The Origin of Life: Not as Hard as it Looks? Jack Szosta, Spring 2023 Ey...

The Origin of Life: Not as Hard as it Looks? Jack Szosta, Spring 2023 Eyring Lecturer ASU School of Molecular Sciences 1.47K subscribers Subscribe 1K Share Download Save 62,267 views Mar 17, 2023 #chemistry #research Nobel laureate Jack Szostak from University of Chicago delivered the Eyring General Lecture on March 17, 2023 at Arizona State University. Please click here to learn more about Dr. Szosta and the distinguished Eyring Lecture Series at ASU. https://news.asu.edu/20230309-nobel-l... #chemistry #research ‪@arizonastateuniversity‬ ‪@ASUNews‬ Transcript Follow along using the transcript. Show transcript Transcript Search in video 0:00 evening can you hear me 0:09 Welcome to the latest in the series of hiring lectures 0:20 the series is named in honor of Professor Leroy hearing iring who was an 0:27 ASU Regents professor and chairman of the department and contributed importantly during his tenure as 0:33 chairman to the the growing reputation and Excellence of the department 0:38 today's speaker is Professor Jack shostak uh Jack is a university professor and 0:47 professor of chemistry at the University of Chicago and an investigator at the Howard Hughes 0:52 Medical Institute prior to this year uh Jack was uh an 0:58 employee at Harvard University and at Harvard Medical School he had multiple 1:03 appointments at Harvard and carried out all of his duties with in a 1:09 distinguished fashion uh his uh training was initially at McGill University for his bachelor's 1:16 degree and then he moved to to Cornell and worked with uh um Ray Wu on his uh 1:23 PhD thesis subject uh thereafter uh he uh he started his uh career uh all in 1:30 the Boston area uh had a number of positions over a period of years at the 1:35 Farber Cancer Center Harvard Medical School uh and then at Mass general uh and uh while he was there he carried 1:44 out a few things that some of you've probably heard about um so uh he uh for example 1:52 worked on genetics and biochemistry of DNA recombination uh which led to the 1:58 double strand break repair model for mentotic recombination uh in parallel he 2:05 made fundamental contributions to our understanding of telomere structure and function uh and uh the role of the telomere 2:12 maintenance in preventing cellular senescence for this work I've been sharing it with two other individuals he 2:19 was awarded the Nobel Prize for his work most people would be satisfied with that 2:25 Jack went on to just as remarkable things in more recent 2:30 years I'll abbreviate it uh for this particular introduction since I have to 2:37 introduce him again tomorrow and I'll talk about it in more detail then but in the 1990s uh Jack and his 2:44 colleagues developed in vitro selection as a tool for the isolation of functional RNA DNA and proteins 2:51 simple concept but incredibly powerful defined molecules with respect 2:58 and special activity of function uh even though it's a discovery of a few decades 3:05 now it's still increasing in in its utilization and the extent to which the world relies on that basic technique to 3:13 to find uh new and highly potent and selective molecules for for uh specific 3:19 uh utilizations um since the year 2000 approximately his 3:27 research interests have focused on self-replicating systems and the origin of life and this leads us immediately to 3:34 the title of this evening's lecture namely the origin of life not as hard as 3:40 it looks please join me in welcoming Jack 3:52 and thank you very much uh secretary very uh kind introduction thanks for 3:58 inviting me to uh come back to ASU and and talk to people 4:04 again I've had a great day talking with uh lots of different people about all kinds of exciting new things 4:12 so um so in in today's lecture I'm going to 4:17 try to give a not a comprehensive overview of the origin of life but sort of focus on some 4:24 of the things that I find particularly interesting and and 4:30 maybe try to give some idea of where we've made progress and what kinds 4:37 of things of held us back from say maybe moving as 4:42 quickly as as we would like so what you see on the slide here is 4:48 just a schematic of our conception of what a really simple primordial cell 4:54 motive look like just a kind of a lipid envelope with some small bits of genetic 5:00 information on the inside and this looks simple I mean it's 5:06 obviously a stripped down version of a modern cell it's got the important things except for proteins 5:13 um but you know there's an enormous number of questions that arise if you 5:18 try to think about how something like this could have emerged from the chemistry of the early Earth 5:25 and then even if you get to this stage then what right how did it lead subsequently 5:32 um to the evolution of more and more complex forms of life 5:38 so uh I was talking to a few people before giving this lecture and they said that 5:46 you know it's always interesting for people to hear how you got into a field so I'll try to bring that out a bit 5:53 um I I talked I thought about different ways of beginning this talk 5:58 and you know I could have you know 6:04 you know everything of course worked before well we were setting up but now I can't 6:11 advance uh site 6:17 okay I can use this good all right okay so I thought about 6:23 Beginning by talking about exoplanets because after all that's been one of the 6:29 just most amazing advances in science in the last two decades we have catalog now 6:34 of over 5 000 planets orbiting different Stars they're must by extrapolation the 6:41 millions of very earth-like planets out there in our galaxy alone and of course we'd all like to know if there's life on 6:49 any of those planets or is it so hard to get to life that maybe we're the only 6:55 place in the Galaxy or even the universe or this life but 7:01 I'm not going to talk more about that I'm going to instead I I also thought well you know I could talk about 7:08 life being a far from equilibrium phenomenon right and it's there's so 7:13 many interesting questions how does how does that generate local order of 7:19 the kind that you see in life like these incredibly complicated metabolic pathways and everything depends on the 7:26 input of energy into the system in the in the right way but you know you have uh uh Paul Davies and Sarah Walker here 7:34 who can tell you all about that uh from their work so instead I decided to 7:41 talk about life from the point of view of information because that's really how 7:46 I got into this field and got interested and and obsessed with it really 7:53 so when we talk about information uh it can be talked about in a lot of 7:59 different ways right so this obviously goes back sorry I'm in trouble with this to 8:05 um you know at the beginning from from Shannon classical information Theory how much information does it take to 8:12 specify a given string of symbols and then 8:19 that led to advances in compression technology which 8:24 I think mostly stem from comogarov algorithms which is how much what's the shortest 8:31 like algorithm or computer program do you that can actually 8:37 regenerate a given string but in biology we don't really care 8:43 so much about the actual sequence of symbols in the string right I mean we 8:51 all have about three billion base pairs of information in our DNA and it's not 8:56 really that much it's prepared on your smartphones right but what's important about it is are the 9:04 parts of it that actually code for something useful and even those parts 9:09 the exact sequence is not usually what's important right because there are many positions in the sequence that don't 9:16 matter that can be anything there are others that Co vary and so the actual 9:21 amount of information to specify say a given functional TRNA or given 9:27 functional protein is is less and even that is not exactly what you 9:35 need or should be thinking about in a biological system and just like in a conversation between 9:42 two people what matters is the meaning of the string right and physical 9:47 complexity doesn't quite get to that because there are many many different 9:52 ways of building different structures that do the same thing 9:58 okay and so that means in effect it takes less information to specify a given meaning in a 10:05 biological system okay so uh okay not these are dead horse 10:12 but there's this obvious parallel between the information stored in in DNA and in long-term storage on computers 10:19 and in biology we have this sort of more transient uh form of RNA which by the 10:26 way also does all kinds of functions just like proteins and and so on and so 10:31 it's very parallel to what we see in all these sort of built devices