Introduction:
Welcome to the Salk Institute’s Where Cures Begin podcast, where scientists talk about breakthrough discoveries with your hosts, Allie Akmal and Brittany Fair.

Allie Akmal:
I’m here with associate professor Julie Law, who is a member of Salk’s plant biology faculty. She studies how chemical tags on DNA influence how genes can be accessed by the machinery of the cell. Even though a plant or animal’s DNA doesn’t change during its life, these chemical modifications do change allowing the organism to adapt to situations without changing its fundamental DNA. Julie Law, welcome to Where Cures Begin.

Julie Law:
Great. Thank you so much Allie for that really nice introduction. I’m super happy to be here today.

Allie Akmal:
You study chemical modifications to the genetic code, which are known as epigenetic modifications. And this includes the addition of chemical tags called methyl groups to DNA, which are like Post-it Notes stuck to DNA saying which genes should be turned on or off. But before all this, you got a bachelor’s degree in biochemistry and biophysics, and then a doctoral degree in biochemistry studying parasites. Is there a common thread running through all of this?

Julie Law:
There has been a really common theme through all of the research, and my interest really began in trying to understand the roles that RNAs play in regulating diverse biological processes.

Allie Akmal:
And RNAs are like DNA’s cousin?

Julie Law:
Exactly. So there’s this central dogma about the flow of information. All the information is kind of hardwired in the DNA code and then it has to be translated into other languages for the cellular machinery to understand and use those instructions. And RNA is one of those intermediary translation steps.

Voiceover:
In other words, genetic instructions encoded in DNA are copied into RNA, which is then sent to the cells’ protein factories to guide the assembly of proteins. It’s like scanning a favorite cupcake recipe from a cookbook and emailing it to a friend who then makes cupcakes in her own kitchen. The book is DNA, this copy is RNA, and the cupcakes are the proteins.

Julie Law:
And so RNAs originally were kind of just this intermediary between DNA and the machinery, then over the course of many, many decades and a lot of research, it’s been realized that RNA plays a really fundamental role in a diverse set of processes outside of that initial translation of information. So yes, understanding how those RNAs might be used for processes other than translating information directly from DNA is something that I’ve been interested in for a long time. So as a graduate student, I studied how small RNAs can guide the editing of mitochondrial transcripts, which is an important step in making sure that mitochondrial proteins can be made and function properly.

Allie Akmal:
And mitochondria are sort of the power stations of the cell? Is that right?

Julie Law:
Exactly. And what was interesting about these RNAs is that they actually guide the sequence of the mitochondrial RNAs so that they can be translated properly by the new cellular machinery into proteins. And so this RNA sequence information played a really important role in making sure that you have proper functioning of the mitochondria.

Allie Akmal:
Okay. So steps in the process that help the organism get energy were not functioning properly?

Julie Law:
Correct.

Allie Akmal:
Okay. So that was your graduate work, then what happened next?

Julie Law:
At the end of my graduate work, I was really interested in trying to understand different processes where small RNAs might be guiding modifications, so I moved from RNAs guiding modifications to other RNAs, to RNAs guiding modifications in DNA.

Allie Akmal:
Oh, okay.

Julie Law:
And so the process that I ended up studying as a postdoc, was how small RNAs can guide the targeting of DNA methylation to specific regions of the genome.

Allie Akmal:
And if I’m understanding it correctly, you’re saying these RNAs, which normally in our high school biology sense of things are what DNA is copied into and then used to make proteins, you’re saying that these RNA transcripts are actually coming back in influencing DNA?

Julie Law:
Exactly. So instead of just having this sort of intermediate role, some kinds of RNAs instead have a kind of very separate life from that central dogma. And instead are going back and interacting with the DNA and regulating how that DNA is used.

Voiceover:
So to understand how surprising this is, in our cupcake analogy, this is like the recipe coming back and either opening the cookbook to a certain page or restricting access to certain pages of the cookbook.

Allie Akmal:
And DNA regulation is really important because we think this is our unchanging code, but every cell in your body or every cell in a plant has the same DNA. And so regulating which genes are on or off, is how you have different types of cells. Right?

