Snapshot of Science for October 2018
Research at Mass General
Massachusetts General Hospital is home to the largest hospital-based research enterprise in the U.S., with an annual budget of over $928 million in 2018.
Snapshot of Science is a monthly digest of publication summaries, press releases and blog posts featuring researchers from Massachusetts General Hospital.
Welcome to the October 2018 edition of Snapshot of Science. 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 11 summaries submitted by the research teams
- 10 new research-related press releases from the Mass General Public Affairs office
- 9 posts from the Mass General Research Institute blog
Publications
IMPROVING MUSCULAR DYSTROPHY PATIENT CARE
Psychosocial Management of the Patient With Duchenne Muscular Dystrophy
Colvin MK, Poysky J, Kinnett K, Damiani M, Gibbons M, Hoskin J [et al.], Weidner N.
Published in Pediatrics on October 1, 2018 | *Summary available
UNDERSTANDING BRAIN MECHANISMS BEHIND FREE WILL
Lesion Network Localization of Free Will
Darby RR, Joutsa J, Burke MJ, Fox MD.
Published in PNAS on October 1, 2018 | *Summary available
INVESTIGATING GENETIC VARIATION AND VETERAN HEALTH
Genetics of Blood Lipids Among ~300,000 Multi-Ethnic Participants of the Million Veteran Program
Klarin D, Damrauer SM, Cho K, Sun YV, Teslovich TM, Honerlaw J [et al.], Assimes TL.
Published in Nature Genetics on October 1, 2018 | *Summary available
REDUCTION IN STRIATAL DOPAMINE TRANSPORTER DENSITY COULD PREDICT MEMORY DECLINE
Dedifferentiation of Caudate Functional Connectivity and Striatal Dopamine Transporter Density Predict Memory Change in Normal Aging
Rieckmann A, Johnson KA, Sperling RA, Buckner RL, Hedden T.
Published in PNAS on October 2, 2018
EXPLORING THE LINK BETWEEN EDUCATION AND OBESITY
Education Can Reduce Health Differences Related to Genetic Risk of Obesity
Barcellos SH, Carvalho LS, Turley P.
Published in PNAS on October 2, 2018 | *Summary available
COMPARAING KETAMINE DOSAGE LEVELS FOR TREATMENT-RESISTANT DEPRESSION
Double-blind, Placebo-controlled, Dose-ranging Trial of Intravenous Ketamine as Adjunctive Therapy in Treatment-Resistant Depression (TRD)
Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C [et al.], Papakostas GI.
Published in Molecular Psychology on October 3, 2018 | See press release
NEW DEVELOPMENTS IN MODELING ALS
Taking on the Elephant in the Tissue Culture Room: iPSC Modeling for Sporadic ALS
Wainger BJ, Lagier-Tourenne C.
Published in Cell Stem Cell on October 4, 2018
CONTROLLING FOR VARIANTS IN PUBLIC GENETIC DATA
Burden Testing of Rare Variants Identified Through Exome Sequencing via Publicly Available Control Data
Guo MH, Plummer L, Chan YM, Hirschhorn JN, Lippincott MF.
Published in American Journal of Genetics on October 4, 2018 | *Summary available
TRANSPLANT PHYSICIAN OPINIONS ON PALLATIVE CARE
What Do Transplant Physicians Think About Palliative Care? A National Survey Study
El-Jawahri A, LeBlanc TW, Burns LJ, Denzen E, Meyer C, Mau LW [et al.], Petersdorf N.
Published in Cancer on October 5, 2018 | *Summary available
TARGETING ROS TO IDENTIFY DNA REPAIR PATHWAYS
ROS-induced R Loops Trigger a Transcription-coupled But BRCA1/2-Independent Homologous Recombination Pathway Through CSB
Teng Y, Yadav T, Duan M, Tan J, Xiang Y, Gao B [et al.], Lan L.
Published in Nature Communications on October 8, 2018 | *Summary available
INSIGHTS INTO THE GUT MICROBIOME AND POTENTIAL PREDICTORS OF DISEASE
Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course
Schirmer M, Denson L, Vlamakis H, Franzosa EA, Thomas S, Gotman NM [et al.], Xavier RJ.
Published in Cell Host Microbe on October 10, 2018 | *Summary available
RECOGNIZING PREDICTIVE POWER OF GENETIC VARIANTS
Distinguishing Variant Pathogenicity From Genetic Diagnosis: How to Know Whether a Variant Causes a Condition
Biesecker LG, Nussbaum RL, Rehm HL.
