Snapshot of Science for December 2021

Welcome to our Snapshot of Science for December 2021

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
12 new research-related press releases from the Mass General Public Affairs office
1 post from the Mass General Research Institute blog

Publications

Chromatin Factors with Putative Roles in DNA Damage Response
Assessing Kinetics and Recruitment of DNA Repair Factors Using High Content Screens
Martinez-Pastor B, Silveira GG, Clarke TL, Chung D, Gu Y [et al.], Mostoslavsky R.
Published in Cell Reports on Tuesday, December 28, 2021 | *Summary available

Omega-3 Supplements Do Not Show Benefit for Depression
Effect of Long-Term Supplementation with Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial
Okereke OI, Vyas CM, Mischoulon D, Chang G, Cook NR [et al.] Manson JE.
Published in JAMA on Tuesday, December 21, 2021 | *Summary available | Press Release

A Blood Test for Early Lung Cancer Detection
Screening Human Lung Cancer with Predictive Models of Serum Magnetic Resonance Spectroscopy Metabolomics
Schult TA, Lauer MJ, Berker Y, Cardoso MR, Vandergrift LA [et al.] Christiani DC, Cheng LL
Published in PNAS on Tuesday, December 21, 2021 | *Summary available | Press Release

Improving Genomic Surveillance of Malaria
Distinguishing Gene Flow Between Malaria Parasite Populations
Brown TS, Arogbokun O, Buckee CO, Chang HH.
Published in PLoS Genetics on Monday, December 20, 2021 | *Summary available

CBT Program Reduces Insomnia in Cancer Survivors
The Survivorship Sleep Program (SSP): A Synchronous, Virtual Cognitive Behavioral Therapy for Insomnia Pilot Program Among Cancer Survivors
Hall DL, Arditte Hall KA, Gorman MJ, Comander A, Goldstein MR [et al.], Park ER.
Published in Cancer on Thursday, December 16, 2021 | *Summary available

A New Strategy for Developing Cancer-Targeting Theranostics
Tumor-Associated Immune Cell Mediated Tumor Targeting Mechanism with NIR-II Fluorescence Imaging
Kang H, Shamim M, Yin X, Adluru E, Fukuda T [et al.], Choi HS
Published in Advanced Materials on Thursday, December 16, 2021 | *Summary available

New Insights into Organelle Distribution
ER Proteins Decipher the Tubulin Code to Regulate Organelle Distribution
Zheng P, Obara CJ, Szczesna E, Nixon-Abell J, Mahalingan KK [et al.], Blackstone C
Published in Nature on Wednesday, December 15, 2021

A Superior Coating Material for Biosensors
Zwitterionic Polymer Electroplating Facilitates the Preparation of Electrode Surface for Biosensing
Kilic T, Gessner I, Cho Y, Jeong N, Quintana J, Weissleder R, Lee H.
Published in Advanced Materials on Friday, December 10, 2021 | *Summary available

The Role of Jpx RNA in Chromosome Looping
Jpx RNA Regulates CTCF Anchor Site Selection and Formation of Chromosome Loops
Oh HJ, Aguilar R, Kesner B, Lee HG, Kriz AJ, Chu HP, Lee JT.
Published in Cell on Thursday, December 9, 2021 | *Summary available | Press Release

IgM Responses as a Marker and Mediator of TB Protection
Robust IgM Responses Following intravenous vaccination with Bacille Calmette-Guérin Associate with Prevention of Mycobacterium Tuberculosis Infection in Macaques
Irvine EB, O'Neil A, Darrah PA, Shin S, Choudhary A [et al.], Alter G.
Published in Nature Immunology on Wednesday, December 1, 2021

Factors Underlying Risk of Severe COVID-19
Age-Dependent Impact of the Major Common Genetic Risk Factor for COVID-19 on Severity and Mortality
Nakanishi T, Pigazzini S, Degenhardt F, Cordioli M, Butler-Laporte G [et al.], Ganna A
Published in Journal of Clinical Investigation on Wednesday, December 1, 2021

