Scientist Stories: Alexandra East-Seletsky, Drugging RNA, CRISPR, and More

Welcome to the Ribosome Podcast for April 29th, 2021. I'm Luke Roberts, and today we're speaking with Dr. Aleksandra Soletsky, a scientist at Arrakis Therapeutics, about her experiences.

Hi Luke, I'm excited to be here to talk to you today.

Great, thanks so much. So how are you? And how's— I mean, the question we have to ask everybody— how's your life doing in this global crisis?

Um, I'm overall doing great. I think I'm honestly very thankful that, you know, I have a job. I'm happy, healthy, and you know, that's all I can ask for these days. Um, and the craziness that is, you know, 2021.

No, exactly. There's, you know, there's a lot of things to be thankful for and most of them are small, so, but it's good to recognize them when we do get them. And so I guess one of the, you know, the big questions— we'll get right into it— is how was it to work for someone who later turned out to be a Nobel Prize winner? I mean, could you maybe describe what an average week was like and how did it compare to other labs? Was it like, did you walk in and go, oh yeah, this is different, or was it just— did it seem kind of the same?

Yeah, so, um, I guess maybe to, to ground this a little bit, we can start out with, um, I I was a rotation student in the Doudna lab in fall of 2012. So that's really kind of at the dawn of the CRISPR age, if you want to put it that way. You know, the Cas9 paper that had come out of the Doudna lab had come out the summer beforehand, and things were just really picking up in the CRISPR world there. But for me, as a rotation student walking into the lab, There was, you know, the Doudna lab was no different than any other lab. It was a well-funded lab. And other than that, I wouldn't say there was anything special about it in regard to like being a Nobel lab. It wasn't at the time. It was just a well-funded, large, you know, biochemistry lab that was doing some, you know, exciting science that I thought was maybe something that I could work on.

No, that's great. And I think that probably is a bit of a relief. It is basically, it is, it is to people like me who go like, okay, you know, it's, it's not like you show up and you go, okay, this is clearly a different level, you know, but obviously the well-fundedness has obviously played a big role, but it's, they're just like us celebrities, you know, like that whole, that whole thing, right? The labs, it's just like ours.

But yeah, and I think, you know, maybe some of the aspects that have really enabled the Dowdell Lab to do well and be the powerhouse that it is over its now 25-year span, it is not necessarily just the funding that helps. I think it's the people that Jennifer recruits and just some of the infrastructure. I think Jennifer even acknowledged this in, I think, some of her Nobel Prize speeches and things, but she's had the same lab manager since day one.

Yeah, I saw that in an article. That was really, that's really cool.

Um, it's really cool. Kai Hong is a powerhouse and like a whirlwind of activity. And, you know, I always tell people like Kai Hong is the magic that makes that lab flow because she knows where Everything is in the freezers. She makes all of our T7. She's like a whiz at transcribing RNA. So she's kind of this institutional knowledge that sits in the lab that really makes things go.

Yeah. And I think a lot of that stuff really probably the behind the scenes people are the drivers because not to take away anything that Dr. Dowden has done, she's done amazing work, but she's not in the lab every day. Bigger fish to fry. And so without people like your lab manager, the research isn't getting done.

Yeah. You know, I think the special touch that Jennifer has is that she's really good at seeing potential in people and potential in projects. And so, you know, she's very good at helping you think through like what the impact of something's going to be or how would you frame this to make it broader interest in not just this niche little field that you've been thinking way too deeply on as a trainee in her lab.

Well, no, that's great. And so what did you work on in the Doudna lab?

Yeah, so I worked on a variety of things. So I honestly probably had the most impact on society that I will ever have as a rotation student Because I was part of the team with Martin Jennek who was working on getting Cas9 to work in mammalian cells. So it was basically my first steps into that lab, which seems crazy now.

Yeah, that's wild. God, in retrospect, you know?

Yeah, exactly. Bright-eyed rotation student being told, like, why don't you try and get this to work? Like, you've worked in mammalian cells before. 'Well, let's just give this a whirl.' Wow.

