Jonathan Stamler

Stamler was born in Wallingford, England on June 23, 1959 {{citation|url=https://www.uhhospitals.org/-/media/Files/HDI/Harrington-Investigators/stamler-cv-full-july-2018.pdf|title=Jonathan Stamler curriculum vitae|access-date=2019-01-11}}{{Dead link|date=December 2024 |bot=InternetArchiveBot |fix-attempted=yes }} to a British father and American mother, and lived in multiple countries (United Kingdom, Switzerland, Israel, United States) as a youth due to his father's global career. He played on the Israeli national (under 18) 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.

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.{{cite web |url= https://www.hhmi.org/scientists/jonathan-s-stamler |title=Jonathan S. Stamler |author= |website=hhmi.org/ |publisher=Howard Hughes Medical Institute |access-date=2019-01-11 }}

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.{{cite web |url=http://blog.case.edu/case-news/2009/09/17/jonathanstamler |title=Director of Institute for Transformative Molecular Medicine, Inaugural Robert S. and Sylvia K. Reitman Family Foundation Distinguished Chair in Cardiovascular Innovation Announced |author= |date=2009-09-17 |website=case.edu |publisher=Case Western Reserve University |access-date=2019-01-11 |archive-date=2016-02-14 |archive-url=https://web.archive.org/web/20160214014116/http://blog.case.edu/case-news/2009/09/17/jonathanstamler |url-status=dead }}

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.{{cite web |url= https://www.cleveland.com/healthfit/index.ssf/2012/02/jonathan_stamler_named_directo.html |title=Jonathan Stamler named director, Bob Keith to head drug development of Harrington project |last=Zeitner |first=Brie |date=2012-02-29 |work=The Plain Dealer }}{{cite news |last=Rosenblum |first=Jonah |date=2016-02-11 |title=Stamler gains 'genius' tag as Harrington Discovery Institute director |url=https://www.clevelandjewishnews.com/features/health/stamler-gains-genius-tag-as-harrington-discovery-institute-director/article_5a6b60c6-d0e2-11e5-a1c1-5fd5ac712f22.html |website=Cleveland Jewish News |access-date=2019-01-11 }}

At the start of Stamler's research career, nitric oxide (NO) gas had recently been identified as a signaling molecule that mediated vasodilation{{cite web |url= https://www.nobelprize.org/prizes/medicine/1998/7543-the-nobel-prize-in-physiology-or-medicine-1998 |title=1998 Nobel Prize in Medicine or Physiology |author= |publisher=Nobel Foundation |access-date=2019-01-11 }} by binding to the heme cofactor in the enzyme soluble guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP).{{cite journal |last1=Murad |first1=Ferid |year=1994 |title= The nitric oxide-cyclic GMP signal transduction system for intracellular and intercellular communication. |journal= Recent Prog Horm Res |volume= 49|pages=239–248 |pmid=7511827 |doi=10.1016/b978-0-12-571149-4.50016-7 |isbn=9780125711494 }} However, most actions of NO being discovered at that time were not mediated by guanylyl cyclase/cGMP,{{cite journal |last1=Garg |first1=UC |last2=Hasid |first2=A |date=August 1990 |title=Nitric oxide-generating vasodilators inhibit mitogenesis and proliferation of BALB/C 3T3 fibroblasts by a cyclic GMP-independent mechanism |journal=Biochem Biophys Res Commun |volume=171 |issue=1 |pages=474–479 |pmid=1697465 |doi=10.1016/0006-291x(90)91417-q }} and high affinity binding of NO to the heme in red blood cell hemoglobin would inhibit NO actions in the vasculature, presenting a quandary.

Stamler would provide a general mechanism to explain NO function in biology, which requires redox-activation of NO to NO+ (nitrosonium ion) to allow its conjugation to all main classes of proteins, and would thereby establish the prototypic redox-based cellular signaling mechanism in biology. Redox activation of NO would also provide a chemical route to stabilize NO bioactivity and escape hemoglobin inactivation.

