Brendan Marsh is a Ph.D. candidate in Professor Benjamin Lev’s research group at Stanford University. He investigates light-matter interactions in many-body quantum systems and explores their use as a computational resource. His work more generally includes experimental quantum optics and theoretical methods to describe open quantum systems. He received a master’s degree in applied mathematics and theoretical physics from the University of Cambridge in 2018 and a B.S. in physics and mathematics from the University of Missouri in 2017.
Besides quantum optics and computation, Brendan has worked on problems in the philosophy of quantum theory (with Jeremy Butterfield at the University of Cambridge) and single molecule biophysics (with Gavin King at the University of Missouri). Along with Gavin King, he invented the Hessian blob algorithm, a general-purpose machine vision algorithm which is finding applications in fields ranging from scanning probe microscopy to medical imaging.
Honors & Awards
Q-FARM Fellowship, Stanford University (2021)
2018 Mark Twain Fellow, University of Missouri (2018)
NSF Graduate Research Fellowship, National Science Foundation (2017)
German DAAD RISE Scholar, DAAD (2016)
Barry M. Goldwater National Scholarship, Barry Goldwater Foundation (2015)
NSF Research Experience for Undergraduates, SRI International (2015)
Discovery Fellow, University of Missouri Honor's College (2013-2014)
Education & Certifications
Part III Mathematical Tripos, University of Cambridge, Applied Mathematics and Theoretical Physics (2018)
BS in Physics and Mathematics, University of Missouri, Double Major in Physics and Mathematics; Minor in Computer Science (2017)
Brendan Marsh, Gavin King. "United States Patent Application: 62/793,596 Hessian Blob Algorithm", University of Missouri
Visiting Scholar, University of Missouri (7/1/2018 - 9/7/2018)
University of Missouri
- Enhancing Associative Memory Recall and Storage Capacity Using Confocal Cavity QED PHYSICAL REVIEW X 2021; 11 (2)
The Hessian Blob Algorithm: Precise Particle Detection in Atomic Force Microscopy Imagery
2018; 8: 978
Imaging by atomic force microscopy (AFM) offers high-resolution descriptions of many biological systems; however, regardless of resolution, conclusions drawn from AFM images are only as robust as the analysis leading to those conclusions. Vital to the analysis of biomolecules in AFM imagery is the initial detection of individual particles from large-scale images. Threshold and watershed algorithms are conventional for automatic particle detection but demand manual image preprocessing and produce particle boundaries which deform as a function of user-defined parameters, producing imprecise results subject to bias. Here, we introduce the Hessian blob to address these shortcomings. Combining a scale-space framework with measures of local image curvature, the Hessian blob formally defines particle centers and their boundaries, both to subpixel precision. Resulting particle boundaries are independent of user defined parameters, with no image preprocessing required. We demonstrate through direct comparison that the Hessian blob algorithm more accurately detects biomolecules than conventional AFM particle detection techniques. Furthermore, the algorithm proves largely insensitive to common imaging artifacts and noise, delivering a stable framework for particle analysis in AFM.
View details for DOI 10.1038/s41598-018-19379-x
View details for Web of Science ID 000422716900112
View details for PubMedID 29343783
View details for PubMedCentralID PMC5772630
An optical lattice with sound.
2021; 599 (7884): 211-215
Quantized sound waves-phonons-govern the elastic response of crystalline materials, and also play an integral part in determining their thermodynamic properties and electrical response (for example, by binding electrons into superconducting Cooper pairs)1-3. The physics of lattice phonons and elasticity is absent in simulators of quantum solids constructed of neutral atoms in periodic light potentials: unlike real solids, traditional optical lattices are silent because they are infinitely stiff4. Optical-lattice realizations of crystals therefore lack some of the central dynamical degrees of freedom that determine the low-temperature properties of real materials. Here, we create an optical lattice with phonon modes using a Bose-Einstein condensate (BEC) coupled to a confocal optical resonator. Playing the role of an active quantum gas microscope, the multimode cavity QED system both images the phonons and induces the crystallization that supports phonons via short-range, photon-mediated atom-atom interactions. Dynamical susceptibility measurements reveal the phonon dispersion relation, showing that these collective excitations exhibit a sound speed dependent on the BEC-photon coupling strength. Our results pave the way for exploring the rich physics of elasticity in quantum solids, ranging from quantum melting transitions5 to exotic 'fractonic' topological defects6 in the quantum regime.
