Best of: The future of plant chemistry

0:00Hey everyone, it's Russ Altman from the Future of Everything. April is Earth Month, and in appreciation of Earth and all of the plants on Earth, we're going to rerun a conversation I had with Beth Sattely on the future of plant chemistry. You know, plants are more than food and pretty things to look at. They're also the potential source of new drugs to fight cancer and solutions for climate change. So I hope you'll take another listen to this episode and my conversation with Beth to appreciate how plants can positively impact both human health and the environment at large.

0:37Plants are around us everywhere, and they're amazing. We use them as food. We use them as shade. We use them to create chemicals like medicines, even cancer chemotherapy medicines, as part of our healthcare system. And we need to worry about them. We need to make sure that they are adapted to climate change. We need to make sure that they don't get infections that ruin their fruit or their plant products. It all comes down to chemistry. Plants are little chemical factories. They make a diversity of chemicals that is quite amazing and that have uses across many aspects of human endeavors. Well, Beth Satley is a professor of chemical engineering at Stanford University and an expert at plant chemistry.

1:20She's using it to look at human health, making plants more robust as the world around us changes, and many other applications. Beth, let's start out with a basic question. Why and how did you decide to devote all of your professional work to plant metabolism and plant engineering? Wow. The reason I decided to focus on plant metabolism is because it really united two pieces of me, two personas. One is as a chemist. My PhD is in synthetic chemistry. I studied molecules. And at the same time on the weekends, I really like spending time in the garden. And so it really united these two passions where I figured out you could think about all these molecules and you could think about them in the context of plants.

2:08Great. So it brings together many of your interests. Exactly. So what is the challenge? What are the challenges that drive you in your lab every day in terms of we need to work on this because there's some challenges on the horizon that we want to kind of anticipate? Sure. I think there's two parts to that one, too. The one big challenge for me is how do we treat the planet better and at the same time take care of ourselves? So, you know, environmental health and human health. And I think that plants are a critically important part there. And our expertise is in plant chemistry and plants use their chemistry to cope with all the same challenges that we have.

2:53So I think that's sort of the big overarching question. But the second part for me is just curiosity of how the natural world works. And I think that some of our most exciting technologies going forward are things that already exist in nature. We just have to go out and find them. So that's the other driver. So I know that one of the things, and I know there are many aspects, and I hope to hit a bunch of them in our conversation. But one of the things that's driving you recently is the idea of making crops that are more robust and to climate change, to all kinds of things. So can you give us a sense of what's the scale of that challenge and how are you approaching it?

3:32Yeah, this is something that we've shifted to more recently. And I think the scale is global. And the challenge is breaking it down into small parts that a lab like mine can start to address. We want to think about how do we produce our food in a way that, again, optimizes human health. We think about environmental stewardship. And we're also distributing that food equitably. But, you know, that's not a research project. So I have to back it all the way out to, you know, what are the micronutrients that a plant might need? How does a particular crop get them right now? How could we make that better, easier, and more sustainable going forward?

4:16Yeah. So when we look at crops, I know you've written about this, that, you know, they've been through husbandry mostly, like old-fashioned evolution, if you will, where the farmers and the just kind of - Directed evolution, I would say. Exactly, where they just get what they want through mating and selection. And so some of the challenges could presumably be done in the old-fashioned way, where the farmers say, okay, I'm having some trouble and I'm going to select species and variants that are well-suited to my land. But I know that you've written that sometimes when you do that, it leaves them not robust to changes that might happen on much faster timescales.

4:59So can you tell me about this tradeoff between old fashioned husbandry and modern biotechnology and how you think about when it's time to deploy the big new technologies versus they don't need us? They'll be fine. Sure. So I think in your question, there's a piece about how do you make a change in a plant? Do you breed them or do you use, you know, new tools in modern molecular engineering? And I think those new tools are incredibly powerful. But the second part is when do we deploy them and what kind of traits are we trying to instill in the crops that we work on? So I think there's a lot of questions to be asked on the individual plant level.

