A breakthrough in synthetic life

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1:21For months now, I've been doing a deep dive into the world of synthetic biology. Talking to researchers about some of the coolest and frankly weirdest science I've ever heard of. Getting down to the very essence of what makes life alive. Because all life is made of cells, but we don't really know how they work. Scientists can see what cells are made of, they can see what they do, but what actually makes them alive is still a mystery. My guest today, Kate Ademala, started thinking about building her own life from scratch, assembling all the bits and pieces of cells, so like DNA, proteins, ribosomes, membranes, and putting them together in just the right way to find that spark.

2:19Just this summer, Kate's lab at the University of Minnesota has been making major headlines after creating lab-made synthetic cells that can feed, that can grow and divide and even compete for resources. These spud cells, as they're called, they aren't quite alive. But other scientists that I've talked to, they've said that this research could be a seminal event in the history of biology. A meaningful step towards fully synthetic life.

3:09All right, Kate. Hi, thanks for having me. Of course, thanks for coming. I feel like we've been talking now for how many months? Almost over a year at this point, right? Yep. Yeah, you've had a really, really busy last few weeks. Could you tell me a little bit about the attention that your work has been getting? It's been very humbling that so many people are interested in what essentially is a foundational research work, I don't think I was born to be a movie star. So while I'm really grateful for people noticing it and paying attention, I will be very happy to crawl back to my cave and go back to work that I was actually trained to do.

3:50So we're doing our best. Could you generally describe what it is that you do? We're trying to teach life to do the things that natural biology never bothered doing. And that means we're trying to build cells that can perform reactions and that can be engineered in ways that natural cells, that cells as you know them, the natural biological cells, cannot do or don't know how to do. And the reason we're doing that is because we, as a civilization, need things, materials, drugs, chemicals that have to be made with biology, but current natural biology doesn't know how to do it. And that's been the driving force behind synthetic biology ever since the field got founded.

4:38And recently, we started realizing that we're running out of the ability to engineer natural cells, just because they come with a lot of evolutionary baggage. They come with constraints that were built in over the last almost 4 billion years of evolution. And so if you want to force that natural cell to make things that it's just not willing to do, you're better off just building cells from scratch. And that's what we're doing is we're building cells from non-chemical components so we can engineer them and convince them to make those things for us. So building cells from non-living parts. What does that mean?

5:19That means we're taking chemicals that are not alive. So just normal off-the-shelf chemicals, white powders, greasy liquids, all the stuff that you're used to from the chemistry lab. So we're taking those chemicals and we're putting them together in a very precise way into something that resembles a cell. And that thing we build from those non-living chemicals has more and more functions of life. it performs functions that up until very recently people only associated with life so for example it can feed it can divide it can grow but it's still the building blocks were non-living and that's the really crucial fundamental thing here because when you think about it there's no organism on earth that wouldn't come from this unbroken line of life for the last almost 4 billion years.

6:14So ever since life started on Earth, new life was only made by existing life, by dividing, giving birth to a new organism. What we're doing is we're breaking that cycle. We're taking chemicals and then we're putting that together into a cell that I still think our cell is not yet alive, but it's getting there. It's getting very close to the point of saying, this is alive. So you're building your own tree of life is the goal. More like grafting branches, but yes. Why cells? Why focus on building cells if you could, you know, I assume, make all sorts of stuff with these chemical ingredients? Cells are the best chemical factories in the world.

6:58There is nothing that can move atoms quite the way a cell does. It moves atoms with extreme precision. It takes CO2, sunlight, minerals and nutrients from the environment and turns them into whatever it needs, whatever it wants, different polymers, different chemicals. And that's actually how our entire civilization has been built. Everything around us is made by cells. It's just right now, most of it comes from dead cells. You know, petrochemicals, that's basically chemicals that come out of oil, which is dead cells. Right. And that has a lot of negative consequences for the planet, for the environment, for humans.

7:41We want to keep that principle going. It's not a bad idea to have cells make all the materials we need. We honestly don't have a better idea. But we want to do it in a way that is more sustainable, that will leave our kids a planet to live on. And so that's why we're making cells from scratch, because we want to make cells that will be willing to do what we need done. So we'll be willing to make all those chemicals, all the plastics, fertilizers, everything that our civilization needs. It's called fermentation. Many people are surprised when I call it fermentation because they think beer and bread.

