By Nuri Kim.

Tyler Guinn (MS3) is a modern-day Renaissance man. Since starting the MSTP at Stony Brook in 2015, Dr. Guinn has juggled medical training, marathon running, reading the longest novels he can find, picking up an instrument (guitar) and foreign language (Ukrainian), and all the while completing his PhD in bioengineering in just three years. This year, he was also one of five recipients of the President’s Award to Distinguished Doctoral Student which is awarded to students for excellence in their research and contributions to Stony Brook University.  

In April, a month into the COVID-19 lockdown, Tyler defended his dissertation built around a cutting-edge tool, the Light-Inducible Tuner (LITer). His graduate research centered around designing an optogenetic system for tightly regulating gene expression in mammalian cells. Tyler received the National Defense Science and Engineering Graduate Fellowship (NDSEG), a highly prestigious award from the Department of Defense, for his visionary work on the application of LITers in cancer biology and toward tissue engineering.

I had the pleasure of chatting with Tyler over an hours-long interview – which was hardly enough time to scratch the surface! In addition to talking about his rich and diverse extracurricular life, we discussed his high-tech thesis, the life lessons that carried him through graduate school, and what it was like to be among the first PhDs defended on Zoom.

Name: Tyler Guinn

Hometown: Rowlett, Texas

Dissertation Lab: Gábor Balázsi Lab, Stony Brook University

Clinical Interests: Transplant surgery

Tips for resilience: Let curiosity pull you through adversity.

Remind yourself monthly, weekly, daily, even hourly (if you have to) what your goals are, why you are pursuing them, and how they are relevant to your life. It takes time to do this, but if you can articulate these goals, it becomes a matter of how, not if, you will accomplish them.

Find a hobby that you are not good at and practice it every day. See what happens with persistence.

Did you always know you wanted to be a physician and bioengineer?

Nooooo. No! In high school, I wanted to be a professional poker player, actually. I played poker every weekend. We had Native American casinos nearby in Oklahoma, so we would drive – this isn’t too good, but I did sneak in a few times under aged to play. But I think that’s like any aspiring professional poker player.

While I was still in high school, I got a job as a clerk at Walgreens. I worked at the front – selling cigarettes, that sort of thing, which is kind of ironic.… But then a job opened up in the pharmacy, which is the opposite of cigarettes. The reason I took it was not that I was [motivated to] go into medicine. It was because there was a $3-4 increase in the pay rate, so I was like, “I’m going for that job! That’s going to help me with poker!”

And that’s where I first started thinking about medicine. What I realized from working in the pharmacy was that the same people came in every week and every month. I’m not always the best with names, but I remember faces very well. So I would remember them, and for the first time I started interacting with patients – not as much from the medical side but from the pharmacy side.

From there, I kind of fast-forwarded a few years to upper level courses. I didn’t do research the first two years at all, but I was taking those pre-med courses. In one of the first weeks of the class, there was a movie of ATPase in the membrane. The professor showed it, turned it on, and it started utilizing hydrogen atoms to produce energy. I thought, “This is insane.” This is a molecular machine. That was the idea that got me into research. [I had taken some] engineering classes earlier and that made me think, “I want to build those things. I want to build little machines just like that.”

So that’s when the research started. I started thinking: “I don’t even know if this exists… are there labs that do engineering and biology?” At the time, our school didn’t have an undergraduate degree in biomedical engineering. They had a PhD program, but the undergraduate degree until the tail end of my undergrad or shortly thereafter so I tried to focus on finding a bioengineering lab instead.

I found a bioengineering lab that was only taking graduate students. I emailed Dr. Leonidas Bleris. I think back to that often. I know I have that email somewhere. It was just kind of funny to re-read those early emails. I basically said, “Hey, I’m thinking about pursuing medicine and research. I have no experience. Can I come in? I can clean some dishes if you want me to. I don’t really have any talents with this, but I’m interested.”

He got back to me pretty quickly and invited me to come over to his office for a meeting. Early on, I was so scared going up to meet him, thinking I had this great opportunity in the nicest building on campus that I hoped I didn’t blow. If you ever have the chance to visit UT Dallas, I’d love to show you around because some of the older buildings were from the 60’s. It actually started as an engineering school out of a company called Texas Instruments – you probably recognize their calculators? A lot of the campus was not pretty when I started. But by the end they had built it up, and I mention all this because there was this one research building on campus that was really nice: the Natural Science and Engineering Research Laboratory. And that’s where Dr. Bleris worked.

I remember going up the elevator and feeling so intense like, “I don’t know how to interact with a professor. I’m always sitting at the back, or quiet, not raising my hand…” But he was like, “Come on in.”

