The Dark Side of the Genome

Q & A with Dr. Rick McLaughlin: The Dark Side of the Genome

Rick McLaughlin, PhD, enjoys wandering through the woods, gathering mushrooms, and contemplating the origins of our DNA. He’s always been interested in big questions, like where our genetic material comes from and why it is the way it is. A scientific revelation in the early 2000s inspired him to make it the focus of his career. 

“When the human genome was first sequenced, we saw this amazing result: Genes only make up about 2% of our genetic material,” he says. “I remember looking at that pie chart and realizing that we don’t understand what a huge chunk of the genome does or how it came to be. That got me obsessed with learning more.”

Ever since, he’s focused his research on the non-coding region of the genome—the other 98% of our genome.   

Much like the Pink Floyd poster outside of Rick’s lab, he is exploring this dark side of the genome. We asked Dr. McLaughlin about the most exciting things going on in his lab and what inspires him to pursue his research each day.  

Q: What is the focus of your lab? 

We used to think that the non-coding region was “junk DNA” that didn’t really do anything. But now we’re learning that it may play a pivotal role in certain diseases. My lab is working to understand exactly how that relationship works, so we can find new ways to treat or prevent diseases.

When the human genome was first sequenced what became utterly clear was that a very small fraction—less than 2%—of our genome is all that’s required to code for (or encode the actual parts that are the full genes that are much larger) all the proteins for our body. So, what’s the rest? Where did it come from? How does it impact the way that our body works? How does it impact disease? 

Now, this is going to sound like a bit of a zombie drama, but in fact, it’s true. Within our genome, there are parasites. These are selfish pieces of DNA called transposable elements that copy themselves. It’s their relentless copying over millions of years that have made our genome so big, and that have created a large proportion of this other 98% of our genome.

But this is where the big difference comes in. Instead of creating a protein that contributes to some aspect of our body, these proteins exist solely because they can make a copy of the original sequence that they came from. They are copy and paste machines.

Over millions of years, and really, even within the lifetime of an individual, you get more and more copies of these genes that accumulate and jump from one location to another in the genome, either in specific cells—or if they’re in the germline, or the early embryo, those cells that are passed on to our offspring. These jumping genes exist, because they can replicate themselves—and they have to continue replicating themselves to continue to exist. It sounds like science fiction, but it’s a topic that has become an important aspect of genetics.

When I was first part of a research effort looking into transposable elements, people thought we were weirdos because we didn’t know if those elements really did anything. But now we’ve come full force into thinking about how transposable elements are important for human biology and disease.

We know these elements can insert themselves into genes and affect gene sequences as they move around. We don’t really know the full extent of the effects this has, but there are strong indications it might play some role in autoimmune diseases like Lupus, Alzheimer’s disease, and cancer. Studying transposable elements might also shed some light on genetic and autoimmune conditions scientists can’t explain or don’t really understand. 

Q: What sparked your interest in this work? Why make evolution of the genome and transposable elements the focus of your research? 

I’m fascinated with nature and the diversity of systems in our natural world—humans, animals, plants, fungi. I’m always thinking about: how do you build a system that can do these amazing things? How does it work, but also how did it come to be? To quote Shakespeare’s The Tempest, “What’s past is prologue.” The way that we answer these questions is through evolutionary biology, which means looking backwards in time and trying to understand how this thing came to be the way it is.

As biologists, we grew up thinking about the early days of molecular biology and biochemistry, where the gene was discovered and double-stranded DNA and then this huge explosion of molecular biology. Flash forward to today. We’ve sequenced close to a million genomes. There’s this huge pool of data sitting there waiting to be analyzed in traditional ways, creative ways, and new ways that we haven’t even thought of yet. It’s up to us to drive that research, make it happen, think creatively about how to utilize this data. This is an exciting time to be alive as a scientist studying genetics and genomics.

The big chunk of non-coding, non-genomic DNA has been collectively described as “junk DNA.” What has become quite clear is that there’s a lot of interesting biology that’s happening in that “junk.” 

As a postdoc, I’d heard the word “transposable elements” a million times but could never really wrap my head around them. I became fascinated when I learned that they are so prevalent that the rest of our genome basically has to function in a sea of transposable elements. They account for 50% of our genetic material and probably even more. I wanted to learn how their presence affects everything else in the genome. 

I also realized that they were the perfect thing to study to understand the evolution of the genome. They’ve been living in the genome, making copies of themselves for millions of years, dating back to beyond the common ancestor of all mammals. So studying these elements is like looking at a history book of our genome in some ways. It presents a really interesting way to answer questions about where our genome came from and how it evolved. 

Q: What’s the most exciting thing happening in your lab right now?  

We’ve known for a while that, in rare cases, transposable elements can cause severe autoimmune diseases. These conditions are so serious and debilitating that people rarely live past age five. Now we’re learning that these elements may also contribute to more common autoimmune diseases like lupus. My team is investigating if and how transposable elements interact with proteins and genes that play a role in lupus, and what effect those interactions have. 

We’re also interested in learning more about the role transposable elements play in other autoimmune diseases where people have symptoms of various autoimmune diseases that don’t fit into one specific disease. My lab is interested in learning whether transposable elements could contribute to what’s going on in these patients. 

