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Research at Mass General
Summaries of recent publications in high impact journals from researchers at Massachusetts General Hospital.
The elegant organization of brain networks important to thought and remembering was revealed in a new study. By examining the details of brain organization in individuals, Rodrigo Braga and Randy Buckner were able to reveal that the human brain possesses multiple networks that connect regions distributed throughout the brain. Strikingly, the multiple networks are intertwined like threads in a tapestry. Prior work blurred over this orderly pattern by averaging across individuals. The newly discovered structure sets a foundation for analysis of the functional properties of the multiple networks as well as clinical endeavors that seek to modulate the networks to treat psychiatric illness.
Summary provided by Randy Buckner, PhD, Director of the Psychiatric Neuroimaging Research Division at Massachusetts General Hospital, and senior author of the study.
The aorta and its branches are large arteries in the human body that carry oxygen-rich blood from the heart to the rest of the circulatory system. Structural malformations of the aorta are common birth defects that even in the mildest cases require life-saving surgery at birth. During fetal life, the aorta is built from transient blood vessels termed the pharyngeal arch arteries (PAAs). However, the mechanisms regulating formation of the PAAs remain poorly understood. This paper reports that TGFb signaling, a molecular pathway that controls cellular proliferation and differentiation in other contexts, initiates and is essential for PAA development in zebrafish. Despite this important advance, further research is needed to identify additional molecular pathways that control PAA establishment and to learn if mutations that affect TGFb signaling in humans result in similar aortic deficiencies. This information can be leveraged to develop new therapies for preventing or treating congenital malformations that involve the aorta and its branches.
Summary provided by Caroline Burns, PhD, d’Arbeloff MGH Research Scholar and researcher in the Cardiovascular Research Center at Massachusetts General Hospital, and co-senior author of the study.
Giving families information on healthy and affordable community resources through novel mapping tools can lead to increased parental satisfaction and positive childhood obesity interventions. Interviewing parents, community partners and experts on child obesity and the “built environment,” researchers created an online interactive map to identify healthy resources in environments with high rates of childhood obesity. Parents identified poor access to healthy food and easy access to fast-food as barriers to healthy weight in their community. Researchers also found that nutrition resources, physical activity and social support were important for success in reducing childhood obesity. Using the map, families were physically active at new locations, shopped at new locations and reported a high satisfaction level with the information they received.
Summary provided by Lauren Fiechtner, MD, MPH, Director for the Center for Pediatric Nutrition at Massachusetts General Hospital for Children, and lead author of the study. Elsie Taveras, MD, MPH, Chief of the Division of General Pediatrics at Massachusetts General Hospital for Children, is senior author.
Following up on findings from an earlier genome-wide association study (GWAS) of type 2 diabetes (T2D) in Latinos, researchers traced an association detected in that study to variants in a specific gene, SLC16A11, and uncovered two distinct mechanisms by which those variants disrupt the gene’s function in liver cells, possibly contributing to the pathogenesis of T2D. The findings offer insights into the biology underlying T2D and suggest new leads in the search for therapeutics.
Summary provided by Jose Florez, MD, PhD, Associate Physician in Medicine [Endocrine Division] at Massachusetts General Hospital.
Previous genomic analyses of many tumors have discovered hundreds of cancer genes with mutations in protein-coding regions. By contrast, we do not yet know much about cancer-causing mutations in non-coding regions that regulate important genes. This study found that breast cancers hide potentially important mutations in the promoters of at least nine genes. Promoters are noncoding stretches of DNA just before genes, where the cell’s DNA-reading machinery latches on to start the transcription process. In addition to highlighting several genes not previously thought to be involved in breast cancer, the team’s findings offer new insights into how one known cancer gene may help breast tumors thrive in the face of treatment.
Summary provided by Gad Getz, PhD, Director of Bioinformatics at the Massachusetts General Hospital Cancer Center and Department of Pathology at Massachusetts General Hospital, and senior author of the study.
Inhibition of the kinases Mek1 and Mek2 helps to maintain cultured embryonic stem cells in a primitive state, which closely resembles cells of the early embryo. This approach is widely used in the field to study the molecular basis of stem cell self-renewal and early development. This study found that capturing embryonic stem cells in a dish comes at a cost- Jiho Choi and Aaron Huebner from Konrad Hochedlinger’s lab discovered that prolonged suppression of these kinases in mouse cells leads to irreversible epigenetic and genomic changes that impair their developmental potential. Further exploration of Mapk signaling could shed light on epigenetic regulation of embryonic development and lead to strategies to generate stable, human embryonic stem cells for research or clinical applications.
