Paul Greengard

Paul Greengard
Greengard in 2009
Paul Greengard
Born	11 12, 1925
Birthplace	New York City, New York, U.S.
Died	Template:Death date and age New York City, New York, U.S.
Nationality	American
Occupation	Neuroscientist
Title	Vincent Astor Professor
Employer	Rockefeller University
Known for	Signal transduction in neurons; protein phosphorylation in the nervous system
Education	PhD, Johns Hopkins University (1954)
Spouse(s)	Ursula von Rydingsvard (m. 1985)
Children	2
Awards	Nobel Prize in Physiology or Medicine (2000), NAS Award in the Neurosciences, Dickson Prize

Paul Greengard (December 11, 1925 – April 13, 2019) was an American neuroscientist whose pioneering research on the molecular and cellular mechanisms of neuronal signaling transformed the understanding of how brain cells communicate. Over a career spanning more than five decades, Greengard elucidated the role of protein phosphorylation—the chemical addition of phosphate groups to proteins—as a fundamental mechanism of signal transduction in the nervous system. This work established that slow synaptic transmission, mediated by neurotransmitters such as dopamine, operates through cascades of intracellular signaling events that modify the function of proteins within neurons. In 2000, Greengard shared the Nobel Prize in Physiology or Medicine with Arvid Carlsson and Eric Kandel for their collective discoveries concerning signal transduction in the nervous system. He held the position of Vincent Astor Professor at Rockefeller University, where he directed the Laboratory of Molecular and Cellular Neuroscience for decades and mentored generations of researchers. Beyond his Nobel Prize–winning work on neuronal signaling, Greengard made substantial contributions to Alzheimer's disease research, served on the Scientific Advisory Board of the Cure Alzheimer's Fund, and was a member of the Scientific Council of the Brain & Behavior Research Foundation.

Early Life

Paul Greengard was born on December 11, 1925, in New York City. His mother died during childbirth, and his father subsequently remarried. Greengard later described his early home environment as difficult, which contributed to his developing a strong sense of independence from an early age. He grew up during the Great Depression and came of age during World War II, experiences that shaped his outlook and determination.

During World War II, Greengard served in the United States Navy. He was stationed at the Massachusetts Institute of Technology (MIT), where he worked on an early warning system for detecting enemy aircraft as part of the war effort. This experience with electronic technology and physics during the war years proved formative, exposing Greengard to scientific problem-solving and the application of technical knowledge to practical challenges. The work involved principles of electronics and biophysics that would later inform his scientific thinking.

Following his military service, Greengard pursued higher education under the benefits provided to veterans. The transition from military service to academic life marked a turning point in his career, steering him toward the biological sciences. His wartime technical experience, combined with his growing interest in biological processes, set the stage for a career that would bridge physics, chemistry, and biology in the study of the nervous system.

Education

After the war, Greengard enrolled at Hamilton College in Clinton, New York, where he earned a Bachelor of Science degree in 1948. He then pursued graduate studies at Johns Hopkins University in Baltimore, Maryland, where he worked under the supervision of Haldan Keffer Hartline, a biophysicist who would himself later receive the Nobel Prize in Physiology or Medicine in 1967 for discoveries concerning the neurophysiology of vision.

At Johns Hopkins, Greengard completed his doctoral dissertation in 1954, titled "Some relationships between action potential, oxygen consumption and coenzyme content in degenerating peripheral axons." The thesis examined the physiological and biochemical properties of nerve fibers, establishing an early foundation for his lifelong interest in the molecular mechanisms underlying neuronal function. Following his PhD, Greengard undertook postdoctoral work in Europe, conducting research at the University of London, Cambridge University, and the University of Amsterdam, broadening his expertise in biochemistry and pharmacology before returning to the United States.

Career

Early Academic Career and Industry Research

After completing his postdoctoral training in Europe, Greengard returned to the United States and joined the Department of Pharmacology at the Geigy Research Laboratories (later part of Ciba-Geigy and subsequently Novartis) in the early 1960s. Working in a pharmaceutical research environment provided Greengard with exposure to drug development and the practical applications of biochemical research. During this period, he began to develop his ideas about how neurotransmitters might exert their effects through intracellular biochemical pathways rather than simply through direct electrical signaling at synapses.

