Imaging Dyes and Microscopy with Luke Lavis

Welcome to the Axial Podcast. Axial is an early-stage investment firm based in San Francisco. We partner with great founders and inventors investing in early-stage life science companies, often when they are no more than an idea. Axial is fanatical about helping the rare inventor who is compelled to build their own enduring business. Okay, Luke, we've been talking for like 30 minutes. Thanks for joining this podcast. We're going to do this every 2 years. I'm a huge fan of your work. Maybe for people listening, you give a brief introduction about yourself and the work you do, and then we can just start the conversation.

That sounds great.

Also, we're doing this in person, so thank you to Playground and Jory Bell for hosting us.

Yeah, no, it's great. I was just at a CZI workshop just up in Redwood City. They're doing a lot of cool stuff in imaging, so that's why we get to meet in person. But I'm Luke Davis. I'm right now a senior group leader and head of molecular tools and imaging at Janelia Research Campus. And my lab makes small molecule fluorescent dyes, and I've been doing this for almost 25 years.

Cool. Well, you're definitely like the key person for a lot of like super resolution imaging, maybe the key person at Janelia in general, and the key person for a lot of people's research. When they want to image anything. Maybe we can like start off from the beginning of how did you get to, you know, chemistry and imaging? Where'd you grow up? How'd you get involved in science? What was your first job like? How did you decide to, you know, how did you decide to like even try to become a professional scientist versus like probably a lot of other options and interests you had?

Yeah, so I grew up in Southern Oregon. My parents were both hippies. My mom grew up in Orange County. My dad grew up in Santa Cruz. They moved up to Southern Oregon in the '70s. My mom lived in a commune and they met, married, and we kind of lived out in the sticks. And, you know, I enjoyed building stuff. I enjoyed hiking around. I didn't necessarily think of chemistry as a first career when I was little, but I was good at math, I was good at science, and so when it came to finish high school, I almost didn't go to college but decided to go to Oregon State University. First-generation college student, and then at Oregon State I kind of bounced around. I was an anthropology major for a little while, I was an English major, and then chemistry really resonated, so I went with that. I had the opportunity to work in a lab run by James Dwight, who sadly passed away a few years ago, and he was a natural products total synthesis chemist. So he gave me a bench, he treated me like a graduate student. I was supposed to work 40 hours a week, I was taking full classes, so Saturday mornings, you know, he would walk through the lab and make sure everything was there. It was kind of old school organic chemistry lab. I learned a ton of chemistry there, and I learned that I really didn't like natural products total synthesis. So, so when it came time to take the next step, I wasn't sure. I loved chemistry, but I didn't want to do natural products total synthesis. And so I found the one job you could get as a chemist in Oregon, and that was at this funny little company called Molecular Probes in Eugene, Oregon.

My mom went to Humboldt State, and she has some hippie values. But I'm not a hippie, even though I try to act as one once in a while. Are you a hippie, or do you have some values? Have those values kind of seeped into you, and how did that influence you going to college? Like, in terms of, were you— when you got to college, were you very oriented towards something humanities or something more like— how do I— not— I don't know how to characterize this the best, but like something more like, um, free and open versus something like chemistry, which is very like— yeah, very old, you know, total synthesis. I, I, I, I don't, I don't know who— I'm not familiar exactly who James White is, but I'm assuming he's A lot of chemists I know wear suits. They're not wearing, you know, Grateful Dead shirts.

And so, yeah, that's a great question. So my original plan was I wanted to go to medical school, and then I wanted to be a missionary doctor in the South Pacific. That was my dream. Um, so, you know, this chemistry thing came in, and I thought, oh, you I'm good at this. And I wasn't sure, okay, grad school, to go to medical school. And that's also why I was doing some of these other things. I thought, oh, anthropology really interests me and it would be distinctive to be an anthropology major with a strong science background and then go to medical school.

I'm just trying to make sure that like, oh, I did chemistry because I want to make LSD or something. I got into chemistry. That'd be a cooler story. It's not reality, but same thing for me. I wanted to join Peace Corps, actually, and then I realized, you know, for me personally, I don't want to go to like Zimbabwe or like Colombia. But how did you realize you're good at chemistry? Was it— did somebody tell you, or did you like— did you synthesize a molecule first try?

Like, oh yeah, I don't know, there was just something about it. It resonated with me. I think I'm a very visual learner, and so the beauty of chemistry is it's all pictures. Right? And so there's a, there's a strategy building molecules, but in the end, you know, there's this, there's these pictures of molecules and you say, I'll make the thing available. And so I can do it. And the other cool thing about chemistry is it's, you know, it's like, it's like a hands-on science, right? There's, it's like cooking in many ways. It's hard to automate, although people are having some success automating it. But in the end, it's a person at a hood you know, finally manipulating these solutions and getting things to work, right? There's this, there's joy in making a new molecule.

Okay, so you're Oregon State in the lab, was this like your freshman year? Yeah, you took some chemistry courses and then you joined the lab. I joined the lab around that same time and I was amazed, like, they just let me do anything.

Yeah.

Like, what? Like, I can just do anything I want in this lab and no one's gonna really tell me what to do? And that kind of got me hooked a little bit. Any kind of horror stories? Any— if you break an expensive glass? Because I remember I broke, I broke like a bench once because like the Bunsen— I put the Bunsen burner underneath. Okay, they got really mad at me. Yeah, any stories like the first like year, 6 months?

Like the first reaction that I did ever? Independently, this production using a catalyst, which is platinum hydroxide. And, you know, I didn't know anything. I was making— I was actually making a natural product found in pine trees, a little project, that little side project that Jim had funding for, and it was meant to be a standard for GC gas chromatography with someone like in the forestry department.

Yeah.

And so, you know, natural product found in pine tree bark. And, and so I made this thing and I was taking off protective group. I didn't know. I was like, okay, what do I do now? Yeah, filter it. So I filtered it and realized that this is plain hydroxide. So then I picked up the filter and it was going hot. It's like, crap, what do I mean? Like, dump it in the sink or something. So I learned, you know, it was, I had a bench, I was treated independently. Jim didn't take very many undergrads in his career. He only took 6 or 7. So it's really an honor to be part of that group.

Cool. Same thing. I worked with Andrew Yeruk and he only, it was only postdocs and undergrads. And it was like me and all postdocs and I could do whatever I want. It was exhilarating, but then terrifying. Yeah, break anything. Okay, so you're at Oregon State, any kind of like, you're doing research in the lab, like, did you, how did you get the leap to, you know, become a professional scientist? Something I experienced too, like, I have science friends, I guess, you know, people who studied engineering, chemistry growing up, but I never really grown, I didn't really grow up like a professor. Professional scientist who made a living publishing papers and doing work. How did you finally realize, hey, maybe something I can do? Like, or did it happen in college or maybe later on?

But yeah, I think I'll be honest, I think part of it after my undergrad work is I wasn't quite sure if I was good enough and So that was one of the reasons to go to industry. Uh, you know, the things that I do now in my lab and for this effort that we call Open Chemistry, where I share a lot of the reagents, is I want to give other folks coming out of undergrad, they go to grad school, an opportunity to work in the lab. I think generally we don't have a lot of these post-bac programs. Hughes is starting a new one, which is great. I'm part of the working group there, but I think those types of opportunities do a few things. They teach people that yes, you can work in the lab. You are a good scientist. You're able to be productive. It also shows folks that it's fun. It's a fun job. You go into the lab and make something new every day. That's pretty cool to do.

Yeah, absolutely. I remember Rich Lopes had a program with HHMI where you get like kids from students from like maybe universities that aren't like a lot of opportunities are, and then get them to like generally a farm again or something.

Yeah, so that's the goal with this new program. And then I've been kind of doing it, you know, on the side, I guess, over the years. Several students have come through the lab and then Most of them have gone on to graduate school.