View details for DOI 10.1038/s41586-021-03945-x
View details for PubMedID 34759361
Precision Analysis of Drug-Induced Conformational Changes of P-Glycoprotein Observed in AFM
CELL PRESS. 2021: 303A
View details for Web of Science ID 000629601401714
Atomic Force Microscopy Reveals Membrane Protein Activity at the Single Molecule Level.
Methods in molecular biology (Clifton, N.J.)
2021; 2302: 81–99
Atomic force microscopy has emerged as a valuable complementary technique in membrane structural biology. The apparatus is capable of probing individual membrane proteins in fluid lipid bilayers at room temperature with spatial resolution at the molecular length scale. Protein conformational dynamics are accessible over a range of biologically relevant timescales. This chapter presents methodology our group uses to achieve robust AFM image data of the General Secretory system, the primary pathway of protein export from the cytoplasm to the periplasm of E. coli. Emphasis is given to measuring and maintaining biochemical activity and to objective AFM image processing methods. For example, the biochemical assays can be used to determine chemomechanical coupling efficiency of surface adsorbed translocases. The Hessian blob algorithm and its extension to nonlocalized linear features, the line detection algorithm, provide automated feature delineations. Many of the methods discussed here can be applied to other membrane protein systems of interest.
View details for DOI 10.1007/978-1-0716-1394-8_6
View details for PubMedID 33877624
Direct visualization of the E. coli Sec translocase engaging precursor proteins in lipid bilayers.
2019; 5 (6): eaav9404
Escherichia coli exports proteins via a translocase comprising SecA and the translocon, SecYEG. Structural changes of active translocases underlie general secretory system function, yet directly visualizing dynamics has been challenging. We imaged active translocases in lipid bilayers as a function of precursor protein species, nucleotide species, and stage of translocation using atomic force microscopy (AFM). Starting from nearly identical initial states, SecA more readily dissociated from SecYEG when engaged with the precursor of outer membrane protein A as compared to the precursor of galactose-binding protein. For the SecA that remained bound to the translocon, the quaternary structure varied with nucleotide, populating SecA2 primarily with adenosine diphosphate (ADP) and adenosine triphosphate, and the SecA monomer with the transition state analog ADP-AlF3. Conformations of translocases exhibited precursor-dependent differences on the AFM imaging time scale. The data, acquired under near-native conditions, suggest that the translocation process varies with precursor species.
View details for DOI 10.1126/sciadv.aav9404
View details for PubMedID 31206019
View details for PubMedCentralID PMC6561738
- Non-locality and quasiclassical reality in Kent's formulation of relativistic quantum theory Journal of Physics: Conference Series 2019
Single-molecule observation of nucleotide induced conformational changes in basal SecA-ATP hydrolysis
2018; 4 (10): eaat8797
SecA is the critical adenosine triphosphatase that drives preprotein transport through the translocon, SecYEG, in Escherichia coli. This process is thought to be regulated by conformational changes of specific domains of SecA, but real-time, real-space measurement of these changes is lacking. We use single-molecule atomic force microscopy (AFM) to visualize nucleotide-dependent conformations and conformational dynamics of SecA. Distinct topographical populations were observed in the presence of specific nucleotides. AFM investigations during basal adenosine triphosphate (ATP) hydrolysis revealed rapid, reversible transitions between a compact and an extended state at the ~100-ms time scale. A SecA mutant lacking the precursor-binding domain (PBD) aided interpretation. Further, the biochemical activity of SecA prepared for AFM was confirmed by tracking inorganic phosphate release. We conclude that ATP-driven dynamics are largely due to PBD motion but that other segments of SecA contribute to this motion during the transition state of the ATP hydrolysis cycle.
