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Athlete-scientists Part 1

Gene Yeo
I was just telling one of my postdocs today that, success in science is definitely not a sprint, right. And analogous to marathon running and training it's all about pace. And it's all about, you know, the big wins rather but celebrating also the small wins, right?
When you're running past mile you know, mile 21. You're like, Oh, good, I survived mile 21. And if I keep the pace, you know, the next few miles, I'll be fine.

Vivien
Hi and Welcome to Conversations with scientists, I'm Vivien Marx. And that was Dr. Gene Yeo, a researcher at the University of California San Diego. You will hear more from him and about him shortly. For my stories I speak with scientists around the world and these podcasts are a way to share more of what I find out.

Some scientists are also scientist-athletes. Neuroscientist Kaspar Podgorski-he's at the Allen Institute for Neural Dynamics in Seattle--sent me some photos from his commute. It's sunrise or maybe sunset and he's on the water in his kayak. That's how he commutes to and from work.
His main sport is climbing, he loves being out in the mountains and he told me it makes him happy and some of his best ideas come to him in the mountains.

I've been talking with some other scientists who are athletes as well as scientists. And Dr. Gene Yeo is one of them. I did a story Nature Methods recently-a link to the story is in the show notes https://www.nature.com/articles/s41592-022-01665-2- the story includes Kaspar Podgorski and Gene Yeo and well as computer scientist and Olympic athlete Liz Bradley. You will hear from her and about her in another podcast.

Back to Gene Yeo. So being an athlete-scientist is beyond being someone who works out regularly, athlete-scientists are serious about their sport and train hard. So this is part one in a series that will come together now and then about athlete-scientists. I will share some things they said about their sport and what it means to them, also how it affects their science. They'll talk a bit about their science, too.

Here, let me introduce you to University of California San Diego researcher Gene Yeo. He has completed two Iron Man competitions , a number of half Iron Man competitions and both full and half marathons. Iron Man that's 2.4 miles of open water swimming, 112 miles on the bike and a 26.2 mile run.

Training is a time for exertion of course but it's also a time when Gene Yeo can think about science.

Gene Yeo
I mean, it's helpful, because on these long long runs and long bike rides, you know, you get the time to sort of zone out a little bit, right. And it helps you focus on on, you know, answering some questions. It's helpful, I think, especially the swim, the swims are great, right? You don't really want to be too distracted riding a bike, you might get run off the road, but the swims and runs are good, because you can sort of keep swimming and while digesting a problem, and you just go through the motions. And I think the added background noise of of doing the these exercises, sort of helped create prioritization, you know of our problems are worth thinking about, right, because then you stop worrying about the smaller things. And so that's helpful, I think.

Vivien
Training for the IronMan and Iron Woman is very intense to my knowledge and this is only from talking to people who do this, I certainly do not. You have to push your body to extremes, which is not for everyone. And I don't want to be ableist here, some people can't practice sports like that or even at all.
For those who can and choose to train hard, like Gene Yeo, there are parallels to science. Being a working scientist takes persistence, endurance and an ability to handle a certain amount of pain. I wondered what kinds of parallels he draws between the skills acquired and used for training for athletic events like the Iron Man and the skills needed in science. Here's Gene Yeo.

Gene Yeo [2.40]
I think I think the values, the habits by that are useful for a long kind of race, endurance races, or even, I mean, I do a lot of other things, these days, too, I do a lot of rock climbing and all that.

And so the all these different activities, which are, you know, long drawn out, but require constant check ins, you know, frequent check ins of your, yourself and your body and your mind. It's very useful and portable to science, right?

