801: Using Gene Editing to Create Enhanced Cell Therapies - Dr. Kyle Cromer
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Hey, everyone. Thanks for joining me today for Episode 801 of People Behind the Science. I'm your host, Dr. Marie McNeely. And today I'm joined by our guest, Dr. Kyle Cromer, to talk about life and science. This episode is made possible with support from our sponsor, Innovative Research.

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They offer small quantities, bulk purchases, and custom purchase orders. From human whole blood to specialized antibodies, innovative research has what you need to succeed in the lab. And today, our guest Kyle is going to tell us more about his lab and his life. So get ready to meet another one of our fantastic people behind the science.

Every day, discoveries are made that will change our understanding of the world around us. Dr. Marie McNeely is here to bring you the brilliant minds who are making these discoveries so they can share their incredible stories and take you on an amazing journey. Welcome to People Behind the Science. ♪

Hello, everyone, and welcome to People Behind the Science. Today, I am excited to be speaking with our guest scientist, Dr. Kyle Cromer. So, Kyle, welcome to the show today. How are you? I'm doing great. Thanks for having me. Well, thank you so much for joining us. And before we get into the details of your work, I'd like to start by telling our listeners a little bit more about you and how you got to where you are today.

So listeners, Kyle is an assistant professor in the Department of Surgery at the University of California, San Francisco School of Medicine. He completed his bachelor's degree in animal and poultry sciences at Virginia Tech and his PhD in genetics at Yale University. Afterwards, Kyle conducted postdoctoral research in genetics at Harvard Medical School. And next, he worked as a postdoctoral fellow and subsequently an instructor in pediatrics at Stanford University before joining the faculty there at UCSF.

Now, Kyle has received various awards and honors over the past several years, including the Stanford BioX Star Mentor Award, the

the American Society of Gene and Cell Therapy Career Development Award, the UCSF Program for Breakthrough Biomedical Research New Frontier Research Award, the American Society of Hematology Junior Faculty Scholar Award, the Mary Ann Cota-Kimball Seed Award for Innovation from the UCSF School of Pharmacy, and the Catalyst Award from UCSF Innovation Ventures.

And Kyle, today we want to get to know you as a scientist and get to know your research. But we'd also like to get to know you more as a person and hear more about life outside the lab. So can you tell us what do you like to do when you're not doing science?

So lately, it's been different than it has over the past 10 years. I'm going on paternity leave really any day now. The due date, it's in 10 days, but I think it's fully determined. And so we've been doing a lot of prep. That's really what I've been doing a lot of lately. Outside of that, I can certainly speak to some other hobbies and other interests that I think really helped me balance out just maternity.

what I spend a lot of time doing as a scientist. Yeah, I'd love to hear more about what was life like before the preparations for the big day. So I've always loved visual art and thinking about this question, that's the very first place that my mind goes.

I've loved going to museums, always felt like I had strong opinions about what I liked and didn't like and always wanted to make it myself. But I think it took me a long time to find the right medium. And what I mean by that is you'll have an idea for something you want to do. But if you're not really practiced at drawing or painting, you'll try to do it and it'll fall way short of your expectations for it.

until you find something that feels like maybe it is a style that you can execute that doesn't take a ton of technical practice. I mean, something that you'd have to do to paint a realistic painting, I think would be really, really difficult if you're not doing it full time. So then that lends itself well to abstract paintings. My wife and I have been stretching our own canvases lately, mocking things up on the iPad. I see how I apply it. It

kind of the structure that I bring to science of kind of hyper planning, very meticulous about how we actually map this thing up that looks kind of random, but it's drawn on an iPad, iterated on, then we use a projector to put it up on the canvas and then sketch it out. And it allows us to capture some level of appearance of randomness, but it's not exactly that.

Oh, absolutely. I think that systematic approach is sort of a hallmark of a scientist there. And I love that you're able to bring this interest of art into your life. I think that's wonderful to combine your interest in science and art. So let's talk about your science next, Kyle. How do you describe what you do in the lab to somebody who's not in science or maybe just not in your particular field? I think the elevator pitch or the sentence or two that I would use if somebody asked me about it is I'll ask maybe, have you heard of CRISPR?

And I guess the unfortunate thing is if they've heard of CRISPR, but not much more, it might be about the CRISPR babies that were created in China. That was kind of a big news story, but also ethically problematic for doing this embryo editing. And so I'll say, oh, we're not doing that. But any disease you would pass on to your children is a typo in your DNA.

And so what CRISPR, it's a genome editing tool that allows us to correct those typos back to what they should be. And I'll usually end there. But then if they show some interest or a sparkle in their eye, then I'll go a little bit deeper and maybe give a specific example or talk about what else you can do with that.

That's usually how I go. I try to read the room and make sure somebody's eyes aren't glazing over. I think that's important for science communication, making sure the audience is staying with you. And I think the work that you do is very exciting. We'll get into some more of the details as we go through our conversation today. But I think in science, sometimes you need a little extra motivation, a little inspiration to get through the day. So do you have a favorite quote or a saying or something that just really motivates you, Kyle? The

Yeah.

anything that you plan to do, whether it's in science or not, it's probably going to be more or less difficult than you thought that it would be. So if you can fail fast and find out where to spend your time, focus on what's working, add everything else if possible. I think it's kind of good life advice. And I think I've realized that I've applied it in many different facets, whether intended to or not. Once I embraced this idea of fail fast, even in dating before I met my wife, it's like fail

fail fast. It could be about trying to get a sense of whether this is working or not and cut your costs when the costs are feeling like they're sunk.

