1 00:00:00,160 --> 00:00:13,690 [Music] 2 00:00:19,460 --> 00:00:16,849 thank you for the introduction and thank 3 00:00:24,890 --> 00:00:19,470 you very much for the kind invitation to 4 00:00:26,779 --> 00:00:24,900 visit LC and and talk about what we've 5 00:00:30,349 --> 00:00:26,789 been up to in the in the recent few 6 00:00:34,100 --> 00:00:30,359 years and that is really have I made it 7 00:00:35,870 --> 00:00:34,110 a rather rather protracted title but 8 00:00:37,910 --> 00:00:35,880 really the basic question is can we make 9 00:00:41,720 --> 00:00:37,920 life in the lab this is what keeps us 10 00:00:43,610 --> 00:00:41,730 occupied at the moment and this comes 11 00:00:45,889 --> 00:00:43,620 from our work on self-replicating 12 00:00:48,860 --> 00:00:45,899 molecules that pop up out of dynamic 13 00:00:51,350 --> 00:00:48,870 like here networks and really all is an 14 00:00:53,750 --> 00:00:51,360 adventure in systems chemistry so we're 15 00:00:56,330 --> 00:00:53,760 in the business of looking at complex 16 00:00:58,340 --> 00:00:56,340 molecular systems and see look for 17 00:01:00,950 --> 00:00:58,350 emergent properties that commodities and 18 00:01:03,529 --> 00:01:00,960 life is probably the most exciting of 19 00:01:07,640 --> 00:01:03,539 all of those of all the emergent 20 00:01:10,730 --> 00:01:07,650 properties you can think of so we're not 21 00:01:15,499 --> 00:01:10,740 so much directly interested in this 22 00:01:16,640 --> 00:01:15,509 question here how did life start in to 23 00:01:20,120 --> 00:01:16,650 the point that it doesn't really know it 24 00:01:21,830 --> 00:01:20,130 doesn't impact directly in what we do 25 00:01:24,670 --> 00:01:21,840 we're very intrigued by the question 26 00:01:27,109 --> 00:01:24,680 nevertheless but our philosophy is more 27 00:01:30,140 --> 00:01:27,119 let's see if we can make something that 28 00:01:33,230 --> 00:01:30,150 looks like life in a lab and not be 29 00:01:38,719 --> 00:01:33,240 constrained by anything prebiotic 30 00:01:40,940 --> 00:01:38,729 irrelevant or not just make life in in 31 00:01:43,880 --> 00:01:40,950 as easy way as we can 32 00:01:46,310 --> 00:01:43,890 helping it in any way that we feel is 33 00:01:49,520 --> 00:01:46,320 necessary and in the process we hope of 34 00:01:51,560 --> 00:01:49,530 course to learn a lot about what it 35 00:01:53,569 --> 00:01:51,570 takes to become a life which then 36 00:01:57,050 --> 00:01:53,579 directly informs on this question here 37 00:02:00,050 --> 00:01:57,060 how did life start so even though we're 38 00:02:04,609 --> 00:02:00,060 not directly targeting it I hope was to 39 00:02:08,529 --> 00:02:04,619 learn a lot so when you want to make 40 00:02:11,839 --> 00:02:08,539 life it's a little bit like trying to 41 00:02:13,760 --> 00:02:11,849 find a lost key in a dark Street so this 42 00:02:18,980 --> 00:02:13,770 is more or less the guidance you have 43 00:02:20,810 --> 00:02:18,990 start now it's not as bad as this 44 00:02:24,800 --> 00:02:20,820 because there are some lampposts in the 45 00:02:28,010 --> 00:02:24,810 street and we know we've heard already 46 00:02:29,600 --> 00:02:28,020 about life probably requiring requiring 47 00:02:34,610 --> 00:02:29,610 a compartment so you can start looking 48 00:02:38,000 --> 00:02:34,620 at things that have compared Monsanto 49 00:02:41,510 --> 00:02:38,010 become a life somehow you can look at 50 00:02:43,100 --> 00:02:41,520 metabolism in the same way you can hope 51 00:02:47,090 --> 00:02:43,110 to find the key and there the lamppost 52 00:02:50,720 --> 00:02:47,100 it says replication and there's the for 53 00:02:52,070 --> 00:02:50,730 so this is usually the three modes three 54 00:02:55,010 --> 00:02:52,080 are identified as the three most 55 00:02:57,680 --> 00:02:55,020 important elements of life but there's a 56 00:03:00,380 --> 00:02:57,690 force that I'd like to emphasize here 57 00:03:01,760 --> 00:03:00,390 that's the the aspect and we all noticed 58 00:03:04,910 --> 00:03:01,770 the aspect that life is far from 59 00:03:10,220 --> 00:03:04,920 equilibrium we usually factored into the 60 00:03:14,840 --> 00:03:10,230 metabolism one but I took it out because 61 00:03:16,880 --> 00:03:14,850 I think there is something really rather 62 00:03:19,520 --> 00:03:16,890 important in the a difficulty reom 63 00:03:23,990 --> 00:03:19,530 aspect of life and rather important to 64 00:03:25,850 --> 00:03:24,000 also develop molecular systems that are 65 00:03:28,220 --> 00:03:25,860 in this similar amic regime here and 66 00:03:29,720 --> 00:03:28,230 that's not trivial this is not at least 67 00:03:33,100 --> 00:03:29,730 for a chemist this is not what your 68 00:03:35,900 --> 00:03:33,110 being being claimed to start off with oh 69 00:03:37,910 --> 00:03:35,910 perhaps already because we're not 70 00:03:41,210 --> 00:03:37,920 trained as chemists to do anything that 71 00:03:43,520 --> 00:03:41,220 is far from equilibrium if you are a 72 00:03:46,280 --> 00:03:43,530 chemist you're trained to make stable 73 00:03:48,230 --> 00:03:46,290 molecules if you're Procter and Gamble 74 00:03:49,580 --> 00:03:48,240 or Unilever and you sell laundry 75 00:03:51,199 --> 00:03:49,590 detergent you don't want lonely 76 00:03:53,150 --> 00:03:51,209 detergent to change it to something else 77 00:03:56,270 --> 00:03:53,160 after the customer bought it and then 78 00:03:59,780 --> 00:03:56,280 there's on his way home so stable is 79 00:04:02,000 --> 00:03:59,790 good for most of chemistry but not when 80 00:04:05,180 --> 00:04:02,010 you want to make something that is a 81 00:04:07,790 --> 00:04:05,190 life because a life is not life is not 82 00:04:11,949 --> 00:04:07,800 at equilibrium is far from it and I'll 83 00:04:18,039 --> 00:04:11,959 come back to that at the end of my talk 84 00:04:23,780 --> 00:04:18,049 so these so where we had like 85 00:04:25,850 --> 00:04:23,790 isolated lampposts and for quite a while 86 00:04:27,650 --> 00:04:25,860 research quite intense research has been 87 00:04:30,260 --> 00:04:27,660 done in East these areas 88 00:04:32,780 --> 00:04:30,270 so more in some areas more than others I 89 00:04:34,430 --> 00:04:32,790 guess making things metabolize and 90 00:04:37,430 --> 00:04:34,440 taking that as a starting point for 91 00:04:39,200 --> 00:04:37,440 making life is still very hurt and also 92 00:04:41,510 --> 00:04:39,210 far from equilibrium systems haven't 93 00:04:44,570 --> 00:04:41,520 received a lot of attention but these 94 00:04:47,330 --> 00:04:44,580 other two have and so the light the 95 00:04:49,310 --> 00:04:47,340 light intensity is increased to the 96 00:04:51,260 --> 00:04:49,320 point ever now you can start thinking 97 00:04:53,630 --> 00:04:51,270 about merging these and have already 98 00:04:56,000 --> 00:04:53,640 alluded to this so maybe the pro best 99 00:04:57,950 --> 00:04:56,010 approach to life is not to focus on any 100 00:05:01,730 --> 00:04:57,960 of these ones individually but try to 101 00:05:05,560 --> 00:05:01,740 look at systems but share two maybe more 102 00:05:09,290 --> 00:05:05,570 but that's got heart of these essential 103 00:05:12,490 --> 00:05:09,300 characteristics of life so what am I 104 00:05:15,740 --> 00:05:12,500 going to talk about today then so I 105 00:05:17,300 --> 00:05:15,750 summarized the main findings on this 106 00:05:19,370 --> 00:05:17,310 slide here so that you know what's 107 00:05:21,290 --> 00:05:19,380 coming your way I'll show you how 108 00:05:23,410 --> 00:05:21,300 self-replicating molecules can emerge 109 00:05:25,790 --> 00:05:23,420 spontaneously from a superfund 110 00:05:27,650 --> 00:05:25,800 interconverting molecules so that's 111 00:05:29,750 --> 00:05:27,660 starting off under the lamppost it says 112 00:05:32,480 --> 00:05:29,760 replication and we do this not because 113 00:05:35,150 --> 00:05:32,490 we think that's the best lamppost but 114 00:05:39,110 --> 00:05:35,160 rather because that was the one we found 115 00:05:41,960 --> 00:05:39,120 ourselves under so whether that's the 116 00:05:44,510 --> 00:05:41,970 best spot to find the key no idea but 117 00:05:47,390 --> 00:05:44,520 that's the best spot for us to look it's 118 00:05:49,760 --> 00:05:47,400 the best place we can actually start get 