Changing the Game in Epigenetics: Sally Mackenzie

Sally Mackenzie is one of the world’s foremost experts on epigenetics, the study of how environmental changes affect the way genes are expressed. In this conversation we cover an epigenetic techniques she’s patented, the biotech company she founded, and the potential role that epigenetics could play in human health.

Relevant Links

• Mackenzie Laboratory Website
• Epicrop Technologies Inc.
• Trailblazers: Sally Mackenzie’s Vision for the Future of Plants

Featured Guest

• Sally Mackenzie
  Director of the Plant Institute; Huck Chair of Functional Genomics; Professor of Biology and of Plant Science

Transcript

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Cole Hons: Greetings fellow Homo sapiens, and welcome to the Symbiotic Podcast. I'm Cole Hons, your host from the Huck Institute of The Life Sciences. And it's really great to be back here in the studio after a month off. We had no podcast last month. I think we all needed to take a little break and now we're back. And we're very excited today, because we've got a super fantastic guest. Dr. Sally Mackenzie is with us today. Sally is a professor of biology and of plant science, the Huck chair of functional genomics and the director of the Penn State Plant Institute. Hi, Sally.

Sally Mackenzie: Hi.

Cole: Thanks for being with us today.

Sally: Very nice to be here.

Cole: So before we get into our conversation, Sally, which I'm super excited about, I just want to let everybody out there watching know that you can chat in live today on this live stream. You just go to the little chat box near the video screen, depending on your device, where that might be located underneath or to the side. And you can chat in, you can use your real name, you could use a pseudonym, whatever you want to do, but you can participate by putting in a question. There's a little button to ask a question for Dr. Mackenzie.

Cole: And at the end of our 45 minute conversation, towards the end, we will do a Q&A session live and we can also let you vote on questions if you don't want to ask your own, or if you like somebody else's question, please vote on it. And we are going to take the highest voted questions towards the end of our conversation and ask those to Dr. Mackenzie live and you get to hear the answers. So with that out of the way, hey Sally. We were talking earlier when you first came in and you were saying you're very busy this summer. Busier than you expected to be. Is that right?

Sally: Yeah, probably everyone is, right? We're sort of post pandemic. And now all of a sudden you've got this mountain ahead of you, of things that somehow slid for a while. So yeah, it's a busy time and it's really a busy time for science. It seems like I'm not the only one who's really busy now. So everybody's big piles are colliding with everyone else's and everything feel urgent.

Cole: Yeah.

Sally: Time dependent.

Cole: Yeah, we feel it too.

Sally: Yeah.

Cole: Yeah. With all the different folks at the Huck we deal with and on our own team. Yeah, we're trying to keep breathing and just keep going, but I'm so glad you found some time in your busy schedule to come out and talk to us. So I know you're familiar with the podcast, so you kind of know what you're in for a little bit. And as you know, I'm going to ask you about yourself a little bit before we get into the science, because one thing we're interested in in this season of the Symbiotic Podcast is, what is it with these people we call risk changers, excuse me, risk takers and game changers, right?

It seems that some folks in science are a little bit more conservative and are happy to just kind of stay in their lane and maybe some incremental things, or just kind of take their time and stay on a track that feels kind of safe and comfortable. And other folks really want to just do something dynamic. They're not satisfied with the status quo. They want to ask deep, challenging, tough questions that might shake people up. And so you made it into that category. That's why you're on the show. And do you think there's anything in your personality, maybe in your upbringing, in your past, that would, would categorize you as somebody who's like a risk taker or a game changer?

Sally: When I was growing up, I was not someone who stayed in one place for a long time. My father, because of his business, we had to move quite a lot. And when you do that, I think you don't really establish deep roots in any one place. You have friends, but your social life really is never a deep one. And so I think it makes you more willing to take whatever comes and make the most of it, without the fear of how others might think or feel about what you do. I think also, I'm interested in this idea that if you're somewhat bored by school.

When you're growing up, you're always sort of looking for something new, I was that way. I was an experimentalist. I didn't like to sit in a classroom and just listen. And so I was considered a little bit of the troublemaker in school because I was impatient and I would become bored and therefore start finding my own way of learning things. I don't know whether that trend is a trend you'd find with people that are willing to back the system a little bit. Either speak their mind or are willing to take things, opportunities that come their way and really pursue them.