I don't know if that's motivational or not. I think it's instructive at the very least. I think being able to find out as quickly as possible where it's worth it to invest your time and energy is really important in science because oftentimes there are so many unanswered questions in your field, it's hard to figure out where you should be focusing. So I think that's great advice. And you mentioned specifically a postdoc mentor. I think these mentors can be instrumental in shaping your career. So

When you look back over your own experiences, Kyle, were there other scientists or mentors or just folks in the field who you looked up to and maybe helped you get to where you are today? There were so many. I think it's what kept me in science. And it also made me want to be a good scientist. It often came in the form of a senior grad student or maybe even more often a postdoc mentor in the different labs that I've been in. It's meeting the right person at the right time. I

I realized also an environment can be really stimulating, really exciting. But if you don't have a good teacher, you might just end up spinning your tires. And so I think for me, I can probably think of a dozen people that I met along the way that kept me going.

I'm not even talking about the PIs because they're not typically the ones that you work with day after day and really refine your scientific expertise, your strategy. That being said, I've learned so much from the PIs that I worked with, but it was oftentimes more high level and zoomed out and seeing how they would approach a problem and not necessarily the day-to-day troubleshooting that is just also essential to make progress and push things forward. So

So I realized from these different postdoc mentors, they all approached it a little bit differently, complimented themselves. And I think we all try to borrow from the people that we admire, the pieces that we admired the most and bring them along with us. And so I have done as good a job as I can of bringing these pieces of wisdom, like the fail fast sort of approach or all the many other little pieces of advice that I would imagine my lab probably hears me say quite often. That's just like that fail fast. Yeah.

I think that's really helpful. And I think oftentimes people consider these leaders in the field, the people who you should be learning from, but there is so much that you can learn from your peers, your students, all of these different career stages that you're going to be exposed to as a scientist. And I think looking for lessons anywhere can be a helpful approach to make sure that you are continuing to grow and continuing to develop as a scientist. So let's talk about your career path, Kyle. Can you take us back to the beginning and

Tell us what first lit that spark for you and got you interested in science. So I grew up on a cattle farm in rural Virginia. It's a different way of growing up compared to the people mostly that I find myself around nowadays in San Francisco in research. My dad and grandfather were veterinarians. My grandfather worked on horses and my dad did both large and small animal, really just serving the community.

So it was a job that I was familiar with. I really did like animals. I actually like cows the most. They're very peaceful creatures. I know they get a bad rap for being dumb, but they're really content as long as people aren't messing with them. They're considered in Hindu culture as sacred because they're kind of meditating all the time. They're not worrying about what they did in the past or what the future holds for them. They're always in the moment, that's for sure. So

So I came to really appreciate cows and working with them, training them. I got into show cattle, livestock judging, all sorts of things that were part of local 4-H or Future Farmers of America in high school. And it was just fun.

I thought that that might be something I'd want to build a career around, maybe being a veterinarian specializing in cattle, maybe reproductive technology. I became really fascinated with how farmers that you don't think are naturally early adopters of cutting edge technology, but that's really where the rubber met the road for artificial insemination, embryo transfer, euthanasia.

Even cloning now, I would bet that most cloning that happens nowadays, at least for mammals, is cattle.

So this was a really interesting world to be part of. Being in the show cattle, the cattle breeding and genetics, it also made me just fascinated by genetics in general. So I went to Virginia Tech, studied animal and poultry sciences, which is really the pre-vet major, thinking that that's what I wanted to do. But also at the same time, knowing that being a cattle vet is just really tough work. I saw my dad leaving in the middle of the night to go help a cow give birth during the calving season.

I think also if you're dedicated to working with large animals like that, you're probably bound to get hurt at some point or another. So it's just a tough life. And at the same time, I took a class, I think it was three students and two postdoc instructors in a biochemistry research lab. It was in a Piaz actual lab was where the class was, just this really small scale teaching environment. It's

It's where I started to realize that this was some different way of engaging kind of the same things that I saw my dad and grandfather engage in, just intellectually challenging, stimulating, whether it be for medicine or learning more about these tiny systems, these cells or how proteins interact with each other. I really started to enjoy that. Also, just I think I'm a pretty practical person. So I

I wanted to have a job and a lifestyle and a routine that I thought was sustainable that I really enjoyed.

And the people in this research lab and the PI, I really thought they enjoyed what they were doing. And you could just see their eyes light up with the passion for their research areas. And I just found it to be a really great environment, really healthy environment. And I think these are some of the great role models that I had early on. People who I thought had a really good balance of life, but really felt like what they were doing was important. After that, that really convinced me to go to grad school. But I also realized it was very, very basic science. And I wanted...

to be closer to medicine. It's just something that I knew about the research I wanted to do. At the same time, I've had friends who said the opposite. They knew they wanted to do the most basic science and be further from the translational end of things. And I went to Yale for, it was their umbrella program, Biological and Biomedical Sciences.

And this was a really vast department. There was everything from fly genetics to viral mediated gene therapies. There was deep sequencing, like next generation sequencing was just becoming a thing really on the heels of the Human Genome Project. It wasn't planned, but I just thought it was a great opportunity also with great mentors, a great teaching environment to go into a lab that was doing next generation sequencing to try to find mutations driving endocrine tumors.

So that's the environment I found myself in, kind of just following what I thought was interesting and a good opportunity. But also it became clear that at some point you've found most of the disease causing mutations, at least the ones that are easier to find of kind of liken them to bitcoins. At some point you found all the easy ones and then it just gets tougher from there. And so I knew I wanted to stay in science and you all wanted to do something that kind of built on this foundation.

But I didn't know what I wanted to do next. But it was fortunate timing because the answer was given to me. This was probably 2012. And I saw a talk by George Church. He was invited to give a seminar at Yale. And he's the first person I heard talk about CRISPR. So I realized that from that foundation of reading genomes like a Microsoft Word document and trying to understand which typo is the one that's causing the disease, because it's probably only one, maybe a secondary or tertiary one that adds to it.