119 00:05:53,240 --> 00:05:49,770 started and I'll show you that these 120 00:05:54,710 --> 00:05:53,250 replicators can acquire information very 121 00:05:57,880 --> 00:05:54,720 very trivial information that this 122 00:06:01,370 --> 00:05:57,890 states but nevertheless and complexify 123 00:06:02,900 --> 00:06:01,380 spontaneously in rather small steps I'll 124 00:06:04,760 --> 00:06:02,910 show you that at least the basic 125 00:06:06,860 --> 00:06:04,770 ingredients of the FIR Darwinian 126 00:06:09,620 --> 00:06:06,870 evolution are there this replication 127 00:06:12,290 --> 00:06:09,630 mutation and selection I'll show you an 128 00:06:14,300 --> 00:06:12,300 example where replicators spontaneously 129 00:06:16,460 --> 00:06:14,310 diversify we start with one we end up 130 00:06:19,210 --> 00:06:16,470 with more and I'll show you an example 131 00:06:21,560 --> 00:06:19,220 where again trivial but where 132 00:06:23,390 --> 00:06:21,570 replication the replicators adapt their 133 00:06:28,280 --> 00:06:23,400 structure to change in the environments 134 00:06:30,830 --> 00:06:28,290 and I'll show you at the end how you can 135 00:06:34,010 --> 00:06:30,840 make dissipative systems and actually I 136 00:06:36,140 --> 00:06:34,020 think this is at least the bit I'm most 137 00:06:37,820 --> 00:06:36,150 excited about right now where you can 138 00:06:39,620 --> 00:06:37,830 start populating thermodynamically 139 00:06:41,240 --> 00:06:39,630 disfavored state so that's what life is 140 00:06:43,340 --> 00:06:41,250 right it's not a kinetic 141 00:06:44,480 --> 00:06:43,350 it's not a thermodynamic product it's 142 00:06:46,460 --> 00:06:44,490 not the kinetic practical in the sense 143 00:06:47,860 --> 00:06:46,470 is the first one you make it's not the 144 00:06:50,690 --> 00:06:47,870 stoma dynamic products something else 145 00:06:52,160 --> 00:06:50,700 how do you populate states that it's not 146 00:06:53,990 --> 00:06:52,170 the first you make it's also not the one 147 00:06:57,770 --> 00:06:54,000 you make when you when you wait a bit 148 00:07:00,980 --> 00:06:57,780 and so I'll come back to that and now if 149 00:07:02,540 --> 00:07:00,990 I have time towards the end I also say 150 00:07:04,370 --> 00:07:02,550 something about compartments is not 151 00:07:06,530 --> 00:07:04,380 necessarily very connected to any of the 152 00:07:09,950 --> 00:07:06,540 the above but we'd like it to become 153 00:07:13,700 --> 00:07:09,960 eventually at one point so what's our 154 00:07:15,830 --> 00:07:13,710 recipe done for life so we start off 155 00:07:17,690 --> 00:07:15,840 with replicators as I said and 156 00:07:20,030 --> 00:07:17,700 exponential replicators allowed them to 157 00:07:23,360 --> 00:07:20,040 mutate then operate the system far from 158 00:07:25,190 --> 00:07:23,370 equilibrium and then that should allow 159 00:07:27,110 --> 00:07:25,200 Darwinian evolution of the replicators 160 00:07:29,420 --> 00:07:27,120 to occur and for a while we thought if 161 00:07:31,520 --> 00:07:29,430 we were there then the Iranian evolution 162 00:07:35,210 --> 00:07:31,530 would this take over and will lead us 163 00:07:38,210 --> 00:07:35,220 places and that was I think now looking 164 00:07:41,570 --> 00:07:38,220 back at it now is probably a bit naive 165 00:07:43,130 --> 00:07:41,580 and there's more required in order for 166 00:07:46,550 --> 00:07:43,140 Darwinian evolution to actually go 167 00:07:49,480 --> 00:07:46,560 places and do things other than make 168 00:07:52,220 --> 00:07:49,490 trivial changes to the system and that's 169 00:07:54,590 --> 00:07:52,230 that go places means invention of new 170 00:07:57,409 --> 00:07:54,600 traits and how that might work is 171 00:07:59,570 --> 00:07:57,419 something where we're trying to find out 172 00:08:02,270 --> 00:07:59,580 but we still haven't got much of a clue 173 00:08:03,680 --> 00:08:02,280 about so where oh I'll probably need to 174 00:08:06,350 --> 00:08:03,690 leave you somewhere between four and 175 00:08:11,240 --> 00:08:06,360 five - it's the end by the end of the 176 00:08:13,400 --> 00:08:11,250 tool so self-replication auto catalysis 177 00:08:15,820 --> 00:08:13,410 we're by no means the first people to 178 00:08:18,880 --> 00:08:15,830 work on this so let me 179 00:08:22,060 --> 00:08:18,890 introduced the topic briefly so this is 180 00:08:24,430 --> 00:08:22,070 the blueprint by which 90 99 percent of 181 00:08:27,340 --> 00:08:24,440 self-replicating molecules work and be 182 00:08:29,650 --> 00:08:27,350 that self replicators based on RNA that 183 00:08:31,420 --> 00:08:29,660 tides completely synthetic molecules it 184 00:08:33,700 --> 00:08:31,430 doesn't matter this they all weigh the 185 00:08:36,339 --> 00:08:33,710 same principle there is a template 186 00:08:38,770 --> 00:08:36,349 molecule with two binding sites there's 187 00:08:41,020 --> 00:08:38,780 food molecules with complimentary 188 00:08:43,180 --> 00:08:41,030 binding motives you make a ternary 189 00:08:45,250 --> 00:08:43,190 complex so the template with the two 190 00:08:47,110 --> 00:08:45,260 food molecules that brings the two 191 00:08:49,360 --> 00:08:47,120 reactive ends of those two food 192 00:08:50,980 --> 00:08:49,370 molecules in close proximity reaction 193 00:08:52,900 --> 00:08:50,990 goes faster if those ends are in close 194 00:08:55,000 --> 00:08:52,910 proximity then they go then the reaction 195 00:08:57,610 --> 00:08:55,010 goes when they're not so you accelerate 196 00:09:00,220 --> 00:08:57,620 the the ligation here you make the 197 00:09:02,500 --> 00:09:00,230 duplex the duplex you dissociates make 198 00:09:04,990 --> 00:09:02,510 two replicators that can eats undergo 199 00:09:06,700 --> 00:09:05,000 their own replication cycle so the idea 200 00:09:08,920 --> 00:09:06,710 is you start with one then after one 201 00:09:10,690 --> 00:09:08,930 round you have two to make four four 202 00:09:12,910 --> 00:09:10,700 make eight eight make sixteen so 203 00:09:14,710 --> 00:09:12,920 exponential replication but as we 204 00:09:16,930 --> 00:09:14,720 already heard yesterday there's a 205 00:09:19,660 --> 00:09:16,940 problem with this template dissociation 206 00:09:21,310 --> 00:09:19,670 step it's actually quite hard to make 207 00:09:23,680 --> 00:09:21,320 this dissociate this is by molecular 208 00:09:25,330 --> 00:09:23,690 complex and their conditions were done 209 00:09:26,950 --> 00:09:25,340 associates this is their molecular 210 00:09:31,000 --> 00:09:26,960 complex but the interactions are the 211 00:09:33,910 --> 00:09:31,010 same so entropy is it's your enemy here 212 00:09:36,970 --> 00:09:33,920 it would really much prefer to make this 213 00:09:38,770 --> 00:09:36,980 over that so if you once you've made it 214 00:09:40,960 --> 00:09:38,780 it's kind of hard to dissociate if this 215 00:09:43,180 --> 00:09:40,970 association doesn't happen then the 216 00:09:45,280 --> 00:09:43,190 exponential growth doesn't happen now 217 00:09:47,020 --> 00:09:45,290 it's that bad well it depends on what 218 00:09:48,880 --> 00:09:47,030 you want to do but if you want to do 219 00:09:50,950 --> 00:09:48,890 that we need evolution it turns out to 220 00:09:53,530 --> 00:09:50,960 be bad for most systems in the most 221 00:09:55,450 --> 00:09:53,540 circumstances because for Darwinian 222 00:09:57,280 --> 00:09:55,460 evolution universe an area like this two 223 00:10:00,550 --> 00:09:57,290 replicators competing for a common food 224 00:10:06,430 --> 00:10:00,560 source and if replicators also die in 225 00:10:08,590 --> 00:10:06,440 some way then for Darwinian evolution 226 00:10:10,300 --> 00:10:08,600 the desired outcome is that only one of 227 00:10:13,300 --> 00:10:10,310 those two replicators survives and the 228 00:10:15,940 --> 00:10:13,310 other one goes extinct and that you can 229 00:10:17,650 --> 00:10:15,950 show mathematically and assess Marius as 230 00:10:19,990 --> 00:10:17,660 describe this and if a for some time ago 231 00:10:22,680 --> 00:10:20,000 and that will only work if the 232 00:10:24,550 --> 00:10:22,690 Replicators are exponential for most 233 00:10:26,670 --> 00:10:24,560 depends a little bit on how your 234 00:10:28,990 --> 00:10:26,680 destruction process works but for most 235 00:10:31,600 --> 00:10:29,000 destruction processes that 236 00:10:33,160 --> 00:10:31,610 what is the situation so exponential 237 00:10:35,350 --> 00:10:33,170 replicators gives the fievel of the 238 00:10:37,510 --> 00:10:35,360 fittest but some exponential ones if you 239 00:10:39,810 --> 00:10:37,520 have product inhibition exponential 240 00:10:43,030 --> 00:10:39,820 growth doesn't doesn't occur completely 241 00:10:44,800 --> 00:10:43,040 you like the growth may still happen 242 00:10:47,260 --> 00:10:44,810 replication may still happen but it be 243 00:10:50,520 --> 00:10:47,270 so exponential and then that leads to 244 00:10:52,960 --> 00:10:50,530 indefinite go existence of a and B and 245 00:10:54,670 --> 00:10:52,970 therefore no Darwinian evolution the 246 00:10:58,780 --> 00:10:54,680 Iranian evolution needs to burn its 247 00:11:02,560 --> 00:10:58,790 bridges so how can you get around this 248 00:11:04,480 --> 00:11:02,570 problem there are some but only very 249 00:11:07,720 --> 00:11:04,490 there are only two or three replicators 250 00:11:09,370 --> 00:11:07,730 in the literature where that actually 251 00:11:12,190 --> 00:11:09,380 has been shown to replicate 252 00:11:13,780 --> 00:11:12,200 exponentially but it's not clear what 253 00:11:15,400 --> 00:11:13,790 makes them replicate exponentially in 254 00:11:17,170 --> 00:11:15,410 these systems we were lucky enough to 255 00:11:19,960 --> 00:11:17,180 run into the system it also does 256 00:11:24,960 --> 00:11:19,970 exponential replication and we we now 257 00:11:30,810 --> 00:11:24,970 and do know why that that works and I'll 258 00:11:34,810 --> 00:11:30,820 show that in an animation biscuits 259 00:11:36,250 --> 00:11:34,820 running of how the system had a 260 00:11:38,950 --> 00:11:36,260 replicator emerged in the first place 261 00:11:40,720 --> 00:11:38,960 and also how they become exponential so 262 00:11:42,520 --> 00:11:40,730 we started off as very simple molecules 263 00:11:46,090 --> 00:11:42,530 which have two reactive ends they can 264 00:11:48,130 --> 00:11:46,100 make with which they can arrange 265 00:11:50,160 --> 00:11:48,140 themselves into rings rings of different 266 00:11:53,230 --> 00:11:50,170 sizes you have large rings small rings 267 00:11:55,720 --> 00:11:53,240 the ligation between the building blocks 268 00:11:57,700 --> 00:11:55,730 here is a chemical reaction that is 269 00:11:59,800 --> 00:11:57,710 reversible so it's a covalent bond but 270 00:12:01,510 --> 00:11:59,810 one that can you can also break again so 271 00:12:05,020 --> 00:12:01,520 you see the exchange for building blocks 272 00:12:07,210 --> 00:12:05,030 between different rings so you have 273 00:12:08,920 --> 00:12:07,220 initially a ring a super rings different 274 00:12:12,250 --> 00:12:08,930 ring sizes that are own equilibrium was 275 00:12:14,100 --> 00:12:12,260 one another after a while and actually 276 00:12:16,750 --> 00:12:14,110 it does take a little while you see the 277 00:12:18,880 --> 00:12:16,760 stacking of rings of one particular ring 278 00:12:21,340 --> 00:12:18,890 size occurring and once you have a 279 00:12:24,340 --> 00:12:21,350 nucleus it grows relatively fast but 280 00:12:26,320 --> 00:12:24,350 initially in a linear fashion and it 281 00:12:28,570 --> 00:12:26,330 actually pulls the equilibrium over to 282 00:12:30,430 --> 00:12:28,580 the ring size that makes the stack but 283 00:12:33,300 --> 00:12:30,440 disks the growth of the stack is still 284 00:12:35,860 --> 00:12:33,310 linear it's not exponential and it's 285 00:12:37,690 --> 00:12:35,870 that it becomes exponential the moment 286 00:12:41,050 --> 00:12:37,700 you start agitating this mixture here 287 00:12:43,210 --> 00:12:41,060 then these stacks start to break and now 288 00:12:46,330 --> 00:12:43,220 you have if you break a stack it 289 00:12:48,430 --> 00:12:46,340 the number of ends so gross process 290 00:12:49,690 --> 00:12:48,440 accelerates so it grows is directly 291 00:12:51,160 --> 00:12:49,700 proportional the rate of growth 292 00:12:53,740 --> 00:12:51,170 proportional the number of ends you have 293 00:12:55,900 --> 00:12:53,750 so you saw one stack become two to 294 00:12:59,530 --> 00:12:55,910 become four four become eight eight 295 00:13:03,160 --> 00:12:59,540 becomes 16 and so on until at the end of 296 00:13:05,350 --> 00:13:03,170 the the animation here all the building 297 00:13:07,810 --> 00:13:05,360 blocks that you have have all been 298 00:13:10,900 --> 00:13:07,820 converted into this one ring size that 299 00:13:12,790 --> 00:13:10,910 make the stacks so in this way the 300 00:13:15,160 --> 00:13:12,800 assembly process of rings into stacks 301 00:13:17,440 --> 00:13:15,170 drives the synthesis of the ring that 302 00:13:19,840 --> 00:13:17,450 makes the stacks in the mixture of 303 00:13:22,270 --> 00:13:19,850 different ring sizes so it's an assembly 304 00:13:25,750 --> 00:13:22,280 driven self-replication process where 305 00:13:27,780 --> 00:13:25,760 mechanical energy allows you to achieve 306 00:13:30,400 --> 00:13:27,790 exponential growth of these systems 307 00:13:34,390 --> 00:13:30,410 mechanical energy it's kind of the trick 308 00:13:37,420 --> 00:13:34,400 that allows you to liberate replicators 309 00:13:40,510 --> 00:13:37,430 from the stacks or at least create more 310 00:13:41,800 --> 00:13:40,520 stack ends so because it's very 311 00:13:44,590 --> 00:13:41,810 important for the rest of the tool cup 312 00:13:46,840 --> 00:13:44,600 summarize what you just seen on the in 313 00:13:48,100 --> 00:13:46,850 the animation in one slide so you see 314 00:13:51,400 --> 00:13:48,110 here a little building block it's 315 00:13:53,140 --> 00:13:51,410 somewhat different to transition to the 316 00:13:54,840 --> 00:13:53,150 actual molecular structure that makes 317 00:13:57,640 --> 00:13:54,850 this all happen 318 00:13:59,110 --> 00:13:57,650 so we have a simple building block that 319 00:14:00,400 --> 00:13:59,120 makes ring that can make rings of 320 00:14:02,020 --> 00:14:00,410 different sizes that they can all 321 00:14:04,510 --> 00:14:02,030 exchange with one another and there's a 322 00:14:06,190 --> 00:14:04,520 slow nucleation phase where you find 323 00:14:08,560 --> 00:14:06,200 where you start forming a short stack 324 00:14:10,630 --> 00:14:08,570 that then grows and at the point it 325 00:14:13,030 --> 00:14:10,640 grows long enough that mechanical energy 326 00:14:16,390 --> 00:14:13,040 can do something with it it will start 327 00:14:18,760 --> 00:14:16,400 entering this gross breakage cycle here 328 00:14:21,010 --> 00:14:18,770 so where long things break into smaller 329 00:14:23,520 --> 00:14:21,020 ones that then in each grow again and 330 00:14:27,610 --> 00:14:23,530 break again and this is how you end up 331 00:14:28,750 --> 00:14:27,620 with this exponential growth process so 332 00:14:31,540 --> 00:14:28,760 this is the building block that does 333 00:14:34,060 --> 00:14:31,550 this so it's a die file that make that 334 00:14:36,300 --> 00:14:34,070 from allowing it to react with oxygen 335 00:14:38,710 --> 00:14:36,310 from the air and just water neutral 336 00:14:42,730 --> 00:14:38,720 ambient conditions 337 00:14:44,520 --> 00:14:42,740 it makes rings of disulfides and the 338 00:14:47,050 --> 00:14:44,530 blue bit here is a peptide sequence 339 00:14:50,260 --> 00:14:47,060 fairly short peptide five amino acids 340 00:14:51,900 --> 00:14:50,270 long designed to have alternating 341 00:14:55,540 --> 00:14:51,910 hydrophobic hydrophilic hydrophobic 342 00:14:56,800 --> 00:14:55,550 amino acids which predisposes it to form 343 00:14:58,840 --> 00:14:56,810 beta sheets 344 00:15:01,030 --> 00:14:58,850 but it's too sure to do this by itself 345 00:15:04,269 --> 00:15:01,040 so it needs quite a few of these 346 00:15:05,860 --> 00:15:04,279 peptides displayed in one ring before 347 00:15:08,620 --> 00:15:05,870 there's enough interaction energy 348 00:15:12,250 --> 00:15:08,630 between the peptides to stack them up 349 00:15:13,780 --> 00:15:12,260 into a beta sheet so in this particular 350 00:15:16,150 --> 00:15:13,790 for this particular sequence this 351 00:15:19,690 --> 00:15:16,160 happens with with ring size six so you 352 00:15:22,210 --> 00:15:19,700 see