8:16Right. Which is obviously, you know, these are the crown achievements of fermentation. I mean, it's hard to improve on the best of the best. It's definitely true. But you can ferment other things and produce things like plastics, chemicals, drugs. So that's the idea. That's why we need to engineer cells, because natural cells are just not going to do it. Why don't we teach cells how to make plastics from whatever grows in every climate, every environment? So, for example, why can't I take prairie grass? I live in the Midwest, so we've got a lot of prairie grass. Why can't I take that prairie grass and ferment it into a plastic toy?

8:56It's totally possible the atoms are there. We just right now don't have a living organism that would be willing and able to do that. And so that's the goal. That's the motivation behind what we're doing is we're making cells that will be able and willing and producing whatever you want, not just materials, but drugs and other substances like fertilizers, anything we need. Got it. So the idea is that life is a better chemist than we could ever dream to be. Way better chemist. And I say that as a trained chemist.

9:32how is that different than say like making special yeasts to produce insulin or other medicines it's exactly the same just taking it further um yeast like any natural cell they have the limits so we can teach them to make natural proteins for example insulin is a great example um we can teach them how to make a protein that biology already knows how to make obviously yeast don't make insulin, but we know that a biological cell can make insulin. And so we just teach another biological cell how to make the same thing that nature already figured out. With the things that we need to make to really run a full economy on biology, there are things that biology doesn't know how to make.

10:16And that's where the synthetic cells come in. And that's the biggest driving force behind what we're doing is let's teach biology how to do that. Let's teach biology how to take digestible biomass. That's just a fancy term for whatever grass you can ferment. So let's take whatever digestible biomass, whether it's grass, wood, whatever can grow, and let's turn it into whatever product we need for advanced economy. Wow. And in some of our previous conversations, you've told me that nature is boring, which I just find so funny. And I was wondering, could you explain to me how a sea slug is the same as like my 11th grade English teacher?

10:59They're exactly the same on the molecular level. If you grind them up and give me a slushie, unless I sequence their DNA, I would have a really hard time telling which tube contains your teacher and which tube contains a sea slug. Those chemicals are identical across the entire tree of life. All the organisms on earth use the same amino acids and it's only 20 of them, 20 or 22 anyway, it's a very small number. Small number of amino acids, only five nucleobases that build your DNA and RNA. So that's a really narrow set of building blocks. And we already know from in vitro experiments over the years that there are literally hundreds, if not thousands, of amino acids that can be incorporated into proteins.

11:47It's just nature doesn't bother using them. And so that's just one example of this expanding of the chemistry. There is so much more cool stuff we could do if we're not limited by this narrow mindedness of biology, by this. Obviously, I say that tongue in cheek. I work with a lot of biologists, so I don't want to piss all of them off. But I'm a chemist and biology just doesn't have that flexibility because it's limited in the amount of building blocks. Why does nature use such a limited chemical toolbox? Ah, that's a great mystery of nature. The genetic code is called a frozen accident. The reason we have those 20 amino acids that we do is probably just because once life figured out how to do most of the functions with the amino acids that it started using, then it just never was able to significantly expand that chemical diversity.

12:43Fascinating. But now you're looking to build your own tree of life and you're seeing a wider sandbox to play in, chemically speaking. That's exactly. And I not only want to expand it, but I also want to keep it flexible. It should be plug and play. And that flexibility is what I'm really after. It sounds like part of what's so important about this project is that you're trying to build cells, build this life that you'll be able to control, to understand. I guess, if you're trying to understand life, then why not just study biology, like study life in cells like they already exist? We've been trying that since the dawn of biology, basically.

13:27And despite this huge field with a lot of resources and a lot of smart people working on it, we still don't have a blueprint of any single living cell. There is not a single natural living cell for which we could have a full chemical ingredient list. So that's been sort of a, it's been a holy grail, but also people are starting to realize that that might not be achievable to get a full ingredient list of a natural living cell just because they're so insanely complex. So people like me coming not from biology, coming from the physics, from the chemistry background, we're just kind of cheating. We're saying we cannot understand an existing living cell.

