Episode 1: Driven by the Question

Rick McLaughlin  00:00

To do this job, you have to be curious. And you have to be interested in the puzzle. You have to be interested in formulating questions and discussing them. And reorganizing your perspective and your opinion on a situation based upon what happens as you acquire more data and reforming that in this plastic way. But it’s really that curiosity that drive to know what is the answer to this question, how can I figure this thing out? Is this an interesting question? Is this an important question? How can it help people? How can it further our basic understanding of biology?

 

Jack Faris  00:37

Hello, and welcome to our Podcast PNRI Science: Mystery and Discovery, where we go beyond the jargon to dig into the passion and people behind the science. I’m your host, Jack Faris, CEO of Pacific Northwest Research Institute, a 68-year-old genetics and genomics research institute in Seattle. I’m also a regular guy that no you are not a regular guy. Oh boy. There we go. That’s my daughter on a Faris, who’s going to help me out so to speak with this endeavor. Anyway, I say I’m a regular guy who happens to spend his day is around really smart people. And I’m here to interview a PNRI’s brilliant scientists to share what excites them about genetic research. What inspired them to become a scientist? And what are those myths that we would love to bust about science? Join me and on as we dig into the mysteries that may very well hold the key to our future health breakthroughs. Dad, that was great. Oh, I’m really proud of you.

 

Anna Faris  01:40

Dr. Rick McLaughlin, driven by the question. In this episode of PNRI Science: Mystery and Discovery, my dad Jack interviews PNRI Assistant Investigator, Dr. Rick McLaughlin, who explains what your genome and IKEA have in common, educates us on zombie parasites in our DNA, demystifies” junk DNA” and makes Darwin smile. As per usual, my dad asks some pretty wild questions, including, do I have more genes than when I was four years old? Dig into this podcast and enjoy the awe inspiring power of science.

 

Jack Faris  02:23

Probably the most important topic for us is the mystery of science, or the way in which science attacks mysteries. So let’s start with mysteries. Okay, I’m going to ask you about the mystery of the placenta, which I had never thought very much about other than being aware that it was part of the birth process. But I recall, just in passing, seeing you in the parking garage, and learning that you were heading off to a meeting about placentas, or on the subject of placenta. So I’m going to be quiet for a minute and let you talk a little bit about your interest in placenta, why it’s significant and what we’re learning?

 

Rick McLaughlin  03:08

Sure. So you know, one thing that I personally in my lab is really interested in thinking about is how do you build a system that can do these amazing things that living systems can do? How does it work, but also how did it come to be? And the way that we access that is with what we call evolutionary biology. And that really means looking backwards in time and trying to understand how this thing came to be the way it is, right? So just like us as people are not snapped into existence, and our personalities are the way they are right now. We’re the product of the things that have happened in our lives and our ancestors lives ad infinitum. And, and that’s, that’s how the human body that’s how living things work, also, so many of the most dramatic changes in organism or evolution, catch my eye, and are really interesting things to think about. Certainly, we can think about the evolution of life as perhaps the most foundational and dramatic instance of this sort of innovation.

 

Rick McLaughlin  04:12

But the mammalian placenta is one that is particularly interesting. So the placenta is extremely important, obviously, for viability and success of the fetus. And it serves a number of purposes. But one of those is really to protect that developing fetus from all the bad things that are out in the world. So viruses, bacteria, etc, maternal antibodies that might recognize that fetus as nonself by mom and initiate what is really an immune process against that fetus. So you need a physical barrier to keep those things out. And a lot of times barriers like our skin, for example, do a pretty good job at this, but there are actually little spaces, little junctions between those cells. And these bacteria and viruses. They’re tricky. They can sneak their way through those tiny spaces.

 