5:40One plant, you know, one particular crop might have been bred for yield or size of fruit or ease of harvesting. But maybe we need to think a lot more about pathogens. And especially given changing climate conditions and transport of plants across the world, how susceptible are they to blights and essentially pandemics, just like humans? So yeah, we need to think about the individual plants, but then we also have to think about the system in which plants are grown. It's not just each plant in and of itself. It's what is the ecosystem that we're creating when we're growing crops and how do we make that really robust to changes that might come down the pipe?

6:22Is the industry worried? So you're an engineer and you build stuff and you create methods. Are the people in the industry of food and of plants, are they telling you that you and your colleagues need to get on the ball because they're seeing kind of looming problems? Or are you just doing this to create the capabilities that we may need in the future? Yeah, I think we're trying to figure out what are the concerns both from the industry side, but also from the consumer side and from the people side. And then we're trying to figure out what are the concerns from the planet side, which isn't even harder because we've really got to listen very closely to understand those environmental needs.

7:07So I think folks in industry, of course, are always trying to come up with the next iteration of a crop. But my understanding is that those are largely driven towards the short term, not necessarily the long term from what I've heard in regards to climate change and stability of food systems. That's just not what businesses are, how they're built to operate. Can you tell me about some of the crops or plants that you're focusing your attention on these days? Yeah, I think we think about plants all across the plant kingdom. I mean, often we're following the interest in chemistry rather than one particular crop.

7:46And just to be clear, we don't just work on crops. We work on a lot of different kinds of medicinal plants that have really fascinating chemistry. One we've worked on for a long time in collaboration with the Mudget Lab at Stanford is tomatoes. Love tomatoes. Yeah, me too. I think it might be one of my favorite foods, actually. And there's the hugest difference, if we can go just a small little sidebar, there's the hugest difference between homegrown delicious tomatoes and the ones that are typically available commercially. That's one of the ones where you really are aware of the differences, in my opinion.

8:24Yeah, and it's all their chemistry, right? It's what are all the molecules? Is it just packed with water or does it have all those flavorful molecules that make it taste great? And then there's other really fascinating things with not just where did it grow, but how do you store it? You know, one of the things that we never really think about is when you purchase a tomato in the grocery store, it's not necessarily dead. It's still alive, right? Those cells could still be carrying out metabolism. And if you put it in the refrigerator, it could really change what's happening there versus you leave it on your counter.

8:56Oh, okay. So what are you doing with these? What are your latest tomato dreams and hopes? Yeah, my latest tomato dreams actually have to do not with what happens to a tomato when you put in the fridge, although I think that's important when you're making a salad. I'm more right now focused on the specific lipids that are made when pathogens touch a tomato leaf. So I'm really interested in this chemistry that gets essentially turned on only under very certain conditions. So normally when a tomato plant's looking healthy, everything's fine. It's not making these molecules. But then if a fungus comes along on the plant leaf, all of a sudden it starts producing all of these interesting metabolites.

9:37One that we're studying with the Mudget Lab are these interesting lipids that get produced and that have an important role in the infection process. Now, sometimes I know, so lipids, many people know, are types of fats. Sometimes fats are associated with things that are delicious. so what is the effect of these lipids on the tomatoes taste yeah so a great question no effect that i know of right now on the tomatoes taste the plants i would say in general don't really care about us so much they're more concerned um you know with the pathogen well i should say that they do care about mammals and mammalian herbivory who's going to be eating them and at what time To spread the seeds and whatnot.

10:23Yeah, yeah. Like there's these other molecules that we've looked at in tomato that actually change over the course of ripening. So there's one form that's there when the tomatoes are green, but then they get converted into a different form and the tomatoes turn red. No one knows why this happens, but we think it's because it's sort of altering how enticing those tomatoes are to herbivory during the course of development. Yeah. Yeah. And I've heard that you're working on or that there are vaccinations for tomatoes. So what is that all about? Yeah, that's a play on words, I would say, a little bit.

