Jonathan Solomon Stamler (born June 23, 1959) is an English-born American physician and scientist. He is known for his discovery of
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
S-nitrosylation, the addition of a
nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
(NO) group to
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
residues in proteins, as a ubiquitous cellular signal to regulate
enzymatic
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
activity and other key protein functions in bacteria, plants and animals, and particularly in transporting NO on cysteines in
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
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 (United Kingdom,
Switzerland
). Swiss law does not designate a ''capital'' as such, but the federal parliament and government are installed in Bern, while other federal institutions, such as the federal courts, are in other cities (Bellinzona, Lausanne, Luzern, Neuchâtel ...
,
Israel
Israel (; he, יִשְׂרָאֵל, ; ar, إِسْرَائِيل, ), officially the State of Israel ( he, מְדִינַת יִשְׂרָאֵל, label=none, translit=Medīnat Yīsrāʾēl; ), is a country in Western Asia. It is situated ...
, 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
, mottoeng = "Truth even unto its innermost parts"
, established =
, type = Private research university
, accreditation = NECHE
, president = Ronald D. Liebowitz
, pro ...
in 1981, and earned his M.D. degree from
Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai (ISMMS or Mount Sinai), formerly the Mount Sinai School of Medicine, is a private medical school in New York City. It is the academic teaching arm of the Mount Sinai Health System, which manages eight ...
in 1985.
His residency and fellowship training in
pulmonary medicine
Pulmonology (, , from Latin ''pulmō, -ōnis'' "lung" and the Greek suffix "study of"), pneumology (, built on Greek πνεύμων "lung") or pneumonology () is a medical specialty that deals with diseases involving the respiratory tract. and in
cardiovascular medicine
Cardiology () is a branch of medicine that deals with disorders of the heart and the cardiovascular system. The field includes medical diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular hear ...
was at
Brigham and Women’s Hospital
Brigham and Women's Hospital (BWH) is the second largest teaching hospital of Harvard Medical School and the largest hospital in the Longwood Medical Area in Boston, Massachusetts. Along with Massachusetts General Hospital, it is one of the two f ...
at
Harvard Medical School
Harvard Medical School (HMS) is the graduate medical school of Harvard University and is located in the Longwood Medical Area of Boston, Massachusetts. Founded in 1782, HMS is one of the oldest medical schools in the United States and is consi ...
.
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
The Duke University School of Medicine, commonly known as Duke Med, is the medical school of Duke University. It is located in the Collegiate Gothic-style West Campus of Duke University in Durham, North Carolina. The School of Medicine, along wit ...
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
The Howard Hughes Medical Institute (HHMI) is an American non-profit medical research organization based in Chevy Chase, Maryland. It was founded in 1953 by Howard Hughes, an American business magnate, investor, record-setting pilot, engineer, fil ...
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
Case Western Reserve School of Medicine (CWRU SOM, CaseMed) is the medical school of Case Western Reserve University, a private research university in Cleveland, Ohio. It is the largest biomedical research center in Ohio.
History
On November 1 ...
and
University Hospitals Cleveland Medical Center
University Hospitals Cleveland Medical Center (UH Cleveland Medical Center) is a large not-for-profit academic medical complex in Cleveland, Ohio, United States. University Hospitals Cleveland Medical Center is the main affiliate hospital of Ca ...
.
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.
Research
At the start of Stamler's research career, nitric oxide (NO) gas had recently been identified as a signaling molecule that mediated
vasodilation
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
by binding to the
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consisti ...
cofactor in the enzyme
soluble guanylyl cyclase
Soluble guanylyl cyclase (sGC) is the only known receptor for nitric oxide, NO. It is soluble, i.e. completely intracellular. Most notably, this enzyme is involved in vasodilation. In humans, it is encoded by the genes GUCY1A2, GUCY1A3, GUCY1 ...
to produce
cyclic guanosine monophosphate
Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in re ...
(cGMP).
However, most actions of NO being discovered at that time were not mediated by guanylyl cyclase/cGMP,
and high affinity binding of NO to the heme in
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
hemoglobin would inhibit NO actions in the vasculature,
presenting a quandry.
Stamler would provide a general mechanism to explain NO function in biology, which requires redox-activation of NO to NO+ (
nitrosonium ion
The nitrosonium ion is , in which the nitrogen atom is bonded to an oxygen atom with a bond order of 3, and the overall diatomic species bears a positive charge. It can be viewed as nitric oxide with one electron removed. This ion is usually obta ...
