Jack Szostak: Origin of life on earth and design of alternatives

thank you I like to thank thanks for inviting me back the molecular frontiers foundation and the Royal Academy and and all the people who helped to organize this this great event so we've heard a lot about questions as one of the things I like about science and what I particularly love about the subject of how life got started if there really a lot of questions and they really occur such a wide range of fields from astronomy to geology chemistry and biology and just getting to two to talk to people from so many different fields and try to figure out how everything comes together it is is really particularly fascinating and I think in addition to this approach to the world is always trying to ask new and interesting questions one of the great things about about science and I think it's really epitomized in in this field is is the way it brings people together to cooperate and collaborate and and try to get answers to some of the mysteries of nature and you know when we see so many divisive and tragic things happening in the world it's really wonderful that we're able to privilege to be able to work together so I thought I'd just say a couple of words about how I came to be interested in this and this subject so as Laurie mentioned and in the 1990s night my lab spent a lot of time learning how to evolve populations of molecules and I think you'll hear more about that tomorrow from Gerry Joyce and it was really fascinating endeavor and we were able to - thank you we were able to evolve new molecules that could do interesting things catalyzed reaction find two targets even lead to molecules that are are now in the clinic to treat diseases but after doing that for roughly a decade I became more and more fascinated by the question of how evolution actually that started spontaneously on the early earth there is one thing to direct evolution in the lab when you have enzymes and you know all kinds of instruments and brilliant students and but somehow the process of Darwinian evolution really got started and since I my original background is in biology to me the origins of evolution and the origins of biology are really really the same thing so so I started to focus more and more on those issues and that's what I'll try to talk about today and what you see on this opening slide is is just a an illustration of what a really simple view of a primitive cell might might look like now I hope I don't yeah okay so a primitive kind of membrane enclosing some very short pieces of genetic material we're not totally sure what that is but we think it's probably something like RNA and so we're trying to understand how structures like this came to exist on the early on the early Earth and and we're able to grow and divide them and start to evolve now one of the things that's really I think rekindled interest in these questions you know people have been asking how we got here you know how life got started for a long time but in recent years in last 10 or 20 years there's been an explosion of interest in this because of work from astronomy and we now know that there are millions probably hundreds of millions of planets that are reasonably earth-like in our galaxy alone and many of them could in principle we're pretty sure could support life so this is just a so diagram of another solar system many of you probably heard of the Trappist one system has been worked on a lot by didier akula's and now in Cambridge this the solar system has at least seven planets and three of them are in this Green Zone where there could be liquid water on the surface so it's quite likely that planets like this actually could support life well we don't know if they do is going to be really hard to figure out I mean the entire field of astronomy has been revolutionized by these kinds of discoveries and everyone is trying as hard as they can to work at the technology to actually detect signs of life on other planets so in parallel with that we can ask simple questions that we can address here in our laboratories and try to understand you know how how could life start on these planets how did it start on our planet you know if we understood the whole process we could have a better judgment as to have easier hard it is how likely it is that they'll be life out there so so there are a lot of questions in this whole pathway everything from planet formation to the early evolution but these are some of the questions I wanted to focus on today just in terms of how life actually gets started from the chemistry that's going on on a young planet so we need to understand how the building blocks of biology are actually synthesized right so this is the whole field of prebiotic chemistry so talk a little bit about that this is not work for my lab this is from from other other laboratories once you have the right chemicals how does have a bunch of chemicals get together and start acting like a living cell and that's the topic that we've been focusing on and then recently things have advanced to the point that we we think we can actually start to deduce something about the necessary environments and and this is bringing us into contact in discussions with planetary scientists and geologists and a spheric chemists to try to be as rigorous as we can in thinking about the right kinds of early planetary environments okay so let's start off with with the chemistry so this is a picture of Stanley miller's famous effer Attis in in which in 1952 he showed that