What does it mean to be alive? Our origins are the horizon of our understanding, and as with the physical horizon, our approach brings us no closer. The more we learn, the more mysterious it all becomes. What if we’re asking the wrong questions? Maybe life did not begin at all, but rather coalesced piecemeal, a set of properties contingent and convergent, plural, more than once? Maybe the origin of life is happening right now, just over the horizon, forming something new anew. Let’s get into the weeds and see if we can find a continuity between biology and physics.
Welcome to COMPLEXITY, the official podcast of the Santa Fe Institute. I’m your host, Michael Garfield, and every other week we’ll bring you with us for far-ranging conversations with our worldwide network of rigorous researchers developing new frameworks to explain the deepest mysteries of the universe.
This week we speak with Kate Adamala, synthetic biologist and professor at the University of Minnesota, about her research to produce synthetic minimal cells that are not technically alive but can perform myriad biological processes. Along the way the distant past and future meet. Can we build life? Or can we grow machines?
Be sure to check out our extensive show notes with links to all our references at complexity.simplecast.com. Note that applications are now open for our Complexity Postdoctoral Fellowships! If you value our research and communication efforts, please subscribe, rate and review us at Apple Podcasts or Spotify, and consider making a donation — or finding other ways to engage with us — at santafe.edu/engage.
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Referenced in this episode:
Nonenzymatic Template-Directed RNA Synthesis Inside Model Protocells
Engineering genetic circuit interactions within and between synthetic minimal cells
Competition between model protocells driven by an encapsulated catalyst
Synthetic cells in biomedical applications
Parasites, infections and inoculation in synthetic minimal cells
Build-a-Cell: Engineering a Synthetic Cell Community
The Andromeda Strain and the Meaning of Life: Monolith Monologues
Sara Walker on The Physics of Life and Planet-Scale Intelligence
What Technology Wants by Kevin Kelly
Matthew Jackson on Social & Economic Networks
The Multiple Paths to Multiple Life
Terraforming the Biosphere by Ricard Solé
Scaling Laws & Social Networks in The Time of COVID-19 with Geoffrey West (Part 1)
Kate Adamala (0s): It was a very slow, very unsatisfying from an external observer's point of view process where you had it a little bit alive, a little bit dead, and at some point it sprouted legs and wings and started talking and making YouTube videos. And it was a gradual process. It was never that there was a boundary. And like same with viruses. I think a virus particle by itself is probably dead, but viruses are a biomarker of biosphere.
There are biomarker without a biosphere. Same like with a piece of hair. Like a piece of hair from my head is dead as a nail, but it is a sign of a biosphere in that it couldn't have that head. So there's very rarely a line like it's super hard to say, this particular biochemical system is living and this one's totally dead. The best we can hope for is everyone will look at it and say, this wasn't alive.
And as you added more, it became more and more alive. But I think you'll never get a system where everyone’s on where that transition lies.
Michael Garfield (1m 20s): What does it mean to be alive? Our origins are the horizon of our understanding. And as with the physical horizon, our approach brings us no closer. The more we learn, the more mysterious it all becomes. What if we're asking the wrong questions? Maybe life did not begin at all, but rather coalesced piece meal, a set of properties contingent and convergent plural, more than once, maybe the origin of life is happening right now just over the horizon, forming something new, a new. Let's get into the weeds and see if we can find a continuity between biology and physics. Welcome to
Complexity
, the official podcast of the Santa Fe Institute. I'm your host, Michael Garfield. And every other week we'll bring you with us for far ranging conversations with our worldwide network of rigorous researchers developing new frameworks to explain the deepest mysteries of the universe. This week we speak with Kate Adamala, synthetic biologist and professor at the University of Minnesota about her research to produce synthetic minimal cells that are not technically alive but can perform myriad biological processes along the way, the distant past and future meet.
Can we build life or can we grow machines? Be sure to check out our extensive show notes with links to all ourreferences at
. Note that applications are still open for our complexity post-doctoral fellowships. If you value our research and communication efforts, please subscribe, rate and review us at Apple Podcasts or Spotify and consider making a donation. We're finding other ways to engage with us at
.
Thank you for listening. Kate Adamala, it is a pleasure to have you on Complexity podcast.
Kate Adamala (3m 26s): Thank you so much. Pleasure is mine.
Michael Garfield (3m 28s): We're gonna get into some crazy places in this conversation, but for that very reason, I want to start in something a little bit more relatable, which is childhood and early life, the backstory, cuz you know this, this whole conversation's gonna be kind of an attempt to understand the backstory of all of life in some respects.
Kate Adamala (3m 54s): So we're going like all the way back to the early life form. Childhood, like 4 billion years back. Alright, how long do we have to record this?
Michael Garfield (4m 3s): About an hour. Yeah, it's gonna be highly compressed but I love starting people with the researchers that we have on this show as human beings and the passion of their mind and how it is that they came to devote their lives in pursuit of the questions of their work.
Kate Adamala (4m 25s): The voting life in pursuit of something sounds much more grandiose and lofty than what it really is. It's just I'm lucky to have a job that I like and that most people can say that about their jobs. So that's the main motivation for I think for most people to do science is it's super cool. We like doing it and we're very, very lucky to get paid for it. So that's kinda biggest motivation is it's something that's fun to do and you can pay bills with it and I always wanted to do science.
So that's why I think I'm so lucky that I get to do it because I always wanted to do it. I always wanted to be an astrobiologist ever since I was a kid and I was watching science fiction movies and there's always an astrobiologist onboard a starship. And then one day I realized that's actually a job. Like it's possible to be a grownup and work as an as. And then I was sold on it and I didn't quite realize how difficult it's gonna be and how much luck is involved in getting to the point where you can have your own lab.
So it was kind of a dumb luck that I just decided, okay, that's what I'm gonna do. And I went for it without kind considering all the things that can go wrong along the way. So it worked out and I'm very grateful for it. I liked science and I was never really good at anything else. So I went and did science and it a lot of fun to do that job.