14:09So why don't we just go build our own? And what we're building, we can actually know what we're putting in there. So we have this ingredient list. And there is another extremely overused quote from a physicist, but I really love it because it very well encompasses what our field is about. Richard Feynman said, what I cannot build, I cannot understand. And that's, to me, is like the exact essence of what we're trying to do. unless we can build a living cell, we'll never be able to fully say we understand what life is. So what does building life actually look like? That's after the break.

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17:41What are cells anyway? Cells are the building blocks of life, Wanda. All living things are made of cells, and that includes you. So we've been in the dream of synthetic biology. Take me more to the day-to-day level. Tell me about your lab. What is a day in the life of making life? Day in the life is that you get to sleep as long as you want. Scientists usually start really late. We're a basic molecular biology biochemistry lab. Most of the things we do is exciting on the conceptual level But if you actually came to watch my students, they're piping clear liquids from one tube to another. And it's not like flashy every day.

18:28It's research. It's very tedious, very complex biochemical research. And the fact that people get excited about the results of it, that's magic to me. I'm really grateful that people pay attention, people appreciate it, and we get to talk about it. That's amazing. How long have you been working on this goal towards building life from scratch? It's been a dream ever since I started my lab. This project particularly, I think, started, it's hard to say exactly when this project started because it kind of builds on other work we've been doing. But about five, six years is as long as I can trace back the first experiments in this project.

19:11Yeah, and it sounds like this in particular, it's a game of inches and like slow and steady progress. Millimeters, we're scientists here. Oh, of course. I'm sorry. All right. So all those millimeters adding up. What is the big research that you shared with the public this summer? We showed how to make a cell that's made of chemical components. So those dead chemicals off the shelf. and that cell can feed, it can grow and it can divide. And that's a first because cells, people have been making cells from dead chemicals for a long time now, for a long time as in like a decade or maybe even longer.

19:54But they never were able to realize those key functions of life. So synthetic cells were never before able to grow grow and replicate based on their own instructions. So this is not growth that I direct. It's not because before what we could do is we could make a synthetic cell and artificially grow it. So like I could make it grow by adding things to it. Those cells that we just made, the spud cells, they grow because they feel like it. They grow because they express proteins inside them that tell them to grow, that induce growth. And same with division. The division is depending entirely on the cell cycle, on the activity of the cell itself.

20:42But it's still a fully chemical system. It's controllable because we know exactly what it's made of. Okay. So it can grow, it can eat, you said? Yes. And it can divide. Are they alive? I don't think they're alive because even though they do all those functions that we think only life does, they're not doing any of it very well. They have to be fed pretty much every building block that they need to make stuff. You know, life needs to be scrappy. Life needs to figure out how to survive. And the cells that we made, even though, you know, on the surface level, they look like they do fulfill the functions of life.

21:25They don't have any. There is no slack there. There is no robustness in there. If the conditions are not absolutely perfect, they will just stop. Got it. There's no ability to improvise or use, you know, new environments or new materials. Yes. And, you know, I just want to, for the sake of being perfectly accurate, I have to say that no one can say whether it's alive or not because we don't have a good definition of life. So that's why I'm saying my gut feeling is that it is not alive. This seems like it should be a simple question, but from our conversation, I get the sense that maybe it's a little bit more complicated than it seems.

22:07What is life? That's a very good question. And I think the best answer I can give is a quote from U.S. Supreme Court Justice Potter Stewart. He said, I will know it when I see it. And that really, it's not a scientific definition, but there is no good scientific definition of life. No. There is a NASA definition of life that NASA has been using when they look for life in the universe. And that definition says self-replicating chemical system that's capable of the Union evolution. And according to the NASA definition of life, you're dead and I'm dead because I'm not self-replicating. If for me to replicate, I need my husband.

22:48So that just shows you that definitions of life are very inaccurate, very context dependent. There's just not good definition of life that would cover everything that we instinctively consider alive and exclude everything that we would all agree is not alive. Which is why I say there's not a good definition, really, because everyone defines life according to some different principles. Right, right. These cells, you've called them spud cells, right? Why call them spud cells? Because we want to invoke Sputnik. It was the first artificial satellite. And even though Sputnik as a satellite was a pretty bad satellite, it didn't really do any of the things that fancy modern satellites do.

