Müller Group

Interferometry for electron microscopy

Transmission electron microscopy (TEM) holds the potential to resolve many questions in life science by providing a close view of the molecular machinery of the cell. However, biological matter is mostly transparent to electron beams, making for poor image contrast. Although biological macromolecules are almost invisible in TEM, their structure is imprinted in the transmitted electron beam as small variations in the phase of the electron wave function.

Both electron microscopy and light microscopy face the problem of visualizing weak phase variations. In optical imaging, this has been solved by the introduction of Zernike phase contrast. In this method, a spatially selective phase retarder ("phase plate") is inserted in the beam path to induce a 90^o phase shift in the weak scattered wave relative to the strong unscattered wave. The interference between the phase-shifted scattered wave and the unscattered wave creates amplitude modulations, giving rise to a visible image.

Phase contrast imaging with an electron microscope requires creating an analogous phase plate for electron waves. However, most designs rely on material placed near the electron beam, which can be charged or damaged by the electron beam, causing unwanted wavefront aberrations or resolution loss.

We have implemented a radical solution to this problem, using a (world-record) high-intensity continuous-wave laser field configuration inside of a near-concentric Fabry-Perot optical cavity. This serves as a transparent, indestructible, controllable, and stable electron phase plate.

Our team is currently focused on exploring the benefits of laser phase contrast electron microscopy, and further developing the laser phase plate technology in concert with our new state-of-the-art aberration-corrected high-throughput transmission electron microscope. Such a realization of reliable phase contrast TEM is likely to bring about many discoveries in structural microbiology, and could lead to further applications for laser-based coherent control of the electron wave function.

Current or prospective graduate students interested in a research position should email Prof. Mueller and the team members listed below! Our multidisciplinary project is looking for those with interests in any of the following: electron microscopy, biophysics, laser optics, image analysis and machine learning, and molecular biology.

Team members

Jeremy Axelrod

Petar Petrov

Jessie Zhang

Jonathan Remis

Shahar Sandhaus

Publications

1. Modern approaches to improving phase contrast electron microscopy. Jeremy J. Axelrod, Jessie T. Zhang, Petar N. Petrov, Robert M. Glaeser, and Holger Müller. Current Opinion in Structural Biology 86 102805 and https://arxiv.org/abs/2401.11678 (2024).
2. Overcoming resolution loss due to thermal magnetic field fluctuations from phase plates in transmission electron microscopy. Jeremy J. Axelrod, Petar N. Petrov, Jessie T. Zhang, Jonathan Remis, Bart Buijsse, Robert M. Glaeser, and Holger Müller. Ultramicroscopy 249, 113730 (2023) and https://www.biorxiv.org/content/10.1101/2023.02.12.528160v1 (2023).
3. Perspective: Emerging strategies for determining atomic-resolution structures of macromolecular complexes within cells. Petar N. Petrov, Holger Müller, and Robert M. Glaeser. J. Struct. Biol. 214, 1, 107827 (2022).
4. High-Power Near-Concentric Fabry-Perot Cavity for Phase Contrast Electron Microscopy. Carter Turnbaugh, Jeremy J. Axelrod, Sara L. Campbell, Jeske Y. Dioquino, Petar N. Petrov, Jonathan Remis, Osip Schwartz, Zanlin Yu, Yifan Cheng, Robert M. Glaeser, Holger Müller. Review of Scientific Instruments 92, 053005 (2021) and arXiv:2012.08638 (2020).
5. Observation of the relativistic reversal of the ponderomotive potential. Jeremy J. Axelrod, Sara L. Campbell, Osip Schwartz, Carter Turnbaugh, Robert M. Glaeser, and Holger Mueller. Phys. Rev. Lett. 124, 174801 (2020) and arXiv:1910.14441 (2019).
6. Laser phase plate for transmission electron microscopy. Osip Schwartz, Jeremy J. Axelrod, Sara L. Campbell, Carter Turnbaugh, Robert M. Glaeser, and Holger Müller. Nat. Methods 16, 1016-1020 (2019) and arXiv:1812.04596 (2018).
7. Near-concentric Fabry-Pérot cavity for continuous-wave laser control of electron waves. Osip Schwartz, Jeremy J. Axelrod, Daniel R. Tuthill, Philipp Haslinger, Colin Ophus, Robert M. Glaeser, and Holger Müller. Opt. Express 25, 14453-14462 (2017) and arXiv:1610.08493.
8. Design of an electron microscope phase plate using a focused continuous-wave laser. Holger Müller, Jian Jin, Radostin Danev, John Spence, Howard Padmore, and Robert Glaeser, New J. of Physics 12, 073011 (2010) and arXiv:1002.4237.