10:58But basically, again, you know, plants are doing a lot more than we realize. I think, you know, if there's anything you remember from today, they might be sitting there very innocently as you walk by, but there's metabolism going on constantly. You know, for example, when that fungus comes on a leaf, all these fatty acids are made. In the question of the vaccines, plants have an immune system, just like humans, right? And so, if there's an infection in one part of the plant, the whole rest of the plant actually responds and there's a heightened level of defense. And so, one of the molecules that we've worked on actually triggers this systemic response across the plant body.

11:37So, there's ways for the plant to signal from one leaf or branch all the way to the other side of the plant when a pathogen arrives. And so these lipids in the tomatoes have caught your attention. Are they a risk to the tomato population? What made you and your colleagues concerned and interested in them? Yeah. So often when I get interested in something, it's because of that chemist hat. I think the structure looks cool on paper and it's kind of unusual. And I think about like the way the atoms are bonded together. And I think this is not like your polyunsaturated fatty acid. This is like a different kind of lipid.

12:17So this is a very unusual structure that we first were drawn to. And then when we found out that it's basically dark until you put a pathogen on the plant and then it gets produced, made us think that perhaps it has an important role in the infection process. Gotcha. Gotcha. So before we move to some other topic, I did, I know you've worked on liminoids, which are some of these things that I think are responsible for citrus flavors. And I did one, I've heard recently, and I don't know if you work on this, about citrus greening. So can you tell me just a little bit about that? Because I think it's an important thing that a lot of people are not aware of.

12:54Yeah. So this is a great question. I actually taught a class this spring that was all about how do we define some of the big challenges in the food space when we think about really reinventing the food system and how do we break that down to some of the big problems that we can go after in a practical way. And one of my student groups chose to focus on citrus greening. So even though it's not something I work on, it was really exciting to learn a lot about it through this class. So citrus greening is a pathogen, a bacterial pathogen that affects citrus trees and essentially destroys the quality of the fruit and can ultimately kill the tree.

13:35It's transmitted through a psyllid, which is an insect that can land on the tree and then deliver the bacteria. So the insect is the vector. And it's really devastated the citrus growth and production in Florida. However, it's not yet, I would say, a big issue in California. Although experts predict, based on my student conversations with farmers and growers across the state, that it's starting to appear and there's a strong likelihood that it will emerge in California as an important pathogen as well. Yeah. So this is what I've heard as well, and that it actually could threaten global, not only global citrus, but because of that, global access to things like vitamin C, where the citrus fruits are the main source.

14:24So I just wanted to highlight it because I knew you worked a little bit on the liminoids, which who knows, Maybe your expertise there might eventually – I mean, you are circling a lot of these things in your expertise. So I wouldn't be surprised if when you're on the Future of Everything for the third time, you're a citrus – here's a prediction from Russ Altman. You're going to be getting involved in citrus craving. Yeah, that would be awesome if the molecules that we've studied in citrus ultimately have an important role. I mean, just, you know, to very briefly say, liminoids are these really fascinating, super complex molecules that are present in citrus trees, also in citrus fruit.

15:04They can lead to bitter taste in fruit. But that's what we really actually don't know what their function is. And there's lots of different cousins in the same molecule class. So they're probably doing a lot of really interesting and cool things. Yeah. So I saw that on your CV in preparation for our chat. And I did Google it. And I read, like, the Wikipedia intro. And I have a little bit of a chemistry background, as you may know. And so I saw that these were very interesting looking molecules. And I said, OK, this explains why Beth would be interested in them. And that's what triggered my citrus greening.

15:34I wanted to move to the idea of plants as factories for chemicals. You've kind of said they bring together your love of chemistry and your love of plants. And I think you've written that there are some of the best chemists in the world are plants. And one of the things you're doing is looking at plants as a factory for medications, even like cancer medications. So can you tell us about that? Yeah. So most recently, we've done some work to try to figure out how do plants make molecules that are used in the clinic and already have been discovered and used as, for example, chemotherapeutics. So the leading example is Taxol, which is produced by the Taxus tree or the Yew tree.