using a spark discharge source of energy in what was then thought to be a realistic primitive atmosphere you could make all kinds of compounds including amino acids some of the quintessential building blocks of biology and it was really a revolutionary advance at the time it generated a huge amount of optimism that the chemistry leading to life would soon be figured out there was a lot of progress in the ensuing 10 or 20 years and then you know things kind of stalled and and some of the problems started to become more evident and in particular if you really start to look at what's in this mixture of compounds the closer you look the more you see there are thousands probably tens of thousands of different chemicals made in this kind of crude approach of just blasting an atmosphere with energy and the materials that you want a lot of them are in there but at very tiny levels and some of the materials we know we need are not there so how how can we think in a more realistic way about generating the building blocks that we need to put cells together and so I think this is really one of the transformations in the field so I'm not going to give a lot of the technical details I just want to try to give an impression of how the field has changed in the last 10 or 20 years and the new kinds of questions that were able to answer so this is the old idea of some kind of primordial soup that had everything in it floating around us I think this kind of now in the old way of thinking and what we're trying to figure out is you know how can we actually make chemical pathways realistic if you have to go through step after step after step to get to something complicated like a nucleotide that you need to make RNA it's not going to happen if you just mix everything together so there are new ideas like organic minerals building up reservoirs of intermediates so you can break a pathway into smaller chunks is it the stunning new term of systems chemistry which means you know not just doing what classical chemistry does if taking two compounds and making them react to make a product that you want but thinking about you know everything that could be around and you know what else can we use to make something work in a better way you know just give a couple of examples so one of the ideas that's actually been around but which has really gained a lot of traction now is that somewhat ironically life began from cyanide cyanides you know not so great for us now but it's a fantastic starting material you can make a huge range of compounds from Sinai how do you make cyanide it actually it's pretty easy to make cyanide in the atmosphere so different sources of energy reacting on a primitive atmosphere will all generate cyanide and from cyanide you can make apparently all the building blocks the trouble is how do you actually make use of cyanide that forms in the atmosphere if it rains out into the ocean it's basically lost it's diluted it will just hydrolyze and go back to starting materials so so here's a scenario devised by my colleague John Sutherland in the UK for how to sort of store up and save cyanide and then later on turn it into useful starting materials so the idea is that if cyanide rains out into a pond or a lake on the surface and that's in an area where there's geothermal circulation of the waters who fractured rocks water recirculating few rocks heated by magma deep below coming up through vents and bringing up iron and other ions and iron ferrous iron reacts very tightly with cyanide to make ferrocyanide ferrocyanide salts with some of these other ions will precipitate so you can see building up layer after layer after layer of the cyanide salts over maybe thousands of years or even longer so you go from having something that's very dilute that you can't really use to a huge reservoir of material that can subsequently be processed by heat by water to make useful starting materials okay let me give you an example of assistant chemistry also coming from the Sutherland lab so this compound here it's pretty simple it doesn't look particularly by all biological but it's very important it's an intermediate on the way to building up nucleotides and RNA how do you make it - very simple starting materials with simplest sugar glycol aldehyde and this cyanide derivative Cyanamid if you just mix them together and this was done a long time ago not much interesting happens you get a huge range of products to get this polymeric materials you get just a little bit of this compound that we'd like to have with what the Sutherland lab found is if you put phosphate in the reaction plus it is not part of the starting materials it's not the product but we think phosphate had to be around anyway because it's part of nucleotides it's part of our innate I had to be phosphate there it's a good buffer it can act as a catalyst and when you have phosphate around these two things react almost quantitatively to make this key intermediate so that's an example of systems chemistry of using things that aren't obvious but that should be around that make things work better and not only that but this compound to media locks is all turns out is is Vil the tile it will evaporate sublime at low temperatures and then you can you can crystallize it out on a cold surface another example of that kind of you know really simple physical way of purifying things is shown in the next step so that intermediate reacts with another sugar and makes this compound which is a little bit closer to nucleotides and amazingly