Because I think success in science isn't really a sprint. I mean, most papers are not, you know, because we sprinted hard for like a year, right? Most things, most discoveries take 5, 10 years, and, and it's all built from many small achievements, right, that you accumulate, and you string together, and they help one another, you know, to strengthen, and all that. So, so those are very similar attributes from when you're training for races, or doing the race, these long races or even, you know, these days, we do a lot of rock climbing with my wife, right.
And, and so we think a lot about, you know, as you as you go from one position on the wall to another position you plan for, for what would provide you a point of rest, and then a point of the next point, when you are energized how you approach the next point, and there's lot of strategy involved. And so it was a very similar thing. I think.
I was just telling one of my postdocs today that, success in science is definitely not a sprint, right. And analogous to marathon running and training it's all about pace. And it's all about, you know, the big wins rather but celebrating also the small wins, right?
When you're running past mile you know, mile 21. You're like, Oh, good, I survived mile 21. And if I keep the pace, you know, the next few miles, I'll be fine. And so just, you hydrate every at every step, every mile after that, I hydrate and, and so you still you know, refuel? Right. I think that's important. So I think a lot of the habits and principles are transferable.

Vivien
When you practice a sport with someone, for example Gene Yeo and his wife go rock climbing together, so that is an effort that they share with one another. When doing a sport with someone else you do something intense together, you can enjoy it together, it can be a spouse or a family member or a friend, or another person from the lab, of course. It's something you enjoy doing with others.
But in general competition in the Iron Man or taking part in races such as biking or swimming, it's you and your body racing against the elements, leveraging your own strength and endurance, playing mind games when you feel too tired to keep going but you just want to complete a race. In that sense it's not really a team experience.

Gene Yeo [4:05]
Yeah, it's funny because even you know, same for these things, right, like marathons, IronMans, and racing. It's not thought to be a team sport, because you do it alone. Or even with rock climbing, you do it with a buddy. Right? At best.
But actually, a lot of the training is done best as in groups of people highly motivated, and they can help one another. So learn about injuries, all that so.
So the lab setting is similar, right, we have a group setting, everyone is working together closely to help one another. But ultimately, the people that that lead the projects and make the discoveries are almost individuals or you know, pairs or small groups rather than the entire lab as a whole, right? But then everyone gets credit. And everyone's part of the journey.

Vivien
Everyone's part of the journey in a marathon and in a lab. It's a longer drawn out exercise to run a marathon and science too tends to be a longer, drawn out matter. Discoveries take a moment.

Gene Yeo [7.00]
Sports and science, it's funny, in San Diego, the triathlon teams here, or the rock climbing gym, there are a lot of scientists. And I think it's, you know, it makes a lot of sense, right? I think, you know, the folks that that attracts people to these achievements are the same sort of people that are trying to to, you know, working at solving a specific problem, and then are happy when they finally solve it, right. Not necessarily for the immediate gratification in like some other sports, right? Like this, these kinds of things are a longer drawn out exercise, I think.

Vivien
So that was the sports side of Gene Yeo now here's a bit about his science, which is experimental and computational. When he's not an athlete he's work on RNAs and RNA- binding proteins in the brain and in stem cells.
I interviewed him when I was working on a noncoding RNA story, the RNAs that do not encode a protein but fulfill other functions. Or maybe they don't have any function at all. Which is why some people have called non coding RNA junk. But we're not going to do name-calling here. But there are distinct groups of scientists who say: I am part of the noncoding RNA science crowd and others who are about the coding RNA. But actually the divide is not so clear in some ways because some non coding RNAs have parts that are coding. Here's Gene Yeo.

Gene [[9:25]
I think of myself as an RNA person, and less so with coding or non coding. Because I think at the end, in the cell, you know, there are a couple of ways of defining what's interesting about RNA, right?
So you can think about, you know, an RNA person is one is interested in how, you know, RNA is synthesized and manipulated, and, and then finally, you know, destroyed, right. Then all you can think about, like, the functions that these RNAs do, right, and I, and I kind of, so I think when we think about the functions that RNA do is when the coding and non coding crowd or groups divide, right. Because the coding crowd will go, okay, these RNAs make the protein. And then we're interested in like, what the proteins do.
And then the other group that focus on the ones that don't become protein. And in fact, many of the non-coding ones still have parts are translated into shorter open-reading frames and peptides. So, one would argue maybe these are also coding.
But then, let's say there are some completely non coding, what are the functions of these RNAs, they're independent of their protein function, right. And so that's the other piece. So I just kind of belong to the what controls the generation synthesis processing and decay? And those are similar principles, I think, similar rules for both coding and encoding.

