Apr 26, 2022
By Mohan Iyer
Wayfinder: Engineering the Future of Smart Biotechnology

Three Ph.D. students at the University of Washington started brainstorming about how they could help each other complete their research and graduate sooner. Jason Fontana was iterating on guide RNAs for CRISPR applications. David Sparkman-Yager was deciphering the rule book for how RNAs dynamically respond to binding. Chuhern Hwang was working on how to make new binding domains (or aptamers). They came together to form Wayfinder, which has a revolutionary way of building biosensors out of RNAs: nucleic acids that fold, like complex origami, into molecular machines. Wayfinder’s biosensors are not simply on-off switches, but are capable of analytically sensing specific molecules, in real time. The genius of their platform reflects their collective genius – it is a unique combination of deep RNA biology expertise, coupled to a powerful computation engine, to design smart, dynamic RNA aptamer biosensors. 

Jason Fontana, CEO, was politely trying to tell yet another VC that his round was already over-subscribed when I waved him down to chat with me for a few minutes.

Dr. Chuhern Hwang demonstrates flawless pipetting technique while building ultrafast, accurate, in vivo biosensors.

I can never get enough of the origin story of Wayfinder. Jason, tell it to me one more time.

David, my co-founder, had been beavering away for years on the biophysics of RNA trying to figure out the ground rules of RNA functionality, e.g., the rules around RNA folding, binding, engineering, and shape-shifting. He came up with a way to computationally design RNA that combines these biophysical insights into a smart search of the design space. His algorithm, even at that time, could quickly narrow down from say 1030 possible sequences of interest (which are impossible to screen through) to just about a million sequences, in a single day. Meanwhile, I was designing guide RNAs for CRISPR and experiencing very erratic results. Some of my designs would work while many would not. I asked David to collaborate with me on using his tool on guide RNAs and it worked beautifully every single time. We then tried it on aptamer-regulated mRNAs and other RNA applications and soon realized we had come up with a generalizable tool for designing reliable aptamer-based biosensors. Not only did we finish our Ph.D.s faster than planned, we also had jobs afterwards. And here we are!

So, you both came to the IndieBio program and made some amazing progress in the last few months. Tell us what you think you have achieved during the program. 

We have taken our tools and tried to apply it to real-world problems in new ways. On the first day in the basement labs, we made engineered RNAs that lit up, which had led us into fresh directions. We kept iterating on our technology platforms and RNA aptamer designs. We also iterated on the business side by speaking with small and large companies who wanted to measure something critical for their business. We suddenly find ourselves running at full capacity with these types of pilot projects. But we have learned from each one by adapting our technology for different needs. We have also met investors who get the potential of our evolving platform and we have raised the money we need for our next stage of growth.

Wayfinder’s biosensors turn off when the target molecule is removed – in about 30 minutes. (300x speed)

What’s the next step on the way for Wayfinder?

We are focusing on improving and expanding our platform so we can address very large markets where our technology can help solve intractable problems. One of these is in drug discovery applications. We are working on biosensors that can target different RNAs in the cell. We think we can design drugs that can continuously sense their microenvironment, and turn modalities like CRISPR both on and off in response to what they are sensing.

Hear how they outcompeted their peers for the most progress in one week in our Killer of the Week podcast: #1218 – Seeing molecules with the naked eye.