He invited me to join the International Genetically Engineered Machine (iGEM) Team for the school that he advised. We tried a lot of things in that lab while working on iGEM projects… and in the end, most everything failed. But there was something about that that was so important to me. Even if you fail at something you scrape off your knees, get back up, and keep going because there’s something about the curiosity that keeps pulling you. I stayed in his lab for basically the whole time until I came to Stony Brook, about four and a half years. And I actually had a picture of him in the last slide of my defense because I had this collage of family and friends and old lab and new lab – everyone that had made a big difference in my life.

You were among the first handful of MSTP Zoom defenses. Can you tell us what that was like? Any surprises?

The internet at my house went out the day of my defense. It went out an hour before my defense, and I ended up going to the Laufer Center on campus and doing the defense there, haha.

Earlier in the day I thought I would relieve some stress, go for a nice walk with my fiancée. When we got back, I was like, “I’ll check the PowerPoint one more time, let me check my email…. Email’s not working. Internet’s not working. Oh my god!” I was panicking.

My dissertation was at 1:00pm, and by then it was 12:15pm. So, I was grabbed my laptop, a monitor, a laptop stand, a charger, and my N95 mask and went to school to school as fast as I could. I thought about making a joke about it at the beginning of the dissertation, but I got so focused on what my advisor Dr. Gábor Balázsi and committee were saying at the beginning of the dissertation that I forgot to do it.

It’s a funny little story. Always have a plan B.

I think whether we go back to physical defenses, having the Zoom component was really cool because my 82-year-old grandma came and watched. That would probably have never happened – one because she doesn’t fly, two because she’s across the country. Some of my old lab mates also got to join, which was cool seeing them. It gave me a boost of confidence.

 

For your dissertation, you built a tool that allows you to manipulate stem cells. How did you become interested in stem cell research?

I had been working on light-based gene regulation, or tools that turn gene expression in a cell on or off only when exposed to light. I was interested in exploring the question: What can light do that chemical signals can’t? At the end of the day, if you build the same tool with light-responsive versus chemical, what is the advantage?

Spatial development kept coming up as a potential answer to the first question. Organisms have spatial development: They have areas that develop first or differently from their neighbors. A question I had was: How do human cells develop? They come from some precursor state. Could a light tool direct a population of these precursor cells and control a single, small step toward development? Then, instead of a population, could we control just one stem cell going from one step to the next, while all the neighbors remain stem cells? The spatiotemporal control was something light could accomplish that chemicals could not.

I came at this project from that angle, first asking how do I apply the tool, then back-tracking to learn about the biology behind it. I don’t know if that’s controversial. People have different opinions on what comes first: the tool building and there’s the science. To me, these always went together. And what’s exciting to me about doing both is if you build the tool, you’re often going to be the first one to apply it.

So you took a technical question, married it to the biological problem of coordinating the development of populations of cells. This led to your designing the Light Inducible Tuner (LITer) system. What does it do, exactly?

The idea was to make a tool that allows you to tune your proteins of interest to very precise levels. Many biological tools could knock down or overexpress proteins, but these often had limited control, acting as ON or OFF switches. Also, unregulated gene regulatory systems often produce very high gene expression noise. Lastly, recent biological findings have suggested the gene dose or how much a gene is expressed can be as important as whether a gene is expressed at all. Systems attempting to address these above issues had been done in chemical systems, but hadn’t been worked out in optogenetic systems. Our light-responsive circuits are designed to minimally perturb what else is going on in the cell and control the single variable you’re interested in. This lets you control, for example, proteins that drive stem cell differentiation or migration or proliferation using a radio knob where you can turn up the volume, essentially.

While that’s similar to well-established chemical gene regulatory systems, a light responsive system also allows you to control the expression spatially. Chemical systems cannot do that because they rely on diffusion which globally activates a cell population, but you can control where to apply light, therefore only stimulating small groups or even single cells.

A third important improvement to existing systems if that LITers include a way to create stable cell lineages. Optogenetic systems were often transiently transfected. When you do transient transfection, you can get uneven distributions, where some cells may get one number of copies and another cell gets another – and that can dilute out from a cell over time. It is not a stable system. That in itself is a source of confounding factors. Our system can be stably integrated into a cell’s genome using CRISPR-Cas9. This ensures that every cell you analyze is truly identical, lineage-wise.

How do you predict or hope this technology will impact not just the landscape of gene engineering research but also your career going forward? How do you see this research project translating to the clinic – in the short term or in the long term?

One thing we’re doing now is using LITer to look at proliferation and migration and how these two cellular processes work during wound healing. For the original work, we did not knock out the endogenous genes. But we do have that capacity and our future directions involve looking at genes involved in epithelial-to-mesenchmal transition (e.g. BACH1 or ZEB1). We’re in the process of making cell lines that have the integrated gene circuit with the endogenous gene knocked out. We’ll be using these cell lines to test a range of gene expression completely under our control from underexpression to overexpression without any interference from the endogenous gene.