Rick McLaughlin  05:00

So the really major innovation in the context of the placenta became that there are many, many cells fused together. So instead of a single membrane, imagine a bunch of balls stacked against each other. Now you have this fused membrane that’s almost like a double layered balloon. And that’s a continuous layer of membrane that has none of these little holes in it, none of these potential shortcuts for bacteria or viruses to sneak into the developing placenta. So this process of creating this double membrane structure, and these cells are called Sitia, trophoblast, that go into form this sensation. It was a really big jump in function for what at that point, were very ancient mammalian cells. And for a long time, it wasn’t completely understood how this happened. But it was known that there was a series of genes that were involved in placental development that were absolutely essential for this to happen. And, you know, 20 years ago or so it was discovered that the way that this function happens, this really fundamental aspect of mammalian physiology, is that 100 million years ago, or so the common ancestor of mammals, in a sense, stole a gene from a virus. So what does that mean? Viruses are really good at doing this function of fusing membranes. So when a virus attacks ourselves, so to speak, it has to get inside. And the way that it does that is by binding and initiating this fusion process between its membrane or envelope, and the mammalian target cell membrane. So the, the way that it does that is really by taking that cell, binding to that cell and using its protein machinery called the envelope to fuse those membranes together. So this protein called an envelope protein, which many, many viruses have, actually was integrated into our genome in a way such that it became expressed in the right place, and provided this amazing benefit of fusing these cells together to create this placenta. So my interest in our labs interest really initiates with that amazing observation that we really needed this viral gene to create this fascinating and somewhat unique placental morphology. So this has actually happened in some other organisms, too. But obviously, we’re most familiar with a mammalian situation. And what becomes interesting there is, how did this happen? And how does that inform or direct how these genes work now in the context of a healthy or, perhaps not perfectly healthy birth. So what becomes interesting now as how those genes play a role in producing a healthy pregnancy, a placenta that’s able to protect that developing fetus, or in some cases, when things might go wrong in the context of that development. So we’re really interested in thinking about how these envelope genes contribute to placental physiology. But also, this is not a one time thing. There are dozens of these genes that are present in the human genome, that have, in some ways been described what they might be doing. But we really have no sense of in the context of human pregnancy, specifically, how these genes might be playing particular roles, and how changes in these genes might have consequences for pregnancy outcomes.

 

Jack Faris  08:24

Should we as a society as a scientific collective, be investing more in trying to understand pregnancy as a phenomenon?

 

Rick McLaughlin  08:32

So many of the very fundamental basic science questions about understanding that fetal development had been studied in the context of mice. And we’ve learned amazing things that are absolutely essential and absolutely relevant to what happens in the human situation. But what’s fascinating to me is that if we go back to this perspective of using evolutionary biology to understand how an organism how a living body works, a lot of things have happened. Since we had a common ancestor with mice, many, many things, you know, along the human lineage along the primate lineage, along the road lineage, to all of those things that happened along the way, had many, many opportunities to change the way the system, the organism, the biology works now. And we know that that’s the case. There are things that are idiosyncratic genetically, developmentally to pretty much any species that you can take a look at. So my perspective and my real interest in stepping a bit more into this field of trying to understand placenta, and pregnancy comes from that perspective, how can we think about this as a uniquely human problem? And how can we think about the genes that might be uniquely human in the way that they contribute to these processes? So I think there’s a lot of work to be done there. There’s been a lot of work from the clinical perspective looking at, you know, genes that are correlated with unintended defects in development, or genes that might have an effect on the outcome of pregnancy. You know, my colleague Lisa Stubbs is really interested in thinking about how genes and stress might interact to alter a pregnancy outcome.

 

Jack Faris  10:25

So the placenta meeting which intrigues me, whoo hoo comes to a placenta meeting. And what do you all talk about when you’re there?

 

Rick McLaughlin  10:33

Well, Jack, we talk about placentas.

 

Jack Faris  10:38

You have to go a little beyond just that. 

 

Rick McLaughlin  10:41

So the the particular meeting that you caught me in the parking lot, just before I went was the North American Placenta Lab meeting, organized by a really awesome Canadian group who studies placenta. And via the magic of Twitter, you can sort of get the message out that there’s a core group of people who are interested in thinking about placental biology and me as sort of an outsider with an interest in this sees this as a great way for me to kind of get a pulse on what’s happening in the research field of placental biology. So this meeting, this meeting this group, it’s sort of a, it’s a Zoom session where folks from all over the world join in. It’s particularly cool, because there will be clinicians, there will be social workers that will be public health specialists, but there also be basic biologists who are thinking about gene expression in genetic variation in the context of pregnancy and placenta specifically. So it’s a really nice collective of very diverse professionals with diverse backgrounds thinking about diverse problems all in the context of placental biology.

 

Jack Faris  11:54

So let’s see, I wanted to return to the idea that your work is largely focused on looking back not hundreds of years or thousands of years, but millennia. And that is something that probably relatively few scientists do. So how, how does that inform what we might be thinking people think of science as sort of looking forward moving forward? How does that inform scientific endeavor today?

 

