Professor of Molecular Metabolism
Director of BPH program
Harvard T.H. Chan School of Public Health
Dr. Manning’s research is focused on the interface between signaling and metabolic control under physiological and pathophysiological conditions. He is particularly interested in defining the control mechanisms and functions of a complex signaling network that is implicated in a diverse array of human diseases, including the majority of genetic tumor syndromes and cancers, metabolic diseases such as diabetes and cardiovascular disease, neurocognitive and neurodegenerative diseases such as autism and Alzheimer’s, and autoimmune diseases. As a postdoctoral fellow in the laboratory of Lewis Cantley, he found that the tumor suppressor TSC2 is the key molecular link between the PI3K and mTOR pathways. This finding helped connect a primary growth factor and insulin-stimulated pathway (PI3K), which is also activated in the majority of cancers, to a ubiquitous nutrient-sensing protein kinase that promotes cell growth (mTOR). Since that early landmark discovery, he has continued to make major contributions to our understanding of this key regulatory hub in mammalian cells and tissues, including the recognition that mTOR is a central player in the control of anabolic processes driving the synthesis of proteins, nucleic acids, and lipids. His laboratory’s findings are providing both underlying mechanisms and potential therapeutic strategies for common complex diseases, such as cancer and diabetes. In the future, Dr. Manning plans to expand his research to explore molecular events contributing to aging and autism spectrum disorders, other areas where this signaling network has been implicated.
Dr. Manning received his PhD in molecular, cellular, and developmental biology from Yale University in 2000. After completing his postdoctoral training in signal transduction, cell biology, and systems biology at Harvard Medical School, he was recruited to the Harvard Chan School in 2004 as the first junior faculty member of the then newly established Department of Genetics and Complex Diseases (which changed its name to the Department of Molecular Metabolism in 2019). Dr. Manning is an affiliated faculty member in the Department of Cell Biology at Harvard Medical School and with the Dana Farber/Harvard Cancer Center.
Cell signaling and metabolism in cancer, metabolic diseases, and aging.
Research in the Manning Lab is delineating how signals from nutrients and growth factors are propagated to coordinately regulate nutrient metabolism, with implications in a wide variety of complex human diseases. Research efforts are focused in part on defining the regulatory mechanisms and functions of the PI3K-mTOR signaling network. This network senses and relays signals from nutrients and other growth cues to control key metabolic processes in cells and tissues. Importantly, frequent dysregulation of this network contributes to a diverse set of seemingly unrelated human diseases, including the majority of human cancers, genetic tumor syndromes (e.g, tuberous sclerosis complex, lymphangioleiomyomatosis, PTEN hamartoma tumor syndrome), metabolic diseases (e.g., obesity, type-2 diabetes, cardiovascular disease), autoimmune and inflammatory diseases (e.g., arthritis, lupus, hepatitis), and neuroglogical disorders (e.g., epilepsy, autism, Alzheimers). This signaling network also influences the lifespan of organisms and serves as a major connection between diet and the aging process. The Manning lab seeks to unravel the complex molecular regulation of the PI3K-mTOR network under both physiological and pathological states, and how its downstream functions contribute to metabolic homeostasis and dysfunction.
The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals.
Torrence ME, MacArthur MR, Hosios AM, Valvezan AJ, Asara JM, Mitchell JR, Manning BD.
Elife. 2021 Mar 01. 10. PMID: 33646118
Valvezan AJ, McNamara MC, Miller SK, Torrence ME, Asara JM, Henske EP, Manning BD.
JCI Insight. 2020 04 09. 5(7). PMID: 32271165
Hoxhaj G, Manning BD.
Nat Rev Cancer. 2020 02. 20(2):74-88. PMID: 31686003
Brown FD, Sen DR, LaFleur MW, Godec J, Lukacs-Kornek V, Schildberg FA, Kim HJ, Yates KB, Ricoult SJH, Bi K, Trombley JD, Kapoor VN, Stanley IA, Cremasco V, Danial NN, Manning BD, Sharpe AH, Haining WN, Turley SJ.
Nat Immunol. 2019 12. 20(12):1668-1680. PMID: 31636464
Author Correction: Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis.
Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O, Liu D, Wan L, Zhai B, Yu Y, Yuan M, Kim BM, Shaik S, Menon S, Gygi SP, Lee TH, Asara JM, Manning BD, Blenis J, Su B, Wei W.
Nat Cell Biol. 2019 05. 21(5):662-663. PMID: 30783264
Hoxhaj G, Ben-Sahra I, Lockwood SE, Timson RC, Byles V, Henning GT, Gao P, Selfors LM, Asara JM, Manning BD.
Science. 2019 03 08. 363(6431):1088-1092. PMID: 30846598
Valvezan AJ, Manning BD.
Nat Metab. 2019 03. 1(3):321-333. PMID: 32694720
Nature. 2019 02. 566(7743):187-188. PMID: 30737501
Ex vivo and in vivo stable isotope labelling of central carbon metabolism and related pathways with analysis by LC-MS/MS.
Yuan M, Kremer DM, Huang H, Breitkopf SB, Ben-Sahra I, Manning BD, Lyssiotis CA, Asara JM.
Nat Protoc. 2019 02. 14(2):313-330. PMID: 30683937
We cannot treat our way out of the rising trend in cancer cases. The only solution is a full-scale defense, so that nobody suffers the disease in the first place.
March 26, 2019—In a new Science paper, Brendan Manning, professor of genetics and complex diseases, and colleagues reveal how a previously understudied enzyme may help fuel the metabolism of cancer cells and contribute to the development of other…
December 8, 2017 – A research team at Harvard T.H. Chan School of Public Health has identified a key metabolic vulnerability in some types of tumor cells and discovered a way to exploit it by harnessing well-known immunosuppressant…
October 20, 2015 — It was announced this week that two faculty members from Harvard T.H. Chan School of Public Health—Xihong Lin and Brendan Manning—received prestigious National Cancer Institute Outstanding Investigator Awards (OIA). These multimillion-dollar seven-year awards, providing…
Findings by Harvard School of Public Health’s Brendan Manning, professor of genetics and complex diseases, are providing new insights into tuberous sclerosis complex (TSC) — a rare genetic disease that causes the widespread growth of benign tumors —…