Michael Garfield (5m 56s): So there's gonna be two kinds of people in the audience, the people for whom this question is gonna seem almost pointless and the people for whom it's gonna illuminate something really important. And the question is why synthetic biology in service of a desire to be an astrobiologist?
Kate Adamala (6m 15s): Because it's useful but it's also fun. So when I was in undergrad and grad school, I did origin of life research. That's like the hardcore astrobiology, how life started on earth, how life started, another planet, can we look for life elsewhere? And that was a lot of fun, but that was completely, absolutely useless from in a practical sense. There is never gonna be a drug that's going come outta origins research.
There is never going to be a therapy, there's never gonna be a life save, there's never gonna be any benefit to the economy. There's never going to be anyone who's gonna say this changed my life. Once we send astronauts to space, origin of life research is not gonna help them to surviving space. So that was this foundational, extremely satisfying but useless part of science. And I enjoy doing it up to the point when I realized I would like to do something that's actually, in addition to being fun for me, is also useful to, you know, saying useful to the society sounds again a little grandiose that I just kinda wanted to do something that other people will agree is worth doing. And so then I went and did a postdoc in neurobiology in a very hardcore synthetic neurobiology that's extremely useful. There's a ton of drugs coming out of it, but it was also not as exciting.
Michael Garfield (7m 44s): Well I mean it kind of surprises me. I I find that you actually say a lot of things about your work when I've heard you speak about it that surprised me and we'll get to some of that later in the conversation. But it's so clear that your work does have bearing on helping us sort of form the constraints within which we can think about questions of the origin of life and all of this stuff that, I mean either you're just completely singular in your ability to reconcile the sort of useful and useless or perhaps you're just not giving the utility of this kind of fundamental theoretical work as much credit as I'm inclined to give it by virtue of being a propagandist for a a fundamental research organization. But just to anchor this a little bit, there's a quote that you and your coauthors start a piece with at MDPI Life and we'll get to this paper later, but I just want to you cite Richard Feinman who says, “what I cannot create I do not understand.” And to me that's where it all kind of, that's where the rubber hits the road.
So I mean really where, where I want to go in this conversation with you is to look at the work that you're doing on synthetic cells and then to from that place sort of back into questions about the origins of life and not just the origins but like really like the, the, the origins of like specific processes, traits, characteristics that we take for granted as ubiquitous now in living systems and how you've managed to kind of, you're reverse engineering them in these synthetic systems.
And so yeah, I'd just like to, I mean maybe what we should do is start with some definitions. Precisely what is it that you're actually doing in the lab and what are we talking about when we're talking about synthetic cells? What are they and what aren't they?
Kate Adamala (9m 50s): They are cell-like structures. So they have a membrane, they have metabolism, they have a genome. They are not alive, at least not currently. And the goal of our work is to make them alive. They're not right now. And I know you're gonna next, your next follow up question will be about the definition of life. So I'm already gonna say there isn't a good one and I can talk about definitions of life for hours and I can show you why every single one is flawed and we do not have a good definition of life.
Synthetic cells are depending on what glasses you put on. They're either a very practical utilitarian bio reactors. So they're basically little biological factors. They're little soap bubbles cause that's what they are. They have a membrane that's very much like a soap bubble membrane. So there're soap bubbles with enzymes inside them. So that's the practical approach or they are the simplest possible lifelike systems that have some but not all functions of life.
And that's more of the foundational basic researcher glasses. When you look at them you wanna study basic fundamental properties of life. What does life need to do life, How does a genome replicate, how does it so grow? How did essence start? So the synthetic cell in and out of itself doesn't care how you describe it, it just does its thing. And depending on who asks or who paid the bills, we can either say they are little by reactors and they've been used in a lot of practical applications already, including biomedical applications.
They've been shown to shrink tumors in life mice, they've been show to grow vasculature in life tissues. So they can be used as smart drugs, smart bio factories, but they can also be used to do foundational research. They can be used to study the history of life and the future of life, too. We can evolve them beyond what natural current life can evolve. And I realized I didn't actually answer you were probably hoping for like a simple answer. Synthetic cell is and here's a nice definition, but there isn't one.
Michael Garfield (12m 6s): Actually. No, that's great because I mean it's my tendency to just swan dive into the philosophical here and there's something that drew my attention in a paper that you co-authored led by Wakana Satoabout synthetic cells and biomedical applications in wires nano med, nano biotechnology that you talk about salient features and lifelike behaviors. And so this is useful just as a framing because what all this suggests is that for most of human history it seems like people have thought about this in terms of trying to find an essence.
Yes. Or you know, something, some thing that divides the living from the non-living. And here you point to characteristics like directed localization, a sense and respond behavior, gene expression, metabolism and stability.
Michael Garfield (13m 0s): So what we're talking about is actually a bouquet of features that thinking about life in this way puts us closer to this perspective that seems pretty widespread or here at SFI, which is that there isn't like living and non-living,
Kate Adamala (13m 19s): It's a spectrum.
Michael Garfield (13m 20s): That we're talking about a continuum of traits that it's modular. And so one of the things that I found really interesting in your work is that you're poking at questions about, for instance the conditions whereby you can simulate and observe like competition between these synthetic cells. But you're not seeing evolution.
Kate Adamala (13m 52s): Yes.
Michael Garfield (13m 53s): You're not seeing cell replication necessarily. And so this is something that I would love to hear you disambiguate because again these are things that we just take for granted being 4 billion years deep in the evolution of the biosphere that they all come together this work, again it lends something to being able to ask these questions about the very, very early earth because origins of life as a discipline seems haunted by this problem of the improbability of life where what it seems like you're saying in your work is that it's a mistake to think that there was just sort of like a moment when this happened.
