we found an exceedingly rare cell type that specializes in balancing hydration at surface of the lung, which is important in staving off infections. We named this intriguing new cell type pulmonary ionocytes, and found that ionocytes also produce most of the gene product that, when mutated, causes cystic fibrosis. Ionocytes are now the most promising cellular target for therapeutic efforts to cure cystic fibrosis.

(Summary submitted by Daniel T. Montoro, of the Rajagopal Lab in the Center for Regenerative Medicine)


AN INTRAOPERATIVE DIAGNOSTIC ASSAY TO IDENTIFY IDH MUTATIONS
Genotype-targeted Local Therapy of Glioma
Shankar GM, Kirtane AR, Miller JJ, Mazdiyasni H, Rogner J, Tai T [et al.], Cahill DP.
Published in Proc Natl Acad Sci USA on August 6, 2018

Gliomas are primary brain tumors which can be difficult to treat. Aggressive surgery to remove as much of the tumor as safely possible is critical for preventing regrowth. This is particularly important for gliomas with mutant IDH genes, typically found in patients less than 45 years old. In this manuscript, we describe two new technologies to improve surgery for glioma patients. First, we demonstrate a rapid mutation detection method, allowing for diagnostic information to be obtained in a short timeframe, during the operation. Second, in collaboration with Dr. Traverso's group from BWH and MIT, we developed an implantable microparticle that secretes drug that selectively eliminates IDH mutant cancer cells. Together, we envision these tools can be paired to improve the workflow for glioma surgery, resulting in better outcomes for patients.

(Summary submitted by Daniel Cahill, MD, PhD, of the Department of Neurosurgery)


INSIGHTS INTO THE ROLE OF THE UNIPORTER IN MANGANESE TOXICITY
MICU1 Imparts the Mitochondrial Uniporter with the Ability to Discriminate Between Ca(2+) and Mn(2)
Kamer KJ, Sancak Y, Fomina Y, Meisel JD, Chaudhuri D, Grabarek Z, Mootha VK.
Published in Proc Natl Acad Sci USA on August 6, 2018

Mechanisms by which heavy metals contribute to cellular toxicity are not well understood. Here, we report that manganese toxicity in human cells and worms is due in part to manganese transported into mitochondria via a channel called the calcium uniporter. We demonstrate that the regulatory subunit of the uniporter, MICU1, provides an additional checkpoint to discriminate between calcium and manganese, enabling the uniporter to transmit ions quickly while maintaining selectivity. This work has implications for understanding the pathogenesis of human MICU1 deficiency, a rare genetic condition, as well as manganese toxicity in neurodegenerative diseases such as Parkinson’s disease.

(Summary submitted by Vamsi Mootha, MD, and Kimberli Kramer, PhD, from the Department of Systems Biology and Department of Medicine)


INSIGHTS INTO GENETIC MODIFIERS OF HUNTINGTON'S DISEASE
Genetic Modification of Huntington Disease Acts Early in the Prediagnosis Phase
Long JD, Lee JM, Aylward EH, Gillis T, Mysore JS, Abu Elneel K [et al.], Gusella JF.
Published in Am J Hum Genet on August 7, 2018

Huntington's disease (HD) is an inherited movement disorder that emerges in mid-life and worsens over 15 years until death. There is no effective treatment to delay HD onset or progression. The disease trigger is a mutation in the HD gene, but naturally occurring DNA variations in other genes can modify HD by hastening or delaying onset. An examination of subtle differences in HD mutation carriers more than a decade before onset has now revealed that these genetic modifiers act early to influence the rate of the process that leads eventually to clinical disease and may provide targets for developing treatments to delay or prevent HD onset.