Rick McLaughlin  12:29

So I think I’ll quote Shakespeare, from the Tempest, “What’s past is prologue.” So really, to, again, understand how things work. Now, we have to understand the past. And I think with the broad adoption of relatively inexpensive genome sequencing, we have come into a huge wealth of genome sequences of not just humans, not just the model organisms like mouse and fly and worms, but literally thousands of species, from every kingdom, from across the globe, from the deep, deep oceans to the highest, you know, most inhospitable, hot climates of the world. And with that comes a huge wealth of information about thinking about, you know, for example, my colleague, Aimee Dudley thinks about genes that are absolutely essential for human biology, and also absolutely essential for yeast biology. So there’s something like 4,000 genes that you can identify as the exact same genes that came from a common origin or common birth of those genes and the common ancestor of humans and yeast, there’s, it’s more than a billion years, that’s, I mean, that’s unfathomable, to my mind, in a sense. But in sequencing all of these species from across the globe, we can have sort of tighter evolutionary relationships where we can look at the evolution of things that are, for example, human specific, that maybe aren’t shared with chimpanzees, or gorillas, or closest ancestors. We can look at aspects or traits of organismal biology, like the emergence of immune systems, which goes all the way back to beyond jawed vertebrates. And with the sequences we can really understand, not just outwardly, what are the traits that are shared or different amongst different phylogenetic groups, as we learned about in basic biology back in high school, but what are the instructions? What are the genes? What are the sequences of those genes, out of those genes interact to produce these beautifully complex and interestingly functional processes and aspects of biology that might be beautifully outwardly visible when you go to the zoo? Or might be some really interesting aspect, for example of an organism’s immune system. That could be particularly interesting not just in its own right, but you know, how might we heart how might we see sort of harness that and adapt that to the human system to better understand why our immune system fails to do that, or why our body fails to regenerate as other organisms might.

 

Jack Faris  15:11

Listening to you talk about this stuff, certainly underscores for me that this must be for biological scientists, just the best time to be doing science.

 

Rick McLaughlin  15:22

It is, it is an amazing time. So I think as biologists we grow up thinking about the early days of molecular biology and biochemistry, where the gene was discovered and double stranded DNA and this huge, huge explosion of molecular biology. There’s a book called The Eighth Day of Creation by Horace Judson that details the shall we say intricate and interesting interactions, all of those personalities, as they came together to make these foundational textbook discoveries. So I think we all look back at that time and think about Wow, how cool it must have been to make those sorts of discoveries. But I think you’re right that now, as we have both sequence, the first human genome, and sequenced now, probably close to a million genomes. And now thousands and thousnds of other species, and many individuals amongst some of those other species, the data has far exceeded our ability to extract interesting patterns and learn things from it. So there’s this huge pool of data sitting there waiting to be analyzed in traditional ways, creative ways, new ways that we haven’t even thought of yet. And it’s really just up to us to drive that research, make it happen, think creatively about how to utilize this data. So I think it is really, really exciting to be alive now in the context of especially genetics and genomics.

 

Jack Faris  17:00

Let’s go to your personal story for a minute. How did you become started out on the path to becoming a scientist?

 

Rick McLaughlin  17:09

I think at at heart, I’m a naturalist. So to me, walking outside, seeing nature is just awe inspiring. And that’s still my Zen space is to be out in the woods, looking up in the trees breathing, the air touching the moss. And I think even as a young child, I had an insect collection, much to my mom’s dismay, because it smelled terrible in my closet. I had a shell collection and a rock collection. And, you know, I was a collector to look at the variation and different types of things that were out there in the world. So that was always sort of in my bones, I think. And as a kid, I had big old, you know, dictionaries of insect species, and was really interested in insects at the time. And when I went to undergraduate at Trinity University in San Antonio, which is a liberal arts school, but also has a really great research program, too. I initially became very interested in ecology and evolution, and worked on a number of projects there characterizing species diversity, for example, at a new state natural area that was to become a state park with my professor David Ribble at the time. And my most memorable project then was setting up what we’re really bird catching nets that we had sort of inherited from the Audubon Society. And we take them and we placed them across a stream. And as the sun set, the bats would come out, and the bats would be echolocating over the water, looking for insects, just distracted enough by the sound and the motion of the water that they would fly into these bird nets. And that would allow us to capture the animal safely determine what species and what sex those animals were. Interestingly enough, this is the first time that I became really interested in thinking about parasites, because I caught this bat. And it was a it was called a, the most common species at the time was Brazilian Freetail. And it was one of these bats. And I picked up the bat and I had, you know, I’d handled dozens or hundreds of these bats, you pick them up, you weigh them, we check their sex, let them fly away. But this one had these weird little bumps on the back. And I was like, What the heck are these things? And my professor was like, huh, those are parasitic dipteran. These are flies that essentially became parasites of these bats. But the amazing thing was that because they only lived on these bats, and they simply essentially jumped from bat to bat wherever the bat roosted, they didn’t need their wings anymore. So they were wingless are very, very tiny little wing flies that had lost the ability to fly around, because now their ecosystem was just infecting these bats. And that that was my first real fascination and thinking about coevolution how species interact and how that can drive very dramatic changes in these organisms.

 

Jack Faris  20:10

I would imagine that hearing that story, Darwin would have smiled.

 

Jack Faris  20:22

Let’s make sure we talk about another facet of your work, which is to nourish young talent and prospective collaborators in the scientific endeavor, which is something that PNRI is committed to. But you do a particularly superb job in my estimation of of coaching young people from high school, in some cases to postdoctoral students, what role do postdocs play in your, your work? 

