George Robert Siggins: Researcher, musician, surfer, mentor, and friend

On September 22, 2023, George Robert “G-Bob” Siggins, Ph.D., passed away. In 2013, he became professor emeritus at The Scripps Research Institute (TSRI) in La Jolla, CA., retiring after a 50-year scientific career. Balancing work, music, surfing, and family, Dr. Siggins was dedicated to all and always attracted people and friends from anywhere. His breadth of knowledge, coupled with fast intellectual processing, enabled him to interact comfortably with a myriad of people. He was brilliant and successful yet truly humble. He made people feel important and full of potential. Conversations with him often involved a cup of coffee or a glass of wine and were often accompanied by music. He kindly shared the premium wines from his cellar with his colleagues and friends at his house. He led an amazing life full of science and music and his humanity will be greatly missed. For all of us in his music, surfing and scientific families, he was an outstanding alcohol researcher, an accomplished musician, a remarkable man, and a good friend. His scientific career started at Harvard University where he graduated in 1960 with a degree in Biological Chemistry. He subsequently earned a M.S. in Biology at Boston University in 1963 and a Ph.D. in Physiology at Boston University in 1967. From 1968 to 1973 he worked in the Laboratory of Neuropharmacology with the National Institute of Mental Health (NIMH) at Saint Elizabeths Hospital in Washington, DC., and from 1973 to 1976 served as Chief, Section of Comparative Neurobiology in the NIMH Laboratory of Neuropharmacology. He was recruited to the Salk Institute in 1976 as Associate Director of the A.V. Davis Center for Behavioral Neurobiology at the Salk Institute in La Jolla. In 1984, he moved to The Scripps Research Institute as a Full Professor in the Division of Preclinical Neuroscience and Endocrinology of the Department of Molecular and Experimental Medicine, which later became the Department of Neuropharmacology, and then the Molecular and Integrative Neurosciences Department. Dr. Siggins was a major leader in neuroscience research. His research focused on the molecular and electrophysiological actions of neuropeptides and other neurotransmitters/neuromodulators of the central nervous system (CNS), and how alcohol and drugs alter neuronal function. His laboratory was one of the only ones in the neuroscience field internationally that routinely used brain slice physiology. In the 1970s and 1980s, he published numerous manuscripts in high-impact journals (e.g., Science, Nature, and PNAS) reporting groundbreaking discoveries on how neurons communicate with each other. One of his key seminal contributions was the demonstration that alcohol has specific cellular actions that could be linked to specific neurons and key neurocircuits that mediate its effects on reward, withdrawal, and craving. A few of the numerous discoveries that he made in his career are outlined here. Early in his career, Dr. Siggins adopted electrophysiological, pharmacological manipulations and tracing methods to measure neuronal activity and neurotransmitter release using ex vivo slice physiology, which enabled him to assess cellular localization and characterize several neuropeptides, including opioid peptides and other neuromodulators in different brain regions. He went on to exploit electrophysiological techniques to test novel hypotheses regarding motivational function that drive occasional and chronic drug intake. For example, he helped elucidate the importance of opioid peptides (endorphins, enkephalins, and dynorphins) with electrophysiology in the nucleus accumbens, amygdala, and hippocampus. He showed that, in the hippocampus, opioids excite pyramidal neurons indirectly by inhibition of neighboring inhibitory interneurons (probably containing gamma-aminobutyric acid). When Dr. Siggins joined The Scripps Research Institute, one of his first seminal contributions was to characterize the neuropeptide somatostatin in hippocampus and its significant actions on ion channels as well as both GABAergic and glutamatergic transmission. Specifically, he showed that somatostatin augmented the M-current in hippocampal neurons, depressed excitatory but not inhibitory neurotransmission, and reduced hippocampal epileptiform activity. Subsequently, his laboratory demonstrated that the somatostatin-induced augmentation of the M-current in hippocampus involved lipidic messengers from the phospholipase A2 cascade, specifically metabolites of the lipoxygenase pathway. This was the first demonstration that an arachidonic metabolite mediated a neurotransmitter effect in the mammalian brain. Dr. Siggins pioneered the field of brain-immune system interactions providing significant insights into the mechanisms of those neuroimmune factors in the mammalian CNS. To better understand the actions of proinflammatory cytokines, he used transgenic models to assess the pathogenic actions of cytokines. For instance, he employed a transgenic approach in which the expression of interleukin-6 (IL-6) was targeted to astrocytes in the intact CNS of mice. The transgenic mice exhibited distinct chronic-progressive neurological disorders with neurodegeneration and cognitive decline due to IL-6 expression. Most importantly, he used electrophysiological tools to demonstrate that cytokines, like IL-1 beta, which has a broad spectrum of biological activity, also modulated electrical properties by increasing synaptic inhibition in rat hippocampal pyramidal neurons in vitro. Dr. Siggins also made prodigious contributions to the neurobiology of addictive disorders. As mentioned above, a key seminal contribution was to unveil the mechanisms of action of alcohol on the CNS. He was an original member of the TSRI-Alcohol Research Center (TSRI-ARC) that is still ongoing at Scripps Research. This NIAAA Center grant initially was awarded to the Arthur Vining Davis Center for Behavioral Neurobiology at The Salk Institute in 1977 with Dr. Floyd Bloom as Director. In December 1983, the Administrative Core and most of the ARC Research Components were transferred from Salk to The