About a month ago, chemists made a synthetic cell capable of eating, growing, and dividing for at least five generations. They called it SpudCell, and the lead author, Kate Adamala of the University of Minnesota, thinks it might be able to reproduce perpetually by 2030; a feat that, she argues, would finally make SpudCell “alive.”
I flew to Minnesota and interviewed Adamala for about three hours. First, I wanted to understand the bottlenecks with SpudCell. What engineering changes will they make to get it to reproduce continuously?
Second, Adamala is one of the leading opponents of creating mirror life, a program funded in part by Coefficient Giving through the Mirror Biology Dialogues Fund. I pushed her on the idea that SpudCell, or the ability to create life from the bottom up, could uniquely enable the creation of mirror life. I wanted to understand how we avoid that.
The third part of our interview was about understanding the point of making synthetic life. SpudCell, as you’ll hear, is nothing like cells on Earth today. I think it stretches the imagination to claim that making these cells teaches us much about biology. It’s more of an exercise in hacking biology to get the outcomes we want! I wanted to understand why that matters, and Adamala had some really good responses about how SpudCell could expand life’s chemistry, enable us to make new types of medicines, and help biologize the economy.
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Timestamps
(00:00:00) – Opening
(00:00:52) – SpudCell is not alive
(00:05:16) – How SpudCell works
(00:13:14) – Recycling as a major bottleneck
(00:19:24) – Genome inheritance and cell division
(00:34:19) – Bottom-up vs. top-down cells
(00:40:38) – What synthetic cells could be used for
(00:46:29) – Evolution and complexity of synthetic cells
(00:54:51) – Why Kate changed her mind about mirror life
(01:01:27) – Why life evolved a single handedness
(01:05:12) – SpudCell as an enabler for mirrored life
(01:14:38) – Biotic
(01:21:58) – China and 2050 goals
Transcript
00:00 — Opening
Kate Adamala (00:00) Life as a phenomenon is probably very easy, given how quickly it started on Earth. Many people were saying that even making growing, replicating cells from chemicals is impossible, that you need some mystery spark of life. And we just did it. We put together molecules, and they’re growing and replicating. There’s nothing magical to me in how molecules make themselves into life if you give them enough time and the right conditions.
Niko McCarty (00:25) I flew all the way to the University of Minnesota to interview Kate Adamala, whose group, about a month ago, published the first synthetic cell that eats, grows, and divides, built purely using molecules that the scientists put there. In this interview, I want to know not only how they built Spud Cell, as it’s called, but also what it’s good for. Kate, welcome.
Kate Adamala (00:51) Thanks for having me.
00:52 — SpudCell is not alive
Niko McCarty (00:52) My first question is: Very few science stories go viral like Spud Cell did. There wasn’t one New York Times article. There were three. I’m wondering what that’s like. In that first week, what did you make of it? Did you expect this would get as much attention as it did?
Kate Adamala (01:12) I definitely didn’t expect as much attention. It was very humbling that something we’ve done generates so much attention, most of it positive. That was very surprising, but also very happy-making. It was amazing to be able to talk about it. I always want to talk about my work, and it’s really interesting to find so many different people wanting to talk about it because it makes me think about it in different ways, from different perspectives. It was definitely weird.
Niko McCarty (01:46) What were some of the weird things that happened?
Kate Adamala (01:48) There wasn’t a single weird thing. Most of my life is pretty quiet; it’s the normal work of a scientist. Then suddenly, most of your day is taking calls and doing interviews, and that’s not the job I signed up for. That was definitely a new experience.
Niko McCarty (02:08) When these journalists came, you told everybody that this thing is not alive, right? It’s a synthetic cell that eats, grows, and divides, but it stops dividing after about five generations. You were tamping down on the hype that other people were writing about. What would be required for you to say this thing is actually alive—at the risk of upsetting other scientists, probably?
Kate Adamala (02:41) It has to keep going. It’s that simple to me. Life, to me, is defined by its robustness, by its ability to keep going—like the famous quote from Jurassic Park: “Life finds a way.” A Spud Cell could not find its way out of a straight tube. It’s just not robust. It’s capable of undergoing all those processes that we normally associate with life, but not continuously, constantly.
To declare this alive, it needs to be able to keep going, keep replicating as long as there are resources. I cannot say indefinitely because no life replicates indefinitely, but with an abundance of resources and no limiting factors like pH or the size of the vessel, it should keep replicating. The Spud Cell cannot do that right now.
Niko McCarty (03:32) What makes you confident that we can engineer robustness when the robustness of the natural world seems to have been emergently shaped over long timescales by evolution, which is pulling on many levers at once in this very multiplex, combinatorial fashion? Doesn’t it seem impossible that we could engineer robustness that matches evolution?
Kate Adamala (03:55) That might be the pride and overconfidence of a scientist, but I think we can do it. When I first started in this field, many people were saying that even making growing, replicating cells from chemicals is impossible, that you need some mystery spark of life, some mystery component we don’t understand. And we just did it. We put together molecules, and they’re growing and replicating.
Niko McCarty (04:16) Wait, you’re saying people believed in vitalism when you—
Kate Adamala (04:20) Totally. There are many biologists who think there’s something unique about biological life, that there’s some life force—who knows what—that is impossible to replicate in the lab. I always thought that it’s chemicals. Chemicals are doing it, so we can put together chemicals in the right way. Until I’m proven wrong, I’ll keep believing that robustness is also possible to engineer.
Niko McCarty (04:45) To clarify, you think, theoretically, it is possible to build a synthetic cell that is as robust as a natural cell if we just hit on the right combination?
Kate Adamala (04:56) Yes, I think so.
Niko McCarty (04:57) You see it as a big search problem in chemical space.
Kate Adamala (05:01) A huge combinatorial chemical problem, which makes it fun. But yes, I think we totally can. I don’t think there’s anything special about natural life in terms of its ability to solve problems and adapt to different environments.
05:16 — How SpudCell works
Niko McCarty (05:16) How long did it take you to make Spud Cell once you decided, “We’re going to try to put these components together and make a dividing organism”?
Kate Adamala (05:25) It was a trial-and-error process. This particular project’s been going on for about five years in my lab. We had a lot of ideas that failed, a lot of ideas that sort of worked and led us to other ideas, until eventually one of them worked. It wasn’t that one day I woke up, wrote up a plan, and we went and did it. It was all failed experiments that informed the next round of also-failed experiments, and so on until something started working. It was more of a Roomba-on-the-floor process. We didn’t go in a straight line; we just browsed.
Niko McCarty (05:59) What is Spud Cell? What are its key components, and how do they work together to give rise to this thing?
Kate Adamala (06:06) Spud Cell is a phospholipid liposome, so it has a membrane just like most natural cells. That membrane is very simple. It’s a two-component membrane. But we do know of a living cell that has a two-component membrane and can live fine with that. It’s not totally crazy; it’s not too simple.
Inside that membrane, we have a genome. That genome is 90 kilobase pairs. It’s tiny by natural cell standards. It’s encoded on several different plasmids, so it’s a multipartite genome. That genome gets replicated by a rolling-circle viral polymerase. We make copies of the genome inside the Spud Cell.
That genome expresses proteins. We have ribosomes, tRNA, all the enzymes that charge tRNAs, all the amino acids, all the small molecules. We have transcription and translation.
That translation produces proteins. One of the proteins it produces is, I think, my favorite protein in the whole world: alpha-hemolysin. It’s a bacterial toxin that creates a pore in the membrane. It’s a very dumb pore. It’s not a gated channel; it’s just a hole in the membrane. But the beauty of it is that it self-assembles. Because we make that alpha-hemolysin, we can have Spud Cells take up nutrients from the media by a concentration gradient and remove waste from the inside of the cell, again by diffusion.
The really cool thing is that alpha-hemolysin is pretty permissive to modifications. We’ve modified it by putting a small domain on one part of it that presents itself on a membrane. That domain is our feeding tag. It recruits feeder liposomes. The Spud Cell is a perfect heterotroph. It makes nothing; it doesn’t biosynthesize anything.
Obviously, then you run into the problem of how you add lipids, how you grow, how you make new ribosomes. We don’t. We feed it all. That membrane protein presents a tag on the membrane that attracts feeder liposomes. Those feeder liposomes bring in ribosomes, tRNA, and other nutrients that are too big to get in through the pore. They also bring lipids. Spud Cell does not make its own lipids; it has to eat all the lipids. Those lipids come in from feeder liposomes.