Vivien
So in his view plenty of the science applies to coding and noncoding RNAs. With RNAs, probes are needed also ways to track the many RNAs and at scale.

Gene Yeo [11:00]
My comments are probably general to RNA, as a field, both coding and non coding, is that tracking the birth, the decay and destruction of these RNA still difficult to achieve at scale, at resolution, but also live, right.
And so that's sort of the big take home is that we can do a lot like we can do many measurements at scale, but there are fixed tissues and not, you know, longitudinal images.
We can do one or two RNAs at a time live. But that's not at scale. And we can do many things at the resolution of you know, what the cell is by identity, because you can, you know, track some of them, but not very good subcellular resolution, and definitely not across complicated tissues, right. So I always think about scale, resolution, and whether or not it's static or dynamic images.

Vivien
The resolution issues seem to be improving; this ability to be able to see individual RNAs. But that's not the only reason why some aspects are still being missed. One challenge with RNAs is that one gene can make many different RNAs, many isoforms. And in situ hybridization approaches cannot distinguish between isoforms.

Gene Yeo [12:30]
I think that's getting better at detecting the identity of what that gene could be that's expressed, coding or non coding. But the problem is, that as you know, it is not, we, you know, we need to step away from thinking that there are over 25,000 genes.
They're probably hundreds and 1000s of alternative isoforms. When I think about RNA, I think really isoforms. And right now, they're, you know, the in situ hybridization technologies cannot distinguish isoforms.
So I would say we're missing, you know, 80% of the picture, because we're not looking at at, you know, whole transcripts, sub-cellular, you know, at scale. And then we're missing another half of that by not being able to do to these things and live cell measurements dynamically. Because I think the movements are best tracked at the end by imaging, not by many, many static snapshots. And maybe we can do that well, for a couple of things at a time, but not, you know, all transcripts at a time, right.

Vivien
RNAs can be at many spots in a cell and so one needs better ways to find them and to watch them. RNAs are usually in the cytoplasm but they can also be in the nucleus. Gene Yeo studies RNAs in a special cell type in which RNAs travel far.

Gene Yeo
Even in the cytoplasm, which is what I think we're we've been looking a lot at RNA granules for stress, right. I think that's where a lot of cell compartments are. And then also, you know, the most interesting cell types--that's my biased perspective, every study, you're like neurons where they are post mitotic. And you have to bring RNAs one meter away, from where they begin.

Vivien (on tape)
Wait one meter. Oh, all along the axon?

Gene Yeo (13:50]
And so every, you know, like from here to like, the tip of your toes, right, that's like a meter. And RNAs have to travel there, from the central nervous system all the way to the synapse, right. Where it hits the muscle junctions and so on. So people forget that, like the most interesting RNA localization problems are actually in these long-range cell types.

Vivien
Given these types of puzzles I wondered if this is an area that will support scientists, his trainees for example. I always like to ask about job areas and areas of growth. And in some of my conversations with scientists on RNA, certainly noncoding RNAs, I did hear people were told: nope it's not a good career choice.

