Snapshot of Science for October 2019

Welcome to our Snapshot of Science for October 2019

Here's a quick look at some recent publications, press releases and stories about the Mass General Research Institute community.

In this issue we highlight:

17 new studies published in high impact journals, along with 13 summaries submitted by the research teams
8 new research-related press releases from the Mass General Public Affairs office
8 posts from the Mass General Research Institute blog

Publications

USING ADENO-ASSOCIATED VIRUS FOR GENOME EDITNG
High Levels of AAV Vector Integration into CRISPR-Induced DNA Breaks
Hanlon KS, Kleinstiver BP, Garcia SP, Zaborowski MP, Volak A [et al.], György B.
Published in Nature Communications on September 30, 2019 | *Summary available

THE INFLUENCE OF THE MICROBIOME ON COLORECTAL CANCER
Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer
Song M, Chan AT, Sun J.
Published in Gastroenterology on October 3, 2019 | *Summary available

THE IMPORTANCE OF UTILIZING GENETIC INFORMATION FOR DIABETES SCREENINGS
Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program
Sarnowski C, Leong A, Raffield LM, Wu P, de Vries PS [et al.], Meigs JB.
Published in American Journal of Human Genetics on October 3, 2019 | *Summary available

BACTERIAL MUTATIONS INFLUENCE ANIMAL MITOCHONDRIA
ROS-based Lethality of Caenorhabditis Elegans Mitochondrial Electron Transport Mutants Grown on Escherichia Coli Siderophore Iron Release Mutants
Govindan JA, Jayamani E, Ruvkun G.
Published in PNAS on October 7, 2019 | *Summary of available

GENETIC RISK OF DEVELOPING PTSD AFTER A TRAUMATIC EVENT
International Meta-analysis of PTSD Genome-wide Association Studies Identifies Sex- and Ancestry-specific Genetic Risk Loci
Nievergelt CM, Maihofer AX, Klengel T, Atkinson EG, Chen CY [et al.], Koenen KC.
Published in Nature Communications on October 8, 2019 | *Summary available

ASSESSING GENE EXPRESSION AND CELL PHYSIOLOGY IN SINGLE LIVING CELLS
Multiplex Live Single-cell Transcriptional Analysis Demarcates Cellular Functional Heterogeneity
Atmanli A, Hu D, Deiman FE, van de Vrugt AM, Black LD, Domian I.
Published in eLife on October 8, 2019

BARRIERS AND THE ROLE OF GENDER IN PURSUING A CAREER IN SURGERY
Barriers to Pursing a Career in Surgery: An Institutional Survey of Harvard Medical School Students
Giantini Larsen AM, Pories S, Parangi S, Robertson FC.
Published in Annals of Surgery on October 9, 2019 | *Summary available

USING LIGHT TO TREAT CARBON MONOXIDE POISONING
Phototherapy and Extracorporeal Membrane Oxygenation Facilitate Removal of Carbon Monoxide in Rats
Zazzeron L, Fischbach A, Franco W, Farinelli WA, Ichinose F [et al.], Zapol WM.
Published in Science Translational Medicineon October 9, 2019 | *Summary available

BET PROTEINS AND THEIR ROLE IN EPIGENTIC REGULATION
Positron Emission Tomography Probes Targeting Bromodomain and Extra-terminal (BET) Domains to Enable In Vivo Neuroepigenetic Imaging
Bai P, Wey HY, Patnaik D, Lu X, Lan Y [et al.], Wang C.
Published in Chemical Communicationson October 10, 2019 | *Summary available

RESTING T CELLS ARE PRE-CONDITIONED TO BECOME MEMORY T CELLS
Migratory DCs Activate TGF-β to Precondition Naïve CD8+ T Cells for Tissue-resident Memory Fate
Mani V, Bromley SK, Äijö T, Mora-Buch R, Carrizosa E [et al.], Mempel TR.
Published in Science on October 11, 2019 | *Summary available