just crystallizes out of solution so a lot of other products are made but the one that we really want crystallizes out you can imagine again this occurring on a geological scale building up a large reservoir of this crystal and intermediate a kind of you know perfectly natural plausible way of building up a reservoir of an intermediate and then waiting at some point the conditions change the next step can happen that you you can process purified material so these these are the kinds of new ways of looking at the chemistry that that has been making it easier for us to understand how complicated intermediates like nucleotides could actually maybe form on the early earth okay all right so what then suppose we have all these intermediates we have amino acids and peptides and nucleotides we have to get them together to start to make something like a cell so this is a diagram of what we think up would have looked like a very simple stripped-down version of a cell again a primitive cell membrane and closing little fragments of something like RNA and here the questions that we're asking are a little different how can we do growth in division right it hasn't been any evolution yet there aren't any enzymes there is no biological machinery so there had to be just very simple chemical and physical processes that made everything work if the question is how would this primitive membrane grow and divide how would these little bits of genetic material get replicated with enzymes that's something we've been working on for the last 10 or 20 years so I'll just give you a few highlights from that is these membranes that we're talking about or not as complicated hours as modern cell membranes the membranes surrounding ourselves they're made of simpler materials they have very different properties but the most amazing thing is the way they've self-assemble so you can take simple molecules simple fatty acids like these molecules kind of thing we find in soap shake it up in water they spontaneously make bilayer membranes and they they close up and make these incredibly beautiful structures like you see here these vesicles those vesicles within vesicles so I want to show you how simple structures like this can grow and divide in with just simple physical processes and to show this I want to show some movies but we might yeah okay nice might work I was a little worried about the lights but this might be okay what you're seeing here is one of these simple vesicles simple fatty acid membrane there's a fluorescent dye on the inside so that's what we're actually saying we're going to watch it in the microscope when we add more food food be more fatty acids we expected this little vesicle model of a primitive cell to just kind of gradually get bigger maybe elongated or something what we didn't expect is what what happened you can see this little filament growing out of the vesicle and this is speeded up but over about half an hour the filament grows gets longer and thicker and everything in the original vesicle gradually spreads out and this process looks in a way very biological there's a lot of movement and shape changes it's just soap and water nothing fancy one of the beautiful things about this mode of growth so you can see there's been a huge increase in the surface area the volume is only increased a little bit these filaments are really fragile and that makes division incredibly easy okay so something that at the beginning we had no idea how we're going to make these things divided turned out once we saw how they grow it's really easy so here's one of these filaments this is already grown look at it and the microscope slide a little puff of air on the slide will come along and and basically snap that filament into and then these two halves when they fit around though gradually round up and make two daughter vesicles that's a way to divide one vesicle into two daughter vesicles just using very gentle shear forces I just want to show you another way that division could work this involves a little bit more complicated chemistry of environments where there would be a lot of sulphur around but again you've seen if seeing here a filament that has grown into vesicles grown into a filament it does this pearling instability and these little beads over time separate from each other and float away so it's a amazing way to make lots of small daughter cells out of one initial cell again it's just soap and water nothing really fancy but by combining these approaches you can take a vesicle grow it into a filament divided into multiple daughters grow divide grow divide and so on you can keep doing this indefinitely so in terms of a primitive cell membrane we now have a cycle of growth and division I have many ways now of doing growth and at least a couple of different ways of doing division so that part of the cell like process of growth and division turns out to be incredibly simple and can be driven by by very gentle and common physical forces okay so what about the genetic material right it if we want our primitive cells to be able to evolve they have to have some some way of having new functions arise that have to be coded in some genetic material so these new functions can be passed on from generation to generation and we like the idea that RNA molecules played this early role RNA to so many things in modern biology and and one of the most important is that it's actually RNA molecules that are responsible for synthesizing all the proteins in our bodies right so we think that RNA was