Specifically, Stamler recognized that NO can be redox-activated {{cite journal |last1=Stamler |first1=JS |last2=Singel |first2=DJ |last3=Loscalzo |first3=J |year=1992 |title=Biochemistry of nitric oxide and its redox-activated forms. |journal= Science |volume= 258 |issue=5090 |pages=1898–1902 |pmid=1281928 |doi=10.1126/science.1281928 |bibcode=1992Sci...258.1898S }} to bind cysteine residues in proteins{{cite conference | last1 = Stamler | first1 = JS | last2 = Simon | first2 = DI | last3 = Osborne | first3 = JA | last4 = Mullins | first4 = ME | last5 = Jaraki | first5 = O | last6 = Michel | first6 = T | last7 = Singel | first7 = DJ | last8 = Loscalzo | first8 = J |editor-last = Moncada |editor-first = S |editor2-last = Marletta |editor2-first = MA |editor3-last = Hibbs, Jr |editor3-first = JB | title = Exposure of sulphydryl-containing proteins to nitric oxide and endothelium-derived relaxing factor confers novel bioactivity and modulates their intrinsic functional properties. | book-title = The Biology of Nitric Oxide: Part 1 Physiological and Clinical Aspects : Proceedings of the 2nd International Meeting on the Biology of Nitric Oxide | pages = 20–23 | publisher = Portland Press | date = 1992 | location = London | isbn = 1855780127 | access-date = }}{{cite journal |last1=Stamler |first1=JS |last2=Simon |first2=DI |last3=Osborne |first3=JA |last4=Mullins |first4=ME |last5=Jaraki |first5=O |last6=Michel |first6=T |last7=Singel |first7=DJ |last8=Loscalzo |first8=J |date=1992-01-01 |title=S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds |journal=Proc Natl Acad Sci U S A |volume=89 |issue=1 |pages=444–448 |pmc=48254 |pmid=1346070 |doi=10.1073/pnas.89.1.444 |bibcode=1992PNAS...89..444S |doi-access=free }}{{cite journal |vauthors=Stamler JS, Jaraki O, Osborne J, Simon DI, Keaney J, Vita J, Singel D, Valeri CR, Loscalzo J |title=Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin |journal=Proc Natl Acad Sci U S A |volume=89 |issue=16 |pages=7674–7677 |year=1992 |pmid=1502182 |pmc=49773 |doi=10.1073/pnas.89.16.7674 |bibcode=1992PNAS...89.7674S |doi-access=free }}{{cite journal |last1=Stamler |first1=JS |last2=Simon |first2=DI |last3=Jaraki |first3=O |last4=Osborne |first4=JA |last5=Francis |first5=S |last6=Mullins |first6=M |last7=Singel |first7=D |last8=Loscalzo |first8=J |date=1992-09-01 |title=S-nitrosylation of tissue-type plasminogen activator confers vasodilatory and antiplatelet properties on the enzyme |journal=Proc Natl Acad Sci U S A |volume=89 |issue=17 |pages=8087–8091 |pmid=1325644 |pmc=49861 |doi=10.1073/pnas.89.17.8087 |bibcode=1992PNAS...89.8087S |doi-access=free }} and thiols in other molecules (e.g., glutathione, coenzyme A) to form S-nitrosothiols (SNOs) that are protected from heme inactivation thus providing a means to stabilize and regulate NO bioactivity,{{cite journal |vauthors=Gaston B, Reilly J, Drazen JM, Fackler J, Ramdev P, Arnelle D, Mullins ME, Sugarbaker DJ, Chee C, Singel DJ, Loscalzo J, Stamler JS |title=Endogenous nitrogen oxides and bronchodilator S-nitrosothiols in human airways |journal=Proc Natl Acad Sci U S A |volume=90 |issue=23 |pages=10957–10961 |year=1993 |pmid=8248198 |pmc=47900 |doi=10.1073/pnas.90.23.10957 |bibcode=1993PNAS...9010957G |doi-access=free }}{{cite journal |last1=Benhar |first1=M |last2=Forrester |first2=MT |last3=Stamler |first3=JS |date=October 2009 |title=Protein denitrosylation: enzymatic mechanisms and cellular function |journal= Nat Rev Mol Cell Biol |volume=10 |issue=10 |pages=721–732 |doi=10.1038/nrm2764 |pmid=19738628 |s2cid=24437719 }}{{cite journal |vauthors=Anand P, Hausladen A, Wang YJ, Zhang GF, Stomberski C, Brunengraber H, Hess DT, Stamler JS |title =Identification of S-nitroso-CoA reductases that regulate protein S-nitrosylation | journal=Proc Natl Acad Sci U S A |volume=111 |issue=52 |pages=18572–18577 |year=2014 |pmid=25512491 |pmc =4284529 |doi=10.1073/pnas.1417816112 |bibcode =2014PNAS..11118572A |doi-access =free }} and he then identified the first endogenous SNOs. Stamler further 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 and his colleagues would show that protein S-nitrosylation is widespread, regulating essentially all main classes of proteins: enzymes, globins, transcription factors, receptors, G proteins, protein kinases, ion channels and micro RNA processing machinery.{{cite journal |last1=Jia |first1=L |last2=Bonaventura |first2=C |last3=Bonaventura |first3=J |last4=Stamler |first4=JS |date=1996-03-21 |title=S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control |journal=Nature |volume=380 |issue=6571 |pages=221–226 |doi=10.1038/380221a0 |pmid=8637569 |bibcode=1996Natur.380..221J |s2cid=4314697 }} 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.{{cite journal |last1=Hess |first1=DT |last2=Stamler |first2=JS |date=2012-02-10 |title=Regulation by S-nitrosylation of protein post-translational modification |journal= J Biol Chem |volume=287 |issue=7 |pages=4411–4418 |doi=10.1074/jbc.R111.285742 |pmid=22147701 |pmc=3281651 |doi-access=free }} Approximately 10,000 proteins, at >20,000 sites, have been reported to be nitrosylated, and it has been predicted that 70% of the proteome is SNO-modified across phylogeny.{{cite journal |last1=Stomberski |first1=C |last2=Hess |first2=DT |last3=Stamler |first3=JS |date=2018-04-01 |title=Protein S-Nitrosylation: Determinants of Specificity and Enzymatic Regulation of S-Nitrosothiol-Based Signaling |journal= Antioxidants & Redox Signaling|volume=30 |issue=10 |pages=1331–1351 |pmid=29130312 |pmc=6391618 |doi=10.1089/ars.2017.7403 }}{{cite journal |last1=Abunimer |first1=A |last2=Smith |first2=K |last3=Wu |first3=TJ |last4=Lam |first4=P |last5=Simonyan |first5=V |last6=Mazumder |first6=R |date=2014-03-27 |title=Single-nucleotide variations in cardiac arrhythmias: prospects for genomics and proteomics based biomarker discovery and diagnostics. |journal= Genes (Basel) |volume=5 |issue=2 |pages=254–269 |pmid=24705329 |pmc=4094932 |doi=10.3390/genes5020254 |doi-access=free }}

