00;00;06;06 – 00;00;55;28
Victoria VO
Welcome to Beyond Lab Walls, a podcast from the Salk Institute. Join hosts Isabella Davis and Nicole Mlynaryk on a journey behind the scenes of the renowned research institute in San Diego, California. We’re taking you inside the lab to hear the latest discoveries in cutting edge neuroscience, plant biology, cancer, aging, and more. Explore the fascinating world of science while listening to the stories of the brilliant minds behind it. Here at Salk, we’re unlocking the secrets of life itself and sharing them beyond lab walls.
00;00;56;00 – 00;01;18;02
伊莎贝拉
Hello, listeners. I’m Isabella, your host today for Beyond Lab Walls. I got to sit down this month with Joe Herdy, a postdoctoral researcher in the lab of Rusty Gage, a professor and neuroscientist here at Salk. Joe took a somewhat slippery, maybe even slimy route to San Diego, thanks to some lamprey research that helped him transition from plant science to neuroscience.
00;01;18;05 – 00;01;43;08
伊莎贝拉
Now, with lab mates in the Gage lab, he’s uncovering the genetic drivers of Alzheimer’s disease and other neurodegenerative disorders. Our conversation goes from exciting things like zombie cells into jumping genes and how they may relate to inflammation and the neurodegeneration that we see in Alzheimer’s. So, let’s get right into our conversation. Joe, where did you grow up and what were you like as a kid?
00;01;43;09 – 00;01;45;15
伊莎贝拉
Were you always a little science-y?
00;01;45;17 – 00;02;18;29
Joe
Yeah, I grew up in Huntsville, Alabama, which is kind of like a science-y town, I guess. My, my family originally moved down there because my dad is an aerospace engineer, so he was involved in designing engines for rockets and jet propulsion and those sorts of things. And there’s, in Huntsville, Alabama, that’s where they designed the Saturn V rocket, which is like the rocket that landed on the moon.
00;02;19;02 – 00;02;48;16
Joe
So Huntsville has a lot of engineers and NASA nerds and that kind of demographic of people. And so it was like, a very science-y type town. And I wasn’t necessarily as interested in the engineering part. I always sort of was more drawn to the biological sciences. I spent a lot of time in the woods. I was flipping over logs and catching snakes and salamanders and then bringing them home.
00;02;48;18 – 00;02;54;04
伊莎贝拉
When did science go beyond an interest into a serious consideration for a career?
00;02;54;06 – 00;03;15;10
Joe
I would say that, like pretty early on, I was I like, understood in more abstract terms. There were like doctors and lawyers and nurses, and there were also scientists. I would say as a kid, I didn’t know like what it meant to go to graduate school or to have like a PhD or any of those sorts of things.
00;03;15;12 – 00;03;34;03
Joe
But I did have an understanding that, yeah, like a scientist was something that that you could be. And like my mom always tells a story that like the first, the first job I ever said or like for years when someone asked me like, what do you want to be when you grow up? I would be like, oh, I want to be a paleontologist, because I want to go—
00;03;34;05 – 00;03;54;08
Joe
Kids love dinosaurs. Obviously. I knew it’s like, oh, this is something that like that someone could do professionally, and it’s related to dinosaurs and science somehow. It’s like, that sounds like the best possible scenario is to be a paleontologist. And then after that, I remember I would like, in middle school I was like, oh, I’m going to be a marine biologist.
00;03;54;08 – 00;04;10;18
Joe
And I was living- Yeah. Another classic. I didn’t really have like, you know, like a real understanding of, like what that entailed or what I would actually be doing. But I was like interested in like, oh, I’m going to go out and like catch fish and like, understand like what it is that fish are up to out there.
00;04;10;20 – 00;04;37;10
Joe
Yeah. And then I think it was when it was I, when I started in like right before, like in high school, before I started like my undergraduate studies at the University of Alabama, I, that was like around the time that the human genome was first published, or like when the Human Genome Project was, like, coming out. And that was what started me on the trajectory to where I am now.
00;04;37;10 – 00;05;05;03
Joe
I thought that this was like really fascinating that they had, like, figured out all of the genetic code for like people and read some of these books like related to the human genome and just sort of discussing like human evolution and how our genes impact so much of like who we are as individuals. So at that point, sort of like at the end of high school, going into undergrad, I was like, oh, I want to do like genetic stuff and like, understand genetics.