Published in JAMA on October 15, 2018 | *Summary available
STUDYING PROTECTIVE ANTIBODY MECHANISMS AGAINST EBOLA
Antibody-mediated Protection Against Ebola Virus
Saphire EO, Schendel SL, Gunn BM, Milligan JC, Alter G.
Published in Nature Immunology on October 17, 2018
EXPLORING USE OF A CONJUGATE VACCINE FOR DRUG RESISTANT STRAIN OF TYPHOID
Extensively Drug-Resistant Typhoid—Are Conjugate Vaccines Arriving Just in Time?
Andrews JR, Qamar FN, Charles RC, Ryan ET.
Published in New England Journal of Medicine on October 18, 2018 | *Summary available
PINPOINTING PREDICTORS OF EARLY-ONSET T1D
The Human Gut Microbiome in Early-onset Type 1 Diabetes from the TEDDY Study
Vatanen T, Franzosa EA, Schwager R, Tripathi S, Arthur TD, Vehik K [et al.], Xavier RJ.
Published in Nature on October 24, 2018
MODELING TASK SWITCHING DURING MRI
Functional MRI in Macaque Monkeys During Task Switching
Premereur E, Janssen P, Vanduffel W.
Published in The Journal of Neuroscience on October 24, 2018
USING GEOMETRIC FEATURES OF MICROTUBULES TO UNDERSTAND PROTEIN REGULATION
Geometry of Antiparallel Microtubule Bundles Regulates Relative Sliding and Stalling by PRC1 and Kif4A
Wijeratne S, Subramanian R.
Published in Elife on October 24, 2018 | *Summary available
Publication Summaries
IMPROVING MUSCULAR DYSTROPHY PATIENT CARE
Psychosocial Management of the Patient with Duchenne Muscular Dystrophy
Colvin MK, Poysky J, Kinnett K, Damiani M, Gibbons M, Hoskin J [et al.], Weidner N.
Published in Pediatrics on October 1, 2018
As medical management of Duchenne Muscular Dystrophy has improved, addressing the often complex psychosocial needs of patients and their families has become more important. The revised clinical care guidelines highlight the importance of psychological care from childhood through adulthood, including regular mental health screenings during clinic visits. There is also increased emphasis on the importance of early screening and/or formal assessment for neurodevelopmental conditions and/or learning disabilities, as there is growing evidence that those with DMD are at greater risk for these conditions. These guidelines also identify targets for future research in this area, as it is still in its relative infancy.
(Summary submitted by Molly Colvin, PhD, ABPP, Department of Psychiatry)
UNDERSTANDING BRAIN MECHANISMS BEHIND FREE WILL
Lesion Network Localization of Free Will
Darby RR, Joutsa J, Burke MJ, Fox MD.
Published in PNAS on October 1, 2018
From a scientific standpoint, free will is considered a combination of two cognitive processes—the desire to act (volition) and the sense of responsibility for our actions (agency). Our team used a process called brain lesion mapping to study 28 cases in which a brain injury disrupted volition, leaving patients with a lack of motivation to move or speak, as well as 50 cases in which a brain injury disrupted agency, resulting in a condition called alien limb syndrome. We found that all injuries disrupting volition were connected to the anterior singular cortex, which is associated with motivation and planning, and all injuries related to alien limb syndrome were connected to the precuneus cortex. The study was performed at BIDMC.
(Summary submitted by Michael Fox, MD, PhD, Beth Israel Deaconess Medical Center (BIDMC), assistant investigator in Neurology at Massachusetts General Hospital)
INVESTIGATING GENETIC VARIATION AND VETERAN HEALTH
Genetics of Blood Lipids Among ~300,000 Multi-Ethnic Participants of the Million Veteran Program
Klarin D, Damrauer SM, Cho K, Sun YV, Teslovich TM, Honerlaw J [et al.], Assimes TL.
Published in Nature Genetics on October 1, 2018
Through a project called the Million Veteran Program, a national research initiative based at the Veterans Health Administration with a goal to identify the genetic underpinnings of health and disease among U.S. veterans, we aggregated genetic data with cholesterol levels from 297,626 veterans and looked for mutations that play a role in cholesterol levels. We confirmed 188 previously known genetic markers of cholesterol and identified 118 new ones. We then honed-in on a small number of genetic mutations that not only dictate the levels of cholesterol in blood, but may also aid in the creation of drugs for the prevention of cardiovascular disease, diabetes, and aortic aneurysm.
(Summary submitted by Derek Klarin, MD, Department of Surgery)
EXPLORING THE LINK BETWEEN EDUCATION AND OBESITY
Education Can Reduce Health Differences Related to Genetic Risk of Obesity.