More recently, Stamler and coworkers have demonstrated that protein S-nitrosylation is enzymatic, entailing specific enzymes that convert NO to SNO (S-nitrosothiol synthases), transfer NO groups to specific residues in proteins (transnitrosylases), and remove specific SNO groups from proteins (protein denitrosylases).{{cite journal |vauthors=Seth D, Hess DT, Hausladen A, Wang L, Wang YJ, Stamler JS |title=A Multiplex Enzymatic Machinery for Cellular Protein S-nitrosylation |journal=Mol Cell |volume=69 |issue=3 |pages=451–464.e6 |year=2018 |pmid=29358078 |pmc=5999318 |doi=10.1016/j.molcel.2017.12.025 }}{{cite news |author= |date=2018-01-19 |title=New Nitric Oxide-Converting Enzymes Discovered |url=https://www.genengnews.com/news/new-nitric-oxide-converting-enzymes-discovered/ |website=genengnews.com |publisher=Mary Ann Liebert Inc }} Enzymatic S-nitrosylation was identified first with hemoglobin (including nitrosylase and SNO synthase activities){{cite journal |last1=Pawloski |first1=JR |last2=Hess |first2=DT |last3=Stamler |first3=JS |year=2001 |title=Export by red blood cells of nitric oxide bioactivity. |journal= Nature |volume= 409 |issue=6820 |pages=622–626 |pmid=11214321 |doi=10.1038/35054560 |s2cid=4387513 }}{{cite journal |last1=Angelo |first1=M |last2=Singel |first2=DJ |last3=Stamler |first3=JS |year=2006 |title=An S-nitrosothiol (SNO) synthase function of hemoglobin that utilizes nitrite as a substrate. |journal=Proc. Natl. Acad. Sci. USA |volume=103 |issue=22 |pages=8366–8371 |pmid=16717191 |doi=10.1073/pnas.0600942103 |pmc=1482500 |bibcode=2006PNAS..103.8366A |doi-access=free }}{{cite journal |last1=Stamler |first1=JS |last2=Hess |first2=DT |year=2010 |title=Nascent Nitrosylases. |journal= Nature Cell Biology |volume= 12 |issue=11 |pages=1024–1026 |pmid= 20972426 |doi= 10.1038/ncb1110-1024 |s2cid=6508227 }}{{cite journal |last1=Premont |first1=RT |last2=Singel |first2=DJ |last3=Stamler |first3=JS |year=2022 |title=The enzymatic function of the honorary enzyme: S-nitrosylation of hemoglobin in physiology and medicine. |journal=Molecular Aspects of Medicine |volume=84 |pages=101056 |pmid=34852941 |doi=10.1016/j.mam.2021.101056 |pmc=8821404 }} and then later with multienzyme machinery in E. coli.