(Summary provided by James Gusella, PhD, of the Department of Neurology and the Center for Human Genetic Research)


CREATING KNOCK-IN MICE FOR VACCINATION MODELS
One-step CRISPR/Cas9 Method for the Rapid Generation of Human Antibody Heavy Chain Knock-in Mice
Lin YC, Pecetta S, Steichen JM, Kratochvil S, Melzi E, Arnold J [et al.], Batista FD.
Published in EMBO J on August 7, 2018

A major challenge in HIV-1 vaccine development involves the validation of immunogens and immunization strategies for inducing broadly neutralizing antibodies (bnAbs). In the field, mouse models bearing pre-arranged human bnAb heavy and light chain immunoglobulin genes obtained from HIV-1 positive patients with improved outcomes are considered to be appropriate for immunogen validation. We describe a CRISPR/Cas9 nuclease-mediated strategy to generate knock-in mice bearing bnAb heavy chains targeted to the native mouse immunoglobulin locus, merely three weeks after oocyte injection. This represents a breakthrough in rapidly evaluating, not only HIV-1 immunogens, but also those specific for other infectious diseases.

(Summary submitted by Usha Nair, PhD, of the Ragon Institute of MGH, MIT and Harvard)


CIRCULATING RNAS AS A BIOMARKER FOR HEART DISEASE
Associations of Circulating Extracellular RNAs With Myocardial Remodeling and Heart Failure
Shah RV, Rong J, Larson MG, Yeri A, Ziegler O, Tanriverdi K [et al.], Freedman JE.
Published in JAMA Cardiology on August 8, 2018

Heart failure is one of the leading causes of mortality from cardiovascular disease worldwide. Treatments for heart failure in its advanced stage are limited, and newer mechanisms are necessary to understand how and why the heart responds to stress. Extracellular RNAs are RNAs floating in circulating (either free, in complex with proteins, or in circulating vesicles) that send signals from one cell to another across the body. In this work, we studied participants in the Framingham Heart Study who had many RNAs measured in circulation, finding several RNAs related to pre-clinical manifestations of heart disease, including thickening of the heart muscle, that were related to long-term heart failure. If verified in other studies, these results may suggest that RNAs are not only useful to understand disease biology and potential mechanisms, but also may serve as biomarkers for identifying at-risk individuals.

(Summary submitted by Ravi Shah, MD, of the Division of Cardiology in the Department of Medicine)


A NEW METHOD TO SUPERCOOL WATER WITHOUT FREEZING
Long-term Deep-supercooling of Large-volume Water and Red Cell Suspensions Via Surface Sealing with Immiscible Liquids
Huang H, Yarmush ML, Usta OB.
Published in Nature Communication on August 10, 2018

In this article we present a very simple approach to keeping large volumes of water and water-based solutions in the liquid phase for very long times at very low temperatures (down to -20 oC / -4 oF) at which they should normally freeze. This approach relies on sealing the water surface with oil phases. Applications include preservation of biological specimens such as cells, tissues, whole organs and food. We demonstrated such an application by preserving red blood cells at a temperature of -13 oC extending their preservation period to 100 days compared to the clinical standard of 42 days.

(Summary submitted by O. Berk Usta, PhD, of the Center for Engineering in Medicine)


LONG-TERM PROTECTION OF CHOLERA VACCINE BY DOSE
Long-term Effectiveness of One and Two Doses of a Killed, Bivalent, Whole-cell Oral Cholera Vaccine in Haiti: An Extended Case-control Study
Franke MF, Ternier R, Jerome JG, Matias WR, Harris JB, Ivers LC.
Published in Lancet Global Health on August 10, 2018

In this study in Haiti, Mass General faculty and their Haitian colleagues found that two doses of an oral cholera vaccine (OCV) were effective in protecting individuals against cholera for at least 4 years. The authors and public health officials ran a campaign to vaccinate over 50,000 people against cholera in 2012 and studied cases of diarrhea for the subsequent four years. This is the first study showing that OCV has long-term effectiveness when used in a cholera outbreak, and the first study of the long-term effectiveness of OCV in a country like Haiti, where the disease was newly introduced. The results add to the evidence needed to improve prevention and control of cholera globally.