00;05;05;05 – 00;05;09;19
伊莎贝拉
Can you explain the difference between DNA, genetic code, and genome?
00;05;09;22 – 00;05;52;14
Joe
Yeah, sure. So they are similar terms. The genome is all is made up of DNA. So DNA is four letters: A, C, T, and G. And these four letters and thousands of different combinations is what leads to the information for making life on Earth, essentially. It’s the common alphabet that bacteria all the way up to humans share. And then when we refer to the genome, that is what would be considered to be the genetic code like specific to, I mean, it can be specific to an individual or a group of individuals, like a population.
00;05;52;14 – 00;06;33;10
Joe
So we might say that someone has sequenced the seagull genome or the baleen whale genome. And that means that they have just figured out all the sequence of letters that is specific to that organism. But the interesting thing about genetics is that although in broad strokes the genomes between individual people are much similar than the genomes between like a person and like a fly, there’s also like a lot of differences between individual groups, like within organisms or like within different species.
00;06;33;12 – 00;07;06;10
Joe
And so the genome can like be different on lots of different scales. And then genetic code, I guess that’s when you’re getting more down into like the nuts and bolts of like how the genome is like read and interpreted because there’s lots of kind of rules in terms of how DNA is read or interpreted by, by a cell and how the DNA is like turned into proteins or like turned from like an individual cell into, like a whole person.
00;07;06;12 – 00;07;18;15
Joe
And so the genetic code, I think, is more related to like regulation on that and how your DNA actually ends up producing a different, a different person.
00;07;18;17 – 00;07;26;18
伊莎贝拉
That’s super helpful. Yeah. So this is what really piqued your interest. And since then you’ve ended up in neuroscience. What’s the connection there?
00;07;26;20 – 00;07;54;19
Joe
My route through science was very, very meandering for sure, because at the University of Alabama, they didn’t have any kind of like neuroscience or stem cell program. But there was a lab I was in Leland Cseke’s lab, and they were studying the genetics of invasive grasses. So, like a lot of people know invasive species, they cause problems with the environment all over the world.
00;07;54;22 – 00;08;18;17
Joe
And, in Alabama, they had this problem with two different types of grasses. There was the wavy leaf basket grass and cogongrass. And both of those are like especially cogongrass, like you see it at Home Depot all the time. It’s a very popular landscaping plant, and it’s sturdy and it looks nice. And so people buy it.
00;08;18;17 – 00;08;45;05
Joe
They like to put it in there in front of their house in Alabama. But the problem with cogongrass is that it can hybridize with some of the local grasses. And then it became like the sort of like invasive species. So it was taking over big swaths of like the forest in southern Alabama, contributing to like wildfire risk because it burns it like the whole understory is, like now filled with like, cogongrass.
00;08;45;08 – 00;09;13;11
Joe
And basically that lab was involved in kind of like tracking the spread of these hybridized grasses. And so people would send us, we would get little plastic bags of grass blades. We’d grind them up, take the DNA out of them, and then we had these different, these different types of probes we could use to look to see if it was like, did it have the DNA of like the native grass? Or did it have the DNA of like these invasive grasses?
00;09;13;13 – 00;09;43;13
Joe
And and then so that was my work in undergrad, purely genetics, all plant biology, no neuroscience at all. And then after that I did a master’s degree at the University of Kentucky in Jeremiah Smith’s lab. And in Kentucky, we studied the sea lamprey, which I don’t know if you’ve ever seen a picture of a sea lamprey before. They’re really, like, terrifying looking.
00;09;43;13 – 00;09;48;04
Joe
They’re like one of the most probably terrifying looking like sea animals that’s out there.
00;09;48;06 – 00;09;50;23
伊莎贝拉
Aren’t they those eel-looking guys with sharp teeth?
00;09;50;23 – 00;10;16;27
Joe
Yes, so, they’re the eels. They have these really sharp teeth. They don’t have jaws. They’re totally jawless. And they’re not even technically eels, they’re like 600 million years old. So like, evolutionarily they’re super, super old. But lampreys are invasive in the Great Lakes. They like parasitized trout. So they have like these really gnarly sucker mouths, they grab onto the side of fish, and they like suck their blood, essentially.
00;10;16;29 – 00;10;34;07
Joe
And we would get them- people in Michigan, like the state of Michigan, is like, really hates the lamprey. And so they would send any lab in the world, they’d be like, “We’ll send you this giant cooler.” You get these big like like straight up like cooler. You’d have like, your beer and but you would open it up and just be a bag like, full of, like, lamprey.