Summary provided by Konrad Hochedlinger, PhD, of the Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine at Massachusetts General Hospital, and senior author of the study.
Scientists in the Hung lab discovered a new inhibitor against Mycobacterium tuberculosis, the causative agent of tuberculosis, which is the leading cause of infection-related deaths worldwide. There is a desperate need for new TB antibiotics in the face of rising drug resistance. The small molecule functions by inhibiting tryptophan biosythesis, a process that has not been previously targeted by antibiotics. Importantly, tryptophan biosynthesis is essential for the survival of M tuberculosis in animal models. The unique and complex mechansim of the molecule suggests general strategies for the design and discovery of new inhibitors.
Summary provided by Deborah Hung, MD, PhD, from the Center for Computational and Integrative Biology at Massachusetts General Hospital, and senior author of the study.
Apolipoprotein E is a molecule that is present in both the blood and the brain. It can be inherited in one of 3 forms, called E2, E3, or E4. While people who inherit E2, E3 or E4 are completely normal in almost every way, individuals who have the E4 gene have a 3 times higher chance of getting Alzheimer’s disease as they age. To understand what is different between E2, E3, and E4, Dr. Eleanna Kara in Dr. Brad Hyman’s lab developed a way to measure the shape of the molecules, which she found differ from one another in a substantial way. This may be the first step to understanding how E4 increases the risk for Alzheimer’s, and a tool to develop drugs to change the shape of E4 to something that is more like E3 and E2.
Summary provided by Bradley Hyman, MD, PhD, Alzheimer's Unit Director for the MassGeneral Institute for Neurodegenerative Disease at Massachusetts General Hospital, and senior author of the study.
Folliculin (FLCN) is a tumor suppressor gene, which is mutated in the germline of patients with Birt-Hogg-Dube (BHD) disease. BHD patients may develop kidney cancer in both kidneys, benign skin lesions and lung cysts. FLCN protein controls the activity of G proteins (proteins that are involved in a variety of important cellular processes), but how this function relates to its ability to suppress the formation of kidney cancer was unknown. This study provides for the first time significant insights on why FLCN is a tumor suppressor gene: through its effect on specific G proteins, FLCN alters the activity of cell surface growth factor receptors that drive cell proliferation. This work paves the way for the treatment of FLCN-deficient tumors.
Summary provided by Othon Iliopoulos, MD, Clinical Director of the von Hippel-Lindau Disease/Familial Renal Cell Cancer Program at Massachusetts General Hospital, and senior author of the study.
Traditional adjuvants that increase the effectiveness of vaccines for infectious diseases may induce inflammatory reactions in tissues that mobilize and activate immune cells that may result in local and systemic adverse reactions. This study shows for the first time that a non-damaging, low-dose infrared laser delivered to the skin for just one minute, can both activate and enhance migration of a type of skin-resident immune cells called dendritic cells, which can lead to enhancement of vaccine responses without inflammation. The team’s laser vaccine adjuvant has proved safe in initial human studies. Next steps are to test the efficacy of this new technology in the context of vaccination in the clinic under the direction of Dr. Gelfand and Dr. Poznansky.
Summary provided by Satoshi Kashiwagi, PhD, MD, Assistant Professor of Medicine in the Vaccine and Immunotherapy Center at Massachusetts General Hospital, and senior author of the study; and Mark C. Poznansky, MD, PhD, Director of the Vaccine and Immunotherapy Center at Massachusetts General Hospital, and co-investigator of the study.
The millions of bacteria living in our body, called the human microbiome, play a key role in both keeping us healthy and putting us at risk for chronic diseases. But how do these bacteria get there? In a study focused on workers who care for mice in research facilities, Dr. Lai and her collaborators demonstrate that just as there is a human microbiome, there is also a microbiome in our external environment. A small part of the human microbiome in these workers was traced to the environmental microbiome of their workplace. More research is needed to better understand the health implications of these findings.
Summary provided by Peggy Lai, MD, from the Division of Pulmonary and Critical Care at Massachusetts General Hospital, and lead author of the study.
