Building Life from Scratch with Kerstin Göpfrich

0:00So Matt, she's making aliens in the laboratory. She is the puppet master. She's the new creator of the universe, and it's quite terrifying, but fun. It's informative, but terrifying. Scientifically enlightened, I would say. Very. Coming up on StarTalk. Welcome to StarTalk. Your place in the universe where science and pop culture collide. StarTalk begins right now. this is star talk neil degrasse tyson your personal astrophysicist i got with me today matt kershyn hey welcome back thank you so much neil it's good to be back yeah it's been too long it's been a while it's nice to be back in new york in the office it's great but where are you based i'm in la i'm still in la you're a la guy i knew that i knew that yeah so it's nice to be back over on this coast so we nab you every time you slip by anytime i'm anywhere near i will i I will hit your people up and...

0:57And now you're on tour, apparently. Oh my gosh. Yeah, well, I'm on two sort of... So I'm touring at the moment with opening for Sarah Millican, who's a great UK comic. So I'm doing lovely theaters with her. But she's coming through the States. She's doing the US. And then I'm also doing my own headlining spots kind of off the back of those shows. So I'm like, hey, loads and loads of people, if you enjoyed me for 15 minutes in this massive room and want to see me do a headline show in a significantly smaller room, then... So yeah, I'm doing those. So yeah, StarTalk listeners. Okay, cool. So we can find you mattkirchen.com.

1:28mattkirchen.com. Yeah, and all the tour dates and the links are up there. Very cool. Such a big fan of comedians. Thanks for being a part of civilization. Oh, well, I've never heard it put like that. That is a much deeper way than I've ever had my job described before, and I love that. Tell your parents that, too, in case they were wondering. Mom, Dad, you know that degree that I did nothing with and then ran off to join the circus? Well, I am a deep part of civilization. Exactly. There you go. Well, today's topic, oh my gosh, oh my gosh, we're talking about making life from scratch. Speaking of parts of civilization.

2:08Making life from scratch, which technically would be alien life, if you think about it that way, right? I mean, if it's life that has never existed on Earth before. Yeah, what are the rules? Because if it's made from scratch on Earth, is that alien? I don't know. I guess we're getting into immigration questions now.

2:28illegal aliens or legal aliens yeah is there birthright laws for if you make them in the united states they're native to america right right all right or if you make them on an army base in another country then i don't know like what are we doing here so i don't have sufficient expertise on this yeah and as as what we do on star talk is find the expertise wherever it is And that took us to Heidelberg. Nice. Oh my gosh. Beautiful city. Join me in welcoming Kirsten Goprich. Did I pronounce that correctly? Excellent. I'm very excited to be here, Neil. That was two thumbs up. Two thumbs up. Two thumbs up.

3:08Kirsten, thanks for agreeing to this conversation. You are professor at the Center for Molecular Biology at Heidelberg University. Love it. And you led the Max Planck Research Group in Biophysical Engineering of Life. Ooh. Now, just remind me, because there's a Max Planck Institute for Astrophysics. So there are Max Planck Institutes for many different branches of science, correct? Indeed. There's more than 80 Max Planck Institutes across Germany and abroad, actually. Yeah. I didn't know there were even that many. Max Planck is basically birth quantum physics. Right. with a paper he published in 1900 saying, hey, wait a minute.

3:51Maybe energy is not a continuum. Maybe it comes in quantized amounts. I didn't know. So he would be considered the father of, or one of the fathers of quantum physics. He planted this seed that completely blossomed a century ago, like Max Planck. And he's duly honored in all of these institutes throughout Germany. You got your PhD at the University of Cambridge and where you were a Marie Curie fellow in synthetic biology. Wow. That means you are Dr. Frankenstein creating life in a laboratory. Have I mischaracterized you in any way by calling you that? I'm not Dr. Frankenstein. No, and that's not our aim.

