1 00:00:00,160 --> 00:00:14,169 [Music] 2 00:00:17,450 --> 00:00:15,499 thank you 3 00:00:20,300 --> 00:00:17,460 I appreciate the opportunity to talk to 4 00:00:22,790 --> 00:00:20,310 you all today I'm from Georgia Tech it 5 00:00:24,410 --> 00:00:22,800 which is in Atlanta Georgia and I'm 6 00:00:26,839 --> 00:00:24,420 gonna be talking to you today about a 7 00:00:29,089 --> 00:00:26,849 research that I've been involved in in 8 00:00:31,519 --> 00:00:29,099 the Center for chemical evolution the 9 00:00:33,410 --> 00:00:31,529 title is a system-level viewpoint on the 10 00:00:34,790 --> 00:00:33,420 chemical origins of life probably the 11 00:00:36,560 --> 00:00:34,800 word polymer should appear somewhere in 12 00:00:38,780 --> 00:00:36,570 this title because it's very a polymer 13 00:00:41,240 --> 00:00:38,790 focused in terms of the research we've 14 00:00:42,229 --> 00:00:41,250 been doing and by system-level there are 15 00:00:44,990 --> 00:00:42,239 a lot of different things that could 16 00:00:46,910 --> 00:00:45,000 that could mean but I'm coming from a 17 00:00:47,840 --> 00:00:46,920 background in engineering I'm in the 18 00:00:50,510 --> 00:00:47,850 school of chemical and biomolecular 19 00:00:52,580 --> 00:00:50,520 engineering at Georgia Tech and I'm in 20 00:00:54,770 --> 00:00:52,590 the the field subfield called process 21 00:00:56,360 --> 00:00:54,780 systems engineering usually what that 22 00:00:58,700 --> 00:00:56,370 means is that we use mathematical models 23 00:01:00,560 --> 00:00:58,710 to help encode our understanding and 24 00:01:03,950 --> 00:01:00,570 then make predictions and design systems 25 00:01:05,600 --> 00:01:03,960 my particular original area of research 26 00:01:06,530 --> 00:01:05,610 is in feedback control although I'm not 27 00:01:08,660 --> 00:01:06,540 actually going to talk to you about 28 00:01:12,140 --> 00:01:08,670 feedback control today but certainly I 29 00:01:13,340 --> 00:01:12,150 think that's relevant to the research 30 00:01:16,700 --> 00:01:13,350 we're all talking about this meeting as 31 00:01:18,560 --> 00:01:16,710 well and so I'm gonna I'm gonna try to 32 00:01:20,570 --> 00:01:18,570 talk about some of the research that 33 00:01:22,999 --> 00:01:20,580 we've been doing and some of the 34 00:01:27,499 --> 00:01:23,009 insights that we've learned from this 35 00:01:33,690 --> 00:01:31,590 so the research goal is to design and 36 00:01:36,029 --> 00:01:33,700 demonstrate prebiotic ly plausible 37 00:01:37,770 --> 00:01:36,039 minimal systems that can first of all 38 00:01:40,260 --> 00:01:37,780 polymerize so we're not assuming that we 39 00:01:42,779 --> 00:01:40,270 start with the polymers but we are we do 40 00:01:45,419 --> 00:01:42,789 have a polymer focused a research 41 00:01:47,399 --> 00:01:45,429 program we want to store information in 42 00:01:49,649 --> 00:01:47,409 those polymers transfer the information 43 00:01:50,969 --> 00:01:49,659 through replication catalyzed reactions 44 00:01:54,319 --> 00:01:50,979 or perform other functions and 45 00:01:56,789 --> 00:01:54,329 ultimately undergo chemical evolution 46 00:01:58,559 --> 00:01:56,799 now ideally it would be nice to find a 47 00:02:02,010 --> 00:01:58,569 common environment in which all of these 48 00:02:05,100 --> 00:02:02,020 steps could occur for nucleic acid 49 00:02:07,169 --> 00:02:05,110 polymers peptides other biopolymers 50 00:02:08,460 --> 00:02:07,179 maybe polysaccharides we don't 51 00:02:10,199 --> 00:02:08,470 necessarily have to find a common 52 00:02:12,809 --> 00:02:10,209 environment but if we do start to find 53 00:02:14,940 --> 00:02:12,819 key features common features in the 54 00:02:21,150 --> 00:02:14,950 environment that might might be helpful 55 00:02:22,650 --> 00:02:21,160 going forward and in order to design and 56 00:02:24,569 --> 00:02:22,660 demonstrate these systems we need to not 57 00:02:26,220 --> 00:02:24,579 necessarily solve but address what are 58 