The beauty of the system is that, because the feeding happens as a result of that protein being displayed on the surface of the cell, and the protein is encoded by the genome, if the genome encodes for strong expression of that protein, the cell will grow faster because it’s going to have more of that feeder protein on the surface. If that feeder protein is encoded at lower levels, the cell is going to grow slower.
Then comes division, which is also induced by a tag—a different tag—on the surface of the membrane protein. We have two populations of those membrane proteins. One is for feeding; one is for division. That division, because it’s dependent on a membrane protein tag, depends on how much of that membrane protein you make. If you encode that division protein at higher levels, the cell can divide into more daughter cells.
It’s always daughter cells. They never talk about son cells in the literature, so we talk about daughter cells too. We always make those daughter cells, and the number of them depends on how much of the protein you make. That couples the genotype of the cell to the phenotype, which means how big they grow, how much they can eat, and how much offspring they can produce. That’s it. That’s all there is in a Spud Cell. It’s the simplest possible metabolism.
Niko McCarty (09:50) There’s a lot to unpack there. My first question is: Inside this lipid bubble you’ve made, you’re surrounding something called the PURE system. This is more than 20 years old. In the early 2000s, this Japanese—2001.
Kate Adamala (10:10) I think.
Niko McCarty (10:12) This Japanese team showed that they could reconstitute transcription and translation in a test tube. They figured out all the proteins and cofactors responsible, put those into a mixture, and they sell that mixture. You can buy it online. It’s called the PURE system.
It doesn’t seem so crazy to me to go from that to shrouding PURE in a lipid bubble and adding a few things. You’ve added a couple of clever proteins like alpha-hemolysin and these tags. I know progress takes a long time. I’m not poo-pooing progress, but why did it take 25 years for someone to get this to work if we already had some of the key components for a very long time?
Kate Adamala (10:58) I think part of the reason is that the description I just gave you was very simplified. For example, we’re not using the PURE system—the God-given, original PURE system. We’re using a heavily modified PURE system to make it compatible. It turns out that if you’re trying to replicate a genome and express proteins from that genome at the same time, you really need two different buffer compositions. To make it work in one pot, you’ve got to do a lot of optimization. Some people have already done some of that optimization, but we’re building on that.
Then the yields of expression from different parts of the genome have to be fine-tuned for this to work. There are a lot of annoying details that we give you now as, “This is the concentration to use.” But it took forever and many curse words to figure out what those actual conditions are.
Niko McCarty (11:54) But those things need different conditions. If different buffers are required for genome replication and protein expression, how do bacterial cells do both of those things in the same cell?
Kate Adamala (12:07) They do it in a smarter way than we do. They compartmentalize everything.
Niko McCarty (12:12) But this genome is just sitting there in the cytoplasm.
Kate Adamala (12:14) Most people don’t realize that even bacterial cytoplasm is very compartmentalized. It’s not a freely mixing bag or an aqueous bag. It’s something called deep eutectic, which means it’s not really a freely miscible water solution. It’s very, very dense—almost gel-like.
Water activity in a cytoplasm is pretty low. In theory, it is an aqueous solution, but really, everything has its place. Everything is stuck in different phases; everything has its own environment to be in. We did figure it out eventually—the Spud Cell does use one buffer—but it took a lot of figuring out.
When people originally started doing genome replication and then started doing translation, they thought, “We need different buffers.” But through a lot of trial and error—a lot of error—you finally found out that it’s possible to find one condition under which all of this works. It just took forever.
13:14 — Recycling as a major bottleneck
Niko McCarty (13:14) You went through the components. I think one way to understand how these components work is to start thinking about bottlenecks. I often like to think about problems as troubleshooting, and in troubleshooting something, I learn about the components. Why do you think Spud Cell stops dividing after five divisions? It sounds like it’s many problems.
Kate Adamala (13:41) To me, it’s one problem. Just to be clear, we published the five generations as a stopping point because that’s when we decided, “Okay, we’re going to characterize the hell out of it.” It can go on for a few more, but the yields go down significantly. It’s not like it goes for five generations and then drops down and stops completely. You could get a couple more cycles out of it, but the yields would keep dropping precipitously after each step.
I think the biggest problem is that a Spud Cell does not break anything down. It makes proteins and mRNA, but it doesn’t have degradation pathways other than chemical hydrolysis. You keep accumulating trash: ribosomes that lose activity eventually, tRNAs that get broken one way or another because there’s some chemical hydrolysis error in them. There is nothing to recycle them, nothing to break them down and put those monomers back into circulation.
In a given volume of cytoplasm, with each increasing generation, you have more and more waste—freeloading passengers that sit there and do nothing. That decreases the yield per volume. That’s why I think the biggest bottleneck in a Spud Cell right now is ribogenesis: making new ribosomes. And part of ribogenesis—there’s no good word for it—is “ribo breakdown,” breaking down nonfunctional parts, including ribosomes. Taking out the trash and making new parts. This is a huge bottleneck that I think, once it’s solved, will let it keep going.
Niko McCarty (15:23) This is maybe a foolish question, but instead of breaking things down and recycling them, at least in the early part, wouldn’t it be easier to tag proteins somehow so they sequester on one side of the cell, and then you bleb the waste away every couple of generations? You take out that part, because you’re feeding in new parts all the time.
How do you plan to implement this? How difficult is it to get rid of waste versus recycling broken proteins, which seems harder than just getting rid of waste?
Kate Adamala (15:57) Both breaking down waste and getting the waste out in a little bleb have the same problem: How do you recognize waste? How do you recognize that this particular ribosome has been sitting around and doing nothing for the last two hours? It’s a really big problem that, in natural biology, takes a lot of time and money to solve. There are a lot of chaperones, a lot of proteins that do this quality control all the time. We don’t have any of that in a Spud Cell.
The biggest bottleneck is: How do you figure out who’s the waste and who’s still a productive member of society? I don’t have good ideas right now to solve it. I have some stupid ideas that we might be testing, but I don’t have anything that I know works. That’s definitely the biggest problem.
It’s really easy to break down proteins and RNA. There are nucleases and proteases that I can tag and direct to a specific target. Once I know what the target is, I can break that target down pretty cleanly. But I don’t know what the target is. That’s the problem.
Niko McCarty (17:05) Are you saying that the problem is a lack of basic understanding of biology? Why can’t we just take the known components that do this in cells? What happens when you try to put those into Spud Cells?
Kate Adamala (17:17) There are too many of them. Biology has too many steps. If you start trying to reconstitute all of the natural proofreading processes, you end up with a hugely bloated metabolism, which we’re trying to avoid here. My goal is to try to hack it, like we’ve done with all the other processes—to simplify it. That’s really difficult. That’s turning out to be a huge bottleneck.
Niko McCarty (17:42) But if evolution did not hit on a minimal solution to recycling waste, what makes you confident that you can hit on a minimal solution to recycle that waste?
Kate Adamala (17:52) So far, we got lucky with other things. Our genome replication system is one protein, and cells use huge protein complexes that allow for a lot more regulation but are also much more complex. Same with growth, same with replication. So far, we’ve managed to hack every one of those processes. I think waste removal is also hackable.
Again, that’s my belief. That’s not a fact, because we haven’t done it yet. But I do believe we’ll be able to find a simple way to identify waste. We just need to find it.
Niko McCarty (18:29) It almost feels like if you keep finding hacky solutions, which is possible in principle, you might arrive at a solution in the end that is not robust. It only works in the lab, and then it has none of the applications that the news media was reporting.
Kate Adamala (18:43) Yes. That’s the biggest challenge right now: The solutions we’re looking for cannot just be a one-off trick that works under very specific conditions. They have to be generalizable. That is the biggest challenge. You just identified that it’s not just the challenge of how to make ribosomes or how to break them down. It’s a challenge of how to do that repeatedly under various different conditions.
Niko McCarty (19:09) Seems like a very hard problem.
Kate Adamala (19:11) It’s a hard problem, but so far, every hard problem we’ve encountered that seemed super hard, we managed to solve one way or another. I wouldn’t be doing it if I didn’t believe it’s solvable.
