FOCUS In Sound #37: Jennifer Brophy

ERNIE: Welcome to FOCUS In Sound, the podcast series from the FOCUS newsletter published by the Burroughs Wellcome Fund.  I’m your host, science writer Ernie Hood.

In this edition of FOCUS In Sound, we welcome a young investigator who is pioneering in the field of plant tissue engineering—a remarkable emerging technology that just might eventually save the human race. Jennifer Brophy received one of the Burroughs Wellcome Fund’s Career Awards at the Scientific Interface, or CASI, in 2019. She is an Assistant Professor of Bioengineering at Stanford University, and is a Noyce Family Faculty Fellow and a Chan Zuckerburg Biohub Investigator. 

Jenn received her BS in bioengineering from the University of California, Berkeley in 2009 and her PhD in biological engineering from MIT in 2016. She did her postdoc work at Stanford, where she started looking at plants. Today in her lab, she and her colleagues are developing technologies that enable the genetic engineering of plants and their associated microbes with the goal of enabling innovation in agriculture for a sustainable future. 

Jenn Brophy, welcome to FOCUS In Sound!

JENN: Thank you, I’m happy to be here! 

ERNIE: To get us started, Jenn, why don’t you give us a quick overview of your field, which is known as synthetic biology?

JENN: Certainly. Synthetic biology can mean a lot of different things to different people. In my lab, we think of it as advanced genetic engineering, which is essentially applying the principles of engineering to biology in order to reprogram living cells or organisms to do something new. In our lab, that means changing the shapes of plants as they grow, but for different people they engineer organisms to do different things. 

ERNIE: I see. Building on what you just told us, I’d like to find out more about one of your major areas of research, which is called synthetic gene circuits. I know that it was the subject of one of your most important publications to date, which came out in Science last year. Please explain…

JENN: In that work, using synthetic genetic circuits to control gene expression patterns in multi-cellular organisms. This work is really borne out of the observation that gene expression patterns are important for development. In the 1980s—I’m going to do a little historical bit—in the 1980s, scientists discovered a gene in Drosophila called antennapedia that controls the formation of legs, and stunningly, if you express that gene in cells on the head of a fly, you can actually get it to produce legs where it would usually have antenna. Now that’s shocking, but it’s also really highly conserved across organisms. Where you express genes in the body affects the way it develops. And so we were interested in trying to control where in an organism we’re expressing genes in order to change its development. But it raised this question of how do you control gene expression across the body of a multi-cellular organism? So what people usually do when they want to pick out specific cells within a body to express a gene in is they look for a promoter, a region of DNA in that organism’s genome that usually drives expression in only those cells. And that’s great, it works well, but there are a limited of characterized promoters, characterized tissue-specific promoters, that have this capacity to control gene expression so precisely. And so we looked at that, and we were like, well, we can use synthetic genetic circuits to take a limited number of tissue-specific promoters and combine their activities in new ways in order to generate new patterns of gene expression. So the circuits that we built perform Boolean logic operations. They can take two different tissue-specific promoters, for example, and then say, okay, we only want to express our gene of interest where those promoters are both on, in cells where those promoters are both on. And using this type of Boolean logic, we’re able to generate new patterns of gene expression, which we then use to control development, and we demonstrate in this paper that a combination if tissue-specific control and control over gene expression levels allow us to tune a single aspect of a plant’s root system. We can change how many root branches the plant makes, and that changes that we made don’t affect any other aspect of the plant. So it’s kind of allowing us to do a little bit of design of the structure of the organism. 

ERNIE: Jenn, it all sounds kind of mundane and esoteric until we get to the unbelievable implications of your work. Can you give us that incredibly exciting outlook?

JENN: Yeah, we’re excited about controlling development in plants, controlling the size and shape of plants, because of how important the structure and the shape of the plant is for survival in a challenging environment. So unlike animals, plants can’t run away when conditions get bad, right. If it’s hot, you or I can go find shade to stand in. But a plant just sits there in the sun and takes it. And the shape and angle of its leaves will affect its susceptibility to heat stress, its photosynthetic efficiency. The shape of its root system will affect its ability to acquire water when there is drought. And as climate change advances, these environmental stresses that a plant it expected to endure will increase. And what we want to do is have the capacity to introduce changes in the shapes and sizes of plants that should make them more resilient to environmental stress. But what we don’t want to do is change the aspects of the plants that we like, right? And so this control over gene expression, it’s important for being able to modify one part of a plant without modifying other parts. So we get the best of both worlds. 

ERNIE: That’s very cool. Of course people have been bioengineering plants for a very long time…what is it about this work that represents a major leap forward?

JENN: It’s the specificity. Most of the bioengineered plants we have, in fact all of the ones that are on the market today, they express a single gene in every tissue within the plant throughout the plant’s entire life. And so that works well for getting things like pest resistance, where if an insect bites the plant, you want it to be resistant and producing something that wards off the insect all the time. But for changes in structure, you cannot express a gene throughout the entire plant throughout its whole life. Imagine if you had done the same thing in that fly example, you’d have antenna growing out of every cell in the fly. That’s not a functional organism, so to me, the type of changes that we want to make to improve resilience, you need this precise expression control. 

