Into the Labyrinth and Back
listed in Fellows
Imagine pushing deep into a labyrinth, with an objective and nothing but a dimly perceived thread to guide you back out. You must trust this thread, even if it seems it could be severed in an instant and blown away in the breeze. In executing a research program one must likewise set out into the unknown, accomplish something definite, and bring the results back out to the wider world. A journey into the unknown, science always involves risk. Maybe the current methods are not good enough to answer your question, maybe the question turns out to be ill-posed. Or maybe you discover something new and amazing that never before seemed possible. Allowing for the latter possibility means embracing the risk of the unknown, without losing track of the thread that leads back out to clear, open daylight.
My educational path may seem disjointed, or risky, but I always felt there was a deeper thread of continuity. Looking back, I would describe that thread as a certain combination of creativity, impact, and intellectual rigor. At the time it was an intuition without words, but it led me from a degree in comparative literature with a minor in music composition, to exploring careers in law and architecture, to a decision to do scientific research. I enrolled in basic science classes at a California community college, transferred to UC Berkeley to study electrical and materials engineering, and won the fantastic Hertz fellowship to pursue a PhD at MIT. The Hertz Foundation, and its strong community of Fellows, advisors and supporters, helped me explore my ideas to the fullest extent and made that dimly perceived thread tangible.
At MIT I joined the Boyden lab, where advisor Ed Boyden – also a Hertz Fellow – has set up an environment for students to think broadly about technology needs in biology and to develop unconventional, cross-disciplinary ideas. These projects are inherently risky, but Ed partially mitigated that risk through maximizing serendipity. That meant encouraging us to try radically new ideas, but being open to their working in a different way from how we imagined. The hard part is balancing that openness with intellectual rigor, a balance that is well supported by the Boyden lab and the Hertz Community.
While working on an existing super-resolution method, I decided that rather than developing a more powerful microscope, I wanted to develop a method to physically expand biological specimens. I brainstormed many ideas with colleagues before hitting on an insight. If I could embed the specimen in a swellable material (like the active material in baby diapers), and stain it with dye molecules bearing a chemical anchor, then we could attach the dye directly to the material and dissolve the biological structure away. This leaves the dye molecules anchored to the swellable material alone. The material could then expand unimpeded, taking the dye molecules along for the ride. Achieving uniform expansion would be transformed from an intractable biomechanics problem to a relatively simple materials engineering problem. I teamed up with an extremely talented colleague, Fei Chen, and over the next few years we brought expansion microscopy from the world of ideas to reality.
If I could tell my younger self one thing, it would be to worry less. Set off on an unusual path, and trust yourself to handle the unforeseen twists and turns along the way. Trust the dimly perceived thread. The little stuff does work itself out, as long as you’re ready for it to work out in a different way from what you expected. Because they are unexpected, those solutions are the most exciting. They are sometimes also the most impactful, because they work differently and have complementary strengths compared to existing approaches. Sometimes you find a labyrinth you can’t help but go into—just be sure not to forget your thread. You will have a good chance, like Theseus in the ancient myth, of re-emerging with something well worth the effort and risk.
Paul Tillberg is a fellow at the Janelia Farm Research Campus, HHMI in the Tillberg Lab, where he is focused on further developing and applying Expansion Microscopy, particularly in a complementary role with vivo circuit characterization of the same specimen. Previously, he studied technology development for neuroscience at the Massachusetts Institute of Technology (MIT) and received the Hertz Thesis Prize for his work in Expansion Microscopy. Paul holds a BA in comparative literature with a minor in music composition from the University of Southern California, a dual BS degree in electrical engineering and materials science from the University of California at Berkeley, and a PhD in electrical engineering from MIT.
Photo credit: McGovern Institute and Justin Knight