and so I've been interested for a long 10:38 time in how did the first organisms 10:45 begin to accumulate information about their environment about themselves and 10:51 about how they function in the environment where did that information come from and how did it grow to the 10:58 extent that we see in biology today okay um so the way that I got into that was 11:06 essentially by doing darwinian evolutionary experiments 11:11 on molecules instead of on collections of organisms so 11:17 their winning Evolution has been operating for billions of years and has generated all the diversity of life that 11:23 we see humans if they're doing directed Evolution for thousands probably maybe 11:29 tens of thousands of years in animal and plant breeding um 11:34 and also it really took to sort of extrapolate that from organisms to 11:40 molecules was the technology of patient VCR 11:47 so the experiments that we started doing were to begin with completely a library 11:52 of completely random sequences okay a very large 11:58 sequences and what we wanted to know is How likely is it that a given random 12:06 sequence can actually do something interesting and as an experimenter of course you can 12:12 you can Define the task that will be binding to a Target molecule could be 12:17 catalyzing a reaction I want to know how much information does it take to 12:23 specify a functional molecule and one of the reasons that I decided to 12:30 through this experiment was that by talking to different people I got vastly different answers some people thought 12:37 that oh you can get an RNA molecule to bind to Target it'll be like maybe one 12:42 in ten to the minus thefts random sequences others said no building a structure is like really hard and you 12:48 have so many factors to contribute it'll be like one in ten to the minus 50. so you'll never find one experimental so 12:55 there's 45 orders of magnitude of uncertainty it seemed like worth doing an experiment see if we could narrow it 13:01 down a bit so what we were able to do pretty easily was build libraries of on the order of 13:09 10 to the 15th different random sequences made in DNA transcribed into 13:15 RNA and then take that set of sequences and subject it 13:21 to a selection okay so enriching for the ones that do what we want and throwing away the ones 13:28 that don't and then amplifying those survivors with or without adding a little bit more variation and going 13:35 around and around this cycle 13:41 going around and around that cycle uh until the population is taken over by 13:46 molecules that do uh what we want okay 13:52 okay and and so the answer was that we could actually this actually worked and 13:59 we could get molecules like the one shown here so this is 14:04 uh sort of surface view of the three-dimensional structure of a short bit of RNA that folds up and it makes 14:10 this beautiful three-dimensional shape that has a little cleft on the surface 14:16 that's complementary in shape and electrostatics to ATP so the combined 14:21 ATP at a concentration that's biologically relevant and this was at 14:27 about one in ten to the minus 10 of the random sequences that we started with so 14:33 actually not that hard to get functional sequences out of out of nothing right 14:39 so then I got interested in taking this one step further and 14:45 saying okay this you know this molecule binds with a certain affinity and specificity how much harder is it to 14:53 bind something more tightly right intuitively it's you know to do any task 15:01 more efficiently it's it's harder and so it should take more information the 15:06 question is how much and so to get at that we embarked 15:11 um on a a series of really painful and tedious and laborious experiments that 15:16 were done by James Carruthers when he was a graduate student in my lab and what James did was to select for RNA 15:25 sequences out of this random tool that could bind GTP as a Target 15:31 and he got a whole bunch of different solutions and what I'm showing you on this slide 15:36 are the simplest looking Solutions they're just stem loops the red bases 15:43 have to be what they are the blue ones can be anything and so there's a certain amount of uh 15:50 information in the sense of the Chris adami type of physical complexity that 15:57 is required to specify each of these structures but if you select for Tighter and 16:05 Tighter and Tighter binding then you end up getting more complicated structures so these are a little bit more 16:11 complicated and if you keep going you get these ones which bind a hundred 16:16 times Tighter and they're much more complicated in their secondary structures than in the number of bases 16:23 that have to be what they are and so you can actually you can do the same kind of 16:29 experiment selecting for catalysis so this came out of an experiment that 16:34 was done by Dave Bartel when he was a graduate student in the lab selected for 16:39 riboslines RNA enzymes that could catalyze a ligation reaction and again he got more than one answer to that 16:47 problem and I'm showing you here one ribosome that's fairly small and simple that does 16:53 this reaction with a certain rate and this much more complicated reaction that does a much better job it's a better 17:00 Catalyst and it's more complicated you can see it takes more information to 17:05 specify the sequence that does something better okay all right now can you quantify that 17:13 and well sort of right so if you calculate the information required to 17:19 specify all of those structures and plot it against either the Affinity or the catalytic rate 17:26 there is a lot of scatter about this line but you know 17:32 you'd expect a lot of scouter and the basic lesson is that it takes 17:38 um about 10 more bits of information 17:44 um to specify about a tenfold increase in 17:49 activity and I so this is a very old result 17:57 and I've always wanted to improve on this but the experiments back then 20 to 18:03 30 years ago were so hard that no one's ever wanted to go back and do this again 18:08 but I'm still fascinated by the idea of trying to quantify the relationship 18:13 between information and meaning or function we can also do these kinds of things 18:20 with DNA and with proteins and this is just a pretty picture of how you can 18:27 use the ribosomal Machinery to as the ribosome is reading a messenger RNA 18:34 and generating a Mason peptide chain you can trick it into linking these things covalently this allows you to select for 18:42 function on the basis of what the protein is doing but it drags along its coding messenger RNA so you can tell 18:49 what you got uh and unfortunately so so this one lesson from this is again it's not that 18:55 hard to find functional molecules okay which is a good thing because otherwise I think it would be very hard 19:01 for life to evolve new functions to become more complex to adapt better to its environment in a small scale lab 19:10 experiment we were able to make new proteins that bind for example ATP and 19:15 other people have evolved catalysts this way so 19:21 um so I think this kind of give you some insight into how the first living 19:27 systems got the initial information the way we think about it is that through the cells 19:34 like in that schematic are showed in the very first slide could have been seeded with just random 19:41 sequence bits of for example RNA or whatever the primordial genetic material 19:47 was probably argument and if you have enough of those right some of those sequences carry meaning 19:55 intrinsically and could do something that would help that cell survive better 20:00 or replicate better take over the population and that's the beginnings of 20:06 darwinian evolution okay but to do that requires a few more things 20:15 right it's all in the details like okay to do this kind of acquisition of 20:21 information you have to be able to replicate that genetic material and that has to happen 20:28 with errors so that new variation is possible and it has to happen in a way that 20:35 selection can occur so how can all of those things happen 20:41 so if you look at a modern cell it's very hard to think about how that could 20:48 ever arise right because we have DNA storing information in an archival 20:54 form rnas and intermediate generating proteins that do all the functions in 21:01 the cell and the problem is that all of these things depend on each other right so you 21:08 need RNA and proteins and metabolites to replicate DNA you need DNA to encode the 21:14 RNA you can't make proteins let's say the RNA and the coated and the archival 21:19 information and the metabolites so you know trying to think in a rational way 21:25 about how a system like this could have emerged as I