Greengard subsequently moved to academic positions, joining the faculty at the Albert Einstein College of Medicine and later Yale University, where he served as a professor of pharmacology. It was during these years that his research program on protein phosphorylation in the nervous system began to take definitive shape. He investigated how neurotransmitters such as dopamine activate intracellular signaling cascades, a line of inquiry that challenged prevailing assumptions about how neurons communicate.

Rockefeller University

In 1983, Greengard joined Rockefeller University in New York City, where he was appointed the Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience. He would remain at Rockefeller for the rest of his career, building one of the foremost neuroscience laboratories in the world.

At Rockefeller, Greengard continued and expanded his research into the mechanisms of slow synaptic transmission. While fast synaptic transmission involves the direct opening of ion channels—occurring on a timescale of milliseconds—Greengard's work focused on a slower, more modulatory form of neuronal communication that operates over seconds to minutes and even longer. He demonstrated that this slow form of signaling depends on cascades of protein phosphorylation, in which neurotransmitters bind to receptors on the cell surface, triggering the production of second messengers such as cyclic AMP (cAMP), which in turn activate protein kinases. These kinases add phosphate groups to target proteins, altering their function and thereby modulating the electrical and biochemical properties of the neuron.

DARPP-32 and Dopamine Signaling

One of Greengard's most significant scientific contributions was the identification and characterization of DARPP-32 (Dopamine- and cAMP-Regulated Phosphoprotein, Mr 32,000), a protein that plays a central role in dopamine signaling in the brain. Greengard and his colleagues demonstrated that when dopamine binds to its receptor, it triggers a cascade of events leading to the phosphorylation of DARPP-32, which then acts as a potent inhibitor of protein phosphatase-1. This discovery revealed that DARPP-32 functions as a critical molecular switch, integrating multiple signals that converge on the neuron and regulating a wide array of downstream cellular processes.

The identification of DARPP-32 had profound implications for understanding the molecular basis of various neurological and psychiatric conditions. Because dopamine signaling is central to processes such as motivation, reward, motor control, and cognition, disruptions in the DARPP-32 signaling pathway have been implicated in conditions including Parkinson's disease, schizophrenia, and drug addiction. Greengard's work provided a molecular framework for understanding how these conditions arise and how therapeutic interventions might be designed to target specific steps in the signaling cascade.

Nobel Prize

In 2000, Greengard was awarded the Nobel Prize in Physiology or Medicine, which he shared with Swedish pharmacologist Arvid Carlsson and American neuroscientist Eric Kandel. The Nobel Committee recognized the three scientists for their complementary discoveries concerning signal transduction in the nervous system. Carlsson was honored for his discovery that dopamine is a neurotransmitter in the brain with important functions in motor control; Greengard for elucidating how dopamine and other neurotransmitters exert their effects on neurons through protein phosphorylation cascades; and Kandel for identifying the molecular mechanisms underlying short-term and long-term memory formation at synapses.

In his Nobel interview, Greengard discussed the long trajectory of his research, noting that his interest in the biochemical basis of neuronal function had been a constant thread throughout his career. He described how the field had evolved from a time when the dominant view held that all synaptic transmission was fast and electrical, to the recognition that slow, modulatory signaling through second messengers and protein phosphorylation is equally fundamental to brain function.

Alzheimer's Disease Research

In addition to his foundational work on signal transduction, Greengard made important contributions to the study of Alzheimer's disease. At Rockefeller University, he served as the Director of the Fisher Center for Alzheimer's Research, where his laboratory investigated the molecular mechanisms underlying the production and accumulation of amyloid-beta peptides, which are central to the pathology of Alzheimer's disease.

Greengard's research in this area focused on the enzyme gamma-secretase, which cleaves amyloid precursor protein to produce amyloid-beta. His laboratory worked to understand the regulation of this enzyme and to identify potential therapeutic targets that could reduce the production of toxic amyloid-beta fragments without disrupting the enzyme's other essential functions. This work contributed to the broader scientific effort to develop disease-modifying treatments for Alzheimer's disease.

He also served on the Scientific Advisory Board of the Cure Alzheimer's Fund, reflecting his commitment to translating basic neuroscience research into clinical applications for neurodegenerative diseases.