OBSERVING HOW CELLS CHANGE IN RESPONSE TO INFLAMMATION
Transcriptional Atlas of Intestinal Immune Cells Reveals that Neuropeptide α-CGRP Modulates Group 2 Innate Lymphoid Cell Responses
Xu H, Ding J, Porter CBM, Wallrapp A, Tabaka M [et al.], Xavier RJ.
Published in Immunity on October 15, 2019

EXAMINING ELECTROPHYSIOLOGICAL CONDITIONS ASSOCIATED WITH TACHY-ARRHYTHMIC EVENTS
Cardiac Alternans: Mechanisms and Clinical Utility in Arrhythmia Prevention
Kulkarni K, Merchant FM, Kassab MB, Sana F, Moazzami K [et al.], Armoundas AA.
Published in Journal of the American Heart Association on October 16, 2019 | *Summary available

NEW INSIGHTS INTO EPIGENETIC ABERRATIONS AND CANCER
Altered Chromosomal Topology Drives Oncogenic Programs in SDH-deficient GIST
Flavahan WA, Drier Y, Johnstone SE, Hemming ML, Tarjan DR [et al.], Bernstein BE.
Published in Nature on October 16, 2019

CARDIOVASCULAR RISK IN FOOTBALL PLAYERS
Weight Gain, Hypertension, and the Emergence of a Maladaptive Cardiovascular Phenotype Among US Football Players
Kim JH, Hollowed C, Liu C, Al-Badri A, Alkhoder A [et al.], Baggish AL.
Published in JAMA Cardiology on October 16, 2019 | *Summary available

UTILIZING GENOME-WIDE ASSOCIATION STUDIES TO HIGHLIGHT NEW THERAPEUTIC TARGETS FOR ADHD
Druggable Genome in Attention Deficit/hyperactivity Disorder and Its Co-morbid Conditions. New Avenues for Treatment
Hegvik TA, Waløen K, Pandey SK, Faraone SV, Haavik J, Zayats T.
Published in Molecular Psychiatryon October 18, 2019 | *Summary available

REGULAR USE OF DISINFECTANT AMONG NURSES COULD BE A RISK FACTOR FOR DEVELOPING COPD
Association of Occupational Exposure to Disinfectants With Incidence of Chronic Obstructive Pulmonary Disease Among US Female Nurses
Dumas O, Varraso R, Boggs KM, Quinot C, Zock JP [et al.], Camargo CA Jr.
Published in JAMA Open Network on October 18, 2019

DEVELOPING A POINT-OF-CARE TRIAGE TEST FOR ACTIVE TB
A Rapid Triage Test for Active Pulmonary Tuberculosis in Adult Patients with Persistent Cough
Ahmad R, Xie L, Pyle M, Suarez MF, Broger T [et al.], Gillette MA.
Published in Science Translational Medicine on October 23, 2019 | *Summary available

Summaries

A multidisciplinary team explored whether adeno-associated virus (AAV) integrated into double-stranded breaks (DSBs) created by the genome editing machinery CRISPR/Cas9. We found, both in culture primary neurons as well as after in vivo injection of AAV vectors in the brain, muscle and inner ear, that AAV integration occurred in a high percentage of CRISPR-induced DSBs. Importantly, when looking at the brain in a genome-wide manner, we found no increase in overall AAV integration besides at the intended CRISPR/Cas9 target sites. This work helps better characterize the outcome of AAV vector genomes after CRISPR/Cas9 therapy in vivo.

(Summary submitted by Killian S. Hanlon, PhD, Department of Neurology, and Bence György, MD, PhD, IOB Basel, formerly Department of Neurology)

Increasing evidence indicates a link between elements of the intestinal microbiome and risk of colorectal cancer. Factors that affect cancer risk also affect the intestinal microbiome, such as being overweight, physical activity levels and dietary intake of fiber, whole grains, and red and processed meat. We review epidemiologic and laboratory evidence for the influence of the microbiome, diet and environmental factors on the incidence and outcomes of colorectal cancer. Based on these data, leveraging features of the intestinal microbiome might be a promising strategy for colorectal cancer prevention, screening or treatment.

