Prof. Matthew Shoulders
Title: Continuous Evolution in Complex Living Systems
Bio:
Matt Shoulders pursued undergraduate studies at Virginia Tech, receiving a B.S. in Chemistry in 2004. He earned his Ph.D. in Chemistry from the University of Wisconsin–Madison in 2009, advised by Prof. Ronald Raines. Following an American Cancer Society Postdoctoral Fellowship with Profs. Jeffery Kelly and Luke Wiseman at the Scripps Research Institute in La Jolla, California, Shoulders joined the MIT Department of Chemistry as an Assistant Professor in 2012, earning tenure in 2019 and promotion to full Professor in 2022. At MIT, he is now the Class of 1942 Professor of Chemistry and Department Head.
The Shoulders Laboratory is interested in (1) understanding how cells fold proteins and (2) using the tools of evolution to elucidate proteostasis and develop next-generation biomolecules with important applications in medicine and agriculture. Prof. Shoulders has received numerous awards recognizing his lab’s work, including the National Institutes of Health Director’s New Innovator Award, the National Science Foundation CAREER Award, and the Camille Dreyfus Teacher-Scholar Award. He was also named an American Cancer Society Research Scholar and the 56th Edward Mallinckrodt Jr. Foundation Faculty Scholar. Most recently, Prof. Shoulders received the Ono Pharma Foundation’s Breakthrough Science Award. Shoulders has also received MIT’s Committed to Caring Award for Outstanding Graduate Student Mentoring, MIT’s highest honor for mentorship. He was named a MacVicar Faculty Fellow in 2022, MIT’s leading teaching award recognizing outstanding and sustained contributions to undergraduate education.
Abstract:
A key limitation of all directed evolution workflows performed in test tubes, Escherichia coli, or yeast is that these approaches often yield products that fail to function when introduced into relevant settings, such as valuable bacterial species, plants, and especially mammalian cells. Instead, functions evolved in other or simpler systems are often derailed in more complex environments by off-target interactions, poor stability, inappropriate modification/localization, or many other serious problems. This frontier challenge could theoretically be addressed by always leveraging the relevant cell system itself as the design, engineering, and quality control factory for biomolecule discovery and optimization. With these challenges in mind, we developed the first broadly applicable and efficient system for continuous directed evolution directly in living mammalian cells. In our approach, termed Mammalian cell-enabled, Adenovirus-mediated Continuous Evolution (MACE), the ability of a highly error-prone, gutted adenovirus to propagate is coupled to the activity of a biomolecule of interest within the human cell itself. The system is designed for safety, speed, and ease-of-use. Critically, mutagenesis, selection, and amplification all occur concurrently in this platform, maximizing the benefits of natural selection and the throughput of protein engineering campaigns. I will discuss recent progress in the application of mammalian cell-based continuous directed evolution to develop novel genome engineering tools (e.g., Cas proteins). I will also discuss the development of advanced targeted mutagenesis techniques based on our MutaT7 platform, which can enable continuous directed evolution in many diverse cell and in vivo settings. MutaT7 was most recently used by us to drive improvement of the catalytic properties of one of the world’s fastest known Rubisco enzymes.
Keywords: Protein evolution, biotechnology, directed evolution, genome engineering
Host: Prof. Tina Wang