But I do think that people who become passionate about things later often have something like that in their background, sort of an impatience. You'll see it in their school life as being, not particularly good students or maybe students that got themselves into trouble. Kids who got themselves kicked out of school a time or two. But ultimately, that turns into something that really translates into passion for the things they care about. I've never done that study, but I wouldn't be surprised if that's the case. And I was that way.

Cole: Got it, got it. Yeah, you're making me remember my high school. Once my principal said to my mom, "Your son just doesn't fit in here, Mrs. Hons."

Sally: Yeah.

Cole: So I can relate to that. So good to know. Yeah. But it's fun because a lot of times the kids who have that kind of trouble later on turn out to have some wild, original ideas. And like you say, find their passion. I'd love to see an educational system that could do a better job with kids who have that kind of quality earlier on to help them find their lane faster and not have to be disciplined like that. But I guess that's another conversation. We're here to talk about plant science today, but then again, at The Huck, we're all about all the disciplines coming together and how do they relate, right?

Sally: Right.

Cole: And that's why we educate our graduate students a little differently at the Huck as well. Give them more freedom to try out different disciplines and just sample this and that, and find their way and see how different things blend together. And we'll be talking about how you're blending together some disciplines in your work as well in just a little bit here. But Sally, if you don't mind, I think I'd like to play a little clip for everybody, a little teaser.

It's a sneak preview, folks of, a video we're working on about Sally's work. It's from our Life From All Angles series, which run about five minutes and explain the science of some of these game changing scientists. And this will be a little precursor to our conversation to give you a sense of what Sally's up to. So we've been working real hard on this. We're very excited about it. Dan, if that's ready, why don't we cue that up and play that for the audience, then we'll be back and talk about the research.

Narrator: Every summer, this string of pearls plant sits outside on a porch enjoying near ideal growing conditions. But as the days grow shorter and the temperature drops, this plant will only survive if brought indoors. Though we may not see it, there's a lot going on inside this plant that helps it adjust to its new winter home. And as it turns out, the more precisely we understand the mechanisms regulating a plant's response to changing environmental stimuli, the better we'll be able to help farmers maximize their yields and more successfully adapt in a climate stressed world, and the better we'll be able to understand human health as well.

Sally: Plants are really interesting creatures because they have to process their environmental information and make use of it in how they will adapt to their environment.

Narrator: Sally Mackenzie is a professor of biology and of plant science at Penn State, Huck Chair of Functional genomics, and director of the Penn State Plant Institute.

Sally: You know, a plant makes a decision every day, "Do I hunker down and deal with this stress, or do I spread out my leaves and grow as fast as I can to outcompete my neighbors?"

Narrator: Mackenzie works in the rapidly growing field of epigenetics and has pioneered an entirely new way of manipulating plants to improve their resilience and yield.

Sally: When most people think of epigenetics, they think about the way genes are expressed. But more recently it's become clear that there's another feature of epigenetics and that is it isn't just the way genes are expressed, but the way that expression is transmitted as a pattern to the next generation.

Narrator: To produce next generation plants pattern for desired traits, Mackenzie's team has devised an ingenious, but simple method. First, a plant like this canola is epigenetically reprogrammed to behave as if it's experiencing extreme environmental stress. That plant is then turned into a root stock by trimming off flowering branches. A cutting is taken from the wild variety of the same kind of plant. This cutting called a cion is then grafted onto the distressed root stock forming a hybrid. Mackenzie has discovered through careful field testing that the seeds produced by these hybridized plants are significantly more resilient and productive than wild type versions of the plant. And this holds true, not just for canola, but for every species of plant Mackenzie's team has tested to date.

Cole: Very cool stuff. We had so much fun going to the greenhouse and in your lab and checking that out. And I've been showing the footage to even people in my family. Everybody just thinks it's so cool. Just even the grafting process and to think where we go next with that video is the deeper explanation of what happens after the grafting of that epigenetically modified of the cion onto... Excuse me, the wild cion onto the epigenetically modified plant. And let's talk about what happens after that, Sally, when you do this work and why do you do that? Let's get into why, why that happens.

Sally: Yeah, so that system in my lab is the product of our efforts to exploit what we know about the way that plants use their epigenetic system to change. So when we think about a plant or a human, you think about the genetic information, and we know a lot about that. Now, we have complete genomes, but the genetic information is basically static. That means genetic information from the beginning of life to the end of life doesn't change. But epigenetics means that there are decorations, if you will, proteins and small RNAs and methylation events that will come in and modify that DNA, and it's open or closed features in order to change the way it expresses.