Barcellos SH, Carvalho LS, Turley P.
Published in PNAS on October 2, 2018
Our genes affect our obesity risk, but can this relationship be modified by getting more education? Using a compulsory-schooling reform in the UK, we compare students who left school at age 15 to those forced to stay until age 16. Among those affected by the reform, we observed no measurable change in obesity among those with low genetic risk, though we saw a substantial decrease in obesity in the high genetic risk group. Our study highlights that that the role of genes is not fixed and that policy can improve health even when health differences are related to our genes.
(Summary submitted by Patrick Turley, PhD, Analytic and Translational Genetics Unit)
CONTROLLING FOR VARIANTS IN PUBLIC GENETIC DATA
Burden Testing of Rare Variants Identified Through Exome Sequencing via Publicly Available Control Data
Guo MH, Plummer L, Chan YM, Hirschhorn JN, Lippincott MF.
Published in American Journal of Genetics on October 4, 2018
A commonly used approach for finding the genetic causes of a disease is to compare genetic data from cases (people with disease) to controls (healthy people). Publicly available data from hundreds of thousands of controls has the potential to be a powerful resource for this approach, but because different methods are often used to generate genetic data, false discoveries can arise from “comparing apples to oranges.” We overcame this barrier by identifying the systematic differences between genetic data generated through various methods and developing a new method to determine whether these differences have been properly corrected by examining silent changes in the genetic code (called synonymous variants). We then demonstrated that a properly corrected comparison of cases and publicly available controls confidently identifies disease-causing genes. We provide the methods in a new user-friendly software package TRAPD (Test Rare vAriants with Public Data) that can be used by researchers to rapidly advance our understanding of the genetic basis of disease.
(Summary submitted by Margaret Lippincott, MD, Reproductive Endocrine Unit)
PHYSICIAN OPINIONS ON PALLATIVE CARE
What Do Transplant Physicians Think About Palliative Care? A National Survey Study
El-Jawahri A, LeBlanc TW, Burns LJ, Denzen E, Meyer C, Mau LW [et al.], Petersdorf N.
Published in Cancer on October 5, 2018
We conducted a national survey of hematopoietic stem cell transplant (HSCT) physicians to examine their perception of palliative care. The majority of transplant physicians stated they trust palliative care clinicians to care for their patients, but 40% felt that palliative care clinicians do not have enough understanding to counsel HSCT patients about their treatments. Most physicians also expressed substantial concerns about patients’ perception of the term ‘palliative care’. This study highlights the need for future work to promote collaboration, improve perceptions, and enhance integration of palliative care for HSCT recipients.
(Summary submitted by Areej El-Jawahri, MD, Department of Hematology/Oncology)
TARGETING ROS TO IDENTIFY DNA REPAIR PATHWAYS
ROS-induced R Loops Trigger a Transcription-coupled But BRCA1/2-Independent Homologous Recombination Pathway Through CSB
Teng Y, Yadav T, Duan M, Tan J, Xiang Y, Gao B [et al.], Lan L.
Published in Nature Communications on October 8, 2018
Reactive Oxygen Species (ROS) can induce DNA base damage and strand breaks, and unrepaired or inappropriate repair of these damage lead to mutations, indels and translocations in critical genes. BRCA1 and BRCA2 are critical for canonical homologous recombination (HR) for repair of DNA strand breaks. In this study, researchers identified and characterized a R-loop initiated, but BRCA1/2-independent, alternative HR pathway triggered by ROS. This pathway is likely to be particularly important for suppressing ROS-induced genomic instability associated with tumor growth and degenerative neurological diseases. Given elevated ROS level is detected in almost all tumors, this study may open a new area to selectively target ROS relevant repair pathway in therapy.
(Summary submitted by Li Lan, MD, PhD, Mass General Cancer Center)
INSIGHTS INTO THE GUT MICROBIOME AND POTENTIAL PREDICTORS OF DISEASE
Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course
Schirmer M, Denson L, Vlamakis H, Franzosa EA, Thomas S, Gotman NM [et al.], Xavier RJ.
Published in Cell Host Microbe on October 10, 2018
The incidence of inflammatory bowel disease (IBD) is quickly rising, but treatment options for patients are limited. Our current approach to treatment consists of pharmacologic immunosuppression, which is often only partially effective and usually comes with significant comorbidities for the patient due to being poorly tailored to individual disease phenotypes. In this study, investigators looked at pediatric patients diagnosed with ulcerative colitis (UC), a form of IBD, to understand the correlation between disease severity and microbiome characteristics, and how this changes over time with treatment. Researchers uncovered several important associations between microbiome characteristics, disease severity, and response to treatment. Several of these disease-associated microbiome characteristics were predictive of refractory disease and seen in patients who ultimately required colectomy for treatment. These findings provided an important step forward in predicting individual prognosis and response to treatment based on pre-treatment microbiome characteristics.