Cool. Okay, so you're at Oregon State and you join, do industry, and it's amazing to hear, oh, maybe I wasn't good enough, but now you look at you, you're like the best person in imaging. It's crazy. You know, that kind of tells you that journey is a little unique and there's no like standard path to being the best. And so, so you go to Oregon State Why did you want molecular probes? Was it just because it was down the street or a friend worked there?

Or it was— I mean, it was, it was partially because I love, I love Oregon, okay? And my, my wife, my awesome wife, also from Oregon. Um, and, and so I just never ever wanted to leave. And so I'm like, okay, I want to find a job here and I'll figure it out, right? So I walked in, I think I mentioned Jim might only take a few undergraduates. Well, one other undergraduate was working at Probes, more of a former undergraduate was working at Probes, this awesome person Kyle Gee. And so I think that got me a little bit in the mix. And so I walked in and I remember during my interview sitting with Kyle and I asked him, you know, well, how, you know, you know, how hard is this, how hard are these things to make, how much do you care about stereochemistry, which is kind of the bread and butter of natural products total synthesis. He said, oh no, no, no, we're not trying to make fancy molecules, we're trying to make useful molecules. And that's really what sold me on this idea of molecular probes, and that's why I wanted to go there. And that, I think that one thing, you know, making useful molecules versus cute, interesting, complex molecules, is something that I really go after still to this day because it's all about the utility, not just about how sexy they look.

Okay, so this is probably a very formative time in your life where you begin to establish like what you actually want to work on. So like, what did you do on Lockwood Probes? Was it just the same thing you do now, or maybe related, or just—

Yeah, yeah, it's my first my first project there, they had just identified all the Alexa Fluor dyes. So this was in 2000. Yeah. And, and so my first project is you're going to make a gram of Alexa Fluor 633, one of these Alexa Fluor dyes. And, and so, you know, I mean, that synthesis— they'd already identified this as a candidate, so I just had to go through and and do this. And the other funny thing about, you know, dye chemistry and working in industry is, you know, you don't necessarily care about the yield. You know, the rules that I learned in academic natural products lab where it's like it's got to be 80% yield or try again, you know, I did my first reaction, I got 65% yield, and I felt really bad. And then I told my boss, he's like, oh, that's best anyone's ever done on that. So I realized, oh, this is, this is kind of fun because it's not about, you know, calculating how much you get at the end. Yeah, you know, these dyes are so useful, so valuable, and you don't need that much. So it's just about making them at all.

Cool. Maybe, um, we'll give a primer on imaging dyes later on. I think the story is more important. Um, so you've been up there, probes for a few years, and then you moved to molecular devices. Yeah, unrelated, I think.

Well, are they related? So what happened was, so I was on probes Probes. Again, I love Oregon, but I worked for my supervisor, this, uh, he goes by Dr. Wu. He owns AT BioQuest down in Sunnyvale. Really fantastic mentor and teacher. And so he left Probes and went down to Molecular Devices. And so he got there and he recruited me down. And so I was only at Probes for about a year and then moved to, you know, down Silicon Valley, Sunnyvale, right around the dot-com bust, which was an interesting time to be in this area. And then just started there. The Molecular Devices was a company that made plate readers and other equipment for high-throughput screening, and they had just started a reagent business. So there were 3 directors, and under each director there were 3 people. So it was a team of 12 in cell biology, biochemistry, and organic chemistry. And in a year or two, we had, you know, $10 million in consumable revenue. So we built up these kits rather quickly, and we had nice facilities. It was a really fun time because then I started interfacing with Engineers who were building equipment and were trying to build kits that would work well with this installed base of instrumentation.

Yeah, Molecular Device was one of the best instrument companies in the early 2000s.

Yeah. So you're—

Molecular Device is, um, at the time was like, hey, maybe I start my own company, or maybe I should just keep on, get promoted and become a VP. But then you go to Wisconsin for grad school. How did you, like, at the time you're having all the success, you probably, you have a wife, is it? You have a wife, so maybe house, a kid, you know, like you want to, you know what I mean? But then you decide to go to grad school. Was the, like, was that part of the plan or is it just like kind of just came up and you said, you know what, I really want to work on the science problem? Go back to academia.

Yeah, so again, you know, this was sort of supposed to be a holding pattern for me, right? Do I go to medical school?

Do I go to grad school?

The other issue, which maybe it's different now, but without a PhD in R&D, it's hard, right? I remember one of the other directors told me, you know, the PhD is a union card. It allows you to get other jobs. I still think that's, that's true, although, you know, there are exceptions. And, um, you know, I've been brought in to Molecular Devices at basically the highest level, Associate IV or whatever, that I could have as a bachelor's degree. And, and so, you know, I had to make the decision, right? Either I, I could go into sales or, uh, customer support, I guess, or, you know, there are other avenues to to code it, but not within R&D. I think at that point I realized I really like this, solving problems, research development, doing nerdy science. I guess maybe I figured out I was a real nerd and I should keep doing it.

Interesting. How was it like to work at— like, so maybe one quick question is like, um, how did you— do you have to dress differently when you work in industry, when you work at like— I mean, any kind of— or student I had some of my impressions of like being a scientist versus being a CA professional. It's just there's things that you have to pick up about like how to present stuff. And sometimes in science, it's, it's, you're so much in the weeds about the technical details. Sometimes you lose why it's important. And sometimes what I've realized, not being in academia, you get the better skills that you guys had about that science. And so do you think having those experiences or high school helped you like do things that are useful, not so much?

No, that's a great question. So I guess I can think of two things that I gleaned during my time, especially in in, um, at Molecular Devices. So Molecular Probes was this fun, uh, privately owned company, uh, and so that was, you know, run by essentially one person, the founder, along with his wife. Um, and, and so that was interesting because, you know, they— their mantra was, hey, if we're making money on something, let's keep selling it. So they had this list of thousands of compounds and, you know, it wasn't the best business model, but it was great for the community. I bring that with me now, you know, let's keep molecules that are useful accessible, even if we're, you know, they're not the biggest sellers. So that was something I learned from Dick, and I really appreciate that. At Molecular Devices, especially You know, something that a lot of graduate students don't come in with is this idea of fail early and often, right, which I think is mantra in the business world. And so we— I learned that at Molecular Devices, right? And so, you know, you try something, and if it doesn't work, move on. And then, you know, sometimes someone else is going to try that, they're going to get it to work, and you're going to kind of quasi-scooped, and you have to learn just to be okay At the time I made this decision, I trusted my gut, I killed it, I'm going to go on to this other project. And so that's something I learned. And then, you know, we were a small team and so I had to, you know, I was 22, 23 years old, I had to give presentations to the CEO and other things. I remember being talked about the reagent kits that we had developed, right? And so I learned a little bit of how to present things, how to sell things.

I think trying to present science and research to people who know or know nothing and are trying to make money off it, you have to really distill what's valuable. It makes it hard initially.

Yeah, I mean, this— yeah, the nice thing about probes is usually the cost of making things after they aren't as expensive, but the ultimate cost of things is cheap, right? We were selling a kit for, I think, $1,500, and the bill of materials was $5. So the CFO— that was, that was the message the CFO understood.

Okay, so you go to Wisconsin for grad school. Yeah. Um, I'm always jealous of the people— something I wish I should have done— probably should have like done 3 years between college and grad school and then just get experiences and then make the best decision.

Yeah.

Go to college and grad school unless like you're a genius or some sort of like savant. Otherwise, even if Luke Levis has to get a job before grad school, I think everybody should. But why Wisconsin? So you're in Sunnyvale, yeah, one of those, you know, Wisconsin.