And so those features will change over the lifetime, and then into the next generation. And those features influence not the genes themselves, but how they're expressed once. Once you know what that system is and how it works, you can start exploiting it. So what you're seeing there is that we take a plant and we basically fool it epigenetically into thinking it's under stress. It grows differently, it's slower, it's hunkering down and it's expressing lots of defense related genes. We use that as a rootstock, and then we graph to it.

Sally: And that wild type or unmodified plant we put on the top as a cion basically is going to receive small RNAs, which are basically messages of stress coming from that lower part. Those messages of stress are received in the upper part of that plant to the progeny and actually modify the progeny. It turns out, something that couldn't have been predicted is that when you take that stress signal and put it in what we call a naive genome one, that's never seen that stress, you get an enhanced growth figure. You get a plant that wants to outcompete its neighbors, that gives you higher above ground biomass, higher yield, more resilience.

Higher above ground biomass, higher yield, more resilience. And that vigor is the outcome of those small RNAs basically encountering what we call a naive genome, a genome that hasn't seen that stress. So that's more or less the big discovery, but we can now, of course, capitalize on that. In agriculture we can capitalize because we can make crops more resilient than we can just with traditional breeding, which takes much longer. A graft takes you a matter of a few months and you're there. But we can also capitalize on that in a more fundamental way to understand what those signals are that allow a plant to change its whole growth dynamic within its generation and to its progeny. And as I said, those small RNAs we know are vital and we can use genetic tricks, mutations that cut off those small RNAs so we can show that that is really the ideology, the cause of that change. So, you can do beautiful biology to fundamentally understand something that really has utility in agriculture and really in human health as well.

Cole: Right, right. We had that conversation. And that's where this video, again, is going to go deeper into something a little bit more fundamental, because as we say later in the video, it's not just plants that change because of the conditions around them, but all life changes. And you had sent me an article recently about this being an issue in science writ large in evolutionary biology, this idea that how fast will change happen and are we really seeing the fuller picture? And maybe we need to add some subtlety in there to account for these epigenetic changes that can occur very rapidly and be passed on to progeny just very quickly. Could you speak to that a little? And this is going to give us the ability to read, as you've talked about the methylome. And I'd like to hear about your partnership with a colleague in computational biology and this methyl IT system you've developed. So maybe we could hear a little bit about that for the audience?

Sally: Sure. So, as we initially conceived of evolution, as Darwin initially conceived of evolution, we really thought about evolution in the DNA context, your genetic information. And it does change over time, longer time by mutation, recombination, chromosome breakage, et cetera. Those kinds of changes do take place, we've document it. And we understand that evolution fairly well and its subsequent selection for the very best combinations that will go on. And that evolution is intact. But what we never really factored in to that was the epigenetic component. Meaning that change was over the long period of time. And epigenetics allows the system to accelerate evolution. And the way that happens is now you take that genetic information, mostly static, and now you add epigenetic changes or changeability to it. And suddenly you have the ability over the lifespan of an individual to come across and introduce changes, maybe by environment and stress, disease, et cetera. Those changes could then be inherited to the next generation and have some stability for X number of generations, that becomes this accelerated view of change we never factored into our original models.

It doesn't in any way invalidate our understanding of fundamental evolution. It just helps us to enhance, enrich our understanding of the long time span. And that second element of epigenetics we don't understand fully. And what I mean by that is, for us to really understand genetics, we had to decode it. You have to systematize this process. So we decoded it by understanding that DNA sequence could be interpreted as basically words of three we called codons. And those words of three could be mixed in various combinations to give rise to new proteins or products. And so the more we could decode that, the more we could predict it, the more we could manipulate it. Thus, here we are today with molecular biology.

Epigenetics will be the same, but the code is different. Because now what you have is, instead of looking at nucleotides, some of those nucleotides can be changed. You can add methyl groups, for example. And by changing these decorations on DNA, if you will, you can change the overall local landscape, and that will impact gene expression. So just as we understood how genes could be decoded, we could now take that methylation pattern and decode that into, what does that tell us? So now an organism sees a stress, a change in development, what have you, a change in epigenetic state. We can read that methylome, decode that information, and it tells us two fundamental things. It'll tell us what genes are responding and what networks does that involve. So suddenly you're now looking at when I create that stimulus, who's responding, what networks respond, and that tells you how an organism is perceiving its environment.