held back progress in understanding 21:32 the origin of life for decades right because people were generating all kinds 21:37 of crazy theories about every how everything could just emerge at once which 21:44 is basically not possible and there's a clue in the structure of this diagram 21:51 that maybe RNA this molecule in the middle is is the answer to that that to 21:58 that sort of paradox um and that was recognized in the 60s by 22:04 a few smart people like Francis Crick and Leslie orgale and Carl Lewis more recently 22:11 um the structure of the ribosome was solved by several groups and I'm showing you here a picture 22:17 of uh the large subunitive the ribosome from work by Tom Stites 22:23 and what this is a huge and complicated molecular machine right whose job is to 22:29 make all of the proteins in our body and if you look at this sort of face-on 22:34 view of the large subunit of the ribosome which is the one that actually catalyzes peptide bond formation 22:41 what you see in the very Middle where this little green squiggle is this is a 22:47 transition state analog that is occupying the catalytic center of the ribosome 22:55 all around that is only RNA which are these gray squiggles the proteins of the 23:00 ribosome are these gold structures but it's clear from the 23:06 structure that the ribosome is a ribosyme that makes proteins so all 23:13 the proteins in all the organisms in the world are made by catalysis by RNA molecules the large 23:21 subunit it's a ribosome so logically the only the conclusion we draw from that is 23:29 that RNA came first and that early life was a lot simpler 23:35 um so we imagine primitive cells looking kind of like 23:40 this still cells as a membrane boundary inside RNA as the genetic material 23:49 um encoding for ribosomes that carry out different kinds of functions including 23:54 the replication of the RNA okay so now our problem of how 24:02 to get to this point has become a lot simpler right all we have to do all is 24:07 figure out how to go from the chemistry of the early Earth to RNA molecules and then figure out how 24:14 they could replicate and develop to this stage so we can deal with other 24:19 complexities of Modern Life DNA proteins metabolism 24:27 all of that you can think of as phenomenon that arose through the 24:32 process of darwinian evolution they're evolved features they don't have to be 24:37 there from the very beginning all right so when could this have 24:43 happened so this is uh adapted from a review by Jerry Joyce I think you can take all the 24:50 numbers on the timeline with a grain of salt obviously the Earth had to cool down 24:57 from its molten lava surface to the point where you 25:02 could have water on the on on the surf with liquid water on the surface 25:07 there's evidence from the chemistry of zircon crystals that that was actually 25:13 pretty early maybe maybe as little as 100 million years after the Earth was actually formed or after the moon 25:20 forming impact uh and then somewhere between that period and the earliest 25:28 convincing evidence of life on the earth there's a period of about seven or eight 25:33 hundred million years so somewhere in there life got started we don't know when 25:38 but there must have been chemistry going on on the surface of the planet that gave rise to all the building blocks of 25:46 biology very nucleotides lipids sugars amino acids all made by just 25:55 chemistry happening in different environments on the surface of the young planet 26:00 and then somehow that gave rise to RNA which gave 26:06 rise to replicating RNA and eventually to the first cells of the RNA world and 26:13 then the RNA World evolved the ability to make all kinds of complexity and adaptation 26:19 okay so so then the problem is now 26:25 simpler no I wouldn't say simple but it's it's simpler right we can ask how did this RNA based type of Life emerge 26:33 from the chemistry of the early Earth and you can talk actually to 26:39 more than a few uh synthetic organic chemists and they'll say that is just completely ridiculous 26:46 um and I think the preconception that doing complicated multi-step 26:54 Pathways that give rise to a complicated and delicate product like the 27:00 preconception or the bias that that's impossible has also held back the field 27:05 for a long time and it's only in the last I'd say 10 or 20 years that we're starting to actually 27:12 address that problem head on and think about well how can you overcome the problems right the idea that 27:20 that life emerged from this primordial soup where everything was mixed together and sort of magically assembled into 27:27 cells is completely um ludicrous and people now are developing 27:34 uh ideas doing experiments and showing that there are ways to break down long 27:40 Pathways into shorter subsets there are ways of concentrating materials that you 27:46 need crystallizing intermediates there's a this buzzword of systems chemistry which 27:54 means thinking about things in a bit a little bit of a different way instead of you know mixing A and B and trying to 28:00 get only C you you say well what else have to be around and can you make use of other things that were present to 28:07 actually give you the products that you want so so so 28:13 um what I would say is so you've probably all heard about the famous military experiment right so Stanley 28:19 Miller is a graduate student with Harold Geary um passed an electric discharge through a 28:26 reducing atmosphere what they thought the atmosphere of the earlier looked like and found 28:33 precursors to amino acids were generated and so at the time it was revolutionary 28:41 right it said that making at least this subset of building blocks of biology is not that hard and and I think there's a 28:48 period where people thought well maybe everything uh will be that that easy and and that 28:55 uh there were a few examples that that raised that hope again so for example 29:01 one a row uh showed that you could take hydrogen cyanide all right and just uh reflux it in water 29:08 just boil it in water and and make adenine that means just a pentamer of hydrogen cyanide and and so people 29:15 started to think well maybe maybe all of the steps in making all the building blocks will be easy 29:21 and then things kind of stalled because people realized well in these reactions in the 29:28 Miller type reactions in in this Oro type of reaction what you actually make is a mess right there are often 29:36 thousands of products and they're all present at parts per million or parts per billion the more sensitive your 29:42 techniques are the more you see there but the but the way to build biology is 29:47 to make a lot just a few compounds just the ones we need right and so that's the real 29:54 problem and that's where progress has been made in Prebiotic chemistry uh in 30:00 recent years now this idea of cyanide is the ideal 30:05 building block is something I really love um you know partly because there's a certain irony in in cyanide giving rise 30:13 to life but uh I kind of like that there are lots of different ways to make cyanide in in in the atmosphere 30:21 we don't really know what what is the most uh important quantitatively 30:29 um but it's pretty clear that you can make HCM and it can rain out onto the 30:34 surface and and my colleague John Sutherland and others have figured out 30:40 very elegant ways to to make use of cyanide to efficiently generate the right product 30:47 molecules but there is a problem in the cyanide that's generated in the 30:53 atmosphere can dissolve in raindrops and render the surface but it's going to be very dilute 31:00 right very dilute cyanide doesn't do anything interesting it just sits there 31:05 and hydrolyzes it's a formabide ammonium formate and then you have nothing 31:11 so how can you actually make use of the cyanide that would be generated in the 31:17 atmosphere and um so John came up with this very uh 31:22 elegant idea that cyanide could rain out into surface lakes and if you're in a region where 31:31 there's hydrothermal circulation of the water through fractured Rock 31:36 for example volcanic regions like like you see in Yellowstone today or impact 31:42 craters what can happen is this Lake water will circulate it will percolate down it will 31:49 be heated by the underlying magma Reservoir and then rise back up to the surface 31:55 carrying with it ions that have been leached from The Rock and Prime among those will be iron iron two 32:03 and iron two reacts very rapidly and avidly with cyanide to make ferrocyanide 32:11 and the idea was that ferrocyanide salts could build up in concentration they're 32:16 a stable very stable form of cyanide could build up and precipitate out and 32:24 