I think there was still a little bit of imposter syndrome here. And so I wasn't quite sure I should, you know, maybe, you know, I don't regret anything. Yeah, I could have I now know I could have stayed. But, um, so we were, we were a little tired of the bustle of the Bay Area. Um, you know, I— we were— we lived in Sunnyvale, so I didn't usually commute. My wife, uh, worked, uh, dietitian. She worked at Menlo Park, just downtown, at this assisted care facility. And so, you know, our life was get up really early. She would take Caltrain up and I would drive to work. And, you know, and it was, it was, you know, with two kids from Oregon, it was, it was, you know, it was a, it was a difference, right? It was a different life. And so we thought, let's go somewhere crazy. And so we thought, okay, where's, where's a crazy place? And it's like I had been to Madison before on a chemistry conference trip. And so I'm like, oh, this place is amazing. So we decided let's, let's live somewhere kind of different.

I've been to Ann Arbor, and grad school, and like, this place is too cold.

Yeah.

And I guess Madison's not as cold as Ann Arbor most of the time. Yeah, there's a little snow, but it can get pretty cold. Okay, so you go to Wisconsin. Did you kind of know exactly what you want to work on?

No.

Or you just show up and say, I'm doing rotations, I'm going to explore and try to— like, did you think about trying to continue to work on probes, or were you just open-minded about anything? Hey, maybe I'll do something in stem cells, or—

Yeah, I mean, it was the chemistry department, and at the time, you know, they had a great chemical biology program.

Yeah.

So, you know, now my PhD advisor and his wife, Laura Keesling— PhD advisor was Ron Raines. They've now moved to MIT, so You know, so that it's still, still a great community there, but I think some of, some of the people have moved on. And, you know, I was, I was sort of pegged as the fluorophore nerd within my class from the beginning. And so I would always ask questions about fluorescence. So I kind of wanted to keep doing this. And fortunately, Ron had Ron's an incredibly creative scientist, and he had come up with this interesting strategy to make fluorogenic probes, probes that would turn on in response to enzyme. And so I went to Ron's, and at the time, Ron didn't know my name, but he would call me the probes guy. And so, you know, he said, sure, yeah, you can join my lab. Probes guy. So in the middle, we all had nicknames. My nickname was Prober. So we would all call each other by our— so it's kind of a fun—

I did a podcast with Peter Turnbull. I had to publish it, but his old mentor called him the professor. Hey, professor, just because, you know, just to kind of give him the encouragement. He can do it. Okay, so you're kind of doing graduate research, working on probes, enzymes. Like, maybe you can describe your project, but like more in the context of like, how did you think of— like, I think when you're in graduate school, you have a higher level of independence, and only in terms of like maybe undergrad lets you do anything, but then you're often being told what to work on maybe. But in grad school, you're kind of now expected to formulate your own hypotheses. Maybe establish a project. How did you— did that come easy to you, or how did you get those skills? Like, for your project, how did you, like, drive forward? That kind of can definitely be, like, the biggest— it can be a lonely existence sometimes as a grad student, where, like, often it's just the mentor, to be honest. Yeah, probably the mentor that helps.

Yeah, I mean, In industry, we, we had a bit of leeway. So at the time, the big product, which is actually still a product, are these calcium screening kits, right? So we would make it— we were actually making one of the components, and then the company was moving money around to reimburse us for that time. It only took a few days a month to do this. And so the rest of the time, that would pay for all of our salaries and everything, so we could really just do R&D. So that was fun, uh, you know, and that gave me a little bit of freedom to explore. So I learned that from industry too, and that's something I try and do for the technicians in my lab, is they're not just doing what they're told. They eventually get their independent project and get to struggle with it and try new things.

Yeah, this is all build up to the culture you have now, Janelia, where you built like a really like a center of excellence and he'd be able to recruit and retain Jonathan Grimm, Brian English, a bunch of great people to like just continue to pioneer imaging dyes and probes. And so it's kind of all, it's a consequence of these experiences though. And so you're in grad school, any kind of like low moments you realize, did you ever, okay, everybody has that moment where like, Maybe it's year 1, maybe it's year 6, you're like, I don't wanna do this anymore. Did you have that moment? Or maybe not that extreme, but did you have like an existential moment where you're like, no, maybe I should go back to industry?

Yeah, yeah, it was actually the opposite. So we had a little workshop for the team for potential entrepreneurs in science at Wisconsin. So they, I got invited to this and I mean nothing against industry or VC or anything like that, but you know, I, at that point I really realized I was a nerd and I couldn't help it, right? It was like, you know, they were, they were like, oh, this is great. You know, you can start companies or do whatever. Me in this world. And I realized, okay, I'm gonna do the science thing.

Cool.

Um, yeah, cool.

Okay, so kind of what was it that turned you off? Was it just the clothing? Was it the lack of curiosity? Sometimes, you know, I think about VC and startups are really fun because you can take— you can actually make a direct impact on people. But then the other end is like, it's hard, you can't explore as much.

Yeah.

Yeah, that's the trade-off.

And again, you know, this is something I learned in industry, and I, you know, this is a constant struggle with me is, you know, scientists, you have to tell a story in the form of a paper, right? But we, we can often make tools that work that are really useful, but then we still have to publish a paper, and there's a lot of stuff that goes into a paper that isn't necessarily what you need to get a tool out there. And so sometimes I kind of yearn for the industry days where it's just like, oh, we need this thing. We tested it, it works. We could just, you know, start sending it out and, you know, forget about a paper. But the flip side of that is, you know, sometimes you want to follow up on something. Like, I think this is interesting and, you know, there's no market. There's nothing that, you know, it's like, well, no, we got to move on to this other thing because this is more important for strategically for the company. And actually, one of my projects in grad school stemmed from something I had done in industry, and it was something I never followed up on, but I could adapt it for this system that we developed in, in grad school.

Cool.

Hey, what was your order?

So what was the project?

So Ron had, uh, has a little company on this, but he's a trained enzymologist. I learned, you know, sort of the importance of precision and grounded in physical organic chemistry principles from him. And he worked on these ribonucleases, very common proteins that are found everywhere. He discovered variants of these that would kill cancer cells. Selectively. So we have this protein in our cytosol, its sole purpose is to bind any stray ribonucleases that would get in. And so he developed variants that would evade the ribonuclease inhibitor protein, and it seemed to selectively kill cancer cells. So we started, um, get a little startup on this, and what we wanted to do is actually visualize the protein getting inside the cell and then track it. Where did it go? What were the kinetics of it? You know, it would get endocytosed and escape the endosome. And so we wanted to figure out, you know, trace the path of this protein in cells. And so we had developed a strategy where we had a fluorescent dye. It would be quiescent, dark, until it got internalized. And then what we had other probes that would stay dark even after internalization, but then only glow when it escaped the endosome to the cytosol. So that was my job.

So like, he has this kind of maybe overall overarching project. You got there, did you totally revamp the whole work? Because you're the probes guy. Like, did you just enable things that like he didn't even imagine in terms of like imaging like trafficking.

Yeah, Ron probably doesn't remember this, but he, you know, he presented this project, said, okay, you have this, you have this probe scaffold, um, that a postdoc had worked on. And then he said, okay, your job is to get this thing working on the protein, the cellular experiment. And so he's like, if, if you do this, we, we have to give you your PhD. And so I said, it's kind of easy. And so We had an idea, again, stemming from stuff in industry. And so 8 months later, okay, I think we got it. And then he's like, well, I can't give you your PhD, so just do whatever the hell you want for 3 years. So that's what I did.

That's pretty sweet.

Okay. I mean, it took a little while to like flesh out the— Yeah, yeah.

