Snapshot of Science for September 2021

Welcome to our Snapshot of Science for September 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:

22 new studies published in high impact journals, along with 19 summaries submitted by the research teams
7 new research-related press releases from the Mass General Public Affairs office
4 posts from the Mass General Research Institute blog

Publications

New Insights into How the Brain Stores Working Memories
Synchronization Patterns Reveal Neuronal Coding of Working Memory Content
Mamashli F, Khan S, Hämäläinen M, Jas M, Raij T [et al.], Ahveninen J.
Published in Cell Reports on August 24, 2021 | *Summary available

Insights into the Mechanisms of RNA Copying Chemistry
Structure-Activity Relationships in Nonenzymatic Template-directed RNA Synthesis
Giurgiu C, Fang Z, Aitken HRM, Kim SC [et al.], Szostak JW.
Published in Angewandte Chemie on August 24, 2021 | *Summary available

Miniaturizing Lasers for Biomedical Analysis and Single Cell Imaging
Submicrometer Perovskite Plasmonic Lasers at Room Temperature
Cho S, Yang Y, Soljačić M, Yun SH.
Published in Science Advances on August 25, 2021 | *Summary available

Immune Cells Congregate in Stereotyped Patterns in Tumors
Spatially Organized Multicellular Immune Hubs in Human Colorectal Cancer
Pelka K, Hofree M, Chen JH, Sarkizova S, Pirl JD [et al.], Hacohen N.
Published in Cell on August 26, 2021 | *Summary available

The Impact of Palliative Care on AML Patients
Palliative Care and Coping in Patients with Acute Myeloid Leukemia: Mediation Analysis of Data from a Randomized Clinical Trial
Nelson AM, Amonoo HL, Kavanaugh AR, Webb JA, Jackson VA [et al.], LeBlanc TW.
Published in Cancer on August 30, 2021 | *Summary available

Cognitive Profiles of Children with Genetic Predisposition to Alzheimer's Disease
Sex Differences in Cognitive Abilities Among Children with the Autosomal Dominant Alzheimer Disease Presenilin 1 E280A Variant from a Colombian Cohort
Fox-Fuller JT, Artola A, Chen K, Pulsifer M, Ramirez D [et al.], Quiroz YT.
Published in JAMA Network Open on August 31, 2021 | *Summary available

Pupil Dilation as an Indicator of Neuromodular Activity
Decoding the Brain State-dependent Relationship Between Pupil Dynamics and Resting State fMRI Signal Fluctuation
Sobczak F, Pais-Roldán P, Takahashi K, Yu X.
Published in Elife on August 31, 2021 | *Summary available

Effective Strategies for Pediatric Weight Management
Comparative Effectiveness of Clinical and Community-based Approaches to Healthy Weight
Fiechtner L, Perkins M, Biggs V, Langhans N, Sharifi M [et al.], Taveras EM.
Published in Pediatrics on September 1, 2021 | *Summary available

Inherited Variation in Organelles and Age-associated Disease Risk
Human Genetic Analyses of Organelles Highlight the Nucleus in Age-related Trait Heritability
Gupta R, Karczewski KJ, Howrigan D, Neale BM, Mootha VK.
Published in Elife on September 1, 2021 | *Summary available

Sacituzumab Govitecan Improves Survival Rates in Metastatic Triple-Negative Breast Cancer
Biomarker Analyses in the Phase III ASCENT Study of Sacituzumab Govitecan Versus Chemotherapy in Patients with Metastatic Triple-Negative Breast Cancer
Bardia A, Tolaney SM, Punie K, Loirat D, Oliveira M [et al.], Hurvitz SA.
Published in Annals of Oncology on September 1, 2021 | *Summary available

Model Systems for Cancer Metabolism
Patient-derived Xenografts to Study Cancer Metabolism: When Does X Mark the Spot?
Nabel CS, Vander Heiden MG.
Published in Cancer Research on September 1, 2021 | *Summary available

Factors Underlying the Loss of Spontaneous HIV Control
Functional Impairment of HIV-specific CD8+ T Cells Precedes Aborted Spontaneous Control of Viremia
Collins DR, Urbach JM, Racenet ZJ, Arshad U, Power KA [et al.], Walker BD.
Published in Immunity on September 2, 2021 | *Summary available

