B.S. Bioengineering University of California, Berkeley, 2004
Ph.D. Massachusetts Institute of Technology, 2009
Honors and Awards
- NSF CAREER Award, 2018-2023
- NIH New Innovator Award, 2016-2021
- Cancer Research Institute fellow, 2010-2013
- MIT Presidential fellow, 2004
- UC Berkeley Regents' scholar, 2000
- Assistant Professor, Molecular Biology
- Associated Faculty, Department of Chemical and Biological Engineering
- Associated Faculty, Lewis-Sigler Institute for Integrative Genomics
The Toettcher lab focuses on understanding and controlling the signaling pathways that drive complex cell decisions. We are driven by a fundamental question: how does a relatively small, core set of signaling pathways mediate so many diverse biological processes (such as cell growth, death, differentiation and movement)? This question motivates many research directions in the lab:
- What dynamics or combinations of pathways encode specific cell fate choices?
- How are signaling pathways repurposed for different functions depending on cell type?
- How much spatial and temporal information can be encoded by each pathway?
To make headway on these questions we take advantage of a number of tools, especially:
- High-resolution microscopy
- Biochemistry/cell biology
- Systems biology
- Signal processing
- Control theory
Cellular optogenetics - controlling protein activity in time and space
Optogenetics – the control of protein activity with light – allows us to control when and where a given signaling pathway is active with unprecedented resolution. Unlike diffusible chemical stimuli, light can activate a desired protein species without off-target effects, and the intensity of activation can be exquisitely controlled with high spatial and temporal resolution.
The Toettcher lab is working to harness optogenetic tools, focusing especially on the Phytochrome B and PIF6 proteins borrowed from plants. By fusing Phy and PIF to mammalian signaling proteins of interest, it is possible to reversibly control their association (and by extension, their activity) using two wavelengths of light: 650 nm light to drive association, and 750 nm light to drive dissociation. This two-wavelength system makes high spatial and temporal control possible, even achieving tunable, "grayscale" activity levels by varying the intensity ratio of both wavelengths. Our lab seeks to:
- improve these technologies by building the next generation of optogenetic tools
- expand their scope to control key intracellular events
- develop approaches to integrate light stimulation with more complex biological systems (multi-color experiments and model organisms)
What pathway combinations and dynamics specify cell fate?
One major function of mammalian cell signaling is to control the differentiation of pluripotent cells. Using engineered control over two key signaling proteins downstream of receptor tyrosine kinases – the small G protein Ras and the lipid kinase PI3K – we are investigating how the level, duration and spatial organization of signaling activity controls cell differentiation. We picture this process in analogy to a “phase diagram” in physics, where control parameters (temperature and pressure) specify a material’s phase (solid, liquid or gas). By systematically varying pathway activity levels, dynamics and molecular organization, we aim to determine what these control parameters are, and whether the boundaries between different cell fates are as sharp as those between material properties.
How do signaling input-output relationships vary across different cellular contexts?
By combining dynamic inputs and live‐cell reporters, it is possible to directly measure input/output relationships at the single‐cell level with quantitative precision. For instance, we have determined that in fibroblasts, signals delivered to Ras take about 3 minutes to traverse the MAP kinase signaling cascade and activate Erk, and this transmission is equally efficient across a broad range of input levels and timescales. We are interested in extending these approaches to ask whether these commonly reused pathways change input-output relationships in different cellular contexts. Does a T cell, tasked with quickly sampling antigen-presenting cells to identify pathogenic peptides, alter its MAP kinase input-output relationship? What about cancer cells, in which key pathway components are often mutated?
- Bugaj LJ, Sabnis A, Mitchell A, Garbarino J, Toettcher JE*, Bivona TG*, Lim WA*. Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras/Erk pathway. Science 361:eaao3048 (2018).
- Dine E, Gil AA, Uribe G, Brangwynne CP, & Toettcher JE. Protein phase separation provides long-term memory of transient spatial stimuli. Cell Systems 6:655-663 (2018).
- Johnson HE, Goyal Y, Pannucci NL, Schüpbach T, Shvartsman SY, & Toettcher JE. The spatiotemporal limits of developmental Erk signaling. Developmental Cell 40:185-192 (2017).
- Shin Y, Berry J, Pannucci NL, Haataja MP, Toettcher JE*, & Brangwynne CP*. Spatiotemporal control of intracellular phase transitions using light-activated optoDroplets. Cell 168:159-171 (2017).
- Toettcher JE, Weiner OD, & Lim WA. Using optogenetics to interrogate the dynamic control of signal transmission by the Ras/Erk module. Cell 155:1422-1434 (2013).