and you could build up over maybe thousands of years layers of sediment highly enriched in 32:30 ferrocyanide cells and this idea has been refined very nicely by recent work from 32:37 David kotlin at the University of Washington in Seattle tuition uh that that this actually can 32:45 work in very nicely in alkaline carbonate Lakes which are again a likely 32:51 Prebiotic type of environment so I think this is kind of a major 32:57 conceptual breakthrough right you start with something that's very dilute that you can't use you figure out how to 33:03 build up a concentrated reservoir of material that at later times can be 33:08 thermally processed and then can go on and do subsequent reactions but going from cyanide to nucleotides 33:16 the building blocks of RNA that's a complicated process right there's a lot of steps to go from 33:23 something as simple as cyanide to something as complicated as the nucleotide so how could that happen 33:30 and again I think one of the real conceptual breakthroughs has been in realizing 33:37 that some of the intermediates on the on these pathways 33:43 tend to selectively crystallize out and this is a particularly beautiful example 33:50 um so this is a crystal from a paper by Donna Blackman 33:55 um this compound is ribose amino oxalene which is a one of the key intermediates on the way to making all of the 34:02 nucleotides so the idea is that the reaction that generates this molecule 34:07 generates the one we want plus a bunch of side products right but the one we want 34:13 crystallizes out we can build up a reservoir we can wash away all the impurities and then at some later time 34:20 when conditions change you're ready to go on to the next step in the pathway 34:26 okay so I'm not going to go into any more detail on the Prebiotic the 34:31 pathways kind of because I want to talk about so what came next okay so so back to how to make RNA which 34:39 we have to we really have to understand right because this is going to be the basis of primordial heredity and 34:45 evolution okay so we're going from cyanide through a pathway to making nucleotides uh 34:52 nucleotides when their phosphate is chemically activated something I'll talk about a little bit 34:59 uh later and more tomorrow you can make short chains of RNA 35:04 and then making the complementary strands you have a duplex a double-stranded RNA is is a little bit 35:12 more complicated but that's a step that we've worked on in my lab I mean I think a fair bit of progress on recently 35:19 so um 35:28 really is this a really nice movie 35:34 um I don't know any idea how to start the movie 35:47 Bitcoin is a mysteries of science so you can test everything and it always works perfectly and then it comes to the real 35:53 thing and nothing works 35:58 okay well we can skip this one but the next couple I really need so hopefully 36:04 we can figure this out yeah 36:17 okay well I can't show you the structure it's a beautiful elegant structure and I 36:22 think it's really incredible that you can actually assemble it just using chemistry and with no fancy evil enzymes 36:30 so one of the huge advances again a conceptual advance 36:36 in how to do that came from the late Leslie O'Dell who's really one of the uh 36:41 founding fathers of the whole field of Prebiotic chemistry and what Leslie realized was that 36:49 thinking about how biology does this is it can be misleading right and so so 36:55 in biology the molecules that are used by enzymes to make RNA and DNA are 37:03 nucleoside triphosphate so they all have this chain of three phosphates and these are great substrates when you have an 37:10 enzyme that's a really good Catalyst right if you don't have an enzyme if you're trying to let things happen 37:17 spontaneously these molecules just sit there and they don't do anything and 37:22 what Leslie realized is you need to make things that are more reactive and she explored a lot of possibilities and in 37:30 by the early 1980s had settled on these molecules like what you see here these 37:35 are phosphor midazolides and they're chemically reactive enough to start polymerizing all by themselves without 37:42 an answer and to some extent they can polymerize on a template and build up a 37:47 copy of that now uh we've had some advances in the chemistry 37:54 recently that make this work better um and and I'll talk more about that a 38:00 little bit later and tomorrow but first I wanted to just mention another kind of preconception that I say 38:08 held back progress for a long time and again it came from thinking that how 38:13 does all this template copying the synthesis of long polymers how does it work in biology 38:20 right so in biology we always have a primer that will bind by Watson Creek 38:26 base pairing to a template Strand and the enzyme comes along and uses these 38:32 monomers as substrates and incorporates them one at a time to grow the chain the 38:38 complementary sequence and so for a long time everybody who is 38:45 trying to do this kind of copying chemistry without enzymes figured it had to work 38:51 like this right you have a primary you extend it one base at a time we thought 38:56 well this is maybe too simplistic for Prebiotic system or a primordial system 39:02 we thought of well maybe you can make it a little bit Messier by having a whole 39:07 bunch of primers scattered along the sequence and then extend them a bit join them all together that seems like a move 39:14 in the right direction uh but uh turns out it's not enough 39:20 so okay here's another uh really it came out seem to play any of 39:30 the movies which is really sad huh 39:38 uh let's say some true 39:44 uh okay I do I really do that actually 39:52 yeah you can just turn off the laser pointer maybe we can 40:03 sorry about this 40:16 oh all right yay okay so this is how 40:22 we're thinking about things when I started to work on them so imagine a little bit of RNA floating around and 40:28 really chemically Rich environment and activated monomers coming in finding 40:34 their partner by base pairing and building up a complementary strand okay 40:39 so it seems easy and beautiful when you see these animations that were made by 40:44 Janet dewasa but when you try to do the chemistry it turns out to be not so great 40:49 and there's a whole list of problems here just trying to get that to work 40:55 experimentally and what I can say at this point is that 41:01 we've solved most of these we're still working on optimizing a few but I think 41:08 we're pretty good now at doing copying chemistry and so I'm just going to show you one 41:16 thing about that that illustrates how a bias a preconception can get in 41:23 the way okay so this is the way copying a template actually works using these 41:28 reactive building blocks so we thought at the beginning we would have this so 41:34 this is a primer that's bound to a template we want to copy this part of the template we saw monomers would come 41:40 in one at a time sit down on the template react with the primer which would grow by one unit and then we 41:47 repeat that process until we built up the full copy so it turns out doesn't 41:53 work that way and so for the Chemists in the audience you can look at the right hand side here 42:00 for the rest you can get the schematic view here what happens is that two 42:05 monomers react with each other they make this bizarre 42:11 dinucleotide this dimeric product this binds to the template by two Luts 42:17 and Crick base stairs and what's really amazing is that the structure of the 42:23 bridge the linkage between the two monomers is perfectly set up in 42:29 three-dimensional space so that the reaction goes really quickly 42:35 and and so it really took us a while to overcome this idea that popping had to 42:41 work like it does in biology but apparently we now think that primitive copying worked in this chemically 42:48 distinct way and only later when enzymes ribosomes or enzymes evolve did we get 42:54 to the modern way of doing things okay now 42:59 that's good for copying a template but what we need in order to do evolution is 43:06 to actually replicate that we've got to make copy the template and copy the copies copy those copies indefinitely 43:12 right and that turns out to be really hard for a lot of different 43:18 reasons and so uh one of the one of the uh 43:24 things that happened over the course of the pandemic was my lab was shut down for a while like everybody's and so it 43:30 had nothing to do except stay home and think and came up with this uh model that you 43:37 see here called the virtual circular genome model which we think is a way of 43:42 actually replicating RNA sequences that overcomes all of the problems that had 43:49 blocked us for so long and so the idea