Jonathan Stamler
Jonathan Solomon Stamler is an English-born American physician and scientist. He is known for his discovery of protein S-nitrosylation, the addition of a nitric oxide group to cysteine residues in proteins, as a ubiquitous cellular signal to regulate enzymatic activity and other key protein functions in bacteria, plants and animals, and particularly in transporting NO on cysteines in hemoglobin as the third gas in the respiratory cycle.
Early life and education
Stamler was born in Wallingford, England on June 23, 1959 to a British father and American mother, and lived in multiple countries as a youth due to his father's global career. He played on the Israeli national tennis team.He graduated with a bachelor's degree from Brandeis University in 1981, and earned his M.D. degree from Icahn School of Medicine at Mount Sinai in 1985. His residency and fellowship training in pulmonary medicine and in cardiovascular medicine was at Brigham and Women’s Hospital at Harvard Medical School.
Career and research
Academic appointments
Stamler was appointed Assistant Professor in Medicine at Harvard Medical School in 1993, and Associate Professor then Professor in Medicine at Duke University School of Medicine in 1993 and 1996, respectively, with recognition as the George Barth Geller Professor for Research in Cardiovascular Diseases in 2004.He was an Investigator with the Howard Hughes Medical Institute from 1997 to 2005.
In 2009, Stamler became Robert S. and Sylvia K. Reitman Family Foundation Distinguished Chair in Cardiovascular Innovation and Professor of Medicine, Professor of Biochemistry and founding Director of the Institute for Transformative Molecular Medicine at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center.
In 2012, Stamler founded and became Director of the Harrington Discovery Institute at University Hospitals Cleveland Medical Center, and in 2016 was named Harrington Discovery Institute President. He is a founder of the Harrington Project, a tripartite collaboration among non-profit and for-profit organizations to shepherd laboratory discovery through translation and into biotechnology commercialization and approved therapy.
Research
At the start of Stamler's research career, nitric oxide gas recently had been identified as a signaling molecule that mediated control of blood pressure. NO gas released from blood vessel endothelial cells travels into surrounding vascular smooth muscle cells to vasodilate arteries by binding to the heme cofactor in the enzyme soluble guanylyl cyclase to produce cyclic guanosine monophosphate that activates the cGMP-dependent protein kinase to phosphorylate proteins regulating muscle contraction, among other targets.NO gas is unsuited to widespread signaling throughout the body. Its actions cannot be controlled and it exhibits high affinity binding to the hemes in red blood cell hemoglobin, whose vast quantity should prevent NO activity from traversing the bloodstream. Furthermore, most biological actions that were being discovered for NO were not mediated by guanylyl cyclase/cGMP. Stamler would provide a general mechanism to explain NO function in biology, which requires redox-activation of NO to allow its conjugation to all main classes of proteins, and would thereby establish the prototypic redox-based cellular signaling mechanism in biology.
Specially, Stamler recognized that NO can be redox-activated to bind to thiol groups, including those of free cysteine residues present in most proteins, by conversion to nitrosonium ion, to form an S-nitrosothiol that is no longer subject to inactivation by heme and provides a means to stabilize and regulate NO bioactivity. Stamler then demonstrated that SNO modification of proteins, which he coined 'S-nitrosylation' to denote a signaling function, can regulate enzyme activity by modifying active site or allosteric site cysteines. He went on to show that protein S-nitrosylation is a widespread mechanism for NO to be carried by proteins, including by hemoglobin, but also for regulating essentially all main classes of proteins: enzymes, transcription factors, receptors, G proteins, protein kinases, ion channels and micro RNA processing machinery. That is, NO in the form of an SNO is a cellular signal that acts through post-translational modification of target proteins, akin to protein phosphorylation or ubiquitination. At this time, approximately 7000 proteins have been reported to be nitrosylated.
In addition to proteins, Stamler demonstrated that low molecular weight metabolic thiols also can be S-nitrosylated under physiological conditions and can act as carriers of NO bioactivity, and he identified the first endogenous SNOs. He further demonstrated that specific enzymes convert NO to SNO, transfer S-nitrosyl groups to specific residues in proteins, and remove specific SNO groups from low-molecular weight or protein thiols.
Stamler's studies have identified numerous physiological and pathophysiological roles for protein S-nitrosylation and its regulation, demonstrating that SNO-based activity accounts for many physiological actions originally attributed to NO gas and to vasodilator drugs such as nitroglycerin, as well mediating previously unknown actions. Notable examples include inhibition of apoptosis, skeletal muscle contractility, the fight-or-flight response, regulation of gene expression, neuroprotection, and development and discovery of red blood cell mediated vasodilation. His work has established that hemoglobin in red blood cells not only carries oxygen and carbon dioxide to support cellular respiration, but also carries NO as an S-nitrosothiol that is critical for autoregulation of blood flow through tissue microcapillaries. Thus, the respiratory cycle may be viewed as a 3-gas system where oxygen delivery to tissue by hemoglobin is linked to oxygen-dependent R- and T-state conformational changes of hemoglobin to load NO on cysteine 93 of beta-globin in high oxygen and to deliver this SNO to dilate blood vessels in low oxygen. The SNO-hemoglobin content of RBCs is low in multiple clinical conditions, including pulmonary hypertention, COPD, vascular disease and sickle cell disease, which impairs vasodilation by RBCs. For example, the ability of hemoglobin to undergo conformation-dependent S-nitrosylation is impaired in red blood cells from sickle cell disease patients, impairing vasodilation beyond that caused by red blood cell sickling. Further, since hemoglobin S-nitrosylation is rapidly lost upon blood storage, the lack of S-nitrosylation within stored red blood cells limits the effective oxygen delivery capability of transfused blood, which can be improved by treating stored red blood cells to replace lost SNO.
But hemoglobin is only one example where aberrant S-nitrosylation may contribute to disease. Accumulated evidence has demonstrated that S-nitrosylation of proteins plays important roles in many diseases, from heart failure to cancer to neurodegenerative disease. Stamler’s studies have shown that SNO dysregulation is important in asthma, pulmonary hypertension, heart failure, diabetes, kidney injury,
and infectious diseases, and he has worked to create therapeutic interventions to alleviate these dysfunctions that are in preclinical and clinical development.
Examining the hemoglobins of microbes and the parasitic worm Ascaris, Stamler found that these ancient forms of hemoglobin either eliminate NO enzymatically or utilize it to eliminate oxygen from its anaerobic environment, showing that the primordial function of hemoglobin was in NO processing not oxygen transport. Stamler also identified trans-kingdom SNO signaling, since microbiota that produce NO can lead to widespread protein S-nitrosylation in a Caenorhabditis elegans host with profound genetic and physiological consequences. Stamler also identified an enzymatic mechanism of nitroglycerin bioactivation to produce NO bioactivity, thus solving a longstanding mystery and he demonstrated how nitroglycerin tolerance develops during therapy.