NEB Podcast #36 -
Interview with Professor Tom Ellis: Using synthetic biology to scale Engineered Living Materials

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Transcript

Interviewers: Lydia Morrison, Marketing Communications Writer & Podcast Host, New England Biolabs, Inc.
Interviewees: Professor Tom Ellis, Ph.D., Department of Bioengineering, Imperial College London


Lydia Morrison:
Welcome to the Lessons from Lab and Life podcast from New England Biolabs. I'm your host, Lydia Morrison, and I hope this episode offers you some new perspective. Today, I'm speaking with professor Tom Ellis, who's a member of the Department of Bioengineering at Imperial College London. His lab focuses on using synthetic biology to enable scalable production of engineered living materials. Good morning, Tom, and good afternoon to you. Thanks so much for joining me today.

Tom Ellis:
Thanks. Thanks for the invite and good to see you.

Lydia Morrison:
Yeah, nice to see you too. I wanted to jump right in, and I was wondering if you could tell myself and our listeners what engineered living materials are and what they're being used for.

Tom Ellis:
Yeah, sure. Engineered living materials is kind of a recent concept that brings together expertise and research in the area of materials and biomaterials, with expanding research in biotech, and particularly in synthetic biology and engineering cells and engineering biology. And together, these subjects coming together allow us to think about engineering biology, to grow materials, and engineered living materials are materials that are grown either entirely or partly of living cells, making a material around them as they grow, or even the cells themselves being something like the material, like you could see in some parts of nature, but with the engineering applied. So we're genetically modifying the cells to define the kind of material that they grow and make, or engineering the way the cells are brought together and the way the material is produced together, maybe through non-genetic engineering methods, to end up with a material.

Tom Ellis:
Now, these engineered living materials can be living during the production of the material, which is unlike materials we're producing like plastics and things, and they can go further than that. They could be materials that are living during their use, so that they contain cells within them that maybe can sense and respond and do things to interact with the environment.

Tom Ellis:
So at the moment, it's kind of a very new area, and so applications of this are early stage. But it's exciting and I think people should care about it, because you only have to look around in nature, or even just in your house, at how many different materials come from biology. You can easily think, obviously, of wood, it comes from trees, but then so do things like paper, and then we have, obviously, a lot of our clothes are products of materials that are grown by animals or grown by plants, things like silk, all sorts of cool things. All of these materials we use day-to-day are made by biology. So it's exciting to think that maybe we can control the processes of how biology makes materials and grows them, and we can gain more understanding of how to make even more advanced and interesting materials in the future.

Lydia Morrison:
That's interesting. These materials could essentially be turned into anything, from clothes to protective outer layers of spacecrafts?

Tom Ellis:
Yeah. Okay. Those are two extremes, but they're not actually too far away from one another. I can already think, we have projects in our research group that are close to clothes and we have projects that are close to things on the outer layer of spacecraft. I'm not just joking there, we are actually talking to people at a European Space Agency about some of the materials we can grow that have anti-radiation properties that can be useful to protect in space.

Lydia Morrison:
Well, that's amazing. I'm impressed that my guesses were so spot-on.

Tom Ellis:
Well, this is a field where this is a foundational technology. Basically, biology makes most materials that we care about, and the other ones that aren't made by biology, like plastics, we would like them to be made by biology so that we don't have to rely on fossil fuels and those harsh chemical processes. So really, if you can think of any material out there, biology is useful for trying to make better versions of it or improvements and enhancements to it.

Lydia Morrison:
Absolutely. And just since you mentioned plastics, I'm curious, when you're designing these biomaterials and thinking through the process, do you also think about where these materials would end up after they've been used and how they might degrade or be broken down or dealt with as trash or refuse at some point in their life?

Tom Ellis:
Yeah. That's an interesting and slightly challenging question, because I guess if you have engineered cells, and especially if they're living within the material, then you're, at least in our case, making genetically modified cells and hoping that they can be used in an environment. And obviously, there's a lot of different regulations from place to place about the disposable of genetically modified cells. Most of it, it's regulations with almost no safety concerns at all, but people will be interested, people would like to know that they'd be disposed of properly and not potentially causing any environmental risks in the future.