Kate Adamala (14m 36s): Yeah, it's not very satisfying cuz I know a lot of people would really like to see a hard line, this is dead, this is living, but that's not the case. And the more we learn about life, the more we're discovering that it's really a gradient, it's a spectrum, It's a continuum, you know, just like it used to be with humans, people used to think that you are alive and then you get dead. And then as the medicine progressed we discovered that there is a lot of states in which a human can be like shredding this cut sort alive sort of dead and that's why all those different clinical definitions of death arrive and that's why people can be artificially kept alive.
All of those kind boundary conditions where someone is in some aspect alive and in some, some aspects not alive. And the same applies to every other living form. If you take a living cell and you grind it up and burn it, then sure there is a clear line, it's been alive and now it's dead. But if you think about the process of making a living cell from component, there is no clear line. There is never gonna be a case in which you can look at it and say this is definitely dead and this is definitely living. As much as like that there just isn't, there's always gonna be a cell or a cell entity that has some functions of, but all of them and at which point you decide.
That's why our field pretty much adopted the ports to our definition of life, which is I will know it when I see it. That's a quote from a Supreme Court Justice that was originally used in a very different context. But we use it to say once we create something in the lab that performs all of the functions that we commonly expect out of life, then most people will look at it and say, yeah that's probably alive but it's not gonna be the satisfying like one day I go to the lab, I do some piping and outcomes to me and I'm that be super satisfying that it's never gonna happen.
Michael Garfield (16m 49s): So just to give people a sense for what this like, let's get into the weeds here a little bit and I want to ask you about this 2013 paper you led with Jack Szostak
Non Enzymatic Template Directed RNA Synthesis Inside Model Protocells
. This is a system where this does certain things, it doesn't do other things. And I found this particular paper again really interesting because it seems to me, and this is, I don't want to jump ahead but I just wanna know, like I want you to know that where I want to take our conversation here ultimately is that it seems like research like this starts to provide us with contextual clues about the ancestral environments, the prehistoric environments in that enabled some of these chemical processes to occur.
And there's some weird nuance in this paper that seems like again to bring it back to astrobiology, it seems to like it helps us sort of narrow search field at least in terms of understanding how and where to look for life chemically similar to our own.
Kate Adamala (17m 57s): Yes, that's key chemically simlar.
Michael Garfield (18m 0s): So tell us about this paper and about what you and Jack were working on here please.
Kate Adamala (18m 5s): So what we did there is we demonstrated that RNA world is possible inside a compartment. That sounds super simple but that was one of the biggest kinda unsolved questions about the origin of life. And as you emphasize this only applies to this very narrow set of conditions of terrestrial life. So how provide a evolution could have looked like on earth and how it could look like with the same components on another planet with liquid water.
So we're not talking about some crazy life, we're wet life as we wet life. And so what we did there is people speculated in the eighties, the first genetic material and the first enzyme in evolution of life was RNA. And we have a lot of evidence that supports that. For example, to this day, every single life form on earth uses an RNA catalyst to make all of our proteins.
Everyone knows what a ribosome is. It's this machine that makes proteins but ribosome is actually an RNA enzyme. The catalytic core of the ribosome is an RNA. There's a whole bunch of peptides around it, but the business end is RNA. And so that shows that the RNA was crucial in the origin of life. It was crucial to get started and we also knew that all life on earth as we know it right now has membranes.
And how did those membranes start? That's a very good question and there is a very plausible way to imagine how membranes started and that is take fatty acids at the right PH, which happens to be physiological PH, what we know now as a physiological PH. They just self-organized into membranes how convenient, right? The problem was though that RNA to do anything needs magnesium, these days it's magnesium, it used to be iron but these days it's magnesium.
Now those membranes, those very plausible fat acid membranes, when they even smell a divalent ion, they precipitate. It looks like cottage cheese. When you take a sample of liposomes, those probio plausible liposomes like they could look on early earth, it's a nice kind of milky solution. You show them a divalent ion, you add even a little bit of magnesium to that sample to precipitate it all looks like cottage cheese. So basically your membranes have gone.
And so this was a unsolved problem. How could membranes form? And at the same time this RNA world hypothesis, which was pretty much acknowledged that that's how life as we know it started, how could those two things come together? So how could we have RNA cells doing anything useful inside? And so that's the question that we answered in this paper, and we demonstrated that it’s possible to have RNA do its thing inside a vesicle that was probiotically plausible, which means it could have originated on an _____ and like with all origins research, we're not saying this is exactly how it happened. Until the time machine is invented, we will never be able to say that's exactly how it happened because we don't have a sample of that provider environment.
But we do have now a plausible scenario and that's the best we can ask for in this field. We have a plausible scenario that says that's how it could happen. And another really cool thing about this work was that the molecule that ended up being the one that makes it possible is citric acid. If you took any biochemistry you will recognize that citric acid is a base molecule of the most ubiquitous energy cycle that citric acid cycle.
Every organism, every breeding organism on earth right now uses citric acid to generate their energy, to regenerate their energy. What a nice constant. The molecule that was needed for the original probiotic plausible membrane to coexist with the probiotic genome of RNA happens to be the molecule that also at the core of existing metabolism right now. It's very elegant, it's almost too elegant if you ask me if you know, if someone speculated that this is gonna be the case, I would say this would align too perfectly and yet this worked.
So that's why I'm really happy about that work because it kind put together those three different essential parts of metabolism, the genome, the compartment, and here's citric acid and once it's there we might as well use it to make energy later in evolution.
Michael Garfield (23m 6s): So I'm really glad that you brought up, it's almost too perfect because one of the last things that you discuss in this paper is, I don't quote you here, in the absence of a prebiotic citrate synthesis pathway, it is of interest to consider probiotically plausible alternatives to citrate that could potentially confer similar effects such as short acidic peptides. So again, the lions seem to converge on the horizon, but you're also implying here that the question is where is the citrate even coming from in this prehistoric context?
And we're talking about a system that is so simple it's not really doing manufacturing at the level of a living cell as the way you know in the way that we think about it now. Then it begs the question of what kind of environments might be providing citrate or might be providing peptides that would act in its place. So that's one of two questions I have for you about kind of like reverse engineering, the ancestral environment in which this is all happening. So like what are your thoughts on that?
