Research Highlights (more...)

  • Macrophages

    Cardiac macrophages charging ahead

    While we knew for a while that the healthy heart contains tissue resident macrophages, these cells’ organ specific functions were unknown. Triggered by a serendipitous finding of ECG abnormalities during a cardiac MRI scan of a mouse after macrophage ablation, a CSB team of investigators now describes previously unknown electrical properties of macrophages. When coupled to myocytes via gap junctions, macrophages depolarize in sync with conducting cells. In a sink-source relationship, electric current flows back and forth between macrophages and cardiomyocytes. Macrophages influence conduction through the atrioventricular node, the electrical connection between the heart’s chambers. When macrophages are manipulated, the flow of electricity slows down, and may even cease altogether. Such a condition requires pacemaker treatment in humans. These surprising findings, published in Cell, jolt the field of electrophysiology and may lead to new therapeutic opportunities for patients with cardiac arrhythmias. The collaborative effort was spearheaded by teams at MGH but also involved investigators at the BWH and in Freiburg, Germany.

  • Tiny_nanoparticles_hunt_for_macrophages

    Tiny nanoparticles hunt for macrophages

    Macrophages are white blood cells that can turn against us in atherosclerosis. Instead of cleaning up tissue as usual, they attack the arterial wall and destroy its architecture. The resulting stoppage of blood flow causes myocardial infarction and stroke. An entire field of research focuses on understanding these cells, and how to stop them from becoming turn coats. Until now, it was not even possible to detect them reliably in patients. In a recent Nature Communications report, a modified polyglucose nanoparticle (18F-Macroflor) was developed for imaging macrophages by PET. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. This work marks an important step towards a clinical tool to non-invasively monitor macrophage biology in patients. Such an imaging tool can then be used to spot danger spots in several diseases, and test new macrophage-targeted therapeutics while directly watching the cells.

  • Iron_highlight_sm

    Ingest, Digest, Recycle: Where red blood cells and the iron they contain are recycled.

    Iron gives blood its red color. The metal is essential to life, but it can be toxic because of its oxidative properties. Remarkably, we receive relatively little of our daily iron needs through diet. By far the majority of the iron we need is recycled. According to current thinking, as red blood cells age, large phagocytes residing in the spleen capture them, digest the cell structures, and recycle iron. A new paper from CSB published in Nature Medicine shows that most red blood cell disposal actually occurs in the liver, especially when demands for disposal increase (as they do in many physiologic and pathophysiologic situations). Moreover, specialized white blood cells consume old red blood cells in the circulation before migrating to the liver to shuttle iron for storage and new red blood cell production. The process buffers against dangerous fluctuations in iron availability, keeping the body in balance.

  • Rnai

    Quintuple-target RNAi: hitting five targets is better than just one

    Vascular endothelial cells express five adhesion molecules to recruit leukocytes from the blood stream: E- and P-selectin, ICAM-1 and -2, and VCAM-1. In atherosclerosis, activated endothelial cells express high levels of these signals, thus expanding the number of neutrophils and monocytes that migrate from blood into a growing plaque. After myocardial infarction, the adhesion molecule expression increases even further due to higher autonomic nervous activity. A collaborating team of groups at MIT and MGH now used a new class of nanoparticles with high avidity to endothelial cells to decrease endothelial cell adhesion molecule expression. The polymeric nanoparticles made of low-molecular-weight polyamines and lipids were loaded with 5 distinct siRNAs silencing the expression of all adhesion molecules. Multiple gene silencing was enabled by exquisite silencing efficiency after nanoparticle delivery. Hitting five targets at once, the therapy reduced recruitment of leukocytes to atherosclerotic plaques in mice, dampening vascular wall inflammation and making plaques smaller. Furthermore, RNAi decreased migration of leukocytes into infarcted myocardium, improving the recovery after ischemia. Such a strategy may help to prevent reinfarction and heart failure in high-risk patients with acute MI.

  • Padfigure

    Ultrafast bacterial ID

    Rapid and efficient diagnosis of bacterial infection is critical in combating infections, esp. in the hospital setting where drug resistance to antibiotics is on the rise. CSB investigators have developed a new device to shorten the diagnosis of bacterial infection to less than 2 hours. The “PAD” system (short for polarization diagnostics) is a combination of optical read-outs of genetic bacterial information and can ultimately performed in a physician’s office at low cost.

