BrautiganProfessor David Brautigan is a Professor of Microbiology, Immunology, and Cancer Biology and the Director for the Center for Cell Signaling at the University of Virginia School of Medicine. Professor Brautigan first received a B.A. in Chemistry from Kalamazoo College in Michigan. He then continued his academic career at Northwestern University, where he received an M.S. in Chemistry and Ph.D. in Biochemistry/Molecular Biology, and finished his Biochemistry postdoctoral fellowship at the University of Washington School of Medicine. Finally, he served as a Professor of Medical Science at Brown University for eight years, before coming to the University of Virginia for his current position in 1994. During his career, he has authored over 160 peer-reviewed publications. His research interests focus on examining the mechanism of action of protein phosphatases and their impact on cell growth, proliferation, movement and metabolism.

DeSimoneProfessor Douglas DeSimone is a Professor of Cell Biology and has been an Ivy Foundation Pratt Distinguished Professor of Morphogenesis at the University of Virginia since 1989. Professor DeSimone obtained his B.S in Life Sciences at the Worcester Polytechnic Institute. He then continued his academic career at Dartmouth College and obtained a Ph.D. in biology, and later went on to the Massachusetts Institute of Technology to finish his Postdoctoral Fellowship studying “cDNA cloning and characterization on the integrin beta1 subunit”. Afterwards, he became a professor at the University of Virginia and has published over 48 peer-reviewed publications to date. His research interests include examining cell adhesion and adhesion-dependent cell signaling in vertebrate morphogenesis.

Presentation

On Tuesday, February 4, Professors Brautigan and DeSimone gave their talk in the 1023-BEC Classroom in McKim Hall. Brautigan began the lecture by explaining that McKim hall was originally built in 1901 as a dormitory for nursing students and wasn’t re-appropriated for lectures and office space until the latter half of the century. After this interesting introduction to the lecture space, he began his formal presentation on “Molecular Transducers for Human Perception of the Physical World,” covering the senses of sight, smell, and taste. Brautigan specifically focused on the role that G-Protein Coupled Receptors (GPCRs) play in allowing us to perceive our world. Brautigan’s chemistry background influenced his overview of human senses which is depicted below in Figure 1. Initially, some form of a stimulus – such as a molecule for taste and smell, or a photon of light for sight – interacts with the GPCR that is located within the plasma membrane of the detection cell. Reception of the stimulus occurs through the specific GPCR for that stimulus. GPCRs have a unique genetically pre-determined structure, comprised of seven hydrophobic helices spanning the plasma membrane, which are connected by hydrophilic peptide chains on both sides. Despite a wide genetic variety, nearly all GPCRs have roughly the same helical structure and similar inner peptide chains, indicating that the specificity of each receptor is due to a variation in the peptide chains on the outside of the membrane. The GCPR can be thought of as a sandwich: the bread represents the helical structure which does not change; the meat is subject to a low degree of variability (chicken, turkey, beef, pork), representing the inner peptide chains; the rest of the toppings are highly variable and serve as the component that makes each sandwich unique, representing the outer peptide chains.  When the stimulus binds to the GCPR, it induces a conformational change in the structure of the protein, thereby configuring the inside peptide chains to allow a G-Protein to bind and start the transduction process.

Brautigan Figure 1

Transduction begins with the binding of the G-Protein, which is comprised of three subunits (Gα, Gβ, and Gγ). Once the G-Protein is bound, a GTP molecule (an energy source) binds to Gα and Gα disassociates from Gβγ. Both then can activate multiple secondary messengers such as cyclic-AMP (cAMP) which will dramatically increase the intensity of the signal and eventually result in the phosphorylation of other proteins. This phosphorylation causes changes in metabolism, gene activation, and protein synthesis, indirectly leading to neurotransmitter release. Because GCPRs are so important in a variety of cell functions, over 50% of all pharmaceuticals target GPCRs. Neurotransmitters then cause a signal to be sent to the brain via electrical conduction along nerves, whereby perception occurs. There can be multiple stimuli involved for a single overall perception (e.g. the smell of a strawberry is due to multiple molecular stimuli), and our brains recognize the pattern of all the stimuli, not each individually.

