Alexander Chesler, PhD
The central question guiding my research is how is sensory input detected and processed by the brain to evoke specific behaviors. My work focuses on identifying peripheral somatosensory neurons tuned to specific types of stimuli, the molecules they use for transduction, and the neural circuits that they activate. Through my research I seek to understand the basis by which some stimuli are perceived as innocuous while others noxious and how these distinctions are modulated by physiological state or prior experience. The hope is that improving our knowledge of these basic mechanisms will be useful in developing new therapeutic approaches for treating acute and chronic pain. The need for better treatment options for pain is dire. As laid out in the Institute of Medicine report “Relieving Pain in America” (2011), chronic pain affects as much as 30% of adults. In the United States alone, the lack of effective treatment options has led to tens of millions with a decreased quality of life, hundreds of billions in lost revenue, and has fueled the current opioid epidemic.
My interest in sensory biology began as an undergraduate at Bard College (B.A., 1995). I was a Biology major with a keen interest in fine arts who found himself drawn to the astounding morphological and behavioral diversity of insects and, in particular, the field of chemical ecology. After graduating, I moved to Arizona where I spent a year studying with two entomologists, Reg Chapman and Elizabeth Bernays, on the role of chemosensation in host plant selection. As my appreciation of insects grew, so did my understanding of the importance of sensory cues in guiding animal behavior. These insights sparked my interest in the neurobiology of olfaction and led me join the lab of Stuart Firestein at Columbia University as a graduate student (Ph.D., 2005). My work in Stuart’s lab focused on olfactory sensory neurons. In mammals, the detection of odorants relies on the expression of a large family of G-protein coupled receptors. Each olfactory sensory neuron chooses to express one of many possible odorant receptor genes and the axons of neurons expressing that particular receptor converge to target a small number of specific glomeruli. For my thesis, I investigated the mechanisms by which odorant receptors govern the physiology and wiring of individual neurons (Chesler et al. 2007 Proceeding of the National Academy of Science; Zou et al. 2007 Journal of Neuroscience; Zou et al. 2009, Nature Reviews Neuroscience). It was also during this time that I read a paper from David Julius’ group that captured my imagination and changed the course of my research.
In their landmark paper, Caterina et al. (1997) described the identification of the receptor for capsaicin and by doing so provided a mechanism by which a natural product in plants elicits a specific sensory experience, in this case burning. In so many ways, this work encapsulated all of my scientific interests at the time. Upon graduation, I was fortunate to be able to join David Julius’ lab as a postdoctoral fellow at the University of California, San Francisco and continue the tradition of using natural products to probe sensory pathways. There I developed an imaging based screen to test the function of animal venom libraries on somatosensory neurons. Using this screen, we identified an unusual heteromeric toxin complex from the Texas Coral Snake that targets ASIC1 ion channels expressed on nociceptors to produce long lasting pain (Bohlen*, Chesler* et al. 2011, Nature). My second line of research, in collaboration with Allan Basbuam’s group (UCSF), sought to leverage the discovery of specific ion channel receptors to gain genetic access to sensory neurons important for thermosensation and pain (Cavanaugh*, Chesler* et al 2011, Journal of Neuroscience). Together, these studies laid the conceptual foundation for my work as an independent researcher.
I joined the National Institutes of Health (NIH) intramural program in 2013 as a tenure track investigator. My work at the National Center for Complimentary and Integrative Health (NCCIH) focuses on determining the properties that define specific types of sensory neurons. My lab takes advantage of our carefully curated colony of transgenic mice to interrogate the function of genetically-defined classes of sensory neurons in physiology and behavior. We use a wide variety of methods for our studies that include in vitro and in vivo electrophysiology, in vivo two-photon imaging, bioinformatics, and behavior. Together, these approaches help us to better understand the importance of specific molecules for the responses of defined classes of sensory neurons and to map the neural pathways activated or modulated by different types of neuron types.
Recently my research program has added an important dimension by working with human subjects. For these studies, I leverage the unique power of the intramural research program at NIH to facilitate basic scientists, clinicians and patient populations to work together to fight human diseases. In particular, we take advantage of the power of genome sequencing to unlock the genetic causes of heritable diseases. In collaboration with a team of clinical scientists, we have identified a cohort of patients with a rare inherited disorder affecting mechanosenstion due to damaging mutations in the gene PIEZO2. (Chesler et al. 2016, New England Journal of Medicine). Studying these patients helped define the role of this particular gene in human mechanosensation and allowed us to probe basic questions about the role particular sensory inputs play in perception. Most importantly, working with these patients allows us ask questions about human experience that, by definition, are impossible to answer using animal models. We are now positioned to take what we learn from these patients to guide our studies in mice. Furthermore, we continue to expand our pool of patients with sensory deficits with the hope of uncovering additional molecules important for touch, thermosensation, and pain.