Julie Law:
Exactly. So I like to think about it as a Choose Your Own Adventure [book], where you have your whole genome and then as you go through the course of developments, decisions are made about where you’re going to lay down these different modifications, and that affects the trajectory of a cell. Just like when you have a Choose Your Own Adventure book, when you’re deciding which page to go to, you are kind of going down a one-way path.

Allie Akmal:
That’s a great analogy. How did you end up choosing to do this work in plants? Why were plants particularly good to study these processes?

Julie Law:
Yes. DNA methylation and a wide variety of different modifications to the proteins that package DNA called histones, are very highly conserved across a diverse array of eukaryotic organisms.

Voiceover:
In biology, saying something is highly conserved, indicates that it’s important because evolution has maintained it in lots of different types of organisms over time. In other words, DNA methyl tags and packaging proteins, are pretty important for life.

Julie Law:
And so it’s a great question of why study this in plants, why not study it in other systems? The strength is several fold. First is that you can get viable genetic mutants, and that allows you to manipulate the process. So you can figure out when you tweak this what goes wrong. In the context of a living viable organism, that’s developing more or less normally. And this is a very different situation from mammalian systems, where analogous perturbations lead to embryonic lethality, or very severe developmental defects, making it hard to understand what’s the cause and consequence of particular things. Is it the defect in development, or is it the defect in the modifications?

So that’s one thing that makes plants a good system to study. Because you can make very large perturbations and study their effects, independent of defects in development. And another reason why plants are a great system for this is that they have a very short life span allowing us to look at things over multiple generations and a large amount of genetic resources. So we can for example, introduce new things into the plant genome, or remove things from the plant genome and understand how that affects the process.

Allie Akmal:
But the processes are very similar in plant cells and animal cells, right? So you could actually find relevance for animal cells by studying plant cells.

Julie Law:
Yes. There are a lot of very shared sets of machinery and very shared processes. A number of the very early seminal discoveries from plants have now been shown to be very similar in the mammalian systems. And so the information generated in the plant biology community has really helped inform and expedite studies in other systems.

Allie Akmal:
Wow, that’s really cool. And you do your work in the model plant Arabidopsis thaliana, is that right?

Julie Law:
Correct.

Allie Akmal:
And if you can talk us through what is a model plant and why is this particular one so good?

Julie Law:
Yes. So a lot of areas of science use model systems for a variety of different reasons. Most of the time it’s because of the simpler organization of the organism. For example, a tree which we may or may not know very much about. We know a lot about the Arabidopsis model. First of all, its life cycle is very short, so that allows us to make more rapid discoveries. And then early on, there was a lot of community efforts in building out resources. We know a lot about the sequence of the genome, and now we know information about how the genomes even vary in different geographic locations and how the different patterns of chromatin marks are set up in different stages.

Allie Akmal:
That’s really interesting. What are some of the big questions you’re trying to answer in your work?

Julie Law:
Some of the questions we’re trying to answer are related to how diversity is generated in these patterns of DNA modifications. So you beautifully introduced earlier this idea that different cells or different cell types might have different patterns of methylation. This is very well characterized in mammalian systems and also in some different plant species, but it’s very poorly understood how that diversity is generated, because you don’t want to be changing around the patterns of DNA methylation every time you divide. You don’t want to move backwards in your Choose Your Own Adventure [book].

Allie Akmal:
Okay. Mm-hmm (affirmative). So that sets up this question. If you’re always copying the same information from the previous generation into the new cell, then how is it that when you look across a given organism, you actually see diversity in these patterns? And is this diversity something you can see with your eye if you look at a whole bunch of plants?

Julie Law:
For example, there are cases in our plant model Arabidopsis, where if you have a change not in the DNA sequence, but just in the pattern of where the methylation is, you can get the flower to have a delayed development. So it will wait longer before it makes flowers.

Allie Akmal:
At Salk, one of the things you’re working on is the Harnessing Plants Initiative. Can you talk a little bit about that first, what it is and then maybe how your work fits into the Harnessing Plants Initiative?

