In Memory of Steven Brown

On Wednesday, 14^th December 2022, the sleep research community was left devastated by the sudden loss of Steven A. Brown (1970-2022), a brilliant chronobiologist and sleep researcher, who passed away after a tragic plane crash. Steve was a unique mind, excellent scientist and generous mentor, with a huge spectrum of research interests and talents, as impressively witnessed by his diverse and important contributions to the scientific development of the field.

Steve initially studied biochemistry at Harvard University, Cambridge MA, USA, and received his doctorate in 1997 from the Department of Biological Chemistry and Molecular Pharmacology at Harvard. He then moved to Switzerland as postdoctoral fellow in the laboratory of Prof. Ueli Schibler, at the Institute of Molecular Biology at the University of Geneva (1998-2005), where his interests in circadian biology first evolved. In 2005, he joined Prof. Achim Kramer’s lab as Humboldt Fellow at the Charité in Berlin, Germany. Since September 2006, he was a Professor and Section Leader for chronobiology and sleep research at the Institute of Pharmacology and Toxicology, University of Zurich.

As postdoctoral fellow in Geneva, Steve was the first to purify circadian clock protein complexes and to identify their components, including both chromatin modifiers and members of the Drosophila Behavior, Human Splicing (DBHS) family of RNA-binding proteins (Brown, Science 2005). Following up on these discoveries, he elucidated in his own laboratory essential roles of these proteins within the circadian clock (Kowalska, MCB 2012), the cell cycle (Kowalska, PNAS 2013), metabolism (Benegiamo, Cell Metab 2018), as well as cognition (Mircsof, Nat Neurosci 2015). Based upon these insights, he was currently investigating their specific roles in neuron-specific “sleep speckles” that also contain prion-like proteins and are implicated in neurodegenerative disease.

A second major accomplishment of Steve’s postdoctoral years was the brilliant invention of a skin-cell-based lentiviral reporter assay for human circadian function (Brown, PLoS Biology 2005). This assay is now a standard approach for many investigators worldwide. In his own lab, Steve used it for a cell-based, genome-wide association study to identify common regulatory variants that affect circadian clock function (Gaspar, eLife 2017), and to show detailed circadian control of mitochondrial processes (Schmitt, Cell Metab 2018).

Bridging the circadian clock and sleep in controlling cellular functions of the cerebral cortex, his lab and international collaborators performed the first biochemically fractionated, subcellular multi-omics studies of neuronal synapses. In two back-to-back publications in Science (Noya, Brüning Science 2019; Brüning, Noya Science 2019), the authors further demonstrated that these cellular processes are orchestrated by compartment-specific phosphorylation. Among the regulated processes, Steve focused on the importance of voltage-gated potassium channels in the circadian control of sleep (Muheim, Curr Biol 2020).

Coming back to circadian neuroscience and turning to the molecular mechanism for circadian adaptation: Steve’s laboratory elegantly demonstrated dynamic DNA methylation within “master clock” neurons (Azzi, Nat Neurosci 2014). This study was one of the first examples of de novo neuronal DNA methylation in response to behavior in adult organisms. Surprisingly, in spite of the cell-autonomous origin, follow-up experiments showed that such “circadian plasticity” is effected by changing the network properties of hypothalamic neurons, rather than the molecular clocks within individual cells (Azzi, Neuron 2017). As a result, specific populations of “master clock” neurons change their phase to regulate sleep at different times (Collins Neuron 2020). The further investigation of the circuitry underlying the circadian control of sleep was currently one of Steve’s major interests: his curious mind was constantly chasing “the brain switch of diurnality and nocturnality”.

Steve’s innovative thinking also pioneered the use of metabolomics to measure human circadian clock functions in real time (Dallmann, PNAS 2012). He and his colleagues recently extended this technology to mass spectrometry-based metabolomics of exhaled human breath during sleep, and demonstrated that many of the same metabolites are controlled by sleep (Nowak Cell Rep 2021). Finally, in honor of the recent Covid-19 caused lockdown, he flew himself and his students north of the Arctic Circle, to perform circadian metabolomics in reindeer. This study was recently written up to a manuscript, which documents ultradian cycles of metabolism in these animals.

Steve lived a rich life, full of adventures and persistent positivity, in the same way as he viewed science: in continuous motion. Despite the deep big he leaves behind, his unique legacy remains with his numerous students and collaborators, his “Dear friends”, with whom he shared memorable moments and all kinds of adventures. He will continue to guide us in our memories and scientific thinking, “In Science and in Life”, as in the words of a close friend.

Konstantinos Kompotis, PhD & Hans-Peter Landolt, PhD
Section of Chronobiology and Sleep Research
Institute of Pharmacology and Toxicology
University of Zurich, Switzerland