  • Scs_macrophages_s

    An immune cell that protects against cancer

    Macrophages are mostly viewed as tumor-promoting cells. They can infiltrate solid tumors in high numbers, and their presence at the tumor site is often associated with decreased patient survival. However, much less is known about macrophages located outside the tumor stroma. Mikael Pittet and colleagues now show that a population of lymph node macrophages, called subcapsular sinus (SCS) macrophages, unexpectedly protects against melanoma. The study was published in Science on March 17, 2016.

  • Immunotherapy_s

    A recipe to improve cancer immunotherapy

    Novel immune checkpoint blockade therapies can be extraordinarily effective but may benefit only the minority of patients whose tumors are pre-infiltrated by antitumor immune cells called CD8+ T cells. In a study published in Immunity, the Pittet lab at MGH Center for Systems Biology reports that rationally selected immunogenic chemotherapy can convert tumor microenvironments lacking T cells into ones displaying antitumor T cell immunity. This process makes unresponsive tumors sensitive to immune checkpoint blockade therapies and consequently raises hope to feasibly expand the proportion of human cancers responding to these therapies.

  • Epr

    Are nanomedicines right for you?

    Nanoparticles promise to deliver toxic chemotherapeutics more safely and efficiently to solid tumors, but clinical responses to such treatments have been mixed: some patients respond extremely well while others do not. Using advanced imaging techniques, researchers at CSB have discovered a way to repurpose FDA-approved magnetic nanoparticles for predicting how effectively nanomedicines can accumulate in tumors. Published in Science Translational Medicine, this “companion diagnostic" approach suggests that clinical imaging can be used to select patients most likely to benefit from the most advanced nanomedicine treatments.

  • Tam

    Macrophages act as drug delivery depots of nanomedicines

    Solid tumors often contain large numbers of immune cells including macrophages that feed cancer growth and metastasis. CSB researchers discovered that these tumor associated macrophages can be co-opted by nanomaterials to serve as drug depots, gradually delivering chemotherapy to neighboring cancer cells. Driven by new intravital imaging technology and published in Nature Communications, this research presents a new paradigm for therapeutic design and for selecting patients into clinical trials.

  • Stem_cells

    Bone marrow stem cells are alerted to heart attack

    Blood cells, including inflammatory monocytes, are made in the bone marrow and ultimately derive from hematopoietic stem cells. Until now it was unknown which bone marrow cells expand in acute myocardial infarction. Recent work published in Cell Stem Cell identified a subpopulation of short-term stem cells as the most upstream activation point after MI. The surface marker CCR2 identifies, in mice and in humans, the cell subset that sit almost at the very top of the hematopoietic tree as particularly responsive to an injury of the heart. The myeloid translocation gene 16 regulates their emergence, and may provide a therapeutic target to dampen leukocyte production that could otherwise jeopardize resolution of inflammatory activity in cardiovascular organs.

  • D3

    Smartphone Sees Cancer

    With their ubiquitous presence and superb computation power, smartphones now bring unprecedented opportunities to realize mobile healthcare. Reported in PNAS, CSB researchers have developed a new smartphone-based system, D3 (digital diffraction diagnosis), for on-the-spot molecular detection. This system, complete with a custom App, was used for cervical cancer screen and diagnosing aggressive lymphomas, prevalent cancers in low and middle-income countries.

  • Sepsis

    A new lead in solving sepsis

    The complication of an infection known as sepsis (or “blood poisoning”) is extremely dangerous, claiming up to half a million lives in the United States every year. A study from the Swirski lab has shown that a growth factor called interleukin-3 (IL-3) amplifies inflammation in sepsis and potentiates septic shock, the most severe form of sepsis. The authors show that IL-3 induces the emergency production of inflammatory monocytes and neutrophils, which are sources of the hallmark cytokines that comprise a lethal cytokine storm. A subset of B-1 B cells, discovered in the Swirski lab and named IRA B cells, are abundant sources of IL-3 in sepsis. Patients diagnosed with sepsis with high IL-3 in their blood die more often than those containing low IL-3. The findings are reported in the March 13th issue of Science.

  • Eribulin

    When our drugs don't work.

    Eribulin was developed as a potent anticancer agent, but it fails in many patients for unknown reasons. In a recent study, CSB researchers used microscopic imaging in tumors to show that resistance is primarily due to MDR1-mediated drug efflux. It was discovered that a new nano-encapsulated MDR1 inhibitor was able to restore drug efficacy. These studies show that in vivo imaging is a powerful strategy for elucidating mechanisms of drug resistance in heterogeneous tumors and for evaluating strategies to overcome this resistance.

  • Stress

    Stem cells get stressed out too!

