Single-cell proteomics

This project is directed toward implementing massively multiplexed arrays of microscale electrostatic traps (µESTs) to provide single-peptide / sub-single-charge resolution for high-throughput, bottom-up proteomic analysis. Our goal is to enable fast («1h) and deep profiling of the entire single-mammalian-cell proteome, which comprises ~3B proteins distributed amongst ~15K different basic protein types.

This work is being carried out in close partnerships with the groups of Dr. Alexander Makarov at Thermo Fisher Scientific (Bremen, Germany), Prof. Selim Hanay at Bilkent University (Ankara, Turkey), Prof. Ken Shepard at Columbia University, and with a team at FlexRadio Systems (Steve Hicks, CTO). At Caltech, our übergroup includes Dr. Jeff Jones (project lead, scProteomics; senior bioinformatician), Prof. John Sader (lead; theory & computation) and Prof. Tsui-Fen Chou (lead; proteomics) along with her team in Caltech's Proteome Exploration Laboratory.

We are grateful for support for these efforts from the Wellcome Leap Foundation through its Delta Tissue program, and from the National Science Foundation.

Single-molecule native mass spectrometry of large, intact proteins and protein complexes

This work is directed toward multi-physical, top-down analysis of large, intact proteins (>100KDa) and protein complexes (>1MDa) via arrays of ultrasensitive nanoelectromechanical systems (NEMS).

This work is being carried out in close partnerships with the groups of Prof. Amir Safavi-Naeini at Stanford (who've developed exceptional phononic-crystal-isolated piezoelectric NEMS for these efforts), Prof. Selim Hanay at Bilkent University (Ankara, Turkey), and Dr. Alexander Makarov at Thermo Fisher Scientific (Bremen, Germany), and with a team at FlexRadio Systems (Steve Hicks, CTO.)

We are grateful for support for these efforts from the Wellcome Leap Foundation through its Delta Tissue program, from the National Institute of Health, through its Director's Transformative Research Award Program, and from the National Science Foundation.

Spatial proteomics

This work is directed toward realization, optimization, and application of a new form of mass spectrometry with unprecedented spatial resolution to enable imaging and identification of proteins in cells and tissues with sub-cellular precision and single-molecule resolution.

This work is being carried out in close partnerships with the groups of Dr. Alexander Makarov at Thermo Fisher Scientific (Bremen, Germany); Prof. Julia Laskin, Analytical Chemistry, Purdue University; Prof. Ken Shepard at Columbia University; Prof. Amir Safavi-Naeini at Stanford; and with a team at FlexRadio Systems (Steve Hicks, CTO.) At Caltech, our übergroup includes Prof. John Sader (lead; theory and computation), Dr. Jeff Jones (lead; bioinformatics), and Prof. Tsui-Fen Chou (lead; proteomics) and her team in Caltech's Proteome Exploration Laboratory.

We are grateful for support for these efforts from the National Institute of Health, through its Director's Transformative Research Award Program.

"Listening to molecules"

This work is focused on implementing and utilizing novel, single-quantum methods based on quantum acoustics for interrogating individual macromolecules at ultralow (mK) temperatures to elucidate their internal nonlinear quantum dynamics. To implement this work, we have developed custom ion optics that provide single-analyte transport and delivery to a specially-configured, cryogen-free horizontal dilution refrigerator housing state-of-the-art NEMS arrays operating from several GHz to >100 GHz. An overarching goal of this work is to understand the nonlinear dynamical cascades within large proteins that lead to internal energy downconversion and energy delocalization -- to ultimately induce wholesale molecular conformational changes that are fundamental to allostery.

This work is being carried out in close partnerships with the group of Prof. Amir Safavi-Naeini at Stanford, and with theoreticians Prof. Mark Dykman, Physics, MSU, and Prof. Rob Phillips, Biophysics & Molecular Biology, Caltech. Rob has recently written a wonderful book on allostery, "The Molecular Switch" (Princeton University Press, 2020).

We are grateful for support for these efforts from the Gordon and Betty Moore Foundation through its quantum imaging program.

Fundamental physics and applications of nanoscale systems

Through large-scale integration, we are exploring new physics with nanoscale systems and are engineering novel realizations of nanoscale sensor arrays to provide advanced levels of functional complexity and performance. These efforts include exploration of: alternate forms of novel nanoscale computational logic gates (bits)... including simultaneous measurements of their underlying dynamics and energetics, nanoelectromechanical systems (NEMS) based nonlinear oscillator networks and their complex synchronization dynamics, and new forms of highly-responsive nanoscale sensing.

Our collaborators in these efforts include the groups of Prof. Jim Crutchfield at UC Davis, Prof. Philip Feng at the University of Florida, Prof. Hong Tang at Yale University, Prof. Silvan Schmid at TU Wien (Vienna, Austria), Prof. Selim Hanay at Bilkent University (Ankara, Turkey), Prof. Guillermo Villanueva at EPFL (Lausanne, Switzerland), Prof. Jukka Pekola at Aalto University (Helsinki, Finland), and Prof. Amir Safavi-Naeini at Stanford University.
Driving complementary theoretical efforts along with Prof. Crutchfield are Prof. Mark Dykman, Physics, MSU, and Prof. John Sader, Caltech.

We are grateful for support for these efforts from the Army Research Office's Complex Dynamics and Systems program, the DARPA OpTIm program, and the DARPA NaPSAC program.