08. Domitilla Del Vecchio: A control Systems Approach to Cell Fate Reprogramming

Abstract. Today, reprogramming the fate of human cells is becoming possible thanks to remarkable advances in genetic engineering. A future in which an individual's cells are reprogrammed to any cell in need to repair damaged tissues does not seem that far away. A critical capability to achieve the required efficiency in target cell generation and acceptable quality of these cells is accurate control of the concentration of specific proteins that drive the fate of a cell. Unfortunately, this capability has been a major bottleneck in the stem cell field. In the past decade, however, advances in engineering biology have reached a place where we can implement nonlinear controllers to regulate the cellular level of key molecular players. In this talk, I will describe critical challenges to accurate control of protein levels inside the cell and will show how overcoming these is a classical disturbance rejection problem. I will introduce designs of quasi-integral feedback and feed-forward controllers in mammalian cells to achieve set-point regulation robustly to disturbances. Finally, I will show some of our controllers in action both as a means to uncover optimal trajectories conducive to pluripotent stem cells and as a tool to enforce more accurately optimal transcription factor levels during pluripotent stem cell reprogramming. This is the first instance in which biomolecular controllers are used for cell fate reprogramming. With this work, we hope to have set the foundations for future research on engineering sophisticated biomolecular networks as controllers of complicated biological processes.
Bio. Domitilla Del Vecchio received the Ph. D. degree in Control and Dynamical Systems from the California Institute of Technology, Pasadena, and the Laurea degree in Electrical Engineering (Automation) from the University of Rome at Tor Vergata in 2005 and 1999, respectively. From 2006 to 2010, she was an Assistant Professor in the Department of Electrical Engineering and Computer Science and in the Center for Computational Medicine and Bioinformatics at the University of Michigan, Ann Arbor. In 2010, she joined the Department of Mechanical Engineering at the Massachusetts Institute of Technology (MIT), where she is currently the Grover M. Hermann Professor in Health Sciences and Technology and a Professor of Mechanical and Biological Engineering. She was awarded a 2024 Vannevar Bush Faculty Fellowship, she is a Fellow of the International Federation of Automatic Control (2022), an IEEE Fellow (2021), a recipient of the Newton Award for Transformative Ideas during the COVID-19 Pandemic (2020), the 2016 Bose Research Award (MIT), the Donald P. Eckman Award from the American Automatic Control Council (2010), the NSF Career Award (2007), the American Control Conference Best Student Paper Award (2004), and the Bank of Italy Fellowship (2000). Her research focuses on developing modeling and biological engineering techniques to understand and control the behavior of genetic circuits in bacterial and mammalian cells. Her lab is particularly interested in applications to biosensing and regenerative medicine.