00:02:29,520 --> 00:02:26,230 some long-standing problems in the field 59 00:02:32,670 --> 00:02:29,530 many of which were articulated in Shaw 60 00:02:34,199 --> 00:02:32,680 stacks a list of eight problems that was 61 00:02:35,819 --> 00:02:34,209 referenced in the in the past talk one 62 00:02:38,309 --> 00:02:35,829 is the the water problem if we're trying 63 00:02:39,720 --> 00:02:38,319 to make biopolymers or proto biopolymers 64 00:02:42,180 --> 00:02:39,730 through condensation reactions that's 65 00:02:43,979 --> 00:02:42,190 just not favored in water the hydrolysis 66 00:02:44,849 --> 00:02:43,989 is driving us backwards so that's 67 00:02:46,979 --> 00:02:44,859 something that we need to deal with 68 00:02:49,740 --> 00:02:46,989 another one is the Strand inhibition 69 00:02:53,009 --> 00:02:49,750 problem in order to have copying we 70 00:02:55,680 --> 00:02:53,019 could use thermal cycling in order to 71 00:02:57,030 --> 00:02:55,690 drive strand separation but upon cooling 72 00:02:59,039 --> 00:02:57,040 then the strands might just come back 73 00:03:00,089 --> 00:02:59,049 together so that's another another 74 00:03:02,759 --> 00:03:00,099 problem that we've been trying to 75 00:03:05,970 --> 00:03:02,769 address and a third is the single winter 76 00:03:08,039 --> 00:03:05,980 scenario survival of the fittest so many 77 00:03:11,159 --> 00:03:08,049 especially theoretical models especially 78 00:03:13,470 --> 00:03:11,169 particularly eigen have selection based 79 00:03:14,789 --> 00:03:13,480 on replication and that doesn't 80 00:03:17,629 --> 00:03:14,799 necessarily need to lead to a productive 81 00:03:20,190 --> 00:03:17,639 outcome in terms of designing minimal 82 00:03:21,330 --> 00:03:20,200 evolutionary systems so really we need 83 00:03:25,500 --> 00:03:21,340 to select for function not just 84 00:03:27,509 --> 00:03:25,510 replication and we also need to generate 85 00:03:28,949 --> 00:03:27,519 and sustain diversity in our system so 86 00:03:34,320 --> 00:03:28,959 that we can continue to have evolution 87 00:03:41,160 --> 00:03:37,560 and we're as a systems engineer I'm very 88 00:03:43,470 --> 00:03:41,170 focused on designing an entire system 89 00:03:45,120 --> 00:03:43,480 out of parts ideally these are parts 90 00:03:47,460 --> 00:03:45,130 that we understand well we may that may 91 00:03:49,080 --> 00:03:47,470 or may not be true in the system and the 92 00:03:50,850 --> 00:03:49,090 research I will be talking to you about 93 00:03:52,260 --> 00:03:50,860 going forward but we look at parts and 94 00:03:54,600 --> 00:03:52,270 how they interact with each other so 95 00:03:56,490 --> 00:03:54,610 it's the interactions between the parts 96 00:03:58,740 --> 00:03:56,500 that ultimately lead to this system 97 00:04:00,030 --> 00:03:58,750 level or emergent behavior and so we 98 00:04:02,100 --> 00:04:00,040 really want to understand not only the 99 00:04:05,040 --> 00:04:02,110 chemistry but also the environment and 100 00:04:06,780 --> 00:04:05,050 the coupling between them and the main 101 00:04:09,390 --> 00:04:06,790 concept that we have been looking at in 102 00:04:12,000 --> 00:04:09,400 this research is the environmental cycle 103 00:04:14,400 --> 00:04:12,010 so here maybe we have the Sun that's 104 00:04:17,009 --> 00:04:14,410 driving water evaporation and then that 105 00:04:20,009 --> 00:04:17,019 gives us maybe this viscous layer here 106 00:04:23,040 --> 00:04:20,019 that has low water activity then we have 107 00:04:24,810 --> 00:04:23,050 rehydration at night maybe cooling and 108 00:04:27,180 --> 00:04:24,820 then we have this cycle that goes on so 109 00:04:29,220 --> 00:04:27,190 you know we all we are we all know we're 110 00:04:31,500 --> 00:04:29,230 all driven by cycles those of us who 111 00:04:33,780 --> 00:04:31,510 came from abroad very aware of it 112 00:04:36,300 --> 00:04:33,790 through the jet lag that we're now out 113 00:04:38,130 --> 00:04:36,310 of sync but we do