But the second is, you also have the ability to now understand on a global scale just the, let's say the energetic properties, the entropy properties in that system. In other words, is that system a healthy system, or is it a system that's dysfunctional? It's in a new state that's not a good state, that maybe is a less ordered state. There you get into early disease diagnostics, places I never knew my lab would go. But in fact, you can see this very easily in the methylome profile. So, as we think about our genetic characterization and understanding our predisposition to genetic disorders based on our gene sequence, I believe we could now use DNA methylation profiling. Imagine having that taken in your life at age two, again at age 10, again at age 16 and 30 and 45. And you'd be able to actually look at the changes and the impact of your lifestyle, your environment, your development on those profiles. And you'd have a much better understanding and predictive ability about your own health and wellbeing as a system.

We never really envisioned we could use the system in that way. So that's why we're putting so much time into this decoding, if you will, the understanding. The more we turn this into the language that we want it to be, the more we'll understand in agricultural context how crops can respond to their changing environment and how human health responds to its changing environment over time.

Cole: I've heard you say again and again that this is like a new language that you're decoding. You're decoding this new language similarly to when we map the human genome that this could be just as impactful. And we had a conversation earlier about, when it became available to the public to do 23andMe and everybody's going and getting their DNA tested, but it's not giving you the utility that you'd have from this methylome profile, which is, what can change in your lifetime? Because our genetics are going to stay static for our entire lives. But what we're talking about with epigenetics is how they are expressed, which in practical terms in somebody's life for their health, their wellbeing is maybe more impactful. Once what your genes are your whole life that's your norm, but all those different changes you go through are epigenetic changes fundamentally, right?

Sally: Right, right.

Cole: Yeah, it's phenomenal. And you have, you've put together, how many patents do you have now worked out from the research that you've done in this area?

Sally: So then, yeah, then you get into, how do you protect this information in a way that can be of most utility to whomever would use it? So some of the patents we've sought have been sort of agriculturally leaning. And that means we've sort of developed IP around this idea that you could introduce epigenetic variation that could be of agricultural value. And the reason we seek protection for that is so that we can in fact control the way that it's used, because we want to be able to deploy that in the ways that we think would be most efficacious and let's say advantageous to the broadest group that might benefit. And they were really just patenting the technologies as they're applied to crops, the grafting methodologies, the understanding of how to create epigenetic change.

On the other path is this idea of decoding, it's the methyl IT platform, it's various decoding efforts that we do to understand, as I was saying, entropy, energy features of the methylome, as well as identifying gene networks that are responsive. There you get into identifying genes that are good targets for drug design, or understanding pathways that would be good targets for drug or treatment design, as well as just understanding predictive capabilities. Are we likely on the decline here in this particular system? Is this individual actually headed for health problems and why are those arising? That capability we also think needs to be protected so that it can be deployed.

And there we envision perhaps creating a platform where there is the opportunity to let's say, instruct others on how to use that platform. Those that are in diagnostics, those that really want that predictive capability. That will never be a 23andMe kind of, "Here, you can get it in the mail." Because the real key there is the interpretation. That won't be left in the hands of just anyone. That clearly is going to be a much more robust dataset and an informative dataset that's going to need expertise to mediate that. And that's kind of what we're trying to learn now.

Cole: Got it.

Sally: What can we read? What can we understand, and what can we predict?

Cole: Yeah, with that in mind, I mentioned earlier, you've got a colleague in computational science. If you could speak about him a little bit and what he brought to the table, because I was fascinated when you explained, you have all this data and a lot of folks have had this data. But the thing that's different with what you're doing is you teamed up with a computational biologist who can see the math and interpret that data differently and find these signals, these specific areas in the data that are significant and that can give you the kind of power you're talking about for diagnostics, et cetera?

Sally: Right, so I'm the plant geneticist in the team and Dr. Robersy Sanchez is the computational biologist/statistician/applied mathematician in the deal. And so, Robersy obviously sees the world through a very different lens. So, his thinking is it runs along the realm of information theory that in fact everything that has thermodynamic properties adheres to certain principles and methylation wouldn't be any different. And so we can use what we understand of response and thermodynamic principles and bioenergetics and entropy relationships to derive meaningful information. So you treat it like a communication system, and you apply mathematical principles to that. And what you derive is the capability to look at changes in state. And then to be even more refined and ask if you're just using signal detection to siphon out only those methylation changes that are happening in response to whatever the perturbation is you're creating.