is the Genome of a primitive cell would be 43:56 this green circular sequence right so this is an RNA sequence just shown as a line 44:03 but there's no actual circular molecules the idea is you have a whole bunch of little pieces little fragments that map 44:11 to the circular sequence okay and the result is they can come together in all 44:16 kinds of different configurations and whenever they come together in a like 44:22 this you can extend one using the other is template so the the difference is 44:28 that now replicate the active replication has become distributed across the whole circular sequence 44:34 instead of working like it does in biology where you start at the beginning you go through the middle and you get to 44:41 the end here you do a little bit of copying all over the place that's everything everywhere all at once 44:49 and we're starting to test it and it's I think it's looking pretty exciting and 44:55 figuring out exactly how to get this to work and under what conditions is is one of the big things that were that we're 45:02 working on now okay so if we can get that to work 45:07 then we're we should be much closer to being able to actually build protocols 45:13 like you see here so little membrane sacs that include bits of RNA but with 45:19 the chemistry to actually drive replication okay so I haven't said anything 45:27 it's the membrane that encloses us and that also has to grow and divide right we want to have a primitive cell systems 45:33 go to be able to grow and divide and do that forever also and so we started working 45:40 on that uh about 20 years ago actually and I was pretty nervous about getting 45:47 into this field because I'd never worked on lipids and the Technologies for working with lipids are not as easy or 45:55 uh um how should I say effective as the technologists are working on nucleic 46:01 acids so but it's turned out to be a fascinating uh Venture and I've learned 46:08 a lot of biophysics and one of the nice things is you use microscopy to get 46:13 beautiful images so like what you see here is when a vesicle made of a simple fatty acid oleic acid you just shake it 46:21 up in water under the right conditions and it spontaneously makes beautiful membrane structures and here you can see 46:27 smaller vesicles trapped inside a big one they're really really quite beautiful 46:33 but they also have the amazing property that they can grow in very interesting 46:39 ways and so what I'm going to show you here's another movie this is one of these vesicles it's encapsulating a 46:46 fluorescent dye which is what you can actually see we had food which is more fatty acids 46:52 and it grows like in this really an unexpected way right I almost fell 47:00 off my chair when I saw this the first time this is there's a whole series of experiments that were done by Ting 47:05 tingju when he was a graduate student in the lab so it turns out that uh if you have 47:13 these vesicles that are kind of complex and they have multiple membrane layers you can throw in more of the building 47:19 blocks of the membrane fatty acids in this case still and get incorporated into the membrane which will grow and 47:25 will grow in this unusual way into filaments which we kind of understand 47:31 but not completely these are very fragile so they can break down to 47:36 smaller the other vesicles which can grow and the cycle can repeat but then in more recent years we came up 47:43 with a completely different way that this can happen and this is work that was done uh by Stephanie Zhang a 47:50 graduate student and Anna Wang when she was a was stuck in the lab and here we're making much bigger 47:58 vesicles but they only have a single membrane we start to feed them with 48:05 um with more fatty acids and what you'll 48:11 see we look carefully is that this this the spherical structures start to 48:17 fluctuate and and they stick to spontaneously divide 48:22 okay so it turns out we have two completely different ways now of driving growth in 48:28 division that works basically very with very simple physics and with 48:34 it's just soap and water there's nothing elaborate or fancy 48:41 for the center okay so so some of the things that we thought were like super 48:47 hard I had no idea how we were going to get growth in division turn out at least in some cases to be really easy 48:54 and um whereas some of the other things like doing RNA synthesis and replication 49:00 we're still working okay so I think putting those things together is getting us closer and closer to being 49:07 able to build in the lab A system that can grow and divide and evolve which is 49:12 what we really want to see uh and if we can do that that would be I think giving us some understanding 49:19 not necessarily of how life actually evolved but at least how it could have written okay so I'm almost done I just 49:26 want to am by saying a few words about the origin of coated protein synthesis 49:32 so a lot of people think that you know I mean protein synthesis is universal in 49:39 Life as we know it now um and and so it's obviously Central and 49:45 it's important uh so it's it's it would be nice to understand how a system that 49:51 complicated could have Arisen spontaneously by evolution and I the way I think of it is that 49:58 there are kind of Threes major mysteries about this process the one that almost everybody likes to 50:05 think about is the origin of the genetic code right how did certain amino acids become associated with certain uh 50:12 three-letter RNA sequences I'm not going to talk about that I have no idea 50:17 arose but I think there are two other equally important questions 50:24 so the ribosome that machine that builds proteins 50:30 uses very special substrates right it builds proteins using RNA molecules 50:36 which have an amino acid attached to them you could not evolve the ribosome unless 50:42 molecules like that were already around why on Earth would Amino isolated rnas 50:48 have been around and so we think maybe they were doing 50:53 something else before they were involved in protein synthesis and that led to the emergence of perhaps 51:01 ribosomes that that made them more efficiently and with specificity so that 51:07 a given amino acid would be attached to a given RNA that would set the stage for the 51:13 evolution of protein synthesis the other thing we're starting to think about is the other requirement for evolution 51:21 you couldn't evolve the ribosome again unless the thing that it made is useful 51:26 right it has to contribute to the survival the growth of the cell that 51:31 it's in and what could that function again we really have no idea I mean there are 51:37 a few possibilities but it's completely up in the air okay so so let me just uh so it's just a 51:44 diagram showing how the way the ribosome works you know your rnas trnas that have 51:50 an amino acid attached they come in the ribosome hooks things together builds the growing chain kicks out the empty 51:57 tRNA when it's done so why would you have molecules like this around 52:03 Okay so we think that these Amino isolated rnas 52:09 might have been doing something else what could that have been Well turns out that 52:16 um the amine of the amino acid if it's not protonated like it's drawn 52:22 here sorry uh is a good nucleophile it's more reactive it can attack activated 52:28 phosphates and it turns out that it can facilitate the Assembly of little bits 52:34 of RNA into more complicated structures which can be RI designs 52:40 so we think there could have been an early role for these molecules in 52:45 Building Up structures and then that kind of set the stage by by having 52:53 a selective pressure for making more of these Amino isolated rnas and then that 52:58 chemistry was co-opted uh during the evolution of the ribosome to actually make proteins 53:05 okay all right so just to uh to summarize 53:11 um I think you know we what we've actually learned about the process is is that a 53:17 lot of things that looked really hard if you overcome your preconceptions you can figure out ways that they happen easily 53:24 okay and and almost all the big advances in this field have come from overcoming 53:31 some kind of bias or preconception personally I feel that this is a great 53:39 bills to be in because there's been so many surprises and there's just been 53:44 this enormous wealth of totally surprising and unanticipated 53:49 chemical and physical phenomenon that we never would have stumbled across if we weren't trying to figure out how life 53:55 got started um and I think that we're 54:01 close to maybe having a coherent pathway that it gives us 54:07 a picture of how things could have happened step by step where none of the steps are 54:14 are just