To do this, we’re zeroing in on how transposable elements are different in people with these diseases. Until recently, this was nearly impossible. New technologies are allowing us to collect more detailed data about each of these elements, which is allowing us to catalog the differences between them and explore patterns that might help us find answers that have eluded scientists for decades. 

Q: How is your lab impacting science and medicine right now? 

The idea that the genome is a stable set of instructions that has passed down with high fidelity from generation to generation is really a fallacy. Imagine that you have your instruction booklet for putting together an IKEA bookshelf and along comes this copy-paste virus parasite and starts putting random sentences throughout it. That’s going to destroy your ability to use the information to make your bookshelf. This is happening in our genome all the time. 

Our genome usually has ways to deal with this. Even though the code in the genome is being degenerated or changed or mutated in this way, it doesn’t seem to matter too much. We’re pretty robust at being able to fight through these variations and continue to exist. But that is obviously not always the case. 

In the context of rare diseases these variations can drive unfortunate consequences in individuals. We’re collaborating with PNRI’s Claudia Carvalho, PhD, to study the genomes of patients with autoimmune diseases without a clear cause. What’s difficult about these diseases is that when you sequence the patient’s genome, it looks like nothing is wrong—but they clearly have a severe genetic disorder. We want to understand whether transposable elements may be part of what’s causing this disease.  

We’re also working with Miriam Rosenberg PhD, at the Hebrew University of Jerusalem and an affiliate of PNRI, to study a crazy phenomenon: kids whose immune systems cause major regression of brain tumors, without any treatment. Unfortunately, those kids are left with a rare and severe syndrome called Opsoclonus-myoclonus-ataxia syndrome (OMAS). We think that the immune system may be going into overdrive to fight off the tumor, but doesn’t stop when the tumor is gone. Children then experience seizures and other debilitating neurological symptoms. It’s quite mysterious, but we have some clues suggesting transposable elements or viral proteins could play a role in this immune reaction that also gets rid of cancer. 

Q: Why PNRI? How does working at an independent research institute benefit your work? 

When I first came to PNRI, the first half of my research notebook was filled with standard “meat and potatoes” research ideas. But PNRI has given me the space to fill the other half of my notebook with these outside-the-box ideas. Then, I go through and put stars by the ideas that still interest me months or years later.

As I’ve gone through my life, some of these questions have accumulated more and more stars. And those are the questions that I think are really interesting. But sometimes they’re too out there, or they’re inaccessible, technologically, to begin to tackle. One of the things that I came to love about PNRI is that I can tackle these questions that I don’t even know how I’m going to answer yet, or that might require me to invent a completely new technology. And for me, that’s super fun. 

I love conceptualizing and thinking about how can we do this new thing in a way that hasn’t been done before. At PNRI, we are approaching problems in a way that could fundamentally alter the way we think about certain diseases and that’s really exciting to me. 

Q: How is creativity part of your work? 

To do this job, you must be curious. You must be interested in formulating questions and discussing them—and then reorganizing your perspective as you acquire more data. But it’s really that curiosity, that drive to know what is the answer to this question? Is this an interesting question? Is this an important question? How can it help people? How can it further our basic understanding of biology? 

My team is made up of scientists from different fields—ecology, evolution, microbial ecosystems—which leads to creative and exciting research questions. We have a “Random Ideas” meeting a few times a year where we get really creative. Everyone listens. No bad ideas, or dumb questions. We build this powerful space where nothing is dismissed. And sometimes these random, crazy ideas turn out to be brilliant ideas. 

Q: How is your work advancing science? How will it benefit people in the future?

Right now, we don’t know enough about how the non-coding region of our genome impacts disease. There’s still a long way to go, but our lab will make a significant contribution to understanding more about how the noncoding region of the genome determines whether a person is likely to develop cancer or an autoimmune disease. 

I also help organize our summer internship program for undergraduate students. We make a point to reach out to people from historically excluded backgrounds and community colleges where students may not have access to this type of hands-on research. We hope to spark their interest in these problems and give them the chance to do research in really boundary-pushing ways. One of our biggest legacies will be our trainees who build experience here and go on to do great things. 

Q: Why is donor funding important in your research? 

As you have heard, I like to tackle big questions and sometimes grants aren’t open to those bold ideas. Grants from traditional funding sources like the government typically require preliminary data before you apply, so it’s very difficult to get funding for new, non-traditional ideas. Donor funding allows us to explore these new and exciting lines of inquiry that have the potential to open up entirely new avenues of research. We are on the precipice of understanding how transposable elements influence disease, what a powerful investment to make in shaping the future of healthcare.

Q: What’s one thing you like to do outside of work? 

At heart, I’m a naturalist. So, to me, walking outside, being in nature is awe inspiring. My Zen space is to be out in the woods, looking up in the trees, breathing the air, and touching the moss. Even as a young child, I had an insect collection, much to my mom’s dismay, because it smelled terrible in my closet. 

Now, I have three kids, so I spend most of my time outside with my family. We really like hunting for edible mushrooms and wandering through the woods. I love bike riding, cooking and being outdoors with them as much as possible. I even tolerate the stinky insect collections.

Dive Deeper

Dive deeper into Dr. McLaughlin’s work by listening to his podcast episode “Driven by the Question” (link coming soon!) Learn more about the McLaughlin Lab and connect with PNRI to meet Rick and experience his groundbreaking science in person.