    For decades, doctors knew that chronic stress is bad for you. The study by Heidt and Sager found that psychosocial stress activates bone marrow stem cells, which in turn triggers overproduction of inflammatory leukocytes, including neutrophils and monocytes. These leukocytes are more numerous in blood and accumulate in atherosclerotic lesions, putting the individual at higher risk for myocardial infarction and stroke.

  • Nanoholes

    Tiny holes enable big measurements

    A new technology developed at CSB allows profiling of small subcellular structures such as exosomes. The technology uses tiny gold grids studded with nanoholes in array format. Each of the holes has been modified with different antibodies. Biomarkers interacting with these tiny nano holes change the light properties (nano-plasmons), an effect which can optically detected. This technology (”nPLEX”) will allow high-throughput analysis of a number of clinically important biomarkers.

  • Dna_barcode

    More (proteomic) bang-for-your-buck

    Extracting maximal information from minimal, easily acquired samples is the holy grail for patient monitoring in clinical trials. A new technology developed at the CSB, holds promise for revolutionizing clinical monitoring by allowing vast amounts of proteomic information to be obtained from minute samples.

  • Ascites_1

    Repurposing often discarded ascites

    Buildup of cancer-containing fluid in the abdomen (ascites) is a common occurrence suffered by many patients with advanced malignancies. Researchers have developed and tested a novel microfluidic chip, reported in PNAS, to selectively detect ascites tumor cells and enable further testing. This approach seeks to repurpose ascites for serial pharmacodynamic readouts.

  • Plaque_sm

    Proliferation rules

    According to a recent study by CSB researchers, the primary driver of atherosclerotic plaque growth is local proliferation of plaque-resident inflammatory cells. This finding not only challenges previous assumptions that plaque growth is the exclusive result of cell recruitment from the blood, but now raises hope for the future development of targeted atherosclerotic treatment. Findings are reported in Nature Medicine.

  • Bact

    Cracking bacterial code for quick diagnosis

    Researchers have developed a quick and sensitive method for identifying and characterizing infectious bacteria in patient samples. The genetic test uses specially designed DNA probes that seek out and magnetically label regions of bacterial RNA. Reported in Nature Nanotechnology, this diagnostic technique is powerful enough to detect and differentiate single bacteria in under 2 hours.

  • Device_med

    Faster cheaper TB diagnosis

    A nanotechnology inspired genetic test has been developed to detect tuberculosis (TB) directly in sputum. The method not only distinguishes different forms of TB but also sheds light on drug resistant strains. The innovative device, described in Nature Communications, is also capable of comprehensive diagnosis in two hours and is sensitive enough to detect single bacteria.

  • Exosome3

    The magic of “cell dust”

    A novel diagnostic platform has been shown capable of detecting minuscule particles shed by cells, known as microvesicles, in a drop of blood. In a groundbreaking study, published in Nature Medicine, we demonstrate that by using nanotechnology together with nuclear magnetic resonance (NMR), microvesicles shed by brain cancer cells can be reliably detected in human blood samples.

  • Beating_heart

    Imaging the beating heart in the living body

    Imaging individual cells in a live beating heart has been nearly impossible. Yet, this would offer unprecedented opportunities to better understand heart diseases. A new imaging method - reported in the October issue of Nature Communications - and developed by researchers at the Center for System Biology now allows single cell resolution imaging in cardiovascular research.

  • Ctcs

    Finding a needle in a haystack

    Researchers have developed a novel microchip that can rapidly scan through the enormous number of cells in a blood sample to find very rare circulating tumor cells. Using a combination of microelectronics, microfluidics, and nanotechnology, this new system, described in the July issue of Science Translational Medicine, now has the potential for rapid and accurate on-the-spot cancer diagnosis and treatment monitoring.

  • Athero

    Not just a ‘plumbing’ disease

    New research at the Center for Systems Biology (CSB) has shown that heart attacks are not just a “plumbing” problem in the arteries but a ‘whole system’ condition, resulting in widespread inflammation and a predisposition for a secondary attack.

  • Sicklecells4

    Sickle symptoms linked to cell flow

    The genetic abnormality that causes blood cells to deform and clog vessels in sickle cell disease results in wide symptom variability across patients. Until now, there has been no way to distinguish patients with severe from patients with mild disease. A novel technique, however, has shown promise in differentiating patients based on the rate at which their blood stops flowing under low oxygen.

  • Ira_cell

    A new cell discovered

    Sepsis is a life-threatening condition characterized by whole-body inflammation to overwhelming infection. A newly discovered cell type known as “innate response activator” has been found to protect against sepsis. This discovery will likely provide insight into the development of sepsis and potentially lead to new avenues for therapeutic intervention.