View details for DOI 10.1126/sciadv.aat8797
View details for Web of Science ID 000449221200043
View details for PubMedID 30397644
View details for PubMedCentralID PMC6200364
The conformation and dynamics of P-glycoprotein in a lipid bilayer investigated by atomic force microscopy.
The membrane-bound P-glycoprotein (Pgp) transporter plays a major role in human disease and drug disposition because of its ability to efflux a chemically diverse range of drugs through ATP hydrolysis and ligand-induced conformational changes. Deciphering these structural changes is key to understanding the molecular basis of transport and to developing molecules that can modulate efflux. Here, atomic force microscopy (AFM) is used to directly image individual Pgp transporter molecules in a lipid bilayer under physiological pH and ambient temperature. Analysis of the Pgp AFM images revealed "small" and "large" protrusions from the lipid bilayer with significant differences in protrusion height and volume. The geometry of these "small" and "large" protrusions correlated to the predicted extracellular (EC) and cytosolic (C) domains of the Pgp X-ray crystal structure, respectively. To assign these protrusions, simulated AFM images were produced from the Pgp X-ray crystal structures with membrane planes defined by three computational approaches, and a simulated 80 Å AFM cantilever tip. The theoretical AFM images of the EC and C domains had similar heights and volumes to the "small" and "large" protrusions in the experimental AFM images, respectively. The assignment of the protrusions in the AFM images to the EC and C domains was confirmed by changes in protrusion volume by Pgp-specific antibodies. The Pgp domains showed a considerable degree of conformational dynamics in time resolved AFM images. With this information, a model of Pgp conformational dynamics in a lipid bilayer is proposed within the context of the known Pgp X-ray crystal structures.
View details for DOI 10.1016/j.bcp.2018.08.017
View details for PubMedID 30121251
Conformations and Dynamic Transitions of a Melittin Derivative That Forms Macromolecule-Sized Pores in Lipid Bilayers
2018; 34 (28): 8393–99
Systematically evolved from the primary active component of bee venom, MelP5 is a lipophilic peptide with important physical properties that differ from wild-type melittin, including the ability to create large equilibrium pores in lipid bilayers at low peptide to lipid ratios. Self-assembly into stable membrane spanning pores makes MelP5 a promising candidate for future applications in the pharmaceutical arena. Despite significant interest, little is known about the mechanism by which MelP5 remodels the lipid bilayer upon binding. We demonstrate by direct atomic force microscope imaging of supported lipid bilayers in solution that MelP5 remodels 1-palmitoyl-2-oleoyl- sn-glycero-3-phosphocholine (POPC) in one of two ways. It creates either highly localized voids in the bilayer or diffuse nonlocalized thinning. Thinning of the bilayer was measured to be 3.0 ± 1.4 Å (mean ± standard deviation) below the surface of the upper leaflet of the bilayer. Pores, defined as highly localized voids in the bilayer, exhibited several sizes. Approximately 20% of pores exhibited large footprint areas (47 ± 20 nm2) which appear capable of passing bulky macromolecules. The peptide-effected bilayer was observed to reversibly exchange between membrane-thinned and pore states in an apparent dynamic equilibrium. Analysis of time-lapsed images suggested upper and lower bounds (0.2 < τ < 180 s) on the characteristic time scale of transitions between the membrane-thinned and pore states. Moreover, pores were found to colocalize with membrane-thinned regions, a novel observation that is consistent with the notion of cooperativity among membrane-bound peptides when forming pores.