4:36Our aim is really to create a synthetic cell from the bottom up. So to achieve a transition from method to life in the laboratory, that's right. Yes. So just to be clear, you don't have to wait for lightning to strike the lab before? No, not really. Not really. And we are also doing it with the best intentions, I have to say. The lightning is metaphor for an energy source that would then infuse the life form. So why don't we just start from the beginning? Do we have a sufficiently good definition of life for us to then know the moment you may have created it? Yeah, so there's many definitions of life out there, right?

5:18And there's not really consensus on one, but I would say in my field, bottom-up synthetic biology, what we really use as a working definition, and you'll be happy to hear this, Neil, is a self-sustaining chemical system capable of Darwinian evolution. And that definition was put forward by the NASA. And we extend it. We don't just want a system capable of Darwinian evolution. We actually want a system capable of open-ended evolution. So it can essentially increase itself in complexity. It can evolve to perform any desired task in the end. So that's what we are after. So what's the difference between Darwinian evolution and open evolution?

6:00So Darwinian evolution, there can be open-endedness in Darwinian evolution. So what we are really after is a system where the evolutionary landscape is large enough so that at any given time, the number of genotypes only exploit a sufficiently small space on that evolutionary landscape, so to say. So there is really a lot of space to introduce serendipity, to introduce changes, to introduce, well, also some kind of emigrant properties that are inherent to living systems. So Darwinian would presume that the change is favored only for the survival of the organism. And you're suggesting there might be forces operating that just simply change the organism without reference to its survival.

6:51Is that a fair way to think about open-ended evolution? Yeah. Well, yeah. To essentially go for systems that increase in complexity and do interesting things. So that's what we are after. So if an organism never dies or lives sufficiently long, then it can't undergo Darwinian evolution. So on the population level, I think introducing death into living systems is absolutely crucial because otherwise, you know, you just have exponential growth and the resources will be exploited i've never heard anybody say that before we have to make sure you die in order to that for us to evolve you that kind of that makes perfect yeah again that that's sort of a little mind-blowing but yeah of course i'm not saying it doesn't make sense i'm just saying i never heard anybody admit that yeah so you're the first biologist i've heard be honest about the fact that darwinian evolution requires that everybody dies Yeah, so I mean, on the population level, at least when we think about synthetic cells, we really think about very, very minimal and living entities that are much simpler than the simplest cell that we currently know on Earth.

8:07So much simpler. We are really talking something where essentially we want to get to the point where chemical evolution becomes biological evolution, right? That's where we want to get. And in that context, I'm saying that if we manage to construct a system which is capable of self-replication, then eventually resources will be exploited, especially if you have, of course, limited resources, right? And in this stage, this is where, you know, we have a situation where survival of the fittest is what's driving evolution, essentially. We have a situation on our hands. So this conversion from complex chemistry to simple biology, that harkens back to the Miller-Urey experiment.

9:00Very famous experiment. When was that? In the 1960s, was it? Perhaps early 70s. Could you remind us about the Miller and Urey experiment and what that did in your field back then? Yeah. So I think it was earlier even than that. It was around 1950, 1952 or so when. Yeah, so it was the first time that essentially Miller was performing chemical reactions in a way that is kind of similar to the early Earth, to the environment on early Earth. So he was trying to recreate the atmosphere that was present on early Earth. And then he could see that very simple building blocks of life, such as some amino acids, which build proteins, so to say, were present in that solution after he provided the system with energy.

9:53So that kind of shows that organic synthesis is possible under prebiotic conditions, essentially. And, you know, that's far away from a biological system. So we're talking really individual amino acids, but it shows that prebiotic conditions can give rise to organic molecules like amino acids that build proteins today. So in the Miller-Urey experiment, they knew to start with organic molecules, right? They knew to start with that and they went to then see what the organic molecules might do for themselves. when left unmonitored and left alone, but they had to give it an energy source, right? And if memory serves, that energy source was a little spark, very Frankenstein-like.

10:43Simulating lightning, so to say, in early Earth. Yeah. You want a big light switch or something? Yeah, I want a massive lever that a henchman... Do you have a henchman? I'm hoping you have a henchman. A henchman in the lab. I'm afraid not. But what I find interesting about this experiment is that, you know, even before that, about 100 years earlier, there was the common belief among chemists at the time was that organic molecules are molecules which can only be synthesized by living things, right? Like that organic synthesis in the laboratory is essentially impossible. And then chemists at that time, like 1800 something, managed to actually make the first organic molecule synthetically in the lab.