So you now introduce an environmental change. Who's changing in direct response to that perturbation? Those are the treatment associated changes that we now weave into gene networks to say, who is responding and how are they responding. And integrating all that information suddenly gives you this power, this ability to say, "When I introduce this change, that, that, and that network all come to the fore and become quite active. Now, how they're responding takes additional information, but just that power of being able to siphon through all that information, because this is a highly complex or stochastic system. So, being able to decipher out just those pieces you need from the myriad of noise in the system is vital. And that's what you need an applied mathematician to do is to teach you those tricks, so.

Cole: We love it. I mean, that's what the Huck's all about, right? It's like getting people with different disciplines seeing the same thing in a completely different way. And then being able to share that and translate it across, which is generally the challenge, because usually the first early conversations with folks like this tend to be, "What are you talking about? No, you're totally wrong. We can't be right." And then eventually they, "Oh no, no. Okay, oh now I see what you're saying." Yeah, and it's amazing what can come forward to evolve the entire process.

Come forward to evolve the entire process. So very cool. Very cool. I feel like there's one more thing I wanted to touch on and then I see the questions are really popping up here. So I want to take some of these questions from our viewers here, but I just thought this was such a cool idea and image that stuck with me, Sally, since you talked to me about it. The idea that a woman could be in the future in a hospital giving birth, and you said that you'd be able to take like from placental cells and if you had the right technology and people trained and knowing how to read the methylome, you could just tell from a placental cell so much about that infant that we are not able to see right now.

Could you just speak about some of the things that people might be able to see? I mean, this would be down the road. We're not there yet-

Sally: Yeah.

Cole: But that's the potential of what we're looking at.

Sally: Yeah. And so, one of the challenges for my lab is, of course, we don't do biomedical research. So we are sort of limited in testing our system to those available data sets that are robust enough that we can extract from them information we want. And one of them we started with was an autism related data set where they had basically taken placental tissue from births where that child had then later been diagnosed with autism and then those that where you had a normal child that was presenting as normal later in development.

And the real challenge with autism, of course, is that any mother having a child won't necessarily know for at least three, maybe seven, maybe even 10 years that child really is dealing with something different going on in their system neurologically. And so, and yet we know that if you could have intervened from day one, we could have really changed a lot of those outcomes when it comes to autism because so much remains undeveloped when a child is born. And so imagine from that infant on, you would really have a way to sort of reprogram a lot of those neurological behaviors had we had that information.

So we took this autism data set that had already been published with relatively little information coming from the original publication, but then applied our methods of analysis and suddenly you see all these networks emerging. Really interesting and very exciting things. In fact, certain genes in some networks had already, we found out, been patented by companies thinking about autism, so we knew we were on the right track in finding these. But we could see so much more in these datasets that it really did convince us had we had this dataset at the time that those placental tissues had come forward and not years later, would we have had the capability, or whoever would've had them, of notifying that physician you need to be talking to that mother.

There's a really high probability, you're going to see autism presented in this child. And the changes that a mother might have imposed in that situation, having that information would've been huge. So, that system's in place. It's just now presenting it to the right people who could now start to implement it. But yeah, we have published that work trying to get interest by the community. But I would say cancer's the same. I would say that we're able to really see, for instance, in pediatric leukemias, we were able to see all of the really vital networks quite early-

Cole: Wow.

Sally: So I think you can be predictive there as well.

Cole: Wow. That's phenomenal.

Sally: Yeah.

Cole: Who knew you'd start with plants and end up with this kind of capability like at your fingertips. It's amazing. I'm going to look at some of these questions that we have here. If I look at poplar, what do I see? Looks like Mark is at the top of voted up here. Mark, 11 minutes ago, asked "Could we create epigenetic seeds to help native plants like Chestnut trees defend themselves against invasive pests?" Wow. What do you think?

Sally: Yeah. So, that's really an exciting area. Because remember that with a lot of trees, what they have, not all, but most in common is not only can they be grafted, but they can also be vegetatively propagated. And so we're starting with a really simple system in poplar. And we're not very far along there because I'm still learning the language of trees, if you will, just how to grow them and how to vegetatively propagate them. But there are a lot of tree species where this would be feasible. We've also been working on things like, for instance, strawberry.

Strawberry also a species where you can vegetatively propagate it easily, and that's how they do this commercially. So we're also interested in can we introduce these features? And there, the trick is that you don't want to go through seed. You want to be able to vegetatively propagate and then have those changes occur without what we call gametogenesis, the producing of seed or going through reproduction. So we're using strawberry as that model, but that would be equally vital to trees because you don't want to wait until that tree is flowering, is putting out seed.