(Summary submitted by Louise Ivers, MD, of the Division of Infectious Diseases)


A NEW GENETIC RISK FACTOR FOR HEART ATTACK
Genome-wide Polygenic Scores for Common Diseases Identify Individuals with Risk Equivalent to Monogenic Mutations
Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH [et al.], Kathiresan S.
Published in Nature Genetics on August 13, 2018

Our team of researchers has identified a new genetic risk factor that could identify millions of people at more than triple the normal risk for heart attack – and millions more at high risk for type 2 diabetes, breast cancer, or atrial fibrillation. This approach involves newly developed scores that tally genetic risk information from millions of sites in our DNA where one patient differs from another. Most importantly, these high-risk individuals are currently flying under the radar within our clinical practice, but if identified, would benefit from targeted prevention efforts.

(Summary submitted by Amit Khera, MD, of the Division of Cardiology in the Department of Medicine)


A DISTINCT MOLECULAR ORIGIN FOR HÜRTHLE CELL CARCINOMA
Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma
Gopal RK, Kübler K, Calvo SE, Polak P, Livitz D, Rosebrock D [et al.], McFadden DG.
Published in Cancer Cell on August 13, 2018

Hürthle Cell Carcinoma (HCC) is a type of thyroid cancer distinct for its striking accumulation of mitochondria. With a tendency for aggressive behavior, a better understanding of the genetics of HCC is needed in order to motivate new therapies. In this study, we performed whole exome sequencing on a cohort of HCC patients representing a clinical spectrum of disease, including those with metastases. A joint analysis of the nuclear and mitochondrial genomes of HCC revealed widespread chromosomal losses and recurrent mitochondrial DNA mutations to be prominent molecular features of this tumor. Analysis of metastases showed these chromosomal and mitochondrial DNA alterations to be early events during tumor evolution. 

(Summary provided by Raj Gopal, MD, PhD, of the Mass General Cancer Center and the Department of Molecular Biology)


IMPLICATIONS OF REVAMPING MEDICARE PAYMENTS FOR OFFICE VISITS
The CMS Proposal to Reform Office-Visit Payments
Song Z, Goodson JD.
Published in New England Journal of Medicine on August 15, 2018

A new federal proposal to reduce documentation burden while flattening physician reimbursement for office visits has good intentions, but could have harmful side effects and unintended consequences for many patients and physicians. The plan—while reducing administrative burden among doctors—would allow for payment of a flat fee for office visits to physicians who care for Medicare patients regardless of the severity and complexity of their condition, or the time physicians spend seeing them. This article argues that the proposal would threaten Medicare patients with complex conditions by creating incentives for shorter and more frequent visits. Policymakers should consider alternative strategies to reduce documentation burden while maintaining the incentive to take on patients with complex medical needs.

(Summary provided by Zirui Song, MD, PhD, and John Goodson, MD, of the Department of Primary Care and Department of Medicine)


ANXIETY AND ONSET OF ALZHEIMER'S DISEASE
Association of Anxiety with Subcortical Amyloidosis in Cognitively Normal Older Adults
Hanseeuw BJ, Jonas V, Jackson J, Betensky RA, Rentz DM, Johnson KA, Sperling RA, Donovan NJ.
Published in Molecular Psychiatry on August 16, 2018

Alzheimer's disease is characterized by the accumulation of abnormal brain proteins, amyloid-beta and tau, a process that begins when older adults are cognitively unimpaired. Our research aims to define very early neurobehavioral and biological markers of Alzheimer’s disease prior to cognitive impairment. In a neuroimaging study of normal older adults, we found that high amyloid-beta in subcortical structures, a region of advanced accumulation, was associated with higher levels of anxiety and particularly in carriers of theAPOE ε 4 genetic marker. These findings point to anxiety and specific genetic and regional biomarkers that may identify individuals at highest risk of cognitive decline.