16:18Um, so we figured out how does the plant make this molecule, but that's, you know, just the tip of the iceberg. Um, this is a super important drug that's been around for a long time. There was a huge race to make it chemically. Like how could, um, scientists make it at the bench? Now we're trying to figure out how does nature do it? How does the tree do it? I think that could be an important way that the molecules produce. But again, I think the story is much bigger there. These trees live literally for thousands of years. They make over 500, 600 different versions of these metabolites, all different structures.

16:56We use one in the clinic. So I think that the other molecules, the other 499, are also worth investigating, understanding what are they doing for these trees that are able to live for thousands of years? And then furthermore, how could they be leveraged perhaps as medicines for human disease? Yeah, I'm glad you said that because it kind of buries the lead. Like, why is a yew tree making a cancer drug? So can you get what is known about what it's doing? Presumably trees don't get cancer. Well, actually, who knows? But do we have any insight as to why it's making? Because these are very complicated molecules.

17:33And my understanding is it took a long time for humans to figure out how to make these molecules kind of from scratch. Yeah. Often, I think when we use a molecule in the clinic for treatment of humans, that it's sort of a coincidence that there's something about the target in humans that is similar to the evolved target in the plant. Yeah. So certainly, again, you know, that you tree likely the selective pressure was not for cancer treatment. However, it was for cells that are growing really fast, likely pathogens. I mean, just think about like, if you had a cut and you sort of buried it in dirt, you know, how quickly you might get an infection.

18:20these plants are living for thousands of years in the soil and they just don't get sick right that they're able to persist so these molecules have a really important role in in dealing with that my guess for something like taxol which actually binds to tubulins that's like the the skeleton of cells the skeleton is super important when cells are dividing especially when they're dividing fast is that it targets perhaps like a fungal pathogen that might be growing on the plant and it prevents growth on the plant tissue. This is The Future of Everything. I'm Russ Altman, and we'll have more with Beth Satley next.

19:08Welcome back to The Future of Everything. I'm Russ Altman, and I'm speaking with Beth Satley from Stanford University. In the last segment, we heard about how chemicals created by plants can be used and engineered to help them adapt to the climate or to resist diseases. We also heard that they might have applications in human health. In this segment, we're going to learn a little bit more about how those human applications might go. And we'll also hear about how the field in general is moving towards engineering a better future for plants. So Beth, I'm amazed at the range of things that you do.

19:40The things I just mentioned, synthetic biology, you've begun to look now at food allergies and plants as food. What are you thinking about doing next? I mean, I already suggested that you work on citrus greening. But other than that, what's the future hold and where are you seeing the best opportunities? Yeah, I think one of our biggest questions up until now has been how do plants make these molecules and what are the cornucopia of different molecular entities and plants. Going forward, I think we're really excited to better understand what do these molecules do. And there's sort of two arenas.

20:19One is what do they do for plants? So how do they benefit plant health? And then the other side is how does the chemistry of plants benefit human health? Great. And so how do you reduce that to a research project in your lab? Who are the collaborators? How do you situate yourself in some of these issues, which are very complex? For example, anything having to do with health will involve clinical systems, regulatory folks, industrial folks. How do you think about that? Yeah, so I'll talk about it on the human side. I'm really interested in how plant chemistry, again, how it functions and how it can be valuable in a preventative context.

21:01So when it comes to human health, I think where my heart really lies is how do we prevent disease going forward. And so there, I think that diet is a really exciting place to work. When you think about it, it's like our biggest exposure to the environment is what we put in our mouths at every meal. You know, the area of your digestive tract is like, you know, it's bigger than a tennis court. So that's where all our exposure is happening. And so I think we need to think a lot more critically about what is coming in and how does it influence human health and the prevention of disease. One concrete place that we're starting to work is in the area of food allergy, because that's a very clear connection between diet and then your immune system.