TERRA is a noncoding RNA that is produced from the ends of all chromosomes. This paper answers questions regarding TERRA’s function by (i) developing a method of TERRA depletion, (ii) mapping where the RNA binds in our nucleus, (iii) showing that it interacts with a major protein implicated in cancer — ATRX. To become a cancer cell, cells must overcome the fact that they no longer express telomerase (the enzyme needed to replicate chromosome ends). One way of doing this is to use a mechanism called alternative lengthening of telomeres whereby ATRX is shut down. Researchers found that TERRA expression antagonizes ATRX function. They also discovered that TERRA is very important for telomere stability. When TERRA RNA was depleted, the ends of chromosomes developed duplications, deletions, ring structures, and other anomalies. Taken together, these data support a key role of noncoding telomeric transcripts in maintaining genome stability and preventing cancer.
Summary provided by Jeannie Lee, MD, PhD, Molecular Biologist at Massachusetts General Hospital, and senior author of the study.
When only one allele of a gene is actively transcribed, how is this expression established through sex chromosome pairing, and how do these chromosomes find each other in the 3D nucleus? This paper shows that sex chromosomes of both male and female embryonic stem cells briefly pair when they develop from a less specialized cell to a more specialized cell type. This pairing is critical for inactivating the X chromosome and is directed by a transcription made from the homologous sex-linked ends of the sex chromosomes, called PAR-TERRA. PAR-TERRA tethers the sex chromosomes together via the ends of the chromosomes (telomeres) at the nuclear periphery. The telomeres in turn enable the inactivated X chromosomes to find each other by constraining the space around them. This work demonstrates the essential nature of long RNA in 3D nuclear dynamics that is transcribed from DNA but not translated into proteins.
Gut microbiota is a collective term for the diverse consortium of microorganisms residing in the gastrointestinal tract. Accumulating evidence supports previously unrecognized roles for gut microbiota in many physiological and pathological processes, for example, gut microbiota is critical to determine the tumor killing effects of many chemotherapy drugs. In this paper, Dr. Shen et al. provide evidence that chemotherapy-induced pain, a major dose-limiting side effect of many chemotherapy drugs, is fueled by gut microbiota. Findings from this study may lead to new mechanistic insight on chemotherapy-induced pain, and new therapeutic avenues to treat this devastating pain symptom.
Summary provided by Jianren Mao, MD, PhD, Chief of the Division of Pain Medicine at Massachusetts General Hospital, and senior author of the study.
What does a catalytic converter have to do with drugs? A lot, it turns out. Catalytic converters in our cars convert toxic gas emissions into into acceptable ones. A key element is the metal palladium, which catalyses the oxidation of pollutants like carbon monoxide to carbon dioxide. In a recent article in Nature Communications, researchers have developed a medical version of nano-palladium to enable chemistry to take place inside cells in our body. The discovery allows the administration of harmless prodrugs, which then get specifically activated at sites of cancer. This work demonstrates the possibility of using palladium as a catalyst for treatment of disease in mammals.
Summary provided by Miles Miller, PhD, from the Center for Systems Biology at Massachusetts General Hospital, and lead author of the study.
Cancer patients who have metastases in the lymph nodes surrounding the tumor have a worse prognosis than patients whose lymph nodes are cancer-free. This observation has traditionally been explained by a progression model in which lymph node metastases come before lethal organ metastases. However, no conclusive evidence for this model existed so far. In this study, researchers investigated the “family tree” of metastases in colorectal cancer and found that in most cases, lymph node metastases did not come before organ metastases. They concluded that lymph node metastases are indicators of an aggressive primary tumor, but not necessarily the cause of distant metastases.
Summary provided by Kamila Naxerova, PhD, from the Edwin L. Steele Laboratories for Tumor Biology in the Department of Radiation Oncology at Massachusetts General Hospital, and lead author of the study.
Chronic imaging windows in mice have been developed to allow high resolution images of multiple organs in living animals. These techniques have proven to be of paramount importance in advancing our knowledge of normal and disease processes. However, no model system that allowed long-term, live animal imaging of lymph nodes had been developed. This has been a major limitation in the study of cell behavior in lymph nodes during the generation of immune responses as well during the spread of cancer to lymph nodes. This manuscript describes a novel surgical preparation to facilitate long-term, live animal imaging of a lymph node in mice.
Summary provided by Timothy Padera, PhD, from the Edwin L. Steele Laboratories for Tumor Biology in the Department of Radiation Oncology at Massachusetts General Hospital, and senior author of the study.