Kate Adamala (24m 15s): So the citrate is absurdly simple. The fact that we right now don’t have a provided way to work on it doesn't mean it doesn’t exist. It just means that the chemists are too lazy to work on it. Guys out there, please prove that citrate can be made probiotically. We've discovered under provided conditions that synthesis of molecules that are much more complex than citrates. Saying we don't have a way to make citrate provided doesn't mean it's impossible, it just means no one went and bothered to do it. I still strongly believe that there is a way to provide to make citrate. Someone just someone actually has to show it. And then there are many peptides that can behave like citrate, diet peptides that have two side chains on both ends that kind mimic the citrate carbolic acids kinda hugging the molecule. That's how citrate works basically hugs the magnesium molecule with its carbolic acid ends.
So you can have diet peptides or even type peptides that do little molecules of cuts. For example, people that take magnesium supplements probably are familiar with supplements that come in a form of, for example, magnesium glutamate. That's a magnesium that's correlated by an amino acid. And so that absolutely possible and we know that amino acids are provided possible all the way since the Miller-Uray experiment.
So we know that amino acids were abundant on provider earth, we know they're abundant in space, we know they exist in internal clouds. So making amino acids is not difficult. Combining amino acids into diet peptides is also provided to plausible. You just need to hit them up and dry them and they're gonna polymerize. So either citrate was available right from the beginning or there was something else that had this huggable site chains that could surround a magnesium.
Michael Garfield (26m 22s): I mean, you know again this totally speculative, but there is a kind of recurring strain or theme in evolution that things start out kind of, you know, they start out kind of unnecessarily complicated and then the selection pressure widdles things down to a fighting trim. So in a way it almost makes sense that it would've been an abundant but kind of energetically messy situation.
And that citrate is something that maybe was like stumbled on later as like an improvement on this kind of…
Kate Adamala (27m 1s): Once the citrate was around then we might as well use it for something else. That's another trait of evolution is once something's around, let's reuse it.
Michael Garfield (27m 10s): So okay so there's another piece in this in this paper I wanna address before we move on and that's this you were in the, the monolith monologues that we did here at SFI and so was at Jeremy England a link to this, it was great. It was like a who's who thing where everybody took turns and passed these, this conversation around. And Jeremy is one of these folks that has been working on articulating the theory around, you know, non-equilibrium processes and life being calling back to Ilya Prigogine work on dissipated structures that like life is a pattern that forms in response to the flow of energy through an environment.
And so you say in this paper that you were able to achieve the results that you did by mimicking the flow of external solution of fresh monomers over vesicles. You have to do it in this study by the periodic dialysis of modern model protocells. But like going back to that again to that question of ancestral environment, it does seem like it would sort of restrict the search. So there are these different candidates for the location of the origin of life.
It's kind of like hilarious how heated this debate is between like the deep sea event people and the warm little pond like geothermal pool people. But I'm curious whether you feel like this skews that weights things towards one side or another of that debate. Like would it be easier in a geothermal pool to achieve the kind of results that you've achieved in this or is it a wash?
Kate Adamala (28m 54s): I actually, one of the reasons why I love the results we got is because it is a wash. It doesn’t either side and I personally don't have a side in this debate because I'm friends and I respect people on both sides. I love hydro vents and I love warm little pond. I also, you know, there's a third very vocal side which is hydrothermal but fresh water. So when people normally when people talk about hydrothermal vents, they talk about sea, they talk about salt water, but there's also ways to get hydrothermal in fresh water like in Yellowstone.
There are many ways of doing it all way as long as there’s water and heat involved. So every possible environment could give you those conditions. And we also don't answer the question of freefloating versus minerals because as long as some monomers over my vesicles I'm happy and can be done under all of those conditions. So in a way that that paper was really annoying for a lot of people that were hoping that it would settle the debate because it didn't.
It just shows that it's possible to do it under all of those conditions.
Michael Garfield (30m 13s): Okay, awesome. So from there you did it this other paper with Jack Szostak competition between model protocells driven by an encapsulated catalyst in nature chemistry in in 2013. This is another one where reading this I almost get a sense for the piece meal innovation of the traits that we now bundle under the heading of life. And I, if you can just give us a little exposition on this paper before I dive into it with you please.
Kate Adamala (30m 46s): So one of the hallmarks of life that people often cite is ability, ability to compete with others for resources and winning defined as growing bigger, growing faster, and on the guts that you have, what's inside you. And in this case, in case of that work, we show that this extremely simple dumb peptide, it's a tiny little peptide.
It's not even I feel like I'm a fraud calling it as a peptide. It's just a dye peptide two amino acids linked together that provides advantage to synthetic cells. They can compete, they can literally eat resources away from those poor little cells that have none of the dipeptide. And this is the absolute simplest possible example of the survival of the fittest of the competition.
It's, which is, you really call it Darwinian evolution that we understand Darwinian evolution. But if you imagine making on template the cell has the ability to make those peptides something, so that was biggest selling point of that.
So, so a peptide can impart advantage on a population of cells that they grow faster and they grow and compete for resources. They eat faster basically.
Michael Garfield (32m 37s): So just to situate this as you do in this piece, this is reflecting on and adding necessary nuance to an earlier way of thinking about an earlier model in which you have this competitive growth between RNA replication mutations that led to greater replicas activity would result in a more rapid increase in internal RNA concentration and internal osmotic pressure, faster vesicle swelling, all of the stuff that you just said.
But you make the point that this model suffers from the lack of a plausible mechanism for the division of osmotically swollen vesicle. Yeah, so like that's the thing that I was like wait a minute, you know you need to have not just sell growth but replication and you can have sell growth without replication
Kate Adamala (33m 30s): And that's still an unsolved problem. We still have no freaking idea how those things could self replicate. Actually that's a very important distinction. We can replicate them but they do not self-replicate. That's a big difference and that's a difference in the all current origins and synthetic cell research. We can replicate those guys by forcing them either through a little filter or through minerals but they do not self-replicate. And that's one of the biggest kinda a milestones or boundaries.