Yeah, that's incredible to think of, especially, you know, with all the, you know, the potential for therapeutics and everything down the road. It's, you know, you can go back and look at your one lab book from that day and be like, 'Here's the day I got it to work.' Yeah.

So, I mean, you know, I think that was just eye-opening. You know, I don't know everything that was going through Jennifer's head when she was, you know, pitching that project to a rotation student, um, but for, for me, as the the new person, really in some ways overenthusiastic first-year grad student, it was an amazing project to be part of, and I'm really grateful for the opportunity. So then I went off, I did two other rotations at Berkeley, and then at the end of the year, decided to come back and join the Doudna lab. And I made either a very stupid decision or a smart decision, depending on who you talk to, to try and stay as far away from Cas9 as possible because I didn't want to work on a field that was quite that hot and competitive.

Okay. Yeah.

And so I spent the next 2 years of my time in grad school in the Doudna lab working on an aspect of CRISPR biology called acquisition, which is basically within the CRISPR biology field. It's the way that a bacteria discovers and remembers a new target that it's going to want to target with the CRISPR system. So I worked on that for 2 years, admittedly had zero success, and ended up switching projects at the end of my 3rd year. And so from there on, I was working on a project that was trying to target Cas9 to RNA. So how can we repurpose this great molecular machine to then have applications on RNA? Evolved into what became kind of my thesis project, which was working on the actual CRISPR enzyme that is the Cas9 for RNA, which is called Cas13. And so really the, crux of what I worked on and graduated out of the lab on was this project doing kind of the biochemical characterization of Cas13, understanding what its various enzymatic activities could do, and turning that into an actual RNA detection assay.

Oh, that's, I mean, that's great. And I think it's also nice every so often, you know, as unfortunate as it is to hear that, you know, your first 2 years didn't really pan out, it's just sort of like, everyone else, you know, goes through those as well. You feel good, you feel better about your own sort of projects like that when you go, yeah, all right, good. Even, you know, every— not everybody is, you know, it's not just me. Um, but I'm glad you managed, you know, to switch and still get a very, you know, productive PhD out of it. That's, that's very good.

I think the other lesson learned is that you can look at my CV and see, you know, these really cool high-impact papers. But the time in between those two papers was not so successful. So there was a lot of, you know, challenge and failed projects and dead ends in between. So just because, you know, it looks like there's been a lot of success or someone has that big paper, it doesn't mean that things were always working for them.

Yeah, absolutely. A lot of failures on the way to those successes. And so, yeah, important to keep in mind, hard to conceptualize when you're just seeing the new papers come out every week and, you know, in Science and in Nature, right? But you go, okay, for every one of these, there's like 100 projects that didn't get there.

Right. And I feel very lucky that I was on projects that did have that potential to publish well, or that we were in kind of the right place at the right time working on science that other people are going to be interested in, because that's not necessarily the case.

So yeah. Yeah, sometimes just like you mentioned, sometimes you get a hot field. And if you're just fortunate enough to be in the right place or you see it coming and you've got the tools to work at it, you can really cash in. But yeah, sometimes, you know, as much of the stuff as you're doing right now, like if nobody's reading about it, cool as you think it is, it's hard to, to get it out there in those higher impact journals. And so I guess after your time in the Doudna lab, why did you choose to leave academia?

I would actually challenge you on that question because for me it was not about leaving academia, it was about going back to industry. So to again maybe walk it back a little bit more, I had taken 3 years off in between undergrad and enrolling in grad school at UC Berkeley. And in those 3 years, I worked at Merck, which is a very big, large biopharmaceutical company, and then spent 2 years working at the Broad in one of their core groups that really functions a little more in an industry-like setting than an academic setting. And so, you know, through those 3 years, I really figured out that I was— I loved the team-based science that was going on in, in those groups. And I was part of, you know, these— at the Broad, I was part of like an 8 to 10 person team that was pushing together this big project to screen 500 cancer cell lines by a genome-wide shRNA library. And so it was this huge part where everyone played a key role and we were passing things back and forth. And it was just really invigorating to me to be part of this larger team. And so I actually had a harder time when I transitioned into academia, going into this model where it was just you working on your project, trying to push your thing forward. And, and that was so foreign to me. So when I was finishing up, I knew, and that, you know, my ultimate goal was to go back to that more team collaborative science as quickly as possible. So I was, you know, lucky enough to land a job straight from my PhD.