11:28And that was actually urea. And that proved that we as human beings can synthesize organic molecules, which are otherwise made by living things from scratch. And I see synthetic biology or the bottom-up creation of synthetic life a little bit at a similar point right now where kind of a proof of principle is needed to show that we cannot only make organic molecules like the ones that were made in the Miller-Urey experiment, but that we can also actually achieve a transition from matter to life in a laboratory setting. How does your work follow this? And what's different about your approach? So essentially, we start at a much, much later point.

12:10So we start with biomolecules and we ask ourselves the question whether it's possible to actually assemble molecules in such a way that we can create a system that's capable of undergoing, create a self-sustaining chemical system that's capable of evolution. So that's our starting point and end goal. And what we do in order to get there is we are making lipid vesicles, so kind of the envelope of a cell. And we are building, constructing our own molecular machinery. And we do so with RNA, RNA nanotechnology. And that may be a little bit reminiscent of the RNA world hypothesis and the origins of life.

12:56field as i understand your work or any work that anyone does you are only as effective as the tools you use and if you're trying to assemble molecules you need something that can are they tweezers are they you need some tools that are small enough to take this molecule over here and attach it to that molecule over there. And it seems like this is the RNA nanotechnology that you're referring to. Your toolkit are not mechanical tools. They're biological and chemical tools. Is that a fair way to characterize what you're doing? Indeed, indeed. So we don't use tweezers on a nanoscale, although they exist, right?

13:48That's actually an amazing part of physics. they do exist. But what we do is we actually do something very similar to what a protein designer would do, right? Protein design won the Nobel Prize last year. And we do something similar, or we're trying to do something similar with RNA. And that's a much less explored field indeed. So RNA origami is quite new. But what we are essentially trying to do is we are trying to assemble a synthetic gene from scratch, a piece of DNA, which encodes for an RNA that folds up during transcription. So while the DNA is read off, it folds up into a desired structure.

14:29So that could be something that resembles a cytoskeletal element, or it could be something that resembles a nanopore that assembles into the lipid membrane of a cell. So we can feed it, for instance. So So the functionality, so the forms are really driven by the function that we would like to create. And design happens with computational tools, essentially. So the folding, I'm fascinated by the folding. Absolutely. As a kid, I was into origami. And I still am a little bit. I have big pudgy fingers, but I'm very delicate with my little birds. And I can still do it. I got like three left in my repertoire.

15:19I'm Nicholas Costella, and I'm a proud supporter of StarTalk on Patreon. This is StarTalk with Neil deGrasse Tyson.

15:38do you know in advance how you need to fold your proteins because the protein itself is obviously not yet life so you you do you know what you're doing if if you don't know no i mean it's this It's rumored that this is what Einstein said. Research is what I'm doing when I don't know what I'm doing. Right. So if you're not targeting a life form you already know about, then how do you direct the decisions you make towards a life form that has never existed before? Well, essentially, we know what functions we need to realize, right? So we want, in the end, a self-replicating system, which is capable to evolve.

16:24And in order to have that, first of all, the system needs to be able to build up its own molecular machinery and that machinery we build from RNA. And one piece that we think is crucial for such a machinery is actually kind of a machinery which can divide a lipid vesicle. So essentially impose a certain amount of membrane curvature on the membrane of a vesicle. And in natural cells, this happens via an architecture that's called the cytoskeleton, the skeleton of a cell. So one of the first kind of things that we build with RNA, that we build from RNA was actually cytoskeletal mimics, so to say, but all from RNA, not from protein.

17:07So we look at them. We look at how they look in nature. We look at how they function in nature. And we are trying to design something which looks very similar. So that could be, first of all, small building blocks that then assemble into micrometer-long filaments that then can, for instance, attach to the membrane so that the membrane can be deformed. And because they are genetically encoded, we now have actually a quite powerful helper, and that's evolution. So essentially, we can then start to go to the DNA level again and introduce mutations so that we can evolve the RNA structures towards even better function.