Scripps Research Institute. A competitive review of the Center program in the new location was performed in the spring of 1985, leading to its fourth 5-year funding period in December 1992. Dr. Bloom assumed the editorship of Science in 1995, and Dr. George F. Koob assumed directorship of the TSRI-ARC until 2014, when he went to lead the NIAAA. Many of Dr. Siggins' early studies (often in collaboration with Drs. Bloom and Koob) demonstrated how alcohol affects neuronal functions in specific brain regions and neurocircuits in the cerebellum, hippocampus, and nucleus accumbens. He showed how alcohol concentration dependently modulates a variety of cellular targets (e.g., ion channels, GABA, and glutamate subtype receptors) to produce its effects on reward, withdrawal, and craving. He demonstrated the physiological correlates of ethanol intoxication, tolerance, and dependence, and how distinct neurobiological mechanisms contribute to the different stages of the addiction cycle. In his later career, at the beginning of 2000, the TSRI-ARC embraced the framework for the etiology of addiction that follows a trajectory from intermittent alcohol use motivated by positive reinforcement to more frequent episodes of excessive alcohol intake that lead to a state of dependence, in which alcohol consumption is motivated by negative reinforcement (i.e., self-medication) resulting from withdrawal. Thus, Dr. Siggins' interests in the neural substrates shifted to study the central nucleus of the amygdala as one of the brain regions of the extended amygdala, the macrostructure that mediates this dark side of addiction. His extensive electrophysiological work in the central nucleus of the amygdala demonstrated that both acute and chronic alcohol strongly facilitates GABA release in this brain region. This work was led by Dr. Marisa Roberto, his postdoctoral fellow, who rose through the ranks at Scripps to Professor and remained his close long-term collaborator until he retired in 2014, when he transferred his laboratory to her. For instance, the studies by Siggins and Roberto in the amygdala revealed how both pro-stress peptides (CRF) and antistress (nociceptin) peptides play a critical role in the development of alcohol dependence in rats, with recruitment of stress systems and blunting of the antistress systems. Dr. Roberto's laboratory has followed in the Siggins' footprint, in that it remains one of the few laboratories that routinely quantifies brain functions using traditional electrophysiology in brain slices to provide critical insights into the mechanisms of alcohol effects in the brain, thereby laying the foundation for human clinical studies. One of the most difficult goals of a scientist is to obtain NIH grants and Dr. Siggins was an excellent scientist who developed novel ideas that led to receiving extramural grants throughout his career. That enabled him to recruit many postdoctoral fellows and staff members across the world to study brain cell functions using electrophysiology. He was an excellent teacher and mentor. Many of his postdoctoral fellows have gone on either to lead independent laboratories at universities or in the pharmaceutical industry. His mentorship style was to present opportunities for postdoctoral fellows to direct their own projects and to become independent and able to obtain scientific independence. His mentees include Donna Gruol, Ed French, Quentin Pittman, Scott Moore, Paul Schweitzer, Mellanie Tallent, Gilles Martin, Zhiguo Nie, Marisa Roberto, and Michal Bajo. Dr. Siggins also had numerous active and enduring collaborations with colleagues at TSRI and around the world and was highly esteemed by his peers and colleagues. He served on numerous NIH Study Sections and provided ad hoc service for The Scripps Research Institute. He published extensively in high-quality, peer-reviewed journals, publishing more than 160 research reports, as well as reviews and book chapters. In addition to being a distinguished neuroscientist, Dr. Siggins was an accomplished musician. He went by the name Bob and later G-Bob in his musical life. His mother was a talented piano player, so he had ample opportunity to appreciate music and take up an instrument at an early age, learning to play the banjo in high school. It was as a student in the Boston area that he really began his music career. He co-founded the Charles River Valley Boys who were an American bluegrass group that toured and recorded in the 1960s and were best known for their 1966 album, Beatle Country, a compilation of 10 Beatles tunes, which was released in 1966 and is still available at Amazon. They performed locally at Club 47 in Cambridge (later Club Passim), a music venue where budding artists such as Joan Baez and Bob Dylan performed early in their careers. He also performed with leading figures such as folk legend Joan Baez, according to a profile in the Los Angeles Times and went on to become an original member of the Jim Kweskin Jug Band, with Fritz Richmond, Geoff Muldaur, and Bruno Wolfe. The Jug Band was a significant part of the folk and blues revival of the 1960s. After Dr. Siggins settled in Del Mar, California, to start his very successful scientific research career, he maintained his membership in 1 or 2 local bands to entertain at local gatherings and clubs. He became an accomplished pedal steel player. He and his friends also performed at many Saturday evening receptions at the annual RSA meeting. Proximity to the sun and surf of Del Mar led to another circle of lifetime friends for Dr. Siggins. Although he took up surfing a bit later in life (around age 38), he enjoyed being an active member of the Del Mar Surf Club and later served as President of the Club. Dr. Siggins is survived by his only sibling, brother Sam (and his wife Judy) Siggins, daughter Leah (and her husband John) Ridpath, daughter Shannon (and her husband PJ) Erskine, son Graham Siggins (and his partner Serena Santoni) and two grandsons, Jake Ridpath and Waylon Erskine. Dr. Siggins is remembered fondly by his three former wives: Betsy Siggins Schmidt, Anne Louise Fuhrman, and Marcia Siggins Jonas. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.