Assessing the Methods and Findings of COVID-19 mRNA Vaccine Study
Safety Surveillance of COVID-19 mRNA Vaccines Through the Vaccine Safety Datalink
Blumenthal KG, Phadke NA, Bates DW.
Published in JAMA on September 3, 2021 | *Summary available

Machine Learning Model for Quantifying Polygenic Risk Scores
Translating Polygenic Risk Scores for Clinical Use by Estimating the Confidence Bounds of Risk Prediction
Sun J, Wang Y, Folkersen L, Borné Y, Amlien I [et al.], Lage K.
Published in Nature Communications on September 6, 2021

Noninvasive Measure of Blood Velocity
Assessment of Single-Vessel Cerebral Blood Velocity by Phase Contrast fMRI
Chen X, Jiang Y, Choi S, Pohmann R, Scheffler K [et al.], Yu X.
Published in PLoS Biology on September 9, 2021 | *Summary available

Stress Experiences May Interfere with Disclosure of Self-Injurious Thoughts and Behaviors in Minorities
Disclosure of Self-Injurious Thoughts and Behaviors Across Sexual and Gender Identities
Burke TA, Bettis AH, Barnicle SC, Wang SB, Fox KR.
Published in Pediatrics on September 14, 2021 | *Summary available

Inosine Treatment Has No Significant Effect on Parkinson's Disease Progression
Effect of Urate-elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial
Parkinson Study Group SURE-PD3 Investigators, Schwarzschild MA, Ascherio A, Casaceli C, Curhan GC, Fitzgerald R, Kamp C [et al.], Mestre T.
Published in JAMA on September 14, 2021 | *Summary available

Osteoblasts Produce tiRNA-laden EVs in Response to Infection Stress
tiRNA Signaling Via Stress-regulated Vesicle Transfer in the Hematopoietic Niche
Kfoury YS, Ji F, Mazzola M, Sykes DB, Scherer AK [et al.], Scadden DT.
Published in Cell Stem Cell on September 15, 2021 | *Summary available

Endothelial Lipase Is Important for the Breakdown of Triglycerides in the Blood
Endothelial Lipase Mediates Efficient Lipolysis of Triglyceride-Rich Lipoproteins
Khetarpal SA, Vitali C, Levin MG, Klarin D, Park J [et al.], Rader DJ
Published in PLoS Genetics on September 20, 2021 | *Summary available

Locus Coeruleus Integrity as a Biomarker of Alzheimer's Disease
In Vivo and Neuropathology Data Support Locus Coeruleus Integrity as Indicator of Alzheimer's Disease Pathology and Cognitive Decline
Jacobs HIL, Becker JA, Kwong K, Engels-Domínguez N, Prokopiou PC [et al.], Johnson KA
Published in Science Translational Medicine on September 22, 2021 | *Summary available

Comparing Mucosal and Cutaneous Melanomas
Mucosal Melanomas of Different Anatomic Sites Share a Common Global DNA Methylation Profile with Cutaneous Melanoma But Show Location Dependent Patterns of Genetic and Epigenetic Alterations
Jurmeister P, Wrede N, Hoffmann I, Vollbrecht C, Heim D [et al.], Capper D
Published in The Journal of Pathology on September 26, 2021

Publication Summaries

Auditory working memory is a brain system that keeps things that we just heard in our minds for a short time. We used machine learning analyses of magnetoencephalography (MEG) recordings of brain activity to investigate this function. During MEG, human participants memorized one out of six possible "sound items" for a few seconds. The researchers were able to decode the memorized items by inspecting how different brain areas worked together during the task. The results provide a new perspective on the brain stores working memories and may help those suffer from working memory problems.