 

Rick McLaughlin  21:00

So postdocs are individuals who have received their doctoral degree in could be any topic. Oftentimes, the ones that work at PNRI are in biology, or genetics, or genomics, or chemistry, or math or physics, something like that. And these are individuals who, for one reason or another would like additional training beyond that PhD process. And a lot of times this time, I mean, for me, it was a particularly fulfilling and really exciting time of my training, where I was relieved of the constraints of being a student and having certain classes to do and having to meet certain expectations. And at least in the environment, where I did a postdoc and Dr. Harmeet. Malik’s lab at the Hutch, it was just an intellectual carnival, you know, there are people working on all kinds of different projects, from yeast to mammalian genomics to virology to you, you name the model system, something was happening there in the context of the lab. But the point of that process of being a postdoc is really to learn how to, in some cases, be a principal investigator, if that’s your pursuit, there’s a lot of postdocs who are also interested in going to biotech or teaching or doing other things like that as well. But one route is to go on and hope to have your own lab, as I am so fortunate to have done. So those individuals come for a certain kind of training, which is often really learning how to write grants, write papers, manage people, and build your own scientific research program. So how can you make something that is your own, that is distinct from your mentors, lab and your mentors, major research program, that you could see yourself working on for, you know, maybe not the rest of your life, but maybe the rest of your life. So these individuals are highly skilled, highly advanced in their craft, often have recently published some of the top papers in the field. And when you’re lucky enough to get a good person like this to come join your lab, they can really be amazing intellectual drivers that push projects forward in ways that, for example, junior scientists might not be able to because they haven’t had that experience. So these postdoctoral students, and also staff scientists, others who have PhDs, but maybe aren’t yet running their own labs are really crucial facet of what happens at PNRI and really, in the research endeavor much more broadly.

 

Jack Faris  23:27

It’s really is a cohesive team if you get it right. And maybe that happens just spontaneously doing the work, but are the things that you do to kind of build a team spirit in your, in your lab?

 

Rick McLaughlin  23:40

Absolutely. It’s a very active and energy intensive process to do that, as I think anyone who runs a team knows. But I think in its essence, there’s really a need to both sort of buy in intellectually, to be excited and really driven by the question that you’re working on. And be thinking about it kind of all the time, right? But it’s not, it’s not a task to be thinking about this research question you’re working on. It’s something that is engaging and motivating to you as an individual. So I think really giving people ownership of a project, even if they’re an undergrad in the lab, even if they’re a high school student in the lab. To me, it’s absolutely crucial that they have something that is their own. And to me that maybe is one of the most exciting things of science is to own this thing that is this intellectual body of work. That is this really cool question that you want to answer that you want to figure out. And to figure out how to move that forward and working with others to learn skills and to learn how to test that question in different ways. Thank

 

Jack Faris  24:47

you high school students. What one thing would you like every high school student to know you’re not not all of them are going to become postdoctoral collaborators, not all of them are going to become some answers. But what one thing would you like all high school students to know about science and at least the potential of careers in or related to science.

 

Rick McLaughlin  25:12

I would say all you need is the curiosity. There are ways to get you where you want to go. There are amazing support networks now that are they’re not adequate. And they’re not sufficient yet, but they’re there. And they’re being built to bring access to science to people of all levels all over the world. And it doesn’t matter if you’re not good at math, or you’re not good at basic biology. I got to see in my cell and molecular biology class, the first year of undergraduate, and here I am doing that for a living, right. But to do this job, you have to be curious. And you have to be interested in the puzzle. You have to be interested in formulating questions and discussing them. And reorganizing your perspective and your opinion on a situation based upon what happens is you acquire more data, and reforming that in this plastic way. But it’s really that curiosity that drive to know what is the answer to this question, how can I figure this thing out? Is this an interesting question? Is this an important question? How can it help people how can it further our basic understanding of biology, or whatever scientific fields you might work in?

 

Jack Faris  26:29

Until January or so 2024, I had never heard the term transposable elements. And I’m pretty sure I’m not alone. Talk a bit about their significance and how to how to think about this aspect of our physiology.

 