Gene Yeo [15:00]
I think it's a an amazing choice, because actually, you know, if you look at all genes in the genome, they're all transcribed as multiple different isoforms depending on cell type, and developmental stage and disease. So first of all, like, nothing's really, really well understood about these different isoforms what they do.
And then many of these RNAs, you know, go on to become proteins, but they're modified and plotted all along the path. And just, you know, if you think about therapeutics, today, you know, I would argue it's, it's all about RNA therapeutics, right. RNA as a drug, RNAs as a drug substrate. And if you can actually think about RNA as a drug or drug substrate, why do you ever worry about proteins or small molecule inhibitors to kinases? Why do you worry about any of that, right?
Like, you have both sequence specificity with RNA as a target, as well as the ability to hit the many different isoforms? You know, before they're made, right. And so I think of RNA as the, I don't know, I'm completely biased here. But I think that there's so much opportunity in this space, because you know, if you think about RNA is very interesting molecule, right. It is not only a good substrate, but also a good, good a reagent.
So you can use RNA itself as a drug, like the vaccines, you can use RNA as a drug, because you can do in vivo CAR-T in cancer, for example. And, and at the same time you can target it with and antisense-oligonucleotides, si-RNAs, these small molecules. If the 3D structures of RNAs are just at its infancy, whereas proteins have been done a lot of it already, but RNA structure is not not clearly defined. So I think that there's a much more room to grow for new ideas, here in this area, than any, any other area.

Vivien
Gene Yeo has been involved and is involved with spin outs, biotech and pharma companies such as Takeda and Genentech and is a co founder of a number of companies including Locana, Eclipse Bioinnovations, Enzerna and Protean. Many companies have focused on genomics, and on DNA and not so much on RNA. But for treatment of disease in Gene Yeo's assessment, RNA has a big role to play.

Gene Yeo [17.25]
I don't know, I always felt that the, the genetic and genomic basis of diseases is very clearly, you know, very clearly exciting. But to know what the function of these variants are, you kind of have to look at the downstream expression of the RNA, if there is, or generation of protein if there is. Otherwise, you know, it's like, it's like you have a, parts list , but not an understanding of how the parts actually work.

Vivien
Neurodevelopmental disorders and psychiatric illness are all difficult to treat and often poorly understood also neurodegenerative disease, too. Perhaps RNAs play a role in these conditions.
But RNA drugs can be challenging such as one gene therapy Zolgensma for spinal muscular atrophy, which is an inherited often fatal condition that can kill children before they reach their second birthday. The drug does not cure the condition. There had been some hope that RNAs could be targeted by drugs which help in this condition and address symptoms.
Gene Yeo sees positives in these drugs and his perspective reaches beyond that scope of addressing symptoms and in targeting many types of diseases at the RNA level.

Gene Yeo [18:35]
I would argue, yeah, I mean, it would be not just symptoms, I will say there are cures. The first anti-sense oligonucleotide drug to a severe neurodegenerative disease, spinal muscular atrophy. And that was a Eisai drug from Biogen right. And so, you know, that, that is a clear, win. And then the siRNA drugs after whatever 15,20 years from Alnylam have now like sort of taken hold and now, it's all about making products in that space.
And as cancer evolves, because of nucleotide somatic variation, the nucleotide-targeting drugs can also be adapted quickly, fast, right. Whereas small molecules, you can't. Then for diseases like the Coronavirus, right, you can, you know, you can, in theory, have your vaccines pace your mutations that show up in in these Coronavirus variants, right.
So, I don't know of any, I don't know many other modalities in the pharmaceutical world where you can outpace these variants or given cancer mutation all that right. So, so the sequence level alteration cannot be done at the genetic level. They can really only be targeted at the RNA level.
To me, it was always kind of obvious. So it wasn't like I, that was an aha moment for me. But I think, I think for the field, there was an aha moment when the SMA oligonucleotide worked to alter splicing and then the siRNAs worked for a variety of different diseases. And then now you have small molecule drugs targeting RNA that seem to be working also. Then the RNA vaccines from the pandemic. So I can't imagine any other areas that's both a platform modality, but also, you know, a basis for understanding disease.

Vivien
That was Conversations with scientists.
Today's guest was Dr. Gene Yeo from the University of California San Diego talking about being an athlete-scientist and why RNAs matter. The music used in the project is Smoothy Moody by Mac A DeMia licensed from Artlist.io.
And I just wanted to say because there's confusion about these things sometimes. The University of California San Diego didn't pay for this podcast. And nobody paid to be in this podcast. This is independent journalism that I produce in my living-room. I'm Vivien Marx, thanks for listening.