Posted August 15, 2012 by Natalie Geld in brain networks

Stuart Firestein, PhD: Pleasures of Scientific Mystery and the Cultivation of Doubt

Dr. Stuart Firestein is the Chair of Columbia University’s Department of Biological Sciences where his highly popular course on ignorance invites working scientists to come talk to students each week about what they don’t know. His colleagues and he study the vertebrate olfactory system, possibly the best chemical detector on the face of the planet.

His laboratory seeks to answer that fundamental human question: How do I smell?


My laboratory investigates the sense of smell, olfaction.  We take a wide ranging approach beginning with the chemistry of odors, their detection by the specialized cells in your nose and the ways in which that information is processed by your brain to produce a perception of a rose from the blend five kinds of molecules.  The sense of smell is critical in detecting dangers, finding food, locating receptive mates and caring for young, and that is true not just for other animals but for humans as well.

However, another and perhaps more important reason for studying the olfactory system is that it serves as an especially effective model system for investigating fundamental mechanisms at work in the brain.

  Most obviously, molecular recognition, the ability to detect and discriminate between a large and diverse collection of molecules is critical to every neuron in the brain which must recognize neurotransmitters, hormones, nutrients, drugs and a host of other important molecules.  Olfactory neurons accomplish this using proteins and chemical  processes that are used by neurons throughout the brain – but it’s easier too study this in olfactory neurons.  Other crucial questions in neuroscience that can be profitably studied in olfactory cells are gene regulation (each olfactory sensory neuron chooses only one receptor gene, indeed only one allele,  to produce all of the receptor protein it will express), axon path finding (how axons find  the appropriate cells to connect to), neural regeneration (two of only three populations of neurons in the entire nervous system that can be regenerated in the adult brain are found in the olfactory system), local circuit processing (from the outside world to the first area of cortex that receives olfactory input, the pyriform cortex, there are only two synapses in the direct pathway), aging in the brain (because of lifelong regeneration of new neurons the olfactory system does not age in the same way as other sensory systems).

There are many other questions in olfaction not being addressed in my laboratory but in the laboratories of many other workers in the field; they include olfactory memories, pheromones and behavior, sensory pyschophysics, early development of the olfactory system, genomics of olfaction, and others.

The activity of all cells in the nervous system is regulated by the interaction of various chemicals, such as neurotransmitters, hormones, and peptides with membrane receptors. The ways in which these "Olfaction Science Brain Image"substances exert their influence is known generally as signal transduction. We use the vertebrate olfactory receptor neuron as a model for investigating general principles and mechanisms of signal transduction – receptor-ligand interactions, modulation by second messeng ers, ion channel gating, and the long term mechanisms of adaptation and desensitization. The olfactory neuron is uniquely suited for these studies since it is designed specifically for the detection and discrimination of a wide variety of small organic mo lecules, i.e. odors.

The most recent work in the lab utilizes Adenovirus vectors to drive over-expression of cloned odor receptors in olfacotry neurons. Because odor receptors make up the largest family of G-protein coupled receptors (also including many neurotransmi tter ands hormone receptors) they are excellent receptors to try and understand the relation between amino acid sequence and ligand binding affinities. We are able to overexpress particular receptors as well as receptor clones with targeted mutsations and then screen these for specific ligand sensitivities. These data are then included in computer models of the protein receptor to understand precisely why one receptor is able to recognize the odor of say, roses, while another is specific for pizza.

In another vein, olfactory receptors are unique among neurons for the ability to regenerate throughout an animal’s life. Several experimental manipulations have been developed to induce neuronal regeneration and proliferation in vivo , a llowing one to harvest neurons with a known date of birth. By applying physiological techniques for cell recording we are quantifying biophysical parameters, such as the appearance of ion channels or receptors and the development of synaptic contacts, in developing neurons.

Multiple approaches are brought to bear on these questions including electrophsyiological (from patch clamp to field potential recording techniques); molecular biological, immunohistochemica l and anatomical techniques and tools.

More about Stuart…

Dedicated to promoting science to a public audience, he serves as an advisor for the Alfred P. Sloan Foundation’s program for the Public Understanding of Science and was awarded the 2011 Lenfest Distinguished Columbia Faculty Award for excellence in scholarship and teaching. Also, he was recently named an AAAS Fellow.


Knowledge is a big subject, says Stuart Firestein, but ignorance is a bigger one. And it is ignorance–not knowledge–that is the true engine of science.  Turning the conventional idea about science on its head, Ignorance opens a new window on the true nature of research. Stuart’s book, Ignorance: How It Drives Science is a must-read for anyone curious about science.

Stuart’s Cool Website:


Stuart on What Conversations to have with Favorite Scientists Dead… or Alive


MedLine Listing of Dr. Firestein’s Publications

Representative Recent Publications

  • Otaki, J. M., and Firestein, S. (2001) Length analyses of mammalian g-protein-coupled receptors J Theor Biol 211: 77-100.
  • Araneda R. C., Kini A. D., Firestein, S. (2000) The molecular receptive range of an odorant receptor Nature Neuroscience 3 (12): 1248-1255.
  • Zhao, H., Ivic, L., Otaki, J., Hshimoto, M., and Firestein, S. (1998) Functional Expression of a Mammalian Odorant Receptor Science 279: 237-242.
  • Menini, A., Picco, C. and Firestein, S. (1995) Quantal-like current fluctuations induced by odorants in olfactory receptor cells Nature 373: 435-437.

Natalie Geld

Co-founder + Creative Director of mbSci, Natalie Geld is a writer, communications specialist, producer, and educator, and has spent much of her life fostering educational opportunities for activating vivid human potential. She researches the integral nature of energy and the relationship of science, consciousness, and our health.