00;10;34;10 – 00;10;49;26
Joe
And I don’t even know how they would survive like the shipping, because they would, like, ship it to us like USPS would come drop this cooler off. You would have like, oh my God, there’s all these fish in here. Because you can’t you can’t breed them in a lab because they have to parasitized fish as part of their life cycle.
00;10;49;26 – 00;11;27;21
Joe
So you can only get them sort of from the wild. Yeah. One of the unusual, one of the many unusual things about sea lamprey is that it’s like. Yeah, I was talking about like, genomes, how you have, like, the genome, it’s like all the DNA that is within an individual cell or like an individual’s body. And usually when we’re talking about genomes, we consider every single cell in our body has the exact same DNA, because at one point we were a single cell from like sperm and egg that fuzed and that cell divides, divides, divides millions of times.
00;11;27;21 – 00;12;06;13
Joe
And you have like a whole person. And one of the cool things about lamprey is that their DNA actually isn’t the same across their entire body. There’s, they undergo this process that they described as programed genome rearrangements. So this happens when the lamprey are developing from like an individual cell into a fully grown lamprey. So like when they’re around like a thousand cells, they delete 20% of all of their DNA from all of the cells that are going to, like, become their body as an adult.
00;12;06;15 – 00;12;16;05
Joe
And that little extra bit of DNA stays only in the cells that are going to become their sperm cells in their egg cells, so they can get passed on to the next generation.
00;12;16;07 – 00;12;17;08
伊莎贝拉
That’s so weird.
00;12;17;15 – 00;12;44;05
Joe
Which is very weird. Yeah. It’s like a it’s like a very unusual strategy for organizing your genome because like in, in us there’s like parts of your DNA that you don’t want to be expressed all the time, that you don’t want to be turned on. And like a famous example of that would be like cancer, when you have cancers, this means that oftentimes certain DNA that should be turned off is actually turned on.
00;12;44;08 – 00;13;11;08
Joe
And then the lamprey strategy for dealing with this seems to be, well, we can’t accidentally turn this DNA on if it’s like not there at all. So they delete all of this and the stuff that gets deleted, it’s enriched for like these cancer genes and things like related to like cell proliferation, cells growing, and things like that. So the hypothesis was, is that okay, this deletion is related to preventing cancer in some way.
00;13;11;10 – 00;13;30;18
Joe
You know, this is basic science that like this is a cool discovery, we’re trying to figure out like how this works and how they do it. And because of that work, my boss at the time, he invited someone from the Salk Institute to come and give a talk at the University of Kentucky because they also studied this phenomenon.
00;13;30;18 – 00;13;54;11
Joe
So Rusty Gage, my my boss here at the Salk Institute, he studies like kind of a similar process. So when we’re talking about differences between the DNA of, cell individual cells within a person’s body, the lamprey have like a really extreme version of this where they have like 20% of all their DNA deleted from, like, all their cells.
00;13;54;14 – 00;14;17;25
Joe
But in humans, we discovered that- and then he published a paper on this back in 2016- that there’s actually differences in the DNA between individual neurons in our brain. It’s like the neurons are the electric cells in your brain that, like, kind of are firing electrical activity and control our whole entire, like conscious experience and like all of our behavior.
00;14;17;27 – 00;14;57;23
Joe
And one of the interesting things about neurons is that they have really very diverse morphologies, very diverse functions, there’s like billions of them in your brain, and it’s it’s been a big mystery for a long time about how you could have such diversity within this organ but everyone is starting with the same DNA. And one of the theories that Rusty put forward, or that that he sort of discovered, was that actually there are differences between the DNA between these neurons in your brain.
00;14;57;26 – 00;15;31;27
Joe
And this is mediated through one of these jumping genes. So there’s a class of genes called transposable elements. Some people call them like selfish genes or or they’re they’re like unique among all the genes in humans in that they can like copy and paste themselves. So over millions of years, they’ve copy and pasted themselves, like a lot. So a lot of our genome is kind of made up of like these old fragments of like the copy and pasted gene, but they’re still active, they’re still with us.
00;15;31;29 – 00;15;53;15
Joe
And that copy and paste mechanism happens in us as we develop, and that causes there to be differences in the DNA between neuron A and neuron B in your brain. And so yeah, that like basically then I like met with this postdoc who came and gave a talk at the Salk Institute and I was like, oh, this sounds really cool.