17:47So you are introducing your own mutations? Well, we have biological machinery introduce them, essentially, yes. You're not going to wait around a billion years or a million years. You're doing it yourself. We're doing two things here. We start with a rationally engineering starting point, right? So we already know what we want to get. So we have a very simple version that already works a bit. And then we let evolution brush it up, so to say. Where does information theory fold into this? Because when we're taught DNA in school, we think of it less of a molecule, of course, that's what it is, but as something that encodes biological information.

18:31And so how do you make sure that the information that's in there is the information you need? So that's where computational design really comes in, right? So we really start with, we think of what kind of 3D architecture do we want to create from RNA. And then we essentially design a synthetic gene, a synthetic piece of DNA, which upon transcription, so when it's read by the biological polymerase, will make an RNA that folds up on itself in the desired way, essentially. How much of the sort of design in the fold, you said it's done computationally. So how much of it is sort of designed computationally and how much is it you physically do it and then you see what you end up with and adjust?

19:19First we design computationally and then we physically do it. We check it in the lab with experimental techniques like cryo-electron microscopy to really visualize single molecules and their architecture. And then we can essentially see if the structure is entirely correct or if we need to make improvements. on the DNA sequence level in order to fix certain things that we would like to look ever so slightly different. Is there a difference between you creating a life that we already know about, so synthetically creating a simple life? Because it seems to me that would be easier because you already know exactly what you're aiming for versus putting all this together and creating something no one has ever seen before.

20:06You'd still get a lot of credit in this world If you created a life form that already exists on Earth, just out of raw ingredients, that would still be amazing. But that's not good enough for you. You want something else to crawl out of the test tube. So essentially, there are different branches in the field of bottom-up synthetic biology, which use different types of molecules, different types of molecular building blocks. So either the very natural ones, so really taking pieces from cells, essentially proteins that you just encapsulate and boot, so to say, inside of a lipid vesicle. And then there is others who take entirely synthetic pieces.

20:46And then there is us who are somewhere in the middle. And, you know, there is pros and cons to using the biological machinery. But in the end, you know, I could imagine that bottom-up synthetic biology brings about multiple examples of synthetic life, the ones that are very similar to life as we know it and ones that are quite far away. The problem with biology as we know it is that it's already extremely complex, right? So to give you an example here, all life on Earth that we know adheres to the central dogma of molecular biology, which states that DNA makes RNA, RNA makes proteins. And now this machinery alone requires this step from RNA to protein requires 150 components, 150 genes just for this step.

21:37So if we can circumvent the use of proteins and we just build a functional machinery from RNA, so we have our genotypes stored in DNA, but we have the function in the RNA, the phenotype is introduced by RNA, then we can reduce the complexity of the system quite a lot. And, you know, life has not always been that complex. At the origins of life, simpler solution must have been capable of sustaining self-replication and evolution. And therefore, I believe that building our own molecular building blocks, so to say, can actually be a shortcut. But we'll see, you know, all of these approaches are super cool.

22:17And in the end, it would be amazing to have not just biology 2.0, but also 3.0, 4.0, 5.0 and so on. So all of this is valid. I like the fact that you took a look at life and said, I can do a better job. You can simplify it. It's very complex. Yeah, I can simplify that. That's delightfully audacious. Essentially, it's a little bit similar to, you know, we came from the Miller-Urey experiment, right? Where also you start with very, very simple building blocks. And I'm sure at the origins of life, self-replication and evolution have been sustained by a simpler set of building blocks. And, you know, one can ask if it's possible to use such building blocks to start not from where life is right now, because that took four billion years to get there, right?