But that's, that's good. Just to just do things that are kind of, you're really good at and it comes easy and then you begin to like, so at Wisconsin you had this maybe period of time where you kind of knew you'd get your PhD, you had a few years to kind of explore. That seems pretty formative where you can kind of explore ideas, read papers, go to talks. Yeah. Like, what was in your mind at the time? Like, was it like, what kind of problems did you— maybe a better question is around this time, or maybe earlier or later, when in your head did you start solidifying these are the problems I want to work on, these are things I'm really excited about? Was it around this time, or maybe—

one of the things that I struggled with in grad school was, this is going back to chemistry roots, even though I was making probes and interfacing with cell biologists and biochemists in the lab, you know, the struggle is really making these molecules, right? And, um, you know, we were making the simplest rhodamine dye called Rhodamine-110. It's got very little. It's got nothing on it, right? It's like the simplest dye. It's in the original Rhodamine patent from 1887. And, you know, here it was, 21st century, and I was making it the same way that Marie Serrasol, this German chemist at the ASF in 1887, was making it. And, you know, this involves boiling things in sulfuric acid. And, you know, come on, I'd have the holes in my hands. Dripping sulfuric acid. It was quite nasty. So I think it was that point when I realized, okay, if we want to break this field open, we gotta stop using this 19th century chemistry. This is really stymied the field.

That makes a lot of sense. It just seems like, you know, you're in college, you like chemistry, you don't like this whole stuff, natural product stuff. It's kind of really complicated and kind of hardcore culture. A lot of the natural product people I know are like hardcore chemists, like borderline abusive. Some of them are— not all of them, but borderline abusive. Some friends who—

sure, it's like 2 hours on Sunday to do your laundry type.

Yes. I don't want to name names, but I have some professors at Harvard I do, and they're very, uh, very hardcore. Yeah. Uh, so then you get into pro because you join this company And then you work in industry, and then you go to grad school and be the probes guy, and then you just, oh, do something real easy, get a PhD. And I'm just trying to like understand, like, it seems like, uh, you're just really good at chemistry. It seems to join in molecular probes.

What's creating—

um, yeah, no, that, that was the—

yeah, that was the thing. I mean, I never looked back, right?

It seems like that was like the key, like just having a friend who I've made being at that company as well. You just join, like, that seems to be like the key thing where it's just like, whoa, okay, I'm gonna just join this company and then that sets you up for a very long time. Okay, so you're near the end of your PhD. How did you decide Genelia Pharm? Genelia Pharm's a pretty sweet place. It's in Chevy Chase, Maryland, or?

No, no, so Genelia is part of HHMI, so the Howard Hughes Medical Institute. HMI is one of the largest philanthropies funding biomedical science in the country, started by Howard Hughes in 1953. And back in early 2000 or so, they decided to start their own research campus. So before that, they were funding investigators all over the country, but they had no lab space of their own, really. And so they decided to do this, and it's actually in Northern Virginia, so it's about 35 miles west of DC.

I'm sure the place is perfect for you. Think about like, you know, hey, Google Oregon in a cabin, or not a cabin, but like something equivalent. And you're like, I wanna— generally a farm is like, it has to be like, I think about for Luke, like probably the best place for you to do research.

Yeah.

Kind of fits you, you know, it meets all your criteria.

Yeah.

It's like your dream job, essentially. Is Erin Roche still president of H2O?

Yeah.

You know, she got her PhD in 2 years.

Oh yeah.

At MIT. She brags about that.

I know.

So maybe that could be you.

There it is, upscale.

That could have been you, 2 years at Wisconsin. Okay, so it's like 2008, I think.

Yeah.

7, 8.

Yeah, yeah. So at that point I've been in the lab 4 years.

Yeah.

And, um, you know, to be honest, I was kind of having an issue finding a postdoc. I was sort of an odd, odd candidate.

Um, really?

Yeah, yeah.

What?

Yeah, what? So it's been a hard time. Um, and then kind of on a whim, I, uh, I applied to this new place, this place called Janelia Farm at the time. Now it's called Janelia. Uh, we dropped the farm name because everyone thought we were like a—

I know, exactly. Kind of old school. I think it's perfect job for you because you have this hippie connection. Janelia Farm. Yeah, it's like a scientific commune. Yeah, um, almost.

And, um, yeah, when I told my wife about this place called Janelia Farm, in her mind, she's more into her mind, you know, she's like, okay, so it's going to be like science, but then you also have like you grow your own vegetables or something, right? And it's like going to be this like peaceful thing, you do yoga in the afternoons or something, right? So that was her sort of, uh, when she heard the name, that's part of the reason we changed the name.

I think I like Jilley Farm. I think, uh, it's— what's that Bob Dylan song, Maggie's Farm?

Yeah.

So when I think of Jilley Farm, I think of Maggie's Farm.

Yeah.

Okay, so what was the— how did, how did, how did Janelia get on your radar?

Yeah, they had a, you know, there were a few calls. I think one interesting thing about the model there was hiring guys straight out of grad school. So there were, you know, there are a few of these Y-Dev fellows, et cetera, but Janelia explicitly said we're gonna hire heads straight out of grad school, though I applied, and yeah, I was sort of, I applied cold, right? They recruited a lot of other folks, but I was sort of the dark horse there. Yeah, cool.

I love it. They just, they didn't expect you.

Yeah, no one. Yeah, I showed up and yeah.

Okay, so I think Tijan was president of HHMI at the time.

Actually, Tom Scheck. Yeah, so this was one of Tom's brainchilds. So Tom's still president. It's before Tijan.

Okay, so Tom Scheck, he discovered ribozymes. Yeah, he's an amazing person too.

Oddly, the cool thing about Tom, Tom's brother lives 15 minutes from my hippie childhood home. Really? Yeah, yeah. Yeah, in this little town called Williams.

Sometimes things are meant to be, you know what I mean? There's sometimes like, like, uh, like reality kind of meets— is this stranger than fiction? And sometimes things— they used to— the oddities of life, and you realize, well, you, you know, things like that show up and you start realizing, okay, this is some sort of order of the universe. Um, so Nelia was always, from understanding, focused on the gene. That's the core, because you Eric Betzig had joined, and Eric has a weirder story.

Yeah, yeah, Eric's story is—

he worked in like a family business. Yeah, yeah, he had a crazy career. Yeah, uh, yeah, so Janelia is this new thing.

The founding director is Jerry Rubin. Yeah, Jerry did a lot of cool stuff, figured out how to make transgenic flies, led the public effort to sequence the fruit fly genome. So Jerry's the founding director, and Jerry has this idea, I guess when he was at the MRC LMB, to create this place where we do science differently, right? Where it's all about collaboration, the labs are small, and then it's all internally funded. So that allowed us to have sort of some, what you'd call, atypical group leaders at the time. So Eric Betzig, was the first leader, and he and Harold Hess had hooked up this super-resolution microscope in Harold's living room. Yeah, so then, but yeah, Eric was the first group leader at Janelia. And this was after a 10-year hiatus where Eric had worked for his family.

Oh, he's in Berkeley. He actually, I need to figure out, I need to go visit him. But, uh, um, yeah, his story is crazy. He was like, what?

Yeah, he was a bellhops and he just kind of— get to know Eric. With Eric, uh, Eric, uh, you know, he's not afraid to make big changes.

He's a quote— he said, without Luke Levis, some— it's the equivalent— without Luke Levis, uh, you know, he's our secret weapon.

That's the quote. That's the—

yeah, it's, it's so What was your first job at Janelia? Was it like just technician or—

No, no, no. So, so I think that— so this was early days. There were like one round of hires and then, you know, I show up at this interview for Janelia. I have really no clue what's going on. I walk in with my suitcase and, uh, a good friend of mine now, Scott Sternson, another chemist, um, or at least trained chemist. He's a neuroscientist currently at UCSD. So Scott's just sort of loitering in the foyer, and then I walk in, and then he comes up and he's like, are you Will Davis? And I said yes. He's like, let's have a seat. And so you started at that point, I guess. And so we had a 2-hour dinner, and then you get up next morning, there were 8 of us, we gave 20-minute talks, we had panel interviews. Went to dinner at Jerry's house, and then we flew out the next morning. And then exactly one week later, got a call saying, we want to offer you a 5-year, at the time, fellow position.