(Summary provided by Nancy Donovan, MD, of the Department of Psychiatry at Brigham and Women's Hospital, and Bernard Hanseeuw, MD, PhD, of the Gordon Center for Medical Imaging and Department of Radiology at Mass General)


MODIFIED METHOD TO REDUCE GENOMIC INSTABILITY IN NAIVE HESCS
Reduced MEK Inhibition Preserves Genomic Stability in Naive Human Embryonic Stem Cells
Di Stefano B, Ueda M, Sabri S, Brumbaugh J, Huebner AJ, Sahakyan A [et al.], Hochedlinger K.
Published in Nat Methods on August 20, 2018

Human embryonic stem cells (hESCs) have the remarkable ability to proliferate indefinitely while retaining the potential to give rise to any specialized cell type of the body, underscoring the usefulness of this cell type in basic and applied research. Scientists have recently developed strategies to maintain hESCs in a primitive state that more closely resembles the early human embryo compared to hESCs maintained in classical culture conditions. However, most hESC lines cultured under these novel conditions accrue severe chromosomal abnormalities over time, which compromises their utility in research and potential therapeutic applications. Our lab has identified the MAP kinase cascade, a key signaling pathway involved in transducing external stimuli inside the cell, as the main culprit behind these abnormalities. Importantly, we show that modulation of this pathway in cultured hESCs leads to a dramatic reduction of chromosomal abnormalities in hESCs. We expect that our approach will facilitate the expansion of hESCs with a normal genome, thus reducing a major safety risk for the ultimate use of human pluripotent cell types in a therapeutic setting.

(Summary provided by Konrad Hochedlinger, PhD, of the Department of Molecular Biology, Center for Regenerative Medicine and Mass General Cancer Center)


ROLE OF AUTO-FATTY ACYLATION IN THE REGULATION OF CILIOGENESIS
Auto-fatty Acylation of Transcription Factor RFX3 Regulates Ciliogenesis
Chen B, Niu J, Kreuzer J, Zheng B, Jarugumilli GK, Haas W, Wu X.
Published in Proc Natl Acad Sci USA on August 20, 2018

Defective cilia are associated with various developmental and degenerative disorders known as ciliopathies. RFX3 is one of the key transcription factors involved in cilia formation and functions, and pancreases development. Using chemical biology methods, we find that RFX3 can be automatically modified by specific fatty acids, called auto-fatty acylation. RFX3 fatty acylation is required for cilia gene expression, thereby regulating cilia formation and elongation (ciliogenesis). Our results indicate a major role of auto-fatty acylation in the regulation of RFX3 function and ciliogenesis, providing a potential link between deregulation of fatty acid metabolism to ciliopathies and diabetes.

(Summary provided by Wu Xu, PhD, and Baoen Chen, PhD, of the Cutaneous Biology Research Center and Department of Dermatology)


IMPROVED CHARACTERIZATION OF THE GENETIC CONTRIBUTION TO PLASMA LIPIDS
Deep-coverage Whole Genome Sequences and Blood Lipids Among 16,324 Individuals
Natarajan P, Peloso GM, Zekavat SM, Montasser M, Ganna A, Chaffin M, Khera AV [et al.], Kathiresan S.
Published in Nat Commun on August 23, 2018

Technological advancements have reduced the costs of whole genome sequencing, the most comprehensive test to profile a human genome. We now performed the largest analysis of whole genome sequences with any trait to date. In nearly 17,000 people across different ethnicities, we are able to significantly better characterize the genetic contribution to plasma lipids, which are key modifiable risk factors for heart attacks, compared to current genetic tests for plasma lipids. For example, the yield of current gene panel tests for severe hypercholesterolemia is 2% but is nearly 25% for whole genome sequencing. Ongoing studies are required to understand clinical relevance as well as to improve interpretation of whole genome sequences.