Rick McLaughlin  26:47

So when the human genome was first sequence, and we had a complete, reasonably complete picture of the 3 billion base pairs, that are in a single strand of the human genome, what became utterly clear and had been sensed for decades and decades was that a very small fraction of our genome is all that’s required to make all the proteins that are essential to make our body and that fraction is about, it’s less than 2%, of all of the nucleotides in our genome, are needed to make the proteins that are required for the form and function of the human body. Now, there are other aspects that are not proteins that are important for organism will function for human body function, but those are quite small as well. So what’s the rest? What’s this other, you know, at least 90% of the genome? Where did it come from? What is it doing? How does it impact the way that our body works? How does it impact disease? It turns out, stay with me for a minute here, this is gonna sound like a bit of a zombie drama. But in fact, it’s very, very true. Within our genome, there are parasites. And these are selfish pieces of DNA that can copy themselves. And it’s their relentless copying over millions and millions of years that have made our genomes so big, and that have driven the presence of this other 98% of our genome. So, if we think about a gene, some kinds of genes make RNA that encode proteins, and those proteins do something for our body. For example, maybe they contribute to the physiology of your kidney, or, you know, the structural integrity of your skin. So there you have this piece of DNA, RNA protein, you know, it’s the very central dogma. And together those many, many genes create via development and the rest of our lives, a functioning human. These transposable elements, or transpose ons, or jumping genes, just like regular genes are pieces of DNA, and they make RNA and some of them make these proteins. But this is where the big difference comes, instead of creating a protein that contributes to some aspect of our body. These proteins exist because they have the ability to make a copy of that original sequence from which they came from. So they’re really copy and paste machines. They make these proteins because these proteins are able to make another copy of that sequence from which they came. So now, instead of there being one of these copies, there are two of these copies. And over millions and millions of years, and really even within the lifetime of an individual, you get more and more copies of these jumping genes that accumulate in the genome, either in specific cells, or if they’re in the germline or the early embryo, those cells that are passed To onto our offspring, that might be heritable genetic variation that comes from us and goes to our our offspring. So these exist, because they can replicate themselves, and they have to continue replicating themselves to continue to exist. So it sounds like science fiction, but it is a topic that has been recognized as an important aspect of genetics for a long time. You know, the grandmother of this field was a woman named Barbara McClintock, who, before an understanding of DNA as the heritable unit of our cells, figured out that there were these pieces of the genome that were jumping around in her model organism was maze, and, you know, extracted the biology and genetics of these transposable elements. And we’ve really come full force through thinking about these not just in model systems, but how they play a role and how they’re functioning, and how they’re really important for human biology and disease. 

 

Jack Faris  31:01

So two questions, do I have more genes now than I did when I was four years old. And you allude to some function of these, but I would like a little bit more clarity around what, what we think we know about what those functions might be.

 

Rick McLaughlin  31:23

So this idea that the genome is a stable set of instructions, that it’s a Word document with pages and pages of instructions, and that is passed down with high fidelity from generation to generation is really a fallacy. And, you know, my colleague, Claudio Carvalho, uses these amazing new genome sequencing technologies to study just this, how these big changes in human genomes, for example, could cause a rare disease. But this is also happening in apparently healthy individuals, there are changes at the single nucleotide level where maybe a C in your genome flips to an A, because it’s been mutated in some way. And there are much larger changes that happen in our genome on the scale of our lifetime, or on the scale of generations. And if these happen in the germline, they’re passed on to an individual, but these can also happen in what we call somatic cells. So that’s everything else that’s in our body. That’s not the cells that are passed down. And we know that there’s what we call mosaicism, within those somatic cells. So if you took a handful of cells from your brain, I’m not going to do that right now. But if you did, and you sequenced the genome of each of those cells, you would see that there are as many different genomes perhaps as there are cells. That, you know that that sense that this is a really stable set of instructions becomes quite clear when you’re able to resolve these genomes on the scale of that single cell. And some of that variation, especially in the brain comes from these jumping genes moving around. So there, imagine you have your instruction booklet for putting together your IKEA shelf or something, right. And along comes this copy paste virus parasite things and starts like taking panels and copying and pasting it throughout that, it’s going to really destroy your ability to use the information in that document to make your stable structure your shelf in the end. And this is happening in our genome all the time, our genome just has ways to deal with this. Even though the code the genome is being degenerated or changed or mutated in this way. Doesn’t seem to matter too much, you know, our were pretty robust in that context of being able to fight through those punches of these variations and continue to exist. You know, that is obviously not always the case. And Claudia and Amy’s work at PNRI are really interesting investigation investigations of what happens in the context of rare diseases, where these variations drive really unfortunate consequences in individuals. But, you know, we are a mosaic of genomes at any point in our life. And with age, you get more and more of these mutations. And I think an interesting topic of study now is how these accumulated mutations throughout your lifetime contribute to aging phenotypes, or age related diseases.

 

Jack Faris  34:22

From time to time, one hears the phrase “junk DNA.” What does that mean? And is it in fact, in any way misleading?