19:24 — Genome inheritance and cell division
Niko McCarty (19:24) You mentioned that one big bottleneck is recycling or getting waste out because it accumulates with each division. Another problem you write about in the preprint is that you have this 90-kilobase-pair genome. It’s partitioned across many different plasmids or minichromosomes—I’m not sure what you’re calling them. Every time Spud Cell divides, they randomly segregate. There’s some probability during each generation that the daughter cell did not inherit the full genome. How big a bottleneck is that, and how are you thinking about solving that problem?
Kate Adamala (20:02) That’s a very easy problem to solve. The only reason it’s partitioned into small plasmids right now is for ease of working with it, because we were trying to figure out what genes are necessary. Adding and removing genes is much simpler when it’s a plasmid that you can normally clone in bacteria.
There is a way to make a megaplasmid, basically the thing that John Glass does for his mycoplasma-based cells. We already know how to encapsulate the megaplasmid in a liposome. Once we’ve settled on, “This is the genome that I want to persist,” we can put it all on a megaplasmid. I cannot say it’s trivial, because it’s still a technical project to do it, but we know how to do it.
The thing is, those megaplasmids are technically difficult to work with. You need to clone them in yeast. You cannot just amplify them in bacteria like any normal plasmid. That’s why we were using the multipartite genome at the optimization stage: I can clone a new gene or mutate that gene within a day. With a megaplasmid, it is about two weeks to make the whole thing. That’s purely a technical difficulty. That’s not a scientific problem that I don’t know how to solve.
Niko McCarty (21:15) As you add components to Spud Cell to make it more robust or to recycle waste, the genome will get bigger and bigger.
Kate Adamala (21:21) Yes.
Niko McCarty (21:22) Do you have any sense of how big the genome will be at the end of the—
Kate Adamala (21:29) I do, actually, thanks to George Church and Tony Forster. A few years ago, they published a paper where they speculated about the minimal size of an independently living, autonomous cell built from scratch, with the PURE system as an assumption. They speculated that about 120 kilobase pairs is going to be the size. It’s a very well-written paper. They reason through each function and how many genes would be assigned to each function. It all makes sense to me, so I agree with that.
Niko McCarty (22:03) When they wrote that paper, which I’ll link in the video description, they presumably were not thinking about all these hacky workarounds you’re finding. They couldn’t have assumed that the solution to cell division was to express alpha-hemolysin with a tag. They were probably making that genome size assumption based on existing biology.
Kate Adamala (22:26) It’s an upper boundary.
Niko McCarty (22:28) You see it as an upper boundary. You’re already at 90 kb. The upper boundary is 120.
Kate Adamala (22:34) We’re at 90 kb right now. The size of the genome is mostly driven by the fact that it’s eight different plasmids. Each of those plasmids brings its own junk—all the parts a plasmid needs to be a plasmid: the antibiotic resistance, the bacterial origin of replication. The actual protein-coding part of that plasmid is usually about a quarter of the plasmid itself. Once you put them all onto one plasmid, that is going to become much smaller.
Niko McCarty (23:04) How big?
Kate Adamala (23:05) About half the size. The megaplasmid that encodes all the genes we now have in a Spud Cell is going to be about 40 to 45 kbp.
Niko McCarty (23:15) Assuming you can put these onto a single megaplasmid, get that into Spud Cell, and it continues to work as expected—going back to this idea of robustness—now you have a single megaplasmid that you need to partition during division. That means you need to express many copies if it’s randomly segregating. If you only have two copies, there’s a very high probability that one daughter doesn’t get a copy. Even with four or five copies, you’re going to suffer the perils of noise in random division. You might need to express lots of copies, but then that throws off the energy balance and all these other balances.
Kate Adamala (24:00) Which is why random partitioning is not going to fly. I want a cytoskeleton. I want a very simple cytoskeleton. There’s already been great work from people like Petra Schwille and Marileen Dogterom that demonstrated that an actin-based cytoskeleton can be constructed inside a liposome. I want to anchor my plasmid somehow and then partition it into daughter cells in a more controlled way.
Niko McCarty (24:31) Can you say anything else? How do you think this is going to work?
Kate Adamala (24:36) We can have a plasmid with a DNA sequence that’s recognized by a DNA-binding protein, and then have some sort of tendril of actin, which we already know can be formed inside synthetic cells. That tendril of actin can go into the membrane. It doesn’t have to be perfect. You don’t have to have poles like in a natural cell. You just have to have two or three of those tendrils that go somewhere into the membrane.
The most likely scenario, just geometrically, is that they’re going to be going in opposite directions because of steric hindrance. When a cell starts dividing, they’re going to pull apart, and they might influence the geometry of the segregation. It won’t be perfect, but it’s going to be much better than this smoothie we have right now, where things partition randomly.
Niko McCarty (25:25) That’s also related to cell division. The solution you hit on for cell division is very strange. It’s really not how cells divide at all. It’s bulky crowding of proteins that repel each other and lead to a sort of schism. One thing I noticed in the preprint is that you have these proteins sticking out of your cell, and these proteins are grabbing onto the bulky molecules that cause cell division. My understanding is that that interaction is permanent.
Kate Adamala (25:59) It is. Like every interaction, it has a k-on and k-off, but it’s pretty tight binding.
Niko McCarty (26:06) What that means is that after the first division, the daughter cells already have these proteins attached to them. Does this make them divide faster? By the time you get to the fifth generation, is the cell just studded with all these things and completely incapable of dividing for that reason? How do you get them off?
Kate Adamala (26:25) These are two independent problems we’re looking at. We’re looking at one of those problems, the persistence of the bulkiness, with a modeling collaborator.
This division process is pretty well characterized. People act like this is the first time they hear about it, but it’s been really well characterized by Reinhard Lipowsky and others working on it for over a decade now. It was never genetically encoded before, but as a physicochemical process, they’ve done quite a bit of membrane dynamics to figure out how it works. There are some models of it. We’re following those models now to see how many of them there are and how that affects the daughter cell’s geometry.
There are two competing theories. One is that it makes it harder for them to divide because the new alpha-hemolysin is being made and the membrane’s already crowded, so it’s harder to go in. But then you also are possibly pre-poised to divide because you’re already coming in with a lot of those bulky proteins. One or both might be true.
That also circles back to this huge problem we have, which is waste removal. Ideally, I would love to start each generation with a clean slate. I would love to find a way to recycle those alpha-hemolysin proteins: have some sort of protease that goes into the membrane and either cuts the FLAG tag that holds that bulky protein or cuts the whole thing away. Right now, we don’t have that. That’s definitely limiting the number of generations.
When we want to get to a higher number of generations, we have to solve that problem. We have to find a way to either completely remove those proteins or at least limit their number at each generation. It’s one of the problems we’re still working on.
Niko McCarty (28:15) With Spud Cell, you have waste accumulating inside the cell because ribosomes and tRNA stop working. You have waste accumulating outside the cell, which is all these proteins that have bound to Spud Cell. Are those two completely different recycling problems?
Kate Adamala (28:32) I don’t think so. The membrane problem is obviously a little more complicated because of the presence of the membrane. You have to figure out a way for this protease to poke its head up above the membrane to be able to cleave it. But the general problem is the same: How do you recognize what’s waste?
I’ve been thinking of scenarios like, what if, between each generation, you just hydrolyze all of your hydrocarbons? Would that be possible? Then start from scratch. That’s obviously resource-intensive. I don’t have a good solution yet. That’s one of the problems we’re working on. But to me, it definitely will not be continuously capable of division, so it won’t be able to claim aliveness until we solve that problem.
Niko McCarty (29:24) Energy intensiveness doesn’t matter, right? You just want one of these things to keep dividing. Theoretically, you can supply infinite energy for a Spud Cell.
Kate Adamala (29:35) Right now, yes, because it’s in the lab. But eventually, we do want applications for it. They cannot be hungry little caterpillars all the time. They have to find a way to metabolize things and make their own energy.
Niko McCarty (29:48) Natural bacteria divide using things like contractile rings, where they express proteins that form rings toward the middle of the cell, and the rings pinch down and cleave it in two. That system has been so well—
Kate Adamala (30:03) Yes.
Niko McCarty (30:04) Right? Every microbiology department in the US has somebody who studies bacterial division. But earlier in this interview, you said that you didn’t even try that. From the beginning, you were using this bulky alpha-hemolysin approach, which is so unnatural. Why did you not try the contractile ring?
Kate Adamala (30:24) That’s because a contractile ring has been an obvious choice for synthetic cell division, and other people, better microbiologists than me, tried already. There are a few labs that have been trying to build a protein-based division system for—not forever, but a very long time—and they still haven’t succeeded.
