Research Highlights (more...)

  • Running_mouse

    CSB work discovers exercise benefits on bone marrow

    Modern life comes with many dangers. This includes sedentary behavior, as we all spend increasing time sitting: on the office chair, in the car, and on the sofa. This is risky and leads to obesity, myocardial infarction and stroke. A manuscript published in Nature Medicine describes a new pathway how sedentary behavior causes cardiovascular disease. Mice with access to treadmills had lower blood stem cell proliferation in their bone marrow. On the flip side, sedentary mice, resembling a large proportion of the American population, work out 20-fold less. As a result, they had higher blood levels of the hormone leptin, which triggered over-production of inflammatory leukocytes, resulting in more atherosclerosis and heart failure. The team also looked at clinical data from the CANTOS trial, observing similar relationships between physical activity, leptin and leukocytes.

  • Myeloid_cells_lg

    Discovering Myeloid Cells In Lung Tumors

    Myeloid cells can promote or limit tumor outgrowth but remain poorly understood. In a study published in Immunity, the Pittet lab at the MGH Center for Systems Biology and the Klein lab at Harvard Medical School teamed up to map myeloid cells at the single cell level in human and mouse lung cancer. They made the following findings: 1) Consistent complexity: the same tumor myeloid populations are repeatedly found across patients, indicating that the myeloid microenvironment within lung tumors is stereotyped. 2) Conservation across species: many myeloid populations are highly conserved across patients and mice, suggesting that studying myeloid cells in mice can help understand the human disease. 3) New therapeutic targets: the map of tumors’ myeloid populations identified in this study points to new targets for cancer immunotherapy.

  • Sleep_emoji

    Study helps solve mystery of how sleep protects against heart disease

    Researchers say they are closer to solving the mystery of how a good night’s sleep protects against heart disease. In studies using mice, they discovered a previously unknown mechanism between the brain, bone marrow, and blood vessels that appears to protect against the development of atherosclerosis, or hardening of the arteries—but only when sleep is healthy and sound. The discovery of this pathway underscores the importance of getting sufficient, quality sleep to maintain cardiovascular health and could provide new targets for fighting heart disease, the leading cause of death among women and men in the United States. In a study published in Nature, the Swirski Lab at the MGH Center of Systems Biology identified a mechanism by which a brain hormone controls production of inflammatory cells in the bone marrow in a way that helps protect the blood vessels from damage. This anti-inflammatory mechanism is regulated by sleep, and it breaks down when you frequently disrupt sleep or experience poor sleep quality.

  • Iel

    A metabolic checkpoint that contributes to cardiovascular disease

    The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways, how our bodies handle nutrients depends on strategically-positioned metabolic sensors that link a meal’s intrinsic nutritional value with intermediary metabolism. In a study published in Nature, the Swirski Lab at the MGH Center of Systems Biology identifies a subset of immune cells in the gut that modulates metabolism. The team shows that gut intraepithelial T leukocytes (IELs) modulate systemic metabolism. Mice lacking natural IELs are metabolically hyperactive and, when fed a high fat and sugar diet, resist obesity, hypercholesterolemia, hypertension, diabetes, and atherosclerosis. The phenomenon depends on the incretin GLP-1, which IELs normally control via IEL GLP-1 receptor expression. While its function may prove advantageous when food is scarce, overabundance of diets high in fat and sugar render this metabolic checkpoint inimical to health.

  • Anti_pd_1

    A Small Population of Immune Cells Is Key For Cancer Immunotherapy

    The anti-PD-1 immune checkpoint blocker can induce sustained clinical responses in some patients. This drug is used to release the “brakes” on T cells but how it functions in vivo remains incompletely understood. In a study published in Immunity, the Pittet lab at the MGH Center for Systems Biology uncovers that effective antitumor responses to anti-PD-1 therapy requires a subset of tumor-infiltrating dendritic cells, which produce interleukin 12 (IL-12) and apply “gas” to fuel the antitumor reaction. The findings may lead to new treatment strategies that benefit more patients. [Image: KA-POW! A dendritic cell (yellow) interacts with antitumor T cells (blue) to get rid of cancer.]