Stamler's studies have established physiological significance for protein S-nitrosylation in diverse cellular processes (receptor signaling, apoptosis, gene regulation, metabolism and immunity), and fundamental physiological functions (skeletal muscle contractility, airway tone, cardiac response to adrenergic stimulation, neuroprotection and development).{{cite journal |last1=Seth |first1=P |last2=Hsieh |first2=PN |last3=Jamal |first3=S |last4=Wang |first4=L |last5=Gygi |first5= SP|last6=Jain |first6=MK |last7=Coller |first7=J |last8=Stamler |first8=JS |date=2019-02-21 |title=Regulation of MicroRNA Machinery and Development by Interspecies S-Nitrosylation |journal=Cell |volume=176 |issue=5 |pages=1014–1025 |pmid=30794773 |pmc=6559381 |doi=10.1016/j.cell.2019.01.037 }} He has also discovered novel cellular functions (red blood cell mediated vasodilation) {{cite journal |last1=Stamler |first1=JS |last2=Jia |first2=L |last3=Eu |first3=JP |last4=McMahon |first4=TJ |last5=Demchenko |first5=IT |last6=Bonaventura |first6=J |last7=Gernert |first7=K |last8= Piantadosi |first8=CA |date=1997-06-27 |title= Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient |journal=Science |volume=276 |issue=5321 |pages=2034–2037 |pmid=9197264 |doi=10.1126/science.276.5321.2034 }} and revealed a new physiological principle: NO carried by an invariant hemoglobin cysteine residue is essential for oxygen delivery to tissues through vasodilation of the microcirculation, redefining the respiratory cycle as a 3-gas system ({{chem2|O2}}/NO/{{CO2}}).{{cite journal |last1=Zhang |first1=R |last2=Hess |first2=DT |last3=Qian |first3=Z |last4=Hausladen |first4=A |last5=Fonseca |first5=F |last6=Chaube |first6=R |last7=Reynolds |first7= JD|last8=Stamler |first8=JS |date=2015-05-19 |title= Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia |journal= Proc Natl Acad Sci U S A |volume=112 |issue=20 |pages=6425–6430 |doi=10.1073/pnas.1502285112 |pmid=25810253 |pmc=4443356 |bibcode=2015PNAS..112.6425Z |doi-access=free }}{{cite news |last=Paddock |first=Catherine |date=2015-04-13 |title=Study shows blood cells need nitric oxide to deliver oxygen |url= https://www.medicalnewstoday.com/articles/292292.php |website=Medical News Today |publisher=Healthline Media UK |access-date=2019-01-11}}{{cite journal |last1=Zhang |first1=R |last2=Hausladen |first2=A |last3=Qian |first3=Z |last4=Liao |first4=X |last5=Premont |first5=RT |last6=Stamler |first6=JS |date=2022-02-08 |title=Hypoxic vasodilatory defect and pulmonary hypertension in mice lacking hemoglobin β-cysteine93 S-nitrosylation. |journal=JCI Insight |volume=7 |issue=3 |pages=e155234 |pmid=34914637 |pmc=8855790 |doi=10.1172/jci.insight.155234 }}