(Summary submitted by Jyrki Ahveninen, PhD, of the Department of Radiology and the Martinos Center for Biomedical Center)

Insights into the Mechanisms of RNA Copying Chemistry
Structure-Activity Relationships in Nonenzymatic Template-directed RNA Synthesis
Giurgiu C, Fang Z, Aitken HRM, Kim SC, Pazienza L, Mittal S, Szostak JW.
Published in Angewandte Chemie on August 25, 2021

Life is not possible without nucleic acids. What makes DNA and RNA special? Why were these molecules selected and could any other take their place? These two questions have fascinated scientists ever since the double helix revolutionized the way we think about life. New research from the Szostak lab fortifies the hypothesis that life could have started with self-organizing RNA molecules. Looking at frozen atoms in a crystal, the authors explain how RNA could have outcompeted its rivals and jumpstarted biology. It all comes down to the shape of the ribose ring embedded in the backbone of the nucleic acids.

(Summary submitted by Constantin Giurgiu, Szostak Lab)

Miniaturizing lasers—from a 5 cm-long laser pointer to 5 a cm-wide particle—is a daunting task but exciting because it can open up new applications. We have created such nanolasers by using a semiconductor known as perovskite. Our main finding is that attaching metal next to a semiconductor nano-cube can greatly enhance optical resonance and amplification in the submicron structure to generate an ultrasharp laser emission. We are currently making "plasmonic" laser particles compatible with cells and working on applying the nanolasers for bioimaging and single-cell analysis to advance life sciences and medical diagnosis.

(Summary submitted by Sangyeon Cho, PhD, from the Wellman Center for Photomedicine)

The immune response in tumors tends to look disorganized, but by observing more refined functions of each immune cell type, we observed a spatial organization of cells that was previously invisible. These clusters of cells are very likely involved in seeing the tumor and eliminating it, and are now being studied in more depth to improve immunotherapies.

(Summary submitted by Nir Hacohen, PhD, from the Mass General Cancer Center)

Acute myeloid leukemia (AML) is a potentially life-threatening disease often requiring urgent initiation of intensive chemotherapy. In this study, we examined data from a multisite randomized trial comparing palliative care integrated with oncology care versus standard care for hospitalized patients with AML being treated with intensive chemotherapy. We found that patients who received palliative care experienced positive changes in coping that mediated the effect of the intervention on quality of life and mood. Supportive care services that help patients manage the demands of AML and its treatment are beneficial and needed for patients with AML receiving intensive chemotherapy.

(Summary submitted by Ashley Nelson, PhD, Department of Psychiatry)

Cognitive Profiles of Children with Genetic Predisposition to Alzheimer's Disease
Sex Differences in Cognitive Abilities Among Children with the Autosomal Dominant Alzheimer Disease Presenilin 1 E280A Variant From a Colombian Cohort
Fox-Fuller JT, Artola A, Chen K, Pulsifer M, Ramirez D [et al.], Quiroz YT
Published in JAMA Network Open on August 31, 2021

Alzheimer's disease (AD) is a debilitating neurodegenerative condition, and the identification of early cognitive markers of AD is of paramount importance to the efforts to enhance early detection and prevention of the disease. This study examined, for the first time to our knowledge, the cognitive profiles of children who have an AD variant in the presenilin-1 gene and who are destined to develop early-onset dementia by their 50s. We found that boys with the AD variant had decreased working memory abilities compared with girls with the variant, and with boys and girls without the variant, suggesting a sex-specific genetic risk in early-life cognitive performance among individuals with this variant. We hope this study informs our understanding of sex-specific cognitive profiles in the early stages of AD.

(Summary submitted by Joshua T. Fox-Fuller, BA, MA, Arabiye Artola, MHS, Department of Psychiatry, and Yakeel T. Quiroz, PhD, Departments of Psychiatry and Neurology)

Pupil diameter is used as an index of the brain's arousal system and has traditionally thought to be a non-invasive index of specific neuromodulatory activity. Therefore, it has been heavily used as a measure in neuroscience. More recent data suggests a more complex picture whereby a pupil dilation might track a cocktail of different neuromodulators. Our paper provides firm data supporting this view and introduces the new view that the make-up of this cocktail changes significantly over time. Pupil dynamics are linked with different neuromodulatory centers over different intervals of time. This is clearly important data across a broad range of human and animal systems neuroscience.