Cool.

Um, please come. So it was, it was, you know, they, they, it was like trust your gut type stuff. Uh, they did not, you know, they did not, this was not a long interview process. This was not a You know, a long decision.

And did you have like a pitch going in? Like, hey, this is the problem I want to work on, or was it just more like, this is what I've done, who I am, and what I like?

It was a bit of both. You had to write a research proposal. I, you know, honestly worked on very little of what I proposed, or, you know, but I can think of two. I know when I got the job, and there's another thing that I think helped. So during my talk, I presented all this work on making all these different fluorescent probes for studying this problem of protein internalization. And one of the questions I got at the end is, hey, you know, we work a lot in vivo in intact animals, you know, how are these probes going to be useful? And, you know, the standard chemistry response would have been, well, we're going to make the probes and you guys got to figure this out. And I said, yeah, it's a huge problem and it's something that we're going to— the chemists have to deal with, right? It's not 'Not your problem, it's my problem.' Yeah. And I know that was the moment where they realized I was going to be collaborative. It was— we were going to work together to solve problems. I wasn't just going to be there making molecules hoping that someone was going to use them.

Oh, interesting. Yeah, cool.

Yeah. And then the other, the other thing, a good friend of mine now, Josh Studman, asked me during the panel interviews, he's like, 'You realize this, this idea that you proposed probably won't work?' And I said, 'Yeah.' And I think the whole room got silent, but at least I was honest, right? And that's something we value at Janelia is being honest and, you know, having constructive criticism of each other's work, right? It's not a bad thing to say, I think this is a terrible idea, right? And you respect one another. Why is that?

Because like, I think I have a lot of friends who run labs, and when they make that progression from grad student, postdoc, to running a lab is grant writing. And that is another something. I'm assuming you don't write grants.

No, we don't write grants.

Exactly. So like, you avoided the grind of grant writing. Do you think that's a big reason why Janelia has a different culture? Or—

Yeah, it's— you have to— no one else is going to hold us accountable. Funding agencies aren't. And that is what makes Janelia special, right? We can We can move fast, we can be nimble, but we do need to make sure we're not fooling ourselves. And so we rely on our colleagues to say, hey, you know, what do you think about this idea? This is dumb. Because I mean, early on, you know, they hired a bunch of folks straight out of grad school and gave us very large budgets and with no oversight, right? And so a lot of, you know, I remember sitting with Josh, late at night, do you think we can be here? And he's like, well, I guess we're lab heads, so we can do whatever we want. And, you know, they're still in that kind of grad school moment, you know, grad school mindset. And so, yeah, you know, we— the problem with, with that is you can have an idea in the morning, you can order, you know, $20,000 worth of reagents or chemicals or something to try that idea, and then actually go to the literature and figure out someone did this in 1986 and it didn't work. That was the— that was a problem. And so I think we learned as a group that we have to really discuss these ideas because we're not going to, you know, that we have to rely on our colleagues to vet our ideas.

So maybe that's the reason why you went to CZI today or to present or just kind of just showing your research trying to get feedback.

Yeah, I think, I think, you know, I mean, we wrestled with a lot of these problems. CZI just started this awesome new imaging institute. And, you know, I think they're, you know, we're going to work in a collaborative fashion with them, making sure that, you know, we're all just going to try and solve this problem about biological imaging. Yeah, but, you know, we've, we've sort of lived through this. We figured out a way to, to identify important problems and then solve them without wasting time or resources.

Cool. Is there like— is there— I've never been to Janelle actually. I should go visit. You come visit me now and we can go look at the microscopes. But also, you should have like something. You should bring like some sort of calming thing to it, like apple picking. Cook your own potato, pick your potatoes and cook a potato or something.

But yeah, no, I mean, like, that's, you know, during the recruiting phase, my wife and I are there.

Yeah.

And, and we're being, you know, we're having lunch with another head at Janelia now, the guy who had also come straight out of grad school. He came, he, you know, a lot of us did something interesting, then went to grad school and then to Janelia. So he had worked and then went to Caltech and then came. And so, you know, Vivek's trying to sell us on this place, right? And, and, you know, he like left to go do something at lunch and my wife leans over and says, is this a cult? I think so. Yeah, well, it's not a cult, but it sort of felt that those early days of that energy You know, because like, this is kind of too good to be true.

Exactly.

You get to come here, you get anything you want, it's a beautiful campus, it's a cool place, and you can just really do whatever you want.

Okay, I need to, you know, let's all get rich. And I think it's really, I think getting scientists rich, uh, hopefully make more genialians. I think that it'd be nice to have, um, and So if you could talk about the research you do and the lab you created, the group you created. How did you establish your programs? Influenced by other groups and what they needed? Or did you have like a set game plan? And then maybe we talk about 2013 paper you published or 2013 papers you published maybe 5 years apart. One led by Brian, another led by Jonathan. Where you just create these libraries of imaging eyes, uh, floral series, um, which is kind of probably the most impactful work you've done so far, in my opinion. Maybe we can talk about, um, the research you do and then kind of the stories of those papers. Yeah. Um, yeah, so you're, you're an alien. How did you determine— how did you figure out to work on Yeah, yeah, because like you have a sweet gig. Yeah, 5 years, I can basically do whatever I want. Yeah, I'm in Virginia, pretty sweet. I'm in like a place I like living. Like, yeah, I would be— I would be nervous. Exactly. No, no, at the time it's like, this is my shot, right?

Yeah, I gotta do something interesting.

Yeah, like I'm just trying to get through, like, because it seemed like even in grad school you had time to reflect and think about what you want to do. And that can also, that can be a privilege, but also can be kind of hard because you have all this optionality. How did you narrow down what to work on? You had the world's, the world's your oyster right now at Janelia. How did you mess up? How did you actually like work on things that are useful?

Yeah, you know, one of the limitations of Janelia, which is engineered into the system, is the labs are small. So I started out with 2 people. So, you know, I hired a couple people, and then what I decided was, yes, I have all these resources and I can do whatever I want, but, you know, I was like the one chemist. I'm still kind of the one chemist. It's terrible if I was here just doing random chemistry and not really being integrated into to the larger Janelia community, right? So we decided that every project we would do would be a collaboration. Collaboration is huge at Janelia. It's one of our founding principles. And so initially we were working on imaging probes, but also working on neuroscience. At the time it was 1/3 imaging, 2/3 neuroscience. Now it's evolved a little bit. So I had folks like Eric Betzig, Harold Hess, the super-resolution and localization microscopy, PALM, and all those things had come out just a few years before. It was still a really big deal at the time. And then there was all this neuroscience stuff. So we had projects along both lines. And I'll admit it was hard to balance those two. So our first, papers were on imaging probes. We also had this paper on targeted molecular delivery, and the idea was to target indicators or dyes or drugs to specific neurons in the brain. I was trying to balance both of those things with a very small lab, but everything was collaborative.

Okay, that sounds overwhelming. That sounds like a lot of work. Sounds like a lot of stuff on your plate. Sounds like a lot of people, like, Do you seek out the collaborations? I'm trying to just understand. You're the enabler for a lot of people at Janelia and just imaging in general. Do people come to you with ideas and then you have to curate them?

Yeah, I wasn't very good at the beginning. I think the spirit of Janelia is you just You know, it's what I tell people is I will— I'm willing to try anything 4 to 6 times, right? Um, because, you know, it's like I, I don't have to swing for the fences. I can swing for the fences more than once because I have that freedom.

Yeah.