But really, there's one typo. How do you interpret that? How do you read this language that is DNA? I thought that was a perfect foundation to build on top of that and start using the editing tools to edit that DNA. And it really was a great way to complement the training that I had. However, anytime you're trying to acquire new tools or learn

learn anything new. You have to be in a good teaching environment. And I think George Church's lab was a massive lab. It was really, really stimulating. I think it was the right place and right time for me to break into something. But I think I needed more special guidance and more attention. And so this is when I continued my postdoc training at Stanford in Matt Gordius' lab. And this was a clinical genome editing lab.

I knew nothing about hematopoietic stem cells or blood disorders before this lab outside of just you would come to hear about sickle cell disease as a non-clinician. So I found myself using these genome editing tools to correct sickle cell disease or beta thalassemia in this lab. And I thought if I'd always wanted to go closer to medicine, this really was about as close as it could get in an academic setting. And I

And I've just been following that path ever since, building on top of that foundation that's the genome editing tools and thinking about what comes after typo correction, because there's something that comes after correcting typos. And I think there are a lot of examples of just taking patient cells and making them wild type again, healthy again, isn't enough because they will just behave like a normal cell then. But we have the tools and knowledge to make them more therapeutically potent.

And I think that's where the genome editing tools are a means to an end. And that end is engineering new properties into cells to give them more therapeutic efficacy, make them safer. And so that's what I'm trying to do in my own lab.

But I mean, it took us from the cattle farm to now in San Francisco. Yeah, it's been a journey. Well, can you tell us then what led you to, from Stanford, establish that independent lab that you're running now at UCSF? It was a Zoom call. Ultimately, in June of 2020, everything was on Zoom during COVID.

And my professor at the time in the lab at Sanford, he'd given a talk at a conference or symposium and somebody from UCSF, he was showcasing some of the work that he and I had done using these genome editing tools to correct beta thalassemia. It's very like sickle cell disease, but it's just a little bit more challenging because it's not a single mutation that everybody has. Everybody kind of has a different mutation, but in the same gene. So it was kind of the logical next step after sickle cell disease, the next higher hanging fruit.

So we had used genome editing tools to create a one size fits all sort of therapy, a genome editing strategy that could work regardless of what mutation that you had. So he presented that work and somebody came up to him afterwards at UCSF, a trainee, and said, hey, we're thinking a lot about alpha thalassemia. That's probably the next higher hanging fruit after beta thalassemia. The disease presents just like beta thalassemia. You don't make enough functional red blood cells.

but each patient has some sort of different typo that's leading to that. Could we do something similar for that? So it led to a collaboration with folks at UCSF and that really helped me get my foot in the door. And, and,

I think I caught attention of people who were interested in bringing in somebody who had expertise in genome editing. So it was a right place at the right time for me, but also just one of the benefits of being open with your science and sharing your ideas. And one of the things I've just loved about being in academia is just

The goal is to do good science and collaborate and share information as much as possible. Not that that's not true in a lot of other spaces, but I think it's especially true. So that's kind of how it worked out for me. Definitely. I think this story really brings out the value of making these connections. So you're not just another faceless applicant in this pile.

So I think that connection, like you said, getting your foot in the door can be really valuable for folks out there. And we talked about your research a little bit, but perhaps you could share in more detail one of these projects that you are working on at the moment right now, Kyle, is there something that you are particularly excited about in the lab? I think it's the paper that we published that led to you reaching out to me. So I've

I've been editing hematopoietic stem cells to fix red blood cell disorders. And I think it's been great training to work in these rare disease spaces. I mean, the patients really need it, but it's tough. These are rare diseases and you have to create a therapy and get it through the FDA. And it's just a really, really costly time and cost intensive process. So just thinking about what else we could use the tools for. And when I got to UCSF, I was telling somebody,

that we were taking human clinical genetic data and using that information to create enhanced cell therapies. And what I mean by that is what's the next step after correcting typos? I think it would be to, okay, let's make even more potent cells

Let's introduce a change into the stem cell that allows it to make even more healthy red blood cells than you would get just normally from you or me. And so we found this great example of an Olympic cross-country skier from the 60s

who was accused of blood doping. And it took 30 years for genetic mapping technology to get to the point where he was exonerated. And they realized, oh, no, he had a typo in his DNA, but it wasn't something that caused problems. It actually was kind of the equivalent of genetic blood doping. It caused hyperproduction of red blood cells, but not so much that it caused problems, which

is a really great thing if you're wanting to correct these red blood cell diseases. It really becomes a matter of, okay, well, you can correct the typo, but if you're not correcting it in 100% of your stem cells, it's not going to be as maximally effective as it could be. So we started combining these corrective mutations with this Olympic skier mutation, and it worked really, really well. The mutation he had, I would imagine most people have heard of EPO, maybe through Lance Armstrong,

He had a mutation in his EPO receptor, which made his stem cells hypersensitive to EPO. And so we just started working with the EPO receptor. It was really easy to introduce these changes into it and they had really big effects. I remember the very first experiment looking in the dish and I could tell already that we had produced more red blood cells from the samples that had gotten that Olympic skier at it.

It was just immediate, huge effect. And the fail fast approach, it worked great. And we knew that we had a cool story there. So we shared this with one of my new colleagues then at UCSF. And he said, wow, this is really cool. It reminds me of the first presentation that I gave at UCSF. He pulled it up. He had to take five minutes to dig this presentation up from a few years ago. And it was, why don't we make red blood cells and bioreactors?