 

Rick McLaughlin  34:32

So that term really reflects our understanding of this non protein coding part of the genome that I mentioned before. So even though less than 2% of our genome was important for making these proteins, we have these huge swaths of DNA that don’t do that. And what we’re left with asking is, what do they do? And how can we figure out what they do? And that last part is really the difficult thing. How do you how do you test a function? And outside of this region of the genome that we’ve been studying for 100 years. So that big chunk of non coding, non genomic DNA has been collectively described as junk DNA. That made a lot of sense at the time, right? Like, there’s all this stuff, you can make mutations, there doesn’t seem to do anything to the context of the organism. What’s become quite clear is, there’s a lot of interesting biology that’s happening in that junk. There are these replicating pieces of DNA that we talked about called transposable elements that have really fascinating biology in and of themselves. But that replication of these elements, that change in the DNA sequence that’s driven by these transposable elements can have dramatic consequences to human health. There’s also some amazing other pieces in this junk. There are new genes that have been historically called processed to genes, but are also called retro genes. And all that means is that one of these transposable elements was there was trying to replicate itself, but they’re not perfect. They don’t always replicate themselves. Sometimes they accidentally make a copy of one of our genes that’s required and essential for normal physiology, any of these sorts of 30,000 genes that are described in the context of the genome, maybe even one of these 4000 genes that we share with yeast. So then you get a new copy of a gene that might be present only in you might be present only in some of your cells, it might be present only in one of your children. And we don’t really know for the most part, what these genes do, most of the time, they probably don’t do anything. But we have some really interesting examples where these new genes or retro genes are having important consequences. And there’s a subset of my group led by Dr. Lei Yang, who studies these retrogenes in the context of human genomes. The other piece that’s within the junk DNA are pieces, and chunks and functions from these transposable elements that in one way or another have become important for our existence. So what does that mean? You know, if you’re building a home, you will look around you. And you see what materials are present, which ones are prevalent, if you’re in the Pacific Northwest, there’s a lot of wood here, we see a lot of wood homes in the South that are a lot more brick homes. So you kind of take advantage of the materials that are around you to create structures to make innovation to build things. And genomes are the same way. So they don’t really care how something gets there. If it proves to be advantageous or even neutral, they’ll keep that around. And that will become integrated as a part of our biology. And because these transposable elements sequences, because this junk DNA is so voluminous, just by probability, sometimes a piece lands in a place that lends some function to the context of our biology. We talked a little bit about these viral envelope genes and their contribution to making the mammalian placenta. So there, that’s really the genome in a sense, making lemonade out of lemons, as the field likes to call it, sometimes taking advantage of the presence of the sequences that have all these really important and potentially useful functions to drive our central biology. And sometimes those functions are a little bit, shall we say? They’re pretty dumb. Like, if you were to create this mechanism, this is not how you would make it. So for example, some of the RNA created by these transposable elements is required for progression through development. So like, if you get rid of them, if we get rid of these parasites, development doesn’t happen. And that’s because those transposable elements have been replicating in this stage of development. reproducibly, very, with high integrity over millions and millions of years. And our genome has used that presence as a signal of that cell state of that step in development. And instead of using one of its genes, this thing is always there at the exact same time. So by chance, it’s been integrated as a signal. And now we’re stuck with that transposable element, we tried to get rid of all of them, we’re gonna die because we brought the sequences into our basic genome. So within that junk, there’s all sorts of really interesting things that we have identified. And there are so many things that we have yet to really begun to understand.

 

Jack Faris  39:46

So, one of the things that PNRI does, that’s significant in terms of nourishing talent for the future is a summer program involving community college students. I’d love to hear you play a key role in coordinating and leading that, please tell us about how that works. And in particular, I’d love to hear about, you know, the impact on these young people of having an extraordinary experience in an institute that’s really devoted to the frontier of science. So there are

 

Rick McLaughlin  40:21

really, I would say, two major goals. For me personally, for my lab, one of those is do cool research that’s important and creative and interesting and fun. And the other is to bring the opportunity to do research, to think about science to much broader audiences. And we do that through a number of mechanisms, including hosting graduate students from the University of Washington Molecular and Cellular Biology Program and other programs, bringing high school students into the lab. But one of the the central parts of PNRI’s education efforts is the summer undergraduate research, internship ship or story. And story really came about to try to provide access to a laboratory based research experience for individuals who historically might not have had access to that for one reason or another. And one of the populations or groups of individuals that we have been particularly interested in bringing this experience to our students who have been at or currently are at community colleges or other two year universities. So that population is particularly important, because number one, it’s a very diverse population. But number two, the research experiences are extremely limited for these individuals. And often, that’s because the, the logistics of such an experience would be prohibitive for them, they can’t volunteer their time because they need to make some money over the summer for them to provide or pay their rent throughout the school year. So our program is really becoming interested in bringing as many of these students as possible into this internship program, we have a program that is called CC Community College to PhD, that is been being run by a number of us at the institute, including Amanda Norseen who’s an individual in my lab, who came from a community college. And that was a really accomplished and awesome research technician in the lab. And we’re really, really trying to give them more people that ability to come from the community college, maybe they’re transferring in the University of Washington soon or another school, but how do they get their feet on the ground and really get that experience of learning what it is to be a scientific researcher.

 

Jack Faris  42:45

So some might think listening to you, this is all very fascinating. We have, you know, study of evolutionary processes extending over millions of years, we have these mysterious transposable elements. And from the point of view of just cool science, that’s cool. But is there any kind of translation into improving human health? 