The SNO-hemoglobin content of RBCs is low in multiple clinical conditions characterized by microvascular dysfunction and tissue hypoxia, including pulmonary hypertension, chronic obstructive pulmonary disease, peripheral arterial disease and sickle cell disease, thereby impairing vasodilation by RBCs.{{cite journal |last1=Pawloski |first1=JR |last2=Hess |first2=DT |last3=Stamler |first3=JS |date=2005-02-15 |title=Impaired vasodilation by red blood cells in sickle cell disease |journal=Proc Natl Acad Sci U S A |volume=102 |issue=7 |pages=2531–2536 |pmid=15699345 |pmc=548996 |doi=10.1073/pnas.0409876102 |bibcode=2005PNAS..102.2531P |doi-access=free }}{{cite news |last=Leary |first=Warren E |date=1996-04-23 |title=Findings Intrigue Sickle Cell Experts |url=https://www.nytimes.com/1996/04/23/science/findings-intrigue-sickle-cell-experts.html |work=The New York Times |access-date=2019-01-11 }} Further, since hemoglobin S-nitrosylation is rapidly lost upon blood storage, the oxygen delivery capability of transfused blood is impaired.{{cite journal |last1=Reynolds |first1=JD |last2=Ahearn |first2=GS |last3=Angelo |first3=M |last4=Zhang |first4=J |last5=Cobb |first5=F |last6=Stamler |first6=JS |date= October 2007 |title=S-nitrosohemoglobin deficiency: a mechanism for loss of physiological activity in banked blood |journal=Proc Natl Acad Sci U S A |volume=104 |issue=43 |pages=17058–17062 |doi=10.1073/pnas.0707958104 |pmid=17940022 |pmc=2040473 |bibcode=2007PNAS..10417058R |doi-access=free }}{{cite journal |last1=Reynolds |first1=JD |last2=Bennett |first2=KM |last3=Cina |first3=AJ |last4=Diesen |first4=DL |last5=Henderson |first5=MB |last6=Matto |first6=F |last7=Plante |first7=A |last8=Williamson |first8=RA |last9=Zandinejad |first9=K |last10=Demchenko |first10=IT |last11=Hess |first11=DT |last12=Piantadosi |first12=CA |last13=Stamler |first13=JS |date=2013-07-09 |title=S-nitrosylation therapy to improve oxygen delivery of banked blood |journal=Proc Natl Acad Sci U S A |volume=110 |issue=28 |pages=11529–11534 |doi=10.1073/pnas.1306489110 |pmid=23798386 |pmc=3710799 |bibcode=2013PNAS..11011529R |doi-access=free }}{{cite magazine |last=Park |first=Alice |date=2007-10-08 |title=Why Banked Blood Goes Bad |url=http://content.time.com/time/health/article/0,8599,1669438,00.htm |magazine=Time |access-date=2019-01-11 }}{{dead link|date=July 2021|bot=medic}}{{cbignore|bot=medic}}

More broadly, accumulated evidence has demonstrated that S-nitrosylation of proteins plays important roles in many diseases, from heart failure to cancer to neurodegenerative disease.{{cite journal |vauthors=Foster MW, McMahon TJ, Stamler JS |title=S-nitrosylation in health and disease |journal= Trends Mol Med |volume=9 |issue=4 |pages=160–168 |year=2003 |pmid=12727142 |doi=10.1016/S1471-4914(03)00028-5 }}{{cite journal |vauthors =Foster MW, Hess DT, Stamler JS |title=Protein S-nitrosylation in health and disease: a current perspective |journal= Trends Mol Med |volume=15 |issue=9 |pages=391–404 |year=2009 |pmid=19726230 |pmc=3106339 |doi=10.1016/j.molmed.2009.06.007 }}{{cite journal |last1=Nakamura |first1=T |last2=Lipton |first2=SA |date=2017-12-01 |title='SNO'-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders |journal=Trends Endocrinol Metab |volume= 28|issue=12 |pages=879–892 |pmid=29097102 |pmc=5701818 |doi=10.1016/j.tem.2017.10.004 }}{{cite journal |last1=Reis |first1=AKCA |last2=Stern |first2=A |last3=Monteiro |first3=HP |date=2019-04-05 |title=S-nitrosothiols and H₂S donors: Potential chemo-therapeutic agents in cancer |journal=Redox Biol |volume= 27|pages= 101190|id=101190 |doi=10.1016/j.redox.2019.101190 |pmid=30981679 |pmc=6859576 }}