If you ask most people what would be the biggest line if they had to draw a line between life and non-life, a lot of people would say self-replication. That's also flawed. That argument is flawed because for example, I do not self-replicate neither do you. So we're not alive by that definition. If self is required for life then we're all dead. That's too bad. But in this particular case of that dipeptide competition we just show that they grow faster. If you then for example you exclude them so artificially divide them into daughter vesicles, the ones that grow will make more kids, will make more daughters.
I dunno why vesicles are always daughters. When you replicate vesicles you always call them daughter vesicles. There's no son vesicles. So replication is essential but it doesn't always have to be self replication.
Michael Garfield (35m 0s): So, okay, so I, I wanna linger here on the point that you just made because I loved hearing people take you to task on this in the recent multiple life workshop at SFI. You know when you said where they're like, well why not alive? And you answered because we have to tell it to divide.
Kate Adamala (35m 17s): To me that that's my personal boundary. If we have to tell it to divide then it's not alive. And a lot of people disagreed with me at that workshop. They said it's already alive.
Michael Garfield (35m 28s): Yeah but I to what you just said and I remember getting into an argument with my high school biology teacher about this when you know she was not one of these life is a spectrum kind of people and she was trying to impart on us that viruses are not alive. And I was like, well okay now wait a minute cuz like it gets to this kee issue around context and dependence on context. You know, I think about the essay that David Wolpert wrote for a Covid transmission series where he was talking about the way the Covid virus leverages external computation of a cell in order to achieve its goals in much the same way that we rely on cloud computing now to assist in human cognition.
And that everywhere you look living processes are running as fast and cheap as they can by offshoring as much of the labor as possible is like one kind of dangerously general way of thinking about this. But again, that gets to this question about people tend to think about the emergence of a biosphere from a geosphere. But, and there's another way of thinking about it and I'm curious about where you sit with all of this, that it may be less that the origin of life was about a fundamental shift in the capacities of the geosphere, more about the concentration of behavior that was already happening in a kind of diffuse way in the environment and a focusing of these characteristics into compartmentalized lineages.
And so again, as this question of like, well does it even make sense to define life in opposition to non-life when one of the things that if you look at papers like the Information Theory of Individuality puts individuals on this spectrum where you've got even on the end of the spectrum where you're talking about individuals in a kind of conventional sense as being defined by lineages of information that are passed on through processes of inheritance.
They're still to some degree like scaffolded by these relationships with their environment and this idea which is sort of like almost, I don't know what you call like a transhumanist fantasy, that we're ever going to fully escape, that we will be able to become completely self-contained and self-reliant just seems to be constantly challenged by work like yours and the work of your colleagues. So again, this is a less a scientific question maybe than a philosophical question, but in light of all of this stuff, yeah, perhaps what I'm really pointing to for is the question of does this shift in our framing change the question that we're even asking in the first place when we're asking about the origins of life and how to think about the processes of life.
Kate Adamala (38m 48s): Definitely it used to be that people were hoping to be able define a moment when life just sprouted. So like if you had a dead planet on Monday and then you have a living planet on a Tuesday and that never happened. We're more and more we're working on it. We're realizing that there was no hardcore transition like that. It was a very slow, very unsatisfying from an external observer's point of view process where you had a little bit alive a little bit dead and at some point it sprouted and started talking and making YouTube videos and it was a gradual process.
It was never that there was a boundary. And like same with viruses, I think a virus particle by itself is probably dead, but viruses are a biomarker of biosphere. There are a biomarker because you cannot have a virus without a biosphere. Same like with a piece of hair. Like a piece of hair from my head is dead as a nail, but it is a sign of a biosphere because couldn't have that hair without my head.
So there's never, or there's very rarely a clear line like it's hard to say that this particular biochemical system is living and this one's totally dead. The best we can for is everyone will look at it and say this wasn't alive. And as you added more functions it became more and more alive. But I think you'll never get a system where everyone agrees on where that transition lies.
Michael Garfield (40m 32s): So there are two points that came up reading this that I'm really curious to explore with you. One of which is actually three, three points that came up reading this. You mentioned earlier that there is this question of cell reproduction that dangles beyond the answers about cell growth. And you say in this paper “we observed that low levels of phosphates can drive the competitive growth of fatty acid vesicles in a manner that circumvents the problem by causing growth in filamentous structures that divide readily in response to mild sheer stresses.”
So like this, in thinking about what it means, the origins of replication and the origins of like death and these kinds of things and thinking of them perhaps less as chemical processes or processes that are living by nature. But it again, it bridges things like the sheer forces that break rocks in half and being like these are mechanical strains.
And so you get from there it seems like we're, you know, we're kind of groping towards a bridge between physics and biology that we can actually walk across.
Kate Adamala (41m 48s): And there will always be a gradual transition. It will never be like there is a gate on that bridge. It's always going to be a just a slow leisure walk. And I think people just have to get okay with it. I know a lot of people would like to see the moment with first made life in the moment started on earth, but it was never like that. It was always just this very gradual process.
Michael Garfield (42m 14s): So to that point, there's another kind of curious thing in this paper, which is that you note that the dipeptide that you used as a catalyst in this, at least in your system is not heritable. So you've got it, it's again, it's the citrate thing, it's being supplied by the environment. Yep. But they have not internalized that order. They haven't folded it into their own.
Kate Adamala (42m 39s): That's why it's not parable, that's why it's, that's why it's not true Darwinian evolution because cells just happen to get lucky to have this catalyst but they don't make it themselves and the offspring doesn't make it either.
Michael Garfield (42m 52s): That's funny. Maybe I'm drawing too tenuous of an analogy but I, you know, our former Chairman of the Board, Michael Mauboussin has written about in finance about the difference between strategy and luck and a lot of like a lot of our like the economics work, I think, I'm trying to think Scott Page I thinking others have challenged this idea of of meritocracy because like the story is that people are, again, people are self made and it's like well you know, they're not so much of it is the conditions of birth.