To me, that was, “I’m not going to compete with the people who have been doing it since I was in undergrad, and they still haven’t figured it out. I’m not smarter than them. I’m not going to figure it out where they failed.” I still don’t think it’s a lost cause. I think there is a way to figure it out. We just need more work on it.
Niko McCarty (30:59) When you say they have not succeeded, I’ve seen papers where people get liposomes to divide.
Kate Adamala (31:05) Not by genetically encoding the division. That’s the key. There are many ways to make a liposome divide, including protein-induced division. But to me, the key is that you have to couple phenotype to genotype. You have to genetically encode what makes you grow and divide, because otherwise you don’t have the selection pressure; you don’t really undergo a full cell cycle.
At the beginning, you asked why Spud Cell achieved what others couldn’t. People have made liposomes grow and divide before, but we’re the first who actually made it happen as a result of the metabolic activity of the cell itself. It’s the same with the protein-based division systems. People have made the blebbing work, but not as a result of internal protein expression.
Niko McCarty (31:57) It’s a fine line, though, right? You’re providing a genome, but you’re also providing tons of nutrients and everything else.
Kate Adamala (32:04) Wait.
Niko McCarty (32:05) It’s kind of like moving the goalposts.
Kate Adamala (32:07) Totally. That’s why I don’t know what alive means. On one hand, I don’t think it’s alive because it doesn’t keep going, and I have to provide everything, including ribosomes. But then every life form needs something provided to it. There is no life form that’s going to completely live on its own.
Even if you have, for example, HeLa cells in a dish, they’re alive. No one questions that. But if you forget to come on a Saturday to passage them, on Monday they’re going to be dead because you didn’t provide for them. Life always needs to be provided for. That’s why I don’t have a good definition of the limit of what we should provide.
Niko McCarty (32:50) Going back to the contractile ring and people who have been trying to make cells that divide with the contractile approach, that system is so well studied. As someone who has looked at that field—you might caveat and say, “I’m not an expert”—why do you think that’s not working? Is this a problem of unknown unknowns? Are there other factors involved that we don’t know about? What is it? Why is it so difficult to get this to work?
Kate Adamala (33:25) Obligatory: I’m not an expert. I think the protein cytoskeleton is very close to working. I don’t think it’s an unknown-unknown problem. I think it’s an engineering problem, a stoichiometry problem. Some other groups, for example Cees Dekker, have shown that they are getting really close to totally autonomous, multiple cycles of blebbing. It’s just pushing it through this final finish line.
That’s why, when people ask me what’s the future of Spud Cells and whether they’re going to be dividing by this protein crowding model, I keep saying, “I don’t think so.” I think in the next-generation tater tot cells, we’re going to be able to replace this protein crowding system with something better, some actin-cytoskeleton-based division. I think we’re really close.
34:19 — Bottom-up vs. top-down cells
Niko McCarty (34:19) What would falsify this program for you? Your goal is to get continuous divisions. Let’s say it’s 2030, and it’s still only seven divisions. Would you ever admit defeat and say, “Actually, maybe it’s not possible to create a synthetic cell that divides in perpetuity”?
Kate Adamala (34:46) Two answers to that. One is that I think we’re going to have a perpetually dividing cell by 2030, because we already have a cell that can grow and divide, and now we can have more selection pressure on it.
But if we get to a few years from now—and not just me; I’m not the only lab working on it, there are other labs working on this technology—and we all fail as a field, then that means there is an unknown unknown. There’s something about a living cell. At that point, I would say the bottom-up approach has not proven viable, and we should focus on the top-down approach, the Craig Venter approach, the minimal cell approach.
That cell is growing and dividing. We still don’t understand it fully. But that’s more of a tractable engineering problem because that’s a limited set of components, and we just need to figure out what they are. I hope we don’t get there, but if we do, and if it really looks like we can’t hack it from the bottom up, then I would switch to putting all the resources into the top-down approach.
Niko McCarty (35:53) What else needs to be done in the top-down approach? I haven’t carefully followed the J. Craig Venter Institute’s progress. They’ve been working on it for so many years. All I ever see in the media is that it has 400-and-something genes, and they still don’t know the function of X number of these genes. But surely there are deeper problems limiting it. What else is there?
Kate Adamala (36:15) That’s the biggest problem: What are those essential genes of unknown function? Right now, they already have a defined medium for that cell. It’s no longer a kitchen sink. They can use chemically defined media to grow it. They can minimize the lipidome. That’s what I meant earlier when I mentioned there is a living cell that uses two lipids in its membrane. That’s the Craig Venter cell grown under certain conditions. It can have a membrane made out of two lipids.
Niko McCarty (36:45) This has been published?
Kate Adamala (36:46) Yes, it’s been published. I’ll send you the link. It’s work out of James Saenz’s lab. It’s really minimal. The biggest bottleneck keeping it from being fully understandable and engineerable is the fact that there are several dozen genes we know are essential, but we don’t know what they do. We have not even the faintest idea what the hell those proteins do. They have to be there because if you knock them out, the cell gets dead, but that’s all we know about them. Figuring out the functions of those is what stands between that cell being fully knowable and where we are right now.
Niko McCarty (37:23) But after throwing tens or hundreds of millions of dollars at a problem—and maybe I’m taking too aggressive an approach on this question—why is it so hard to figure out the function of proteins? Why can we not grow these things in a hundred little flasks, give them to people, and do some super-resolution microscopy? Well, they do. So what’s the holdup?
Kate Adamala (37:47) That’s the unknown unknown. I don’t know. I’ve been very closely following that field, and I’m friends with a lot of people who have been in it for a long time. It’s a very difficult problem, partially because biology has only two states: live or dead.
That’s the beauty of a Spud Cell: It can be mostly dead; it can be a little bit dead. You can figure out a lot of functions in a suboptimal way. Right now, the Spud Cell divides very slowly. If you break something, it’s not going to completely stop dividing; it’s just going to divide slower. I can still figure out what went wrong because my system is still working. It’s experimentally possible.
With the minimal cell, if you break something, the cell gets dead, and you have no cell. That’s the problem with living biology in general: To figure something out, you have to do it on a cell that’s still viable, because if it stops being viable, you don’t have a cell anymore. I think that bottleneck, the fact that we do not have a slightly dead biology, makes it much harder to work with because you have to keep it viable in order to work on it.
That’s why I think this gray area where a Spud Cell sits right now, where it’s not really dead but it’s not yet alive, is a very comfortable place to be in. I can break a lot of essential things. I can mess with the fundamentals of metabolism. With the minimal cell, they’re stuck with either studying a fixed, dead cell or trying to figure it out on a living metabolism without making it dead. I think that’s just technically really challenging.
Niko McCarty (39:30) Isn’t it so sad that so many of the tools of molecular biology require that we kill cells, extract their molecules, and study their molecules? Even then, almost everything we study is in isolation. We study RNA on its own; we study proteins on their own. We sequence the genome only to later realize that the genome has a particular 3D shape, a topology that also really matters for how the genes are expressed.
Kate Adamala (39:59) Mm-hmm.
Niko McCarty (40:00) Isn’t this also a rallying cry that if we actually want to understand biology, we need methods that enable us to study it across space and time on living samples?
Kate Adamala (40:11) Or somewhat living samples. That’s the thing to me. I think that’s why it’s so hard to study living biology: You have to keep it alive. If we had a state in which we could study it, kind of like a breadboard for biology, where we could see if a particular circuit is ticking without turning the whole thing on, then at least some of those problems might become easier.
40:38 — What synthetic cells could be used for
Niko McCarty (40:38) That’s a very good segue, because the next thing I was going to ask you is: What is the point of Spud Cell? The argument I really understood was that Spud Cell could be a very interesting platform, like you said, to test things. I want to add a new genetic circuit in my cell: Does it work or not? You’ve stripped away all the complexity, so it’s good for troubleshooting. But the question I always had was: If you made a circuit work in Spud Cell, does that have anything to do with making that circuit work in an actual organism?
Kate Adamala (41:11) No, it doesn’t.
Niko McCarty (41:13) You’re saying that’s not the point. It’s that we would actually move over large swathes of the biotech industry.
Kate Adamala (41:19) Large swathes of it. Not all of it, but big swathes of it.
Niko McCarty (41:22) We would have bioreactors not of CHO cells making drugs, but of Spud Cells making drugs.
