Professor of Chemistry
Adjunct Professor of Physics
Ph.D. Princeton University, 1995
(Biophysics and Physical Chemistry)
Our group investigates a broad array of problems involving self-assembly, complex fluids, and soft matter systems, with an emphasis on lipid membrane biophysics. Below are vignettes of only four of our research topics, followed by general descriptions of our group and techniques. To learn about other projects in our lab, click on the link above for “Keller group website” to access a full list of publications.
RESEARCH VIGNETTE 1: Phase separation in yeast membranes (BJ 2017)
For decades, scientists have argued about the mechanism by which cell membranes acquire and maintain regions enriched in particular lipid and protein types. These regions are thought to influence essential cellular processes of signal transduction and protein sorting. One of the more contentious theories has been that membrane lipids and proteins can spontaneously phase separate to create regions that differ in their composition. In this project, we teamed up with Prof. Alex Merz to image vacuoles, a yeast organelle. First, we discovered that domains in vacuole membranes can merge quickly, consistent with fluid phases, just as droplets in a recently-shaken oil and vinegar dressing quickly coalesce when they collide. Next, we discovered that vacuole domains reversibly disappear above a transition temperature and reappear below that same temperature over multiple heating and cooling cycles. Our results proved for the first time that large-scale organization within membranes of living cells under normal physiological conditions can be driven by reversible phase separation.
RESEARCH VIGNETTE 2: The strength of interleaflet coupling (BJ 2015)
Signaling across cell membranes can involve co-localization of lipids and proteins on both sides of the membrane. This project was inspired by our surprising discovery that liquid domains in one leaflet of a planar bilayer induce domains in an apposed leaflet that would not phase separate on its own (PNAS 2008). That discovery implied that the interleaflet coupling, which is the energy to maintain liquid domains in one membrane leaflet in registration with domains in the opposite leaflet, is high. Our results motivated predictions of the value of the interleaflet coupling parameter. Here, we constructed microfluidic chambers in which we sheared supported bilayers in order to make the first measurement of this fundamental physical parameter. Our result was consistent with one prediction, ruled out other theories, limited the parameter space for models, and may help explain how lipid organization is communicated across cell membranes.
RESEARCH VIGNETTE 3: Origins of Life (PNAS 2013)
A predominant hypothesis regarding how life arose on the young Earth is that the earliest primordial cells consisted of simple fatty acid vesicles encapsulating RNA. Here, we addressed three fundamental questions: 1) How were nucleobases concentrated in aqueous pools to form RNA? 2) How were the four bases in RNA selected from a heterogeneous environment? 3) How were fatty acid vesicles stabilized against flocculation in the salty environments of Earth’s early oceans? Addressing the first two questions, we found that micelles of decanoic acid, a prebiotic fatty acid, bind nucleobases better than most related bases. Addressing the third question, we found that the same bases that bind to decanoic acid micelles stabilize vesicles by inhibiting flocculation. Moreover, the sugar in RNA, ribose, inhibited flocculation better than its stereoisomer, xylose. Our results are exciting because mutually reinforcing mechanisms of bases and sugars binding to fatty acid aggregates, followed by stabilization of vesicles, could have driven the emergence of protocells.
RESEARCH VIGNETTE 4: Dynamic critical exponents (PRL 2012)
Here we measured a universal physical constant governing time scales of critical correlations. This constant had eluded experimental assessment for over 30 years, despite careful attempts. Our measurement is important because time-dependent critical phenomena are well studied except in systems that have the same constraints as lipid bilayers. Specifically, we were the first to accomplish the longstanding goal of measuring the correct dynamic critical exponent of a 2D Ising system with conserved order parameter. We found excellent agreement with the predicted value of the exponent. Our measurement is relevant to biology because other groups have found that membranes derived from intact cell membranes exhibit critical fluctuations.
TECHNIQUES: To tackle the interdisciplinary subjects above, group members come from a range of backgrounds (e.g. physical chemistry, physics, biophysics, and bioengineering) and they earn degrees in a variety of fields. Work in the lab is problem-driven rather than technique-driven, so group members acquire whatever skills are necessary. We collaborate closely with biochemists, and we meet weekly with theory and simulation experts to ensure that our experimental results have strong theoretical foundations (at this time, the group supports no members who conduct solely theory or simulation work). Our group benefits from close proximity to the UW NanoTech User Facility, the UW NNIN Nanofabrication Facility, the UW NESAC/BIO User Facility, and UW Chemistry spectroscopy facilities (mass spec, NMR, and UV/Vis) and machine shops.
OUR GROUP: Graduate students and postdocs in the Keller group have written successful NSF, NIH, NASA, and Bettencourt fellowship proposals. They have won national and international awards including the Anna Louise Hoffman Award, the Skinner Prize, Biophysical Society SRAA Awards, Lindau Fellowships, and multiple travel grants. UW has recognized Ph.D. theses in the Keller Group with the Arts & Sciences Dean’s Medal, the Graduate School’s Distinguished Dissertation Award, and the Karrer Prize in Physics.
"Hallmarks of Reversible Separation of Living, Unperturbed Cell Membranes into Two Liquid Phases" S.P. Rayermann et al., Biophys. J. 2017, 113, 2425-2432.
"n-Alcohol Length Governs Shift in Lo-Ld Mixing Temperatures in Synthetic and Cell-Derived Membranes" C.E. Cornell, et al., Biophys. J, 2017, 113, 1200-1211.
“Transbilayer Colocalization of Lipid Domains Explained via Measurement of Strong Coupling Parameters” M.C. Blosser, et al., Biophys. J., 2015, 109, 2317-2327. (Cover article).
“Nucleobases bind to and stabilize aggregates of a prebiotic amphiphile, providing a viable mechanism for the emergence of protocells” R.A Black et al., PNAS, 2013, 110, 13272-13276.
“Experimental Observations of Dynamic Critical Phenomena in a Lipid Membrane” A.R. Honerkamp-Smith et al., Phys. Rev. Lett., 2012, 108, 165702.
REVIEW: “Seeing Spots: Complex Phase Behavior in Simple Membranes” S.L. Veatch & S.L. Keller, Biochim. Biophys. Acta (Invited), 2005, 1746, 172-185.