Insights for Developing New RSV Vaccines
Upper and Lower Respiratory Tract Correlates of Protection Against Respiratory Syncytial Virus Following Vaccination of Nonhuman Primates
Zohar T, Hsiao JC, Mehta N, Das J, Devadhasan A [et al.], Alter G.
Published in Cell Host and Microbe on Tuesday, November 30, 2021 | *Summary available |

Machine Learning to Quantify Risk of Thoracic Aortic Aneurysm
Deep Learning Enables Genetic Analysis of the Human Thoracic Aorta
Pirruccello JP, Chaffin MD, Chou EL, Fleming SJ, Lin H [et al.], Ellinor PT.
Published in Nature Genetics on Friday, November 26, 2021 | *Summary available | Press Release

Insights Into Severe COVID-19 Immune Response
Functional Convalescent Plasma Antibodies and Pre-infusion Titers Shape the Early Severe COVID-19 Immune Response
Herman JD, Wang C, Loos C, Yoon H, Rivera J [et al.], Alter G.
Published in Nature Communications on Thursday, November 25, 2021

A Noninvasive Method to Map and Quantify Enzyme Activity
Enzyme Control Over Ferric Iron Magnetostructural Properties
Wang H, Cleary MB, Lewis LC, Bacon JW, Caravan P, Shafaat HS, Gale EM.
Published in Angew Chem Int Ed Engl on Tuesday, November 23, 2021 | *Summary available

Improving Health Care for LGBTQIA+ People
Electronic Health Records as an Equity Tool for LGBTQIA+ People
Keuroghlian AS.
Published in Nature Medicine on Monday, November 22, 2021 | *Summary available

Directly Visualizing APP Processing in Neurons
Presenilin/γ-Secretase Activity is Located in Acidic Compartments of Live Neurons
Maesako M, Houser MC, Turchyna Y, Wolfe MS, Berezovska O.
Published in Journal of Neuroscience on Friday, November 19, 2021 | *Summary available

Publication Summaries

Repair of genetic damage is coordinated in the context of chromatin, therefore cells dynamically modulate accessibility at DNA breaks for the recruitment of DNA Damage Response (DDR) factors. The identification of chromatin factors with roles in DDR has mostly relied on loss-of-function screens while lacking robust high-throughput systems to study DNA repair. In this study, we have developed two high-throughput systems that allow the study of DNA repair kinetics and the recruitment of factors to DSBs in a 384-well plate format. Using a customized gain-of-function ORF library ("ChromORFeome" library), we identify chromatin factors with putative roles in the DDR. Among these, we find the PHF20 factor is excluded from DNA breaks, affecting DNA repair by competing with 53BP1 recruitment. Adaptable for genetic perturbations, small-molecule screens and large-scale analysis of DNA repair, these resources can aid our understanding and manipulation of DNA repair.

(Summary submitted by Raul Mostoslavsky, MD, PhD, from the Mass General Cancer Center)

A Blood Test for Early Lung Cancer Detection
Screening Human Lung Cancer with Predictive Models of Serum Magnetic Resonance Spectroscopy Metabolomics
Schult TA, Lauer MJ, Berker Y, Cardoso MR, Vandergrift LA [et al.], Christiani DC, Cheng LL
Published in PNAS on Tuesday, December 21, 2021 | Press Release

Lung cancer, the leading cause of cancer death, is usually diagnosed at a late stage when the survival rate is extremely low. Early-stage lung cancer is mostly asymptomatic, and low-dose spiral CT imaging, the current method for detecting early lung cancer lesions, isn't feasible as a widespread screening test for the general population due to high cost and the radiation hazard of repeated screenings. Our study provides proof-of-concept for the ability of a drop of blood to reveal lung cancer in asymptomatic patients.

Omega-3 Supplements Do Not Show Benefit for Depression
Effect of Long-Term Supplementation with Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial
Okereke OI, Vyas CM, Mischoulon D, Chang G, Cook NR [et al.], Manson JE.
Published in JAMA on Tuesday, December 21, 2021 | Press Release

Experts have recommended omega-3 supplements for reducing risk of depression in some high-risk patients. However, it was unknown whether omega-3 supplements might be useful for preventing depression or improving mood in the general population. Results from this large clinical trial, which included nearly 20,000 adults and ran for more than 5 years, showed there were no benefits from taking omega-3 supplements for preventing depression or boosting mood over the long term. Although omega-3 supplements may improve certain aspects of health, such as heart heath, they should not be taken simply for the purpose of preventing depression in the general population.