We always have these blood shortages. The American Red Cross is always trying to get people to donate blood. And yet frequency of donations is decreasing. So essentially, the national blood supply has been decreasing. So it just seems like a problem that is bound to get worse before it gets better. And so really just asking that question, you know, we have these companies that are making artificial meat from animal cells.

in bioreactors. And then pharmaceutical industry uses these big stir tank bioreactors up to 20,000 liters. Why don't we do that for red blood cells? And the answer is, well, it's really difficult. But if you start to read the literature, you realize that most of the advances in the space have been made by mechanical engineers making a better bioreactor, but then they just put normal cells in them for the most part. So as genome engineers...

And we're already, from a therapeutic standpoint, introducing these mutations that give you like 10 times more red blood cells just from the same starting material. With one simple change, this Olympic skier mutation, you can use less EPO and get more cells. So we have just been thinking more seriously about why don't people do that and what are the real bottlenecks that need to be solved in order to make red blood cells in bioreactors. Dr. Justin Marchegiani

And I think there's everything to like about red blood cells except for the fact that they're donated. So in terms of competing with something that's donated, it's tough to hit those costs, but there are a lot of needs for rare patients who have something that's rarer than O-p.

blood. Or if you're getting chronic transfusions with sickle cell disease or thalassemia, you can start to gain sensitivity to some of these minor elements on the red blood cells where your body does, when you're repeatedly given blood transfusions, it can start to cause problems. And so we think there are some unmet medical needs we could start to get towards now. Also thinking about making engineered blood products to treat things like hemophilia and other disorders, I think there could be some real potential there if we're already doing the genome engineering. So I

It's one of the things that I can't tell if this is the five-year problem or the 25-year problem. But I think the nice thing in academia is I don't have to have a product right now. I can just start pushing things forward, doing our best to try to address some of the bottlenecks. Also, while we're doing this, we're learning so much about how do you manufacture cell-based therapies at scale?

I mean, the lessons we're starting to learn for making red blood cells could apply to these highly engineered T-cell therapies. Anything that you would want to make it scale and deliver to patients, we're learning a lot about that because...

There's so much similarity when you take any stem cell and try to make it into a differentiated cell. And so we've been having a lot of fun with it. It's pretty sci-fi. I kind of like that kind of big picture. It's easy to understand why this might be important. And so, yeah, that's what we're really excited about in the lab. But we're trying to be realistic with ourselves and be patient here because it might take a while for us to really get there.

There's a lot of things that I really love in this story that you brought up. This idea of bringing together different disciplines to solve a big problem. You mentioned that you've got the genome engineer approach, but also thinking about how other people could contribute to solve this big problem. And I think getting all those data and methods together is really important from a scientific perspective. And then perhaps you can work with industry or others to think about how to scale up these things that you're doing in the lab to get to this level of manufacturing and production.

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And returning to our interview with Kyle, Kyle, the story you told about your research was fantastic. And I know the story that you tell at the end is always very polished and it sounds like everything just fell perfectly in place. But I know often in science, that's usually not the whole story of how it actually happened in the lab. There are struggles and failures and difficult days. So do you have an example of maybe a major challenge you faced or a failure you had to overcome that you could tell us more about today?

I think it's a matter of staying resilient because biology is complex, maybe infinitely complex. Cell biology just feels unpredictable too. You can't tell ahead of time how good this idea is. Is it going to work or not? Is it going to be easier or more difficult than you thought that it would be? We're always running up against problems. It's so many and maybe a testament to this idea of fail fast that we try not to spend that long on something that's not giving us some

fairly consistent feedback that it's moving forward, that these problems are solvable. So I don't have the best example in the lab of something. I mean, there are major failures. We've had entire mouse experiments that we've spent what felt like half a year planning and then executing, and then we just got no human engraftment.

But that was also a learning lesson for me, too, to say, well, maybe by definition, mouse engraftment transplantation experiments cannot be fail fast. You cannot learn right away whether it's going to work or not. You just have to invest the time and then cross your fingers six months from then that it will work out the way that you want.

So I think it discouraged me from really going and doing our second, our next mouse experiment and going deeper into the expertise that would be required to do a really good job of that in my own lab and going towards other directions that are maybe easier to model. I think that making red blood cells and bioreactors, I mean, it's all in a dish. The goal is to take it out of the body and put it into a dish. And so I think some of those things, I'm just trying to make us more streamlined and efficient if

if we can, and do experiments that can give us some constant level of feedback and encouragement to allow us to follow this trail of breadcrumbs to say that we're on the right path. That's probably the biggest thing that I would think of from just like a scientific single experiment, biggest failure in terms of time, cost, effort that was just lost. And I think that's just a fact of doing wet lab biology.

There are going to be times where you will feel like, well, you've done an experiment and maybe it took a month to do the experiment and then it failed or you got contamination or something bad happened that made the whole house of cards come tumbling down. And you would say to yourself, well, gee, I could have just been on vacation and then I would have been in the same place. Well, that's not entirely true because you probably would have come back from vacation and then tried to do the experiment the way that you did the experiment and then it would have failed.

It kind of requires that time and investment and failure. It's probably like being a good chef. You get a good sense of what to do when you see something for the first time or whatever you're baking is starting to burn or dry out or something. And I think there's a sense that you gain as a cell biologist of, are the cells doing all right?

ooh, if not, what can I do to help them recover? So I think it just requires that time investment, most certainly. Those are the ways that you deal with failure. It's just to understand that even though it doesn't look like progress, there is some level of progress there that you got something out of that experiment.

Maybe you learned a tough lesson. That's what I try to do when I just know that there's going to be some likelihood of failure priced in is it's just the cost of doing business. And nobody has ever done science without failed experiments.