(Summary provided by Pradeep Natarajan, MD, MMSc, of the Division of Cardiology in the Department of Medicine)


NF-2 GENE MUTATIONS MAKE CELLS HYPERSENSITIVE TO GROWTH FACTOR SIGNALING
Merlin/ERM Proteins Regulate Growth Factor-induced Macropinocytosis and Receptor Recycling by Organizing the Plasma Membrane:Cytoskeleton Interface
Chiasson-MacKenzie C, Morris ZS, Liu CH, Bradford WB, Koorman T, McClatchey AI.
Published in Genes Dev on August 24, 2018

The NF2 gene is mutated in the hereditary tumor syndrome Neurofibromatosis type 2 and in other cancers, including malignant mesotheliomas. We found that cells lacking the NF2-encoded protein merlin hyper-respond to growth factors by forming dramatic waves on their surface that engulf extracellular nutrients, which may allow them to survive outside of their normal environment. This ancient form of nutrient uptake, known as macropinocytosis, presents new therapeutic opportunities for NF2-mutant tumors. For example, interfering with macropinocytosis may impair the growth of NF2-mutant tumors. Alternatively, macropinocytosis is an important pathway for delivering large drugs that cannot pass through the cell membrane.

(Summary provided by Andrea McClatchey, PhD, and Christine Chiasson MacKenzie, PhD, of the Mass General Cancer Center)


UNDERSTANDING THE MIGRATION OF MATURE DENDRITIC CELLS
The Chemokine Receptor CCR8 Promotes the Migration of Dendritic Cells into the Lymph Node Parenchyma to Initiate the Allergic Immune Response
Sokol CL, Camire RB, Jones MC, Luster AD.
Published in Immunity on August 24, 2018

Immune responses start when dendritic cells–innate immune cells that survey the body for signs of damage or infection–move to the lymph node to activate the adaptive immune response. Researchers from Massachusetts General Hospital show that allergen-activated dendritic cells use a two-step pathway to move from the skin to the lymph node. The first step is common to all dendritic cells, but the second step is dependent on the chemokine receptor CCR8 and its ligand CCL8, and is specific to allergen-exposed dendritic cells. Interfering with this CCR8-CCL8 step the researchers blocked allergic immune responses, defining a new pathway that could be targeted to treat and prevent allergic diseases.

(Summary provided by Caroline Sokol, MD, PhD, and Andrew Luster, MD, PhD, of the Division of Rheumatology, Allergy and Immunology and Department of Medicine)


MECHANISMS FOR IMPROVED DELIVERY ACROSS THE BLOOD BRAIN BARRIER
Mechanisms of Enhanced Drug Delivery in Brain Metastases with Focused Ultrasound-induced Blood-Tumor Barrier Disruption
Arvanitis CD, Askoxylakis V, Guo Y, Datta M, Kloepper J, Ferraro GB [et al.], Jain RK.
Published in PNAS on August 27, 2018

The blood-brain barrier (BBB) can hinder drug delivery in brain malignancies. In this article, the authors revealed, for the first time, the mechanisms underlying the improved delivery of drugs across the BBB into brain tumors using focused ultrasound. Using advanced microscopy techniques and mathematical modeling, they demonstrated that ultrasound leads to increased flow of interstitial fluid between tumor cells resulting in better drug penetration, provided evidence of increased drug uptake by endothelial cells and identified optimal conditions for improved transport of therapeutics. By unraveling the potential of combining focused ultrasound with different drugs for the treatment of brain metastases, their work provides important scientific insights that can inform future clinical trials.