21:47Yeah, you know, that really rings true because we've heard ever since I've been a little kid, and that's a long time ago, you know, eat your vegetables, eat your fruits. It's good for you. But I don't know the degree to which we've gotten. And then, of course, it became because there's fiber there. Okay, fine, fiber, check. But as you've just said, there are tons of other molecules. Many of them are probably beneficial. Some of them might not be. Do we have a good understanding of the full range? It sounds like no, we don't have a good understanding of the full range of molecules, even in the foods that we are eating routinely, the fruits and vegetables that we get at the store.

22:23And it's interesting to think about from your perspective, these are all uncharacterized chemical systems that might have a lot of gold in there. Yeah. What's even more interesting to think about is you've already sort of prescribed yourself with these molecules. You're taking milligram quantities of drug-like molecules at every meal when you eat, and we don't really know how they affect your health. So it's sort of the reverse of drug discovery. You're already taking them. Now we have to ask about what exactly do they do. Yes, and then for all the good ones, as you point out, every now and then there's an allergy.

22:58I've had food allergies, and it was a huge deal, and I had to go through very high-tech treatments in order to be able to eat lobster rolls. We won't go through that. But but like things like peanuts, peanuts come up all the time. So when you look at allergens and allergies, what is the opportunity that you see for your group with your expertise? Yes, I think the food allergy space is very new to us. We do not have immunology expertise. We've been collaborating with others that, you know, are seeped in the language of the immune system. And what I've come to understand is that there's a lot that we're starting to dissect.

23:33once you are sensitized to a food, how does an allergy progress? What is the response, the allergic response? What does that look like on a cell and molecular level? But there's this big open question about why do you develop allergies in the first place, the sensitization part. And so my lab's trying to contribute our understanding of the chemistry of plants. A peanut, after all, is a bunch of proteins and small molecules and lipids all bundled together. It's the embryo of the peanut. So what about that is resulting in sensitization at much higher frequencies compared to other foods? That's where we're trying to make some strides.

24:12Yeah. And so I picked peanut as an example, but are you actually looking at that system or are there other allergy systems that have caught your initial attention? Yeah, it's interesting. One of the places that we've actually started is to think about the other side of the coin when it comes to allergy. So not necessarily things that ultimately cause allergy, but your immune system is not just hanging around doing nothing when you normally eat food and you don't have an allergy. In fact, it's seeing all that food and it's dampening the immune response. So we're thinking about tolerance. So in the more normal state that we'd like everyone to be in, what are the molecules from food that are recognized by immune cells and interpreted as totally safe, no immune response needed.

24:57So we're thinking about that chemistry on that side. Yeah, that makes sense because it is two sides of a coin and understanding how the tolerance happens, obviously, I think I can say obviously, will give you insights into the differences when there's not tolerance and also how maybe to bring the tolerance. So I was going to ask, as a chemical engineer looking at these systems, what is the ideal, like what would you love to happen with respect to your relationship to this research? Would you like to figure out like maybe cocktails of small molecules or plants that you could give to try to help increase tolerance for things that are otherwise causing allergies?

25:37Yeah. So I think one of the fundamental questions we have also has a lot of translational aspects. So I would like to know when you eat a peanut, it's filled with proteins. There's tons of different molecules there. How much of that peanut, What percent is it? 1%, 0.1 % of the protein does your immune system have to recognize in order to determine that the whole thing is essentially safe? What are the signatures? And are those signatures that are valuable in the context of tolerance, the same thing you become allergic to, or are they different? Because if they're different, then we might be able to just use those small portions of a peanut in order to get someone who is currently allergic back to a tolerant state.

26:19Yeah, this is really interesting stuff. There was just a paper in Science Magazine about how birds have lost some ability to taste sourness. It's, you know, because you're always seeing these birds eating berries that we can't eat. And it turns out that they don't taste the same to them. And so this is a little bit related in that as we get exposure to these plants, we're tasting, tasting, I'm using tasting in quotes, these different small molecules. Um, what about for diet? So is there a sense that, um, you, you would start engineering plants to be more healthy or to provide, um, to provide nutrients that they don't normally provide?