around right from the beginning catalyzing simple reactions but before there were enzymes before there were enzymes that could make it replicate better which you'll hear about a lot from Jerry Joyce tomorrow there must have been we think chemistry that could have driven the copying of RNA sequences and so how would that work so I just want to show you a simple movie and animation made by Janet iwasa to just show what we're trying to do we think there were little bits of RNA floating around and a really rich chemical environment filled with activated building blocks activated nucleotides they can find their partners by base pairing G with C a with you and just click into place building up a complementary strand ok so so people have been thinking about this and working on this problem for a long time this is not a new problem much of the most important early work was done by the late Leslie Orgel and his students and colleagues including Jerry so I want to just start by pointing out what I think is is Leslie's probably greatest single contribution out of many many Leslie recognized that the materials the chemicals in our bodies in all modern life that are used in DNA replication and in making RNA is nucleoside triphosphates they're great molecules if you have sophisticated enzymes if really good catalysts they can use these molecules to do polymerization but if there's no enzyme these molecules don't really do much except severe they hydrolyze so at the beginning of life these are probably not the appropriate kinds of building blocks and so Leslie worked out that different kinds of chemistry activation chemistry would work much better and this these this is an example of one of the best of those types of molecules that were made in Leslie's lab so this part of that this pyrophosphate moiety appear has been replaced with this imidazole group as a result these molecules are much more reactive they don't need an enzyme that will start to polymerize and make RNA chains even without an enzyme they can be used to copy very simple sequences so give you just show you one example using this kind of much more reactive building block to copy a short bit of RNA so the experiment I'm showing here here's a little piece of RNA six nucleotides long it's base paired to a slightly longer piece of RNA and what we want to do is copy dc's by putting in this activated g building block G's should pair with C's and then they can get added to the primer and the primer can get longer in this direction and so what you see is in this time course we start off down here with just this primer this new six nucleotide bit after a minute you see the first nucleotide being added the first G has been added few minutes later the second one few minutes after that you see the third right so this is like amazing chemistry there's there's no enzyme but we're copying this RNA template okay so so that's the good news about this chemistry the bad news is that that's really the only reaction that works really well and if we try to copy a sequence that has all four nucleotides in it it basically doesn't work and we put in all four activated building blocks and let them sit around and nothing happens alright so the question is you know are we thinking about this in the wrong way is there some missing chemistry and I personally don't have time to go through a lot of really interesting advances I'm just going to cut to an advance from the last year or so in my lab and basically over 30 years of thinking about it and working on this problem we've realized that if we change what was a carbon atom here to a nitrogen atom and make this new leaving group things work much better right so it gives you an idea of the pace of progress in this field that sometimes a little slow but nonetheless we're getting there bit by bit and so these molecules are nice because they're on the one hand more stable they hang around longer but they react much better in this coughing chemistry and so now again we have in green here and RNA primer we want to extend it with these nucleotides in red by copying this part of the template and what you can see is we start off with this just the primer over half an hour you can already see the basis being added and after 18 hours we've completely copied seven nucleotides and some a bit more so you know we need to make this work even better we have a lot of ideas that had a copy longer sequences we think if we could get up to copying templates that were 20 to 30 nucleotides long that might be good enough to get evolutionary processes going we know we can make RNAs that are catalysts by assembling little little chunks that are 20 30 nucleotides long and and so that's the goal so I want to just say something though about this this new activating group is two amino images all the question of course is you know is this just something clever that was that works in the lab does it have anything to do with the origin of life right would molecules like that have been around in the early chemistry and we think this time that we might have something that's really relevant and I think the way to explain it is shown here so this is a molecule I mentioned right at the beginning to me no ox is all goes on to build nucleotides okay from chemistry that's really well worked at the Sutherlin lab here's our new molecule that we're using to activate nucleotides so that they'll polymerize it's only one atom different which contains oxygen to nitrogen and it turns out you can make this in the same reaction that you