(Summary submitted by Ramnik Xavier, MD, PhD Department of Gastroenterology)
RECOGNIZING PREDICTIVE POWER OF GENETIC VARIANTS
Distinguishing Variant Pathogenicity From Genetic Diagnosis: How to Know Whether a Variant Causes a Condition
Biesecker LG, Nussbaum RL, Rehm HL.
Published in JAMA on October 15, 2018
Genetic and genomic testing are being increasingly applied to the clinical management of both symptomatic and asymptomatic patients to understand the basis for their symptoms and possible risk for future disease. Genetic analysis involves a joint effort between the laboratory and the physician in order to determine if any of the millions of variants found in a person’s genome might explain a patient’s symptoms and lead to a disease diagnosis. This paper discusses the process by which clinicians must incorporate genetic testing results into their diagnostic assessments and neither overestimate nor underestimate the predictive and correlative power of genetic information in arriving at an accurate diagnosis.
(Summary submitted by Heidi Rehm, PhD, FACMG, Center for Genomic Medicine)
EXPLORING USE OF A CONJUGATE VACCINE FOR DRUG RESISTANT STRAIN OF TYPHOID
Extensively Drug-Resistant Typhoid—Are Conjugate Vaccines Arriving Just in Time?
Andrews JR, Qamar FN, Charles RC, Ryan ET.
Published in New England Journal of Medicine on October 18, 2018
Antimicrobial resistance (AMR) is a significant public health threat. A highly drug resistant strain of the bacterium that causes typhoid fever has been identified in Pakistan. The window to contain this outbreak is rapidly closing. We propose rapid incorporation of a recently WHO-prequalified typhoid conjugate vaccine into both local and global control programs. This would not only assist in containing the outbreak, but would lessen the burden of typhoid fever globally, and would lessen the inappropriate use of antibiotics.
(Summary submitted by Edward T. Ryan, MD, DTM&H, Division of Infectious Diseases)
USING GEOMETRIC FEATURES OF MICROTUBULES TO UNDERSTAND PROTEIN REGULATION
Geometry of Antiparallel Microtubule Bundles Regulates Relative Sliding and Stalling by PRC1 and Kif4A
Wijeratne S, Subramanian R.
Published in Elife on October 24, 2018
Fundamental cellular processes, such as cell division, growth and development, require the arrangement of polymers, called microtubules, into specialized architectures, such as the mitotic spindle. Microtubules are typically thought to form passive tracks for motor (e.g. kinesin) and non-motor proteins (e.g. tau). Here, the authors show that the micron-scale geometrical features of microtubule bundles, such as polymer length and overlap length, can modulate the activity of nanometer-sized proteins to define the stability and mechanics of microtubule-based architectures.
(Summary submitted by Sitara Wijeratne, PhD, Department of Molecular Biology)
Press Releases
Nonradioactive Magnetic Marker for Breast Tumor Localization
Featuring Leslie R. Lamb, MD, MS
Radioguided and radioactive seed localization were introduced as alternatives to wire-guided localization, but these techniques also have disadvantages.
Focus on Neuroscience, Nociception to Improve Anesthesia, Paper Says
Featuring Emery Brown, MD, PhD
People sometimes mistakenly think of general anesthesia as just a really deep sleep, but in fact, anesthesia is really four brain states – unconsciousness, amnesia, immobility and suppression of the body's damage sensing response, or "nociception."
Massachusetts General Hospital to Participate in Clinical Trial Evaluating Experimental Treatment for Ebola Virus Disease
Featuring Erica Shenoy, MD, PhD, Paul Biddinger, MD, and Ana Weil, MD, MPH
Mass General to take part in an international multi-center trial evaluating ZMapp™, an experimental treatment consisting of three antibodies to treat Ebola Virus Disease.
Mass General-led Study Supports Ability of Regular Aspirin Use to Reduce Liver Cancer Risk
Featuring Tracey Simon, MD, and Andrew Chan, MD, MPH
The results of a study led by Massachusetts General Hospital investigators support evidence from previous studies suggesting the regular use of aspirin can reduce the risk of developing primary liver cancer – also called hepatocellular carcinoma.
Eczema Drug Restores Hair Growth in Patient with Longstanding Alopecia
Featuring Maryanne Makredes Senna, MD
Massachusetts General Hospital physicians describe how their patient with alopecia totalis—a total lack of scalp hair—along with eczema, experienced significant hair regrowth while being treated with dupilumab.