You're talking lifetimes to do that. So what we really need is that ability to create the graft, transmit the change, and then vegetatively propagate from the meristem regions of that cion so that we can now emulate those effects we've created in a whole forest of newly improved trees. And that is really my goal. That's part of what moved to me to Penn State-

Cole: Wow.

Sally: Was that we are sort of the keepers of the Mid-Atlantic forest region and we've got a lot of problems that would really be addressed by this. So-

Cole: That's right.

Sally: Yeah. I think you could.

Cole: Pennsylvania was not named Pennsylvania for nothing. That's right. I'm a big tree person myself.

Sally: Yeah.

Cole: Very cool. All right. Let's check another question. Michelle has asked "How is this pathway to cell signaling in humans" oh, this is live people. I make mistakes. Sorry, Michelle. Let's try that again. "How similar is this pathway to cell signaling in humans and bacteria?"

Sally: So in terms of the epigenomic language of methylation and methylation re-patterning over chromatin, excuse me, how you get there is a little different in those different organisms, the machinery used, but the outcomes are really quite similar. So we use the methyl IT platform and our various methods of analyzing data pretty much the same way in human datasets as we do in plant data sets. Now we don't look at microbial right now, but I'm assuming that there would be similarities at least down to yeast, whether you can go to bacteria. That's all together a different system.

But the idea of the outcomes and the decoding, amenability to decoding of the outcomes, that works fine. So we can work in a pediatric leukemia system and work in an epigenetic reprogramming of crops and have that be going on in parallel in the lab. No problem. There are features that are different, but they don't impact the outcome. Yeah.

Cole: Right on. Thank you. And I've got, let's see, one, two more, two more questions. We've got Tony Flores, nine minutes ago. "What are some medical conditions that could be seen in the methylome?" I heard you speak about autism. I heard you speak about cancer. And perhaps that question was submitted before we got to that. Are there some other ones you could name?

Sally: Yeah. Yeah. So for me personally, when I read the literature, I'm always looking for evidence that somewhere in that abstract or in that initial description of the disorder, they refer to it as complex. This is really particularly applicable to what we call complex traits in plants and animals. Often we'll call those quantitative traits, but complex traits. That's just code for saying there's a strong environmental influence on the expression of that trait. So, there's a genetic component and then there's this what we call G by E genetics or genotype by environment interaction that happens.

So, anything that has turned out to be a complex trait, and there are just whole myriads of them in humans. I mean, most of our traits are complex. We are defined by our environments, what we eat and where we've grown up and whether we're exposed to pollution and so many features of our environment define how we grow, how well we grow and the same with plants. So anything that is a trait that is defined by a huge environmental feature, like yield in crops would be really amenable to epigenetic analysis because that is a trait that is changing over time within a generation, and then of course transgenerationally.

So, it's really amenable to decoding in this way and you get the most value from decoding in this way.

Cole: You're making me think about some of the social justice environmental stuff in terms of where pollution is and who lives next to the pollution.

Sally: Right.

Cole: If you think about water, Detroit, just horrible stories and you probably could check out and learn more about kids and people living close to that stuff, that could gather more powerful data about it faster. I mean, that comes to mind for me. But yeah, that's really something.

Sally: Well, not only that, but even thinking, I mean, going back to the autism idea, we don't really know the ideology of autism. We don't know where it comes from. How much of that actually could be a consequence of the way parents lived or the environment that they had basically experienced before they've had that child? We've never asked that question, but we could. And with a lot of traits like that, to what extent can we link things that would be heritable that we've never known to be heritable? There are studies now about the way that populations lived during war time and living long periods of time with inadequate nutrition and the fact that they may have in fact had transgenerational effects subsequent to that.

You could use the decoding system to basically trace that. What were the gene networks that were really vital to that process and how were those inherited? And we don't really have that power in the systems that we use currently. There isn't methylome data in the literature, but it does not have that power. Yeah.

Cole: Ladies and gentlemen, I meant to say Flint, Michigan. I think I said Detroit. So please, people, and if Beth McGraw is watching, I particularly apologize to her. She's from that area. Yeah. You're just blowing my mind. Let's look at one more question. I think we've got one more here. And there's Michelle, there's Mark, there's Abby. Oh, "You've figured out methods to manipulate epigenetics in plants. Can it be done with animals?"