make this just by adding ammonia and then amazingly there's another molecule very similar to amino sighs I'll change the oxygen to a sulphur you make this again you can make it in the same reaction mix just by adding the right kind of sulphur and this will will act to store and accumulate other intermediates in the process so these these three really closely related molecules all made in simple chemistry from simple starting materials all potentially made in the same or very similar environments can go on and do play different roles in building up RNA molecules so what do we think this primitive genetic material really looks like you know I kept saying we think it's RNA or something like RNA I think from everything that we've learned about making variants of RNA we think that primordial material was more or less the same chemistry of RNA but a kind of Messier version and with some small changes we think the backbones not not necessarily always linked up in the same way these different kinds of linkages can form and they're not harmful we used to think these were terrible but it turns out there we think there could be some small chemical changes in some of the nucleotides like putting a sulfur here makes everything work much better and and this is actually still seen in biology and part of the protein synthesis apparatus it could be some other small changes but it's close enough to RNA that you can see how it could evolve step by step and give us the modern version of RNA okay so so what are we really missing them from from all this from all this chemistry it's been a huge amount of progress we know how to make we think from the Sutherland lab how to make the per imitating nucleotides you can see we still don't really know how to make the purines there is a paper that's recently come out from mat pounders lab who used to work with John Sutherland used to work with knees now got his own lab he's figured at this beautiful chemical pathway where you can make an intermediate and process it in one way to make you NC and process it and another way to make some of the purines not exactly the natural modern purines yet but something close we we still don't know how to get the phosphate onto nucleotides in the right way it's interesting that in a lot of this chemistry the phosphate ends up in the wrong position so there's something missing there right we need to figure out how to get phosphate on in the right way so that's something a lot of people are working on and then what are the sources of chemical energy right we can drive all these reactions in the lab but we don't we don't have the right source of chemical energy to understand how this could have happened in a primitive early Earth environment we have lots of ways of doing that for peptides for example this volcanic gas carbonyl sulfide is a great activating agent and if you bubble carbonyl sulfide through amino acids you will make peptides and do lots of other interesting chemistry as well so we're looking for something kind of analogous to that - to activate nucleotides and get them ready for copying chemistry okay so those are some of the questions people are asking and we're also now trying to think about what environments on the early Earth could have supported all this chemistry what environments could have nurtured very primitive self and driven their growth and growth division and evolution okay so we want environments where organic compounds can accumulate we don't want them to fall into the ocean and get diluted and lost we want them to be in surface lakes or ponds this is a picture of Yellowstone Lake in the western US you can imagine if this was on the early earth that organic materials could get concentrated here and build up over long periods of time so we're looking for sources of chemical energy we like environments that are kind of cool most of the time like this because RNA is a delicate molecule right you don't want to cook RNA for hours or days it'll just totally degrade so we want an environment that it's pretty cool but we do think that you might need short periods of high temperature so that once you've copied a template made a double helix get the strands apart to copy them again and these geothermally active areas can do that so we'd like these hydrothermal systems so so volcanic systems are an example so in Yellowstone Lake you see these these these vent structures that emit plumes of hot water and and so you can imagine primitive cells been caught up in these and heated quickly and then cooled back down another environment that can do this is that's got this kind of geothermal activity is cratered Lakes impact craters so the early Earth of course was bombarded a lot by by large asteroids and comets that would create large crater lakes it's another environment that we think could have played a role in nurturing the beginnings of life and and this is just a diagram of how we think that would have worked how the environment could have essentially controlled and driven the whole processes of growth division and replication so cold most of the times those cells living in this cold water with all rich environment full of other building blocks it could have RNA copying going on and growth of the membrane every now and then they get swept up in a plume of hot water serves to separate the strands of the RNA duplex also allows for a rush of nutrients to the inside of the cell and then you can go through another round of growth so this is a way that the environment could drive a primitive