(Summary submitted by Olivia Okereke, MD, MS, from the Department of Psychiatry)

Malaria control programs benefit from understanding how malaria parasites are spread between geographic locations. Genomic surveillance, using geolocated genetic data from malaria infections, provides an important tool for studying connectivity between malaria populations in different locations. This study evaluates how much data is needed to distinguish different levels of gene flow between parasite populations ("Are the malaria populations in locations A and B linked by higher or lower connectivity than those in locations C and D?"). We use malaria genetic data from southeast Asia and numerical simulation to determine data size requirements (including the number of genetic markers and number of individual infections analyzed) for surveillance studies intended to answer these questions.

(Summary submitted by Tyler Brown, MD, from the Division of Infectious Diseases)

The strategy of structure-inherent targeting is getting more attention because no chemical conjugation of targeting moieties is required since it was first introduced in Nature Medicine (2015). In this study, a tumor-associated immune cell mediated targeting mechanism for "structure-inherent tumor targeting (SITT)" strategy is newly suggested, which enables ubiquitous uptake of near-infrared fluorophores in the tumor microenvironment. The new SITT mechanism suggests that bone-marrow-derived and/or tissue-resident/tumor-associated immune cells can be a principal target for cancer detection due to their abundance in tumoral tissues. The reported heptamethine cyanine-based fluorophores provide not only noninvasive NIR-II imaging but also immune-cell mediated tumor targeting in various tumor models including pancreatic, breast and lung cancers. This strategy can be used for developing cancer-targeted theranostic agents.

(Summary submitted by Homan Kang, PhD, and Hak Soo Choi, PhD, Gordon Center for Medical Imaging, Department of Radiology)

After completing treatment, 30%-50% of cancer survivors report having chronic insomnia that can persist for years. Cognitive behavioral therapy for insomnia (CBT-I) is an evidence-based treatment but requires personalization when delivered to cancer survivors. In this 2-phase study, a multidisciplinary team of researchers at Mass General developed and tested the Survivorship Sleep Program, a synchronous, virtual CBT-I treatment for cancer survivors. The program was found to be feasible, acceptable, and associated with large, clinically meaningful improvements in sleep that were sustained by 1-month follow-up.

(Summary submitted by Daniel Hall, PhD, from the Mongan Institute and the Health Promotion and Resiliency Intervention Research Program)

Proper positioning of organelles is important for cellular health. Scaffolding proteins such as microtubules play important roles, but less is known about how specificity is maintained. The endoplasmic reticulum (ER) is unusual among organelles because it has interconnected but distinct structural domains that need to be specifically distributed. In this study, we show that specific ER proteins bind microtubules with different levels of a modification called glutamylation, distributing ER domains in their familiar pattern. Since the ER also interacts with other organelles, this interaction between ER and modified microtubules plays a key role in the overall distribution of cellular organelles.

Minimizing nonspecific adsorption of proteins is crucial to biosensing for accurate diagnostics. We have developed a new zwitterionic ("oppositely charged") molecule, ZiPPy (zwitterionic polypyrrole), as a superior coating material for biosensors. ZiPPy can be easily deposited onto a sensor surface through electroplating, rendering the sensor highly resistant to nonspecific protein binding. In the current study, we used the ZiPPy-coated sensors to detect neutralizing antibodies against SARS-CoV-2 from saliva samples collected from vaccinated and non-vaccinated individuals. The approach enabled antibody detection without need for sample purification or additional labeling. ZiPPy would be of great interest for the broad biosensing community.

(Summary submitted by Isabel Gessner, PhD, from the Center for Systems Biology)

For our genetic material to fit inside our cells, the DNA must be folded in 3D and organized precisely into chromosome "loops." Loops determine spatial proximity of genes to regulatory elements and enable proper developmental regulation of gene expression. Loops form dynamically throughout our lives. How they form and dissolve has been of great interest. An RNA component has long been suspected but not found until now. Here our study found a first noncoding RNA that plays a key role in determining where along a chromosome loops can form—and therefore what genes can be expressed. Jpx RNA does so by controlling the behavior of CTCF, a protein that anchors loops. This discovery has implications for how disease can arise from aberrant loop formation and how we might restore health by targeting noncoding RNA.