I would say maybe the biggest obstacle that I've personally faced that wasn't just like a failed experiment. And I'd imagine some of our listeners could certainly relate. A PhD is a long time. It is. And I felt pretty burnt out at the end of grad school. I'll just be completely honest. It was hard work and there were things about it that I tired of. There were a lot of things at play there. I mean, your life is changing as you face graduation, whatever you're graduating from. It doesn't just have to be grad school, but...

It's a journey and you're leaving your friends behind and...

you can't continue to do the exact same thing you did before that big life event, which was graduating and finding a job or going on to that next thing. And I think probably part of that burnout was not knowing what I wanted to do next. I liked sequencing. I like finding these bitcoins, which were disease causing mutations. But I knew that that golden era was coming to an end, at least doing the same thing that I was doing. And I think it was just that professional existential question, a bit of what do I want to do next?

For me, I just took time off. I think I've always taken time off when I was between things. And it's a really great way to collect your thoughts. Go do something fun. You can distract yourself for a little while. But I think my goal, too, after grad school was to travel for long enough that I wanted to come back and be a contributing member of society again. And I did. I

I spent three months at home with my parents on the farm, just helping out. That's a much different way of life anyway. And then I spent three months in Southeast Asia, just backpacking, mostly solo. And by the end of it, I did want to come back. And...

be a contributing member of society and be a good scientist. I had enough good mentors. I saw the satisfaction they got from it. But I think I still needed to build some more confidence in thinking that I could be a good scientist and can find a path and a research area that maybe I have a unique perspective on or could excel at. So that eclipsed the failed mouse experiment by a lot.

I think this time that you're describing this sort of period of transition is something that you have to go through, unfortunately, a couple of times, usually during an academic career. And so I think giving yourself the time, the space to kind of reflect on what do I really want to be doing rather than just rushing into anything that's available can be really helpful for people. And I think it's good for listeners to hear that this works. People aren't going to question, well, where were you the past three months? Why weren't you writing papers? I think

It is acceptable to take that time and then come back to science when you're ready. Well, it's been wonderful to hear about the challenges and how you get through them. But Kyle, we don't want to dwell on those. We'd love to talk about some of your successes. So do you have a favorite scientific success, whether it was a big win or even just a small one that really meant a lot to you that you'd like to tell us about?

Yeah, I think starting a lab is a different sort of journey than becoming a good scientist as a postdoc with hands on pipettes. And it feels like an uphill battle a little bit. But my lab just published in the past month in

in January, two papers where I'm last author. And I think to me, this represents a transition from hands-on pipettes, at least in biology, the first author is the one who was usually the grad student or the postdoc that handled all the cells, did all of the physical experiments for the most part. And I think that transition from training other people to take that lead author spot and become good experimentalists. And now I'm more in an advisor role and

and guiding experiments. That's what the last author is in these cell biology papers. So these are the first of my career of where I'm serving that new role and kind of showing myself that I can do that. I can assume that role and do a good job with it. So one of these is our first step into making red blood cells in a bioreactor for

And actually, the other of the two papers that we published was that one on alpha thalassemia that started with a Zoom call in June of 2020. This tells you how long it takes for projects to go from start to finish. I mean, actually, one of them was the alpha thalassemia project, the one that started by a Zoom call, had that failed mouse experiment in it.

It's what kicks the timeline down the road in such a big way. And really, it highlights that you have to have patience. Nothing seems bound to work in the first attempt. Maybe that first attempt tells you how to make it work the next go around. So I'm really proud of those. But actually, by the time that they get out, the thrill of knowing that you can do it and this project is going to work has long since passed.

It feels like it was years ago that we crested the hill and said, oh, this is working as well as it needs to work for it to become a paper. And then it's just this kind of protracted process of, okay, let's do all of the final experiments. Let's send it out to a journal. Well, rejected. Let's send it out to another journal. Okay, we got reviews. Let's address the reviews. And so it's just this long outro, it feels like, for a lot of these scientific papers. I think the

cresting of the hill and knowing that the critical experiment or the critical piece of data, the critical finding worked. I think that might be the best feeling. And you don't have to remind yourself to celebrate those wins. It's just a great feeling. And even recently for a project that started in my lab, we felt like we just crested a hill.

We'd been working at the same problem. We're getting a little bit of encouragement over the last six months to a year that we could solve this problem, but we didn't know how we would solve it. And then finally it started working. It's combining a bunch of these little small incremental improvements. But if you combine them all together, they stack really nicely and then we've solved the problem. And so I

I would say, actually, that's probably been the best feeling in the last month is cresting the hill for this new project more than, OK, the final piece of this puzzle of the two papers that we finished up being published. That feels like a great accomplishment. But I think now we're thinking about the next thing and trying to embrace this idea, have confidence that what we're working on today is cooler than what we were doing yesterday and what we'll work on tomorrow is cooler than what we're doing today. And so, yeah, these are the great feelings that string you along and keep you in science.

I think it's a roller coaster of emotions. Sometimes you submit the paper, you're sort of at the top of the hill and then you get the reviews back and you crash back down to the bottom. But I think it's a wonderful thing to be able to celebrate these successes. And I'm so glad that you're getting to this point where you're being able to see the hard work coming directly out of your own independent research lab kind of coming to fruition now. And I think this can motivate you to dig in deeper, spend even more time in the lab. But we try to encourage our listeners to take a break, to read

broadly and give their minds a break from their own specific science. So do you have a book that you can recommend for listeners out there who might be looking for their next great read?

There are two that come to mind. One is science related and the other one is not. I would say most books that I read are not exactly science related. I think I get enough of that. I read papers. I think that kind of scratches my genetics research or cell biology itch. But I did read a really good biology related book recently. One of my friends in a lab at Yale, there was a postdoc in that lab.