that stacking and then growing so 353 00:15:25,500 --> 00:15:22,220 chemically this is the again the same 354 00:15:28,000 --> 00:15:25,510 building block Dicer the dithiol 355 00:15:31,060 --> 00:15:28,010 oxidized to disulfide so you make these 356 00:15:35,680 --> 00:15:31,070 disulfide rings that initially arrow in 357 00:15:37,450 --> 00:15:35,690 equilibrium with one another now as I 358 00:15:38,829 --> 00:15:37,460 said mechanical energy and also it was 359 00:15:40,570 --> 00:15:38,839 also apparent from the from the 360 00:15:43,960 --> 00:15:40,580 animation mechanical energy is crucial 361 00:15:45,760 --> 00:15:43,970 here so if we don't provide it if we 362 00:15:47,710 --> 00:15:45,770 don't stir in the system would just have 363 00:15:50,890 --> 00:15:47,720 a homogeneous solution of these building 364 00:15:54,220 --> 00:15:50,900 blocks in water and what happens you do 365 00:15:56,170 --> 00:15:54,230 form rings but the rings don't then you 366 00:15:57,940 --> 00:15:56,180 may even form a few nuclei but the 367 00:16:00,280 --> 00:15:57,950 process of converting primary nuclei 368 00:16:03,370 --> 00:16:00,290 into secondary and making long stacks is 369 00:16:04,630 --> 00:16:03,380 very very slow so you you get stuck at 370 00:16:06,490 --> 00:16:04,640 the states where there's only super 371 00:16:10,360 --> 00:16:06,500 there are only small rings Reimer and 372 00:16:13,690 --> 00:16:10,370 tetra mer if you do stir the system the 373 00:16:15,640 --> 00:16:13,700 outcome is quite different in this case 374 00:16:17,560 --> 00:16:15,650 you make a cyclic heptamer so a seven 375 00:16:21,520 --> 00:16:17,570 membered ring with this building block 376 00:16:23,380 --> 00:16:21,530 when you stir it but if you ask this guy 377 00:16:26,380 --> 00:16:23,390 here how you should prepare a cocktail 378 00:16:28,480 --> 00:16:26,390 he says shaken not stirred so what 379 00:16:31,360 --> 00:16:28,490 happens if you do that you actually end 380 00:16:33,790 --> 00:16:31,370 up with a different replicator so the in 381 00:16:38,470 --> 00:16:33,800 this for this particular peptide the 382 00:16:40,199 --> 00:16:38,480 exact way of agitation decides the 383 00:16:42,400 --> 00:16:40,209 outcome between two competing 384 00:16:45,160 --> 00:16:42,410 replicators a six membered and the seven 385 00:16:48,520 --> 00:16:45,170 membered ring and we understand why this 386 00:16:50,790 --> 00:16:48,530 why this works why this difference is if 387 00:16:54,690 --> 00:16:50,800 you want to know you can ask me later 388 00:16:57,610 --> 00:16:54,700 but bottom line is agitation allows 389 00:16:59,170 --> 00:16:57,620 replication and this is just some 390 00:17:02,290 --> 00:16:59,180 electron microscopy to show you that 391 00:17:03,940 --> 00:17:02,300 there are really stacks of of rings that 392 00:17:05,980 --> 00:17:03,950 have a diameter that corresponds to the 393 00:17:07,960 --> 00:17:05,990 diameter of the ring for both the hexa 394 00:17:10,630 --> 00:17:07,970 mirandy and the and the epimer but if 395 00:17:12,880 --> 00:17:10,640 you look at try and find any of these 396 00:17:18,100 --> 00:17:12,890 thanks in the Trimurti tumor sample you 397 00:17:19,990 --> 00:17:18,110 see nothing it's also catalytic and the 398 00:17:23,110 --> 00:17:20,000 kinetics of this it's also slow as she 399 00:17:26,800 --> 00:17:23,120 dad the kinetics of this already hints 400 00:17:29,320 --> 00:17:26,810 at it so this is the distribution of 401 00:17:31,120 --> 00:17:29,330 ring sizes with time if you start off as 402 00:17:33,430 --> 00:17:31,130 monomer it oxidizes initially you make 403 00:17:36,460 --> 00:17:33,440 trimaran tettemer rings and then after 404 00:17:38,200 --> 00:17:36,470 about three weeks you see after my rings 405 00:17:40,870 --> 00:17:38,210 growing so there's a slow process and a 406 00:17:43,300 --> 00:17:40,880 lot of credit to d2 jackie the pc 407 00:17:46,240 --> 00:17:43,310 student to discover this for not 408 00:17:47,680 --> 00:17:46,250 stopping after a week and just keep 409 00:17:49,420 --> 00:17:47,690 monitoring and seeing of anything 410 00:17:53,370 --> 00:17:49,430 changes actually not done that we would 411 00:17:56,170 --> 00:17:53,380 have missed an awful lot of fun so this 412 00:17:57,490 --> 00:17:56,180 sigmoid l growth curve suggests thoughts 413 00:17:58,720 --> 00:17:57,500 of catalysis if you want to prove it 414 00:18:00,580 --> 00:17:58,730 what you do is you take some of this 415 00:18:01,870 --> 00:18:00,590 material at the end you introduce it in 416 00:18:03,790 --> 00:18:01,880 the beginning you see the moment you 417 00:18:08,410 --> 00:18:03,800 introduce it immediately shoots off so 418 00:18:10,000 --> 00:18:08,420 it's all the catalytic definitely so we 419 00:18:12,460 --> 00:18:10,010 have an exponential replicator 420 00:18:14,920 --> 00:18:12,470 how about mutations well if you want to 421 00:18:17,800 --> 00:18:14,930 mutate allowed us to mutate and the 422 00:18:20,530 --> 00:18:17,810 simplest thing is simplest thing to do 423 00:18:22,330 --> 00:18:20,540 is to offer it a set of different 424 00:18:23,560 --> 00:18:22,340 building blocks not only one but 425 00:18:25,660 --> 00:18:23,570 offering the choice and then he can 426 00:18:28,000 --> 00:18:25,670 decide to change the structure but 427 00:18:29,980 --> 00:18:28,010 before we offered it any choice we first 428 00:18:31,540 --> 00:18:29,990 made those building blocks and looked at 429 00:18:33,640 --> 00:18:31,550 what they did individually to get a bit 430 00:18:35,050 --> 00:18:33,650 of a feel for what the system I do so 431 00:18:36,790 --> 00:18:35,060 this was the original building block 432 00:18:38,530 --> 00:18:36,800 that has this peptide sequence here we 433 00:18:41,560 --> 00:18:38,540 played around with that physician there 434 00:18:44,380 --> 00:18:41,570 made it and then initially less 435 00:18:46,030 --> 00:18:44,390 hydrophobic and we found we lose now the 436 00:18:47,470 --> 00:18:46,040 seven membered ring we only make six 437 00:18:49,690 --> 00:18:47,480 membered rings if we change this to a 438 00:18:51,760 --> 00:18:49,700 phenyl alanine in that position make it 439 00:18:54,130 --> 00:18:51,770 less hydrophobic still we go to even 440 00:18:56,410 --> 00:18:54,140 smaller rings like pentamer and for a 441 00:18:58,540 --> 00:18:56,420 nafta lien trimer and tetramer rings 442 00:19:00,070 --> 00:18:58,550 already start stacking so there seems to 443 00:19:01,870 --> 00:19:00,080 be a correlation between hydrophobicity 444 00:19:03,790 --> 00:19:01,880 of the peptides stickiness of the 445 00:19:05,740 --> 00:19:03,800 peptide if you like and ring size of the 446 00:19:07,180 --> 00:19:05,750 replicator that we're making also goes 447 00:19:09,550 --> 00:19:07,190 the other direction if you make it more 448 00:19:11,860 --> 00:19:09,560 hydrophilic with a serine or an alanine 449 00:19:16,540 --> 00:19:11,870 in that position there we make octomorg 450 00:19:18,330 --> 00:19:16,550 rings so there appears to be a kind of 451 00:19:20,710 --> 00:19:18,340 selection rule for the emergence of 452 00:19:23,110 --> 00:19:20,720 replicators and selection rules when it 453 00:19:24,430 --> 00:19:23,120 comes to ring size the stronger we make 454 00:19:25,660 --> 00:19:24,440 the peptide peptide interaction 455 00:19:27,970 --> 00:19:25,670 so the more hydrophobic we make the 456 00:19:29,740 --> 00:19:27,980 peptides and the smaller the ring is 457 00:19:31,450 --> 00:19:29,750 that can already stack and that makes 458 00:19:33,850 --> 00:19:31,460 sense if you regard this from the 459 00:19:35,140 --> 00:19:33,860 perspective of multi valency that sides 460 00:19:37,600 --> 00:19:35,150 already glued that hold the Rings 461 00:19:39,730 --> 00:19:37,610 together if you make the glue stronger 462 00:19:43,810 --> 00:19:39,740 you need less of it so already smaller 463 00:19:46,120 --> 00:19:43,820 rings can start stacking so this is a 464 00:19:48,490 --> 00:19:46,130 structure of the drawing laid out of the 465 00:19:51,250 --> 00:19:48,500 octo marygreen to suit impress upon you 466 00:19:52,900 --> 00:19:51,260 that we're really making maybe not such 467 00:19:54,730 --> 00:19:52,910 complex structures because a time the 468 00:19:58,210 --> 00:19:54,740 same building block but certainly large 469 00:19:59,800 --> 00:19:58,220 structures well we are making the 470 00:20:02,260 --> 00:19:59,810 molecules are making them we only make 471 00:20:04,000 --> 00:20:02,270 the building blocks so this you see the 472 00:20:09,460 --> 00:20:04,010 autonomous emergence of these types of 473 00:20:13,510 --> 00:20:09,470 of complex molecules from from really 474 00:20:15,640 --> 00:20:13,520 rather simple experiments so now going 475 00:20:17,230 --> 00:20:15,650 back to our mutation so we've now looked 476 00:20:18,970 --> 00:20:17,240 at the individual building blocks what 477 00:20:20,560 --> 00:20:18,980 do they do when we mix them well what 478 00:20:22,360 --> 00:20:20,570 happens when we offer in a system a 479 00:20:25,180 --> 00:20:22,370 choice as to which building block and 480 00:20:26,470 --> 00:20:25,190 incorporates so we started off mixing 481 00:20:27,970 --> 00:20:26,480 the serine in the phenyl alanine 482 00:20:30,070 --> 00:20:27,980 building blocks the serine by itself 483 00:20:31,750 --> 00:20:30,080 wants to make eight membered rings the 484 00:20:34,090 --> 00:20:31,760 phenyl alanine wants to make six 485 00:20:35,800 --> 00:20:34,100 membered rings so this question then was 486 00:20:37,690 --> 00:20:35,810 what would happen if we mixed them and 487 00:20:40,990 --> 00:20:37,700 it we didn't really have a clue so we 488 00:20:43,270 --> 00:20:41,000 destroyed it and this is the outcome you 489 00:20:45,010 --> 00:20:43,280 so again if you look at the at what 490 00:20:45,940 --> 00:20:45,020 emerges with time and he started off 491 00:20:47,950 --> 00:20:45,950 with the building blocks that I'm 492 00:20:50,140 --> 00:20:47,960 oxidized you first see the emergence 493 00:20:53,370 --> 00:20:50,150 after about three four days of her first 494 00:20:56,050 --> 00:20:53,380 set of replicators in blue and those are 495 00:20:57,520 --> 00:20:56,060 six membered rings rich in the phenyl 496 00:20:59,140 --> 00:20:57,530 alanine building block which by itself 497 00:21:03,010 --> 00:20:59,150 wants to make six membered rings so this 498 00:21:08,320 --> 00:21:03,020 is f6 and here's F 5 s 1 F 4 s 2 and F 3 499 00:21:12,220 --> 00:21:08,330 s 3 so he makes these one-to-one but as 500 00:21:15,210 --> 00:21:12,230 you see the one to the the the 3 plus 3 501 00:21:20,050 --> 00:21:15,220 macro cycle is not the most abundant 502 00:21:24,270 --> 00:21:20,060 then after about 10 days after about 10 503 00:21:28,900 --> 00:21:24,280 days and we see the emergent of set B 504 00:21:30,220 --> 00:21:28,910 which consists of also hexamers and this 505 00:21:32,560 --> 00:21:30,230 was a bit of a surprise because you 506 00:21:34,750 --> 00:21:32,570 would expect the left over building 507 00:21:37,360 --> 00:21:34,760 block the serine by itself forms octamer 508 00:21:38,140 --> 00:21:37,370 but in this system with phenyl alanine 509 00:21:42,240 --> 00:21:38,150 present 510 00:21:48,100 --> 00:21:42,250 does 4x immerse and even foams the six 511 00:21:50,640 --> 00:21:48,110 hexamer there so what happens here is 512 00:21:53,740 --> 00:21:50,650 that you first see the emergence of a 513 00:21:55,810 --> 00:21:53,750 set of replicators that are six membered 514 00:21:57,430 --> 00:21:55,820 rings rich in phenyl alanine and then 515 00:21:58,870 --> 00:21:57,440 after a little while nothing happens and 516 00:22:01,030 --> 00:21:58,880 the ECD merges of a second set of 517 00:22:03,670 --> 00:22:01,040 replicators and it turns out the second 518 00:22:05,680 --> 00:22:03,680 set there's an ancestral relationship 519 00:22:07,630 --> 00:22:05,690 between the first and the second set so 520 00:22:11,530 --> 00:22:07,640 the second set is promoted by the 521 00:22:13,900 --> 00:22:11,540 presence of the first and we could even 522 00:22:18,130 --> 00:22:13,910 test weights of the mutants within the 523 00:22:19,870 --> 00:22:18,140 first set of of if you call it quasi 524 00:22:21,640 --> 00:22:19,880 species I don't know whether that term 525 00:22:23,800 --> 00:22:21,650 is quite appropriate here but it's 526 00:22:25,810 --> 00:22:23,810 shares a lot of similarities to quasi 527 00:22:27,850 --> 00:22:25,820 species which within the first set of 528 00:22:29,650 --> 00:22:27,860 replicators is most responsible for 529 00:22:32,050 --> 00:22:29,660 giving rise to the second and it's those 530 00:22:36,790 --> 00:22:32,060 that are most structurally similar to 531 00:22:39,070 --> 00:22:36,800 the second set of replicators so this 532 00:22:41,770 --> 00:22:39,080 starts to have some similarity to how I 533 00:22:44,140 --> 00:22:41,780 guess speciation occurs and in in 534 00:22:46,180 --> 00:22:44,150 biology but it's with completely 535 00:22:49,390 --> 00:22:46,190 inanimate system of self-replicating 536 00:22:53,200 --> 00:22:49,400 molecules okay then 537 00:22:56,530 --> 00:22:53,210 back to our recipe so we have a 538 00:22:58,930 --> 00:22:56,540 replicator that commute AIDS now let's 539 00:23:00,520 --> 00:22:58,940 see what happens if we start operating 540 00:23:03,280 --> 00:23:00,530 this far from equilibrium so anything 541 00:23:05,020 --> 00:23:03,290 I've showed you so far was only looking 542 00:23:06,400 --> 00:23:05,030 for a system that went so it was only 543 00:23:08,200 --> 00:23:06,410 looking at systems that went to 544 00:23:10,150 --> 00:23:08,210 inanimate feet downhill we started with 545 00:23:12,670 --> 00:23:10,160 building blocks tiles they oxidize give 546 00:23:15,310 --> 00:23:12,680 dye so fights also an anomaly downhill 547 00:23:16,960 --> 00:23:15,320 so the only thing we the only difference 548 00:23:19,200 --> 00:23:16,970 there is we end up with one product or 549 00:23:21,970 --> 00:23:19,210 another is the kinetics and the 550 00:23:25,440 --> 00:23:21,980 thermodynamics of formation of those 551 00:23:28,540 --> 00:23:25,450 products but we're not necessarily 552 00:23:30,850 --> 00:23:28,550 having we're not making systems that are 553 00:23:35,350 --> 00:23:30,860 dissipating energy or in a continuous 554 00:23:38,890 --> 00:23:35,360 way yet life of course is far from 555 00:23:41,140 --> 00:23:38,900 equilibrium and and it does exhibit a 556 00:23:43,720 --> 00:23:41,150 continuous turnover of pretty much all 557 00:23:46,690 --> 00:23:43,730 its constituents add a quite stunning 558 00:23:49,510 --> 00:23:46,700 rate so if you look at the half-lives 559 00:23:52,090 --> 00:23:49,520 for instance of mammalian messenger RNA 560 00:23:52,480 --> 00:23:52,100 it's about nine hours if you look at 561 00:23:54,700 --> 00:23:52,490 protein 562 00:23:58,799 --> 00:23:54,710 half less on average sterve there are 563 00:24:01,990 --> 00:23:58,809 two days so every protein on average is 564 00:24:04,470 --> 00:24:02,000 broken down and resynthesized every 565 00:24:07,390 --> 00:24:04,480 second day 566 00:24:12,160 --> 00:24:07,400 so also Darwinian evolution requires is 567 00:24:16,000 --> 00:24:12,170 making an degradation or burst and death 568 00:24:18,910 --> 00:24:16,010 so if you have if you start with some 569 00:24:21,040 --> 00:24:18,920 species makes mutant it replicates and 570 00:24:23,290 --> 00:24:21,050 does this in a sloppy way so you have 571 00:24:25,570 --> 00:24:23,300 different mutants some survive some 572 00:24:27,760 --> 00:24:25,580 survive others die the ones that survive 573 00:24:28,840 --> 00:24:27,770 can mutate again and and and so on so 574 00:24:31,450 --> 00:24:28,850 that's the idea of Darwinian evolution 575 00:24:35,950 --> 00:24:31,460 only works or a virtue of there also 576 00:24:37,930 --> 00:24:35,960 being deaths in the system so if you 577 00:24:39,669 --> 00:24:37,940 want to move in this direction what you 578 00:24:42,730 --> 00:24:39,679 learn really should do is read our 579 00:24:44,410 --> 00:24:42,740 replicators is also make them die that's 580 00:24:45,730 --> 00:24:44,420 kind of tough on you when you're sorry 581 00:24:46,930 --> 00:24:45,740 when you're a chemist you make stuff 582 00:24:48,940 --> 00:24:46,940 you're not in the business of destroying 583 00:24:51,540 --> 00:24:48,950 it again the least you usually try to 584 00:24:53,860 --> 00:24:51,550 avoid this but now we we have to do it 585 00:24:56,200 --> 