This study finds evidence that propofol, an anesthetic drug frequently used in clinical practice, disrupts activity in the parts of the brain responsible for awareness and coordination by inducing highly synchronized oscillations within and between these brain structures. The study also found that during recovery of consciousness, these synchronized oscillations dissipate in a distinct “boot-up” sequence, one that did not simply mirror loss of consciousness. This implies that recovering consciousness is not just a passive process, but an active one involving a different set of brain areas responsible for “waking up” the brain. Overall, this study advances understanding of what it means to be unconscious under anesthesia, and establishes principled neurophysiological markers to monitor and manage this state.
Summary provided by Patrick Purdon, PhD, from the Department of Anesthesia, Critical Care, and Pain Medicine at Massachusetts General Hospital, and senior author of the study.
Shah’s team has developed stem cells that can deliver cancer-killing oncolytic viruses and applied them to metastatic tumors in the brain of clinically relevant mouse models which his team built in parallel to developing the therapeutic strategy. The investigators report the elimination of metastatic skin cancer cells from the brain of these preclinical models, resulting in prolonged survival. The study also describes a strategy of combining this therapy with immune check point inhibitors. This work will have direct implications for designing clinical trials using oncolytic viruses for metastatic tumors in the brain.
Summary provided by Khalid Shah, PhD, formerly from the Center for Stem Cell Therapeutics and Imaging in the Department of Radiology at Massachusetts General Hospital, and senior author of the study.
Human metabolism is “wired” to allow us to go from rest to running by efficiently burning sugars, fats and proteins to harness their energy. However, patients with certain genetic conditions like McArdle disease who cannot access glycogen stores or mitochondrial disease who have broken respiratory chains have symptoms that are exacerbated by exercise. Scientists from the Mootha lab studied the exercise-induced changes that occur in hundreds of plasma metabolites in healthy individuals, patients who have McArdle disease and mitochondrial disease patients. By comparing these disorders they shed light on the typical metabolic processes that allow us to exercise and also revealed potential disease biomarkers.
Summary provided by Rohit Sharma, PhD, from the Department of Molecular Biology at Massachusetts General Hospital, and co-investigator of the study.
To better understand how body fat is regulated, a team led by Dr. Alexander Soukas of the MGH Center for Genomic Medicine performed a genome-wide screen in the microscopic roundworm Caenorhabditis elegans, identifying 475 fat regulatory genes, most of which are shared with humans. The study, which appeared in the journal Cell Reports, found that high fat genes tend to lead to starvation resistance, while low fat genes promote early death from starvation. With this information, the Soukas laboratory can now determine how starvation defenses developed during ancient times of feast or famine now, in times of nutritional excess, lead to the development of obesity, diabetes, and associated cardiometabolic diseases.
Summary provided by Alexander Soukas, MD, PhD, from the Center for Genomic Medicine and Diabetes Unit at Massachusetts General Hospital, and senior author of the study.
Giant cell arteritis (GCA) is the most common form of blood-vessel inflammation. Complications include blindness and aneurysm. Up to now, the only known effective treatment was a steroid called prednisone which caused many complications. Now a phase 3 clinical trial has confirmed for the first time in the history of this disease that regular treatment with a drug called tocilizumab successfully reduces the need for high-dose steroid treatment. Patients who received tocilizumab plus a prednisone taper were nearly four times more likely to achieve disease remissions compared to those who received prednisone alone. Results of the trial were the basis for the Food and Drug Administration’s approval of tocilizumab to treat GCA in May 2017.
Summary provided by John Stone, MD, MPH, Director of the Clinical Rheumatology in the Rheumatology Unit at Massachusetts General Hospital, and lead author of the study.
Possible pathways for the nonenzymatic replication of RNA, in which RNA replication is driven purely by chemical and physical processes, have been studied for decades, but the underlying chemistry is still poorly understood. Szostak and his team recently showed that the basic copying reaction proceeds through a previously unsuspected chemical intermediate. To explore this mechanism, they investigated the structure of an RNA complex with several analogs to the intermediate. The closest equivalent, GpppG, binds to RNA in a structural arrangement that explains the high reactivity of the intermediate. This study provides insight into the fundamental mechanism of nonenzymatic RNA self-replication.
Summary provided by Jack Szostak, PhD, Alex. A. Rich Distinguished Investigator in the Department of Molecular Biology at Massachusetts General Hospital, and senior author of the study.
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