(Summary submitted by Jeannie Lee, PhD, from the Department of Molecular Biology)

To map the humoral correlates of immunity against RSV, antibody responses across six different vaccines were profiled in a highly controlled nonhuman primate-challenge model. Viral loads were monitored in both the upper and lower respiratory tracts, and machine learning was used to determine the vaccine platform-agnostic antibody features associated with protection. Upper respiratory control was associated with virus-specific IgA levels, neutralization, and complement activity, whereas lower respiratory control was associated with Fc-mediated effector mechanisms. These findings provide critical compartment-specific insights toward the rational development of future vaccines.

The aorta carries blood from the heart to the rest of the body. Aortic diameter is used to determine risk of aortic tears, or dissection which can cause suddenly lack of critical blood flow to the heart or other organs, resulting in death or significant disability. Little is known about the genetic determinants of aortic size. A multidisciplinary team of Mass General researchers developed deep learning models to measure aortic diameters from cardiovascular magnetic resonance images of 40,000 UK Biobank participants. These images, along with genetic analysis identified 114 new genetic loci associated with aortic diameter, and supported regions of the genome near known aortic disease genes such as FBN1 (the causal gene of Marfan syndrome). The top genetic variants were used to determine a polygenic score, which predicted clinical diagnoses of aortic disease. Finally, genetic loci were further explored on a cellular level to begin elucidating mechanisms aortic dilation. This work helps identify high priority gene targets for therapy, and suggests that genetic prediction of aortic enlargement may be possible to guide screening, medical therapy and prophylactic surgery in preventing devastating aortic dissection and rupture.

Iron dissolved in water can exhibit rich and diverse magnetic properties, but the chemistry is difficult to control. Iron atoms tend to cluster in a way that has been long viewed as an unproductive "thermodynamic sink." We introduce a strategy to precisely control the magnetic properties of iron in water, and then leveraged this chemistry to demonstrate proof-of-concept for a new class of MRI contrast agent that is switched from "off" to "on" by enzymes. This basic science discovery will be applied to non-invasively map and quantify activity of enzymes that are pathologically upregulated in inflammation and cancer.

(Summary submitted by Eric Gale, PhD, from the Martinos Center for Biomedical Imaging and the Department of Radiology)

This paper outlines the ways in which electronic health records can be used as a tool to reduce health disparities affecting LGBTQIA+ people. It is part of Nature Medicine's "Series on Diversity, Equity and Inclusion," and anchors the journal's reporting on how lack of diversity in medical research data affects patient populations. The paper details how sexual orientation, gender identity and sex development data collection can improve patient and community care and offers actionable ways to implement this data collection in health care settings.

(Summary submitted by Alex Keuroghlian, MD, MPH, Director, Mass General Psychiatry Gender Identity Program)

Directly Visualizing APP Processing in Neurons
Presenilin/ᵧ-Secretase Activity is Located in Acidic Compartments of Live Neurons
Maesako M, Houser MC, Turchyna Y, Wolfe MS, Berezovska O.
Published in Journal of Neuroscience on Friday, November 19, 2021 | Press Release

Many mutations that cause early-onset Alzheimer's disease (AD) are discovered both on Presenilin, a critical molecule in an enzyme called ᵧ-secretase, and on the amyloid precursor protein (APP) that ᵧ-secretase cuts. These indicate that APP cleavage by ᵧ-secretase is essential in AD. However, exactly where inside of the neurons this crucial cleavage occurs is not clear. By using state-of-the-art molecular imaging assays and special molecular biosensors that we have developed, we were able for the first time to directly "visualize" APP processing by ᵧ-secretase in late endosomes and lysosomes. Since these are the vital compartments within the neuron that degrade misfolded proteins spread from neuron-to-neuron, our study could speed the development of effective new medications.