00:24:53,870 so what I've showed you so far was only 586 00:24:58,120 --> 00:24:56,210 this we have food making replicator and 587 00:25:00,660 --> 00:24:58,130 once we've made a replicator it was 588 00:25:03,250 --> 00:25:00,670 there there wasn't really any way if 589 00:25:05,710 --> 00:25:03,260 that any process that let it that lets 590 00:25:07,600 --> 00:25:05,720 do its destruction but that's what we 591 00:25:10,060 --> 00:25:07,610 now want to introduce some way some way 592 00:25:13,000 --> 00:25:10,070 of making replicators go to save some 593 00:25:15,910 --> 00:25:13,010 waste product and the easiest and 594 00:25:19,060 --> 00:25:15,920 perhaps trivial way of doing this is to 595 00:25:22,540 --> 00:25:19,070 convert is to do this in a flow system 596 00:25:25,270 --> 00:25:22,550 you keep adding food and you remove the 597 00:25:30,640 --> 00:25:25,280 food you remove some of this the system 598 00:25:32,680 --> 00:25:30,650 and the same flow rate again so that you 599 00:25:34,450 --> 00:25:32,690 your urine basically a continuously 600 00:25:36,820 --> 00:25:34,460 stirred tank reactor you start off with 601 00:25:39,070 --> 00:25:36,830 a replicator in here and as long as it 602 00:25:42,730 --> 00:25:39,080 replicates faster then it's being flown 603 00:25:46,930 --> 00:25:42,740 out it persists the nice thing about 604 00:25:48,310 --> 00:25:46,940 this system is you can still do you can 605 00:25:51,340 --> 00:25:48,320 change the environment while it's 606 00:25:53,799 --> 00:25:51,350 replicating and we did this in one 607 00:25:56,410 --> 00:25:53,809 particular way we added a bit of trifler 608 00:25:58,990 --> 00:25:56,420 ethanol so kind of a useful solvent 609 00:26:01,630 --> 00:25:59,000 known from biochemistry and from protein 610 00:26:03,280 --> 00:26:01,640 peptide chemistry to make the 611 00:26:05,080 --> 00:26:03,290 interactions between peptides stronger 612 00:26:05,830 --> 00:26:05,090 so if you increase the amount of tyrel 613 00:26:07,570 --> 00:26:05,840 fluorescent 614 00:26:09,909 --> 00:26:07,580 should start making replicators that 615 00:26:11,169 --> 00:26:09,919 have a smaller ring size if our 616 00:26:15,190 --> 00:26:11,179 understanding of the replicator is 617 00:26:16,630 --> 00:26:15,200 correct so this is what we then done in 618 00:26:18,039 --> 00:26:16,640 the experiment we started with octamer 619 00:26:19,600 --> 00:26:18,049 replicator so what you see in the 620 00:26:22,060 --> 00:26:19,610 background here is the concentration of 621 00:26:24,970 --> 00:26:22,070 try fluorescent oh we start off in 50% 622 00:26:26,740 --> 00:26:24,980 fry fluorescent oh we're probably the 623 00:26:28,690 --> 00:26:26,750 octamer is not the idea the best 624 00:26:30,549 --> 00:26:28,700 replicator indeed it withers away and 625 00:26:33,820 --> 00:26:30,559 you see the hexamer replicator taking 626 00:26:38,049 --> 00:26:33,830 over to the point here where it's almost 627 00:26:41,830 --> 00:26:38,059 completely but certainly dominance then 628 00:26:43,690 --> 00:26:41,840 we flowed out the we didn't add more try 629 00:26:46,299 --> 00:26:43,700 for ethanol with the food we just flown 630 00:26:48,159 --> 00:26:46,309 in the food with in in pure water so we 631 00:26:51,519 --> 00:26:48,169 see the try for ethanol content go down 632 00:26:53,769 --> 00:26:51,529 and you see that the that the hexamer 633 00:26:57,130 --> 00:26:53,779 replicator Goes Down and the octamer 634 00:26:58,389 --> 00:26:57,140 replicator comes back up so we see that 635 00:27:02,769 --> 00:26:58,399 the nature of the environment dictates 636 00:27:06,220 --> 00:27:02,779 what replicator we have and also what we 637 00:27:07,899 --> 00:27:06,230 showed was previously already the 638 00:27:10,149 --> 00:27:07,909 October and hexamer replicator also 639 00:27:12,250 --> 00:27:10,159 cross catalytic to some extent so you 640 00:27:15,580 --> 00:27:12,260 can consider October and hexamer to be 641 00:27:17,950 --> 00:27:15,590 mutants of one replicator set so this 642 00:27:19,720 --> 00:27:17,960 experiment here then shows that by 643 00:27:20,380 --> 00:27:19,730 changing the environment we favor one 644 00:27:23,529 --> 00:27:20,390 mutants 645 00:27:26,470 --> 00:27:23,539 over another selectively and reversibly 646 00:27:28,600 --> 00:27:26,480 as well so it's having this now has all 647 00:27:30,659 --> 00:27:28,610 the ingredients and all the essential 648 00:27:35,289 --> 00:27:30,669 characteristics of Darwinian evolution 649 00:27:36,669 --> 00:27:35,299 replication mutation selection but in a 650 00:27:38,169 --> 00:27:36,679 very trivial way the only thing we 651 00:27:43,330 --> 00:27:38,179 change is macrocycle size if our 652 00:27:44,710 --> 00:27:43,340 replicator so we did a similar type of 653 00:27:45,669 --> 00:27:44,720 experiments with guanidinium chloride 654 00:27:48,539 --> 00:27:45,679 now I don't 655 00:27:50,740 --> 00:27:48,549 that doesn't really per se add anything 656 00:27:52,389 --> 00:27:50,750 but I still want to show it because it 657 00:27:54,250 --> 00:27:52,399 leads home to the next point which is 658 00:27:57,029 --> 00:27:54,260 doing the same as I showed you before 659 00:27:59,799 --> 00:27:57,039 and the flow but then in in dissipative 660 00:28:01,899 --> 00:27:59,809 conditions and chemically fuelled so 661 00:28:03,639 --> 00:28:01,909 with this system is the phenyl alanine 662 00:28:05,440 --> 00:28:03,649 Ian's if you put this in water it wants 663 00:28:07,029 --> 00:28:05,450 to make the hexamer replicator if you 664 00:28:08,350 --> 00:28:07,039 put it in wanted indium chloride for 665 00:28:11,529 --> 00:28:08,360 reason we don't quite fully understand 666 00:28:12,940 --> 00:28:11,539 yet it makes drawing a replicator so the 667 00:28:15,279 --> 00:28:12,950 timer replicator is the most stable 668 00:28:17,740 --> 00:28:15,289 compound in guanidinium chloride so it's 669 00:28:19,190 --> 00:28:17,750 also the first one that forms so if you 670 00:28:21,170 --> 00:28:19,200 start off with food 671 00:28:22,730 --> 00:28:21,180 the lowest barrier is to make destroy a 672 00:28:26,020 --> 00:28:22,740 replicator and it's also destined when 673 00:28:28,580 --> 00:28:26,030 I'm with the most stable structure now 674 00:28:30,020 --> 00:28:28,590 why do I show this here you think okay 675 00:28:32,570 --> 00:28:30,030 I've seen you know these replicators now 676 00:28:35,270 --> 00:28:32,580 I think this is may we here now we have 677 00:28:36,980 --> 00:28:35,280 a nice opportunity to try and see if we 678 00:28:38,630 --> 00:28:36,990 can push the system away from what it 679 00:28:39,860 --> 00:28:38,640 wants to make kinetically away from what 680 00:28:41,810 --> 00:28:39,870 it meant to make them more dynamically 681 00:28:44,060 --> 00:28:41,820 because there's this hexamer replicator 682 00:28:46,820 --> 00:28:44,070 also it's so many that mcclee disfavor 683 00:28:49,270 --> 00:28:46,830 did we start here it actually goes there 684 00:28:51,800 --> 00:28:49,280 we just don't if we don't do anything 685 00:28:53,360 --> 00:28:51,810 it's also not the kinetic product if we 686 00:28:54,620 --> 00:28:53,370 start here it doesn't make any of this 687 00:28:58,580 --> 00:28:54,630 it actually makes the trimer 688 00:29:00,320 --> 00:28:58,590 so we have a system which is making a 689 00:29:02,360 --> 00:29:00,330 kinetic lien thermodynamically favored 690 00:29:05,090 --> 00:29:02,370 replicator can we do something to this 691 00:29:05,990 --> 00:29:05,100 system to populate the hexamer and why 692 00:29:07,850 --> 00:29:06,000 is that important 693 00:29:09,800 --> 00:29:07,860 because I guess this is where life's 694 00:29:13,580 --> 00:29:09,810 it's not here here's thermodynamic 695 00:29:15,710 --> 00:29:13,590 equilibrium here's death here is your 696 00:29:19,010 --> 00:29:15,720 out of equilibrium at least by some by 697 00:29:20,810 --> 00:29:19,020 by a little bit can we populate it so 698 00:29:26,570 --> 00:29:20,820 anybody has any idea how you could do 699 00:29:29,030 --> 00:29:26,580 this how could you get here so you need 700 00:29:32,060 --> 00:29:29,040 to do something to the the barrier and 701 00:29:34,390 --> 00:29:32,070 you need to do this in and also in a in 702 00:29:37,100 --> 