Tom Ellis:
But for the material itself, then we are predominantly talking about biologically-made materials that, out there in nature, they're already, the enzymes, the machinery, and the organisms that are evolved to be able to break them down in reasonable timeframes. So for example, in my research group, the base bulk material we make most of our products with is cellulose, and cellulose is made in massive abundance by nature and there's a huge ecosystem of organisms which love to break down cellulose to get their sugars.

Lydia Morrison:
Yeah, that makes a lot of sense and I certainly appreciate that your team has thought through the whole life cycle of the living materials. Why is it advantageous to use the living cells in materials, as opposed to using enzymes like the ones that are in everybody's laundry detergent?

Tom Ellis:
Yeah, that's a good point. There are a lot of efforts out there, particularly in making things like plastics or bioplastics, to have the polymerization of the material done by enzymes rather than by environmentally detrimental chemical reactions. And so there's a body of people doing that. But even then, when you do that, you basically, it's still more chemistry. You're having to make in advanced, a huge amount of plastic monomer, then you need to make a large amount of enzyme and purify it out so it's pure, mix the two together, do lots of downstream processing from this reaction to start pulling out the polymer.

Tom Ellis:
Now, cells, especially cells in things like plants, they worked all this out by evolution over literally hundreds of millions of years. If you want to make a material, you can get a specialized cell which has lots of machinery within it, including the enzymes, to make the precursor, to polymerize those molecules into a polymer, to arrange the polymer so that is extruded through this outer layers of the cell, and so that it can start winding upon each other to make a fiber, to then stop making a material. And so, it's amazing to think we can sort of now, based on our knowledge of biology cells, molecular biology, and now synthetic biology, think about harnessing those capabilities. It'd be really hard to harness all of those capabilities by ripping them all out of the cell and somehow using them just as the enzymes, especially because a lot of those enzymes need to be held within membranes for them to work correctly and things like that. So it's just easier to, instead, use the cell, because it's basically a natural production factory at a very small scale for the kind of thing we want to make.

Lydia Morrison:
And so how would you potentially scale up that production to meet the needs that are being met through more synthetic means now?

Tom Ellis:
Yeah, that's a real key question and a tough one for a lot of people who work with these engineered living materials. For example, most work in engineered living materials so far has been in, maybe, engineering E. coli bacteria, which are tiny, but obviously used a lot in the lab and often grown at scale in some factories that make enzymes for industry that will make molecules. But even then, the kind of materials that they produce that are engineered living materials might be protein polymers that form on the outer surface of the E. coli cell, and they're kind of small and they're produced at a reasonably small scale. So you see a lot of research paper that go, "Hey, we've made a really amazing new adhesive material or protective material." But they may have done a huge amount of growth and managed to get back a gram or so of material, which is really not that much.

Tom Ellis:
That's why we've been working predominantly with cellulose made by bacteria instead, because the bacteria can actually make a pretty large amount of it quite quickly and easily. And I think that's basically because it's a carbohydrate rather than a protein. So carbohydrates just economically are lot cheaper, easier, and quicker for a cell to make than something complex like a protein.

Tom Ellis:
Is it ready for scale-up to be actually used as a product? I think so. You can grow bacterial cellulose for food. There's an industry making a sweet dessert called nata de coco in the Southeast Asia, predominantly places like Vietnam and the Philippines, and they will grow this bacteria on sugary coconut water in trays round the back of a farm. And after a few days, they'll go back and there'll be meter-squared sheets of this material, full of wet sugary liquid, and they can cut it up into squares and seal it up and it's kind of like a jelly that you can then sell to people to chew on and eat with a nice sweet taste. They make this stuff at scale. So when I'm talking about scale here, you could go on the internet, the Southeast Asia equivalence of Amazon, and you can buy a metric ton of this stuff for only a hundred dollars.

Lydia Morrison:
Wow.