(Summary submitted by Masato Maesako, PhD, from the Department of Neurology)

Press Releases

Researchers Uncover New Details Behind Inflammation That Promotes Heart Disease
Featuring Matthais Nahrendorf, MD, PhD

White blood cells trigger inflammation that contributes to heart disease. New research indicates that high blood pressure, atherosclerosis, and the occurrence of a heart attack each can cause bone marrow changes that increase white blood cell production.

Clinical Trial Reveals That Omega-3 Fish Oil Supplements Do Not Help Prevent Depression
Featuring Olivia Okereke, MD, MS

A large clinical trial observed no benefits from taking omega-3 supplements for preventing depression or boosting mood.

Study Compares COVID-19 Vaccines' Ability to Stimulate Immune Protection Against the Coronavirus
Featuring John Iafrate, MD, PhD

A team of scientists at Mass General has conducted one of the first comparisons of how effectively each of the three COVID-19 vaccines authorized or approved in the United States stimulates a protective immune response against the virus.

Alcohol Consumption During the COVID-19 Pandemic Projected to Cause More Liver Disease and Deaths
Featuring Jagpreet Chhatwal, PhD

A one-year increase in alcohol consumption in the U.S. during the COVID-19 pandemic is estimated to cause 8,000 additional deaths from alcohol-related liver disease, 18,700 cases of liver failure, and 1,000 cases of liver cancer by 2040.

New Research May Identify Infants Who Face High Asthma Risk After Viral Lung Infections
Featuring Yoshihiko Raita, MD, MPH, MMSc

A type of viral lung infection called bronchiolitis is the leading cause of hospitalizations in U.S. infants as well as a major risk factor for developing asthma. New research has revealed a complex interplay among the infecting virus, the airway's microbial composition and function, and the infant's immune response that all contribute to a child's risk of developing asthma after bronchiolitis.

Early-Stage Lung Cancer May Be Detected from a Drop of Blood
Featuring Leo Cheng, PhD, and David Christiani, MD, MPH

A new published study provides proof-of-concept for the ability of a drop of blood to reveal lung cancer in asymptomatic patients.

Time of Day Matters in Antibody Response to COVID-19 Vaccine
Featuring Elizabeth Klerman, MD, PhD

Health care workers who received the SARS-CoV-2 vaccine in the afternoon had higher antibody levels than those who were vaccinated in the morning, suggesting vaccine response may be affected by the body's circadian rhythm.

After Breast Reconstruction, Cardiovascular Imaging Can Be Inaccurate
Featuring Ohad Oren, MD

Research is needed to identify the most accurate imaging technologies to prevent cardiac misdiagnoses and over-testing in women whose breast cancer treatment leads to a high risk of cardiovascular disease.

Researchers Identify Key RNA "Gatekeeper" In Gene Expression, Pointing to Possible New Drug Targets
Featuring Jeannie Lee, MD, PhD

An important player in the healthy development of female embryos turns out also to play a key role in regulating the behavior of chromosome loops and gene expression in both sexes, according to a new study by researchers at Mass General.

International Study Reveals COVID-19 Vaccination Rates Among People Living with HIV
Featuring Steven Grinspoon, MD

Those who were vaccinated against COVID-19 were more likely to be living in high-income regions and to be white, male, older, have a higher body mass index, face a higher risk of developing atherosclerotic cardiovascular disease, and be taking antiretroviral therapy for a longer period of time.

Magnetic Resonance Imaging (MRI) and Artificial Intelligence Can Detect Early Signs of Tumor Cell Death After Novel Therapy
Featuring Or Perlman, PhD

A recent study demonstrates that magnetic resonance imaging and artificial intelligence can be used to detect early signs of tumor cell death in response to a novel virus-based cancer therapy.

Machine Learning May Help Identify People at Risk of Thoracic Aortic Aneurysm
Featuring James Pirruccello, MD

A team led by investigators at Mass General recently used a type of artificial intelligence called deep learning to uncover insights into the genetic basis for variation in the aorta's size.

Blog Posts

Research Wrapped for 2021: The Year in Research at Massachusetts General Hospital
Welcome to Research Wrapped for 2021, our annual look back at the year in research at Massachusetts General Hospital. Here are some research highlights from the past twelve months.

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Snapshot of Science for December 2021