00:29:34,400 a if you if you only do catalysis then 703 00:29:39,170 --> 00:29:37,110 you might just you need to do this in a 704 00:29:41,060 --> 00:29:39,180 way that breaks microscopic 705 00:29:43,970 --> 00:29:41,070 reversibility as well so you need to 706 00:29:45,350 --> 00:29:43,980 lower the barrier in one direction but 707 00:29:46,010 --> 00:29:45,360 not on the other so I'll come back to 708 00:29:50,620 --> 00:29:46,020 that in a minute 709 00:29:53,210 --> 00:29:50,630 so the way to do this is to start 710 00:29:56,930 --> 00:29:53,220 linking the system up with an energy 711 00:30:00,080 --> 00:29:56,940 source fuel it chemically somehow and so 712 00:30:05,420 --> 00:30:00,090 we have to make replicators dying go 713 00:30:07,340 --> 00:30:05,430 back to food and in that regime not 714 00:30:09,740 --> 00:30:07,350 someone anomic stability rules but as 715 00:30:13,130 --> 00:30:09,750 adi process calls its dynamic kinetic 716 00:30:15,110 --> 00:30:13,140 stability so here's how to do it 717 00:30:17,900 --> 00:30:15,120 chemically so we start off with our 718 00:30:20,900 --> 00:30:17,910 building block a file makes bor and we 719 00:30:23,240 --> 00:30:20,910 add oxidants makes the disulfides we add 720 00:30:25,100 --> 00:30:23,250 reductants at the same time she'd make 721 00:30:27,320 --> 00:30:25,110 the disulfide go back to style so we go 722 00:30:30,080 --> 00:30:27,330 around in a circle but it's fueled now 723 00:30:33,110 --> 00:30:30,090 by having oxidants and reductants in the 724 00:30:36,340 --> 00:30:33,120 system so experimentally this is 725 00:30:38,570 --> 00:30:36,350 looks now so we have they now we have a 726 00:30:41,150 --> 00:30:38,580 system where we don't fly anything out 727 00:30:42,920 --> 00:30:41,160 again the only thing we flow we only 728 00:30:45,050 --> 00:30:42,930 fell in and we flow in oxidant and 729 00:30:47,510 --> 00:30:45,060 reductant at the slow flow rate so 730 00:30:50,390 --> 00:30:47,520 there's not mature circuiting and we do 731 00:30:52,790 --> 00:30:50,400 continues oxidation and reduction and 732 00:30:55,010 --> 00:30:52,800 then and on this regime if you start out 733 00:30:57,530 --> 00:30:55,020 with the one-to-one or derivates mixture 734 00:31:00,380 --> 00:30:57,540 of timer and extra my replicator you see 735 00:31:02,780 --> 00:31:00,390 the hexamer it's the one that wins if 736 00:31:04,220 --> 00:31:02,790 you do to control we just allow things 737 00:31:06,440 --> 00:31:04,230 to go through equilibrium was the same 738 00:31:11,630 --> 00:31:06,450 starting point you see the timer is the 739 00:31:13,310 --> 00:31:11,640 one that wins so why does it work we're 740 00:31:16,820 --> 00:31:13,320 playing around with the various we have 741 00:31:19,040 --> 00:31:16,830 now a reduction process and an oxidation 742 00:31:21,680 --> 00:31:19,050 process so we may convert thiols to dye 743 00:31:25,040 --> 00:31:21,690 sulfites and disulfide spectra styles in 744 00:31:27,800 --> 00:31:25,050 separate pathways this is shown here so 745 00:31:30,440 --> 00:31:27,810 the oxidation is the solid line and the 746 00:31:32,840 --> 00:31:30,450 reduction is the dotted line and the way 747 00:31:36,590 --> 00:31:32,850 the system works out is that the 748 00:31:39,140 --> 00:31:36,600 reduction of the trimer the most similar 749 00:31:41,840 --> 00:31:39,150 maquis table replicators faster than the 750 00:31:43,640 --> 00:31:41,850 reduction of the thermodynamically less 751 00:31:46,070 --> 00:31:43,650 stable hexamer replicator so this 752 00:31:48,770 --> 00:31:46,080 barrier is smaller than that barrier so 753 00:31:51,740 --> 00:31:48,780 that if the system runs it will go very 754 00:31:53,510 --> 00:31:51,750 fast to here but very fast 755 00:31:56,810 --> 00:31:53,520 out of there again it can go uphill 756 00:31:59,570 --> 00:31:56,820 because it's linked to another reaction 757 00:32:03,830 --> 00:31:59,580 this basically the oxidation of the 758 00:32:06,770 --> 00:32:03,840 reductants that drives that and you then 759 00:32:09,050 --> 00:32:06,780 go if you're here once every while 760 00:32:11,210 --> 00:32:09,060 you're able to jump that barrier and 761 00:32:13,580 --> 00:32:11,220 well and once you're end up here you're 762 00:32:17,810 --> 00:32:13,590 very slow to return so it's now 763 00:32:22,160 --> 00:32:17,820 selection is now by basically resistance 764 00:32:24,020 --> 00:32:22,170 to us and reduction that now populates 765 00:32:26,540 --> 00:32:24,030 the thermodynamically least stable 766 00:32:30,230 --> 00:32:26,550 replicator okay I've already gone over 767 00:32:33,650 --> 00:32:30,240 time so I think I should skip sorry cap 768 00:32:36,560 --> 00:32:33,660 out the vid on compartmentalization and 769 00:32:38,690 --> 00:32:36,570 leave you with some thoughts and I'll 770 00:32:45,370 --> 00:32:38,700 leave up here while the discussion is 771 00:32:50,139 --> 00:32:47,009 [Applause] 772 00:32:59,499 --> 00:32:50,149 thank you for that lovely talk we'll 773 00:33:01,299 --> 00:32:59,509 take questions start with to think about 774 00:33:04,869 --> 00:33:01,309 emergence of self replicators is not 775 00:33:06,609 --> 00:33:04,879 uncommon so we're in the on earth can I 776 00:33:20,529 --> 00:33:06,619 look at such a system that is not 777 00:33:22,269 --> 00:33:20,539 biological well maybe I should should 778 00:33:24,549 --> 00:33:22,279 have said it's less common than I would 779 00:33:27,129 --> 00:33:24,559 than I expected it's less uncommon than 780 00:33:30,190 --> 00:33:27,139 I expected so the reason the motivation 781 00:33:32,980 --> 00:33:30,200 I say that is that we actually never we 782 00:33:34,840 --> 00:33:32,990 never designed any of this and we ran 783 00:33:37,029 --> 00:33:34,850 into one and then knowing there was one 784 00:33:38,590 --> 00:33:37,039 we looked at all the data other systems 785 00:33:40,690 --> 00:33:38,600 other molecules and we had similar we 786 00:33:42,879 --> 00:33:40,700 had also self-replicating molecules in 787 00:33:45,669 --> 00:33:42,889 there so the moment you have a system I 788 00:33:47,279 --> 00:33:45,679 guess if I kind of generalize our system 789 00:33:52,090 --> 00:33:47,289 in the moment you have a system where 790 00:33:54,249 --> 00:33:52,100 molecules interconvert and assemble the 791 00:33:55,930 --> 00:33:54,259 assembly process them drives the 792 00:33:58,600 --> 00:33:55,940 replication the moment you have a system 793 00:34:01,509 --> 00:33:58,610 like that you stand the pretty good 794 00:34:05,169 --> 00:34:01,519 chance of finding self replicators there 795 00:34:06,730 --> 00:34:05,179 no geological environments that would 796 00:34:09,220 --> 00:34:06,740 work in AI 797 00:34:11,049 --> 00:34:09,230 I'm insufficient of a geochemist 798 00:34:12,549 --> 00:34:11,059 Darwin's answer to this was as soon as 799 00:34:14,799 --> 00:34:12,559 some molecule becomes interesting you'll 800 00:34:17,079 --> 00:34:14,809 be gobbled up by existing life yeah 801 00:34:19,089 --> 00:34:17,089 but presumably you can go a little bit 802 00:34:20,889 --> 00:34:19,099 down this path without becoming too 803 00:34:22,809 --> 00:34:20,899 interesting to extant life and therefore 804 00:34:27,280 --> 00:34:22,819 you would see some of these things 805 00:34:29,379 --> 00:34:27,290 maybe I doubt it because I think I think 806 00:34:31,299 --> 00:34:29,389 the problem with life now I mean where 807 00:34:32,740 --> 00:34:31,309 would you find with I think the relevant 808 00:34:36,639 --> 00:34:32,750 question is where we do have found it 809 00:34:37,960 --> 00:34:36,649 before life became competitive to the 810 00:34:40,659 --> 00:34:37,970 building blocks that it needs because 811 00:34:42,700 --> 00:34:40,669 it's still I mean this just works but in 812 00:34:45,190 --> 00:34:42,710 and they're rather specified conditions 813 00:34:48,820 --> 00:34:45,200 and it takes three weeks right first 814 00:34:52,690 --> 00:34:48,830 emergent one says there is faster but 815 00:34:53,680 --> 00:34:52,700 yeah I said finding it now I wouldn't 816 00:34:55,480 --> 00:34:53,690 know where to start looking 817 00:35:05,920 --> 00:34:55,490 I wouldn't know what it would be 818 00:35:06,580 --> 00:35:05,930 worthwhile effort even thank you very 