00;15;53;15 – 00;15;57;22
Joe
Maybe I’ll see if there’s like an opening in this lab where I could come in and work.
00;15;57;27 – 00;16;04;08
伊莎贝拉
Wow, that is so strange. And is this happening just in neurons or other brain cells? Do we know yet?
00;16;04;10 – 00;16;31;26
Joe
Yeah. Well, it in theory can happen to any cell in your body, really. It seems like it happens more often in neurons than in other cells and in your brain. There probably are important examples of it happening in other cell types, too, but at least in terms of a matter of like scale, it seems like neurons are one of the cell types in your body that have the largest amount of this event.
00;16;31;28 – 00;16;43;02
伊莎贝拉
So is this the kind of thing, the copying pasting, is that happening throughout our entire lives, or is it more concentrated to development in the womb or even when we’re younger and our brains aren’t fully developed yet?
00;16;43;05 – 00;17;12;02
Joe
Yeah, well, in it, it can happen throughout your entire life, but you’re much more likely to observe when it copy and pastes early in your life, because you can imagine that if you’re, when you’re eight cells, if you have a copy and paste that happens in one of those eight cells, then that’s going to get propagated out and millions of cells then will have that edit.
00;17;12;04 – 00;17;37;15
Joe
Whereas if it happened when you’re an adult and your brain has already developed once neurons, once neurons are born, they never divide ever again. So if it happens in a neuron later in your life, it can happen for sure, but your chances of seeing that one are much lower just because it makes up a much lower fraction of like all of your cells.
00;17;37;18 – 00;17;40;15
Joe
And we can’t exactly go and take someone’s entire brain.
00;17;40;20 – 00;17;47;29
伊莎贝拉
Do you think starting in genetics has added a particular dimension to the way that you study neuroscience that’s helpful in the lab?
00;17;48;01 – 00;18;09;16
Joe
Russ’s lab is is in the laboratory of genetics at Salk. So he definitely approaches like neuroscience from like a genetics perspective. So I think that I like to the field at large, though, I think that yeah, bringing in the genetics component is like really important. For years and years people have been wondering how does vision work? How does taste work?
00;18;09;16 – 00;18;34;14
Joe
We need to figure out which neurons are responsible for processing these types of information. And to like, define and describe these things they would rely on, like the morphology of the cell. And now as the field has like advanced and genetic techniques in the brain have advanced, people are like, “Oh, well, we found that there’s this one type of neuron that expresses this one very specific gene.”
00;18;34;17 – 00;19;01;13
Joe
And so we can look for this gene in this part of the brain. And it’s like a it perfectly describes like this group of cells that are important for processing fear or something. And, and there’s more and more cases of this now where people are getting much more sophisticated in their understanding of like, different individual types of neurons in the brain based on genetics.
00;19;01;15 – 00;19;03;12
Joe
So it’s yeah, it’s fun time to be a geneticist.
00;19;03;12 – 00;19;08;00
伊莎贝拉
Yeah, then is this the kind of question that you’re asking in Rusty’s lab?
00;19;08;02 – 00;19;29;25
Joe
So in Rusty’s lab, we’re definitely interested in aging and neurodegeneration. A lot of these questions about like this copy and paste mechanism, these are like really important for your development. Like it’s going to change how you how your brain like, grows and becomes mature and therefore how you process information and a lot of those types of things.
00;19;29;28 – 00;19;52;05
Joe
But then we’re like more towards, that’s like the beginning of someone’s life, and we’re a lot of a lot of the focus of the lab now is towards the end of someone’s life. So why is it that some people experience this really profound like dementia as they get older, as their neurons start to die off and they lose all their cognitive capacity.
00;19;52;05 – 00;20;16;20
Joe
And like and develop Alzheimer’s disease, which is like, you know, the most common form of dementia. And it’s a really big it’s like a huge question in the aging field now as to why some people get Alzheimer’s disease and some people don’t. So that means like there’s a lot of different types of diseases where there’s like a really strong genetic component.
00;20;16;20 – 00;20;46;24
Joe
So it’s like, okay, well, if you inherit this gene, then you’ll almost certainly develop certain types of Parkinson’s disease, for example. And there are examples of that in Alzheimer’s disease, there’s these mutations in certain genes that they discovered back in the 80s. And they’re like, these people get Alzheimer’s when they’re really young, like in their 40s. And, but like 95% of the people that get Alzheimer’s disease, they don’t have these mutations.
