Synthetic Cells: The Next Bioengineering Frontier

There are more human cells in your body than there are stars in the Milky Way galaxy! Cells are the fundamental building blocks of life but that doesn’t mean they are simple – biology still doesn’t have a full picture of how exactly a living cell works. Host Regina G. Barber https://www.npr.org/people/1082526815/regina-g-barber talks with bioengineers Kate Adamala https://en.wikipedia.org/wiki/Kate_Adamala and Drew Endy https://engineering.stanford.edu/people/drew-endy about why scientists are trying to build a cell from scratch, piece by piece. They dive into what it would look like to be inside of a cell, why scientists are bothering with making a cell from scratch and how engineers are leading the field. Want more bioengineering stories? Email us at [email protected] mailto:[email protected]. Listen to every episode of Short Wave sponsor-free and support our work at NPR by signing up for Short Wave+ at plus.npr.org/shortwave http://plus.npr.org/shortwave. See pcm.adswizz.com https://pcm.adswizz.com for information about our collection and use of personal data for sponsorship and to manage your podcast sponsorship preferences. NPR Privacy Policy https://www.npr.org/about-npr/179878450/privacy-policy

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• 0:00Speaker 00

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• 0:16Regina Barber?

  You're listening to Short Wave from NPR.

• 0:23Regina Barber?

  There are more cells in your body than there are stars in the Milky Way galaxy. Our galaxy has a couple hundred billion stars, and inside me and you, each of us has around 30 trillion human cells. 30 trillion. Cells are the fundamental building blocks of life, but that doesn't mean they're simple. Biology still doesn't have a full picture of how exactly a living cell works.

• 0:48Speaker 02

  There is no natural living cell that we can have a full chemical ingredient list for, and we don't know all the genes even in the simplest cell. So it's really kind of like a black box.

• 0:59Regina Barber?

  That's Kate Adamala, a biological engineer at the University of Minnesota. She wants to do what only nature has done: build a cell from scratch. A synthetic cell that replicates itself but was made in a lab.

• 1:13Speaker 03

  All of bioengineering right now is Edisonian. Tinker and test, tinker and test. We don't know when we go to make something happen, if it'll work or not, until we build it and test it.

• 1:25Regina Barber?

  Drew Endy is an engineer at Stanford University and part of a community cofounded by Kate called Build a Cell. This is an international group of researchers with the same goal: to build a cell from the bottom up, piece by biological piece.

• 1:39Speaker 02

  If you look at the entirety of biology, it actually, and I'm going to piss off a lot of biologists by saying that, but biology from the chemical point of view is actually really boring. It uses only 22 amino acids out of hundreds possible amino acids. And that's another motivation for engineering cells from scratch, is we want to be able to invent things, to do things that biology never bothered doing.

• 2:01Regina Barber?

  If scientists can create cells, they can be programmed to do all sorts of things. And scientists have touted the dream of synthetic cells as a new solution to the world's problems. Synthetic cells could be programmed to act as part of new cancer therapies, can create new medicines easier and cheaper. They could even be made to produce artificial photosynthesis to help with green energy projects. And somehow, that would just be the beginning.

• 2:28Speaker 03

  I truly believe that as the engineers learn how to construct cells, there will still be profound mysteries in biology and life that will lurk underneath.

• 2:38Regina Barber?

  Synthetic biology is not a reality yet, but it's on the horizon, especially now that engineers have taken the helm.

• 2:45Speaker 03

  Building cells from scratch is no longer a research project. It's now an engineering project, which means we can plan to do it and anticipate deadlines, and it's right in front of us.

• 2:59Regina Barber?

  Today on the show, DIY Cells. We dive into what it would look like to be inside of a cell, why scientists are bothering with making a cell from scratch, and how engineers are leading the field. I'm Regina Barber, and you're listening to Short Wave, the science podcast from NPR.

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• 4:45Regina Barber?

  Okay Drew, before we can build a cell, we have to understand them. And I've always had a really hard time visualizing like what's happening inside of a cell. But you have this like really cool way to think of them like as a building, right?

• 4:57Speaker 03

  Yeah, the question that motivates thinking about a cell as a building is are cells intrinsically complicated? Or are they just, do they just appear to be complicated because they're so darn tiny? And so we can't see what's going on. And so as a mental exercise, imagine taking a cell that might be a millionth of a meter across, a micron, super tiny. And now imagine making it magically 100 meters long.