Stamler’s studies have shown aberrant S-nitrosylation in asthma,{{cite journal |last1=Gaston |first1=B |last2=Sears |first2=S |last3=Woods |first3=J |last4=Hunt |first4=J |last5=Ponaman |first5=M |last6=McMahon |first6=T |last7=Stamler |first7=JS |date=1998-05-02 |title=Bronchodilator S-nitrosothiol deficiency in asthmatic respiratory failure |journal=Lancet |volume=351 |issue=9112 |pages=1317–1319 |doi=10.1016/S0140-6736(97)07485-0 |pmid=9643794 |s2cid=28776994 }}{{cite journal |last1=Que |first1=LG |last2=Liu |first2=L |last3=Yan |first3=Y |last4=Whitehead |first4=GS |last5=Gavett |first5=SH |last6= Schwartz|first6=DA |last7=Stamler |first7=JS |date=2005-06-10 |title=Protection from experimental asthma by an endogenous bronchodilator. |journal=Science |volume=308 |issue=5728 |pages=1618–1621 |doi=10.1126/science.1108228 |pmid=15919956 |pmc=2128762 |bibcode=2005Sci...308.1618Q }} pulmonary hypertension,{{cite journal |vauthors=McMahon TJ, Ahearn GS, Moya MP, Gow AJ, Huang YC, Luchsinger BP, Nudelman R, Yan Y, Krichman AD, Bashore TM, Califf RM, Singel DJ, Piantadosi CA, Tapson VF, Stamler JS |title=A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension |journal=Proc Natl Acad Sci U S A |volume=102 |issue=41 |pages=14801–14806 |year=2005 |pmid=16203976 |pmc=1253588 |doi=10.1073/pnas.0506957102 |bibcode=2005PNAS..10214801M |doi-access=free }} heart failure,{{cite journal |last1=Hayashi |first1=H |last2=Hess |first2=DT |last3=Zhang |first3=R |last4=Sugi |first4=K |last5=Gao |first5=H |last6=Tan |first6=BL |last7=Bowles |first7=DE |last8=Milano |first8=CA |last9=Jain |first9=MK |last10=Koch |first10=WJ |last11=Stamler |first11=JS |date=2018-05-03 |title=S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence |journal=Mol Cell |volume=70 |issue=3 |pages=473–487 |doi=10.1016/j.molcel.2018.03.034 |pmid=29727618 |pmc=5940012 }}{{cite news |author= |date=2018-05-14 |title= Heart disease severity may depend on nitric oxide levels |url=https://www.sciencedaily.com/releases/2018/05/180514132501.htm |website=ScienceDaily |access-date=2019-01-11}} diabetes,{{cite journal |last1=Qian |first1=Q |last2=Zhang |first2=Z |last3=Orwig |first3=A |last4=Chen |first4=S |last5=Ding |first5=WX |last6=Xu |first6=Y |last7=Kunz |first7=RC |last8=Lind |first8=NRL |last9=Stamler |first9=JS |last10=Yang |first10=L |date=2018-02-01 |title=S-Nitrosoglutathione Reductase Dysfunction Contributes to Obesity-Associated Hepatic Insulin Resistance via Regulating Autophagy. |journal=Diabetes |volume= 67|issue=2 |pages=193–207 |pmid=29074597 |doi=10.2337/db17-0223 |doi-access=free |pmc=10515702 }} kidney injury,{{cite journal |last1=Zhou |first1=HL |last2=Zhang |first2=R |last3=Anand |first3=P |last4=Stomberski |first4=CT |last5=Qian |first5=Z |last6=Hausladen |first6=A |last7=Wang |first7=L |last8=Rhee |first8=EP |last9=Parikh |first9=SM |last10=Karumanchi |first10=SA |last11=Stamler |first11=JS |date=2019-01-10 |title= Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury |journal=Nature |volume=565 |issue=7737 |pages=96–100 |doi=10.1038/s41586-018-0749-z |pmid=30487609 |pmc=6318002 |bibcode=2019Natur.565...96Z }}{{cite news |author= |date=2018-11-28 |title=Re-programming the body's energy pathway boosts kidney self-repair |url=https://medicalxpress.com/news/2018-11-re-programming-body-energy-pathway-boosts.html |website=medicalexpress.com |publisher=Science X |access-date=2019-01-11 }}