(Summary submitted by Xin Yu, PhD, from the Department of Radiology and the Athinoula A. Martinos Center for Biomedical Imaging)

Childhood obesity is a growing problem, with especially high rates in Hispanic and Black children and in families with low income. In a recent randomized clinical trial in a largely Hispanic, low-income population, children who participated in a pediatric weight management program delivered at health centers by a team including a pediatrician, dietician and community health worker significantly lowered their body mass index over the course of one year. Children in the healthy weight clinic program also lowered their intake of sugary beverages and fast food, got more sleep, decreased their screen time and boosted their physical activity. The program has now been packaged for use in other primary care settings. We hope that this effective pediatric weight management intervention can help those most disproportionately affected by overweight and obesity.

(Summary submitted by Lauren Fiechtner, MD, Center for Pediatric Nutrition, Mass General for Children)

Aging is one of the biggest risk factors for common diseases such as heart disease, diabetes and dementia. A deterioration in organelles, specialized cellular substructures, has been documented in many tissues as they age and become diseased. A decline in the functioning of the mitochondria, the major site of energy production within cells, has even been referred to as a hallmark of aging. An important question is the degree to which inherited variation in organelles predisposes one to risk for age associated disease. We tested if genetic variants associated with 24 age-related traits tended to be linked to genes associated with ten organelles. To our surprise, the only organelle with a consistent signal across many diseases was the nucleus, and in particular, the nuclear transcription factors. This work highlights the nucleus over other organelles in the inherited genetic risk for age-related disease, setting up future efforts to unearth the influence of transcription factors on age-related organelle decline.

(Summary submitted by Rahul Gupta, Department of Molecular Biology)

The landmark phase III ASCENT trial demonstrated improved survival associated with sacituzumab govitecan (SG), an anti-Trop-2 antibody-drug conjugate linked with topoisomerase-inhibitor SN-38, over single-agent chemotherapy of physician's choice (TPC) in metastatic triple-negative breast cancer. In this study, we evaluate the association between Trop-2 expression and clinical outcomes. Overall, the median progression-free survival (PFS) was 6.9, 5.6 and 2.7 months for high, medium and low Trop-2 H-scores, respectively with SG compared with 2.5, 2.2 and 1.6 months with TPC. The study confirmed that all biomarker subgroups derive benefit from SG as compared to standard chemotherapy.

(Summary submitted by Aditya Bardia, MD, MPH, rom the Mass General Cancer Center, Division of Hematology/Oncology, Department of Medicine)

We were invited to write an expert opinion piece about model systems for studying cancer metabolism in the basic science laboratory. An increasingly popular way of studying cancer is the use of patient-derived xenografts in which tumor tissue from a patient is grown in an immunocompromised mouse. We highlight the critical questions in the cancer metabolism field, emphasizing the aspects of these patient-derived laboratory models that are well-suited for further study while cautioning potential shortcomings to avoid overinterpretations.

(Summary submitted by Christopher Nabel, MD, PhD, from the Mass General Cancer Center, Division of Hematology/Oncology, Department of Medicine)

Most people living with HIV must adhere to daily medication to suppress the virus. However, a rare but remarkable group known as HIV controllers achieve viral suppression without medication. This spontaneous control of HIV is typically durable, but sometimes fades. We longitudinally evaluated 34 HIV controllers with differential outcomes to distinguish mechanisms by which control is maintained or lost. We report that deterioration of immune cells' ability to multiply and kill infected cells, rather than mutations in the virus to escape detection, preceded loss of HIV control. Our findings will help researchers develop immunotherapies to achieve durable remission of HIV.

(Summary submitted by David R. Collins, PhD, Ragon Institute of Mass General, MIT and Harvard, Department of Medicine)

People in the U.S. have received >380 million doses of COVID-19 vaccines with the majority being mRNA vaccines. A recent landmark U.S. study by Klein et al. assessed mRNA vaccine safety across 8 U.S. health plans and 23 serious outcomes through the Vaccine Safety Datalink. The mRNA COVID-19 vaccines were determined to be safe for the population overall with no difference for any of the serious outcomes assessed, but an excess risk of myocarditis/pericarditis was identified for ages 12-39. Anaphylaxis was rare. In this accompanying editorial, the methods and findings of this landmark study are described and placed into context of vaccine safety surveillance in the U.S.