cell cycle okay so that's that's kind of an overview of where we are on our thinking about how life got started on the early Earth but thinking about that kind of problem also raises other interesting questions so in everything I've talked about so far we've been trying to think of you know the chemistry and the physical processes that would give rise to life as we know it right modern biology but then you start to realize well maybe there's other ways of doing sex could we think of designing kinds of life where the biochemistry is different and I think that's a really interesting a huge challenge for the field of chemistry and so I just wanted to point out a few examples both for my life in other labs of how this might be approached and again we're thinking about it from the process of membranes which can be made from non-biological building blocks and genetic materials again that can be made from a non-biological chemistry so so here's an example of membrane chemistry from Neil devvra's lab at UCSD and what neil has done is to take advantage of this very widely used copper click chemistry where a violin and alkyne can be joined together with a copper catalyst and so here you're making a molecule it's got two carbon chains a charged head group it looks close to our biological phospholipids but it's chemically a little bit different and it's made in a very different way but these things make membranes and in fact the catalyst that does this can also catalyze its own replication so these membrane systems can grow indefinitely as long as you feed them building blocks so this is a potential route into making a non-biological membrane system that could grow and divide one of the molecules related to RNA that we've been working on in my lab for quite a while as shown here it's called through time NP DNA or phosphoramidite DNA it's it's very close to DNA except that this oxygen atom has been changed in nitrogen and that has the advantage that in the building block the nucleotide this hydroxyl has been changed to an amine so it's much more reactive so these molecules are actually easier to copy the copying chemistry is just much faster and easier than with RNA and we're not there yet but again what we can at least imagine the possibility of building living cells from a genetic material that's different from RNA and DNA okay so these things are pretty close to biology can we go further afield can reimagine making kinds of living systems where the chemistry is really completely different and a lot of this thinking was stimulated when the cassini-huygens mission discovered these lakes on Saturn's moon Titan these are not lakes of water their likes of liquid methane and ethane and that may a lot of people start wondering you know can you imagine anything living in an environment like this now liquid methane is kind of hard to work with it's not very pleasant thing to work with the lab but we can work with organic solvents we do that routinely and in fact here are some vesicles formed in decane this is from the Commuter lab in japan from quite a long time ago more than 20 years ago but these are the kind of inside-out membranes that the polar parts are in the middle the hydrophobic parts stick out into the hydrophobic solvent they make vesicles they look like completely normal vesicles but they're just inside it and the chemistry is totally different what kind of genetic material can you imagine in a solvent like this right and so we're I just at the moment have one person in my lab working on this it's at a very early stage but it's a it's a really fascinating project so here's here's what we're trying to make this is work from Carlstrom you can see it's it's kind of a double-stranded polymer and if you look closely you'll see that the nitrogen is either on this side or on this side so in terms of building blocks it's an it's an aldehyde and an amine so instead of base pairing by hydrogen bonds here we have a reversible covalent linkage we only have two kinds of building blocks at the moment but we can start to see replication chemistry happening in systems like this it's not easy working on things like this one of the wonderful things about it is it makes you appreciate RNA and DNA even more you realize how totally amazing DNA is and how hard it is to design something different that has the same properties but that's one of the things that makes it so fun to work on so so just to summarize I've tried to to give you a kind of overview of new ideas and new questions in the chemistry leading to to life on the early Earth and and just point out the some of the tantalizing beginnings which i think is people keep working on this will in the coming years lead to the ability to make living systems that are chemically completely different I think that's going to be really fascinating so I didn't do any of this work is all fantastic students brilliant postdocs and collaborations with labs in many different fields so thanks again for inviting me back and thanks for listening [Applause]

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Views: 17,909

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Keywords: molecular, frontiers, origin of life, RNA, RNA world, synthetic cells, synthetic biology, Jack Szostak

Id: rAZTiWZU6Cc

Length: 40min 38sec (2438 seconds)

Published: Sun Jun 04 2017

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Dr Jack Szostak's lecture at the Molecular Frontiers Symposium at the Royal Swedish Academy of Sciences, Sweden, May 2017.