(Summary submitted by Mingyang Song, MD, ScD, Department of Medicine, Clinical and Translational Epidemiology Unit)

Genetic variants may influence how accurately hemoglobin A1c (HbA1c) reflects blood-glucose levels in people with diabetes. By analyzing the genomes of 10,338 individuals representing several ancestries (Europeans, African-Americans, Hispanics, and East Asians) from the Trans-Omics for Precision Medicine (TOPMED) program, we were able to better characterize two genetic regions in which variants, only present in African-Americans and Hispanics, lowered HbA1c. The study demonstrated that genetic information should be considered when using HbA1c for diabetes screening so as to reduce under-diagnosis in high-risk minority groups.

(Summary submitted by Aaron Si Arn Leong, MD, MSc, Department of Medicine, Endocrine Division)

The animal mitochondrion, the powerhouse of the cell, has a bacterial origin. In this study, we identified 44 bacterial mutations that cause distress to the C. elegans mitochondrion. Cultivation of C. elegans mitochondrial mutants with any of four E. coli mutations that affect an iron scavenger chemical caused growth arrest. Antioxidants strongly suppressed this sickness, showing that reactive oxygen species are the cause of the growth arrest. Thus, the animal mitochondria can be attacked by weapons that bacteria use to attack universal elements of energy production across the Tree of Life.

(Summary submitted by Gary Ruvkun, PhD, Department of Molecular Biology)

Post-traumatic stress disorder (PTSD) is a common and very debilitating mental disorder that occurs in some people after they have experienced a traumatic event such as a sexual assault, combat or a disaster. While the type and severity of the trauma are important predictors of who gets PTSD, it has long been recognized that other factors play a role. This study, using data over 200 researchers across 12-countries, reveals that genetics accounts for five to 20 percent of the variability in PTSD risk following a traumatic event. We hope these findings will be used to further understanding of the biological basis of PTSD and ultimately develop new treatments for the disorder.

(Summary submitted by Karestan C. Koenen, PhD, Department of Psychiatry, Psychiatric & Neurodevelopmental Genetics Unit)

Despite an equal number of men and women in medical school, fewer than 25% of surgeons are women. To understand why these gender ratios change between medical school and practice, we conducted an anonymous survey of Harvard Medical School students on perceived barriers to the career. Men and women were equally interested in surgery, but 69% percent of all students—both men and women—were verbally discouraged from pursuing the career. Significantly more women than men stated reported discouragement based on their gender, age and family aspirations. Additional support within the surgical field is needed to mitigate these concerns and support trainees in both their career and familial aspirations.

(Summary submitted by Faith C. Robertson, MD, MSc, Department of Neurosurgery)

Carbon monoxide (CO) is a common cause of human poisoning. When inhaled, CO binds with high affinity to hemoglobin in the blood, but the bond between CO and hemoglobin can be broken by visible light. We designed a novel extracorporeal membrane oxygenator (ECMO) transparent to light to remove CO from blood. In rats with acute lung injury, treatment with ECMO combined with red light removed CO three times faster and improved survival as compared to animals treated with 100% oxygen. If the development and testing of our technology in large animals is successful, this may represent a unique treatment for CO poisoned patients with concurrent lung damage.

(Summary submitted by Missy Flynn, Department of Anesthesia)

Epigenetic mechanisms have emerged as promising targets for the development of new therapeutics. Of these mechanisms, the Bromodomain and extra-terminal domain (BET) family of proteins that function as epigenetic “readers” have been shown to play a key role in epigenetic regulation of gene transcription. We developed a PET radiotracer to quantify BET density in the brain and body for comparison to disease states and for assessing in vivo BET target engagement to assist therapeutic discovery. The next step is to image BET in humans in the near future.