incredibly contrived for example so that's at least the goal 54:20 I think we're getting that so let me just end by I've tried to mention some of the key people my lab has had so many 54:27 brilliant graduate students and postdocs over the years uh here are the few of the ones that have contributed recently 54:34 to some of uh the advances that I I talked about so I'd like to thank all the people who have worked in my lab 54:40 contributed to this and all the people who've helped us sell all of our collaborators and and people who've 54:47 supported the work and they deserve a lot of thanks and thank you for listening 55:03 I'm happy to take questions oh please if you'd like to ask a 55:10 question which broadly encourage please please 55:22 um hi hello um I'm an astrophiologist my name is Jonathan I was um you mentioned the 55:30 isolated uh immuno amino acid RNA and how they um 55:36 and they form um what was the um origin of of that or is 55:41 that also a mystery like the uh okay how how did that amino acid end up yeah 55:46 because at the end of the RNA yeah yeah no that that's a great question 55:51 um there are some simple uh kinds of chemistry that you can 55:57 use to do that I'm not convinced yet that we have something that the 56:05 right one the one that looks prebiotically realistic there are a lot of different ways to do it it's not a 56:10 hard reaction but we're still still searching for something that looks 56:16 more likely to have happened and you also mentioned you were um in the many 56:22 ways that like broke the immortal suit Paradigm that one of them was the um 56:28 these cyanide diluting in the water with the uh hydrothermal fence mixing life 56:35 um is that like your main belief or is that like that's just one step right that's it's it's the the important thing 56:43 is is the idea that you can build up a reservoir of material and accumulate it 56:48 and then use it later on and there that happens or can happen at many steps in 56:54 all of these pathos I only gave that as one example but there are a lot of other examples thank you very much 57:03 yeah where do you imagine the chirality coming in we have the chirality amino 57:09 acids and the sugars and the lipids and so on and they all had to become chirally pure 57:15 at some point so um that could be a whole lecture uh 57:21 you know uh if you like 20 years ago it was this 57:27 huge mystery that how could you end up with 57:32 you know all the molecules of a certain type having the same handedness right and they're just you know there was this the uh so I 57:40 reaction it's an auto catalytic way of doing uh there were there's no one ever 57:45 figured out how to do that in a way that would get you the right molecules 57:50 um there were other many other ideas about how it could happen then 57:55 I forget maybe five six seven years ago uh Crucible Vietnam a Spanish geochemist 58:03 came up with a process called at the beginning called Crystal grinding later 58:08 chiral Amnesia now Vietnam ripening and the idea that if you have something 58:14 that crystallizes to make separate right and left-handed crystals and you 58:20 put energy into the system by grinding them down they get grind down to a finer powder 58:26 that dissolves recrystallizes on the bigger crystals and there's a cycle and 58:31 that leads the crystal the solid form to diverge spontaneously to the all right-handed or all left-handed simple 58:38 physical process no one believed it at the cell countering too but then it was 58:43 quickly replicated then turns out again no no we can't figure 58:50 out how to get that into the chemistry at the right stage and now there's a whole lot of exciting 58:57 work that's just coming at about how to use spin spin interactions magnetic 59:02 field um to to essentially to drive an angel 59:08 selective nucleation Of crystallization and this works beautifully on exactly 59:14 the right molecule so maybe that's the answer 59:19 yeah it's that whole Field's been transformed multiple times 59:27 just um thank you for your wonderful talk so RNA is very negatively charged yes so so has that worked to its 59:34 advantage or disadvantage it's I think it's a really 59:42 one of the most important things about a genetic material is that 59:49 it should be fairly uniform right you you want to have a be able to have an 59:54 arbitrary sequence right because you needed you need different sequences to to do different 1:00:00 things and so to copy those sequences you want to have the structure the surface and the 1:00:07 chemistry be fairly uniform independent of the sequence and so being having a a 1:00:13 highly negatively charged backbone I think helps with that right if you don't 1:00:19 have that you make molecules that that are have an uncharged background they tend to just glom up into little 1:00:25 three-dimensional you know Blobs of Goo which you can't replicate so I think 1:00:31 that poly and ionic backbone is an essential aspect of the chemistry of RNA 1:00:41 uh there's an online question would you care to comment on the concept 1:00:46 of the lipid world the idea that the earliest organized structures were lipid my cells and that the catalytic and 1:00:53 catalytic entities were different Arrangements of the hydrophilic lipid head groups 1:00:59 so so the way I think about this is the the yeah the lipids are critical they 1:01:06 could be very simple maybe just fatty acids maybe more complicated I am a little bit skeptical but I could 1:01:15 be totally wrong I bet the idea of weather interactions between the head groups contribute to specific 1:01:21 interesting catalysis I think they're more important for making the bilayer membrane structure that encloses all 1:01:30 this other stuff of the cell and and does it in a dynamic way that 1:01:35 allows for growth and division and as well as permeability to to substrate 1:01:41 some exit of waste materials so I think it's those physical properties that are 1:01:47 important but what's missing so far is a really effective 1:01:53 past life for generating things as simple as fatty acids it's one 1:01:58 of the least explored areas of Prebiotic chemistry 1:02:06 hi um in one of your slides you had a plot of 1:02:12 um the amount of bits it takes to describe a certain yeah Arrangement and the amount of effective 1:02:19 like work it can do or right right yeah um I was wondering how you were 1:02:25 um how you go about looking at a structure and giving a number for the 1:02:30 amount of bits it takes to describe it sure good good question so uh what we do 1:02:36 is we we by individual selection we'll find a structure and and then we can 1:02:42 take that structure and make a new library in which we've doped every position with all the other 1:02:49 possibilities right so if there's an a we put in mostly a but a lot of also some GC and you do that at every 1:02:56 position so now we have another huge library then we again we select out the variants that work and then we align all 1:03:04 those sequences and we can immediately see okay this position you have to be in it but this position you have to be a c 1:03:11 at this position you can be anything that these two positions you have to be able to make a Watson quick base clear 1:03:17 and so from that information we can calculate the information content required to specify that structure 1:03:29 what is the difference between RNA and DNA yeah 1:03:35 so so the difference is a small chemical difference it's just one oxygen atom at 1:03:42 a particular place on the sugar it has a very important consequences 1:03:50 [Music] and and and so DNA is very stable it 1:03:56 doesn't degrade very quickly just in water whereas rnas it tends to fall 1:04:02 apart and and you know you can ask is that a good thing or a bad thing you know why 1:04:07 didn't everything begin with DNA instead of RNA there are some Prebiotic Pathways that 1:04:14 might give us the building blocks of DNA at the beginning so this is actually something people are still debating 1:04:23 oh hello I have a question so is there any biological evidence for your proposed 1:04:31 Pathways like uh is this special uh nucleotide exists in some Asian bacteria 1:04:37 and still take part in some very large Pathways some every biological evidence like that no all of this early chemistry 1:04:44 is kind of gone I mean it's only laboratory 1:04:50 chemistry nothing like this happens in biology um despite rather intensive searches 1:04:58 people have made for the so-called Shadow biosphere you know small 1:05:04 remnants of this earlier RNA world nothing like that's been seen and I think the answer the reason for that is 1:05:11 is just that early life wasn't very efficient it wasn't very well adapted to 1:05:17 its environment like Modern