want to look at 114 00:04:39,750 --> 00:04:38,140 environmental cycles they're not only 115 00:04:41,880 --> 00:04:39,760 prebiotic ly possible but probably 116 00:04:44,940 --> 00:04:41,890 prebiotic ly necessary that could be 117 00:04:48,240 --> 00:04:44,950 daily or tidal or seasonal cycles these 118 00:04:50,790 --> 00:04:48,250 could be hot cold wet dry pH swings all 119 00:04:52,380 --> 00:04:50,800 of the above the hot cold could really 120 00:04:55,250 --> 00:04:52,390 drive the wet and dry and that could 121 00:04:57,570 --> 00:04:55,260 then drive the pH swings in fact so 122 00:04:59,970 --> 00:04:57,580 having this sort of cycle driven by the 123 00:05:02,820 --> 00:04:59,980 influx of solar energy gives us non 124 00:05:06,510 --> 00:05:02,830 equilibrium behavior and it induces 125 00:05:08,040 --> 00:05:06,520 reversible phenomenon that are lifelike 126 00:05:11,940 --> 00:05:08,050 in some ways I'm not going to define 127 00:05:13,200 --> 00:05:11,950 life for you but but over the course of 128 00:05:14,940 --> 00:05:13,210 the cycle we want to sometimes have 129 00:05:16,680 --> 00:05:14,950 polymerization and then sometimes have 130 00:05:18,690 --> 00:05:16,690 hydrolysis and we don't want to just 131 00:05:20,280 --> 00:05:18,700 drive ourselves into a thermodynamic 132 00:05:23,000 --> 00:05:20,290 dead-end we might want to have duplex 133 00:05:25,260 --> 00:05:23,010 formation but then separate then 134 00:05:27,210 --> 00:05:25,270 separation later on in the cycle and 135 00:05:31,130 --> 00:05:27,220 that these sorts of dynamic reversible 136 00:05:33,390 --> 00:05:31,140 systems are lifelike in some sense and 137 00:05:34,770 --> 00:05:33,400 then the other feature in addition to 138 00:05:36,360 --> 00:05:34,780 the environmental cycles that we have 139 00:05:40,290 --> 00:05:36,370 really been focusing on are non aqueous 140 00:05:42,420 --> 00:05:40,300 solvents so we are water-based or not 141 00:05:44,909 --> 00:05:42,430 trying to argue that life the origins of 142 00:05:46,770 --> 00:05:44,919 life did not involve water but that 143 00:05:47,250 --> 00:05:46,780 might not be the whole story in terms of 144 00:05:49,320 --> 00:05:47,260 this 145 00:05:51,660 --> 00:05:49,330 either the solvent being an 146 00:05:53,490 --> 00:05:51,670 environmental condition so there were 147 00:05:55,950 --> 00:05:53,500 many organics present in the prebiotic 148 00:05:58,830 --> 00:05:55,960 inventory and some of these non aqueous 149 00:06:00,900 --> 00:05:58,840 solvents could have been created from 150 00:06:04,650 --> 00:06:00,910 non volatile organics after water 151 00:06:07,080 --> 00:06:04,660 evaporation and some of the desirable 152 00:06:08,280 --> 00:06:07,090 features of non aqueous solvents in this 153 00:06:10,350 --> 00:06:08,290 context are that we can drive 154 00:06:12,180 --> 00:06:10,360 condensation polymerization forward if 155 00:06:16,290 --> 00:06:12,190 we remove the water that's off the water 156 00:06:17,640 --> 00:06:16,300 problem for us we can also these 157 00:06:19,590 --> 00:06:17,650 solvents might be more viscous than 158 00:06:21,570 --> 00:06:19,600 water and that can give us differential 159 00:06:24,660 --> 00:06:21,580 mobility between different species in 160 00:06:27,150 --> 00:06:24,670 these solvents and also it can promote 161 00:06:29,430 --> 00:06:27,160 intermolecular folding by suppressing 162 00:06:31,890 --> 00:06:29,440 intermolecular reactions so if we have a 163 00:06:33,090 --> 00:06:31,900 viscous solvent then the species might 164 00:06:35,130 --> 00:06:33,100 not be very mobile and they might have 165 00:06:37,530 --> 00:06:35,140 more time to fold before they undergo 166 00:06:42,890 --> 00:06:37,540 intermolecular interactions or the 167 00:06:47,220 --> 00:06:45,660 so in order to understand the system 168 00:06:49,110 --> 00:06:47,230 level behavior one of the tools that we 169 00:06:52,340 --> 00:06:49,120 have available to us is mathematical 