Matt Jackson is another one of these people that it's like actually it's real estate is location, location, location. So that seems like that was true from the very start,
Kate Adamala (43m 34s): From the very beginning there were the cells and the peasant cells that were being eaten.
Michael Garfield (43m 43s): One thing that actually I do think is to make this a little less ridiculous, you mentioned in this paper that competitive growth happens in conditions with like a low salt concentration, but then my sole uptake happens in conditions with a high salt concentration. So this gets us back to the question of does this result answer or start to answer where we ought to be looking because I know that like when you're talking about freshwater geothermal hypothesis, like that's Deemer and Bruce Damer are one of the teams working on that and a crucial feature in their model is that the hot springs are drying out periodically and so they're actually dilute and highly concentrated.
The cyclicity is key to their model. And I don't really know how that works with like a deep sea vent where everything is in a kind of a continuously, you're just surrounded by the ocean all the time. So do you think that this is a point in favor again or do you think that there are ways in which a deep sea event model can accommodate and address this particular challenge?
Kate Adamala (45m 4s): A again to the frustration of people that have one favorite location, there are ways to build that model in every possible location. Because for example, oceans have currents of different solidity as well. There are parts of the ocean where there are those currents that have different solidity, different concentration of different ions, different concentration of organic molecules. So it's not impossible to imagine that around a deep sea event where there is a lot of current going on anyway there could be areas that have lower solidity and areas that have higher solidity. That particular scenario is easier to, because it's already built into the deemers freshwater event theory. But that doesn't mean that deep see people throwing the towel because it's possible for them to imagine that scenario too. And that's why I cannot say which one is better, which one is more likely. It would be really funny if none of them, it would be really funny if actually all of them can work and life actually started in few of those places simultaneously and then they put it out like there was this first great battle of cells where they all meet each other.
Michael Garfield (46m 20s): I mean that doesn't seem totally implausible based on just the fact that you think about in human history, how very common it is that something is invented simultaneously in multiple locations at the same time. Like Thomas Edison being the 23rd person who applied for a patent on the light bulb. Kevin Kelly actually has a great chapter in his general audience book what technology wants about this particular thing. And again it speaks to the challenges to a kind of a modern framework or a modern concept of the individual because his point is that there's something about an idea whose time has come. Again to your earlier comments about life using pieces that are just lying around and then repurposing them that it may be it.
Kate Adamala (47m 12s): It does it all the time.
Michael Garfield (47m 13s): It doesn't seem beyond the pale at all. At least for me to consider exactly what you said.
Kate Adamala (47m 19s): It actually seems more likely than coming up with it once and be done. I mean life is lazy, we're all lazy and that's a good thing. So if you can reduce something that already existed, why wouldn't you?
Michael Garfield (47m 33s): Now that's kind of funny because at the multiple life workshop you were making a point about the possible applications of your work to agnostic astrobiology, to thinking beyond just the one lineage that we can study here on earth, that we can create alternatives. And you said there biology is incredibly boring because it all comes from the same place. So that may seem kind of paradoxical at first, but it just draws attention to the way that like in complex systems thinking you've got multiple different points of focus at different scales or like different ways of course graining something, so that you zoom out enough and you're talking about an end of one and you zoom in and fur far enough and you're talking about multiple competing points of origin and these are not statements that are actually in conflict with each other.
Kate Adamala (48m 27s): Absolutely. And you see that at every level of biochemistry. If you were an alien coming to the solar system, you look at terestial life and like okay it's all the same, it's super boring, it's all uses the same molecule. So it's all one life form. But if you are a dog person and you look at a white golden retriever versus red golden retriever, completely different personalities. The same breed but completely different dogs. And so it all depends on how deep down you look at it.
Michael Garfield (48m 58s): So to that point Michael Lachmann likes to think about this lineages of information and when we had Sara Walker on the show, she cited him and how he likes to talk about how he is the one holding the baton for like a nearly 14 billion year old informational lineage. And so in that way, and I’m just curious what your thoughts are on this in that way, no matter how alien the chemistry of a synthetic system that we're talking about here, that there is a sense in the way that like Chris Kempes and David Krakauer talked about it in their multiple paths to multiple life paper or the way that Hans Moravec talks about machine intelligence and robotics as mind children in his book, that no matter how wacky the artificial life forms we can create, they are nonetheless part of this informational lineage that shares a common ancestry with everything else on earth
Kate Adamala (49m 59s): Because we made them.
Michael Garfield (49m 60s): Them. Right. So there's that you can never actually escape your own perspective kind of thing going on there. So I'm curious how you hold the tension between those two statements, the statement of we can learn something about something that's fundamentally alien and also we're basically just creating more of ourselves.
Kate Adamala (50m 20s): Both are true. And I'm glad you brought up Sara's work because she touches on that a lot in her work. It all depends on how finely or coarsely you grain it. What are you looking for? Cause you know there's this gravity well of life that we cannot escape cause we're it, And when we make a synthetic cell that looks completely different than our own cell, it will still be a cell, that fundamental thing that a guy looked at under the microscope two years ago and said, oh this this like a cell, let's call it cell.
And when we make a synthetic cell it's still gonna be a cell, it's still gonna have a membrane or some sort of a compartment. It's still gonna have some sort of a genetic heritability. It's still gonna make enzymes. So in a way we're not actually reinventing a wheel from scratch, we're just building a wheel from different material. And it’s gonna be a different wheel, it’s gonna spin differently but it’s still a wheel so in that sense we’re incapable of making something that’s completely different and because we’re not it we don’t know if it’s completely possible.
And now that we're, you know, switching to intelligence done by computers, you think it would be fundamentally different. But it isn't because we made it. And the same with any form of artificial life. As long as our hands make it, it's gonna look something like the life that we are. Which is kinda depressing when you think about it.