I mean, that's great. And that's even, you know, as somebody who hasn't had an experience like that, that's It's very— the only experiences I've relatively had are, you know, self-driven science. That's really interesting. I hadn't considered being part of a larger group and that being, you know, more amenable to other work styles. But, you know, good job challenging me on my question. If you know what you like, there's no reason to be in the academia ivory tower if, you know, industry is your fit.

Exactly. And I think the other piece of it is that, you know, I hope and wish that there was more conversations within academic settings, that there are other options of what you can do with a PhD, and that you don't just have to train as a, as a grad student to go do a postdoc, to become a PI, to, to be on this track. And that's not to say that that track works for some people, and it's a great way to do science, right? But there are other options out there, and it's not like one size fits all.

You said you were lucky to get a job out of your PhD. Would you have any any advice for maybe some young PhD students who are looking to do just that? What, what should their next steps be sort of looking like?

Yeah, so I think as someone who's now sat on many hiring committees on the other side, the things that at least my company is looking for— and this is not necessarily every company, right? I can only speak for my own experiences, but The things that companies are looking for is for you to be productive on the job from day one. So generally that means that you have some skill set that they need, right? And that can be really broad, right? That can be, you know, an easy one to think about is having bioinformatics skills, right? And so, you know, if you were someone who worked on a, you know, very basic biology project but handled a fair amount of sequencing data, like, your ability to handle sequencing data is actually a pretty good marketable skill set within an industry setting. And we at Arrakis have hired, you know, multiple people of that phenotype of kind of being a mixed wet lab computationalist for pure computational roles. Um, you know, other ways to think about it is like when you are, you know, approaching the end of your PhD, think about what your skill set is and try and find companies that care about that skill set. So for me, I was a protein RNA biochemist, right? That doesn't necessarily in and of itself lead, you know, shout translational medicine. Yeah, at all. It's not like I did mouse work. It's not like I was a cancer biologist. You know, I was a biochemist. So as I was searching for companies, I was looking for companies that cared about nucleic acids and really had— were going to be solving problems within their research organization that were going to be more molecular, biophysics, biochemistry based. And so that, I think that's what landed me at Arrakis. Arakis is a company that is trying to develop RNA-targeted small molecules. So a lot of what Arakis as a company thinks about is how do we connect RNA structure to function so that we can target it therapeutically. So me as an RNA protein biochemist fit pretty nicely into let's try and figure out RNA structure function questions.

And I think maybe one of the intimidating things about these larger companies is they've got a huge amount of staff and you go, I don't really know how to— when you say it right there, like, I don't know how to target RNA, target small molecules, what could I be doing? You go, well, you know, that's not— you don't show up and they go, let us know when it's done. They go, we have very specific problems, you know, that we're solving on like the fundamental level. And as long as you can like work through those problems, it's not like you're you mentioned, by yourself and you don't have to wear all the hats.

And so, and I think I got lucky that I'm at a company where there, there is good acknowledgement that, you know, no one person is going to solve this. And so you're, you're leveraging, you know, expertise all the way from medicinal chemistry because they're the ones who know a whole lot about how to make good small molecules, you know, through computational biology, through RNA biochemistry.

I guess, do you think the CRISPR technology or gene editing in general is going to soon reach, you know, humans, or is this something that we're still 10 to 20 years away from?

I feel like I should preface this by saying that I do very little CRISPR-Cas9 research anymore. I work for a small molecule drug company, and admittedly, I'm very happy sitting in the stands cheering all of the, you know, companies who are trying to develop CRISPR-based therapies. So I just want to make sure people know I have no insider info here.

Yeah, don't buy stocks based on this, anyone. This is not advice.