• 5:27Regina Barber?

  Yeah, scale it up.

• 5:27Speaker 03

  So we're gonna scale up. We're gonna multiply the size of a cell by a factor of 100 million with a magic wand. You know, the cell's not this solid object. It's an object comprised of smaller objects, molecules. And so now we can, at this scale of 100 meter cell, a building sized cell. By the way, I would love for somebody to build a building that's a cell.

• 5:49Regina Barber?

  Yeah, and just have like actors like doing the things inside the cell and like moving things.

• 5:53Speaker 03

  Totally. Or like Roombas or whatever. But so a protein inside this building sized cell is gonna be about as big as a basketball. And then the thing that makes proteins, the ribosome, this molecular machine that makes proteins from genetic instructions, that's gonna be about as tall as a person. And then the DNA, the inside cells is DNA, the genome, the genetic instructions. That DNA for our cell is gonna go back and forth across the cell over 1,000 times. Right? If the building's 100 meters long, the DNA is gonna be kilometers long. And it's gonna be coiled up and wrapped up and packed inside the cell.

• 6:35Speaker 03

  And then another thing that shows up is if you're inside a cell in this building, the building's gonna be packed maybe 20% to 40% of stuff.

• 6:45Regina Barber?

  Wow.

• 6:46Speaker 03

  It's like a hoarder of molecules.

• 6:48Regina Barber?

  It's like those terrible bookstores, you know, where they have those piles of books and you're like, get organized, like that place?

• 6:54Speaker 03

  But like, imagine a books, imagine a bookstore that's 50% full of books almost, and you could just barely move through it. All right? Now, there's, there's one more wrinkle that blows my mind. The, the molecules inside the cell are moving. They're not fixed in one position. And they're moving spontaneously because the molecules are free to move due to the energy of the system. And so that protein, that's a little basketball in this big building, is moving so fast, it's able to go through the entire building within a second.

• 7:29Regina Barber?

  Wow.

• 7:29Speaker 03

  And so that's what's incredibly interesting to me. When we start to think about how are these systems working? How are these cells making other cells? How are they alive? If we could see it and follow it in real time, I'm 100% certain we could figure it out. It's just that it's moving so fast and it's so darn tiny, we haven't been able to follow it exactly right yet.

• 7:50Regina Barber?

  Well, see, this is where we get to the next question, Kate, is that what if we could build a cell so that we could understand it better? So like, how would you describe the synthetic cell you're building towards?

• 8:02Speaker 02

  The synthetic cell would be like a bookstore that you're filling one shelf at a time. You know what sections you want. And using Drew's analogy, you're filling it to have all the books that you're interested in, but because you're putting them in, you know where they go. You know what books you put in and you know where they're supposed to move. It's still tiny, but because we built it from the parts that we know about and we know what they're supposed to be doing, then we can actually understand and, most importantly, predict where they go. Because it's not just about understanding where they used to go, it's about predicting where they are going to go where you do something. And that would be a synthetic cell.

• 8:44Speaker 02

  It would be a bookstore with a really good inventory because we know what goes into a synthetic cell.

• 8:49Regina Barber?

  Yeah.

• 8:50Speaker 02

  And we can grow it. And that's the most fascinating to me as an engineer is I don't want to just build something complex. I actually want to know why it works the way it does.

• 8:59Regina Barber?

  Okay, so Drew, when did the idea of building a cell, a synthetic cell, start to seem possible? Like, what's the history here?

• 9:06Speaker 03

  Yeah, I'll give my version and then I beg Kate to chime in too. I see there's three different factions or groups that were interested and are interested in the topic. One are the folks who are interested in the origins of life. Where does life come from? And so that tribe, if you will, or group, has been working towards building cells for a very long time. Then there's another group that's been taking natural cells and whittling them down to remove all the extra pieces they can and building synthetic genomes with just the stuff needed to keep it going and making a type of minimal synthetic cell, starting from natural cells. And that's been going on for a couple decades.

• 9:51Speaker 03

  And then, over the last decade plus, the third group, the engineers are arriving. And genetic engineering is 50 years old. That starts by moving small numbers of genes around. By 2010 or so, the people from that group are getting good enough that they can begin to put together 30 or 40 gene systems, making sophisticated biochemical pathways in natural cells.

• 10:18Regina Barber?