and infectious diseases.{{cite journal |vauthors=de Jesús-Berríos M, Liu L, Nussbaum JC, Cox GM, Stamler JS, Heitman J |title=Enzymes that counteract nitrosative stress promote fungal virulence |journal=Curr Biol |volume=13 |issue=22 |pages=1963–1968 |year=2003 |pmid=14614821 |doi=10.1016/j.cub.2003.10.029 |doi-access=free |bibcode=2003CBio...13.1963D }}{{cite journal |vauthors=Elphinstone RE, Besla R, Shikatani EA, Lu Z, Hausladen A, Davies M, Robbins CS, Husain M, Stamler JS, Kain KC |title=S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria |journal=Infect Immun |volume=85 |issue=9 |pages=e00371-17 |year=2017 |pmid=28674030 |pmc=5563579 |doi=10.1128/IAI.00371-17 }}

Examining the hemoglobins of microbes and the parasitic worm Ascaris, Stamler found that ancient forms of hemoglobin either eliminate NO enzymatically (bacteria and yeast) or utilize it to eliminate oxygen from its anaerobic environment (Ascaris), showing that the primordial function of hemoglobin was in NO processing not oxygen transport.{{cite journal |last1=Hausladen |first1=A |last2=Gow |first2=AJ |last3=Stamler |first3=JS |date=1998-11-24 |title=Nitrosative stress: metabolic pathway involving the flavohemoglobin |journal=Proc Natl Acad Sci USA |volume=95 |issue=24 |pages=14100–14105 |pmid=9826660 |pmc=24333 |doi=10.1073/pnas.95.24.14100 |bibcode=1998PNAS...9514100H |doi-access=free }}{{cite journal |last1=Liu |first1=L |last2=Zeng |first2=M |last3=Hausladen |first3=A |last4=Heitman |first4=J |last5=Stamler |first5=JS |date=2000-04-25 |title=Protection from nitrosative stress by yeast flavohemoglobin |journal=Proc Natl Acad Sci USA |volume=97 |issue=9 |pages=4672–4676 |pmid=10758168 |pmc=18291 |doi=10.1073/pnas.090083597 |bibcode=2000PNAS...97.4672L |doi-access=free }}{{cite journal |last1=Minning |first1=DM |last2=Gow |first2=AJ |last3=Bonaventura |first3=J |last4=Braun|first4=R |last5=Dewhirst |first5=M |last6=Goldberg |first6=DE |last7=Stamler |first7=JS |date=1999-09-30 |title=Ascaris haemoglobin is a nitric oxide-activated 'deoxygenase' |journal=Nature |volume=401 |issue=6752 |pages=497–502 |doi=10.1038/46822 |pmid=10519555 |bibcode=1999Natur.401..497M |s2cid=3486708 }}{{cite news |last=Blakeslee |first=Sandra |date=1999-10-05 |title=Thanks to a 'Horrible Worm,' New Ideas on Hemoglobin |url=https://archive.nytimes.com/www.nytimes.com/library/national/science/100599sci-hemoglobin.html |work=The New York Times |access-date=2019-01-11 }} Stamler also identified trans-kingdom SNO signaling (operating between species as a general language between microbiota and animal host), 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 the enzymatic mechanism of nitroglycerin bioactivation and tolerance, thus solving a longstanding mystery (i.e., the generation of NO from nitroglycerin was awarded a Nobel Prize in 1998, but how was not understood).{{cite journal |last1=Chen |first1=Z |last2=Zhang |first2=J |last3=Stamler |first3=JS |date=2002-06-11 |title=Identification of the enzymatic mechanism of nitroglycerin bioactivation |journal=Proc Natl Acad Sci USA |volume=99 |issue=12 |pages=8306–8311 |pmid=12048254 |pmc=123063 |doi=10.1073/pnas.122225199 |doi-access=free }}

Stamler is a co-founder of multiple biotechnology companies, including several that have had public offerings, and he has also licensed additional discoveries to large pharma. He is also known for a track record of innovation and entrepreneurship as a founder of institutes, medical societies, innovation platforms and impact investment funds. His work has been covered in numerous lay publications, including the front page and science sections of the New York Times, as well as Time Magazine and The Economist, in books on the history of science and luck, and in works on outlier innovators.