Exactly. I feel very privileged that something that I worked on in grad school at some point may be part of therapy that goes into a human at one point, right? And I think that's super exciting, and I think that, you know, it would not have as much buzz and as much money being thrown around at it if there wasn't real potential there for CRISPR-Cas9-based therapies to be, to be helping patients. CRISPR-based therapies definitely have are going to make it to market. I don't think anyone really doubts that at this point. I mean, if you look at the headlines, Vertex just gave $900 million to CRISPR Therapeutics to really—

A small investment. Yeah.

Yeah, just teeny, to really push their hemophilia drug to market, I believe. I think I have all the details there correct. So, so there is definitely interest, and that's going to be impactful. But where, honestly, I think that CRISPR-based technologies are, you know, making a bigger difference is every day in the lab, right? You know, people listening to this podcast have used CRISPR-Cas9, you know, in their work to do something. And so that, to me, is where the real power of the technology comes from. It is just doing those, you know, basic science aspects of, okay, well, now you can actually make mutants. Now you can engineer cell lines so much easier and faster in a way that, like, opens up fields of science in a way that wasn't possible or wasn't easy before. Not to say it wasn't possible, it just wasn't as easy. In the long run, where do I think CRISPR-based technologies are going to have the biggest impact is, like, actually in basic research. To me, that's where I think if you were, you know, if I was a I'm a betting person, if you're to go, you know, 20 years into the future and look at the therapies on the market, I bet there's some step in their development that involved CRISPR for basically everything.

You get so caught up in this, you know, "Ah, we'll cure every disease," you know, "We'll get rid of sickle cell anemia because we'll just edit it out," all these things like that, right? And you go— but yeah, it's something I guess that's probably overlooked is just how much of an advantage this allows basic researchers. And how much of every research idea is based on these basic principles, right? It's like the PCR, what that did for basic research. This is probably just going to be looked at as one of those, even in terms of its huge change it's having on everything. Yeah, I guess it's easy to get caught up in all the hype about the things getting injected into people, but the basic research thing is very important to keep in mind. So yeah, thank you. That was a good answer for that. Do you have any more advice for like junior researchers if they're trying to make a decision regarding how to like join a specific group? What was it about the Dowden group that you said, okay, this is the group I want to go with? And I guess which leads to follow in a project even now in your time in industry? How do you know? What's, what's, what do you think is one of some of the most important factors for going, I think this is good, or this is like, this is a dead end and I need to know when to call it?

You had a lot of questions.

I know that was like 7. I can hit it again if you want.

I think the first of those that is easy to answer is like, how— what advice would I have for people when they're thinking about joining a lab or joining a company or making their next step? And I think for me, it's all— every step that I have taken in my path to where I am now I've been always focused on trying to find a good fit. So where is a good fit for me personally, where I'm going to be in an environment where I can thrive? And I've honestly cared very little about what the actual science I, I was doing. I'm a curious person who likes to solve problems. I'll solve those science problems on just about anything. My undergrad research was on plants. I worked on actually viral vaccines at Merck. I worked on genome-wide shRNA screening at the Broad. I worked on CRISPR nucleases and microbiology for my PhD. And now I work on cancer biology, right? So like, really broad set of fields. And the thing that has kept me engaged those whole times is finding environments where I could thrive. So having the people around me, whether that be my peers and probably more importantly, you know, either my mentor or boss, be someone who I knew that I could work with. Because that, that's what was actually going to impact my ability to succeed more so than like what precise science I was doing.

No, I think that's a great answer. As much as projects might be cool, if it's a toxic lab environment, you're going to end up hating it.

And so, right, and one person— and, you know, what works for one person is not necessarily gonna be a great environment for someone else, right? So, you know, some labs are really deep and focused in one area, and the PI can be an extreme expert on this one system, and they're understanding every new facet of a project. And there are people who totally thrive in that environment, right? Because you get to ask really precise questions and dig into really precise mechanism. And I know maybe this is starting to become apparent after listening to me talk, but like, I would get so bored in that situation, like working on like one thing on one topic, hearing every talk at lab meeting being on like a similar topic would have been mind-numbing to me. So like, I knew going into grad school that I wanted variety. I wanted, you know, a lab that was working on a diverse set of problems, maybe using a similar technology sort of thing. So that was just something that I looked for. And but, you know, there are other people who don't necessarily want that.