And he was saying, oh, she wrote this book that you might like. It's called A Brief History of the Female Body. I got a copy. It was really great. I think it also just highlights this is somebody who was a postdoc at Yale in the lab with my friend who was a grad student there. And there are all sorts of alternative career paths that have nothing to do with academic science or going into industry. You can be a writer. You can be a podcast host. I think there's so much great stuff that you can do with that education that you have in

And this was a great book. I think the thing that I liked the most about it is so as I've seen my wife go through pregnancy, the body changes a lot. And I think one of the coolest things in that book, A Brief History of the Female Body, was why do problems still happen in childbirth? We think of evolution as making us bigger, better, faster, stronger.

But then why do complications occur like hemorrhage, like gestational diabetes, mortality from delivery? You would think that evolution would clean that up. Isn't there a heavy negative selection pressure for dying during childbirth? And while that yes is true, there are problems that have remained because there are different motivations for a baby and the mother. They're kind of at odds with each other at times.

The baby wants to grow as big as possible. The mother wants to keep the baby a manageable size so she can give birth. So I think that it's just one of those really interesting explorations of this idea that evolution is messier than we think of it as being. And it's just more complicated than that and actually usually far more interesting than just simply bigger, better, faster, stronger, progress, healthier. It can sometimes lead to these weird paint-yourselves-into-a-corner situations of...

Now, as humans have invested so much in our intelligence and our brains going really big, but then that creates a problem for getting this large brain beat us outside of the body. And that can cause these problems, too. I just really enjoyed that. I think it's a good reminder to the listeners that there are a lot of things you can do with your education. It could be your full time gig or a side gig. But I think it's an encouraging thing to think outside of the box.

Absolutely. This sounds like a wonderful book. And you mentioned a second one you'd like to recommend as well. Yeah, this is probably more like what I like to read. So my grandmother gave it to me Christmas a few years back. It's called My Life as an Indian. It was written, I think, in the late 1800s, maybe mid 1800s.

It's a real life kind of account of like Dances with Wolves, if folks have seen that. It's this guy who grew up in Connecticut or something and really tired of polite New England society. So went off in search of adventure, something that felt more authentic. So he went out west and into the Dakotas and lived with the Blackfeet Indian tribes.

married an Indian woman and had a child or two. It is very, very well written. It's just fascinating of this bygone era. It's back when the tribes would travel around when buffalo were plentiful and they lived in this nomadic way. And I think it's a helpful reminder. Humans lived like this for tens of thousands of years before the modern day. I mean, that's really where our brains and societies evolved.

And just understanding this way of living, but also a reminder to romanticize nothing. They lived very close to the land, of course, very peaceful, but also perilously close to death at all times. So it's a helpful perspective on a day in time where we all stay indoors, work from home, order everything off Amazon and wonder why we feel a little disconnected. I can't recommend that one highly enough.

Well, we will definitely add this to our website for our listeners to find. And I appreciate you sharing these recommendations with us today. And we've talked about some of the stories about your academic career path. And I think one of the things that we haven't yet brought up are some of the opportunities that you get to travel as a scientist. This is something people may not realize comes along with the career. So

Do you have a favorite place that you've traveled for science, whether it was to work with collaborators, to go to a conference, etc.? And if so, can you tell us where it was and why it was so memorable? So I've been to some great places, places that I'd never traveled before. Korea, Italy at the time, I'd never been.

Science is also very international. I mean, it's this community that you can plug into. But I definitely think that the conference that made the biggest impact and probably affected me the most was I saw San Francisco for the first time. I think I'd maybe passed through kind of, at least flown into the airport and then went to Berkeley at some point. But I'd never spent any sort of extended time in San Francisco. And this was 2012 American Society for Human Genetics. It was in the fall. It was like a

and right as the Northeast is getting ready, buckling up for the ride that is wintertime there. It was beautiful here.

It was probably like 60 degrees and sunny every single day. I was with other folks from my lab that I was good friends with. We rented this big like Airbnb. Where the Airbnb was situated, we were able to take the cable cars to the conference every morning. There were also not enough beds in the house. And so it was so nice outside that I slept on the patio on the couch out there under a lot of blankets. But I could see Golden Gate Bridge way off in the distance. I could see stars.

And I just made me really feel like there's something special about this city. And so I think that planted a seed that that was before I moved to California. I think it was a carrot on a stick for me a little bit, seeing that there's something about this place.

And now even being out here, we see self-driving cars all the time. It's where they're starting. It does feel like this is where the rubber meets the road for futuristic technologies. And I just like living near that. Oh, definitely. Do you remember on this first trip to San Francisco, were you able to take some time to see the sights there?

Oh, yeah. This was at a time where I was getting towards the end of grad school and the burnout was starting to creep in a little bit. And so I think I went to the Museum of Modern Art. I think I ran across Golden Gate Bridge doing some distance running. I saw the city more than I saw the conference. That's for sure.

Well, I think it is wonderful to get outside to experience a different city, experience a different place. And I think that's part of what makes these scientific travel opportunities so valuable. So I appreciate you sharing this travel opportunity. And I think one of the other things that we've touched on throughout our conversation are some of the people that you've been able to work with. And I think, unfortunately, there are some stereotypes out there about what scientists are like, and they're often not very good.

And they often don't match what I've experienced myself in terms of meeting scientists who are these funny, creative, amazing, multifaceted people. So do you have an example, Kyle, of whether it's a quirky lab tradition or just a funny or fond memory you've shared with colleagues that maybe shows this human side of science that goes against some of these traditional stereotypes?