Julie Law:
The Harnessing Plants Initiative involves all of the plant biology faculty at Salk, and we’ve kind of banded our collective expertise together to try and address a globally important problem, which of course is climate change. And so this initiative has a main goal of trying to use plants and plant biology as a way to draw down CO2 from the atmosphere and help mitigate climate change. And so the main goals that we have in the initiative—or one of the main goals, is to use our plant biology expertise to engineer row and cover crops to store more carbon in the soil. And the strategy that we’re taking is to try to engineer or breed versions of plants that actually take the CO2 from the atmosphere during the normal process of photosynthesis, they take the carbon out of that CO2 and use it to build up the biomass of the plant.

Allie Akmal:
Mm-hmm (affirmative). Okay.

Julie Law:
At the end of the growing season, of course, a lot of that carbon is rereleased into the atmosphere as CO2 by the activity of microbes and these kinds of things when the plant is decaying. But some of those carbons can be stored in molecules that are not easily broken down, and that way can stay in the soil for long periods of time. So then over the course of many growing cycles, you can be trapping carbon and more stable molecules in the soil. And so, that’s the overall goal.

Allie Akmal:
Okay. And then how does your research fit into this goal?

Julie Law:
Yes, so the aspects of my research that are most closely aligned with this initiative are understanding gene regulation. And so if we want to identify or generate plants that can shuttle more carbon into these very long-lived carbon storage molecules, we can call them, you want to not have to recreate the wheel. You don’t want to have to engineer every step in the process from taking in the CO2 to generating this carbon-rich molecule. What you want to do is understand how the plant normally turns on the machinery necessary to do that process. And so building on our understanding of gene regulation and gene regulatory processes in different cell types, we’re trying to leverage that information to understand how plants are normally generating these molecules, and then sort of turn up the process and get them to do more as well as have them sort of reallocate those molecules to the parts of the plant that we’re interested in.

Allie Akmal:
So basically you want to increase their ability to lock carbon into these forms that don’t degrade as easily?

Julie Law:
Exactly.

Allie Akmal:
Okay. Very cool. Switching gears, a little bit. What brought you to Salk?

Julie Law:
Salk is a really special place on many levels. For me, one of the huge drawing points was the strength of both the plant biology program, as well as the program studying gene regulation epigenetics. There’s a lot of places that are independently studying those processes, but very few that bring together across a diverse set of species and organisms studies related to those processes. So it was really a unique opportunity to join a world-renowned plant biology institute, but then also be surrounded by people studying the role of epigenetics in cancer and the roles of genome structure in genome stability. I was really drawn to this idea that studying processes from different angles and in different organisms can really give you a great perspective on science, having a place that values that kind of diversity was really attractive to me.

Allie Akmal:
And do you find that you’re having those kinds of cross-species or cross-disciplinary conversations with people now that you’re at Salk?

Julie Law:
Oh, yes. All the time.

Voiceover:
A little bit of cross-species highjinks Law’s lab got into was to see if an animal cell would make plant proteins. I asked her about it here.

Allie Akmal:
What were you trying to do? Just see if it was possible?

Julie Law:
Oh, it was certainly possible. We wanted to know whether a protein that we found in a certain thing in plants was—whether that function was conserved throughout evolution. And so we wanted to know after we discovered a particular protein was involved in a signaling response in plants, we want to know if it actually could recapitulate part of that signaling process in mammalian cells.

Allie Akmal:
Wow! So you had this protein that was involved in a communications process in plants and you wanted to see if it had that same function in animal cells?

Julie Law:
Correct.

Allie Akmal:
And did you find that it did?

Julie Law:
We did not… but it was a fun experiment [laughter].

Allie Akmal:
Were you always interested in science?

Julie Law:
I was always interested in science and math—and science in general, but it really wasn’t until the end of college, that I had this realization that you could work in a research lab, making new discoveries and get paid for it. I had the experience of knowing that people worked in labs, for example in hospitals, but this idea that there was this whole basic science research engine fueling that, was hidden from me.