Kate Adamala (41:28) Probably not the Spud Cell in its current iteration, because it’s just—
Niko McCarty (41:31) Something very robust.
Kate Adamala (41:33) Once Spud Cell becomes more robust, once it can actually replicate under perfect conditions indefinitely, then it can become a biomanufacturing strain.
Niko McCarty (41:44) Can you say what you think some of the likeliest applications would be?
Kate Adamala (41:48) Catalysis that’s not possible with natural proteins. If you need an industrial process that requires very high pressure and temperature, those are very difficult to turn into a bioprocess right now because of those physicochemical limitations. But we know that, for example, if you add fluorinated molecules—basically make Teflon proteins—they can withstand much higher temperatures. We can only do that at a small scale right now because you have to do it in vitro, in a PURE system in a test tube. There’s no other way to introduce those fluorinated amino acids, for example. They’re not compatible with being introduced naturally.
Enzymes that require more chemistry than natural life can give you—that’s one huge field. I think now that the technology is catching up, that field might explode, because people doing protein design were working with what’s available to them. New proteins were being designed with the building blocks that are available. We already know from in vitro studies that there are multiple hundreds—I don’t know the current number, but it’s over 300—of different noncanonical amino acids that can be translated even by a natural ribosome. That huge chemical diversity doesn’t exist in biology right now. We’re not designing proteins taking advantage of that chemistry.
That’s why I firmly believe we can replace the petrochemical industry with bioprocesses. Not with bioprocesses using modern life as we know it, with the 22 puny little amino acids with low chemical diversity—sorry, biology—but with the actual huge diversity that’s available, that’s possible. Bioproduction, especially of molecules that are very far outside the constraints of natural biology, is going to be a big application.
Another one is drugs and biomolecules that are bioorthogonal, that are not made out of natural building blocks. You can, for example, inject a drug into your system, and your proteases don’t chew it up immediately. That’s going to be a big one.
Another one is that right now, Spud Cell needs to be fed everything, and it’s incredibly picky about its nutrients. But because it’s a platform we hope to bioengineer, I want to be able to engineer it so it can eat anything. I want to go from a toddler to a teenager that eats anything you put in front of it.
That enables a globally distributed bioeconomy, because different places, different climates on Earth, can grow different types of biomass. That’s a limiting factor right now in the development of the bioeconomy, because those bioreactors need to ferment a very particular set of biomass. You have this bioreactor that can ferment biomass from soy but not from prairie grass. If you can build a Spud Cell that has enzymes that can chew up a lot of different food sources, then they can ferment anything. That’s another area.
Obviously, we’re far in the future. We’re not talking about a five-year horizon. But by 2050, I think we’ll get there. If we don’t, we’re in trouble as a civilization. We have no choice.
Niko McCarty (45:08) It’s interesting that when I asked you what the point of Spud Cell is, you focused on the technological applications. You did not say what is normally the rallying cry for synthetic biology, which is, “We are building this to understand life”—which honestly has always struck me as a more tenuous position.
I can accept your premise that, yes, if there were a robust Spud Cell, we could engineer with very interesting new chemistries, and we wouldn’t have to worry about crosstalk and all these other factors. But building life to understand it—Spud Cell is so different from natural biology. Does it really tell us anything about natural biology, or does it tell us more about chemistry?
Kate Adamala (45:52) I think it tells us more about chemistry. If you take a pathway from biology and study it in isolation in a Spud Cell, then you can study that particular pathway much better. In that way, it does teach you a little bit about a natural pathway, because you can look at it separately from all the other pathways. But the Spud Cell does not teach us how a complex natural cell works. It’s just too different. Because of all the hacks we did along the way, and more hacks we’re hoping to do, I don’t think it’s going to be a reliable model that teaches me how my own cell works.
46:29 — Evolution and complexity of synthetic cells
Niko McCarty (46:29) Another thing I was wondering: You’re building Spud Cell, and it will improve over time. Let’s say it’s 2030. You have a Spud Cell, and it can still only divide ten times. It’s still not robust. You all get together as a group and say, “I know how to make this more robust. We’re going to evolve it. We’re going to put it in a bioreactor and pressure it, and—”
Kate Adamala (46:52) We’re going to do that way before 2030.
Niko McCarty (46:55) Okay, but then the question is: Hasn’t that destroyed the whole point of Spud Cell? As soon as you let evolution act on this, you don’t understand the components anymore.
Kate Adamala (47:06) That’s the problem with natural evolution, because you’re starting with something you already don’t understand. With a Spud Cell, I can sequence the hell out of it at every generation.
Niko McCarty (47:15) We can do mass spec on all the components.
Kate Adamala (47:18) And I know I have a baseline that I fully understand. Every new thing that pops up, every point mutation, every new functionality will be compared to the baseline. If I don’t understand it, then I throw it out the window, because I’m not going to have something I don’t understand in a system that’s designed to be understandable.
Every tiny improvement, every way to deal with a selection pressure, is going to be compared to the baseline we now understand. It’s not like adding an unknown brick to something you already don’t understand. It’s going to be a baseline platform we do understand. Evolution might create unexpected solutions, but they won’t be unknown solutions.
Niko McCarty (48:06) That’s really interesting to think about: Spud Cell as a benchmark to trace evolution. That’s—
Kate Adamala (48:12) Mm-hmm. That’s why I feel—
Niko McCarty (48:14) Very interesting.
Kate Adamala (48:15) That’s why it’s key to me to couple genotype to phenotype. I think we’re not as smart as evolution. I really think evolvability is a key function that will enable us to improve Spud Cells faster. Now we have a genome that’s coupled to the outcome, to the number of offspring, so now we actually can evolve it.
Niko McCarty (48:36) You could build some kind of assay of robustness. You measure robustness, take Spud Cell, and evolve it. Every few generations, you sequence it and do mass spec. The thesis is that you could actually map what makes things robust under different— That would be very interesting.
Kate Adamala (49:02) Right now, nobody’s doing that because the Spud Cells still need to keep replicating. That minor detail of it not replicating fast enough. We’ll start doing it the moment I have continuous replication. That’s the goal. I have several collaborators who are tippy-tapping right there in their labs now, waiting for it to happen so they can start doing it. But until we can stop worrying about housekeeping—waste removal and the number of cycles—we cannot do that yet. That’s why the first problem is to make it more robust.
Niko McCarty (49:38) Do you think evolution might be required to make it divide longer?
Kate Adamala (49:44) I hope not, because it’s chicken and egg then. You can’t really have evolvability unless you can go through multiple generations. I think we can hack it to the point where it will be replicating. It might not be very efficient at it; that’s why I say “hack it to that point.” But once we have multiple cycles of growth and replication, evolution can improve on it for sure. I think evolution is much better than me. Evolution is much faster, much more efficient than artificial design, than directed evolution that humans do.
Niko McCarty (50:20) This is a difficult question to pose, but bear with me for a second. There are all these knobs that evolution can pull on, even within a single molecule. There was just a paper in Cell where they were studying a particular virus, and they said the infectivity of this virus—how infectious it is—is not only a function of its sequence. It’s an RNA virus, but that RNA, when it enters the cell, folds into a particular shape that also plays regulatory roles in the infected cell’s genome. In other words, the structure and the sequence of the RNA are both playing functions for the virus.
If you look at the evolution of genomes, historically we just sequenced genomes and that was good enough. But we now know that certain types of cancers in human cells emerge not from sequence errors, but because the way chromosomes physically package in relation to each other is off. Clearly, there are these very combinatorial knobs that evolution is pulling on.
The vitalism that people speak of, which I don’t believe in either—I subscribe to the view that life is just chemicals computing—but maybe there is something to this belief that if you strip things down too much, you reduce the levers evolution can pull on, and you just won’t ever match the robustness or sophistication of natural life. I’m wondering if you have takes on that or subscribe to that.
Kate Adamala (52:03) I don’t mind complexity. I love complexity as long as I can understand it. I think both positions can be correct. Life can be an effect of molecules, just physicochemical behavior of molecules, but it has to be complex enough to be robust.
For example, a modern airplane is incredibly complex. I don’t think there’s a single person right now who can understand every single system of a modern airliner and explain every single subsystem, all the avionics, all the aerodynamics of the airframe, everything. There’s not a single person who can control all of that. But that doesn’t mean an airplane is a magical being. It’s still designed, engineered, and you can explain every function of it. It just became so complex. That’s how I think of life—
Niko McCarty (53:07) But the difference is that we can study airplanes because we can see all the components. We can put the transistors under a microscope and see them. But biology—if you were to evolve Spud Cell and it hits on a solution to the division problem, let’s say, and then you study its molecules, do mass spec, and sequence the genome, you’re not actually capturing the topology of the genome, the structures of those molecules.