(Summary submitted by Kimberly Blumenthal, MD, MSc, from the Division of Rheumatology Allergy and Immunology, Department of Medicine)

We establish a method to noninvasively map the velocity of blood in single-vessels using high field functional magnetic resonance imaging (fMRI) based on the phase contrast. In contrast to arteriole-dominated cerebral blood volume (CBV) and venule-dominated blood oxygen level determination (BOLD) fMRI responses, our method, called cerebral blood flow-related velocity fMRI (CBFv-fMRI), enables measurements of cerebral blood flow in individual pial and penetrating vessels. We demonstrate CBFv-fMRI by detecting changes in blood velocity through penetrating arterioles and venules in activated regions of rat brains. Our work completes a scheme for noninvasive single-vessel mapping of changes in blood oxygen, volume, velocity in the same platform.

(Summary submitted by Xin Yu, PhD, from the Department of Radiology and the Athinoula A. Martinos Center for Biomedical Imaging)

Evidence suggests that sexual minority (SM) and gender minority (GM) youth experience higher rates of self-injurious thoughts and behaviors (SITBs) than their heterosexual and cisgender counterparts. However, research has yet to explore whether these differences are observed in SITB disclosure. This study's findings from over 900 adolescents, oversampled for SM and GM youth, found few differences in disclosure of SITBs to friends, parents/guardians, and disclosure honesty to therapists, as well as with related barriers to disclosure. However, results provide some evidence supporting the minority stress model, finding that minority stress experiences may interfere with SITB disclosure, particularly among GM youth.

(Summary submitted by Taylor Burke, PhD, Department of Psychiatry)

SURE-PD3 investigated whether increasing brain levels of urate, a natural antioxidant, through inosine treatment could slow the progression of Parkinson's disease (PD). The trial, conducted by the Parkinson Study Group (PSG) at 58 sites, enrolled 298 individuals recently diagnosed with PD who received the urate precursor inosine or placebo over the course of two years. The results showed no significant effect of inosine, at doses that raised urate levels, on disease progression. While the results provided evidence against urate-elevating inosine treatment in PD, the study's rigor and innovations will improve the likelihood that future trials can establish therapeutic benefits for people with PD.

(Summary submitted by Michael Schwarzschild, MD, PhD, of the Department of Neurology)

Investigators at the Mass General and Harvard Stem Cell Institute have discovered a new process that is independent of hormones and rapidly increases immune cells necessary to fight infection. Based on observations in the bone marrow where blood cells are made, we demonstrated that vesicles from bone cells pass material to blood progenitors. The packets of material are fragments of the bone cells containing very specific payloads. Many different types of RNA are in the fragment or vesicle with a particular abundance of processed tRNA, a type of RNA critical for converting information comprising a gene into a protein. The processed tRNAs (also called tiRNAs) were very specific and had the unexpected property of rapidly increasing protein production in the receiving cell. The receiving cells then had a jump start on making new cells. They did so resulting in more new blood cells and a greater ability to handle severe infection.

(Summary submitted by David Scadden, MD, of the Center for Regenerative Medicine, Mass General Cancer Center)

A multidisciplinary team showed that endothelial lipase, an enzyme known to break down phospholipids on high-density lipoproteins, is also important for the breakdown of triglycerides in the blood. In large human populations and using human genetics, we show that people with a mutation in the gene encoding endothelial lipase that lowers enzyme function have higher levels of triglycerides in the blood. Further work in mice lacking endothelial lipase showed that after a fatty meal, these mice were unable to break down dietary triglycerides. We show that this enzyme may work in partnership with another well-established enzyme for the breakdown of triglycerides, lipoprotein lipase, to make this metabolism more efficient. The ability of endothelial lipase to promote triglyceride breakdown may be due to a special ability of this enzyme in breaking down polyunsaturated fatty acids, a special type of fat that may be protective against metabolic and heart diseases.