No, I think that's, I think that's great advice. What advice would you give people on, you know, coping with their, we can say failures, but you know, when stuff doesn't work, what advice would you like, how do you personally deal with it? And do you find certain strategies allow you to sort of like move on a little easier than others? What have you sort of found works for you?

You know, failure is part of being a scientist. Um, so one, accepting that, that not everything succeeds. And if every experiment you're doing is working, you're probably not doing the right experiments, right? Because you should be pushing the boundaries of what is known or unknown. And a bad experiment is really only an uncontrolled experiment. The other, I think, key thing is ask for help. Ask the people around you if they've encountered these sorts of problems before, or like, is there a better control you could be running? Or I have this perplexing data, I don't know what to do. Like, what would you do next? Because everyone loves to talk and thinks that their ideas are the best. So you're like not actually putting someone out by asking their, for their help. Most people want to help you. Don't be afraid to ask for help.

I think that's really good advice, especially on the grad student type level when you're pushing your own project forward. It's very easy to get caught up in your own ideas and think like, oh, I just need to do this again, right? And sometimes getting that outside perspective is super critical.

Or thinking that you have to be the one with all the answers. Yeah, like you don't. You don't have to be the person who knows everything, who designed every bit of your project, right? Some of the most fruitful things I did during my time in the Doudna lab were because I was talking to other people and they were, you know, throwing out wild and crazy ideas at me. And we tried some of them, a lot of them didn't work, but some of them did.

All right. So I guess, you know, since we just talked about coping and dealing with failure, do you have a particular failure of your own, which you'd be comfortable sharing that, you know, this is one thing that we like to do at the end of our podcast. Is just talk about, as much as we love to celebrate the successes, it's also, I think, equally important to talk about the failures and just even if they're particularly funny, that's always a bonus for me.

I admit I don't think the story that I have is that funny, but I think it's very relatable, which is that I kind of already alluded to this earlier in the conversation, but probably the Biggest, scariest failure I had in grad school was when I realized that I really needed to switch projects because I had been going down dead ends for 2 years and there was, you know, nowhere else for me to go with this project. The, the project that I had that was the biggest failure was, you know, I mentioned it already, was the first project I was working on in the Doudna lab after I joined the lab full-time. I was working on aspects of CRISPR biology that very few other people in the Downer lab were working on. So I was really isolated. I was trying to do basically a microbiology project in a biochemistry lab, which was a poor choice in retrospect. But, you know, I was an early grad student who had big ambitions and wanted to to drive my science in the direction that I thought was really cool. So I spent 2 years developing and working on this project. It's what I proposed for my qualifying exam. And 2 years in, I had to admit to myself that nothing was working. I don't think I had a single piece of positive data. The— to kind of add insult to injury, this was a period of time where my mentor, Jennifer Doudna, at the time did not have an administrative admin, which is kind of crazy.

Wow.

So somehow meeting with me had totally fallen off of her calendar. As I was realizing I needed a new project, I had not met with Jennifer for probably 7 months. So she had no idea that I had dug myself this huge hole. And I had to schedule a meeting and walk into her office and say, I haven't talked to you in 7 months and I need a whole lot of help and a whole new project because I'm not going anywhere.

Takes a tremendous amount of courage, but I think obviously you made the right decision. I think that's really important, especially for some grad students to hear that might be in a similar position, right? Admitting to yourself that this isn't working and I can either bang my head against the wall and be extremely unhappy or as hard as it is, making a change might be the right call.

Well, and I also think I had built up that meeting in my head because I was like, I haven't met with her. I have to have some piece of data, like the next piece of data. That's when I'll schedule the meeting, the next piece of data. That's when I'll schedule the meeting. And it just, you know, snowballed into this. Very, you know, the situation that no one wants to be in, right?

Yeah. Oh yeah. I've been there myself. Yeah. I've done the same thing where you go, I don't want to talk yet. I want to just give me one thing and then I can just have this one thing. Yeah.