00;20;46;24 – 00;21;01;15
Joe
They have like what they would call sporadic Alzheimer’s. So there’s nothing genetic about them that would seem to like really predispose them to Alzheimer’s. But some people get it and then some people don’t. And so we yeah, we we study a lot of that in the lab right now.
00;21;01;17 – 00;21;09;02
伊莎贝拉
So thinking about aging and neurodegeneration, can you explain to me what senescence is or what senescent cells are.
00;21;09;04 – 00;21;41;23
Joe
Yeah. We we do a lot of work now understanding cellular senescence. So the senescence is an interesting field. It started back like in the 50s. These two professors Hayflick and and Moorhead, back in the day, they thought that cells could divide for forever, like people thought that if you took someone’s skin cells and you put them in a dish and you gave them nutrients and water and heat, that they would just divide for forever.
00;21;41;23 – 00;22;08;03
Joe
And the paper- yeah, it’s kind of funny because the initial paper that describes senescence, it’s not, like- it’s on a completely unrelated topic, like they were studying tumor metastasis. So like back then, people didn’t really understand how tumors like moved around the body. And they thought, oh, maybe tumors are actually making, they’re like a little incubator for viruses because they’re all immune compromised.
00;22;08;05 – 00;22;29;18
Joe
And so there’s something about the tumor where they’re like, they’re like a factory for viruses, and the viruses are leaving the tumor and going to other parts of the body and infecting other cells and causing them to become cancerous. So they were just taking media from tumor lines and putting it on to human skin cells, and then seeing how many times they divided.
00;22;29;25 – 00;22;55;02
Joe
So they’re dividing these human cells over and over and over again. And like the very last figure in the paper, they’re like, oh, actually, by the way, guys like we saw like after we made these cells divide like 50 times over the course of like several months, that they just stop dividing. There was like this big drop off in the number of times the cells would divide and they were like, we’ll call this cellular senescence.
00;22;55;04 – 00;23;26;06
Joe
So that’s how the term originally came to the cell biology field is to describe this like irreversible growth arrest. But in the years since that work, people basically discovered that there were lots of reasons why a cell could senesce. Not just this overproliferation, but basically like any type of like injury that a cell could sustain that is like so severe that it wouldn’t want a daughter cell to inherit by dividing.
00;23;26;09 – 00;23;52;22
Joe
So there’s lots of changes in like metabolism from the cells, or damage to their DNA, or like different types of like cancerous transformations, too, like if a cell kind of detects that it’s turning into a cancer cell, it can senescence in response to this, to kind of shut itself down. And so it has like a lot of important like utilities in our in our bodies as we in, in the majority of our life.
00;23;52;24 – 00;24;15;24
Joe
But for reasons that like aren’t super clear, as we get older, we are accumulating more of these senescent cells. Our body is not as good at clearing them as it once was. Now they’re just sitting there for like a long time, and the persistence of these senescent cells within different tissues in our body is associated with a lot of dysfunction.
00;24;15;26 – 00;24;38;06
Joe
Because some people describe these as like zombie cells, they’re sitting there, they’re like not quite dead, but they’re not quite alive. And they’re sort of doing their job, but they’re kind of bad at doing their job. And they’re also trying to communicate to their environment like, “Hey, I’m like, I’ve come off the rails like something is wrong. I need to be like cleared.”
00;24;38;08 – 00;24;59;28
Joe
So they release a lot of these inflammatory factors into their environment, trying to alert the immune system and like the surrounding niches, like, “Hey, like you guys, I’m toast. Like, come get me.” But when we get older, they’re not getting removed anymore. So they’re just like chronically releasing the stuff around. And this degrades that their tissue that they’re in and and causes these issues.
00;25;00;02 – 00;25;32;22
Joe
And so in our paper that we published back in 2022 because of sort of the history of senescence and how it had originally been described. And like these dividing skin cells in a dish, people for a long time thought that it could only happen to dividing cells. And as as I was mentioning earlier, neurons, they don’t divide. But we sort of make the case for, oh, actually, because there’s all these other avenues outside of this, like proliferation that can make the cells in us.
00;25;32;24 – 00;25;44;03
Joe
We think that these neurons, especially in the Alzheimer’s disease brain, are entering into senescence and that they’re causing the inflammation in the brain that’s that’s leading to the energy generation.