Kate Adamala (53:32) That’s why you need to slice it and put it on a cryo-EM.
Niko McCarty (53:35) But what if evolution hits on solutions that our measurement tools are not equipped to even detect?
Kate Adamala (53:42) That’s a really interesting problem. I think we need a better measurement tool, and that measurement tool has to be computational. That’s another thing I think Spud Cell might enable: building a true digital twin of a cell. Now that we’re starting with something simpler, we have a collaborator who is building an atomistic-resolution model of Spud Cell. Because we can. I can tell you what the concentrations are and where those molecules are. You can make a model right now. As we build complexity, that model can grow.
With a natural cell, we don’t have that model because we don’t know where everything goes. But I think the problem you raised is really important: What if the evolutionary process finds a solution that we can’t backtrack, that we can’t figure out? I think computational tools will help a lot with that.
Niko McCarty (54:35) But how long can you run an all-atom simulation of Spud Cell? Even though Spud Cell is very simple, you probably can’t run that for very long at all, right?
Kate Adamala (54:44) Yep. My goal is seconds, which is very long by those standards, but I was told it might be possible.
54:51 — Why Kate changed her mind about mirror life
Niko McCarty (54:51) I want to go to mirror life now.
Kate Adamala (54:54) I don’t. I don’t want to make mirror life.
Niko McCarty (54:56) No, I know. When that big report came out, we covered it at Asimov Press. I wrote a long piece with Finn Morehouse about the report. If somebody were able to make a cell that has the opposite handedness of natural life, meaning all of its molecules had been replaced with their mirrored versions, that mirrored cell could evade the human immune system. It could evade viruses in the environment and proliferate out of control; there would be few things to keep it in check. Most scientists acknowledge that this is a very distant thing. We are nowhere near able to build such an organism.
But I want to go back to 2019. There was a conference, some kind of workshop event, where synthetic biologists got together. You were there; John Glass was there. Everybody looked around and was like, “Yeah, we should make mirror life. This would be amazing.” Why did you think at the time that it would be interesting or useful?
Kate Adamala (56:09) Because I didn’t know enough. I didn’t know enough to know better.
Niko McCarty (56:11) But what were people saying at the event? What was going to be the functional purpose of mirror life?
Kate Adamala (56:17) All the benefits we thought about getting from mirror life are the reasons we now think it shouldn’t be made. We thought it would be stealth to the immune system. Great, it would make a fantastic drug. It would not be possible to infect it with natural phages. Great, it would make a fantastic bioreactor.
We didn’t think about it from the risk-analysis point of view. We only thought from the benefit point of view. Only after we started talking to evolutionary biologists, ecologists, and experts in immunobiology did we realize that all those things we considered features are actually bugs. If it’s stealth to the immune system, it doesn’t just make a perfect drug; it also would make a perfect pathogen. If it’s not possible to eat it or infect it, then if it leaks out of your magic bioreactor, it’s just going to spread in the environment.
Niko McCarty (57:17) Who were the people who first approached you to tell you, “Hey, you should not do this”? Even the NSF funded it. It wasn’t just scientists in a room. Big funding agencies also gave money. Probably hundreds of people were aware of this.
Kate Adamala (57:32) Yes. It was public—NSF grants are public—so we were never hiding that we were doing—
Niko McCarty (57:37) Of course, but I just mean that to get an NSF grant, dozens or hundreds had to say this is a great idea. Who first approached you and was like, “Hey, I want to talk to you about this”?
Kate Adamala (57:48) It was very gradual. It was over a couple of years—really, over a year—of talking in the biosafety and security community about that idea. There was not a single person who came and said, “Hey, I think this is a bad idea.” People started genuinely asking questions. Not in this Midwestern ironic way of “I’m just asking questions,” which means “I’m criticizing you.” No, no. They were genuinely asking questions about, “How do you make sure it doesn’t take over in the environment once it leaks out?” It was coming from curiosity, but also concerned curiosity.
We, the people working on it, realized we actually did not have a plan for that. So, okay, we have to come up with a plan for that. Then we started thinking: How would we prevent persistent infection or persistent replication in the environment? We started realizing that we couldn’t think of a way to do that.
Then we started going out to more people, asking ecologists, for example, “Hey, I have this problem. What if I make an organism that can do this? How would you limit that organism?” Those people could not come up with a way to limit it. Then we started realizing that we have a problem and we should not be enabling that technology.
Niko McCarty (59:12) What’s interesting is that after the big mirror life debate kicked off a couple of years ago, people went and looked in the history books. Louis Pasteur said this would be a problem. In the 1800s, Louis Pasteur was like, “If we made mirror-image life forms, it could be really bad.” In the 1990s—or in 1990—these Purdue chemists wrote a letter and warned about this. There was a Wired article in 2010 saying that mirrored organisms would wipe out the planet. George Church’s book with Ed Regis, Regenesis, devotes a huge share to mirror life.
It’s so confusing to me, the timeline of why, in 2019, despite even a very mainstream Wired article, people were like, “This is an amazing idea.” Again, I’m more techno-optimistic than fearful. I acknowledge that mirror life is so far away. I’m just trying to understand the timeline: How could it have been that these scientists in a room were not aware of this?
Kate Adamala (1:00:24) Now we’re aware of it. This Wired article, for example—I think it’s a great article, but I had no idea it existed until we started digging into the background on safety, when we started considering its safety. I think it became more mainstream as the problem became mainstream. It wasn’t an article everyone was aware of.
Obviously, I did read George’s book, but it was not—like, when we first started thinking about it, we thought, “Okay, we can put safeguards into the organism.” It took a long time to put all those things together. I had no idea Pasteur wrote about it until I was way into writing the Science paper. With all due respect to Louis Pasteur, I of course never read his original writings.
Niko McCarty (1:01:17) It was from a lecture, actually, so even harder to find.
Kate Adamala (1:01:20) Now we know those background materials exist, but they weren’t prominent. I think that shows a short—
1:01:27 — Why life evolved a single handedness
Niko McCarty (1:01:27) When the debate starts, people look for evidence. It’s selective bias. I’ve read books and articles that state as a fact that there’s no reason life adopted the handedness it did. It’s just a fluke of evolution that the cell that evolved to the present day and gave rise to all living organisms adopted those chiralities in its molecules. It chose those handednesses.
Kate Adamala (1:01:59) I agree with that, actually.
Niko McCarty (1:02:01) My question is: How do we actually know that? You’re making the assumption that it could be reversed and that there are no emergent properties or utility of the existing handedness. Also, why would only one handedness survive? It also insinuates that the evolution of life is rare. I’m curious what you make of it.
Kate Adamala (1:02:28) That’s a four-part question.
Niko McCarty (1:02:31) The question was terribly posed.
Kate Adamala (1:02:33) It’s actually a really good question. It’s four really good questions. Let me answer the second question first. The reason we need one chirality is that life has to be interoperable. Life has to be able to eat other life. A pretty strong hypothesis I support is that if you want a biosphere to work, everything in that biosphere has to be interoperable. If you die, you have to decompose to elements that other cells can eat. If a predator comes at you, that predator has to be able to eat you. You have to be able to eat food. Everything eats everything else, so one chirality is kind of necessary.
On the metabolic level, you have to be homochiral, because otherwise the proteins would just not work. You cannot have mixed chirality because you would have too many different stereoisomers, different possible configurations, different possible molecules that wouldn’t physically interact with each other. That’s the reason life had to pick one.
How do we know it probably doesn’t matter? Because we have a lot of evidence that opposite-chirality proteins and nucleic acids interact with each other just like the normal-chirality ones. That’s why we think it could have happened either way.
The third question in your string was: Does it imply that the evolution of life is really rare? I don’t think so. I think the universe might be lousy with life. Obviously, there’s the Fermi paradox, and I think that’s a very different discussion. Intelligent life might be very rare, but life as a phenomenon is probably very easy, given how quickly it started on Earth and how easy it seems to be. My small lab made molecules into a lifelike system. There’s nothing magical to me in how molecules make themselves into life if you give them enough time and the right conditions.