23:15But to start actually at a simpler stage, essentially, but still have a system capable of evolution. That's really the holy grail, I would say here, because, you know, it's A, part of the fundamental definition of life, and B, will help us to get somewhere interesting. So do you think life on another planet is likely to have something very similar to our DNA, RNA, protein system, or do you think it could be a completely different self-replicating thing? Like, is it likely that -

24:15you're saying, yeah, any place we find life, it would have been through this. It would have arrived at the same solution. It would have found the same solution. Are you prepared to say that? In other words, even like if we replay history on this planet, right, would we end up with essentially the same thing? Or could we end up with something quite different? I said the evolutionary landscape is vast, right? We're just with life as we know it, exploring a tiny, tiny, tiny, tiny, tiny bit of that. And I believe that the idea of creating very minimal living systems from scratch will ultimately be able to help us to address these kinds of questions, right?

24:58So you could, for instance, introduce metabolic pathways that are completely different from the ones that we know from life as we know it into such artificial systems and study them. So at the moment, we don't have evidence for silicon-based life, right? But I think there's, personally, I think there's also reasons for that, right? Like both of them can do, can make four bonds, right? But it seems that carbon is just much more versatile. But, you know. The carbon in the universe is also like five times more abundant. So silicon sits right under carbon on the periodic table. So just as she said, they can each bond four ways.

25:40Everything in that column can. And so carbon has four electrons in its outer shell, and it can take four more, right? Which is a highly versatile situation to be in. But silicon can do that too. But we don't need, it'd be fun to find silicon-based life. We just don't need it because carbon is everywhere in the universe. Does the same job, but kind of better. Yeah, so do astrobiologists call you and get your insights into what they might be looking for? I would say the field is very, very interdisciplinary. Bottom-up synthetic biology is very interdisciplinary. And we are for sure keeping the discussion entirely open with astrobiologists and really also think about implementing solutions that evolution may not have explored.

26:37right and so that's for sure a super interesting conversation to be had you know something evolution did not come up with a four-legged vertebrate creature that also has wings but we've we have pegasus pegasus popped some wings out his back right that that is not in the plan okay so when you look at life on earth do you say here's something that evolution coulda, shoulda, maybe, but didn't. But it does seem, again, from my limited knowledge, it does seem that evolution does seem to keep landing on the same solutions for, you know, there are a bunch of different animals that have evolved through different pathways, the same things.

27:23Yeah, yeah, Karsten, is that, I like what he said there. Is that the same at the lower level? Yeah, evolution has found similar pathways to solve its survival problems that, and some are even unrelated, but they land in the same place. So that might give you insight, does it, for what biochemistry likes? Yeah. And I think one place where we could see this, for instance, is that when we build our life, our very, very minimal synthetic cell as the minimal unit of life, and I don't mean really a cell as we know it, but a very, very simple version of that, essentially, that that cell is by far not as efficient as life as we know it because its catalytic activity is based on RNA.

28:13and RNA catalysis is much slower than what proteins can do. And the moment you introduce proteins to the system, so a way of having translation of making, producing proteins inside of a synthetic cell, you may find that this is actually a much more efficient solution. So this may be why we don't see an RNA world around us anymore, simply because, you know, once you have proteins, they win in a direct competition. But again, if we start with a simple system, evolution may bring about these more complex systems, right? So, in fact, if you look at the ribosome, so the ribosome is the component in the cell which is responsible for turning RNA into protein.

28:58So, it's doing this translation inside of the cell. Then that ribosome, the catalytic activity, the core of the catalytic activity actually comes from RNA and not protein. So indeed, we have some of the most intricate molecular machines that cells use today are actually RNA-based. We want, when the aliens come, we want you in the room when that happens so that you might be able to understand what kind of life they are, right? You'd be perfectly suited for this. Is that correct? Well, let's see what they look like, right? I may or may not. As I understand it, correct me if I'm wrong, all life on Earth has a certain handedness in its molecules.

29:40Like it's all left-handed or it's all right, whatever it is, because some molecules are, they're not symmetric. Like they're mirror versions of them. Right. And so we're all one kind of molecule. Which one is it, left or right-handed? I forgot which it is. Left-handed. Yeah. So that origins of homochirality, actually. So the handedness of life, so to say, is another very, very interesting question. So in fact, we talked about the Miller-Urey experiment, right, where amino acids were produced. And actually in that experiment, a racemic mixture of these molecules was produced. So the left-handed version as well as the right-handed version, right?