Sally: So, I'm less well-informed about the capabilities of manipulating animals. We analyze data after it's generated in animals. So, we are great at predictive, but in terms of actually introducing change there, I'm ignorant when it comes to animals. Because with plants, of course, as I said, we can graft. We can introduce genes transgenically fairly easily. And that's really how we do this. We basically go in and target a particular gene our lab discovered, and we downregulate that gene, and that's what creates the signals that create the nuclear response for epigenetic reprogramming.

Whether there's a parallel system in animals, I'm not aware of that. The closest you're going to come is work that you can see in C. elegans, worms-

Cole: Yeah.

Sally: Where they can create, or they can at least induce transgenerational changes and understand the small RNAs that go into to that transgenerational effect. But, in animals, in general, the ability to go in and create that epigenetic change is something I'm just ignorant of. It doesn't mean it can't be done-

Cole: But there again, maybe that knowledge could be translated to somebody working with animals.

Sally: Sure.

Cole: People and all that good stuff. Because we know we're not going to hack somebody's arm off and stick it on another body and see like the wild type version of Fred.

Sally: Yeah.

Cole: And the epigenetically modified Fred. So we have a better Fred baby, Fred Jr. Anyway, just teasing. So, wow, we're at 12:38. We've got just a little more time. This has been an amazing conversation. I would be remiss if I didn't mention Epicrop while we still have you here before we talk about our little friends like we like to do on The Symbiotic Podcast, but-

Well, friends, like we like to do on The Symbiotic Podcast, but could you tell us so that our viewers can hear a little bit about Epicrop in case they wanted to check that out or learn more about that?

Sally: Sure. So when we started on this journey, my thinking was once we recognized there could be implications for agriculture and/or biomedicine, we need to figure out what to do with this. And I was totally naive to commercialization and how to establish relationships with companies. And one way that faculty in general can do this is just to make a relationship with a company, come up with a licensing agreement. Maybe they help support the research. And you're basically sort of funneling information to them that they can then capitalize on.

And I was not really in favor of that model because I wanted this to be more far-reaching. I didn't want this to simply be used by one company simply because I didn't think one company would necessarily know how to use it. I think it really needs to be out more generally. So instead we started our own startup company, which is called Epicrop Technologies Inc. And it starts out strictly agriculture. And it's a company that basically takes our platform and takes our information on how to manipulate crops to introduce epigenetic change and move that into the commercial sphere. So my lab works with a plant species that's just a model. It's Arabidopsis thaliana. It's a little weed in your backyard. It's a weed in my backyard I find really aggravating at home. I pull them up and at work I take extra care of them.

Cole: You don't bring them into the lab.

Sally: But when you then take this into the agricultural sphere, this system will create 30% increases in yield in tomato. It'll create 30% increases in yield in sorghum, which is a major crop of Africa.

Cole: Phenomenal.

Sally: It will work in soybean. It will work in canola. Those are the major crops. We have it now working in strawberry and so on. Now we're starting poplar. So it gives us this opportunity to branch out. And there isn't a crop that won't go through this process. We just need to figure out the way that we want to utilize it. So the company's job is then to do that, to take what we know, turn it into a crop modification, and then try to be a conduit to companies that really could capitalize. So obviously strawberry might go somewhere completely different than soybean would.

And that's what Epicrop is, is just sort of that conduit to get it into the hands of people who could really exploit it and understand it and elaborate it beyond what we can do. And then at the same time, there's this platform of being able to predict how crops are behaving. There, you're getting into understanding crop phenotypes and their gene networks. That's very vital information for a lot of companies that they don't currently have. So that's a different part of Epicrop's goal is to help provide that information so that people can understand their own systems, not just ours, in new ways. So Epicrop is kind of that resource allocation process, if you will, because my lab just can't manage that. So we hand all this off and then the company is expected now to make those connections with who can use this information in the best way possible.

So Epicrop is right now stationed in Lincoln, Nebraska, because it's central for the agricultural community. Now that I'm on the East Coast, I doubt it will stay there forever. It'll probably find a closer home at some point. But it's a good, very little, just a startup now, but that's what we foresee it in its future is to have these relationships with the larger companies that can be really useful to facilitating improvements in agriculture that you really can't make with traditional breeding. Yield resilience. These are not easily bred traits. Complex traits, as I said.

Cole: Complex traits. And as we mentioned in our video, there are implications here as the climate stressed world continues to face more and more stress. This could be really important. It's such exciting work. And in this world of so much bad news and so much that is heartbreaking and hard to deal with, it's wonderful to see this work going on that gives us some hope that human ingenuity and creativity are still alive and there's still a lot of wonderful stuff people can do to make the world better and to deal with the challenges that we have. So thank you for the work that you're doing. I'm going to be watching. I hope others will watch as well. If people want to follow along with your work, is there a particular place they would go, like to your lab website? I know we're going to put it at the end of the video when we publish that, but is there a place that you send people most commonly to follow along?