170 00:06:54,540 --> 00:06:52,350 modeling and this allows us to evaluate 171 00:06:56,310 --> 00:06:54,550 interactions between the environment and 172 00:06:58,800 --> 00:06:56,320 the chemistry in order to predict 173 00:07:01,080 --> 00:06:58,810 overall system level performance this 174 00:07:02,610 --> 00:07:01,090 can be helpful because there are so many 175 00:07:04,260 --> 00:07:02,620 different parameters that we might be 176 00:07:06,960 --> 00:07:04,270 able to vary and a model can help us 177 00:07:08,460 --> 00:07:06,970 clarify what some of the minimal 178 00:07:11,010 --> 00:07:08,470 interactions in our system need to be 179 00:07:13,710 --> 00:07:11,020 and what is the window of performance 180 00:07:18,720 --> 00:07:13,720 that we can get with maybe a minimal 181 00:07:21,060 --> 00:07:18,730 type of experimental system so this 182 00:07:22,860 --> 00:07:21,070 model also can help us or a model can 183 00:07:24,780 --> 00:07:22,870 help to predict trade-offs between 184 00:07:26,250 --> 00:07:24,790 simultaneously occurring phenomena in 185 00:07:30,570 --> 00:07:26,260 our system which is hard to do with a 186 00:07:32,790 --> 00:07:30,580 more reductionist approach and we 187 00:07:34,050 --> 00:07:32,800 considered a particular case study that 188 00:07:36,750 --> 00:07:34,060 I'm going to talk to you about today 189 00:07:38,610 --> 00:07:36,760 which is the idea that the first 190 00:07:40,170 --> 00:07:38,620 functional biopolymer could have been 191 00:07:41,720 --> 00:07:40,180 the monomer synthetase this is an idea 192 00:07:44,490 --> 00:07:41,730 that Naqada has talked about before and 193 00:07:47,070 --> 00:07:44,500 Nick is a really collaborator on all of 194 00:07:52,980 --> 00:07:47,080 this work so appreciate his little setup 195 00:07:54,420 --> 00:07:52,990 in the back but the idea is that if we 196 00:07:55,950 --> 00:07:54,430 want to select for function a simpler 197 00:07:57,900 --> 00:07:55,960 function than say a polymerase would be 198 00:07:58,680 --> 00:07:57,910 to make more monomer so that's what 199 00:08:00,780 --> 00:07:58,690 we're looking at in this particular 200 00:08:02,850 --> 00:08:00,790 study and looking for reactor 201 00:08:04,860 --> 00:08:02,860 and diffusivities in our system that 202 00:08:07,920 --> 00:08:04,870 would allow us to have functional 203 00:08:10,140 --> 00:08:07,930 evolution and we also looked at this 204 00:08:12,570 --> 00:08:10,150 made this assumption of Universal 205 00:08:13,710 --> 00:08:12,580 sequence replication in which all of our 206 00:08:15,180 --> 00:08:13,720 different sequences had the same 207 00:08:16,980 --> 00:08:15,190 replication rate so we weren't going to 208 00:08:18,690 --> 00:08:16,990 get selection based on that inherent 209 00:08:20,730 --> 00:08:18,700 replication rate and so we were going to 210 00:08:26,790 --> 00:08:20,740 look for selection based on other 211 00:08:27,990 --> 00:08:26,800 properties of the system so and in this 212 00:08:30,840 --> 00:08:28,000 particular study that I going to talk 213 00:08:33,170 --> 00:08:30,850 about was led by Sarah Walker who was a 214 00:08:35,370 --> 00:08:33,180 postdoc in the Center at the time and 215 00:08:38,850 --> 00:08:35,380 did this work collaboratively with Nick 216 00:08:42,060 --> 00:08:38,860 and myself so we defined this relatively 217 00:08:44,280 --> 00:08:42,070 minimal a chemical system in which we 218 00:08:46,400 --> 00:08:44,290 had a de phase that was dehydrated in a 219 00:08:49,890 --> 00:08:46,410 night phase which was hydrated and 220 00:08:51,780 --> 00:08:49,900 during the dehydrated day phase we had 221 00:08:53,850 --> 00:08:51,790 different monomers of type A and B so 222 00:08:56,610 --> 00:08:53,860 instead of four nucleobases you could 223 00:08:59,400 --> 00:08:56,620 just think of a two called a and B and 224 00:09:02,460 --> 00:08:59,410 they could form through a spontaneous 225 00:09:03,960 --> 00:09:02,470 polymerization random