00;25;44;06 – 00;25;51;29
伊莎贝拉
Okay, so you said you published a paper about that in 2022. What are the follow up questions to that? What do you ask now?
00;25;52;01 – 00;26;38;21
Joe
I think the the biggest one right now is really the inflammatory piece of it. So yeah, I think we’ve pretty well established that there’s senescent neurons. There’s more of them in the Alzheimer’s disease brain than there are in like healthy brains, and that they’re releasing these inflammatory factors that are causing mischief. But neurons aren’t really, they don’t really have, like, the machinery to produce a lot of these inflammatory factors, like on there own. One of the most well-studied inflammatory factors are these things called like cytokines and chemokines, and neurons release those at their synapses, which are the connection between two individual cells, but they don’t produce like large amounts of these inflammatory factors
00;26;38;23 – 00;27;04;00
Joe
under normal, healthy conditions. And so we’re like, okay, well, we know these cells are becoming senescent, but how are they actually kicking on all of this inflammatory gene expression. And this is where we came back to the jumping genes actually. One of our favorite theories of sort of the thing we’re pursuing right now is the influence of these retro transposons, or jumping genes, on the development of inflammation.
00;27;04;02 – 00;27;46;21
Joe
Ultimately, these genes, at some point millions of years ago in our history, were derived from a virus. It starts out as DNA in the genome, it’s turned into RNA, it goes outside of the genome into the cytoplasm of the cell, like, you know, the part of the cell that isn’t contained within the the nucleus, and then it undergoes a process, a very unique process, called reverse transcription, where it takes from an RNA, it can make a DNA, which is kind of like the reverse of how it usually works. Usually like DNA makes RNA, and then RNA is used to make protein, and the information doesn’t go the other way.
00;27;46;24 – 00;28;12;08
Joe
When the cell sees this RNA-DNA hybrid or a single lone, lonely fragment of DNA on the cytoplasm, the cell’s like, “Oh my God, I have a virus infection. There’s like a virus in here. I’m infected and I need to respond to this.” And so when they see this jumping gene that has this like viral like intermediate, it’s interpreted as an infection.
00;28;12;08 – 00;28;40;27
Joe
And so it elicits an immune response. And this causes the inflammation. And we think that in senescent cells they’re having unusually high level of this jumping gene activity which is causing them to do the inflammation. And this is actually, I think, a really exciting area of research because like I was mentioning for HIV, they have these drugs that can block reverse transcription, like people who have HIV
00;28;40;27 – 00;29;03;07
Joe
they’re, they take these drugs for decades to prevent reverse transcription from happening. So we know they’re safe to give to humans. And we have some evidence now or what, basically, what we’re working on now is like trying to target this process from these jumping genes to prevent them from making this intermediate to cause the inflammation.
00;29;03;09 – 00;29;29;26
伊莎贝拉
That sounds like such a promising overlap there. It’s making me think, of course, of Dmitry, who’s an associate professor at Salk, and he does a lot of work with HIV. And it’s cool to just think about those connections between genetics and neuroscience and immunology, but also the human connections between labs and people. I’m curious if you’ve noticed the neuroimmunology initiative at Salk having any impact or fueling your work?
00;29;29;29 – 00;29;57;28
Joe
Well, I’ve definitely noticed I think like in the lab at large, we’ve definitely noticed a lot more interest in like the neuro component. And I’m not an immunologist. When I like have gone down like this path of like immunology, I’m like, oh my God, this is like sort of like a terrifying field. I’m very, like naive. But right now we’re still not fully sure who is the one who’s responding to these inflammatory signals.
00;29;58;00 – 00;30;16;19
Joe
We have some evidence that like one, at least one other cell type in the brain, astrocytes, which aren’t really an immune cell, they’re they’re like a supportive cell in the brain. We know for sure they can respond. We want to do experiments in these cells called microglia, which are kind of like a resident immune cell in the brain.
00;30;16;19 – 00;30;46;07
Joe
We want to run some experiments to see how they are responding to these, like neuron inflammation. But there is, I think, a huge like open field for other neuroimmunologists now where people are discovering all these interesting types of immune cells that penetrate the brain. People know that, like in Alzheimer’s disease, you have like a a leaky blood brain barrier.