View details for DOI 10.1021/acs.langmuir.8b00804
View details for Web of Science ID 000439398100029
View details for PubMedID 29933696
Quaternary Structure of Small Amino Acids Transporter OprG of Pseudomonas aeruginosa
CELL PRESS. 2018: 236A–237A
View details for Web of Science ID 000430439600432
Depictions of Quantum Reality in Kent's Interpretation of Quantum Theory
At present, quantum theory leaves unsettled which quantities ontologically, physically exist in a quantum system. Do observables such as energy and position have meaningful values only at the precise moment of measurement, as in the Copenhagen interpretation? Or is position always definite and guided by the wave function, as in de Broglie-Bohm pilot wave theory? In the language of Bell, what are the "beables" of quantum theory and what values may they take in space and time? This is the quantum reality problem. A definitive answer requires not just describing which physical quantities exist in a quantum system, but describing what configurations of those quantities in space and time are allowed, and with what probability those configurations occur. Adrian Kent sets out a new vision of quantum theory along these lines. His interpretation supplements quantum theory to infer the value of physical quantities in spacetime from the asymptotic late-time behavior of the quantum system. In doing so, a Lorentz-covariant and single-world solution to the quantum reality problem is achieved. In this paper, the framework of Kent's interpretation is presented from the ground up. After a broad overview, a derivation of the generalized Aharonov-Bergmann-Lebowitz (ABL) rule is provided before applying Kent's interpretation to toy model systems, in both relativistic and non-relativistic settings. By adding figures and discussion, a broad introduction is provided to Kent's proposed interpretation of quantum theory.
Single-Molecule Peptide-Lipid Affinity Assay Reveals Interplay between Solution Structure and Partitioning
2017; 33 (16): 4057–65
Interactions between short protein segments and phospholipid bilayers dictate fundamental aspects of cellular activity and have important applications in biotechnology. Yet, the lack of a suitable methodology for directly probing these interactions has hindered the mechanistic understanding. We developed a precision atomic force microscopy-based single-molecule force spectroscopy assay and probed partitioning into lipid bilayers by measuring the mechanical force experienced by a peptide. Protein segments were constructed from the peripheral membrane protein SecA, a key ATPase in bacterial secretion. We focused on the first 10 amino-terminal residues of SecA (SecA2-11) that are lipophilic. In addition to the core SecA2-11 sequence, constructs with nearly identical chemical composition but with differing geometry were used: two copies of SecA2-11 linked in series and two copies SecA2-11 linked in parallel. Lipid bilayer partitioning interactions of peptides with differing structures were distinguished. To model the energetic landscape, a theory of diffusive barrier crossing was extended to incorporate a superposition of potential barriers with variable weights. Analysis revealed two dissociation pathways for the core SecA2-11 sequence with well-separated intrinsic dissociation rates. Molecular dynamics simulations showed that the three peptides had significant conformational differences in solution that correlated well with the measured variations in the propensity to partition into the bilayer. The methodology is generalizable and can be applied to other peptide and lipid species.
View details for DOI 10.1021/acs.langmuir.7b00100
View details for Web of Science ID 000400232500018
View details for PubMedID 28343391
Transient Collagen Triple Helix Binding to a Key Metalloproteinase in Invasion and Development
2015; 23 (2): 257–69
Skeletal development and invasion by tumor cells depends on proteolysis of collagen by the pericellular metalloproteinase MT1-MMP. Its hemopexin-like (HPX) domain binds to collagen substrates to facilitate their digestion. Spin labeling and paramagnetic nuclear magnetic resonance (NMR) detection have revealed how the HPX domain docks to collagen I-derived triple helix. Mutations impairing triple-helical peptidase activity corroborate the interface. Saturation transfer difference NMR suggests rotational averaging around the longitudinal axis of the triple-helical peptide. Part of the interface emerges as unique and potentially targetable for selective inhibition. The triple helix crosses the junction of blades I and II at a 45° angle to the symmetry axis of the HPX domain, placing the scissile Gly∼Ile bond near the HPX domain and shifted ∼25 Å from MMP-1 complexes. This raises the question of the MT1-MMP catalytic domain folding over the triple helix during catalysis, a possibility accommodated by the flexibility between domains suggested by atomic force microscopy images.
View details for DOI 10.1016/j.str.2014.11.021
View details for Web of Science ID 000349402500005
View details for PubMedID 25651059
View details for PubMedCentralID PMC4317567
- Glass: A Multi-Platform Specimen Supporting Substrate for Precision Single Molecule Studies of Membrane Proteins CELL PRESS. 2015: 170A
Atomic Force Microscopy of Protein Translocation Machinery in Supported Lipid Bilayers
CELL PRESS. 2015: 168A
View details for Web of Science ID 000362849100051