(Summary submitted by Sumeet Khetarpal, MD, PhD, from the Division of Cardiology, Department of Medicine)

The locus coeruleus, a tiny region in the brainstem, is known to accumulate abnormal tau proteins early in adulthood. This tau protein is one of the important causes of Alzheimer's disease. In this study, we used new MRI-methods to visualize the locus coeruleus during life in healthy older individuals and compared this to postmortem data. In all datasets, we found that lower locus coeruleus integrity was associated with tau accumulation and memory decline. These findings have important implications, as they suggest that the locus coeruleus has the potential to identify individuals who are at-risk to develop Alzheimer's disease at an earlier point in life.

(Summary submitted by Heidi Jacobs, PhD, of the Gordon Center for Medical Imaging, Department of Radiology)

Press Releases

Emoji are Proposed as a Powerful Way for Patients and Doctors to Communicate
Featuring Shuhan He, MD

The colorful symbols that are part of mainstream dialogue could provide patients with a new way to be heard by their physicians.

Diet May Affect Risk and Severity of COVID-19
Featuring Jordi Merino, PhD, and Andrew Chan, MD, MPH

Study links healthy plant-based foods with lower risks of getting of COVID-19 and of having severe disease after infection.

Impaired T Cell Function Precedes Loss of Natural HIV Control
Featuring Bruce Walker, MD, David Collins, PhD, Gaurav Gaiha, MD, DPhil, Todd Allen, PhD, and Jonathan Urbach, PhD

The study of a small subset of HIV-positive people whose bodies naturally control the virus—then lose that ability—offers clues to retraining the immune systems for all with HIV.

Study Rules Out an Antioxidant Treatment for Slowing the Progression of Parkinson's Disease
Featuring Michael Schwarzschild, MD, PhD

Researchers at Mass General find no therapeutic benefit to raising the level of urate in the brain.

Investigational Drug SLS-005 (Trehalose) Receives "May Proceed" Notice and Central IRB Approval for the HEALEY ALS Platform Trial
Featuring Merit Cudkowicz, MD

The Sean M. Healey & AMG Center for ALS at Mass General received approval both from the U.S. Food and Drug Administration and the Mass General Brigham Institutional Review Board to proceed with adding SLS-005 (trehalose injection, 90.5 mg/ML for intravenous infusion) as an additional regimen in the HEALEY ALS Platform Trial.

Study Findings Could Provide Blueprint for Regulating Lab-developed Diagnostic Tests
Featuring Jochen Lennerz, MD, PhD

Certain temporary deviations in Food and Drug Administration policy in response to the COVID-19 pandemic may offer a blueprint for regulatory oversight of laboratory-developed tests, according to a new study by researchers at Mass General.

Trial Finds Childhood Weight Management Program Effective for Hispanic Children from Low Income Families
Featuring Lauren Fiechtner, MD, and Elsie Taveras, MD, MPH

A weight management program delivered at community health centers to children from Hispanic, low-income families was effective at improving body mass index.

Blog Posts

Researchers Discover the Mechanisms Behind Cold-related Tooth Pain
Featuring Jochen Lennerz, MD, PhD

In a recent study, the team demonstrated that odontoblasts are responsible for sensing cold and transmitting tooth pain signals to the brain.

Congratulations to the Department of Medicine's 2021 Transformative Scholars
Featuring Benjamin Bearnot, MD, MPH, Rod Rahimi, MD, PhD, Anne Neilan, MD, MPH, and Russell Goodman, MD, PhD, Dphil

The program supports outstanding young faculty in tackling critical health care challenges.

LAB DAY 2021 Takes Participants on a Virtual Tour of Research at Mass General
Featuring Eric Liao, MD, PhD, Dara Manoach, PhD, Ingrid Bassett, MD, MPH, Travis Baggett, MD, MPH, Daphne Holt, MD, PhD, and Olivia Okereke, MD, MS

LAB DAY offered friends and supporters of the Mass General Research Institute a behind-the-scenes look at the hospital's research enterprise.

The Big Picture: How Medical Emoji Could Improve Healthcare Communication
Featuring Shuhan He, MD

Patients and healthcare providers would benefit from a more comprehensive and curated set of medical emoji, say the authors of a new position paper in JAMA.

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Snapshot of Science for September 2021