Sally: Well, right now, this is fairly rapidly merging. And very new information. So usually we have different connections with different people. There's the ag community, which won't read any of the mathematics, and there's the mathematics community that has no interest in how plants grow. And so we're kind of spread all over. But yeah, we're going to try to redesign my lab's website to be a little bit more of a conduit for that beyond our publications.

Cole: Okay. So people can Google Dr. Sally Mackenzie, Penn State, and follow along and reach out and get in touch. I know we're trying to connect you with a Huck graduate who is a lead life scientist with NASA working in the international space station with the garden there. She recently did a presentation to some of our Huck graduate students in plant biology. And I know you've mentioned that your method could be very useful for growing plants in space. So there's just so many cool things that can come out of this work. So very exciting. So wonderful to have you on.

Before we end, and I know I'm going a little long because it's hard to stop talking to Sally, but I do want to do what we do on every episode of The Symbiotic Podcast livestream season, which is to just let folks out there know that when it comes to diversity, we really embrace it at the Huck Institutes, so much so that we decided that we could celebrate the diversity of Penn State people by exploring alternative plushies for Penn Staters.

And so Dan's probably going to pull up a video here in a second and show you. We are no longer limited, ladies and gentlemen, to just the lion. We love the lion, the lion's terrific. We all love to see him at the football games doing gymnastics, et cetera. But if you're not a lion person by nature, you could go other ways now. You could go with a Penn State pink unicorn, for example, or perhaps you could go with a Penn State gnome. Or if you have a little baby child in your life who needs something to play with, a little beanie bear, a little Penn State beanie bear, just to get them indoctrinated the Penn State way before they even get to preschool. That's available to you.

There's even at this stage a llama. That's Lisa Llama, the only one of these plushies that comes with a name. And I'm not hawking these for any local businesses or anything. But if you search around, if you see a plushie here that you really like, and you're a Penn Stater who might be a little different, maybe you check that out. So, like I say, there are gnomes. There are unicorns. There are llamas. There are bears. Penn State's big. There's enough room at Penn State for all of these lovely animals to coexist.

So right now with our audience, Dan's got a screen up and we're just going to ask you, you can vote right there in the chat. You can vote on your favorite plushie. And I really encourage you to do so because we're doing our own research, Sally. We're researching, I don't know if it's a psychological profile, if it's social psychology, I don't know where we're going to publish this research. But the idea is we're going to find out from all the different scientists on the show which audiences liked which plushies, and then we're going to share that data with you at the end of the season. So my last question for you before we wrap up, Sally, is do you have a favorite plushie? What would your favorite be?

Sally: It's the llama, for sure.

Cole: It's the llama. Lisa Llama. Is it the eyes? It's the eyelash? She just has that look. What's about the llama?

Sally: It's the different.

Cole: It's the most different.

Sally: Yeah.

Cole: It's the most different for you.

Sally: It's the difference that I'm attracted to.

Cole: All right. Well, Sally Mackenzie, Dr. Sally Mackenzie is a llama person, ladies and gentlemen. Well, thank you so much again for coming out. I want to let our audience know that we'll be back in one month with Lance Lian, who's doing phenomenal things with stem cells, just mind blowing. He's created pancreatic cells that actually produce insulin from stem cells, which is not an easy thing to do. So he's another one of these risk taker game changer people. So come back. It'll be one month from today, the last Thursday in July. I hope you'll make it back. And if there's other people you think should see this, we are going to have this out in about a week, so others can watch. And then we will also be releasing the full five minute or so video about Sally's work. So watch for that as well. So without any further ado, thanks so much, Sally, again. Thanks everybody for watching. And don't stop co-evolving.

Narrator: The Symbiotic Podcast is a production of the Huck Institutes of the Life Sciences at Penn State University.

Our video and livestream producer is Dan Lesher. Our sound engineer is Brennan Dincher. Our web developer is Jodie LeMaster, and our marketing manager is Keith Hickey. Cole Hons hosts and directs the show, and original illustrations and animations are provided by Sam Muller and Bethany Seib.

If you enjoy our podcast, we hope you’ll subscribe and share it with others. We’d also love to know what you think about our content, so if you want to get in touch, please email symbiotic@psu.edu.