And, you know, I mean, I did— you know, we did crazy stuff, right? Like every once in a while, like I'm cleaning up the lab, I'm like, you know, I find some relic of that time. You know, I have like this $3,000 high shear mixer and we were trying to get carbon nanotubes into resin, so we would fix the charging problem in EM for Harold Hess, right? We tried a bunch of stuff, a lot of it didn't work, but what ultimately, you know, we got traction coming back to, you know, grad school and everything was, was really investing in the chemistry of small molecule fluorescent dyes, because again grad school, I was using this 1887 chemistry to make dyes. At Probes, I was using that chemistry, just cooking things in really long acids. That was the way we made rhodamine dyes.

Yeah.

And, you know, I, I was slowed down during my PhD because of this, right? I could have probably got more stuff done. And so, you know, I show up and, you know, one of the books that I joined— not write it at me, um, but a little bit later was this guy John Green. It was someone I'd known in graduate school, and he had gone to Merck. And, um, and so I eventually convinced him to come, you know, hey, make some dyes with me.

Cool. Yeah, maybe we can maybe give a primer on probes. This is something that's like been going on since the 19th century, like, uh, be the history of dyes, the key moments.

Yeah.

And how do you think in the current era we're in, you know, what do you do? Like, what are the big— what were the big problems in each organelle? And maybe those problems still kind of exist, but maybe like, when you think about the history of imaging, especially imaging dyes, what are the key moments that kind of got us where we're at right now.

Yeah, so, you know, this whole field of dyes in general, just meaning color compounds that are made in a lab, this started in 1856. This guy William Perkin, you know, like kind of goofing off in his parents' attic, accidentally discovers this purple dye, mauveine. And that's like all of a sudden, you know, that turns organic chemistry from this curiosity into, industrial powerhouse. So a lot of the companies that we still think about today, BASF, come from the subsequent decades where dye chemistry became important. And so they made a ton of dyes, really until the 1930s. Some of the early drugs for— was a dye that they screened. You know, we get Tylenol because Tylenol was made because there was a byproduct of dyes, so they're like, oh, we gotta figure out how to, how to use this stuff, this byproduct, in our dye production. That's where we get it. And so, you know, a lot of the fluorophores that we still use today were discovered during that time. So, you know, there's fluorescences sort of in the mix. It's not until the 1940s when Kuhn says, hey, we should have more antibodies. Yeah, and that's immunofluorescence. And then in the '60s and '70s, people figured out you can make lasers using dye solutions. And so a lot of the structures that we still use today to improve photostability or brightness kind of come from the laser dye work. And then in the '90s, we get the Alexa Fluor dyes and Cy dyes and the Atto dyes and others, right? These commercial optimized antibody Most of that was done for dead cell work, either labeling oligos or antibodies. But in the early aughts, aughts, I guess, Kai Johnson developed this SNAP tag technology. Omega developed this HaloTag technology, and this now allowed us to take molecular fluorophores and use them in living cells of the animals, right? So little enzyme-based tags that grab onto a little synthetic piece that we can attach to a fluorophore, and so it forms a covalent bond. So you can label proteins inside the cells with synthetic dyes, and then you shine light, they glow, and you image.

Makes sense. Yeah. So Luke, you wrote this awesome review on it. Thanks for sending it to me. But we'll link it in this, and that kind of goes to the kind of the the history to the big opportunities in imaging dyes, it seems like the big leap was then using fluorescence to image cells. What happened was that, I'm not familiar with all the literature here, but was it around the time you were at Janelia? Yeah. And what were the kind of implications that like, hey, we can actually image live cells and then start imaging protein motion, image like transcription factors and begin to like really peer into the cell as it does things rather than looking at like stains and stuff, right?

Yeah, so the, you know, we managed to hit things just right. I mean, it's a little serendipity. So we have, that's their amazing microscopes. Then Tom Czech resigned, you know, I mean, he's step down from being president of HHMI after 9 years. And so, Tijen was president. And even before he became president, him and Rob Singer and a few others created this transcription imaging consortium at Janelia. The idea was to image transcription factors in mouse cells. So, these people were Secondly, through that's where we got Brian English to come down from. He was in Rob's lab at Einstein, came down. And so we assembled this team and I was sort of on the periphery. But the idea was, hey, there are these labeling tags. We have these amazing microscopes. Mats Skoubsafsson was also developing scopes there before he passed away. And so You know, together we sort of built this little imaging ecosystem to watch molecules move around in live cells. And the idea was to look at diffusion, which is amazing biochemistry, and a lot of in vitro stuff.

I think he discovered the first transcription factor. So something to tip your hat on.

Which is something else. Um, you know, soft-spoken too.

He's like a master. Yeah, he just walks very slowly and you're just like, oh, you're just like, uh, he's— or I first met Teach on a massive screen because he's always somewhere. Yeah, and he's just sitting there, his face kind of like being like, uh, like, like, it's like he's like being somebody on a on a movie screen and then you're like, oh, nice to meet you. And you just like, um, world-class science. So you created a transcription factor for Trorscha.

Yeah.

And you had Jonathan Grimm. We'll also talk about how to build a group.

Yeah.

And the culture you've set. Yeah, yeah. But, uh, Brian English, some real superstars. Yeah. Uh, was that kind of the catalyst for you to— I mean, what I'm trying to figure out is like, what was the catalyst for you to develop the fluorodyes? Yeah, like, what was it, just kind of a collection of projects and you start putting these together? I mean, was it this or something else?

Yeah, so, um, see, I want to say—

and maybe you can describe what the series of dyes you produced too.

Yeah, so, you know, at the time we, we started getting involved with this group, um, you know, there was, there was a little bit of a transition. There was some in vitro work that was being done, some, and then moving into live cell single particle tracking again, watching molecules move around in live cells. And, you know, we had, you know, TJ had a little group of, at Janelia doing the in vitro single molecule imaging things. They had built a nice TIRF system with C2. And so That was sort of the initial project, and I joke about this sometimes in talks, is, you know, Tij came in and said, okay, we need a red dye attached to this HaloTag ligand, the piece that would grab onto the protein. And so we did it, it took like an hour, but I didn't want to give it to you too easily, so we waited. And then I emailed Tij, and Tij was busy, he was posing in Chichime, so I waited a while, and then like I said, I think we finally got it, Tij, and you know, And then, you know, and then we published a paper with them, but that was the beginning. And we learned, okay, there's a single molecule and stuff, but they were still using the dyes from the, from the 1800s to do this. And so John and I thought, oh, should make a better fluorophore. And we had developed chemistry where we could make any rhodamine dye we would want. And then the question is, well, what do we actually make? You know, that's, I think, a big difference in the field now is because of our work and many others, you know, in the before times, the question really was, okay, we're boiling things in sulfuric acid, what can we make? You know, what's going to survive those harsh conditions? Now with all this good chemistry, the question is, what should we make? You know, because we can make almost anything. And And so I, I was just kind of goofing off with some very simple computational chemistry experiments. And, you know, I had this idea, what if we installed a little 4-membered ring to the fluorophore? Would that still look like a dye? What would it be? And so I remember, you know, I ran a calculation, came in the morning, looked at the structure, and it looked promising. So I went to John and I said, hey, check this out. He's like, oh, I'll make it.

Cool.

And that was the beginning. You know, I still work in the lab. That's one of the things Janelia group leaders do. And so I was doing some spectroscopy, and then John was— had made this dye and he was purifying it. There was this eureka moment where you like pulled the fractions out of this HPLC purification system. And, you know, like the brightest thing we'd ever seen. Like, oh, that's going to be a winner. Um, you know, ended up being a really simple modification, so we really only added 2 carbon atoms to this dye from 1887, but we made it much, much brighter, and that pushed us over some limit to really be able to do useful imaging in live cells, right?