  • Scant

    Antibody-DNA conjugates bring patient biopsies to light

    Modern oncology relies on molecular assessments of tumor tissue to develop new therapeutic combinations and select optimal treatments for individual patients. Conventional approaches to cellular fluorescence imaging allow for visualization of just 3-4 proteins at a time, limiting the amount of information we can gain from precious patient biopsy samples. In a new study published in Nature Communications, researchers at CSB developed an approach that uses antibody-DNA conjugates to efficiently “cycle” through the detection and quantification of multiple proteins of interest, dramatically increasing the number of pathways/targets that can be imaged from a single biopsy. This technique allows scientists/physicians to directly visualize complex protein signatures in the biopsied cells and has important implications for understanding how drug therapies affect patients' individual tumors.

  • Shortcut

    Shortcut to the brain

    White blood cells are our key defenders against infection, however if oversupplied, they may turn against us. Neutrophils are made in the bone marrow where they arise from hematopoietic stem cells. The bone marrow is distributed over many bones in our bodies, and the current thinking implies that the supply of leukocytes distributes evenly throughout the body. In work published in Nature Neuroscience, we describe that the skull marrow assumes a special role in inflammatory diseases of the CNS. Its proximity to the brain leads to a preferential supply of neutrophils. We detected a previously unknown shortcut that neutrophils use on their way from skull marrow cavities towards the central nervous system. Rather than traveling through the general blood circulation, leukocytes produced in skull bone marrow migrate through channels that directly connect the skull marrow with the meninges the brain is wrapped in. The channels exist in mice and humans.

  • Intellisense_1

    Artificial Intelli-sense

    Automating cellular diagnostics could have far reaching impact in healthcare. Cells - often obtained by aspirations, biopsies, swabs or through body fluids - typically require sophisticated instrumentation and time consuming experts analysis to provide diagnoses. The CSB engineering team has now developed a highly sensitive platform powered by digital imaging and artificial intelligence to automate such painstaking analyses. Moreover this platform is affordable and portable, thus uniquely suited for point-of-care diagnostics in low and middle income countries (LMIC). A recent study published in Nature Biomedical Engineering highlights the first clinical trial for lymphoma diagnostics.

  • Reeducating_tumors_1

    Re-educating Tumors

    Tumor-associated macrophages (TAM) are abundant in many cancers and often display an immune-suppressive phenotype that promotes tumor growth and resistance to treatment. Researchers at CSB have now developed a TAM targeted nanoparticle loaded with a toll-like receptor agonist which re-programs TAMs to support the immune-system’s fight against cancer. As a monotherapy, administration of the drug-loaded nanoparticle led to efficient drug delivery to TAMs, re-programming of TAMs to an immune-supportive phenotype, and controlled tumor growth. Importantly, the strategy worked synergistically in combination with checkpoint therapy (anti-PD1), dramatically improving response rates even in tumors resistant to treatment by anti-PD1 alone. These findings demonstrate the ability of rationally engineered drug–nanoparticle combinations to efficiently modulate TAMs to better sensitize the tumor microenvironment to standard checkpoint therapies.

  • Bone

    Bones and Neutrophils Control Lung Cancer

    Tumors are often infiltrated by diverse immune cell types, some of which remain largely unexplored. In a study published in Science, the Pittet lab at the MGH Center for Systems Biology uncovers a new type of neutrophil that promotes lung cancer. The production of these neutrophils involves an unexpected remote crosstalk between tumors and bones: lung tumors remotely activate osteoblasts; in turn, those bone cells shape immunity by supplying tumors with cancer-promoting neutrophils. The findings open new avenues for cancer immunotherapy. (Image from Wikipedia)

  • Irf3mi_sm

    Immune cells attend a heart attack masquerade

    Hearts attacks, result from occlusion of coronary arteries, which starves heart muscle cells of oxygen-rich blood and causes them to die. Immune cells respond by entering the dead tissue, clearing cell debris, and stabilizing the heart wall via fibrosis and repair. In their Nature Medicine report, CSB investigators describe the surprising finding that dying cell DNA mimics a virus, which causes immune cells to turn on antiviral programs after a heart attack even though there is no viral infection.