sequences so 226 00:09:07,130 --> 00:09:03,970 that's one of the parameters in our 227 00:09:09,600 --> 00:09:07,140 model is a rate constant for spontaneous 228 00:09:11,010 --> 00:09:09,610 formation of new sequences we also could 229 00:09:13,020 --> 00:09:11,020 have copying of those sequences the 230 00:09:15,630 --> 00:09:13,030 replication rate so those are two of the 231 00:09:17,100 --> 00:09:15,640 five parameters in our model and during 232 00:09:19,080 --> 00:09:17,110 the night phase we could break down 233 00:09:21,450 --> 00:09:19,090 those sequences through hydrolysis and 234 00:09:23,610 --> 00:09:21,460 also during that hydrated phase we would 235 00:09:27,630 --> 00:09:23,620 have diffusion the monomers and polymers 236 00:09:29,370 --> 00:09:27,640 could both diffuse these these monomers 237 00:09:30,660 --> 00:09:29,380 are all assumed to be the same length we 238 00:09:34,050 --> 00:09:30,670 have a lot of simplifications in this 239 00:09:35,790 --> 00:09:34,060 model they're all xx MERS and they form 240 00:09:37,830 --> 00:09:35,800 based on second-order reaction kinetics 241 00:09:39,360 --> 00:09:37,840 from the monomers so the rates of 242 00:09:40,830 --> 00:09:39,370 polymer formation are dependent on the 243 00:09:42,270 --> 00:09:40,840 local resources in the system and that 244 00:09:44,130 --> 00:09:42,280 was that was another property that we 245 00:09:46,220 --> 00:09:44,140 want to bring in so really depending on 246 00:09:48,510 --> 00:09:46,230 where these sequences nucleated 247 00:09:51,180 --> 00:09:48,520 spatially they would be more or less fit 248 00:09:53,310 --> 00:09:51,190 based on the local resources not based 249 00:09:54,780 --> 00:09:53,320 on their inherent sequence because all 250 00:09:57,660 --> 00:09:54,790 sequences have the same rate constants 251 00:10:00,690 --> 00:09:57,670 for replication so this slide just shows 252 00:10:02,190 --> 00:10:00,700 an example of one particular set of five 253 00:10:06,510 --> 00:10:02,200 parameters that are shown there on the 254 00:10:09,120 --> 00:10:06,520 right and what we saw was over time on 255 00:10:14,880 --> 00:10:09,130 the top right the total population in 256 00:10:19,990 --> 00:10:17,850 the total polymer population grew from 257 00:10:21,310 --> 00:10:20,000 monomers and then stabilized but we had 258 00:10:22,900 --> 00:10:21,320 a lot of dynamics in terms of our 259 00:10:36,240 --> 00:10:22,910 individual sequences and I'm just going 260 00:10:40,240 --> 00:10:38,650 okay so early on in the system we didn't 261 00:10:42,340 --> 00:10:40,250 have any sequences and then we had many 262 00:10:43,870 --> 00:10:42,350 random sequences form some of them took 263 00:10:45,970 --> 00:10:43,880 hold in the population like that upper 264 00:10:48,670 --> 00:10:45,980 blue one others went extinct these are 265 00:10:50,230 --> 00:10:48,680 stochastic simulations so we can have 266 00:10:51,819 --> 00:10:50,240 zero one behavior or we can have 267 00:10:53,460 --> 00:10:51,829 actually a large number of species in 268 00:10:55,930 --> 00:10:53,470 our system like 800 for that blue one 269 00:10:57,490 --> 00:10:55,940 and we looked at not only the temporal 270 00:10:59,769 --> 00:10:57,500 evolution but also spatial distribution 271 00:11:01,389 --> 00:10:59,779 because we have these diffusivities so 272 00:11:03,280 --> 00:11:01,399 the polymers are shown in that upper set 273 00:11:04,630 --> 00:11:03,290 of panels and the monomers in the lower 274 00:11:06,699 --> 00:11:04,640 set of panels but you can see these 275 00:11:10,440 --> 00:11:06,709 clusters emerging which actually we did 276 00:11:12,850 --> 00:11:10,450 not expect but it actually came through 277 00:11:15,130 --> 00:11:12,860 recycling of monomers so that when we 278 00:11:17,050 --> 00:11:15,140 had hydrolysis and freed monomers from 279 00:11:18,970 --> 00:11:17,060 polymers they would be more likely to be 280 00:11:20,889 --> 00:11:18,980 taken up by