The person I think of that shatters these science stereotypes that are born on like Big Bang Theory or Enigma Machine sort of movies. I mean, the culture, too. I've met a lot of cool people in science. They're not as they're portrayed on these sitcoms. Let's just say that.

And some of them are dweeby. They definitely are nerds. Many of us that have just followed our interests as far as they may lead. But I think there is some sort of cool with that. And then some people are like actually cool in a way that everybody would recognize. So I think of Joe Davis. He is the resident artist scientist in the church lab.

So that's a different role, right? He's not a postdoc. He's not a grad student. He is an artist scientist. He worked on the coolest projects. I mean, it was just as science fiction as it gets. I remember the best example was he recruited some of the rest of us in the lab that thought what he was doing was really great and interesting and thinking outside of the box. We went to the nuclear reactor at MIT and the idea was...

can we find bacteria, little microbes that can survive ultra high doses of radiation, maybe in like the cooling liquid of this nuclear reactor? So we went there, we were trying to get some samples and take them back to the lab and try to understand, okay, is there stuff that's surviving in here? If so, what is it? And that's cool, but what's the point? Why are you trying to find this? And I remember Joe, his vision for this was even bigger than just can we find bacteria

bacteria that survive really high doses of radiation, his rationale was, well, if we could find microbes that can survive that, maybe we could understand what it is that they evolved, probably with these heavy negative selection pressures against themselves, these high doses of radiation, probably trying to obliterate their genomes, if they could find some way to protect that, it'd be really amazing to understand how they're doing that because

At some point, humans are going to want to colonize other planets that might not have an ozone layer and be shielded from high doses of radiation that can happen on other planets that are not the Earth. So this is something that could be important in the long view of understanding how we could have current microbes that we use engineered or think about engineering human cells to better survive high doses of radiation. I don't think we found anything, not that I'm aware of, but it was really fun and

And I remember going through this nuclear reactor. It was a scene straight up from the 1950s. It was these huge walls of monitors, but like 1950s technology and just wandering around and getting to see the place. Yeah, that was really fun. I mean, that wouldn't be a scene from one of these sitcoms, but to me, that was just another day in the life of the artist scientist in the church lab.

I think that's amazing. And I think just this idea of thinking about the big, big picture of the future, I think is really exciting as a scientist and just the small pieces that you could potentially contribute to it. And I think...

Oftentimes, only being able to contribute a small piece is the case because you're limited in terms of funding, staff, technology, and just the feasibility of solving these huge challenges. So if we took away the barriers that typically hold you back, Kyle, is there one problem or challenge or research question that you would most want to tackle?

So I like the big picture ideas, thinking about why don't we make cells at scale and by reactors and what are the problems preventing us from doing that? So I like working on stuff like that. If I think about a project that I felt like was too big enough for us to bite off, I mean, we're ultimately a small lab, half a dozen people, maybe a couple more. So we do need to think about, OK, if

If we're thinking about the red blood cells, growing them in a bioreactor, we can break the problems down into bite-sized pieces that we can chip away at. And one single grad student during their time in the lab could really help us address one single bottleneck. There was a problem that we thought was really, really cool that was too big for us to tackle ourselves without a lot of help. And it was a year or two ago, it was this idea that

We could use cells to be a delivery vehicle for genome editing tools. So when I tell people about what we do and any disease you pass on to your children is a typo in the DNA, we now have the tools with CRISPR to be able to change that, edit the DNA like a Microsoft Word document.

That's how it works on paper. But then it becomes a matter of delivery and getting the genome editing machinery to this usually stem cells in the body that need it. A way that people have solved that up until now is grab the stem cells, pull them outside the body, edit them in a dish and re-transplant them. But that really works great with hematopoietic stem cells, like essentially integrating these tools into the process of like a bone marrow transplant. But

But there's so many other diseases you could imagine that you can't just pull out the stem cells, edit them and put them back in. So as a solution, people have started to adapt these concepts of taking the genome editing machinery and packaging it in these delivery vehicles that can go straight into the body, into the cells where they sit, say in the bone marrow or anywhere else, whether they're neurons in the brain and introduce these custom genetic changes. Well,

Well, we can do that, but it's really, really low efficiency for the most part anywhere that's not the liver, which is just a big sponge. So what could we do to better enable? Think outside of the box of deliver these big tools for the most part. They're really quite large proteins. So it's a lot of machinery to deliver to a cell and much easier said than done. Well, cells are kind of like little robots. If we think of cell biology, I mean, they're tunable machines and they can deliver painless

to custom cell types. We know from these engineered T-cell therapies that you have a tumor that's growing and your body is not doing anything about it. They're your own cells, so tumors are really good at evading the immune system. But what we can do now, we have the tools and knowledge to take these T-cells out of the body and

and then engineer them to go get after that tumor. We have the knowledge to understand how that tumor is different from the rest of the body, and we can teach the T cells to go do that. What we were thinking about, okay, so you can train a T cell, essentially engineer it, pull it outside of the body, and then get it to go to a very, very, very specific place in the body and deliver something. We were thinking perhaps we could use something like a T cell to deliver in vivo genome editing machinery.

They're really, really good at going and finding specific cell types in the body. The problem is they kill the cell when they get there.

And so we started thinking, okay, is there some way we could neutralize defang T cells? So we started doing that. But the more time that we spent thinking about this problem, we realized how big the problem was. We also talked to a lot of other people about the idea to get their feedback. And it's funny how many people kind of came out of the woodwork and said, I tried this or somebody in my lab tried to do this. And they made a little progress and then hit up against this insurmountable problem. Dr.

this barrier that just they dropped it. And then they spent time working on what was working and haven't thought about it again. It's surprising how many people have talked to me now about this idea or just said the idea out of the blue of like, hey, I've been thinking a lot about that. And I give it a chuckle and say, well, that's funny. You should talk to this student in my lab. We spent probably six months thinking and earnest about this, doing some experiments and just realizing that's probably a 25 year problem. It's just really, really, really tough.

to do that level of engineering. There's so many problems. First, you need to neutralize the T-cells and then engineer them to deliver something. And then you need to figure out how to get them to deliver these large pieces of machinery. If I had a huge lab, I would probably have a couple of people working on it, but I don't. And so I don't.