Tom Ellis:
Yeah. Well, the shipping fees get pretty crazy when you try to get a metric ton of something sent over from there. But basically, it costs very little to make it. It's still more expensive than paper, but then I think we should start challenging people for the cost of cutting down a tree, because paper, we're getting all of that material after hundreds of years of growth. Whereas here, we're getting all of this material from just a few days of growth in a sugary liquid.

Lydia Morrison:
Yeah. That's interesting. Certainly the speed of production is entirely different, and maybe you could even create paper out of these engineered living materials. Is that possible? That you could actually...

Tom Ellis:
Yeah. Particularly, the one we focus most on, this bacterial cellulose, when we grow it, it will first be like a hydrogel. So it's a bit more of like a tough jelly when it's grown, because it's very hydrated. But if you treat it, dehydrate it, it goes down to something a bit more, somewhere halfway between paper and leather in the way it feels, as it loses all that water. It actually loses a lot of the material properties we really love about it when it loses the water, like it's toughness and it's resilience, which makes it a really good protective material. But then when it goes down to more like the paper leather form, it can be useful in lots of other areas. So for example, Samsung have been researching using it as very thin battery separators in its leather paper form, where it can separate between the positive and negative charges inside your cell phone or laptop battery. It can do that a lot better than other cellulose-based materials that have previously been used, like paper.

Lydia Morrison:
Oh, that's very interesting.

Tom Ellis:
Yeah. It's just remarkable. How many different uses there are for some of these materials. You think cellulose, "Okay, sure. That's everywhere." And if you ever read a cellulose paper or go to a cellulose conference, everyone says the same thing, which is, "Cellulose, it's the most abundant polymer on earth." But a lot of people don't really know about bacterial cellulose or microbial cellulose. Cellulose that's made by microbes instead of cellulose that's made by plants. It's longer and tougher and more uniform and higher quality and higher purity than what plants produce, and particularly what the timber industry can produce. So it's really good for very high-end applications.

Lydia Morrison:
Your recent publication introduced the, and I'm probably going to say this incorrectly, the Komagataeibacter tool kit?

Tom Ellis:
Komagataeibacter tool kit. Yeah, we suffer because there's these guys out there called taxonomists are continually changing the names of the bacteria. If we released this toolkit 10 years ago, it would have been the Gluconacetobacter tool kit, even before that, the Acetobacter tool kit, but they keep changing the names of the genus and then we have to use these really long names.

Lydia Morrison:
Well, it does make a nice acronym with the KTK kit. To support the synthetic biology progress of these living engineered materials, your group created this kit. Can you tell me about that tool kit?

Tom Ellis:
Yeah, sure. We do a lot of work in our group doing foundational synthetic biology, working out the best ways to engineer more and more complex things by putting together different DNA bits of code. Now, we started 12 years ago with BioBricks and restriction enzymes, like EcoR1, Spe1, things like that, bringing them together. But at the beginning of the 2010s, saw people start to use Golden Gate assembly, where you can, instead, standardize your parts to only be cut by Bsa1, Bbs1, and these other Type IIS restriction enzymes, and they can allow you to do much more advanced, faster cloning with multiple DNA parts coming together to make the DNA program that you then want to put into a cell.

Tom Ellis:
So we originally started working with this organism as part of a student iGEM project, where iGEM undergraduate synthetic biology competition uses BioBrick® assembly, which is now a bit of an outdated assembly method. And as soon as we finished that competition in 2015, we were like, "Okay, let's see. Can we start building up instead, all the parts and all of plasmid vectors to instead move to using the Golden Gate assembly method so we can do more complex things."

Tom Ellis:
So we've be working on that for many years. It's sort of been the side project of everyone in the group to help make this kit and contribute to it. And so we're finally able now, after many years, to put together this collection. Briefly, it is a collection of the plasmids that could be built in E. coli and then transformed into these bacteria, and they've been designed so that the Golden Gate assembly works nice and efficiently into these plasmids and that they can then be built up into bigger and bigger, more complex DNA programs within these plasmids. And so, the plasmid backbones make up the essential part of the toolkit, and then all of the other stuff in the paper are examples of DNA modular parts that we can then use in this toolkit, because they've been formatted to go with it. So essential little bits of DNA, like promoter sequences, fusion tags, things like green fluorescent protein and stuff like that, that you can use if you're trying to genetically modify and change gene expression in a bacteria like this bacteria.