Michael Garfield (51m 45s): But what I liked about Sara's statement on the show was that that is true and yet the deeper we explore this stuff, the more general and more fundamental like her question was about mathematics and like are is alien mathematics gonna look enough like ours that we would be able to communicate with each other? And what I loved about her point was that basically the more deeply we know something, the more we will ultimately end up identifying with the alien.
And so like in a way her point was that as soon as we are capable of thinking of ourselves in this much less sort of limited and parochial way than whatever alien intelligences we encounter will no longer be alien by the time we encounter them that this whole thing about ongoing research in animal cognition or in mycorrhizal networks in the woods, you know, and suddenly these things that seemed completely, you know like that's not intelligence and now it's like well there are two crows working together to solve a puzzle.
Kate Adamala (53m 1s): That's almost the very definition of synthetic and alien.
Michael Garfield (53m 5s): Yeah. So the last thing I want to, yeah, aliens are weird until they're not right? It's sort of like, yeah, when we're children and boys and girls, it's like that's the alien.
Kate Adamala (53m 16s): Oh wait, that never goes away. Guys are still weird.
Michael Garfield (53m 20s): It's like hopefully we grow out of that or maybe not growing out of that is inhibiting our ability to communicate with extraterrestrials.
Kate Adamala (53m 30s): We can communicate but I still don't understand how do you wanna keep the AC that low? How are you not all the time cold?
Michael Garfield (53m 40s): But I mean but that's built into the sort of fundamental value of diversity in living systems, reservoir is a variation. That's why like sexual recombination exists in the first place, right? So we're a victim of our own success.
Kate Adamala (53m 60s): True.
Michael Garfield (54m 1s): So, okay, so I wanna cool down this conversation about 20 degrees and leave this where you kind of teased at the beginning of this episode with something more grounded and practical than these enormous abstract concerns, which is about the practical medical therapeutic applications of the work that you're doing and you know how this work, whether or not it solves for the origin of life or discovery of extraterrestrial biology, what value it confers to the way that we think about and we practice medicine. So there's this paper that you coauthored synthetic cells and biomedical applications and this is just a fascinating tour of all of the reasons why your work should be funded.
Kate Adamala (55m 2s): Why do you think I wrote that paper?
Michael Garfield (55m 5s): So I would love to hear, Yes. So I'd love to hear you give us a little bit of a tour of why it is specifically that synthetic cells are such potent tools in the delivery of medicine and in other applications
Kate Adamala (55m 21s): It's because they're kind of a middle ground between too dumb and too smart. So too dumb is just a simple molecule that you inject into a patient and then a go does something that you can control it once you inject it because it's just a molecule. So for example, if you take ibuprofen, that molecule gets into your tummy and gets into your bloodstream, goes wherever, screws up your liver in addition to helping your back pain. Then on the completely different end of the spectrum you have those exceedingly smart drugs, for example car T-cells.
They're your own cells that are taken out, your body we combined and then put back and yeah they cure but they also get in trouble cause they get too enthusiastic and they give you leukemia cause they, they're like, Yay, let's now kill everything and that includes yourself and that's how leukemia is born. And so sometimes a drug needs to be smart because you want be able to target it to a particular site. For example, if you have a long tumor, it would be nice to take a drug that's only gonna target your tumor and not you nauseous and all the other side effects if in something to do with that.
And so synthetic cells are kinda like a dumb dog in this comparison. They're trainable. You can, especially if they're food motivated, you can train them to follow directions, but they're not too smart. They're not gonna get in trouble. So they're kind of a middle completely not controllable simple molecules and those very, very complex programmed cell-based therapies. And another reason why we need them is because the biomedical progress is actually extremely frustratingly slow these days that there is this almost Moore's law happening in biomedicine right now.
Michael Garfield (57m 26s): So I'm gonna play the devil's advocate here because guy with a Jurassic Park tattoo grew up watching films like Blade Runner where they've got the program death of the replicates and the replicates end up killing the CEO trying to find a way to get it. So I mean here and you actually do address this in another paper on the Build to Cell Project, which we haven't even gotten to and is really, really cool. But you specifically address this question of public concerns regarding synthetic cells.
I'm hoping to get Ricard Sole on the show soon. And one of the things that I wanna talk with him about is that he has this whole idea about engineering synthetic cells to help sort of terraform our planet to fight runaway climate change. And you have also talked about the idea of life bombs being able to drop cells and like seed biosphere and this kind of thing. So I'm curious how have you thought through these questions about public concerns about the implications of your work and the possibility of unintended, but were it ever to happen everyone would be like, I told you so, so yeah, you're the expert here. Why should I not be worried about this?
Kate Adamala (58m 51s): First, you shouldn't be worried about this because we're not that good at it. I would love if my synthetic cells had the potential to leave the island and replicate on the main land just by some of kind of beets, but they can't, They're too primitive, they're not good enough to do that right now and they won't be good enough for a very long time. And the simple reason is that there is a lot of competition. Life had 4 billion years to basically test every single competition scenario under these conditions.
And we're making those fake cells in the lab that are not good at pretty much anything. So even when they self-replicate, they'll not be robust. And that is a bug and a feature. It's a bug because I would them to be more robust. But it's a feature because in competition with any highly evolved cell, the synthetic cells are meat. They will just be eaten, they have absolutely no chance. And there is no way to build robustness like that into synthetic cells the way we make them right now because we don't have 4 billion years.
And so we can't test every scenario. We can't have those synthetic cells compete under every possible condition. So for example, when you think about biomedical applications, the cells that would be injected into a patient will just not have any self- replicating machinery. So it's not like a kill switch when you take away one thing that's needed for replication, it's no circuits at all. No switch is needed because the circuit doesn't exist.
They don't have anything that's needed for replication. So there is no way in hell they can replicate because they just don't have that hardware to work with to even start developing replication. And then when you think about building, for example, terraforming tools for Mars, they would be optimized and there's such different conditions that they probably wouldn't even be able to survive on earth no matter how hard we try. And then any kind of bio reactor that we release into the environment, the biggest danger of that is not that that bio reactor will self-replicate and go on, it'll be that it'll pass on its genes, at least some of it genes.