00;30;46;10 – 00;31;11;28
Joe
And it seems like as you get older and especially if you have like neurodegeneration, your little shield for your brain starts to break down and different immune cells get in that shouldn’t normally be there. And so it’s like, oh, well, what happens if someone not only has like these T cells or B cells getting in that shouldn’t usually be there, but they also have this population of neurons that are suddenly releasing these inflammatory factors that they ordinarily shouldn’t.
00;31;12;00 – 00;31;31;28
Joe
Maybe it’s actually the interaction between these two different things that is causing the degeneration. But as of right now, we’re very much on the on the neuron side, like trying to figure out how it is that the, the neurons themselves are doing it and then in the future would like to transition to like who’s, who’s responding to it.
00;31;32;00 – 00;31;37;08
伊莎贝拉
And is that related to or could you tell me about your BrightFocus Foundation project?
00;31;37;10 – 00;32;17;05
Joe
Yes. So yeah, that’s that’s on my on my BrightFocus research. The, BrightFocus is, is a, organization that funds like a philanthropic organization that funds different research initiatives and into Alzheimer’s disease. They have, like a long pedigree of, like, important discoveries for for Alzheimer’s disease. And they have calls for, for postdoctoral fellowships. And so we produced some, some preliminary data like kind of indicating that, oh, we think these jumping genes might be involved in the development of this neuronal senescence phenotype and applied to to, to to get some more money for, for research through, through this organization.
00;32;17;08 – 00;32;27;28
Joe
And they thought that our ideas were good enough that they were willing to to give us two, two years of funding to study this further. So it’s been really exciting getting to to work to work with them for this.
00;32;28;01 – 00;32;38;18
伊莎贝拉
Yeah, that’s very, very cool. I’m excited to see what you discover. Outside of science, outside of the lab, do you have any hobbies that aren’t science related?
00;32;38;21 – 00;33;00;13
Joe
Yeah, plenty of non science related hobbies. San Diego is a great place for people. I was saying, like as a kid, I like spending time outdoors. Lots of opportunity for doing that here in San Diego. So a lot of times when I have time away from lab, like to go do the classic, go do some surfing, I’m not very good at surfing.
00;33;00;13 – 00;33;20;27
Joe
Like I’m actually pretty bad at surfing. If I can stand up on the surfboard, it’s like a really great day for me, I’m like “Yeah, I did it. I stood up and like, actually caught a wave!” But it’s fun to be out there in the water and go rock climbing, go doing backpacking in the area, go hanging out in the desert down here, lots of opportunities for camping and things.
00;33;20;27 – 00;33;41;14
Joe
And Anza-Borrego and, San Diego has a nice music scene, like just this last Monday we went to go, me and actually another postdoc in the lab, we went to go or we both saw King Gizzard & the Lizard Wizard playing at the Shell. The Shell is a beautiful venue. Every time I’m down there like, this is like, this has got to be like one of the best venues
00;33;41;14 – 00;33;46;04
Joe
In, in California, it’s just always it’s always nice there being like out on the water.
00;33;46;07 – 00;33;50;20
伊莎贝拉
Was the ocean or surfing something you ever did growing up, or is that all brand new?
00;33;50;22 – 00;34;24;16
Joe
Surfing was completely new to me. Yeah. I never yeah, because growing up in Alabama, when we would go to the ocean, we would go down to like, Pensacola, Florida, and like Navarre Beach and like that area- I love it down there. It’s beautiful. Beautiful, like the whitest sand that’s in the world, like, is gleaming white beaches. And then the beach scene in the Gulf that like panhandle part of Florida is definitely different than out here because I was like, when growing up, I’d be like, oh yeah, when I’ll go down to the beach, you know, we would go like fishing and stuff like that.
00;34;24;16 – 00;34;47;16
Joe
And then people like post up on the beach with their coolers full of beer and they’re blasting country music, and they got their palapas like sitting there and then out California, I’m like, oh, man, everyone’s like running around and people are throwing footballs and people are out running in the waves and people are surfing on boogie boards and oh my God, that guy’s like, he has some sort of like, sailing skateboard thing.
00;34;47;16 – 00;34;51;18
Joe
Like there’s people are so much more active on the beach.
00;34;51;20 – 00;35;04;18
伊莎贝拉
So active, so much energy really guilts you into getting up and doing something. My last question for you is looking into the future. What do you think is the most exciting thing happening in the next few years in your field?