  Okay, so Kate, I was gonna ask you about that. That's more of the bottom-up approach. That's what was going on in 2010 when, like Drew just said, this group of scientists, they like quote "built a genome from scratch and used it to control a cell." Only the genome was synthetic, right? Like, how is "build a cell," your effort, different? And maybe even like improving on that research?

• 10:40Speaker 02

  The "build a cell" is different than the just the construction of a cell with synthetic genome, because there was a living recipient cell that was the recipient of that genome transplantation. So it wasn't building a cell from nonliving components. We learned a ton in the last decade, decade and a half now, about how molecules come together to drive those very basic processes of biology. So now we're finally starting to be able to conceptualize how we would go about not just making a synthetic genome, but booting up the whole thing from scratch. And that gives us this full operational control over every element of it.

• 11:20Regina Barber?

  Yeah.

• 11:20Speaker 03

  There's a subtle point in what Kate's describing that's central to building cells from scratch, which is we're not constrained to any one natural cell. So all of life on Earth in nature descends or derives from the life that's already here. That's lineage, right? We come from our parents and so on. If you're minimizing a natural cell, you're operating within the context of lineage. And if you wanted to understand it, you can take this top-down approach, as you say, which is to begin to remove pieces bit by bit and see if it's still alive. I think of it as whittling or sculpting a block of marble. You're removing everything that's not needed.

• 12:05Speaker 03

  When Kate's talking about building a cell from scratch, we are not subject to that constraint because she gets to choose every block of DNA that goes into that system.

• 12:17Regina Barber?

  And that's the bottom-up method.

• 12:19Speaker 03

  That's the bottom-up, exactly. The way I think about it metaphorically is, I imagine we're all part of this giant world called lineage land. And if we leave that continent or world, go to a new world, you know, we just get to build new things. And it's a very subtle mental shift.

• 12:37Regina Barber?

  Yeah, it makes me think of the Lego movie, of like the different lands. And like ones already built versus like if you just go to like an open area. Or like in Minecraft, where you go into somebody's like realm already that already exists versus like going to your realm where you can build something. Kate's like, yes.

• 12:55Speaker 02

  Yes, every time you build something, you're limiting the possibilities because you have to make choices. And biology has been making those choices for over 3 billion years. So we did reject a lot of possible alternatives. And we're now revisiting all those alternatives. That's the fascinating part of it is we can see what else can be done with biological parts.

• 13:18Regina Barber?

  So where is the field right now? Like, how close are you to creating synthetic life?

• 13:24Speaker 02

  It's very difficult for me to answer that because there is no good definition of life. But we're getting to the point where if it quacks like a cell, moves like a cell, then it's starting to be a cell-like entity. And that's where the field is. We don't have the complexity that approaches the natural biological cell, but we have systems that can perform all the functions of a cell.

• 13:48Speaker 03

  This is not something that's decades into the future. This is something that's a very active field making progress in real time.

• 13:55Regina Barber?

  Yeah. Last question. There are many scientists that are working towards this goal, including both of you. Why is building a cell from scratch so important?

• 14:06Speaker 02

  Building a cell from scratch is absolutely essential to realize the promise of bioengineering. When the field was started by Drew and others, they made huge promises. They said, "We'll be able to make things with biology. We'll be able to have this green economy." Those promises have to be realized. Because the way the world is going right now, we cannot keep running our economy on petrochemicals, on oil. We have to build more equitable economy. And we have to really understand biology on this very fundamental molecular level. And all those things will not happen unless we truly understand this very basic building block,

• 14:51Speaker 02

  which is a cell. And I believe we will not be able to understand a complex natural cell unless we can actually build it.

• 15:02Regina Barber?

  Kate, Drew, thank you so much for talking to me today about synthetic cells. I learned a lot. Thank you so much.

• 15:08Speaker 03

  Thanks for having us.

• 15:09Speaker 02

  Thank you. It was a pleasure.

• 15:13Regina Barber?

  Shortwavers, thank you for listening. And if you want to help us out, follow us on the NPR app or whatever other podcasting app you use. This episode was produced by Burley McCoy, edited by our showrunner Rebecca Ramirez, and fact-checked by Tyler Jones. The audio engineer was Jimmy Keely. Beth Donovan is our senior director, and Colin Campbell is our senior vice president of podcasting strategy. I'm Regina Barber. Thank you for listening to Short Wave from NPR.

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