Stephen Fried is a native of Kansas City. He received two S.B. degrees (2009) from MIT in chemistry and physics and completed his doctoral training at Stanford under the mentorship of Prof. S. G. Boxer in 2014. As a graduate student, Stephen's research focused on understanding the physical principles underpinning enzymes’ great catalytic power. From 2014 to 2018, Stephen was a Junior Research Fellow of King’s College and conducted research at the MRC Laboratory of Molecular Biology in Cambridge, United Kingdom. In Cambridge, Stephen’s research focus shifted to chemical and synthetic biology. His post-doctoral work led to the co-invention of the stapled ribosome, the discovery of many new orthogonal tRNA-synthetase pairs for genetic code expansion, and the first systematic investigation of tRNA decoding patterns in vivo. Stephen will join the Department of Chemistry in 2018 as an assistant professor.
Our lab is interested in elucidating how proteins fold and assemble into complex molecular assemblies in their native cellular context, as well as developing approaches to reprogram and exploit these mechanisms to direct the synthesis of protein materials. The goals of these two lines of research are to uncover mechanisms behind genetic diseases, aging, and cancer, and to create the foundation for a sustainable biologically-derived material culture in the future.
(1) The vast majority of proteins are not reversibly re-foldable, implying that the kinetics of protein synthesis on the ribosome play important – but poorly understood – roles in helping proteins find their native state. Moreover, these co-translational processes are indispensable for cells to construct complex molecular machines, which Nature oftentimes achieves with perfect efficiency. To obtain structural snapshots of protein folding intermediates inside living cells, we combine cross-linking with mass spectrometry. These methods allow structural information to get “frozen” into protein molecules through covalent bonds, which can subsequently be read out with mass spectrometry and other biochemical techniques. These studies are additionally motivated by our desire to establish molecular mechanisms behind genetic diseases caused by synonymous mutations (e.g., haemophilia, cystic fibrosis), maintenance of proteostasis, and some cancers.
(2) On a second loosely-related front, we are interested in reprogramming ribosomal translation and the protein export machinery to synthesize protein-based materials. The goal is to optimize these molecular machines so that communities of microbes can cooperate to ‘nanolathe’ macroscopic objects of defined structure and composition, and which in turn can be readily decomposed into molecular building blocks. To achieve this, we evolve ribozymes that can manipulate messenger RNA and ribosomes during translation, enabling the execution of loops and dynamic controls elements during protein synthesis. This control of translation will facilitate the synthesis, and ultimately the evolution, of complex fibrous proteins with hierarchical structures. This project is aimed at harnessing the considerable developments in synthetic biology toward addressing pressing environmental concerns.