) 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
to bind cysteine residues in proteins
and thiols in other molecules (e.g.,
glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...
,
coenzyme A
Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
) to form
S-nitrosothiols (SNOs) that are protected from heme inactivation thus providing a means to stabilize and regulate NO bioactivity,
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
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
or
allosteric
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the ''allosteric site ...
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.
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
Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural ...
or
ubiquitination
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
.
Approximately 10,000 proteins, at >20,000 sites, have been reported to be nitrosylated, and it has been predicted that 70% of the
proteome
The proteome is the entire set of proteins that is, or can be, expressed by a genome, cell, tissue, or organism at a certain time. It is the set of expressed proteins in a given type of cell or organism, at a given time, under defined conditions. ...
is SNO-modified across phylogeny.
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).
. Enzymatic S-nitrosylation was identified first with hemoglobin (including nitrosylase and SNO synthase activities)
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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
,
gene regulation
Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wide ...
,
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
and
immunity
Immunity may refer to:
Medicine
* Immunity (medical), resistance of an organism to infection or disease
* ''Immunity'' (journal), a scientific journal published by Cell Press
Biology
* Immune system
Engineering
* Radiofrequence immunity desc ...
), and fundamental physiological functions (
skeletal muscle contractility,
airway tone,
cardiac response to adrenergic stimulation,
neuroprotection
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...
and development).
He has also discovered novel cellular functions (red blood cell mediated vasodilation)
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 (O2/NO/CO2).
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
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...
,
peripheral arterial disease
Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain. When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular diseas ...
and
sickle cell disease
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
, thereby impairing vasodilation by RBCs.
Further, since hemoglobin S-nitrosylation is rapidly lost upon
blood storage, the oxygen delivery capability of
transfused blood is impaired.
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.
Stamler’s studies have shown aberrant S-nitrosylation in asthma, pulmonary hypertension, heart failure, diabetes, kidney injury,
and infectious diseases.
Examining the hemoglobins of microbes and the
parasitic worm
Parasitic worms, also known as helminths, are large Parasitism#Basic concepts, macroparasites; adults can generally be seen with the naked eye. Many are intestinal worms that are soil-transmitted helminth, soil-transmitted and intestinal parasit ...
Ascaris
''Ascaris'' is a genus of parasite, parasitic nematode worms known as the "small intestinal roundworms", which is a type of parasitic worm. One species, ''Ascaris lumbricoides'', affects humans and causes the disease ascariasis. Another species ...
, 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
''Ascaris'' is a genus of parasite, parasitic nematode worms known as the "small intestinal roundworms", which is a type of parasitic worm. One species, ''Ascaris lumbricoides'', affects humans and causes the disease ascariasis. Another species ...
), showing that the primordial function of hemoglobin was in NO processing not oxygen transport. Stamler also identified trans-kingdom SNO signaling (operating between species as a general language between microbiota and animal host), since
microbiota
Microbiota are the range of microorganisms that may be commensal, symbiotic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found t ...
that produce NO can lead to widespread protein S-nitrosylation in a
Caenorhabditis elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...
host with profound genetic and physiological consequences.
Stamler also identified the enzymatic mechanism of
nitroglycerin
Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating g ...
bioactivation and tolerance, thus solving a longstanding mystery (i.e., the generation of NO from nitroglycerin was awarded a
Nobel Prize
The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...
in 1998, but how was not understood).
Entrepreneurial and philanthropic activities
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.
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
The mission of the Foundation Fighting Blindness is to fund research that will lead to the prevention, treatment and cures for the entire spectrum of retinal degenerative diseases, including retinitis pigmentosa, macular degeneration, Usher syndro ...
,
Alzheimer's Drug Discovery Foundation,
American Cancer Society
The American Cancer Society (ACS) is a nationwide voluntary health organization dedicated to eliminating cancer. Established in 1913, the society is organized into six geographical regions of both medical and lay volunteers operating in more than ...
, and
Oxford University
Oxford () is a city in England. It is the county town and only city of Oxfordshire. In 2020, its population was estimated at 151,584. It is north-west of London, south-east of Birmingham and north-east of Bristol. The city is home to the ...
(Oxford-Harrington Rare Disease Centre).
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 ~ $650 million for therapeutics research and development.
References
External links
Stamler lab websiteHarrington Discovery Institute website
{{DEFAULTSORT:Stamler, Jonathan
American physicians
American scientists
1959 births
Living people
People from Wallingford, Oxfordshire
Brandeis University alumni
Harvard Medical School alumni