(Summary provided by Costas D. Arvanitis, PhD, and Rakesh Jain, PhD, of the Steele Laboratories for Tumor Biology and Department of Radiation Oncology)


IMPROVING ADHERENCE TO AAP GUIDELINES FOR DOWN SYNDROME PATIENTS
Use of Electronic Health Record Integration for Down Syndrome Guidelines
Santoro SL, Bartman T, Cua CL, Lemle S, Skotko BG.
Published in Pediatrics on August 27, 2018

Published guidance from the American Academy of Pediatrics (AAP) outlines the specific components of medical care for children and young adults with Down syndrome. However, not all patients receive the recommended care. In this study, we added alerts and tracking due dates into the medical record software to remind physicians to place orders. We found that these simple tools led to more patients with Down syndrome receiving the components of care as outlined by the AAP. This approach could be expanded to be used at other hospitals, for other genetic syndromes or for other published guidelines.

(Summary provided by Stephanie Santoro, MD, and Brian Skotko, MD, MPP, of the Down Syndrome Program and MassGeneral Hospital for Children)

Press Releases

Researchers Discover New Type of Lung Cell, Critical Insights for Cystic Fibrosis
Featuring Jayaraj Rajagopal, MD

Researchers at Massachusetts General Hospital and the Broad Institute of MIT and Harvard have identified a rare, previously unknown cell type in airway tissue that appears to play a key role in the biology of cystic fibrosis.


Mass General Team Defines the Mechanisms of Action of Key Genetic Abnormality in Ewing Sarcoma
Featuring Miguel Rivera, MD, and Bradley Bernstein, MD, PhD

A Massachusetts General Hospital research team has used epigenome editing tools to investigate how the genetic abnormality that drives Ewing sarcoma – the second most common bone cancer in children and young adults – unleashes tumor growth.


Rapid Diagnostic Coupled with Local Therapy Developed for Brain Tumors
Featuring Daniel Cahill, MD, PhD

Researchers from Brigham and Women’s Hospital and Massachusetts General Hospital are designing a new, rapid molecular diagnostic and sustained release therapeutic that could be deployed during brain surgery to treat gliomas and prevent their return.


Better Than Before: Mapping Beneficial Brain Injuries
Featuring Juho Joutsa, PhD

A study of rare cases of improvement after stroke sheds light on potential therapeutic targets in the brain.


Novel Approach Keeps Liquids from Freezing at Very Low Temperatures for Extended Periods
Featuring O. Berk Usta, PhD, Martin Yarmush, MD, PhD, and Haishui Huang, PhD

Investigators from the Massachusetts General Hospital Center for Engineering in Medicine have developed a simple method to maintain water and water-based solutions in a liquid state at temperatures far below the usual “freezing point” for greatly extended periods of time.


Predicting Risk for Common Deadly Diseases from Millions of Genetic Variants
Featuring Sekar Kathiresan, MD, and Amit Khera, MD

A research team at the Broad Institute, Massachusetts General Hospital and Harvard Medical School reports a new kind of genome analysis that could identify large fractions of the population who have a much higher risk of developing serious common diseases, including coronary artery disease, breast cancer or type 2 diabetes.


Harmful Side Effects
Featuring Zirui Song, MD, PhD, and John Goodson, MD

The intent behind a new federal proposal to flatten physician reimbursement for office visits is admirable, but the plan could also have harmful side effects and unintended consequences for many patients and physicians.


"It's All in the Eyes": The Role of the Amygdala in the Experience and Perception of Fear
Featuring Lisa Feldman Barrett, PhD

Researchers have long believed that the amygdala, an almond-shaped structure in the brain, is central to the experience and perception of fear. But a new paper from a Massachusetts General Hospital investigator describes how the role of the amygdala has turned out to be more complex than originally thought.


Mass General Study Defines Mechanisms Behind Focused-Ultrasound-assisted Treatment of Brain Tumors
Featuring Costas Arvanitis, PhD, Vasileios Askoxylakis, MD, PhD, and Rakesh Jain, PhD

A study led by a team of Massachusetts General Hospital investigators has analyzed, for the first time, the mechanisms underlying the use of focused ultrasound to improve the delivery of anti-cancer drugs across the blood brain barrier into brain tumors.