Lydia Morrison:
Well, congratulations on your publication. I think that all your hard work seems to have paid off in terms of being able to put together this kit that seems like it will basically be able to enable fellow researchers to test more targets, more gene changes, in DNA manipulation in a faster timeframe than previously.

Tom Ellis:
Yeah. There's some extra things we've done in the lab in the last month or so that can go into that kit. So it might be that this work, which was just published, not published as a peer review just yet, but it's been a pre-print, but it's where the journal right now, it may end up, when fully published, with a few extra things in it, which would be cool as well. We're particularly excited. For example, we have, now as part of the kit, the ability to modify the genome of the cell and not just put in a plasmid, but be able to integrate and delete genes in the genome. That's going to become really useful when we want to modify these bacteria for real scale-up experience.

Lydia Morrison:
Yeah. That's amazing and I could see how advantageous that would be when you're working towards scaling up for a large production of a living material.

Tom Ellis:
Yeah. We want to get it so that we just build cells that are engineered with stable DNA within the genome, because then that allows you really to start growing them at scale, without worrying that maybe the plasma will eventually be removed from the cells.

Lydia Morrison:
Yeah, absolutely. And that way too, you're not having to recheck every time every batch or create the cells fresh each time. I'm curious, where do you see the future of synthetic biology heading?

Tom Ellis:
Oh, well, the whole of synthetic biology, it should be heading everywhere. One thing that I think is very important to consider and I'm seeing a lot from, particularly the students that we teach and that the students that join my lab for research projects, is passionate about doing something about sustainability and thinking about the environment. And so if you think about the technologies that we use on earth that have, probably, the biggest impact in terms of a possibility for helping us deal with the problems of sustainability or lack of sustainability, then biology and bioengineering really should be up there at the top, because ultimately, what we're doing to the earth is largely a biological problem. And so I think that's really where the field needs to think about. Because with all the technologies and all the progress bioengineering, and particularly synthetic biology, is basically the engineering discipline for this century, similar to how electronic engineering was important for the last century and got us from knowing about electrons at the beginning of the last century to the internet by the end of the century.

Tom Ellis:
I'd like to think that with the progress we're making in synthetic biology and other forms of bioengineering, like genome engineering, that we could see some remarkable changes over the next 100 years or next 50 years or so. But we need to do that in a way where it benefits the planet and benefits the way humans live and behave on this planet, because we humans have been so destructive to the planet over the last 50 years. We need to start finding ways that technology can help in the other way.

Lydia Morrison:
Yeah. I love that answer and I think you're absolutely spot-on and it's nice to hear that the scientists being trained in graduate school now are interested in those sorts of endeavors, because certainly, that could play a huge role in changing the impact of humanity on the planet. Obviously, there's a lot of things that humanity needs to do to correct the way that we've treated the planet thus far, but I can see how synthetic biology can really play a role in everything from energy solutions to materials consumption. So I think you're absolutely right, that that would be a great place to see synthetic biology improve the life and the longevity of our planet.

Tom Ellis:
I don't want to be too nasty to cows here, but I would love it if synthetic biology could basically replace our use of cows and cattle within the next 10 years. So we work on these materials, they have leather-like properties, and we're getting better at engineering the cells to be able to understand what material properties we get out of the bacterial cellulose. And so we should be able to produce some pretty good replacements for leather within the next decade from working from our group and from many other groups in this space, and particularly companies in this space. So leather, don't get it from cows anymore. You can get it from other places. And then of course, beef that we eat. There's companies out there using synthetic biology to get the bleeding and the texture and the feel that can be put into plant-based burgers, or even going to the point of understanding how you could grow bovine tissue culture to make a real beef burger, but one that was never required a cow.

Lydia Morrison:
I tried some of those substitute burgers. They're not so bad.

Tom Ellis:
Yeah. I love the Impossible Burger in particular.

Lydia Morrison:
Yeah. I’ve tried the Beyond Burger.