 

Rick McLaughlin  43:19

So just like we need to understand how a system the human body came to be by studying its evolutionary origins, one of the things that really comes from that is understanding not just how and why it works the way it does. But why does it fall into disrepair? When things go wrong? Why did they go wrong? And why did they go wrong from the perspective of how did that thing come to be? So one interesting aspect of what we think about in the context of these transposable elements, these jumping genes is mobile DNA is that we’re all still walking around, despite the fact that these crazy parasite zombie things I told you about are actively trying to replicate in our genomes. And that’s because our body encodes a really elaborate and effective immune system that creates a number of different genes that block these elements, these jumping genes from replicating. So for the most part, they’re kept quiet. They don’t replicate themselves, but at certain points in our development, and at certain times, in our lifetime, in certain cells. They may replicate themselves, but this whole suite of proteins that are a part of the innate immune system that block these things from replicating and prevent the deleterious consequences, the diseases that can be caused by them. There are a lot of the same genes that are now used by our body to combat infectious viruses as well. So there’s this really interesting connection to immunity, as we think about these elements that are inside of our genome. And just like our immune system sent is an infectious virus and activates a subset of downstream signals to try to combat that virus from replicating. Our body can also do the same for these jumping genes that are kind of like viruses, but they’re inside of ourselves. So there’s a set of diseases called Aicardi-Goutieres syndrome. And this syndrome is characterized by a child being born with an apparent congenital infection. So it seems when the child is born, it seems like they have a viral infection, they have clinical signatures that suggest there’s a virus replicating, and the immune system has been activated in response to that. Unfortunately, there’s no real cure or great treatment for these individuals. And these children often die before their three, four or five years of age. But it turns out that even though their symptoms are completely consistent with the presence of an infectious virus, there’s no virus there. What has happened is there’s been a mutation or a change in a gene that has disrupted that genes ability to do its normal function. And it just happens that the mutations that are found in these patients with Aicardi-Goutieres syndrome, are all breaking genes that are required for keeping these transposable elements quiet, and silent, and non replicating. So with these mutations, these transposable elements become hyperactive, there’s nothing there to keep them or not all of the mechanisms are there to keep them silent. And they make more and more and more and more copies of themselves. And now our bodies see these intermediates of these transposable element replication, which look a lot like viruses. And in response, activate the antiviral pathway. But they don’t they can’t clear this, right, it’s not an infectious thing it’s coming from within it’s coming from their own genome. So there’s really, it’s impossible to clear that infection. So the immune system stays in this hyperactive state forever. So that paradigm is is really interesting to think about. It’s a very unfortunate disease. But often, as you’ll hear about from my colleagues, rare disease, really gives us a chance to understand the biology. And the way that we’ve learned about a lot of aspects of human biology and organismal biology is when something is wrong, or something is different. How can we understand the genetic changes that give rise to that difference or that disease. And here we, we think very much about these genes, the aspect of our immune system that keeps these transposable elements at bay, it’s a deep expertise and study of our lab. But what for a long time has been very difficult to study was what’s happening on the other side of the coin. So when we think about virus evolution, we think about a virus changing in a way that our immune system is no longer able to effectively block it. Right. And I mean, we’ve seen this manifest in all sorts of pandemics that have happened to the human population, that virus becomes capable of infecting cells in a new way, and our immune system doesn’t have a great way to combat it. So that is an evolutionary process, where it’s advantageous for the virus to change in a way where it can replicate itself more and it can infect more people. Likewise, it’s advantageous for our genome to try to perhaps select individuals that have a change that combats that variant, but that’s another story. But this process of changing in a way where you evade the immune system, could also be playing out in the context of our genome with these virus like transposable elements. And what’s been very hard to study is the exact variation that’s happening not just in our genes, but in these big pieces of genome that comprise this junk DNA that contain these transposable elements. So they’ve been very hard to sequence in the way that for many, many years we’ve been sequencing human genomes is in a sense by chopping it up into tiny little pieces that are about 300 base pairs long, and then sequencing those and then using this process of assembly to try to piece all of those tiny pieces together to figure out what the full puzzle looks like. Now, if we take one class of these transposable elements, they’re called line ones. You don’t need to worry about that. It’s just a piece of jargon at this point, but they’re called line ones. You have 500,000 copies of these line ones in your genome. Now imagine trying to take a little piece of a puzzle that could fit in 500,000 Different places into the larger puzzle and trying to decide exactly which is the right one, which is the one that it came from, you know it’s impossible but In the last five or 10 years, we have a completely new set of technologies that allow us to make very, very long sequencing reads. So instead of sequencing 300, base pair chunks, we can routinely sequence 10,000, or 30,000, base pair chunks of the genome. And that has really revolutionized our ability to look at variation within the sequences, and what the consequences of that variation might be. sort of come back to the autoimmune disease, and perhaps lupus, one phenomenon that we think could be happening is that just like a virus can figure out a way to get around our immune system and infect our bodies. We think that these transposable elements, which are normally silenced, and kept at bay, by our immune system, can figure out a way to potentially get around those mechanisms. Even though our genes are completely fine, they haven’t had any mutations like we see in these Aicardi-Goutieres patients, it could be that the transposable elements are changing, just like a virus might change. And now becoming active and replicating and activating the immune system in maybe a very idiosyncratic way, maybe in one to a subset of cells within your body, maybe at some stage 1020 30 years into your lifetime. So that paradigm, that idea is something that’s centrally interesting to our lab. And recently, our graduate student, Ricky Padilla Del Valle, who’s defending their thesis on Thursday, very proud to say, has found some really fascinating data where we can take elements from a human genome, these transposable elements, the sequences that are variable amongst different individuals, and show that some of them have the ability to perhaps get around this very vast suite of factors that our immune system uses to block them. So now, our labs really fascinated in thinking about how can we take this really evolution guided discovery, and apply that to what’s actually happening in human genomes and human disease. So now we have this phenomenon that I would say is a really new class of how these diseases might be driven, how autoimmune disease could be driven? And now can we go into patients, like lupus patients, like other autoimmune disease patients, and find evidence that this might be happening?