  • Fourescent_small

    Novel therapy turns off navigation system in disease-promoting cells

    By manipulating the molecular navigation system used by inflammatory immune cells to reach sites of tissue damage, researchers at the Center for Systems Biology may have struck upon an effective novel anti-inflammatory treatment. Given that inflammation is an exacerbator of almost all major diseases, this therapy could potentially have wide-spread benefit.

  • Probing_the_heart_for_infection

    Probing the heart for infection

    A new imaging probe developed by researchers at the Center for Systems Biology can detect acute endocarditis, a rapidly progressing infection of the heart valves. This imaging agent binds tightly to a product released by the most deadly cause of the infection-Staphylococcus aureus-rendering it visible by both optical and PET imaging. Ultimately, the agent could be used to rapidly diagnose, and thus treat, this potentially fatal condition.

  • Spleen

    The spleen's newly discovered function

    While the spleen has long held a reputation for redundancy, recent research has now shown that quite the opposite is true. The spleen, in fact, appears to play an important role in the repair of tissue. Mikael Pittet, one of the four lead investigators responsible for this finding, discusses this work and its possible implications.

  • Glow

    Glow-in-the-dark plaques

    Finding new uses for already FDA approved drugs is a speedy way of translating new biological discoveries into patient benefit. Using a novel catheter-based imaging system, the fluorescent dye Indocyanine green has been shown capable of highlighting the culprits responsible for strokes and heart attacks, namely inflamed arterial plaques.

  • Cell_gray

    When small meets speedy...

    In today's fast paced world, waiting for anything is often frustrating and stressful. But few delays can be worse than that following a diagnostic blood test or biopsy, where results can take days to come back. Recently, a new portable device, known as DMR has been shown capable of on the spot cancer diagnosis.

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...)

Wang CY, Core AB, Canali S, Zumbrennen-Bullough KB, Ozer S, Umans L, Zwijsen A, Babitt JL
Smad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice.
Blood. 2017;:ePub - PMID: 28438754
Hulsmans M, Clauss S, Xiao L, Aguirre AD, King KR, Hanley A, Hucker WJ, Wülfers EM, Seemann G, Courties G, Iwamoto Y, Sun Y, Savol AJ, Sager HB, Lavine KJ, Fishbein GA, Capen DE, Da Silva N, Miquerol L, Wakimoto H, Seidman CE, Seidman JG, Sadreyev RI, Naxerova K, Mitchell RN, Brown D, Libby P, Weissleder R, Swirski FK, Kohl P, Vinegoni C, Milan DJ, Ellinor PT, Nahrendorf M
Macrophages Facilitate Electrical Conduction in the Heart
Cell. 2017;169:510-522 - PMID: 28431249
Seo KJ, Qiang Y, Bilgin I, Kar S, Vinegoni C, Weissleder R, Fang H
Transparent Electrophysiology Microelectrodes and Interconnects from Metal Nanomesh.
ACS Nano. 2017;:ePub - PMID: 28391679
Kim DE, Kim JY, Schellingerhout D, Ryu JH, Lee SK, Jeon S, Lee JS, Kim J, Jang HJ, Park JE, Kim EJ, Kwon IC, Ahn CH, Nahrendorf M, Kim K
Quantitative Imaging of Cerebral Thromboemboli In Vivo: The Effects of Tissue-Type Plasminogen Activator.
Stroke. 2017;48(5):1376-1385 - PMID: 28432262

Recent News (more...)

2017-04-26: Marie Siwicki (Pittet Lab) has been selected to receive the Landry Cancer Research Fellowship. The award, through Harvard’s Landry Cancer Biology Consortium, funds graduate research with an emphasis on multi-disciplinary approaches to cancer biology. Congratulations Marie!
2017-04-26: Congratulations to Dr. Camilla Engblom, from the Pittet laboratory, for brillantly completing her PhD thesis work entitled “Cancer-host interactions influencing disease progression and therapy”. Dr. Engblom graduated from the PhD Program in Immunology at Harvard Medical School.
2017-04-20: Science features CSB research on macrophages in the heart - (pdf)
2017-04-17: Ralph Mazitschek, PhD has received the Young Mentor Award from Harvard Medical School (HMS). The award was established in 2005 to recognize faculty who are still in the early stages of their career, but are devoting time to mentor others. Congratulations, Ralph!
2017-04-06: Hakho Lee, PhD has been selected as a 2017 MGH Research Scholar. Congratulations, Hakho!