ERNIE: I understand that you’re also working on genetically engineering soil bacteria in the plants’ ecospheres. Tell us about that aspect of your research…

JENN: Yeah, so the bacteria research actually predates plant research for me personally. I love microorganisms.  I think they are really fascinating, and the way that they can influence health of an ecosystem, health of a host, there is really fascinating. And when I was a graduate student I got interested in trying to make probiotics for plants, and trying to engineer them to support plant growth. But what I realized while I was doing it was that a lot of engineered soil bacteria especially don’t do that well, and when they are put out in the environment, because they are at a fitness disadvantage and the environmental conditions fluctuate so much, that they can easily get lost and not be able to help the plant much. So what we’re trying to do now is sort of engineer both sides, the plant and the microbes, so that the two of them kind of help each other along. The plant maybe provides some things that help the microbes survive, and the microbes then return the favor when conditions are less favorable for the plant. So most of that stuff in my lab is at a really early stage, so we don’t have a ton to share about it, I guess. But it’s an area that we’re interested in. I love kind of having all of these different organisms growing in the lab. 

ERNIE: So it really becomes a very symbiotic relationship, then, right?

JENN: Yeah, it’s difficult, I mean we certainly don’t ever grow plants in the field without microbes, right, they’re non-sterile environments, and the interactions between the two can influence how fit either one are. There are some super-famous examples of plant-microbe interactions, like the bacteria that form nodules on the roots of some legumes, like some bean plants, to help fix atmospheric nitrogen. So they fix nitrogen and then gives the plant this essential element for growth, and the plant in return gives the bacteria sugars that it needs to survive. Those are interactions that people would love to better understand and to introduce into more of our food crop varieties. But it’s just one way in which the two play together. They’re important in a bunch of ways. 

ERNIE: Jenn, I’d like to turn our conversation now to a dialogue that you and some of your colleagues addressed directly in your July 2023 publication in PLOS Biology, and that of course is the issue of genetically modified plants, which have become so controversial in recent years. In the PLOS publication, you make very compelling arguments for the place of synthetic biology and plant genetic modification to create climate-resilient plants and be vitally important and effective stalwarts in resisting the devastating impacts of climate change. Would you share some of your thoughts on that?

JENN: Yeah. Here I want to emphasize just how challenging it might be to make climate-resilient crops. We have seen a lot of differences across the globe in regulations on transgenic plants, some of which allow for no modifications to be made at all, and some of which are more amenable to small modifications to the plant’s genome being made by tools like CRISPR or TALENs, basically gene editing to be done. But we really think that we should be able to bring to bear all of our tools and creating climate-resilient plants to ensure that we do have agricultural and food stability into the future, and we think that having regulations that facilitate innovation in that space are going to be really important, right? You see already how the regulations shape what seed companies and researchers go after in terms of traits and modifications, but if we were to more fully embrace all of the different types of modifications that we could make, then I think we would have a better arsenal at our disposal for making sure these agricultural systems are really resilient. So in this piece we were really just trying to put forth an argument that changes in regulation, which are also tied in to how people feel about genetically modified plants, are going to be important for actually realizing or producing these resilient crop varieties, and that we would really like to see advancement in that space. 

ERNIE: It sounds like the debate may be really subject to change as the pressures grow.

JENN: Yes, I think that that is entirely possible. It just would be nice to not be in a completely reactionary position, where we are faced with threats that are so urgent that we’re reacting to them by changing regulations, and instead being a little bit more forward looking and thinking like, okay, we can see that these things are likely going to be a problem in the future, like let’s start facilitating the development of the technologies that will get us there now. 

ERNIE: Jenn, as we’ve certainly seen this year of 2023, climate change is no longer on the horizon, it’s happening now and likely to increase in the near future, with huge planetary impacts that we’ve already started seeing. I know you’re working hard to do your bit, but in your estimation are mitigating scientific advances happening fast enough? Are you optimistic at this point? 

JENN: I’m going to have to be optimistic about it just to get through the day-to-day. I have small children, I have to be optimistic about their future, too. But I think we could certainly see more scientific advancement happening. Where I am more disappointed is actually not in the scientific advances but in the politics around all of it. I think there are many things that we could be doing now with the technologies that we have that we are not doing, which would have an outsized impact on the climate. And relying on some magic science silver bullet to fix the environment to fortify us against climate change is kind of silly, and we should really be doing more than just relying on new technological achievements in order to address some of these issues. That’s not what everybody wants to hear, but I do think that those things go hand in hand. You can develop the new technology too, but if there’s not incentives in place for people to switch over to use it, then it won’t matter. 

ERNIE: So Jenn, where is your research headed from here?

JENN: It’s growing, it’s growing, no pun intended, in a bunch of exciting ways. We’re trying to move some of the circuit technologies that we have established in the model plant Arabidopsis into crop varieties. We’re trying to apply it to engineer other traits aside from just this root branching trait, which is what we showed in the Science paper that we talked about earlier. We’re starting up some of the microbe-plant interaction stuff, and we’re really excited about all of the different ways that we are hoping to be able to manipulate plants and modify their growth. It’s been fun over the last couple of years as my lab has started to grow to see there being new plant varieties growing, to watch the growth room spill out and stuff, and we’re really excited about just all of it.

ERNIE: Last but not least, Jenn, I always like to conclude these chats by asking what the support from the Burroughs Wellcome Fund has meant to you, both personally and professionally… 

JENN: The Burroughs Wellcome Fund support has been amazing. It came at a time in my career when we had ideas about using synthetic genetic circuits to make these types of very precise gene expression control elements, and yet very little proof that it was going to work, and Burroughs Wellcome Fund, unlike some other places, were really willing to take a risk on that, and I think it’s paid off really well. And it just helped me gain confidence that we were going to go in a direction that was impactful, that people cared about, and yeah, I couldn’t be more grateful for it. 

ERNIE: Jenn, it’s been a great conversation. I’ve certainly learned a lot, and wish you the best of luck in your ongoing research. Thanks for joining us on FOCUS In Sound.

JENN: Awesome! Thank you so much for having me, it’s been a pleasure to be here. 

ERNIE: We hope you’ve enjoyed the program, and will join us again next time. This is Ernie Hood. Thanks for listening!