The MGH Center for Systems Biology (CSB) was established as one of the five thematic interdisciplinary Centers at MGH. It is home to over 200 researchers in 12 PI groups. The mission of the Center is to analyze at a systems level how biological molecules, proteins and cells interact in both healthy and diseased states.

Through a multidisciplinary approach that combines clinical insight with powerful technologies, CSB faculty pursue systems-level research that is at once fundamental, and yet immediately linked to the diagnosis and treatment of human disease. While these approaches are generalizable to many diseases, the Center has particular strengths in complex human conditions such as cancer, cardiovascular disease, diabetes, autoimmune disease, and renal disease. This goal is enabled by particular faculty expertise in genomics, chemical biology, physiology, bioimaging, and nanotechnology.

The Center has close links with the HMS Department of Systems Biology, clinical departments at MGH, other MGH thematic centers, MIT, and the Broad Institute.

Recent Publications (more...)

Frodermann V, Rohde D, Courties G, Severe N, Schloss MJ, Amatullah H, McAlpine CS, Cremer S, Hoyer FF, Ji F, van Koeverden ID, Herisson F, Honold L, Masson GS, Zhang S, Grune J, Iwamoto Y, Schmidt SP, Wojtkiewicz GR, Lee IH, Gustafsson K, Pasterkamp G, de Jager SCA, Sadreyev RI, MacFadyen J, Libby P, Ridker P, Scadden DT, Naxerova K, Jeffrey KL, Swirski FK, Nahrendorf M
Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells
Nature Med. 2019;:ePub - PMID: 31700184 - DOI: 10.1038/s41591-019-0633-x
Rodell CB, Ahmed MS, Garris CS, Pittet MJ, Weissleder R
Development of adamantane-conjugated TLR7/8 agonists for supramolecular delivery and cancer immunotherapy
Theranostics. 2019;:ePub
Ng TSC, Garlin MA, Weissleder R, Miller MA
Understanding the EPR effect through image-guided systems pharmacology
Theranostics. 2019;:ePub
Parikh AS, Puram SV, Faquin WC, Richmon JD, Emerick KS, Deschler DG, Varvares MA, Tirosh I, Bernstein BE, Lin DT
Immunohistochemical quantification of partial-EMT in oral cavity squamous cell carcinoma primary tumors is associated with nodal metastasis.
Oral Oncol. 2019;99:104458 - PMID: 31704557 - DOI: 10.1016/j.oraloncology.2019.104458

Recent News (more...)

2019-11-08: Miles Miller has been admitted to the Bridging Academia with Industry Training Program at Mass General Research Institute designed to foster collaborations between academia and industry and support a new generation of translationally-minded scientists.
2019-10-21: J. Matthew Dubach, PhD, has been promoted to Assistant Professor of Radiology, Harvard Medical School. Congratulations, Matt!
2019-08-21: New PLoS Biology paper presents detailed, standardized citation data annotated for multiple impact indicators and their composite across science. Ralph Weissleder is in the top 0.01% of scientists based on their impact. Several other CSB PIs are in the top 1%. The raw data are available for download.
2019-08-06: The Chedza Study has started with the first enrollments. This project is evaluating the accuracy of a near-to-care device for the diagnosis of breast cancer and, separately, non-Hodgkin lymphoma. The team opted to name the project Chedza (light in Sekalanga) as the new instrument developed by CSB Biomedical Engineering Program uses the bending of light around cancer cells and a smartphone camera to permit diagnosis in a few minutes.