Daniel Fletcher is the Chatterjee Professor of Bioengineering and Biophysics and a faculty member of the Bioengineering Department, an affiliated faculty of the Molecular and Cell Biology Department, and a Visiting Investigator of the Gladstone Institutes at UCSF. He is also a Chan-Zuckerberg Biohub Investigator, Faculty Scientist at Lawrence Berkeley National Laboratory, and co-director of the Physiology course at the Marine Biological Laboratory. On July 1st, he will begin serving as the faculty director for the Blum Center for Developing Economies at UC Berkeley.
QB3-Berkeley: What’s the focus of your lab’s research?
Daniel Fletcher: My lab develops new technologies to make biophysical measurements and diagnose diseases. We use those technologies to study the basic cell biology of infectious diseases and the immune system and to investigate new therapeutic strategies.
QB3: What’s an exciting question or challenge that your field and or your lab is trying to answer right now?
DF: One exciting challenge is very relevant to the pandemic right now: How do we detect the presence of a virus? There are a number of standard approaches to detect viruses, including rapid antigen tests and PCR tests, but we’ve been involved in developing a CRISPR-based diagnostic that we believe enables the right combination of speed, sensitivity, and quantification to help with current and future pandemics.
QB3: What do you enjoy most about working with trainees?
DF: I love the sense of discovery. Working with students who are motivated to make discoveries is thrilling. I get to join in on the adventure, help to guide these trainees, work with them to interpret the results, and jointly plan next steps. It’s that chance to learn new things and make new discoveries that I enjoy and that keeps me doing this job.
QB3: When you were young, what did you want to be when you grew up? Did you always want to be a scientist?
DF: I wanted to be an inventor. And now as a scientist and bioengineer, I get to do that in multiple ways, both by inventing new technologies that can be translated and through scientific exploration. The discovery process is really about inventing a hypothesis and then testing it. Creativity is a key ingredient. In this way, invention and discovery go hand in hand.
QB3: When did you first become interested in science?
DF: There are two points. One, when I was a small kid, I always wanted to build things around the house. I grew up in Texas and one summer decided that I wanted to be able to just spend the day underwater in the pool and not have to come up for air. So, I was trying to build something that would let me do that and got ahold of an air compressor and some old hoses and rigged up what I thought was a pretty sweet system, without realizing that the air compressor was very oily and was pushing out exhaust air. I set it up and soon found I couldn’t breathe the air. That drive of wanting to understand and invent new things has continued.
For my PhD work at Stanford, I was developing a new microscopy method based on atomic force microscopy. That work was aimed at understanding how molecular scale phenomenon work, but it was very much from an applied physics perspective. In the process of doing that work, I became more and more enamored with the fact that cells are able to do things that were beyond the capabilities of any modern technology. It got me thinking about how cells are the best engineers we have; cells have solved so many problems with such intricate control, and in a way that appears effortless. I was moved to try to understand how cells do what they do so effectively, from a physical perspective.
QB3: Are there any forthcoming papers or current projects that you’d be willing to tell us about?
DF: There are so many papers I should be working on right now! I mentioned above the CRISPR-based diagnostic we’ve been developing with collaborators including Melanie Ott and Jennifer Doudna, and we’ve recently developed an ultra-sensitive version of that diagnostic, based on droplets. By encapsulating this reaction into small, cell-sized droplets—20 or 30 microns in diameter—we’re able to have the reaction take place very quickly, so in under 15 minutes, we’re able to read out the results as a positive or negative in a quantitative way. It is similar to a droplet PCR test, but now with CRISPR reagents that have the advantage of not requiring reverse transcription or amplification. So, this is a direct, droplet based CRISPR assay.
Another aspect of my lab’s work is understanding how macrophages recognize and clear pathogens and diseased cells. We’ve been studying how macrophage receptors interact with target surfaces, and how the deformability of those surfaces influences the process of phagocytosis. We’re using a reconstituted system to simulate cell membranes that is revealing how target recognition and phagocytosis of soft surfaces is different than hard surfaces.
One other project I’ll mention is a computational project. We’ve been trying to understand whether and how the molecular topography of cell surfaces presents a physical barrier to cell-to-cell interactions. I like to think of the molecules on cell surfaces as the hairstyle of a cell: Some cells have, say, a buzz cut, some have bushy hair, and others have a combination of hairstyles—maybe something like a comb over with some long molecules and some short ones. We decided to try to computationally predict the size of all cell surface proteins in the human genome by homology modeling and with the help of AlphaFold. We now have predictions for all the cell surface proteins—all 3000 of them. One interesting thing is that some of the most important receptors, for sample the FC receptor on immune cells including macrophages, are buried underneath other taller proteins on the cell surface. What impact does that have? We’re working on understanding how this molecular topography impacts the biology of immune interactions.
QB3: And understanding that might help future applications, such as developing therapeutics?
DF: Absolutely. Therapeutics don’t just face an affinity problem. If I’m trying to target a tumor cell, I also need to think about the physical interaction of those cells. Immunotherapies need to be both biochemically and physically accessible.
QB3: That makes sense. It’s not enough to have a lock and a key; you’ve got to be able to put the key in the lock, right?
DF: That’s right. If your door is behind a big hedge, it’s harder reach the lock with your key. That’s the problem that immune cells have to solve whenever they encounter anything. And that’s also a defense that some pathogens use; they sometimes have elaborate cell surfaces so that they can mask their true identity from the cell.
QB3: What does being part of QB3-Berkeley mean to you?
DF: Being part of QB3 means being part of a community of researchers who are focused on fundamental aspects of important biological problems. And it means a great building, a wonderful set of core facilities, and the tremendous QB3 staff who we benefit from on a daily basis. The whole community makes QB3 and Stanley Hall a wonderful research and learning environment.