Cyclotron Roads fellows are creating the future of clean energy, advanced manufacturing, and electronics. In this new series, Backstories, we are tracing the decisions and inflection points that landed them here.
Life has evolved to thrive everywhere — even inside volcanic hot springs, where archaea, a type of ancient single-celled organisms, live in environmental conditions that would destroy other microbes. But how do these so-called extremophiles pull that off? That question drove the early scientific careers of our Cohort Four fellows Jill Fuss and Steve Yannone and eventually led them to found CinderBio. Through the startup, Jill and Steve are commercializing the heat- and acid-stable enzymes that allow extremophiles to live in harsh environments. They are grooming these little enzymes—which can be thought of as biological machines—for a range of industrial applications, such as cleaning food processing equipment, as a safe and effective replacement for harmful chemical agents.
Jill and Steve were both well into their careers as Berkeley Lab scientists when they changed course to become entrepreneurs. We spoke to them to learn the how and the why.
It’s fair to say that you two are enamored by — and maybe rather obsessed with — extremophile enzymes. What hooked you? And is this what you always wanted to study?
[Jill] I didn’t like science in high school probably because of how it was taught: as established fact in text books. That’s really not how you do science. It’s lab work, and it’s not knowing — but wanting to learn — how things work. So, once I really did science then I really liked it. In graduate school I worked on DNA polymerase, those are the enzymes that make the DNA in your cells. When your cells divide they have to copy your DNA so that each cell gets a copy. It’s essential for life. Those enzymes faithfully copy the DNA and if they make a mistake they can go back and fix it and then keep going. Everything in us has been made by an enzyme. It’s fascinating to me.
My dad was an engineer and as a kid I used to work with him in the shop, so I like machines — and enzymes are molecular machines.
[Steve] I grew up in an extreme environment, in the desert near Joshua Tree, and our entertainment was to go out and catch lizards and snakes. In high school I realized biology was way cooler than anything else I’d learned about. During undergrad, I saw my first structure of an enzyme in biochemistry class and started understanding how these things have evolved to do all the chemistry that makes us possible. They are nanobots! They make everything that is alive and tear everything down when it’s dead. It was a mind-blowing thing to me and so all I wanted to do was understand them and work with them. Early on, I didn’t think about applications to address some of my social or environmental positions — it was pure curiosity. Just: wow, how does that work?
So when did the first inkling of what became CinderBio emerge?
[Jill] Steve and I co-mentored a summer student in 2004 to grow extremophilic microbes here at the lab because we were really curious to know how something could live, basically, in boiling acid. I was a postdoc learning structural biology which is figuring out what proteins look like at an atomic level and structural biologists love super-stable proteins and enzymes because it makes the methods we use so much easier to do. So, that was another motivation. So, we got these bugs in the lab and had to figure out how to grow them in hot temperatures. That sparked our collaboration. Steve continued to work on molecular biology for the DNA to be able to over-express enzymes in an extremophile and I worked on a single enzyme from those extremophiles. We ended up solving the atomic structure of one of those enzymes.
But that sounds like it was just in pursuit of science.
[Steve] When we started, it was a scientific curiosity but then we started thinking: These enzymes worked under conditions that we usually use to destroy enzymes in lab, so there’s got to be some way we can do something good with that. Working with enzymes for so long, we knew the existing commercial applications and there have been books and articles written ad nauseum about all the potential for these extremophilic enzymes. That’s been going on for 10 or 15 years but no one really moved the ball down the field.
What most people have done is to take genes from extreme enzymes and put them into E. coli or Bacillus or fungi and see if they can make the enzymes. With heat and acid stable enzymes, that doesn’t work. We started studying the hyper-extremophiles, the hyper-thermophiles, hyper-acidophiles, just because we wanted to know how they work, what they do differently and how that manifested as enzymes. The approach everyone else was taking was never going to work for hyper-extremophiles because they do different things that the yeast and bacteria don’t. So, we invested in figuring out how to make archaea make their own enzymes for us.
With archaea, they’re so different and so peculiar that sometimes you get led down the primrose path and say, “oh this won’t work.” And you don’t get past that. We tried to think past that and say why? We invested time and energy into understanding that and ultimately, we were able to crack the nut that people have been banging on for 15 years.
No matter how confident you are in the work you’ve done or the potential to positively impact industry, launching a commercial venture was a big, risky step. Why give up your positions as staff scientists at Berkeley Lab in order to do this?
[Jill] I was fairly well along in my career and I had two really small children, ages four and less than one, when we started the company. I could have taken another path that wouldn’t have been as risky, for sure. I really just want to have an impact with my science.
It’s not to say one path is better than the other–I felt like I had impact when I was publishing papers, and some of them are well cited. But I felt like I could have a bigger impact if I brought something to market and it was usable to the world.
[Steve] You do something for 20 years and it’s like, OK, I could keep doing this and coast into the shore but … where’s the fun in that? Also, I had been working with enzymes for decades and saw stuff that just blew my mind, like an enzyme in boiling acid that just keeps rocking for 15 days! I’d been keeping an eye out for opportunities around stuff we’d been doing in the lab and I started thinking about CinderBio around 2010, maybe even earlier, and started spinning it up and thinking about how to make it happen.
A lot of other fellows are recent entrepreneurs and while they might understand conceptually the science-to-product gap that Cyclotron Road is trying to close, you and Steve probably know it as lived experience. You founded CinderBio in 2012.
[Jill] Yeah! And making progress the whole time. We don’t do it often enough but when we sit down and think about how far we’ve come, we’re both taken by it. But it takes a long time, especially with biology. You might also notice that we’re older than a lot of the cohort.
When we started this company and started hanging around entrepreneurship events I definitely noticed that we were a lot older than the other people. But I went to a talk by a VC and she had a slide that laid out the ages of startup founders by discipline and the oldest founders were of life science companies.
[Steve] To date, we’ve bootstrapped CinderBio as much as possible. To grow faster, startups in other sectors would likely raise venture capital and hire more people — in software, ten programmers will do a lot more than two. But biology doesn’t always work that way. Software doesn’t rewrite itself when you go to bed at night like genetic things do. Biological agents have their own priorities and you have to account for that.
[Jill] For a long time, biologists tried to engineer enzymes and microbes and that’s still happening and there is a place for that. But I am continually humbled by trying to make changes in enzymes and having them not do what I want them to do. Biology has had a lot of years of evolution to try out all these things and we should really listen to that. Steve and I come from a philosophy which is to let biology teach you how to do things.