Mass General Team Discovers Channels Connecting Skull Bone Marrow to Brain Surface
Featuring Matthias Nahrendorf, MD, PhD, and Fanny Herisson, MD

A new study from a Massachusetts General Hospital research team has made two surprising discoveries – that immune system cells responding to a stroke or other brain injury in an animal model are more likely to come from bone marrow in the skull, and that tiny, previously unknown channels through the skull’s inner layer carry inflammatory cells from the marrow directly to the membranes covering the brain.


Mass General Team Finds How NF-2 Gene Mutations Make Cells Hyper-responsive to Growth Factor Signaling
Featuring Andrea McClatchey, PhD, and Christine Chiasson-MacKenzie, PhD

A team of Massachusetts General Hospital Cancer Center researchers has determined one way that mutations in a gene involved in a rare, hereditary cancer syndrome lead to out-of-control cellular proliferation.

Blog Posts

Research Study Helps Improve Feeding Strategies in NICU
Featuring Peggy Doyle Settle, RN, PhD

A research study conducted in the Neonatal Intensive Care Unit at MassGeneral Hospital for Children has led to the adoption of an infant-driven feeding system for premature babies.


Under Pressure: ResQFoam Stops the Bleed
Featuring David King, MD

For 10 years, David King, MD, trauma and acute care surgeon in the Mass General Trauma Center, and an engineering team, have been working to create ResQFoam, a self-expanding polyurethane trauma foam to stop internal bleeding. King says the FDA has now approved the use of this potentially life-saving foam on patients in a clinical trial.


Are Genetics the Body’s Natural Alarm Clock?
Featuring Hassan Dashti, PhD, RD, and Richa Saxena, PhD

In the largest genetic study of its kind, a team at Massachusetts General Hospital’s Center for Genomic Medicine has expanded our understanding of how genetics impact sleep duration and risk for disease. The results could lead to new treatments for conditions such as insomnia, schizophrenia and obesity.


How Insights from Epilepsy Patients Could Lead to New Treatments for PTSD
Featuring Ishita Basu, PhD

A team of researchers at Massachusetts General Hospital is investigating whether deep brain stimulation could help to restore the proper functioning of this conflict resolution system in individuals with treatment-resistant PTSD.


Brain Stimulation During Sleep Could Help Schizophrenia Patients with Debilitating Memory Deficits
Featuring Will Coon, PhD, and Dara S. Manoach, PhD

A research team in the Manoach Lab is investigating the connection between sleep and psychiatric disorders such as schizophrenia, with the hope of finding new treatments.


Marques Brings the Ivory Tower to the Streets with Psychiatry Program
Featuring Luana Marques, PhD

There is a clear need for tailored mental health treatments that cater to the unique needs of underserved communities. Community Psychiatry PRIDE (Program for Research in Implementation and Dissemination of Evidence-Based Treatments) is aiming to address this need.


Snapshot of Science: Genetic Insights into our Food Choices, A New Diagnostic Device for Lymphoma, More

What’s new in research at Mass General? Here’s a snapshot of studies recently published in top-tier scientific journals.


Event Highlights Progress on Brain Disease Research
Featuring Anne Young, MD, PhD, and Merit Cudkowicz, MD, MSc

Determined collaboration and groundbreaking technology have led to exciting advances in efforts to solve the challenges of brain diseases, researchers from the MassGeneral Institute for Neurodegenerative Diseases (MIND) told patients, families and friends recently. On May 16, 2018, nearly 100 people attended the event at the MIND labs at the Charlestown Navy Yard. MIND’s Visiting Day gathering included a reception and presentations by researchers working in amyotrophic lateral sclerosis (ALS), frontotemporal disorders, Parkinson’s disease and dystonia.


Research Awards and Honors: August 2018

Massachusetts General Hospital’s talented and dedicated researchers are working to push the boundaries of science and medicine every day. In this article, you will hear from a few individuals who have recently received awards or honors for their achievements.