nearby polymers and that 281 00:11:22,569 --> 00:11:20,899 stabilized the cluster even though we 282 00:11:27,460 --> 00:11:22,579 did not build in any inherent 283 00:11:30,160 --> 00:11:27,470 interaction between the polymers so as 284 00:11:32,319 --> 00:11:30,170 we varied the monomer diffusion rate 285 00:11:34,870 --> 00:11:32,329 across the top and the polymer diffusion 286 00:11:36,639 --> 00:11:34,880 rate down the bottom we saw differences 287 00:11:38,889 --> 00:11:36,649 in terms of the spatial patterning so we 288 00:11:40,509 --> 00:11:38,899 could have larger clusters if we had 289 00:11:41,860 --> 00:11:40,519 more polymer diffusion the monomer 290 00:11:43,930 --> 00:11:41,870 diffusion was actually important in 291 00:11:44,980 --> 00:11:43,940 order to have good resource allocations 292 00:11:52,090 --> 00:11:44,990 so that the mountain would be available 293 00:11:53,410 --> 00:11:52,100 to all of these replicating polymers ok 294 00:11:55,090 --> 00:11:53,420 so I talked about the importance of 295 00:11:56,350 --> 00:11:55,100 functional selection but up until this 296 00:11:58,840 --> 00:11:56,360 point we had all these replicating 297 00:12:01,000 --> 00:11:58,850 polymers that had no function so in this 298 00:12:03,540 --> 00:12:01,010 particular case study we then introduced 299 00:12:05,590 --> 00:12:03,550 at a later time the appearance of 300 00:12:10,360 --> 00:12:05,600 functional polymer that could make more 301 00:12:12,189 --> 00:12:10,370 a and what we saw was that compared to 302 00:12:14,439 --> 00:12:12,199 the green curve with no functional 303 00:12:16,689 --> 00:12:14,449 sequence once this functional polymer 304 00:12:18,220 --> 00:12:16,699 was introduced we had this this red 305 00:12:20,050 --> 00:12:18,230 curve that really bootstrapped up the 306 00:12:24,310 --> 00:12:20,060 entire population so by making more 307 00:12:26,650 --> 00:12:24,320 monomer it not only was it amplified in 308 00:12:29,079 --> 00:12:26,660 the population but also everybody 309 00:12:32,110 --> 00:12:29,089 benefited but not as much okay so this 310 00:12:34,480 --> 00:12:32,120 Illustrated that really there was a 311 00:12:37,090 --> 00:12:34,490 balance needed between competition and 312 00:12:40,030 --> 00:12:37,100 cooperation to achieve higher system 313 00:12:42,939 --> 00:12:40,040 level performance and and this was 314 00:12:45,190 --> 00:12:42,949 enabled by limited diffusing furthermore 315 00:12:47,170 --> 00:12:45,200 if at a later time and added 316 00:12:50,010 --> 00:12:47,180 different location we introduced the B 317 00:12:52,180 --> 00:12:50,020 synthetase to a different sequence now 318 00:12:53,950 --> 00:12:52,190 we could really bootstrap up the 319 00:12:55,780 --> 00:12:53,960 population with that blue curve up to a 320 00:12:59,320 --> 00:12:55,790 much higher level because we could 321 00:13:02,680 --> 00:12:59,330 better utilize both RA and RB polymer 322 00:13:04,960 --> 00:13:02,690 and so this is a way that we could build 323 00:13:07,030 --> 00:13:04,970 out something like a hyper cycle in 324 00:13:08,440 --> 00:13:07,040 which we did not need to have both of 325 00:13:09,280 --> 00:13:08,450 these functions appearing at the same 326 00:13:11,980 --> 00:13:09,290 time they could appear at different 327 00:13:14,800 --> 00:13:11,990 times in different locations stepwise 328 00:13:21,910 --> 00:13:14,810 building up a cooperative chemical 329 00:13:23,590 --> 00:13:21,920 Network okay so what were some of the 330 00:13:25,510 --> 00:13:23,600 insights that we gained from this one 331 00:13:28,560 --> 00:13:25,520 was that the optimal system behavior in 332 00:13:30,790 --> 00:13:28,570 order to generate and sustain diversity 333 00:13:32,170 --> 00:13:30,800 occurred at sweet spot so it wasn't 334 00:13:33,400 --> 00:13:32,180 always more is better and so this is 335 00:13:36,040 --> 00:13:33,410 something that without a mathematical 336 00:13:37,690 --> 00:13:36,050 model