I don’t think life is a particularly difficult process to get started. We have n equals one because we only have one on Earth, but it started so quickly. The moment Earth had liquid water and a crust, life started. Either aliens came with a salt shaker, or life spontaneously started really quickly—and I take the easier solution: Life started quickly.
Niko McCarty (1:04:58) If it started quickly, it could start often.
Kate Adamala (1:05:01) It could start often, and it could pick a chirality at random.
Niko McCarty (1:05:05) We’ve just never detected it, or it peters out, or it’s outcompeted in its environment. That’s your thesis.
Kate Adamala (1:05:11) That’s my thesis exactly.
1:05:12 — SpudCell as an enabler for mirrored life
Niko McCarty (1:05:12) Another point is: Why are people even having this debate? We haven’t made a synthetic cell, let alone a synthetic mirrored cell, which is even harder. To play devil’s advocate, what is even the point of worrying about this?
Kate Adamala (1:05:30) Because now we can actually do something about it. People wanted to do it. We were funded to do it; others were funded to do it. If you get too close to it, there’s no stopping it. It’s really hard to stop scientific progress when it takes one or two bad actors to get there.
Right now, we’re so early that we could stop this whole field in its tracks by creating peer pressure: All the experts in the field don’t work on it. We’re not building the capacity that gets us closer to it. Now is actually the only time we can stop it. Once we get too close to making a mirror cell, a single bad actor can do it. Right now, we’re too far from it, so we can stop it as a field.
Niko McCarty (1:06:15) One thing I’ve always wondered about this is: If we had the technology to create mirror life, that insinuates that we’re very advanced in biotechnology. If we could make a mirrored organism, surely we could make a mirrored phage.
Kate Adamala (1:06:30) That’s a very safe assumption.
Niko McCarty (1:06:31) Mirrored antibiotics and mirrored—so is it actually as big a threat as people think it would be?
Kate Adamala (1:06:39) That’s a debate. That’s the argument against us being against mirror life that makes the most sense to me: If we can make mirror life, we can also make something that eats it and infects it.
But on the off chance that we’re both right about the dangers of mirror life and wrong about our ability to make a phage for it and release it globally—if those two are true, then we’re totally screwed. There’s nothing about mirror life that would be worth taking that risk. That’s it to me. It’s not like mirror life is completely worthless. It would have applications, but they’re not worth taking that risk. I’m not 100 percent sure we’re right about all those dangers, but I would rather not find out.
Niko McCarty (1:07:37) Personally, I struggle to envision exactly what the point of making a mirrored organism would be. I totally get a mirrored ribosome to make peptide therapeutics. That’s obvious. What do the proponents of making actual, full mirrored cells say are the applications?
Kate Adamala (1:07:55) Biofermentation: You cannot contaminate a bioreactor if it’s made out of mirror life. And drugs, medicine, cell therapies. Imagine a cell therapy where you have a cell you can inject into a patient that has all the properties of a cell. It can detect metabolites, it can produce a drug, and it’s stealth to the immune system. These are the two practical arguments, and—
Niko McCarty (1:08:20) Those are all things you’re saying we can make other ways. It just might be more expensive.
Kate Adamala (1:08:23) Exactly. Which is why I’m now on board for not making mirror cells, because I think the risks are much bigger than the possible benefits.
Niko McCarty (1:08:34) There are two ways to make a mirrored cell. There’s the top-down way, which seems extraordinarily difficult. I don’t even know that this would work, but maybe you could take a minimal cell like the JCVI cell and replace components one at a time, or swap in just the central dogma in a mirrored form. But because of the compatibility issue you talked about earlier, I don’t see how that would work. The only other way is to make it from the bottom up. Isn’t Spud Cell, in a way, the enabling technology to build mirror life?
Kate Adamala (1:09:14) Not really, because the biggest bottleneck in making mirror life is not the actual assembly. It’s the sheer amount of stuff you need that we cannot make right now. Spud Cell is difficult enough to do when all my components come pretty much free from E. coli. All my ribosomes, all the other proteins, everything I use to make a Spud Cell comes from E. coli. It takes pennies to grow it, and obviously it’s a pain in the lower back to purify it, but it’s doable. I can have buckets of it.
With mirror life, you would have to chemically synthesize every single thing because we don’t have a way to make that. That’s a huge technological barrier, and that’s the barrier we’re hoping never to cross. That’s the key enabling technology. That’s why I say a replicating, autonomous mirror ribosome would be my red line, because at that point you can start making all the components that will eventually become a cell.
Niko McCarty (1:10:14) But isn’t it a fear at all that if you know all the components exactly, you’re publishing a recipe where people could just recreate the—okay, so it’s expensive.
Kate Adamala (1:10:26) It’s more than expensive. It’s just not technically possible right now to make that amount of protein. Even state-actor-level resources would not be enough. We just don’t have a way to make that.
Niko McCarty (1:10:38) But what are the things we can’t make? Is it long proteins that are mirrored, too expensive, or—
Kate Adamala (1:10:44) Long proteins, it’s—
Niko McCarty (1:10:46) Because you have to make them using solid-phase synthesis.
Kate Adamala (1:10:48) Then stitch them together and have mirror chaperones that help them fold in the correct way. Resource-wise and technology-wise, we don’t have a chemical synthesis technology right now that would allow us to make those giant proteins. The biggest things we’ve made were those single instances of mirror polymerases. These are not that big an enzyme.
Niko McCarty (1:11:14) You have to make a high concentration of these.
Kate Adamala (1:11:17) High concentration, high amounts of all of them. Then you have to have all the nucleotides to make the mirror nucleic acids. Logistically, you would have to retool your whole scientific enterprise toward it.
Niko McCarty (1:11:32) Is that something you’re monitoring? You said your red line would be a mirrored ribosome that can make copies of itself. Are there other things where you’re like, “We would pause the Spud Cell work if we saw X”? If mirrored solid-phase synthesis becomes really good, what is your line for saying, “Okay, we’re not going to do this”?
Kate Adamala (1:11:53) I think mirror solid-phase synthesis would not give me pause. That’s why we’re pushing to codify what has become a sort of community-enforced red line into law before that technology becomes possible. So then we can—
Niko McCarty (1:12:13) Yeah.
Kate Adamala (1:12:13) We’re trying to frame that conversation. At least that’s my goal. It’s a diverse community. Some people don’t think it should be codified into law. But I would feel much safer if there were something like a Biological Weapons Convention, something that has similar power to the BWC but is about mirror life.
For example, right now no country can come out and say, “I’m making a virulent, weaponizable smallpox,” because international law literally tells you it’s illegal. I would love it if mirror life research got to that point. We’re not there yet. We might never get there, but that’s my goal. That’s the answer to your—
Niko McCarty (1:12:55) Don’t states still make smallpox? There are still bioweapons programs.
Kate Adamala (1:12:57) They do. They don’t admit to it.
Niko McCarty (1:13:02) Yeah, but okay, you know.
Kate Adamala (1:13:04) But also, it’s super cheap and easy to make smallpox, especially if you’re a state actor. That’s the good thing about mirror life now: We’re stopping the development of the technology before it becomes cheap and easy. It’s also a terrible weapon, because bioweapons only make sense if you can immunize your own population against them.
Niko McCarty (1:13:23) What, you mean mirrored?
Kate Adamala (1:13:24) Yeah, mirror life would be a terrible bioweapon.
Niko McCarty (1:13:26) But isn’t it a good ecological weapon?
Kate Adamala (1:13:29) Yes, but you cannot limit it. An adversary—
Niko McCarty (1:13:33) You would also be destroyed.
Kate Adamala (1:13:35) Would also be destroyed. That’s not a state-level weapon. That’s an individual-terrorist-level weapon, and those don’t have the resources.
Niko McCarty (1:13:43) Interesting argument. It’s interesting for me to examine how you justify working on things. Again, I’m a techno-optimist. I am a biotechnologist, but I live in San Francisco, so I’m sort of washed up into the discourse. It’s interesting to talk to someone like you who’s like, “We should stop mirror life,” and then, by the way, we’re making a synthetic cell platform that is the enabling technology.
Kate Adamala (1:14:16) That’s the thing. I don’t see it as an enabling technology, because I think the technical problems toward making mirror life—and I say that as someone who tried to make it, so I know how much it sucks to try to make it—are way beyond what normal-stereochemistry synthetic biology is facing. They’re just huge resource problems.