Stamler is the founder the Harrington Project, a collaboration between the non-profit Harrington Discovery Institute at University Hospitals Health System in Cleveland, (where he serves as president) and two mission-aligned for-profit partner organizations (Biomotiv, Advent-Harrington Impact Fund) to shepherd laboratory discovery through translation and into biotechnology commercialization and approved therapy.{{cite press release |url= https://www.prnewswire.com/news-releases/biomotiv-launches-novel-drug-development-operation-names-leadership-team-160499615.html |title= BioMotiv Launches Novel Drug Development Operation, Names Leadership Team |author= |website=prnewswire.com/ |publisher=PR Newswire |access-date=2022-05-16 }}

Under Stamler’s leadership, Harrington Discovery Institute has partnered with medical charities and non-profit organizations to target specific diseases, including the Foundation Fighting Blindness,{{cite press release |url= https://www.prnewswire.com/news-releases/foundation-fighting-blindness-and-harrington-discovery-institute-partner-to-accelerate-drug-development-for-critical-causes-of-blindness-278515611.html |title= Foundation Fighting Blindness and Harrington Discovery Institute Partner to Accelerate Drug Development for Critical Causes of Blindness |author= |website=prnewswire.com/ |publisher=PR Newswire |access-date=2022-05-16 }} Alzheimer's Drug Discovery Foundation,{{cite web |url= https://www.harringtondiscovery.org/funding/addf-harrington/partners |title=ADDF-Harrington |author= |website=harringtondiscovery.org/ |publisher=Harrington Discovery Institute |access-date=2022-05-16 }} American Cancer Society, and Oxford University (Oxford-Harrington Rare Disease Centre).{{cite web |url=https://fundforcures.org.uk/ |title=Fund For Cures UK |author= |website=fundforcures.org.uk/ |publisher=Harrington Discovery Institute |access-date=2022-05-16 }} He has built philanthropic partnerships with Morgan Stanley Wealth Management (Morgan Stanley GIFT Cures powered by Harrington Discovery Institute) and raised impact funds for investment companies (Biomotiv) and on Wall Street (Advent-Harrington Impact Fund with Advent Life Sciences; Morgan Stanley platform) that have totaled ~ $900 million for therapeutics research and development.{{cite web |url= https://www.harringtondiscovery.org/partners/morgan-stanley-gift-cures |title= Morgan Stanley GIFT Cures |author= |website=harringtondiscovery.org/ |publisher=Harrington Discovery Institute |access-date=2022-05-16 }}{{cite web |url=https://msgiftcures.donorgift.org// |title=Morgan Stanley GIFT Cures |author= |website=msgiftcures.donorgift.org/ |publisher=Morgan Stanley |access-date=2022-05-16 }}{{cite web |url=https://www.morganstanley.com/press-releases/new-morgan-stanley-gift-curessm-program-to-advance-drug-discover |title=New Morgan Stanley GIFT Cures Program to Advance Drug Discovery Research into Life-Saving and Life-Enhancing Cures and Treatments |author= |website=morganstanley.com/ |publisher=Morgan Stanley |access-date=2022-05-16 }}{{cite web |url=https://globalimpactventuring.com/advent-life-sciences-starts-impact-fund/ |title=Advent Life Sciences starts impact fund |author= |website=globalimpactventuring.com/ |publisher=Global Impact Venturing |access-date=2022-05-16 }}

{{Reflist}}

• [https://www.uhhospitals.org/harrington-discovery-institute/harrington-investigators/jonathan-stamler Stamler lab website] {{Webarchive|url=https://web.archive.org/web/20190403115422/https://www.uhhospitals.org/harrington-discovery-institute/harrington-investigators/jonathan-stamler |date=2019-04-03 }}
• [https://www.uhhospitals.org/harrington-discovery-institute/about-us/team/jonathan-s-stamler-md Harrington Discovery Institute website] {{Webarchive|url=https://web.archive.org/web/20201023115300/https://www.uhhospitals.org/harrington-discovery-institute/about-us/team/jonathan-s-stamler-md |date=2020-10-23 }}

{{DEFAULTSORT:Stamler, Jonathan}}

Category:American physicians

Category:American scientists

Category:1959 births

Category:Living people

Category:People from Wallingford, Oxfordshire

Category:Brandeis University alumni

Category:Harvard Medical School faculty