00;35;04;20 – 00;35;40;17
Joe
I think that to me, the most exciting thing in the field is how a lot of some of the new technologies that are coming on board are going to let us answer- they’re going to remove a lot of the barriers that we had in like asking some of these questions about transposable elements. So one of the hard things about studying transposable elements, these genes that copy and paste themselves, is that there’s tons of copies of them in the genome, like millions of them.
00;35;40;20 – 00;36;17;00
Joe
So when you want to look at the RNA to determine if these genes are being turned on, if they’re being expressed, then the kind of traditional method would be with what they would call next generation sequencing. And they have what we would call like short read sequencing. So they basically take your RNA- so you can imagine like if you had like a phone book, you tear it up into like thousands and thousands of pieces and you take each piece that is like 150 letters at a time, and then you can see where the overlaps of these different reads are.
00;36;17;01 – 00;36;46;16
Joe
Okay, the end of this read aligns with the start of this read, which aligns with the end of this read, start of this read, and then you can kind of string together the actual full sequence of, of letters and like know which genes were were being expressed. But this doesn’t work super well for transposable elements or anything in the genome that’s repetitive, because this short 150 read, you’re like, oh, does this belong to this one that’s here on chromosome four, to this one here on chromosome ten?
00;36;46;18 – 00;37;10;12
Joe
And so there’s always all this like ambiguity for measuring the expression of these genes. But now the technology has advanced and we have what they call long read sequencing. Now they can do entire messenger RNA sequencing. So now like instead of chopping all of your RNAs up into little bits, you’re like, I’m just going to sequence the whole entire thing.
00;37;10;15 – 00;37;35;23
Joe
And now this then removes the ambiguity from it. I know that it maps exactly back to this one particular copy in this one particular spot in the genome. And this just removes a huge barrier, I think, to a lot of people that like sort of exists in the field, and so it’ll be really fun to see in the next couple of years as these as more and more people start doing this, like what,
00;37;35;23 – 00;37;38;15
Joe
what everyone discovers with this new technology.
00;37;38;17 – 00;37;55;09
伊莎贝拉
Yeah. I also feel like one of the more interesting applications for me personally of AI in science is in genetics, because there’s just so much data and so many patterns, and I think that it’s really cool to see new tech helping solve this old problem.
00;37;55;12 – 00;38;17;19
Joe
Yeah. I mean, the AI, the AI piece of it is pretty amazing, but it can be applied and all these like really powerful ways. And then in the genetics field, we kind of have a leg up in a lot of ways because for like, yeah, 20 years now, people have produced way more data than you could ever analyze yourself.
00;38;17;19 – 00;38;52;06
Joe
Like when we run one of these big DNA or RNA sequencing experiments, you’ll get in like 130GB of data from all of your patients that you sequenced. But like, you just don’t have, like, the time or the resources to be able to process everything all together. Whereas some of these AI tools, they’re much better at handling, like huge amounts of data like that and can sort of like uncover a sort of hidden structure that exists within data that we wouldn’t, as mere mortals like, have
00;38;52;06 – 00;38;54;01
Joe
Time to like, fully understand ourselves.
00;38;54;05 – 00;39;10;03
伊莎贝拉
Yeah, totally. We’re in such a cool spot with lots of modern tech that I think is really going to accelerate a lot of different science. I’m really excited to see what you learn in the coming years, and I think it’s going to be really surprising. But thank you so much, Joe, for sitting down and chatting with me today.
00;39;10;05 – 00;39;19;13
Joe
Yes, thanks. Thanks for having me. This was great.
00;39;19;16 – 00;39;43;22
伊莎贝拉
I don’t know about you all, but I’m still stuck thinking about the fact that my neurons don’t share identical DNA. These incredible discoveries are only possible when we have dedicated scientists like Joe on the case. I’m especially excited about his new BrightFocus project and the idea of getting inspiration from successful HIV medication to potentially treat inflammation in the brain, since both are related to retrovirus mechanisms.
00;39;43;24 – 00;40;22;11
伊莎贝拉
As Joe was saying at the end, modern tools and technology- not just AI- but things like long read sequencing and new model systems, they’re really invigorating the field. In the coming years, we can expect to learn unexpected, compelling, boundary-breaking information about the brain and about what goes wrong as we age to cause disease and disorder. And these are the stepping stones we’ll use to reach treatment and prevention solutions for Alzheimer’s, Parkinson’s, and the many other neurological conditions we face today.
00;40;22;13 – 00;40;52;26
Victoria VO
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