Really, I think the paper got published 2012, 2015. I'm just trying to remember, but I think the timelines. So you publish that paper. Well, did you have a lot of inbound? I'm assuming everybody's like, how do I get these dyes? So what was the— you publish a paper and now the world knows about it and realize, oh, you can have all these dyes across the spectrum and you can synthesize them and everybody wants a piece of it. What was the— was it overwhelming inbound, or was it just kind of under the radar?

It was a little under the radar after the paper, but I think, um, in general, you know, chemists tend to publish things and then, you know, we'll wait for commercialization. Uh, there's, there's not this culture of sharing, and it makes sense because it's It's time and money, typically of a grad student or a postdoc. You know, they shouldn't be spending their time necessarily making stuff. You know, they should be doing new stuff and, you know, getting on to the next stage of their career. So there's not this culture of sharing. I mean, even in the genetically encoded world with tools that are based on proteins, you know, it's easy to share because you can just share plasmids. And then you have Addgene, fantastic organization that shares things on people's behalf. But the, you know, so we, we got some, some people asking, and then John and I just one day decided, yeah, let's just start giving stuff away. Cool. And, and so, you know, people would ask, you know, where can I buy this? And I said, oh, we'll just send it. Cool. And, and They're like, really? Yeah. And then, and then we also decided just sign paper. Another thing in chemistry, often with the culture is, well, you know, I paid for that synthesis and someone in my lab did it. So we gotta be authors on the paper. Sometimes I gotta be a co-corresponding author because you couldn't have done that work without my molecule. And we just said, let's not do that at all. Let's just say, sign our paper, acknowledge us, and it'll be cool.

I think this is, this is like kind of the epitome of the beginning of your story. Yeah, Expo, having hippie parents, you know, living in Oregon, living on, you know, remote cabin. And now, you know, 20 years later almost, it's just like now you're publishing this work that has a lot of value and then bringing those, bringing your own values to that. Let's make it open access. So there's an Addgene for all these different types of plasmids, and you know, you can just essentially— people will publish a CRISPR paper and make the plasmid accessible through Addgene. You propose AddChem, which should probably exist, and you'll probably build it sooner or later. You already have it kind of quasi-built. Maybe you could talk about that, like how many dyes you send per week to other labs and kind of like how's the growth rate for BIB the last maybe like 7 years?

Yeah, I mean, it started out just word of mouth and then it got— I tend to not I don't do marketing. I mean, you know, I was giving a lot of talks and stuff and, you know, Teach was too, right? So people would be like, hey, I just heard Teach. Talk to me, try this thing out. Right. And then I think people were shocked because we would, they would show up the next day. Right. But didn't really have an automated system. It was just email to me. And so, um, you know, I had, um, At one point I got a new administrative assistant, this awesome person Anastasia, and, and, you know, my old assistant had been dutiful, like, you know, 20 emails on Monday, like, okay, here's a little stuff over the weekend, and then I would, you know, collect everything, handwrite little index cards, and we would get them all shipped out. Um, then Anastasia came and said, yeah, we're not doing this, we're gonna So she created this whole web portal and streamlined the whole thing. To answer your question about how many prizes we send out, I estimate we send out 100 to 200 a week. I actually don't know because I'm out of the loop on purpose. So there's no gatekeeping here. It's something we just do for the community, and I'm actually not involved. We have these awesome technicians, Katie and Sarah, right now who take care of this. They synthesize things, they put little things in bags. We have an organized freezer. And I, you know, I don't know what's going on. And that's— I don't want to put my fingers on any scales or do anything weird like that. I think that's important.

So have you been to a talk or been to some sort of conference or poster session and, oh, it's a pretty cool church, and then you realize, oh, they actually eat the dye. Have you had those moments?

Yeah, a lot of times I go to conferences and people are like, thanks so much, you know, and I am like, I don't know you. I don't know who you are.

I mean, yeah, Johnny Appleseed of imaging chemistry. We're just like, here, give dies away, the legend of Luke Levis grows by the year. And also Jonathan Gritton and Brian English, all the great people. Maybe we could transition towards group culture. I think Janelia is an outlier. I think the whole institution has a great culture. But for your group in particular, how many people is there? I think 6?

Yeah, yeah. So we started with 2 people at Janelia, and the largest lab is 6.

Okay, so then how did you think about What kind of lessons? You've been in Genelia for now for 15 years.

Wow, awesome.

Congratulations. Um, have kids through that time or family?

Yeah, two.

Were they born in Genelia?

Yeah, they were born in Genelia. So yeah, yeah, family. Eric tends to joke that the biggest impact Genelia has had is the number of children. There are a lot of kids. So yeah, my kids, so my son Linus, so we named him after Linus Pauling, another Oregonian chemist.

I think Linus has the same saying where you have this, you know, you're saying, I'm willing to try things 4 to 6 times. Linus has his own little number of ideas. It doesn't matter how many ideas.

I mean, a lot of ideas and a good selection.

Something like that, exactly.

No, Linus Pauling, you know, another Oregon state grad actually.

Really? Yeah, yeah.

Oh, I didn't know that. Yeah, cool. Pauline, amazing person, and you know, also a little bit of a maverick, right?

He was out there. He was— he won the Nobel Peace Prize and, uh, I think chemistry Nobel Prize, and he, uh, you know, that very famous image of him posing in the triple helix. Yeah, this is it.

And then, you know, it was true, but You know what I mean?

Yeah, he definitely did. And then, uh, okay, so you did that for 15 years. What kind of lessons have you learned about leading a scientific group, recruiting people, uh, retaining them, and then trying to set a culture of like— you kind of alluded to this, you know, being useful versus being— Yeah.— Right or something else. Or being like, how do you, over the last 15 years, what kind of lessons have you kind of learned about culture and leadership, especially for scientists? The scientists are kind of a hard group to please, versus like you're at a company, everything's aligned with money or product, but science is this, it's jazz almost. How do you lead a jazz band of scientists?

It's true, right? It's—

everyone is unique.

Yeah. And I think one interesting thing about science, which Hughes and others are hopefully going to help solve, is you're a good scientist and you're chosen to be a PI because you have good hands at the bench and good ideas. And then they place you in essentially a small startup biotech role as CEO, right? And so you have to learn all these management skills kind of on the fly. So the important thing is to have good mentors. Yeah, you know, I had fantastic mentors— Charles Zucker, Columbia, and also my colleague Scott Sternson, the guy that met me and grilled me in my first day at Janelia. Scott and Lauren Luger, also at UCSD now, who's who was just at this workshop, so it was good to see him. Cool. You know, have good mentors who can help talk through things, because, you know, you're not going to know what you need to know starting out running a lab. And then the other thing that I learned is, you know, not everyone is like me. I benefited from a very hands-off management style. Figure things out on my own. I enjoyed, you know, just kind of coming in and doing things. Not everyone's like that. People need some good high touch. They need a lot of, you know, they need to talk about, talk things through, you know, and so you have to figure out a specific management strategy for every single person in your lab.

That's okay. Yeah, again, it's possible for like a smaller group. So maybe, yeah, you know, so there's a— that's kind of a feature of having groups in Generalia versus like 100-people labs.

Yeah, I mean, if I had a 100-person lab, I could do this, but I could have a personalized mentorship style for every single person.

So like, it seems that for a smaller group to be as productive as you are, you really have to find the right people for the problem and the work. Yeah. And you've recruited some superstars. It seems from talking to you, it came from your network. Oh, this person I knew from grad school, come join me. I knew this person from Ruben's lab, come join us. How do you think about, like, how do you cultivate a good taste in people, especially to work with on research? Because like, that seems to be— how do you like It seems like the group you run, it's like Special Forces and versus standard Army. And how do you— how did you get good at filtering, making your group just really cohesive? And it seems to be a challenge for a lot of people.