Mentorship and Scientific Legacy

Throughout his career at Rockefeller University, Greengard trained and mentored a large number of graduate students, postdoctoral fellows, and visiting scientists, many of whom went on to become leading figures in neuroscience and related disciplines. His laboratory was known for its rigorous approach to biochemical and molecular investigation of neuronal function. Colleagues and former trainees described him as an intellectually demanding but supportive mentor who encouraged independent thinking and creative experimental design.

The Rockefeller University noted upon his death that Greengard had "revolutionized our understanding of how brain cells communicate with each other" and that his discoveries had "provided insight into the workings of the brain, as well as a basis for the development of new approaches to the treatment of neurological and psychiatric disorders."

Personal Life

Greengard was married twice. His first marriage produced two children. In 1985, he married the sculptor Ursula von Rydingsvard, a Polish-born American artist known for her large-scale works in cedar and other materials.

Following his receipt of the Nobel Prize in 2000, Greengard used his share of the prize money—approximately $400,000—to establish the Pearl Meister Greengard Prize, an annual award honoring outstanding achievement by women in biomedical research. The prize was named in memory of his mother, Pearl Meister Greengard, who had died giving birth to him. Greengard stated that he created the award to address the lack of recognition for women scientists and to honor his mother's memory. The prize, administered through Rockefeller University, has been awarded annually since 2004 and carries a cash award of $100,000.

Greengard lived in New York City for most of his life. He died on April 13, 2019, at the age of 93, in New York City.

Recognition

Greengard received numerous honors and awards throughout his career in addition to the Nobel Prize. Among his major recognitions were the NAS Award in the Neurosciences, presented by the National Academy of Sciences, and the Dickson Prize from the University of Pittsburgh, one of the most prestigious awards in American medicine and science.

He was also the recipient of the MetLife Foundation Award for Medical Research in Alzheimer's Disease, recognizing his contributions to understanding the molecular basis of the disease. Greengard received the Golgi Medal, an international award recognizing outstanding contributions to neuroscience, further attesting to the global impact of his research.

Greengard was elected to membership in the National Academy of Sciences and held honorary degrees from several institutions. He served on the Scientific Council of the Brain & Behavior Research Foundation (formerly the National Alliance for Research on Schizophrenia and Depression), one of the largest private funders of mental health research grants.

The Pearl Meister Greengard Prize, which he established in 2004, has itself become a significant honor in the biomedical sciences. Recipients of the prize have included leading women scientists from a range of fields. In 2025, the prize was awarded to developmental biologist Maria Jasin of Memorial Sloan Kettering Cancer Center for her research on DNA repair mechanisms and their links to cancer.

Hamilton College, his undergraduate alma mater, recognized Greengard as one of its most distinguished alumni.

Legacy

Paul Greengard's research fundamentally altered the understanding of neuronal communication. Before his work, the dominant paradigm in neuroscience emphasized fast synaptic transmission—the rapid, direct electrical signaling between neurons mediated by ion channels. Greengard's discoveries demonstrated that a parallel system of slow synaptic transmission, operating through second messengers, protein kinases, and protein phosphorylation, is equally essential to brain function. This slower signaling system modulates the electrical excitability of neurons, regulates gene expression, and mediates the long-term changes in neural circuits that underlie learning, memory, and behavior.

His identification of DARPP-32 as a critical integrator of dopamine signaling provided a molecular explanation for how disruptions in neurotransmitter systems give rise to neurological and psychiatric diseases. The conceptual framework established by Greengard's research has informed the development of drugs targeting conditions such as Parkinson's disease, schizophrenia, depression, and addiction, even as the specific therapeutic strategies continue to evolve.

The Pearl Meister Greengard Prize represents an enduring aspect of Greengard's legacy beyond his scientific contributions. By using his Nobel Prize money to create an award honoring women in biomedical research, Greengard drew attention to gender disparities in scientific recognition and created a lasting mechanism for celebrating the achievements of women scientists.

At Rockefeller University, Greengard's laboratory trained a generation of neuroscientists who have continued and extended his research program. His influence is reflected not only in the direct scientific contributions of his former trainees but in the broader adoption of the biochemical and molecular approaches to neuroscience that he pioneered. The Brain & Behavior Research Foundation noted upon his death that he was "one of the giants in modern neuroscience," a characterization consistent with his impact on the field over more than half a century of research.