23:34It was an artificial satellite on Earth orbit. And that basically opened up a space age. It showed people that it's possible to escape the gravity well. If we can put a satellite on orbit, maybe we can put people in orbit. And if we can put people in orbit, maybe we can just escape orbit, go to the moon, go past the moon. It basically showed what's possible. It opened up space age. And that's where I see the role of a spud cell. Yeah, yeah. Almost like a proof of concept, it sounds like. Exactly. That is a proof of concept that you can put together chemicals into a cell. By itself, it's not a really good organism, but it hopefully will show people that you can put together chemicals into something that can grow, divide, can undergo selection.

24:22And that opens up this age of biology to me. How do these spud cells do all of those things differently than a natural cell? Yeah, the process of eating is very similar to how bacteria and other simple cells eat. So the way cells, a lot of bacteria cells, when they see something edible that's pretty big, they will just kind of like take it in. And that's what spad cell does. Sort of like two soap bubbles joining together. Exactly. Two soap bubbles. One of them is bigger, one of them is smaller, and they join together and the smaller one brings in the food. The division, though, that's a different story.

25:05The division is actually very different than how natural cells divide. if the spud cell has enough proteins on a membrane that the cell makes itself. So that's why it's genetically encoded, because the genome of the cell directs making those proteins. And if there's enough proteins on a membrane, the cell starts dividing. And that's very different than how natural cells do division. Yeah. I know you said that these spud cells, in your opinion, are not alive, but does it feel like you've reached a milestone with this project? Definitely. It's a huge milestone because it shows us it's possible. You know, me and my colleagues in the field, we always believed that it's possible.

25:48But a lot of hardcore biologists would look at us and politely pat us on the head and move on and say, yeah, I keep dreaming. Like people genuinely didn't believe that something as magical as life, as a living cell, as a cell at all, can be put together from non-chemical components. It just seems almost like a heresy to some people. And so now we've shown that it's possible to do it. There's nothing magical about life as a phenomena. You can just put together molecules and they'll start doing what needs to be done. And that's definitely a huge milestone because it just opens up this possibility of truly engineering life.

26:28That's just the beginning of work, really. We've shown it's possible. Now we're going to spend the next 50 years making it actually useful. Because I think I strongly believe that this utopia bioeconomy that I was talking about, that's not just a pipe dream. I really think that in some way or form we can see that happen within our lifetimes. But it's not going to happen on its own. It needs a ton of work to get to that point. And so now that the real work really begins. Yeah. How far can you take this technology? Like what are the next steps to get between what you have now as spud cells and the dream bioeconomy utopia?

27:13First, we have to teach spud cells to do a lot of things that will make them more robust, that will make them stronger. So that's priority number one. We also need to, and that's something a lot of scientists don't think about. I wasn't thinking about it before, but we need to make sure that this technology is used in the right way. We have to make sure that it remains used for good, that nobody misuses it for some nefarious purpose. And we have to make sure that the benefits are accessible to everyone who wants to access them and who's able to access them, who has the capacity to work on it. And these are new things to me because I never had to figure stuff like that out.

27:51Right. And spud cell kind of brings it into the realm of this being a concrete possibility, not just sort of some abstract theory. Yes, it puts a clock on it because now it's really doable. I don't just have to say, trust me, we can do it eventually. We've actually done it. So now the safeguarding is not just an abstract problem. We actually have something to safeguard and that's what we're doing. Yeah. Do you feel a responsibility for where other scientists may take this technology in the future? Oh, absolutely. I mean, if you tame it, you're responsible for it. I definitely do feel a lot of anxiety about where people can take it.

28:38And I do a lot of work to both on a policy side and on the actual bench side to prevent the misuse. So we're building technologies into the spud cell that will make misusing it much more difficult. And I also work on the policy side to make sure that this is regulated, that everyone who works on it has to follow certain rules, not just because they feel like it, but because it's actually a law. Right. When you talk about misuse, what would that look like with a spud cell? Like with every biological technology, you could, if you have a cell that can be engineered to do whatever you want, you could imagine engineering it in a way that it makes something harmful.