would be difficult to predict that 337 00:13:39,070 --> 00:13:37,700 we wanted to have some reversibility in 338 00:13:41,290 --> 00:13:39,080 our polymerization so that we could 339 00:13:42,430 --> 00:13:41,300 generate new sequences and continue to 340 00:13:44,320 --> 00:13:42,440 look through sequence space for these 341 00:13:46,510 --> 00:13:44,330 probably small fraction of sequences 342 00:13:48,100 --> 00:13:46,520 that would be functional but if you have 343 00:13:49,960 --> 00:13:48,110 to traverse ability then all have reddit 344 00:13:51,640 --> 00:13:49,970 a would be lost right so we need a 345 00:13:53,320 --> 00:13:51,650 middle ground there we also needed a 346 00:13:57,220 --> 00:13:53,330 middle ground in terms of diffusion of 347 00:13:58,510 --> 00:13:57,230 polymer and and monomer in order to have 348 00:14:01,270 --> 00:13:58,520 some diffusion to efficiently use 349 00:14:03,430 --> 00:14:01,280 utilize all of our resources but by 350 00:14:04,900 --> 00:14:03,440 having limited diffusion we were able to 351 00:14:06,550 --> 00:14:04,910 then generate different functional 352 00:14:08,620 --> 00:14:06,560 sequences and not have a single winner 353 00:14:11,380 --> 00:14:08,630 scenario but to generate and sustain 354 00:14:13,060 --> 00:14:11,390 diversity and have the ability to 355 00:14:14,970 --> 00:14:13,070 continue to explore sequence space so 356 00:14:18,580 --> 00:14:14,980 that we could have this cooperative 357 00:14:20,920 --> 00:14:18,590 catalytic Network evolve our develop 358 00:14:22,180 --> 00:14:20,930 over time and so that's the second 359 00:14:24,400 --> 00:14:22,190 bullet point that these cooperative 360 00:14:25,780 --> 00:14:24,410 networks could emerge stepwise we don't 361 00:14:29,920 --> 00:14:25,790 have to have the hyper cycle if you're 362 00:14:31,240 --> 00:14:29,930 all at one time and the third insight 363 00:14:33,220 --> 00:14:31,250 that we gained was that this clustering 364 00:14:35,650 --> 00:14:33,230 emerged through our recycling dynamic 365 00:14:39,220 --> 00:14:35,660 through breaking down and reusing these 366 00:14:41,140 --> 00:14:39,230 monomers and that was just not something 367 00:14:44,470 --> 00:14:41,150 that we anticipated when we started 368 00:14:46,330 --> 00:14:44,480 running these simulations and and also 369 00:14:48,460 --> 00:14:46,340 that this limited diffusion on surfaces 370 00:14:50,710 --> 00:14:48,470 could provide an early sort of 371 00:14:56,270 --> 00:14:50,720 compartmentalization prior to 372 00:15:02,360 --> 00:14:59,900 so in designing our experiments we took 373 00:15:04,130 --> 00:15:02,370 forward some of these ideas and that 374 00:15:06,350 --> 00:15:04,140 backbone reversibility and monomers 375 00:15:09,680 --> 00:15:06,360 recycling was going to be important to 376 00:15:11,300 --> 00:15:09,690 explore sequence space the environmental 377 00:15:13,580 --> 00:15:11,310 cycling was helpful for driving 378 00:15:15,650 --> 00:15:13,590 condensation and hydrolysis driving 379 00:15:19,040 --> 00:15:15,660 duplex separation and ultimately 380 00:15:20,930 --> 00:15:19,050 replication that we wanted to build in 381 00:15:23,930 --> 00:15:20,940 limited diffusion to bias our mobility 382 00:15:25,610 --> 00:15:23,940 and that we wanted to continue to look 383 00:15:30,530 --> 00:15:25,620 for selection based not only on 384 00:15:31,700 --> 00:15:30,540 replication but really unfunctional so 385 00:15:33,470 --> 00:15:31,710 next I want to talk to you about a 386 00:15:35,840 --> 00:15:33,480 candidate that we have for reversible 387 00:15:37,280 --> 00:15:35,850 linkages and this is a work that Shang 388 00:15:38,480 --> 00:15:37,290 Shang you talked about yesterday and his 389 00:15:39,980 --> 00:15:38,490 poster and we'll talk about again 390 00:15:41,750 --> 00:15:39,990 tomorrow if you want more details so 391 00:15:44,150 --> 00:15:41,760 I'll give some of the highlights the 392 00:15:46,250 --> 00:15:44,160 