Yeah, I think one One lesson I learned, or this has been before, like I was a kind of worked as a janitor from 12 on. You get a church. Yeah. Yeah. This is like a funny story, but my, the, my boss at the time, this guy, Ted or Todd Medder, what Todd taught me was always be willing to do whatever you ask someone else to do. And Todd, yeah, Todd, it's a construction guy, like kind of legendary. Like, you know, you ask someone to do something and, you know, 3 guys said, oh, 3 guys couldn't do this. He went up there and did it all. So, you know, it's like one of these people, but it was a lesson I learned early on. So, you know, it's about treating people with respect and also being willing to do whatever If you're going to ask someone to do something, it should be worth your time, not just their time.

I bet it's pretty inspiring that the people in your group see you in the lab as well. Yeah. And getting your hands dirty and actually like—

Not as much, if they're listening. It's not as much as I'd like and not as much as I used to, but yeah, but I do get in there from time to time. Yeah, that's useful.

Cool.

Yeah.

Yeah.

And then I think the other thing is trust your gut. Yeah. Another important mentor is Jerry Rubin, founding director of Janelia. And what he always says is, you know, your gut's going to be right 85% of the time. So you have a choice. You can either learn to live with the 15% wrong decision or spend the rest of your time trying to get to 90% right decisions. And so he's like, learn to live with the the 50% failure rate, and then you'll be fine. So it hasn't been like— my decisions in general haven't been all perfect, but it's about, you know, this person, this person gets it. You can usually tell just for a brief conversation this person understands, passionate about science, understands the problem, understands what we're trying to do.

We can, um, talk about the And then lastly, maybe penultimately, like what are the big problems working on now for imaging? What are the big problems in imaging probes? Is it trying to make them more photostable, brighter? Is it trying to find applications in neuroscience and trying to like find like biosensors, live animals? What kind of things are you working on now?

Yeah, so one thing we're, I mean, I can list a bunch of different things. One thing we're really trying to do is democratize super-resolution microscopy. Cool. So, you know, this is a technique that came out, you know, 17 years ago now, and it's still not that easy to do. And so we're trying to make super easy to use probes and then also give them away for free. Cool. So that's one thing. You know, even, you know, we want to know anyone can use this stuff, not just an expert, and hopefully not having to invest a lot of time to get some photoactivatable thing to work. Right. So we're working on that. I think the future of all biology is going to be in vivo studies. We're moving from cult cells to tissue, ultimately to in vivo work. So everything we do in a cell culture system now, 10 years we'll probably do in vivo. So for the field I'm in, small molecule fluorescent dyes, we have to figure out how those dyes behave in an intact animal. And we have to treat dyes like drugs. And that's the thing we're not used to as a field. And it's expensive. We get something to work, we get a cell to glow, we get a paper, and that's it. So we've invested a lot of time in figuring out the rules around bioavailability of a lot of our dyes. And now have a suite of fluorophores that work in vivo, and that allows you to do cool experiments like pulse-based labeling. And then the other thing that we are really thinking about, and even this workshop at CZI, we were discussing We've been making fluorophores 150 years now. We don't know the chemistry behind a process called photobleaching. You illuminate them over time, and then eventually there's some photochemical process that destroys the fluorophore that makes it not fluoresce anymore. We just don't have a clue what's going on there. No one's ever investigated this. So it's boring work. Probably would have a hard time getting an NIH grant for this, but it's something Genially can do. That's something we're going to really invest in in the future. Cool.

Okay, so look back at your, like, really varied career. You've been exposed to so much, and it all seems intertwined with growing up in Oregon and just being lucky at approach to where it seems like so from outside looking in, so diverse, but then in reality when you hear it, you realize, oh, it kind of starts from this one small, and it built up from there. Kind of what any lessons you've learned in terms of like choosing a career, you know, figuring out who to work with, especially for scientists a lot of PhDs who are trying to make their own decisions. Kind of any takeaways so far?

Yeah, I remember I had this decision to make. Would I leave? I love— I still love Oregon. Everyone knows I love Oregon. And I had this opportunity to go down here., to work at Molecular Devices. Yeah. And I remember sitting with my then-girlfriend, now-wife, coffee shop, and remember she said, let's just do it, right? And I mean, actually everything in my life is because my wife prodded me and made me like that concrete there. And so the— and if it wasn't for her— but, um, you know, but, but taking risks is important. And sometimes, you know, you don't think you can do it. It's scary. It's like first-generation college student kid, you know, worked in this safe environment at Molecular Probes in a familiar place, and then suddenly moving down to Silicon Valley, you know, crazy, it's a crazy time. But that was worth it. It was a risk to not stay here, to go to Madison, Wisconsin, and then again taking a risk to go to this new institute in Northern Virginia, kind of in the middle of suburbia, that was untested on COVID. But I think taking risks is important. You know, you don't want to be safe, especially when you're early career, right? Never regret not taking a risk.

Yeah, I'm sorry, you never regret taking a risk. Yeah, just like having a good support network and then just going for it. When you have when you don't have more original kids and stuff like that. Yeah, it's— how do you, uh, how do you— something I have struggles with— how did you deal with transition periods? Like, I always— I have a big struggle when I move somewhere else. It's like a 3 to 6 month period where I'm just like not, not established. And how did you like— how did you like move from probes, devices, sounds, and generally, yeah, you've been in jail for 15 years. I'm assuming when you're in your group Probably have routine. There's some advantages to that, but in those early days, how did you like, like, not feel bored and still be productive? Because it's hard to explore and still do things.

Yeah. Something my wife and I talk about a lot is having lived in many different places now, You know, you realize that no place is perfect. And so the goal is, you know, you maximize the good things and then you minimize the bad, right? There are good and bad things. Oregon is amazing. There's forest fires and it rains a lot, right? Virginia, you know, the winters are a little bit rougher. The summers are humid. But you figure out what you can do. I mean, I live very close to the Potomac River, so, you know, I paddleboard every day in the summer. And, you know, it's like you find joy and you find the special thing about a place and you, you, you know, invest in that, do that. Because, you know, it's the old saying, you can't go home again. Sure, you know, if I ever go back to Oregon, I'll be like, oh, this— there's good and bad things here too, right? It's— I, I realize that. I think fine. But, you know, there are great things about living in Silicon Valley, great things about living in Wisconsin, and bad things too. But, you know, cross-country skied in Madison and did a bunch of biking down here. We, like, did all the cultural stuff and, you know, went to the ocean whenever we wanted. Uh, it's minim— it's minimizing the bad things and maximizing the good.

Cool. Okay, take Musk's family, and they all— and you have some notes. I'm very curious about your notes.

You wrote a lot of notes Who knows? Who knows? You're right. You're right. Anything else? I think the one thing I wanted to say is, you know, I think we're entering a new phase of science where generosity and kindness is valued again. I think the cutthroat competitive environment is kind of going away because we realize we have to collaborate. It's really rare for one lab to be able to do all these things well and really dominate a field. And so, you know, working together is going to be a better way. And, you know, it's okay to be generous, be kind, you know, be honest. Sometimes you get a little screwed over, but you get screwed over more if you're like a competitive jerk. So it's totally okay to be be a nice person and do excellent science.

That's awesome. There's the Beatles song, right? Love is the love you make, or maybe— I always get it confused— that like at the end or something, um, where you just want to put more stuff out there and then, you know, you'll, you'll get some of it back. You probably will get it back. And so cool. I mean, um, thanks for doing this. Yeah, you're visiting here, uh, and this is probably the best office in slow them down. We should go get some snacks right now. Uh, and get you— you fly now, or, uh, uh, yeah, yeah, fly back tomorrow. Okay, okay, I don't want to make it— oh yeah, we not flying— I know you're flying out later. Oh no, no, I mean, okay, I feel a little bad. I just want to get something to drink. So like, you've been talking, I was like, take a break, or should we keep going?

But thanks for doing this, I really appreciate it. Fantastic. Yeah, thanks for having