It sounds like this is way beyond the scope of sort of your traditional five-year grant period. Well, this is a remarkable problem and exciting to hear that there's interest from others in the field as well. It's not necessarily this pie in the sky thing, though it would take a lot of concerted collaborative effort. So we appreciate you sharing one of these exciting future projects with us so me and our listeners can ponder it today. But we'd love to end our conversation by talking about advice for listeners out there who are on their own journeys, scientific or otherwise.

Kyle, do you have a piece of advice that really helped you that you can share with all of them today? Yeah, I think stick with it. At least biology, but I think it's so true for so many other fields. Biology is not a field for prodigies like maybe math or economics. Somebody just is wired that way to be brilliant as a mathematician or physicist or something. Biology is not that way. And I think that's true of so many other fields, whether they're science or not.

You can't be brilliant until you've done it for 10,000 hours. That's how it works. I know just at least from my own perspective, I didn't start out passionate and loving cell biology and human genetics. It was a slow burn. You stick with it. If it's a slow burn and it strings you along for long enough, giving you that encouragement that

Every year I spend in this space, I enjoy it more and I think I'm getting better and I'm growing a toolbox or skill set that I think is becoming more and more useful. Sticking with it, I'm so glad that I did. This idea of follow your passion, follow your heart. Well, it's hard to follow your passion until you have a passion. And I think that synthetic biology and cell engineering is absolutely a passion of mine, but it took at least 10,000 hours to get to that point.

And I think it requires enjoying your routine and liking the day-to-day, preventing burnout. If you're talking about at the scale of 10,000 hours, it's a marathon, not a sprint. I felt burnt out at the end of grad school, but I also wasn't really working crazy hours. I wasn't working long weekends. I think it was more I knew I needed to change fields, but I didn't know what I needed to change into. And I just think that that was weighing heavily on me. At the same time, I had friends who burnt themselves out just from like a working hours and weekends perspective. And

And they're not in science anymore. I mean, that's fine. They have great jobs, but they went to grad school wanting to be scientists and they aren't doing it anymore because I think you have to listen to your body. You have to keep it fun for yourself. If you're not having fun doing what you're doing, you're going to get sick of thinking about it. You're definitely not going to think about it when you're not at work or not trying hard to think about it. And I think that's when my favorite ideas happen is when I'm not trying to think about a cool

a cool new idea. And usually when I'm not even at work, it can be on a weekend because I haven't tired of it and I still find it intriguing. And I just think keep it fun. Maybe that sounds basic, but it's a guiding principle for me. Well, I think that's such an important message to share with listeners out there who might be feeling a little burnt out on their own research or the work that they're doing right now. And Kyle, is there any other last message or maybe last note of inspiration that you'd like to leave everybody with at the end of our conversation today?

I think maybe be practical. If I think about what I was passionate about, just to kind of continue the thought before, my favorite subjects through grade school were history. It was not biology. And I thought for a time that I might want to study history. And I remember towards the end of high school, I don't remember who I was talking to, just one of my teachers, I'm sure.

And I said, I really like history. And he paused and he said, do you like teaching? And I thought to myself, no, I just said I like history. I didn't say that about teaching. And then I realized what he was getting at. And I thought more deeply, like that's one of the main jobs that you would have.

as a historian. There aren't a lot of jobs and most of them are teaching, which is great. But if the answer to that question is, yes, I love teaching, go study history then. And it just was a time that I paused and had to really think about, well, do I like the career prospects of where this is leading eventually?

And I know it's only going to get tougher moving from here forward, especially with the threat of AI. I don't really know how the landscape is going to change. And I think it's almost impossible to predict. I think try to be practical, try to understand and forecast as best

best you can maybe about how the landscapes are going to evolve. I mean, I see these headlines where Facebook is no longer hiring mid-level engineers. And so it used to be that studying computer science was the surest thing to like a great life. You don't even have to go to grad school and get a great job. And I don't know if that's still true today. I don't know if it's going to be true in 10 years. Try to be practical, try to understand where the puck is going, but also don't psych yourself out because this stuff is impossible to predict.

That's probably just confusing advice, but things are complicated. No, I think just this idea that even people who are in these faculty positions kind of recognize the uncertainties that are happening right now. Science, the world isn't what it was 30, 40, 50 years ago. So you have to be practical. You have to be willing to be flexible and pivot and go where the opportunities take you, I think, to some extent. So great message for our listeners.

If they want to learn more about you and what you do, Kyle, what is the best way for them to get in touch or to learn more? I don't have a big social media presence. I have a lab website and I created a Twitter when I started my lab. I was encouraged to by other people. They said it's a great way to promote your science. And so I post papers that I publish or other news on my Twitter professionally. I can always be reached by email. I keep it pretty simple and old school, I guess, in that way.

Perfect. Well, listeners, definitely take some time to check out Kyle's lab website and get in touch if you have questions. And Kyle, it's been such a pleasure to chat with you today. Thanks so much for joining us to share some of your story. Thanks. I really appreciate you having me on. Hope you all enjoyed. Well, it was great to speak with you, listeners. It's always wonderful to have you here with us as well. We hope you enjoyed this episode and that you join us again next time for another episode of People Behind the Science.