 

Jack Faris  52:30

The career of most scientists is, is not linear. It’s something else of a journey into the unknown, the mystery of wonderful mystery of our natural world. I’d like you to describe how that is manifest for you. One a personal basis, 

 

Rick McLaughlin  52:54

I’ll go back to this idea of being driven by the question. And I think, at every stage in my scientific career, be it catching bats in the Texas Hill Country, or studying protein evolution or thinking about these transposable elements in genomes. It’s really been asking a question that I find fascinating that we don’t know the answer to. And I think my progress through those different fields has certainly been nonlinear, minimally, you know, going from ecology, to biophysics, to virology to human genetics now. But all the time, I’ve sort of seen a question or seen someone who is studying a field that I’m just fascinated by. And for me, this has been documented in a sense, by it’s not exactly my laboratory notebook, you know, every scientist has a laboratory notebook. But with the advent of digital notebooks, you can have whatever you want in there, right, you can have all your experiments and your data and your your protocols in one aspect, one tab of your notebook and you click another. And you maybe have all sorts of other personal musings on the topic of science who are not. But I have one page that it’s just called ideas. And anytime I have an idea, it’s often in the middle of a seminar or maybe in the middle of the night, or who knows what else I just jotted down there. And I just tried to put enough information that I can reconstruct what the heck it was, I was thinking at that time. And, you know, there’s no judgement at that point. Most of those things are incomprehensible or, you know, Bazeley wrong for some reason. But when I’m writing a grant or thinking about what the next project or the next topic or the next step in my training at some point in the past, I go through that and I I read through it, and I put little stars next to the questions. And as I’ve gone through in my life, some of these questions have accumulated more and more stars. And those are the questions that I think are really cool. But they’re too out there, or they’re inaccessible, technologically, to begin to tackle. And I think one of the things that I really came to love about PNRI, and that brought me here was that I could be doing as my postdoc mentor called my meat and potatoes, right, I could be doing these experiments that I know are going to work. And they’re going to provide important advancements to the field that are interesting. But I can also, you know, try to hit some home runs at the same time, I can tackle these questions that I don’t even know how I’m going to answer that question yet. That might require me to invent and develop a completely new technology that utilizes a number of different approaches that might have been sort of disparate in the past, but we’re trying to bring together to answer these questions. And for me, that’s, that’s just super fun, you know, conceptualizing and thinking about how can we do this new thing in a way that hasn’t been done before? That can answer this question that maybe sounds a little fluffy and insubstantial when it’s written there. But in there is something really fundamental and interesting and deep about some aspect of genetics or genomics or human biology. 

 

Jack Faris  56:27

Rick, your journey from aspiring naturalist to being a very sophisticated naturalist is really illuminating. For all of us listening to this and I just want to thank you for your time and your insights and especially for what you do to nourish people who are going to succeed all of us in charting the future of science. So thank you so much. 

 

Rick McLaughlin  56:50

Thanks very much, Jack. Great talking to you.

 

Anna Faris  56:53

Thank you for joining my father and me for this episode of PNRI Science: Mystery and Discovery. To learn more about PNRI and get connected to our groundbreaking science, go to pnri.org/connect. We would love for you to join us for a tour of our labs or a virtual event with our scientists. Thank you for listening and we hope you’re inspired to learn more about genetics and chat with your friendly scientists neighbor. I’m your host, Jack Faris, CEO of Pacific Northwest Research Institute. I’m also a regular guy. Dad, what do you think? How do I do?

Jack Faris  57:28

Better!