819 00:35:08,230 --> 00:35:06,590 nice talk 820 00:35:10,150 --> 00:35:08,240 I just wanted to push back a little bit 821 00:35:11,680 --> 00:35:10,160 against your statement towards the 822 00:35:13,300 --> 00:35:11,690 beginning where you said that you have 823 00:35:15,730 --> 00:35:13,310 to have exponential replication so that 824 00:35:18,010 --> 00:35:15,740 you can have a single winner to have 825 00:35:19,900 --> 00:35:18,020 evolution because then later you showed 826 00:35:22,260 --> 00:35:19,910 that there was benefit to keeping 827 00:35:25,360 --> 00:35:22,270 diversity in the system to have the 828 00:35:27,450 --> 00:35:25,370 octamer in local amounts as well as a 829 00:35:29,440 --> 00:35:27,460 hexamer when the environment changed 830 00:35:31,590 --> 00:35:29,450 yeah but there you need to be careful 831 00:35:34,600 --> 00:35:31,600 because they're they're cross catalytic 832 00:35:38,020 --> 00:35:34,610 so they're not competing with one 833 00:35:39,670 --> 00:35:38,030 another they're competing for the same 834 00:35:42,160 --> 00:35:39,680 resource yeah but they're also making 835 00:35:45,130 --> 00:35:42,170 each other so then you come to regard 836 00:35:47,020 --> 00:35:45,140 those as two separate replicator they're 837 00:35:49,930 --> 00:35:47,030 part of one speed there are two mutants 838 00:35:52,450 --> 00:35:49,940 of the same replicator that's view does 839 00:35:54,040 --> 00:35:52,460 but but is there any particular reason 840 00:35:58,300 --> 00:35:54,050 why you also wouldn't want to have some 841 00:36:00,580 --> 00:35:58,310 other species that say was not part of 842 00:36:03,420 --> 00:36:00,590 the same quasi species because it might 843 00:36:05,500 --> 00:36:03,430 also be more fit later to generate 844 00:36:08,470 --> 00:36:05,510 metabolic networks or for their 845 00:36:10,540 --> 00:36:08,480 complexity I think I'm all in favor of 846 00:36:12,430 --> 00:36:10,550 having a system that where you have more 847 00:36:17,260 --> 00:36:12,440 than just one molecular species there I 848 00:36:20,140 --> 00:36:17,270 mean we have the ecology already we seen 849 00:36:22,840 --> 00:36:20,150 some arguments for for that but those 850 00:36:25,810 --> 00:36:22,850 the coexistence of different replicators 851 00:36:28,330 --> 00:36:25,820 usually requires there them to have 852 00:36:29,920 --> 00:36:28,340 different say food niches so if there's 853 00:36:31,930 --> 00:36:29,930 only that one single food niche they 854 00:36:33,400 --> 00:36:31,940 should only be and there will only be if 855 00:36:36,880 --> 00:36:33,410 you have exponential replicators one 856 00:36:39,010 --> 00:36:36,890 single occupant of it maybe instead of 857 00:36:43,180 --> 00:36:39,020 mutants of the same species but still 858 00:36:48,220 --> 00:36:43,190 one single species so in order to have 859 00:36:50,230 --> 00:36:48,230 diversity you need to and I think we've 860 00:36:53,710 --> 00:36:50,240 seen this in the the system where we 861 00:36:55,930 --> 00:36:53,720 have the the two sets of replicators one 862 00:36:59,020 --> 00:36:55,940 emerges first the other one later where 863 00:37:01,329 --> 00:36:59,030 it actually one prefers to be one built 864 00:37:03,190 --> 00:37:01,339 itself mostly from one of 865 00:37:05,529 --> 00:37:03,200 Locsin the other mostly from the other 866 00:37:06,729 --> 00:37:05,539 but they they share a little bit of each 867 00:37:08,140 --> 00:37:06,739 other's building blocks so this is 868 00:37:11,219 --> 00:37:08,150 somewhere in between where you can argue 869 00:37:13,809 --> 00:37:11,229 is this there's now two species or not 870 00:37:16,559 --> 00:37:13,819 it's not two species yet because they 871 00:37:19,089 --> 00:37:16,569 there are some intermediates but and the 872 00:37:21,190 --> 00:37:19,099 we've looked at cross catalysis between 873 00:37:24,849 --> 00:37:21,200 these two the the f6 doesn't cause 874 00:37:29,400 --> 00:37:24,859 catalyzed s6 and vice-versa but the f-4s 875 00:37:31,959 --> 00:37:29,410 2 and the s4 f2 are cross catalytic so 876 00:37:33,940 --> 00:37:31,969 so that's all fine but do we really do 877 00:37:35,229 --> 00:37:33,950 we really have to have exponential 878 00:37:37,930 --> 00:37:35,239 replication you know could we have 879 00:37:41,289 --> 00:37:37,940 something that's sub-exponential and 880 00:37:42,729 --> 00:37:41,299 still have system with evolvability I 881 00:37:45,700 --> 00:37:42,739 guess offensive what you want to do but 882 00:37:47,529 --> 00:37:45,710 if you if you're after extinction of and 883 00:37:49,029 --> 00:37:47,539 I guess the Iranian Revolution does do 884 00:37:51,849 --> 00:37:49,039 that right and if you want to if you 885 00:37:54,309 --> 00:37:51,859 want that to happen then that's that is 886 00:37:56,469 --> 00:37:54,319 what you need or to be more precise you 887 00:38:00,640 --> 00:37:56,479 need a growth order and replicator that 888 00:38:01,870 --> 00:38:00,650 is at least equal to do the order of the 889 00:38:04,239 --> 00:38:01,880 replicator in the destruction process 890 00:38:06,009 --> 00:38:04,249 which is usually first so that's why the 891 00:38:21,230 --> 00:38:06,019 growth order also needs to be first and 892 00:38:28,970 --> 00:38:25,160 this is my thing so the my question is 893 00:38:33,049 --> 00:38:28,980 your system do not include the metallic 894 00:38:39,440 --> 00:38:33,059 proteins know and just you camp patoot 895 00:38:41,750 --> 00:38:39,450 right so the therefore it's a I have a 896 00:38:44,420 --> 00:38:41,760 benefiting with with him 897 00:38:48,920 --> 00:38:44,430 it's a still it's quite different from 898 00:38:51,920 --> 00:38:48,930 the analog of what is life in your 899 00:38:55,579 --> 00:38:51,930 experiment so what do you feel the role 900 00:38:58,910 --> 00:38:55,589 of metric proteins and also electron 901 00:39:01,700 --> 00:38:58,920 transfer in your system well we have V 902 00:39:04,480 --> 00:39:01,710 Docs processes right so we're changing 903 00:39:06,740 --> 00:39:04,490 oxidation states not necessarily through 904 00:39:08,990 --> 00:39:06,750 reaction that involves electrons but we 905 00:39:11,150 --> 00:39:09,000 do redox chemistry in this particular 906 00:39:13,910 --> 00:39:11,160 system the chemical fuel in order to 907 00:39:16,160 --> 00:39:13,920 populated it a disfavored replicator 908 00:39:17,539 --> 00:39:16,170 that happens because we linked the 909 00:39:21,190 --> 00:39:17,549 system up with oxidation and reduction 910 00:39:25,430 --> 00:39:21,200 and it continues in a continuous fashion 911 00:39:26,630 --> 00:39:25,440 so in that regard our system also relies 912 00:39:30,559 --> 00:39:26,640 on redox care 913 00:39:33,259 --> 00:39:30,569 redox processes for sure whether it I 914 00:39:38,420 --> 00:39:33,269 could imagine doing the same thing also 915 00:39:44,799 --> 00:39:38,430 is maybe coupling just was it hydration 916 00:39:48,499 --> 00:39:44,809 the dehydration type within metal absent 917 00:39:49,870 --> 00:39:48,509 proteins just but still probably the 918 00:39:54,349 --> 00:39:49,880 redox state 919 00:39:56,839 --> 00:39:54,359 okay changing but I think well in order 920 00:39:59,960 --> 00:39:56,849 to make something so your your questions 921 00:40:01,999 --> 00:39:59,970 more can I imagine life without redox 922 00:40:04,160 --> 00:40:02,009 chemistry yeah metallic proteins it's a 923 00:40:07,789 --> 00:40:04,170 flu before exam three electron like like 924 00:40:13,450 --> 00:40:07,799 Fe or Fe s and the Morrigan a demo as 925 00:40:19,460 --> 00:40:13,460 well so that that is a key a wildlife 926 00:40:22,400 --> 00:40:19,470 can you know continuously yeah I I'm I 927 00:40:24,890 --> 00:40:22,410 would argue I would my gut feeling is 928 00:40:26,870 --> 00:40:24,900 there's nothing that you could probably 929 00:40:28,220 --> 00:40:26,880 think of a life-form if you probably 930 00:40:29,900 --> 00:40:28,230 couldn't make it 931 00:40:32,090 --> 00:40:29,910 our current life we could probably think 932 00:40:34,160 --> 00:40:32,100 of a life form that doesn't do that sort 933 00:40:35,300 --> 00:40:34,170 of chemistry yeah yeah okay let's 934 00:40:40,260 --> 00:40:35,310 continue today after birth 935 00:40:55,260 --> 00:40:42,680 [Applause]