1:14:38 — Biotic
Niko McCarty (1:14:38) I think that’s a good segue to Biotic. After the Spud Cell preprint came out, you announced there’s going to be this big nonprofit initiative. The goal is to raise $100 million. Is that public? The goal is public.
Kate Adamala (1:14:52) The goal is public. The goal is to enable a global bioeconomy. Do the math.
Niko McCarty (1:14:59) There’s not a lot about Biotic that I’ve seen. I want to understand: What is Biotic actually doing? Is it a grant-making organization that’s trying to bring more people into the field? Is it going to be a building where you’re centralizing efforts? What is the goal here?
Kate Adamala (1:15:18) It’s a grant-giving organization. Right now, our goal is not to bring more people into the field; it’s to focus people who are already in the field. Synthetic cell engineering is an amazing, very diverse field. That’s the beauty of it: People have different definitions of what a synthetic cell is. But that makes the efforts rather unfocused. Progress is being made, but not fast enough.
We as a society really are struggling right now. The world is burning. The world is having a lot of societal problems that can be traced back to literally the way we’re moving atoms, the way our industry works. We think many of those problems could be solved by enabling a bioeconomy. We also believe it will not be possible to enable a bioeconomy unless we have a better way of moving atoms beyond the natural cell. That’s why we think synthetic cells have to happen for the world to become sustainable, for civilization as we know it to survive and be sustainable.
That has to happen soon—soon enough to matter. We’re talking about 2050 as the deadline when we have to start seeing things change. Right now, the efforts in the synthetic cell field are not focused enough. They’re not focused on a single interoperable platform.
At its core, what Biotic wants to do is fund the development of a robust synthetic cell that can create all those applications. All the people who work on developing modules and technologies that enable that synthetic cell have to agree on a standard, on a single platform. For example: This is the translation system we’re all using. This is the genome design and architecture we’re all using.
Those types of standards could be created by the community, with “Pretty please use those standards.” That could be one way of enforcing it. But a much more efficient way would be to fund research and say, “We’ll fund your research. We love what you’re doing for this field. We want you to keep doing it. Just please make your work interoperable with our platform, and we’ll pay you to do that.”
That’s what Biotic is. It’s a grant-giving organization, but the grants aren’t a free-for-all for anyone who wants to make synthetic cells. Those are grants for people who will make useful modules for synthetic cells that will work with all the other modules developed within that ecosystem.
It’s like saying we want to make apps for a Linux operating system, and those apps have to work on a Linux kernel. We’ll pay you to write that app, but only if I can boot it up on my computer. That’s an analogy.
Niko McCarty (1:18:11) Who decides what to fund and what the priorities are?
Kate Adamala (1:18:16) Right now, it’s the Biotic board that decides. As we grow, we’re hoping to build an international scientific advisory board, as the decisions will get tougher as we get more granular.
Right now, the guiding principle is that the modules you make have to operate on a Spud Cell. The only reason for that is that Spud Cell exists. There’s no other synthetic cell platform that grows and replicates. If someone makes a better one, and it’s compatible, we reserve the right to move. We’re not “Spud Cell is the one and only platform” people. We’re “Whatever works is the one and only platform” people.
Right now, we want to win by winning. We have a working prototype, so we’re asking people to contribute to making that working prototype better and better and better until it stops being a prototype. The standard now is: Make modules that will make this one thing that exists better.
Niko McCarty (1:19:19) Have you already shown that Spud Cell works in the hands of others? How reproducible is it? What other labs have made Spud Cells in their labs?
Kate Adamala (1:19:29) We’ve reproduced Spud Cells in Drew Endy’s lab. Right now, other people have reproduced other elements of Spud Cell. It’s been a little over a month since we made the whole thing public, so I don’t know of any other lab that has reproduced the whole thing. Elements of Spud Cell have been reproduced in other labs, but as far as I know, not the whole thing.
Niko McCarty (1:19:55) Even if Biotic raises $100 million, what is the plan to keep it sustained through 2050, especially when interest starts to die down? It’s one thing to fundraise when you’re backed by all the hype. It gets progressively harder and harder to fundraise as the progress becomes more incremental.
Kate Adamala (1:20:14) Hopefully, we will not be fundraising by 2050. The goal is to make it a useful technology. The only victory condition for Biotic is to make it into a commercially useful technology that enables biotechnology, that enables a bioeconomy. That’s going to bring in money.
We say this is an open platform for research, but we did file IP on it. It is not a platform that any company can use for free. We will license that and all the future improvements to any company that wants to make it into a useful technology. The royalties they pay back to Biotic will support further Biotic research. That’s the victory condition.
That’s why we have to succeed. Biotic is not designed as an ongoing, indefinite research operation. It has to start producing viable products that will bring in money, and that money will sustain it going forward.
Niko McCarty (1:21:09) Is the idea ever that you would spin out companies? Only licensing the technology may be interesting, but it’s very uncertain. Would you ever consider, “Hey, we did something very promising. We’re just going to spin out our own company”?
Kate Adamala (1:21:25) We do, and Biotic has this plan that once we start having viable product possibilities, we’re going to spin out Biotic Ventures. Think of it as something internal, almost like a family office run out of Biotic. We as Biotic founders will not spin out companies on our own, but we will support people spinning out companies, and their revenue will come back to the research ecosystem. That ties to our victory condition of making a useful product.
1:21:58 — China and 2050 goals
Niko McCarty (1:21:58) When this announcement came out, there was a lot of discourse about China: “We have to do this, and it’s so much better than China. China has its own synthetic cell effort, and we’re so far ahead.” What’s the deal with China? Who cares about China’s synthetic cell effort? Why not be collaborative? Why does it seem so antagonistic?
Kate Adamala (1:22:23) It really bugs me that there is this competitive narrative to it. It’s obviously tied to geopolitics.
Niko McCarty (1:22:29) But in Drew Endy’s Hoover Institution interview, a big chunk is about China and how we’re ahead of China. I’m like, “What does this have to do with geopolitics?”
Kate Adamala (1:22:39) It’s enforced by the political structure that governs the results. If Biotic is the first to produce a functioning synthetic cell that becomes technologically important and powers a bioeconomy, that bioeconomy is going to run by the rules of the country where Biotic is, or the system that supports Biotic. That’s going to be an open ecosystem.
If the first functioning, commercially viable synthetic cell comes out of research supported by a totalitarian government, then access to it and the ways it’s going to be used and deployed are going to be very different. That’s the biggest difference.
Niko McCarty (1:23:26) Are there Chinese labs that are really good that Biotic would fund but cannot fund because they’re in China?
Kate Adamala (1:23:33) Right now, we’re not funding any work in China, but there is a huge institute in Shenzhen led by Chenli Liu that has amazing expertise in synthetic cell engineering. In an ideal world, I want to work with them, not against them.
Niko McCarty (1:23:46) I visited the Shenzhen Institute, visited him, and saw his lab. They have two floors of robotic labs and very impressive scale.
Kate Adamala (1:23:56) Yes. We all would be much better off if we were able to collaborate. The sad reality is the geopolitics, and you can’t get around that.
Niko McCarty (1:24:07) But if Spud Cell is nonprofit, open-sourcing its technology, and publicly revealing things, isn’t the timeline for China to catch up to whatever you publish about a month? Considering how advanced they are—I was just there a couple of months ago, and I was even more impressed on the second visit.
Kate Adamala (1:24:28) Yes, but that’s why we filed IP on it. We filed protective IP. The Spud Cell is—
Niko McCarty (1:24:33) But that doesn’t matter, right?
Kate Adamala (1:24:36) It does and it doesn’t. We still have to pretend we believe in the law.
Niko McCarty (1:24:41) Assuming this works and Biotic becomes a self-sustaining organization, what is the end goal or the success case in 2050?
Kate Adamala (1:24:52) It has to work, because by 2050 we have to make all the products sustainably, and we have to be truly engineering biology. We’ll have a cell that people can work with, and bioengineering will become more democratized. I know it sounds like a utopia right now, but I really think it’s doable that this technology can become a universal jump-start to biological evolution.
People have been talking about the 21st century being the century of biology, and to me that is necessary. We have to engineer cells in an intentional and accessible way. That’s going to happen by 2050 or we’ve failed. I don’t like failing, so it’s not going to happen.
Niko McCarty (1:25:45) Awesome. Kate, thank you so much.
Kate Adamala (1:25:47) Thank you.