And that's a valid concern. And for that we're working on right now on designing those circuits, on designing those kinda genomes in a way that this horizontal gene transfer doesn't happen. And that's something that our community works on. That's kind a big bio safety biosecurity focus on our work is how to make those guys stay in their lane how to make them not spread their good and that draws heavily from other GMO research people that made other genetically modified organisms that have been released to the environment.
You know, we had those conversations ever since ice minus and the world haven't ended so far.
Michael Garfield (1h 1m 48s): That all makes sense up to the point. But past performance doesn't guarantee future results. And given that your work is, you know, there's something kind of recursive going on here where you know, you're identifying the primitives for evolutionary arms races. Like you're seeing the inkling or the prequel to that and being alive at a time of extraordinary rapid change. You know, like talking with Geoff West about the way that the social reactors of cities lead to these increasingly accelerated innovation crisis cycles.
He's really worried we're not going to be able to avoid collapse. And you know, the red queen evolutionary arms race thing does seem to accelerate. It brings you closer to the edge of the cliff faster. And so I'm curious maybe not so much in the way that we were just addressing this, this problem with this the kind of lifelike but non-living synthetic cells. But in terms of the success of finally being able to reproduce all of the conditions of and actually make something that's alive and then you know what that's gonna mean when that becomes a part of the ubiquitous technological toolkit for our species.
And you have, it's sort of like akin to the crisper question, right? When you have like armies of people that are trying to pollute the ecosystem with competing gene drives, you know? How do we think ethically about that kind of question?
Kate Adamala (1h 3m 27s): We should not be doing it. Absolutely. And I mean on one hand I think humanity has better ways to kill ourselves. You know, we can drop few notes and we're done. So I'm less worried about synthetic cells or even gene drives being the civilization ending event just because we head the technology to wipe ourselves out or at least go back to the caves for what, 70, 80 years now. So if it's gonna happen, it's gonna happen and I won't care because I'll be dead.
The dangers of the bio, any bio security risks are mostly in unintended uses and unintended consequences. And you know, the same for gene drives, same for crisper for any sort of thing we release to the environment. We don't know enough to release something safely and you know, we thought we know what we're doing when we were releasing rabbits and other animals in Australia. We know how well that turned out.
And so I'm always extremely cautious when I think about any environmental release because we've proven, and I know past performance is not an indicator, but we've proven that we suck at it.
Michael Garfield (1h 4m 44s): I feel like I'm sort of manic depressive in the bioethics conversation going from like horror to excitement and enthusiasm. It seems like what you're saying about something you said a moment ago about your lack of concern about the release of synthetic cells because they would just be food for the biosphere that already exists seems to point to this question of whether or not like we were addressing earlier the possibility of multiple points of origin of life and that, you know, again, to just get sort of like lofty and philosophical here in the final stretch of this chat, it seems like one of the implications of your work is that we might be completely wrong in assuming that there was one origin billions of years ago and that it's not something that's happening all the time and just getting snapped up before we can even observe it.That you know, that there may be efforts, life may start to emerge and then it's just sort of devoured.
Kate Adamala (1h 5m 54s): Yeah. I think a lot of people would agree that that's absolutely plausible that that probiotic evolution or at least very early evolution can be going on somewhere and as soon as something emerges, it gets such as life.
Michael Garfield (1h 6m 9s): So that speaks to a bigger theme that a thread through SFI work on incumbency and the suppression of innovation. But I don't know if it's worth getting into that.
Kate Adamala (1h 6m 21s): I mean, the same thing would with synthetic cells, if we make a synthetic that's better in some way than natural cells that not as robust even take it and it will be numb and synthetic, it even proves that it's better at that one thing
Michael Garfield (1h 6m 41s): Like beta max, right? It just fails in the market. Well, Kate, this has been really cool. You know, before we wrap this, I just wanna give you the opportunity to stump Build a Cell and if you have anything else that you wanna point people to, to give you the opportunity to do that.
Kate Adamala (1h 6m 60s): So Build a Cell came from understanding that not a single lab or not a single country can and should build life from scratch. And because there's a lot of people that want to build synthetic cells for different reasons with different motivations, but we all have the same goal we decided to start working together and that's how it came to be is where an international community that's open to everyone and by everyone I really mean literally everyone. If you are a physicist or if you're a member of the public, or if you're a teacher, or if you are a biologist and you think current life is perfectly good enough, but you're curious about what possible fake lives could look like, that's what the community is for.
And we are kind of an informal group of nice people that just get together and talks about how to make sales and how to make it safely. One of the biggest kind of goals of our community is to facilitate research that's shareable and safe. So when we do it, we consider all the limitations. We consider all the kinda shortcomings of current protocols, we develop new protocols.
Michael Garfield (1h 8m 10s): Awesome. So just in parting, I'd love to leave people with a sense of wonder and mystery and I would like to know what is the most vexing slash inspiring unanswered question for you that we haven't already addressed in this conversation? Like, what's the frontier? What giant question can you leave us with?
Kate Adamala (1h 8m 33s): My most fascinating question is what if? How could life look like that we can't even imagine right now? So if we make life from a completely different building blocks than the life we know it right now, how is it gonna behave? Is it still gonna evolve and fight for food and make babies, or is there gonna be some completely new property of life that we can't even think about? We've never done it. That's the biggest, most fascinating question for is what life can do that we haven't on.
Michael Garfield (1h 9m 10s): That's a fine place to this. Thank you so much, Kate, for being on this show.
Kate Adamala (1h 9m 16s): Thank you so much for having me.
Michael Garfield (1h 9m 18s): Thank you for listening. Complexities produced by the Santa Fe Institute, a nonprofit hub for complex systems science located in the high desert of New Mexico. For more information, including transcripts, research links, and educational resources, or to support our science and communication efforts, visit Santafe.edu/podcast.