One experiment that worked. But I mean, I also have to, you know, give Jennifer a ton of credit in that moment that she was 100% understanding. And so, you know, she was just like, this is fine, this is normal. We can work through this. Stop trying to do experiments and let's figure out something else for you to work on. You know, I don't think all PIs would've said that in that moment. So, you know, definitely it, you know, it goes to her credit that she knew how to deal with me in that moment. But I think the other thing that she was doing was, was giving me space and not putting more pressure on me to like, Oh, well, let's just do a few more things here. She was like accepting of my conclusion that this was not going anywhere and like, let's find something new. And so she pointed me in the direction of a few other postdocs. And that's where I really just started like realizing I need to be talking to people. I need to be asking for more help. I need to be, you know, working on something that's not off in this corner, but actually like within the bread and butter of the lab of biochemistry, and that's where I'll actually have more success.

Oh no, that's really great. And you know, that's, that's the interaction with a, with a PI that you, you always wish you would have. So it really speaks to her, you know, her character and her ability to run a successful lab is probably due in large part to how well she handles these situations. That's really good to hear. I'm glad it went so well. And so I guess now that we've talked about, uh, your time in the Dowdner lab, you tried the Broad Institute, and you're your current job now at Arrakis. What's next for you? Do you have plans, goals? I imagine you've definitely got them. I guess just what are they?

No, I actually, you know, when I saw this question on the question list of what you wanted to ask, I was like, I don't know what my answer is. I haven't thought about it. I think part of it is like once, you know, in an industry setting, you know, there's kind of less of like, here's your benchmark, right? Like, it's not like I'm aiming to start my own lab and or get the next, you know, R01 funding or whatever. For me, I'm at the moment very happy with my current position. I get to work on a wide variety of science. I'm doing things from NGS assay development to cell line assay, basically validation. And what the next step for me would be would just to find a role that maybe had a little more visibility or more influence across the org. But personally, I'm very happy and content where I am because I get to do cool science with cool people. In an environment where I get to do fun things.

And I think that's a perfectly acceptable answer. I think a lot of people get tied up in the, you know, there must be continual progress. I must get a promotion. I, you know, I have to keep moving up the ladder. I got to do this. I got to do Y. And I think just, you know, recognizing that you're happy in your job, you're thriving. There's, you know, if your plans for right now are to enjoy your life, I don't see how that's a bad plan. So You know, and I think maybe that's a lesson some people can take home as well as, you know, there's nothing wrong with just, you don't have to have a major plan.

So, I mean, I think the other piece is, is, you know, I'm happy right now, but that doesn't mean I don't have ambitions or, you know, there aren't places, you know, where I want to, you know, move up it within the corporate ladder. Although that sounds weird. For, for me, what you know, as long as I'm doing good science, I'm happy. So, you know, I'll slowly develop as a research manager within industry and manage either larger teams or bigger projects. I don't envy the people who want to jump straight from a postdoc to a PI because, because those are two very different jobs. And while there are PI-like roles in industry, you move to them a little bit more slowly and stepwise in a way that's a little more comfortable for me personally.

I think that's great, and I think that's a perfect place to sort of wrap things up. And so I'm going to thank you so much for your time, you know, Dr. Seletsky. Um, and so just so everybody is aware, again, Dr. Alexander Seletsky is a scientist at Arrakis Therapeutics. You can find— I mean, do you have a social media you'd like to plug or something? Do you have a Twitter? Do you just want people to add you on LinkedIn? You want people to leave you alone? What would you prefer?

I am on Twitter, um, @AlexSilecki. Um, I can't say I'm very active, but people are welcome to follow or reach out to me there. Um, I would always plug that Arrakis is a great place to work. Um, so if anyone has any questions about that, you can reach out to me on Twitter or LinkedIn. Um, and we're always looking for you know, good RNA biologists.

All right, well, hopefully there's a number of them listening right now, you know, and you'll get an influx of, uh, junior scientists applying to this. And so if you're interested in more about, uh, the Ribosome Podcast, you can find us on Twitter @theribosompodcast. And so this sort of concludes our episode. If you have comments or suggestions, uh, for the show, you can write us at theribosompodcast@gmail.com. The show was edited and produced by Leanna for us and the rest of the junior scientists. And thank you so much for listening. Keep your bench clean and your RNA pure.