Study Identifies Effective Ketamine Doses for Treatment-Resistant Depression
Featuring Maurizio Fava, MD
A study led by Massachusetts General Hospital investigators identifies two subanesthetic dosage levels of the anesthetic drug ketamine that appear to provide significant symptom relief to patients with treatment-resistant depression.
Regulating Microglial Activity May Reduce Damaging Inflammation in Neurodegenerative Diseases
Featuring Joseph El Khoury, MD
A group of Massachusetts General Hospital investigators is proposing that targeting immune checkpoints – molecules that regulate the activity of the immune system – in immune cells called microglia could reduce the inflammatory aspects of important neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease and ALS.
Combination Drug Targeting Opioid System May Help Relieve Symptoms of Major Depression
Featuring Maurizio Fava, MD
Two clinical trials of an investigational drug that targets the opioid system support its safety and effectiveness in reducing symptoms of major depression, when added to standard antidepressant treatment.
One Month of Abstinence From Cannabis Improves Memory in Adolescents, Young Adults
Featuring Randi Schuster, PhD
A Massachusetts General Hospital study finds that one month of abstaining from cannabis use resulted in measurable improvement in memory functions important for learning among adolescents and young adults who are regular cannabis users.
Minimally Invasive Radical Hysterectomy May Increase Death Risk in Patients With Early-Stage Cervical Cancer
Featuring Alexander Melamed, MD, MPH
A study by a multi-institutional research team, including Massachusetts General Hospital physicians, has found evidence that patients receiving minimally invasive radical hysterectomy for early-stage cervical cancer have an increased risk of death compared to patients treated with open surgery.
Blog Posts
Could Folic Acid Help Reduce the Rates of Autism and Schizophrenia?
Featuring Joshua Roffman, MD, MMSc
Folate levels have, once again, become an area of interest for a Massachusetts General Hospital-based research team after finding that increased in utero folic acid exposure is associated with changes in brain development later in life that could reduce the risk of psychosis and schizophrenia.
A FRESH Look at HIV Prevention and Women’s Empowerment
Researchers at the Ragon Institute of Massachusetts General Hospital, MIT and Harvard recently published an editorial in Science Immunology detailing their efforts to combine basic science and social good to reduce the high rate of HIV infection in young South African women while simultaneously empowering them.
ResQFoam Study Seeks Feedback on Clinical Trial for Trauma Patients
Featuring David King, MD
The REVIVE clinical trial team is seeking feedback from the public on their study testing the use of ResQFoam in severely injured trauma patients.
Could a Light-based Treatment be the Key to Treating Alzheimer’s Disease and Other Brain Disorders?
Featuring Michael R. Hamblin, PhD
Can a light-based treatment called photobiomodulation help to treat degenerative brain diseases?
Not All E-Cigarettes are the Same: What Parents Need to Know
Featuring Jonathan Winickoff, MD, MPH
E-cigarette. E cig. Mod. Tank system. Vape pen. E-hookah. All of them are names for flavored electronic cigarettes’ modern new competitor to smoking that has become incredibly popular with adolescents. But are all e-cigarettes created equal?
Research Awards and Honors: September 2018
Massachusetts General Hospital Research Institute’s talented and dedicated researchers are working to push the boundaries of science and medicine every day. Continue reading to hear from a few individuals who have recently received awards or honors for their achievements:
How We Talk to Children About Obesity Can Make a Big Difference
Featuring Fatima Cody Stanford, MD, MPH, MPA
Obesity has become one of the most talked-about health issues but, ironically, we still haven't mastered how to talk about it yet. With all the stigma surrounding the words like fat and obese, discussing weight issues can be tough for both people experiencing it, and physicians trying to address it.
Research Shows Ketamine Could Be an Answer for Treatment-Resistant Depression
Featuring Maurizio Fava, MD, and Cristina Cusin, MD
Recent research has highlighted ketamine as a potential treatment for treatment-resistant depression, so a research team at Mass General, led by Maurizio Fava, MD, decided to explore the effectiveness of various dosages.
5 Health Benefits of Meditation Backed by Scientists at Mass General
Meditation is an ancient practice that has been used for centuries to achieve a state of calmness and clarity. While it was commonly associated with certain religious practices, it has made its way into everyday Western culture with increasing amounts of research showing it has several positive health benefits.
Research at Mass General
Massachusetts General Hospital is home to the largest hospital-based research enterprise in the U.S., with an annual budget of over $928 million in 2018.