Life is and and it was just all eaten up so and the 1:05:23 conditions of the chemical conditions of the modern 1:05:29 Earth are very different from the chemistry of the early Earth for example there was no oxygen no free oxygen 1:05:36 around uh on the earlier so the kinds of chemistry that could have happened would be very different 1:05:42 and and none of this could happen now we we just have to reconstruct what's 1:05:49 possible from experiments in the lab 1:05:57 so thank you for your brilliant talk uh I'm curious that when you were introducing the central dogma of life 1:06:03 which is a relationship between DNA RNA and protein so your link DNA and RNA 1:06:09 with one Arrow however you linked RNA and protein with three arrows so for that three arrows are you do you have a 1:06:15 specific meaning yes Yes actually the the meaning is that the messenger RNA 1:06:22 codes for the protein sequence the ribosomal RNA makes it 1:06:28 and the tearness bring the amino acids to the ribosome so rnas have three 1:06:34 different roles in building proteins another clue that life began with RNA 1:06:42 thank you for your talk I have a very general question about something I never fully understood over here 1:06:47 um what is the driving force for making things more and more complex over time like usually we talk about systems that 1:06:54 strive towards equilibrium they want to be as boring as possible but once we have an energy gradient of some sort 1:06:59 yeah the generator red race things want to be more complex and more efficient how does this work yeah well there are 1:07:05 many many examples in which uh far from equilibrium systems generate local order 1:07:11 right and that energy is is dissipated uh through locally ordered structures 1:07:18 and biology is just one example of that right so all of this depends on 1:07:23 different inputs of energy chemical energy in the form of reactive molecules that we're still 1:07:30 figuring out we have ideas for how to use thermal energy to drive some parts of the cycle 1:07:38 mechanical energy can drive division there are many ways 1:07:44 in which energy comes into the system so all of this is uh is a collection of far 1:07:51 from equilibrium phenomenon that they're conspired together to generate order 1:07:57 is it possible to describe it as a driving force for complexity is that some way to formalize it in some way uh 1:08:05 those are both my pay grade I mean I know that you need you need energy to drive the Assembly of these systems but 1:08:12 uh yeah Advance non-equilibrium thermodynamics is complicated 1:08:18 thank you very much I have a question yeah this is a good 1:08:23 lecture to make us rethink where we come from so my my question I'm here yeah so 1:08:29 it seems there's assumption most of the this chemistry like involving RNA 1:08:35 happens in solution so is it possible that it happens with assistance of Solid 1:08:41 Surfaces all kind of a closed compartment and hopping from surfaces yeah yeah that's a very actually very 1:08:49 interesting idea um so a long time ago um uh Jim Ferriss 1:08:55 and I think initially with Leslie orgo showed that you could assemble the the surfaces of certain 1:09:06 plays basically could Catalyst the Assembly of nucleotides into RNA strands 1:09:12 and unfortunately it hasn't really gone beyond that I mean the idea persists but 1:09:18 experiments that would show something more interesting haven't you know worked out or been done 1:09:25 I think part of the problem is if you have an RNA molecule absorbed on a surface it won't be in the right geometry that 1:09:33 you need to to copy it into a double helical product and so personally a 1:09:40 little skeptical that minerals would play a direct role in in for example 1:09:46 replication chemistry but they certainly could do all kinds of other interesting things 1:09:52 it is something we think about a lot 1:09:57 um where do amino acids come from cyanide yes 1:10:05 in the beginning and early on in the earlier history there there are very 1:10:11 well worked there very high yielding Pathways to go from cyanide to 1:10:18 not all but most of the biologically important amino acids nowadays they're 1:10:24 made in a totally different way they were made by metabolic pathways inside cells by enzymes so 1:10:32 how how that transition was made from a purely chemical approach before there 1:10:40 was life to this metabolic approach that we see now that is again one of the big mysteries 1:10:48 in this in this whole area there are very few cases where we can see how 1:10:55 something went from a Prebiotic chemical reaction to a metabolic reaction 1:11:03 I had a quick question um so when you're showing oh hi sorry um the vesicle growth um with the 1:11:10 introduction of my cells um it looked it had this uh weird elongated morphology I was wondering 1:11:16 what drove that instead of keeping like a a more uniform circular morphology 1:11:21 yeah we we've wondered about that for a long time I mean I could tell you the 1:11:27 theory that we have I have no idea if this is correct but the idea is if you start off with a vesicle that has 1:11:35 multiple layers of lipid right and then there you feed it with more lipid coming 1:11:41 in from the solution the outermost membrane layer is gonna 1:11:46 be the one that grows first okay and but there's not much volume in 1:11:53 between it and the next layer on the inside and so the result is the extra layer gets sort of 1:12:00 and then over time everything equilibrates to a multi-layered filament 1:12:06 we can sort of see that happening in some of our confocal microscopy images 1:12:12 but I still think that's an area that needs a lot more study to really understand 1:12:19 the biophysics thank you 1:12:28 so a lot of biologists I've met they have varying estimates on how long they 1:12:34 think it takes place a thousand year process et cetera so I was wondering uh your 1:12:42 post model here where RNA developed this way how long do you think 1:12:47 that takes and why yeah okay so so the question of time scales again I think 1:12:54 it's very interesting I think you have to the time scales that are relevant depend on the process you're thinking 1:13:00 about so you know we're in that image that I showed we're 1:13:06 thinking maybe on the order of 100 million years for the earth to cool down enough to have liquid water so that's 1:13:11 100 million in your times once you've got liquid water on the surface okay then maybe you need the right 1:13:19 environment in terms of hydrothermal circulation a volcanic region impact 1:13:25 craters maybe getting the right geophysical environment could have 1:13:31 happened on the scale of millions of years or tens of Millions once you've got the right geophysical 1:13:38 environment then the chemistry can start to happen and maybe it takes thousands of years to build up a reservoir of 1:13:45 cyanide in the form of parasyanide salts once that gets processed by heat 1:13:53 the derivatives that are made are much more reactive and now the chemistry is going to start happening on the time 1:13:59 scale of hours to days to weeks once you start building up nucleotides 1:14:05 that can assemble and can polymerize now you're talking about reactions that happen on time scale of minutes to hours 1:14:14 when we get to an entire protocell system that can grow and divide I think 1:14:19 the time scale will be hours to days because there's a lot of different parts to that so so I think once everything 1:14:27 was in place things started happening really quickly but it may have taken a 1:14:32 long time to get everything that's set up perfect 1:14:39 what role do you envision for the Extraterrestrial delivery of organic 1:14:44 molecules and things like carbonaceous chondrites and so on as opposed to The 1:14:49 Institute synthesis of some of these building blocks on Earth yeah yeah so so 1:14:55 there's no doubt that a lot of carbon and a huge variety of molecules were delivered to the surface of the early 1:15:02 Earth by the impacts of of you know stuff from space the comets asteroids 1:15:10 whatever the problem is that those collections of molecules are 1:15:17 mostly things we don't want very little of the right molecules at very very low 1:15:22 concentrations so I don't think they played a major role in the actual origin 1:15:28 of life I think what played was much more important for that were the the 1:15:35 in-situ the chemistry actually happening in local environments it could give you a lot of just the right things 1:15:45 thank you so much for your talk really fantastic I um on the slide where you're talking about 1:15:50 the various uh forms of energy that drive the production of cyanide I'm wondering specifically about UV 1:15:57 