Tom Ellis:
Yeah.

Lydia Morrison:
I agree, I like them.

Tom Ellis:
Yeah, and so there's a whole industry and many students here that I'm teaching, even undergraduates, are founding companies in this space of alternatives to look anything animal-based, but using biotech to fill in a gap where previously we've got something from animals. I was talking to my wife about this last night. The advert came on with all of the models putting on hyaluronic acid for their face cream, and my wife was like, "Well, where does that come from?" Because I was mentioning that we'd been trying to get some cells to make it in our lab and I think most people don't know when they put that face cream on, it comes from roosters, the male chickens, it comes from the little thing on the top of their head all crushed up.

Lydia Morrison:
Oh, really?

Tom Ellis:
Yeah.

Lydia Morrison:
Their coxcomb? Isn't that it?

Tom Ellis:
Yeah, that's the main source. So it's kind of weird. You see all these models putting it on their face and then you're like, "Okay. Yeah, you're getting that from chicken heads.

Lydia Morrison:
Wow. Yeah. That's interesting to think about. I would actually feel much more comfortable if it came from some cells in a lab, I think.

Tom Ellis:
Yeah. Chickens, I don't think, are necessarily a sustainability problem, like cows are and I think it's well within our reach to end the beef and leather industries within the next couple of decades, similar to how we want to stop transport by automobile that isn't electric or hydrogen, and really, Bio-IT and bioengineering, ELMs and synthetic biology is going to have a huge role to play in things like removing the use of cattle and cows for most of these things. Milk as well, for example.

Lydia Morrison:
Well, I hope to see that prediction come to fruition.

Tom Ellis:
Yeah. Again, I feel sorry for the cows in this, but I prefer to see small numbers of cows in nice pastures and not the slashing and burning of rain forests in South America to make way for soy to feed cattle on large intensive farms.

Lydia Morrison:
Absolutely

Tom Ellis:
Yeah.

Lydia Morrison:
Could you tell us something good? Do you have any stories of silver linings that you've discovered in this pandemic?

Tom Ellis:
Oh, I'll have to think. I was talking to a colleague today that the pandemic for me, the silver lining, was a lot more time at home with my daughter, and that was challenging, but obviously lovely to see her grow.

Tom Ellis:
In terms of silver linings for the lab research, I think we were able, once restrictions were put in for social distancing within our labs, it was frustrating, but it enabled one of my students working in this space to do some much larger-scale cellulose growing than normal, because suddenly he had larger bench space around him because people weren't allowed to have benches that were 2 meters closer. So he was able to do so much larger-scale growths of this material. That was really cool because it allowed us to see proof-of-concept of going from little microbes in a 96-well plate well, to then something that actually is a big enough piece of material that you can wear it as an item of clothing, even though it's been genetically engineered, patterns on it that's been done through genetic engineering and all sorts of cool things. So yeah, there's been very little pluses, especially if a lab work, but that's one of them.

Lydia Morrison:
Well, I think that we hold onto those small wins through the pandemic where we can get them, and I think that speaks to the fact that we've all appreciated, I think, having a little bit more time and a little bit more space to stretch out in during the pandemic, whether it's through some isolation, which can obviously be tough at times. But there's definitely been some space for everybody to grow and appreciate and do a little spreading out of their other personal goals and priorities, and I think that those are good reflections of that.

Tom Ellis:
Yeah. Well, hopefully we can start calling an end to this pandemic soon, but I'm not so sure.

Lydia Morrison:
I know, I'm with you. I'm hopeful, but skeptical. Thank you so much for taking the time out of your busy schedule to speak with us today

Tom Ellis:
No problems. It's been great to talk.

Lydia Morrison:
Absolutely. It's been a pleasure. Until next time.

Lydia Morrison:
Thanks for joining us for this episode of the Lessons from Lab and Life podcast. Join us next time when we interviewed with Professor Karmella Haynes of Emory University. Her work focuses on using chromatin-based systems to control gene expression, and how these methods can be used to improve the accessibility of DNA during CRISPR-Cas-directed gene editing.

 

 

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