(Summary submitted by Changning Wang, PhD, Department of Radiology, Martinos Center)

When our immune system has successfully fended off an infection most infection-fighting T cells die, but memory T cells remain to protect us from re-infection with the same pathogen. Memory T cells either circulate through our blood or take up stable residence in tissues to become first responders to pathogen re-encounter. We discovered how, already in health, some resting T cells are pre-conditioned to become tissue-resident memory cells following a future infection. This happens through interactions with dendritic cells that continuously migrate from tissues to lymph nodes, where both cell types meet. This discovery may become the basis for the development of more effective vaccines.

(Summary submitted by Thorsten R. Mempel, MD, PhD, Department of Medicine, Center for Immunology and Inflammatory Diseases)

Cardiac alternans, a pattern of beat-to-beat oscillation of the electrocardiographic waveform, is associated with an increased risk for tachy-arrhythmic events and sudden cardiac death. Pre-clinical studies have demonstrated the pro-arrhythmic role of alternans in the development of unstable electrophysiologic substrates and clinical evidence links the presence of cardiac alternans with an increased risk of mortality. This work provides a systematic review of the electrophysiological conditions leading to the onset of cardiac alternans. We also present evidence demonstrating the role of alternans in arrhythmia susceptibility and the clinical utility of electrically modulating and suppressing alternans to prevent tachy-arrhythmic events.

(Summary submitted by Antonis A. Armoundas, PhD, Department of Medicine, Cardiovascular Research Center)

While the risk of neurocognitive disease in American-style football (ASF) has received considerable attention, studies have shown that cardiovascular disease is the most common cause of premature death among former ASF athletes. This study tracked a cohort of Division I ASF athletes throughout their collegiate career and found participation was linked to risk of heart muscle thickening, heart muscle stiffening and arterial dysfunction. Predictors of these maladaptations included weight gain and the onset of hypertension during ASF participation. These findings begin to explain why former ASF athletes are at increased risk for cardiovascular disease and identify several targets for prevention and intervention among this unique population of young men.

(Summary submitted by Aaron L. Baggish, MD, Department of Cardiology, Cardiovascular Research Center)

ADHD is a common, highly heritable childhood-onset disorder. Most children and adults with ADHD are treated with stimulant drugs, such as amphetamine. This treatment was discovered by accident in 1937. Although stimulants offer symptom relief, they have major side effects and seem not to directly target the causes of ADHD. Large-scale genetic studies can offer insights into biological underpinnings of ADHD and, thus, can aid treatment improvement. In this study, we demonstrate how it is possible to combine genomic data and drug databases in a search for new ADHD therapeutics. We point to several classes of drugs that might be repurposed for treatment of ADHD and its comorbid disorders.

(Summary submitted by Tetyana Zayats, MD, PhD, Analytic and Translational Genetics Unit)

Active tuberculosis (ATB) is curable but kills more patients worldwide than any other infectious disease. The majority of people at risk live in low-resource areas where care providers may lack the equipment and expertise needed to diagnose ATB. Answering a call to action from the World Health Organization, we have made critical progress towards a simple, rapid blood test that could be used anywhere to identify patients at high risk for TB who most need formal diagnostic testing. This could help ensure sick patients get the treatment they need and can avoid spreading the disease.

(Summary submitted by Michael Gillette, MD, PhD, Department of Medicine, Pulmonary and Critical Care Medicine)

Press Releases

Mass General Performs First Application of Genetically Modified, Live-cell, Pig Skin to a Human Wound
Featuring Jeremy Goverman, MD

Burn specialists at Massachusetts General Hospital announced today they have successfully used live-cell, genetically engineered pig skin (xenograft) for the temporary closure of a burn wound.