radiation and is there a sense of an optimal level of UV radiation to drive the production of cyanide production of 1:16:04 amino acids from there yeah I I mean it's so 1:16:11 people have worked pretty extensively on on photochemical processes that lead to 1:16:17 cyanide production it depends extremely on 1:16:23 um the chemical composition of the atmosphere and the wavelength of the light so this 1:16:31 is high high up and since there's no ozone right you have a lot of very short 1:16:37 wavelengths UV which can basically rip rip things apart into atoms that can 1:16:42 then come back together to make this triple bond species that are very high in energy 1:16:48 but whether that so that nice thing about that is it could be a it's a kind of 1:16:54 global process whereas the cyanide that's made in an impact is localized 1:17:01 so I there's still a lot of debate about what's the best way what would be the 1:17:07 most efficient way to get a lot of cyanide in the right place at the right time 1:17:21 yeah hi so um I'm wondering if after studying this 1:17:27 for all these years if you're convinced or have an idea if uh life is possible in other 1:17:34 planets whether or not you think that that's something that is out there yeah 1:17:40 um so you know I used to say we have no 1:17:46 idea that's why we're doing this we're trying to understand if it's easy or hard to get from chemistry to life 1:17:51 and having worked on this for a long time we still don't really know but there's a 1:17:59 lot of steps in the pathway that we used to think look really hard right you 1:18:06 have no idea and now it turns out they're easy so it's kind of making me think that 1:18:12 well maybe I mean there are gaps that remain to be understood but maybe the whole pathway is actually not that hard 1:18:19 and if that's really the case there are to be 1:18:24 I find a lot of exoplanets out there but then that's a little scary right 1:18:30 because nobody has contacted us it didn't either 1:18:36 getting to intelligent life is really hard which could be or maybe the most likely thing is that 1:18:44 life frequently does get to the point of intelligence and then it self-destructs 1:18:49 which we're very close to now um so we don't know we'll see 1:18:55 sorry to end on a down note 1:19:00 I have a follow-up to my last question so if uh the origin of life when 1:19:06 conditions are right is something you think happens on a very short time scale yeah why is it that we only sort of you 1:19:12 know see one lineage of life here oh okay yes that's a different question right so everything that we see now 1:19:20 traces back to a common ancestor but that common ancestor the Luca the last 1:19:25 Universal common asset was essentially like a modern bacteria it had everything 1:19:30 that Modern Biology has and so we don't see with very few exceptions 1:19:38 anything from before that point right so it looks like 1:19:45 a single unique origin but it didn't have to be that way it could have been that life was popping up all over the 1:19:50 planet and you know it pops up here gets hit by a comet you know it's killed off 1:19:56 pops up again over here um it's possible that there were many 1:20:01 independent Origins and that um you know sell Fusion events resulted in 1:20:08 the exchange of genetic information horizontal Gene transfer right primordial sex if you want to look at it 1:20:14 that way they would have speeded up evolution but all of that period of history is 1:20:20 been erased so all we can really do is speculate and think about possible 1:20:27 mechanisms I was a wondering about like the primary 1:20:33 Earth and how I'm over here and so you were saying it was all localized right based on different environments so I was 1:20:40 wondering hey is there any evidence to see that you know ancient nucleotides 1:20:45 ancient amino acids you know are they different on different parts of the earth and then second of all what was 1:20:51 kind of the driving force to have the standardized nucleotides we see today in the amino acids we see today 1:20:57 right okay so two very interesting questions so so first 1:21:02 um you know if you look for old rocks like the older the rock the the less there is 1:21:08 of it right because the Earth has plate tectonics right and so we're constantly losing 1:21:15 Continental land mass to subduction and so they're only a few couple of two or three places 1:21:21 on the Earth where you have you have uh rocks that date back to 1:21:27 3.8 or more billion years ago and those rocks by and large been fairly heavily 1:21:34 processed so there's there's no record of the 1:21:40 early organic chemistry uh of the Earth that is what is making Mars look so 1:21:47 interesting right Mars never developed like tectonics and so there's a lot of really old surface on Mars and maybe 1:21:57 or maybe not there might be some residue of early either early chemistry or early 1:22:04 life if there ever was early life on Mars it's one of the main things that's driving the exploration of Mars at this 1:22:12 point okay and then sorry the second question was 1:22:22 oh yes right yeah yeah yeah so that's also very interesting and and 1:22:28 somewhat controversial question so there are some people who think that the chemistry just 1:22:35 intrinsically goes towards the standard building blocks of RNA 1:22:41 now is that because people have spent the most effort trying to understand how to make those building 1:22:48 blocks and those neglected other possibilities to some extent Maybe 1:22:54 but we have looked at a lot of Alternatives alternative chemistries and 1:23:01 this is the subject of my talk tomorrow and basically you know this 1:23:08 the the the the summary is that RNA always wins our RNA just looks better 1:23:14 than anything else that could have been made and uh I think that's pretty remarkable 1:23:20 I we it's maybe too early to state that too strongly but it really looks like 1:23:27 the chemistry is just funneled towards making RNA 1:23:33 maybe if we ever get to exoplanets you know some other star will find worms in 1:23:39 life that have the same basic underlying chemistry you don't know 1:23:47 um so I'm also very curious about the third mystery what what is the function of first peptide the third question you 1:23:55 have what is the function of the first peptides that were made by coded synthesis so okay so I think 1:24:04 that you have to go back a step and so there are many ways of making peptides 1:24:10 right it's it's not it's not hard what's hard is to make them in a coded way so 1:24:15 the question at least the way we're thinking about it is could there have been some simple 1:24:22 peptides that were made in a non-coded one maybe just because there are some amino 1:24:29 acids around more than others they come together they make kind of random 1:24:34 sequence strands that are biased to contain certain amino acids if those do 1:24:39 something useful and if so if there's something any a 1:24:44 little bit useful there then it would be worthwhile making more of it right and then you would have a selective 1:24:49 advantage to start start to build in coding to the system now what that primordial function is we 1:24:56 don't really know we're we're thinking about um peptide aggregation phase separation 1:25:04 forming hydrogels other people are thinking about peptides that interact 1:25:09 with RNA stabilize structures there are a lot of possibilities but we 1:25:15 don't actually know what the most likely thing is I was just thinking environmentalization for example for 1:25:21 formation of crystalline like you have a IDP is interesting disorder proteins 1:25:28 which a loss or example not to crystallize so you set out crystals are 1:25:33 important you need certain coasters maybe not do you think the academy a function like you have just tiny peptide 1:25:40 just creating an environment like Mr environment just modulate Crystal 1:25:46 formation or non-crystal formation for RNA could could be could be either either of 1:25:54 those kinds of things we're also thinking about you know peptides like to interact with with membranes and maybe 1:26:00 primitive membranes had not only lipids but also pep buds 1:26:05 adhered to them inserted so yeah what we need are experiments to actually show 1:26:10 like okay this is a way that A Primitive peptide actually could be useful and 1:26:16 that's what's missing 1:26:22 additional question if not in fact thanks again absolutely 1:26:27 grateful [Music] 1:26:42 okay 1:26:47 okay maybe they can edit out the parts where it could get the movie to play 1:27:04 I've seen more information 1:27:21 snakes ASU School of Molecular Sciences 1.47K subscribers Videos 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