Allie Akmal:
How did you stumble into discovering that?

Julie Law:
When I was—since my second or third year in college, I had the opportunity to do a summer internship researching in a lab, and that kind of opened my mind to all of these different possibilities. And actually, that’s what convinced me to switch from premed to the biochemistry and biophysics degree.

Allie Akmal:
How interesting! Do you feel like that was absolutely the right decision for you?

Julie Law:
Oh yes. I really loved it. I was addicted to the lab from the start.

Allie Akmal:
Was it the research itself, was it the collegiality or are a lot of labs like a family?

Julie Law:
I think it was the family atmosphere of the lab for sure. As an undergraduate, when I fell in love with science—like probably many people, my experiments didn’t actually work. I was introduced to the process and the idea in the intellectual space, but what I was actually trying to do didn’t actually work. So I guess it was a good sign that even though all my experiments were failing, I still loved working in the lab.

Allie Akmal:
[laugh] And that’s a really important lesson in science. Right? Most of your experiments are probably not going to work.

Julie Law:
Once you’ve learned something, whether it works or not, that’s like the perfect experiment. You do something and if it works, it tells you something, if it doesn’t work, it tells you something as well.

Allie Akmal:
So it’s a win-win?

Julie Law:
Mm-hmm (affirmative).

Allie Akmal:
What kinds of things do you enjoy doing outside of work?

Julie Law:
I like the outdoors. I grew up camping and riding a motorcycle and—

Allie Akmal:
Oh, wow!

Julie Law:
A bunch of sports. Now I don’t do as many of those things, but I still like hiking and being outdoors.

Allie Akmal:
Did you ride your motorcycle off-road?

Julie Law:
Yes, off-road.

Allie Akmal:
Oh, wow! Okay. That sounds very adventurous.

Julie Law:
Yes. I guess I just grew up doing it, so I didn’t think about it as being so adventurous, but yes. Now looking back on it, I guess it was pretty fun.

Allie Akmal:
Did you have any bad spills?

Julie Law:
Oh, yes, of course. Yes. I ran into a tree once with a lot of people watching. So that was pretty embarrassing.

Allie Akmal:
[laugh] Oh, no. What gets you up in the morning excited to come into the lab or what makes it hard for you to go to sleep at night?

Julie Law:
Yes. I wish I could get excited about coming to the lab right now [laugh]. It’s like we’re all kind of stuck in this restricted interaction mode. Prior to working from home, I just think that getting in, seeing what people are doing, seeing what the day is going to bring, that was always quite exciting. And then keeping up at night—the usual things, getting all of your papers out and getting all of your funding in and preparing all your presentations. There’s a never-ending list of things to do that are necessary to move the science forward, and there’s never enough hours in the day to do all the things that you want.

Allie Akmal:
But would you still recommend a career in science to people?

Julie Law:
Oh, yes. I love it. These are things that keep you up, but not because they’re bad things, just because there’s so many things to do that you always have a running list in your mind of all the things that you want to get to.

Allie Akmal:
And one thing that occurs to me, women are not underrepresented in biology, but you have this sort of math, physics and biology background, which is a little bit more unusual. So do you have any advice for women who are interested in science and maybe some of the “harder” sciences like physics?

Julie Law:
Yes. For me, I just always liked it. I was always drawn to it. And then thinking back, I don’t think there were any courses where I was the only woman in the course, but certainly we were in the minority. But I would just encourage people to follow your passion. If you’re really interested in it, don’t let people convince you that you can’t do it or that you shouldn’t be doing it. Follow your passions.

Allie Akmal:
Well, those sound like very good words to end on. Thank you very much for joining us today.

Julie Law:
Thank you so much, Allie.

Ending:
Join us next time for more cutting-edge Salk science. At Salk, world-renowned scientists work together to explore big, bold ideas from cancer to Alzheimer’s, aging to climate change. Where Cures Begin is a production of the Salk Institute’s Office of Communications. To learn more about the research discussed today, visit salk.edu/podcast.