Learning Not to Fear: Mindfulness Meditation Training Alters How We Process Fearful Memories
Featuring Gunes Sevinc, PhD

A team led by Mass General researchers report that mindfulness meditation appears to help extinguish fearful associations

DISCOVERY Study Seeks to Learn More About the Causes of Post-Stroke Cognitive Impairment and Dementia
Featuring Natalia Rost, MD, PhD

Last month, the National Institute of Neurological Disorders and Stroke awarded Mass General $39M ($62+ million in total direct and indirect costs) for the DISCOVERY (Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on RecoverY) Network.

Study Suggests Why Some US Football Players Have Higher Cardiovascular Risk
Featuring Aaron L. Baggish, MD

Research has shown that while elite athletes overall are at decreased risk of death from cardiovascular problems, a certain group of athletes — football linemen in the United States — actually have higher risk than the general population than other elite athletes.

Study Identifies Role of Specific Gene in Hardening of Blood Vessel Walls, Development of Cardiovascular Disease
Featuring Rajeev Malhotra, MD

A new study published in Nature Genetics implicates a specific gene – HDAC9 – in the calcification of the human aorta, the largest blood vessel in the body.

New Technique May Reveal the Health of Human Hair Follicles
Featuring David Cohen, PhD

A new method developed by investigators at Mass General recently examines the activity of hair follicles and could be useful for testing the effects of different treatments on hair growth.

Mass General Team Publishes on Highest Resolution Brain MRI Scan
Featuring Brian L. Edlow, MD

Anew paper describes a breakthrough 100 micron resolution scan of the human brain that was created by a multidisciplinary team of Mass General researchers.

Immune Response Against Skin-dwelling Viruses Prevents Cancer
Featuring Shawn Demehri, MD, PhD

Viruses get a bad rap as potential cancer-causers, but at least one class of viruses that commonly live on human skin – so-called “low-risk” human papillomaviruses -- appear to play an unwitting role in protecting us against skin cancer according to a new study published in Nature.

Blog Posts

How Mothers Help Build the Immune Systems of their Children During Pregnancy
Featuring Galit Alter, PhD

To understand more about infant immunity and how to enhance it, a research team led by Galit Alter, PhD, investigated how certain antibodies are transferred from mother to child during pregnancy.

Alzheimer’s Disease Expert Says Future Treatment Success Will Require a Shift in Strategy and Timing
Featuring Rudy Tanzi, PhD

Rudy Tanzi, PhD, said future success in treating Alzheimer’s disease will come from earlier diagnosis and treatment guided by an individual’s family history and genetic risk factors.

Flexible Funding Helps Ragon Investigators Identify Key Vulnerability in HIV Virus
Featuring Bruce Walker, MD

The Ragon Institute of MGH, MIT and Harvard have used flexible funding and a collaborative approach to identify a key weakness in the HIV virus.

Study Links Eating Disorders to Childhood Infections
Featuring Lauren Breithaupt, PhD

New data from a Mass General researcher highlights a link between the immune system and the onset of eating disorders.

Five Things to Know About the Center for Systems Biology

The Center for Systems Biology focuses on analyzing how the human body’s biological and physiological functions work together to impact health and disease. Here are five things to know.

Showcasing the Crucial Role of Clinical Research at Mass General

Mass General’s vast clinical research program was showcased recently during the 17th Annual Clinical Research Day.

Three Mass General Investigators Named NIH New Innovators
Featuring Brain Edlow, MD, Alexandra-Chloe Villani, PhD, and Ryuji Morizane, MD

As part of the High-Risk, High-Reward Research program, the NIH New Innovator Award supports exceptionally creative early career investigators who propose innovative, high-impact projects in the biomedical, behavioral or social sciences within the NIH mission. This year, three Mass General investigators were named NIH New Innovators.

LAB DAY 2019: A Behind the Scenes Look at Mass General Research

The second annual Mass General Research Institute LAB DAY event gave friends and supporters of Mass General research an up-close look at science with the potential to revolutionize medicine.

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Snapshot of Science for October 2019