After Professor Brautigan’s talk, Professor DeSimone began his formal presentation on “Transduction of Mechanical Forces in Biological Systems”, which investigated how forces such as gravity, elongation, compression, sheer, and friction influenced biological structures.  His presentation began with gravitropism in plants, the directional growth of an organism in response to gravity.  Plant roots perceive gravity using statocytes, which determine the direction of gravity by sensing where the statoliths touch inside of the cell and ascertains which direction is “down.” Through chemical signal transduction, the statolith communicates that information to other parts of the root to direct growth. Consequently, the plant will incorporate varying levels of auxin to increase growth upwards against gravity.

Professor DeSimone then moved on to discuss the transduction of tympanic sound energy into mechanical energy, through which the sense of human hearing functions. He explained that sound hits the tympanic membrane, pulsating the malleus, incus, and stapes to cause movement of the basilar membrane, along which different pitches generate standing waves at different positions and stimulate the inner hair cells. Once the basilar membrane moves, it pulls the inner hair cells in a certain direction, allowing the potassium in the endolymph to flow into the hair cell and cause it to depolarize. As a result, sound becomes transduced into mechanical energy, which becomes transduced into electrical energy for neuronal activation.

Transduction serves to modulate a variety of biological processes seen in nature. With mechanical force being the primary stimulus, electrical and chemical processes can be instigated to respond to forces external to the biological system. Many connections can be drawn between physical action and energy. For example, otoconia are calcium carbonate crystals that are attached to the inner ear to help orient the body to the effects of motion and gravity. Similar to the statoliths in plants, the orientation of the otoliths will chemically transduce signals to the brain to help the body respond to the effects of motion and gravity, and let the person be aware of what is “up” or “down”.

More Information

Cell Signaling – Brautigan

Transduction of Mechanical Forces – Desimone

McKim Hall

McKim Hall

Response to Brautigan Presentation

A far cry from our first theory lecture, the analysis was certainly biased towards Brautigan’s chemistry-oriented background with a strict mechanism perspective. However, even looking at matter as inherently inert, as contrasted to Jane Bennett’s vital materialistic concepts of “vibrant matter,” can provide a useful strategy for discovering new relationships. These modes of analysis aren’t mutually exclusive, but instead, two sides of the same coin. While looking at any given side of the coin (mode of analysis), no one can ever see “the other side” of the coin, which in this case represents a conflicting mode of analysis. However, knowledge about each side certainly allows for a more complete understanding of the underlying processes and principles.

One of the biggest personal revelations from the lecture was how incredibly subjective our senses are based on the genetic variability between different human beings. It is theoretically possible that some people’s GPCRs for smell are so mutated, compared to some theoretical original, that they do not measure what they were originally intended. For instance, a ripe strawberry has around a dozen different molecules potentially responsible for our perception of its overall smell. One person might have the GCPRs for all twelve different molecules; another person might only be able to detect eight of the molecules. This means that each person’s experience of a strawberry is fundamentally different and explains why there are no “perfect” recipes. Each chef will tailor dishes to his/her preferences, which rely on the particular GCPRs they possess, as defined by their genetics. Following this, one can easily become awestruck at the sheer uniqueness and variety of the life of each and every person that has ever lived, while also becoming more tolerant of other people’s viewpoints and opinions.

Response to DeSimone Presentation

What stuck out to me was how organized these biological processes were. There is a clear methodology to how forces were being transduced to the various energies that communicated with each other. It was reminiscent of a previous reading, Hodder’s Entanglement, which explained how a substance or material can become entwined with another matter that affects us. Granted, when viewing from a micro-scale, it can be difficult to uncover the variety of factors that may lead to certain actions, such as listening or moving; however, once we follow these pathways, we can determine how a certain mechanism can influence our interpretation of reality. For example, the inner hair cells that transduce mechanical motion to interpret sound can also be used to interpret gravitational orientation in a person, varying only in the location of these inner hair cells. Consequently, when one investigates how these mechanisms operate, it is imperative to understand how they all interact with each other and ascertain what the grand picture is.

Mapping Connections:  Preliminary Sketches

Cell Signaling

Brautigan Map

Transduction of Mechanical Forces

photo 3 (1)

Report by Andrew Jones and William Park.

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