Now this is really far off in the future, but maybe in thirty years, this is a conceivable long-term goal for LITers and systems like it. These systems may get to the point where we can take certain cells from a person and utilizing different genetic approaches, develop tissues de novo and replicating them down to spatial architecture.

This could work by integrating LITer gene regulation with a technology similar to something in radiation oncology, where you can shoot X-rays from multiple angles to target cancer while reduce harm from any one angle. The idea would be, instead of killing cells with X-rays, to use light to induce gene expression spatially and specifically without affecting any one cell too much. Having this sort of system could direct cell populations to develop spatially to generate new tissues or organs. I think it is a little science-fiction right now, maybe it’ll happen in our lifetime. That’s what I’m hopeful for.

You completed your dissertation in just three years! What were some habits or perspectives that helped you achieve this?

A bullet journal! I used this to basically map out future tasks, daily things, weekly things, monthly things. I tried electronic calendars. It doesn’t work for me. It works for some people. What I realized for me that you get a little notification at the bottom, I just click “x” and ignore it because I’m in a middle of a task. But if I keep this in front of me before I go to bed, put it on my desk or wherever I look first, it’s facing me in the morning.

I don’t think bullet journals will work for everyone, and I think it’s fine. That’s the other thing. Try new things for a week. If you try it for only a day, you can get annoyed with it, and it’s hard to see if it’s making a difference. But try it for a week, and you can get a better sense if it’s your thing. The only reason why I stuck with this is because it kept working. I know some people on Google Calendar who are super organized, I think, but I guess I’m still in analog for now.

Also, I think it’s important not to count research as the sole metric of success for MD/PhD. When you interact with your peers, are you cordial? Are you respectful? Are you friendly? Are you actually friends with them? If you’re a professor, are your colleagues miserable when they see you? Are they trying to avoid you at the gatherings or the holiday parties? Those seem like subtle and small things, but I think I’ve realized the value of incubating those other aspects of life.

The idea that life starts “after med school” or “after residency” or “after fellowship” – but if you really follow that all the way through, you wake up in fifty years and realize, “I did not live.”

You have to integrate life because the training is important, the career is important – I’m not trying to encourage anyone not to focus on the career. It may be a cliché, but the idea of having well-rounded aspects of life: You need different aspects. Maybe you need family, friends, career, fitness, interests, hobbies, and relaxation. If you like certain things, have them in moderation.

As cohort-mates, you and I have talked a good deal over the years about these ideas – and in particular how we think about them in relation to our shared love of literature. And I’ve been so impressed each time we sit down to chat it seems you’ve read another handful of books for recreation, even while maintaining productivity. Can you share five titles that helped you through your training so far?

The first is Crime and Punishment. Dostoevsky integrated so much psychology and interpersonal dialogue and showed that if you think of yourself as an atom, you’re isolated. And maybe it’s easy to think about that when focused on the career mindset, but you are an atom in a molecule, which is a molecule in a cell which is a cell in a body, which is a person in a nation, which is in a world… It’s so complicated, it’s so connected. To assume that you’re nothing but the atom is to neglect all that complexity. You can’t neglect those other things of life, essentially.

The second was East of Eden by John Steinbeck. It was for me… and I don’t know how other people feel, but for me it was terribly emotional. Terribly emotionally gripping. The multigenerational sins of a family, and how that propagates, and how redemption does and does not relieve that guilt… yeah, that was a very important book to me.

One book changed my career path, research and medicine-wise. That one is called When Death Becomes Life: Notes from a Transplant Surgeon by Joshua Mezrich. It’s by a transplant surgeon. I had played around with the idea of surgery before I came to Stony Brook, but I kind of dropped it when I thought of a research career. That book rekindled my interest in pursuing surgery, and at the moment, that’s what I’m leaning towards now.

That was a second book about surgery I could not put down,The Puzzle People: Memoirs of a Transplant Surgeon. It was written by Thomas Starzl who did the first liver transplant. He wrote that book in the style of an autobiography, but it is also about the development of transplant medicine. And I think from reading both Mezrich and Starzl…what it made me see was the overlap in engineering and surgery – and specifically in transplant surgery. After I read them it became so obvious. How did I not see that? But well, you know now.

I have to add this – The Master and Margarita. The Russians… That book… had some things. Like this parody of the Soviet Union and how terrible it was, punishing innocent people, and how Bulgakov uses Christ imagery – the innocent being put to death. I think the common theme in all of them goes back to the atom analogy. You’re not an isolated quark. You’re connected in different ways. I think that’s what so cool about these narratives.

 

Nuri Kim (GS4) studies codon usage bias in Mycobacteria in Jessica Seeliger’s lab.