hypothesis was that polyesters could be 393 00:15:48,170 --> 00:15:46,260 a prebiotic precursor to peptides so 394 00:15:49,880 --> 00:15:48,180 instead of looking at amino acids look 395 00:15:52,670 --> 00:15:49,890 at alpha hydroxy acids which are also 396 00:15:54,740 --> 00:15:52,680 present in miller-urey type experiments 397 00:15:57,560 --> 00:15:54,750 and there are a number of indications 398 00:16:00,790 --> 00:15:57,570 that polyesters and alpha hydroxy yeah 399 00:16:04,610 --> 00:16:00,800 play this role one is that the ribozyme 400 00:16:07,040 --> 00:16:04,620 that the ribosome catalyzes alpha 401 00:16:09,170 --> 00:16:07,050 hydroxy acid coupling that the 402 00:16:10,460 --> 00:16:09,180 polyesters could also have similar side 403 00:16:11,960 --> 00:16:10,470 chain interactions although they would 404 00:16:14,450 --> 00:16:11,970 not have the backbone hydrogen bonds of 405 00:16:15,770 --> 00:16:14,460 peptides and that the ester bond just 406 00:16:18,710 --> 00:16:15,780 simply polymerize is more readily than 407 00:16:21,290 --> 00:16:18,720 the amide bond and so this could really 408 00:16:22,850 --> 00:16:21,300 help us in generating significant yield 409 00:16:26,600 --> 00:16:22,860 and length in terms of our polymers 410 00:16:28,310 --> 00:16:26,610 through non enzymatic reactions and so 411 00:16:30,290 --> 00:16:28,320 this this idea was put forward by Leslie 412 00:16:32,030 --> 00:16:30,300 Orgel and has been out there for a while 413 00:16:33,680 --> 00:16:32,040 but people thought well maybe polyesters 414 00:16:35,780 --> 00:16:33,690 are just not stable enough but actually 415 00:16:37,670 --> 00:16:35,790 our simulations and actually maybe we 416 00:16:41,170 --> 00:16:37,680 want them to we don't want them to be 417 00:16:43,400 --> 00:16:41,180 too stable if we want to evolve so this 418 00:16:46,280 --> 00:16:43,410 slide shows kind of a comparison between 419 00:16:48,350 --> 00:16:46,290 amino and alpha and amino and hydroxy 420 00:16:51,050 --> 00:16:48,360 acids if you're trying to do non 421 00:16:52,640 --> 00:16:51,060 enzymatic peptide polymerization you 422 00:16:54,950 --> 00:16:52,650 have a couple of problems one is that 423 00:16:58,280 --> 00:16:54,960 it's thermodynamically unfavorable in 424 00:17:00,350 --> 00:16:58,290 terms of drying reactions or or in 425 00:17:02,650 --> 00:17:00,360 solvent and then we also have the dakedo 426 00:17:06,260 --> 00:17:02,660 Pipper zine sink in which we form this 427 00:17:08,360 --> 00:17:06,270 cyclic dimer so the ester solution has a 428 00:17:10,130 --> 00:17:08,370 more favorable bond formation free 429 00:17:12,880 --> 00:17:10,140 energy and although it does form cycle 430 00:17:15,140 --> 00:17:12,890 they're reversible so we've been looking 431 00:17:17,150 --> 00:17:15,150 for the last five years or so and 432 00:17:20,300 --> 00:17:17,160 reactions of these polyesters and this 433 00:17:22,000 --> 00:17:20,310 shows one of our early papers led by 434 00:17:24,350 --> 00:17:22,010 arena Mamedov and 435 00:17:26,660 --> 00:17:24,360 malic acid cycling and we built a 436 00:17:29,930 --> 00:17:26,670 kinetic model to predict the effect 437 00:17:31,790 --> 00:17:29,940 under wet/dry cycles under different 438 00:17:33,770 --> 00:17:31,800 temperatures and we did the experiments 439 00:17:36,680 --> 00:17:33,780 and they agreed pretty well in terms of 440 00:17:38,180 --> 00:17:36,690 the monomer dimer and trimer 441 00:17:40,100 --> 00:17:38,190 concentrations and it showed kind of a 442 00:17:42,680 --> 00:17:40,110 ratcheting behavior in which we could 443 00:17:44,300 --> 00:17:42,690 form the poly malic acid over time and 444 00:17:46,850 --> 00:17:44,310 then achieve kind of a cyclic steady 445 00:17:49,270 --> 00:17:46,860 state in terms of polymerizing forward 446 00:17:55,310 --> 00:17:49,280 and then hydrolyzing somewhat during the 447 00:17:59,000 --> 00:17:55,320 wet period so the idea here was that the 448 00:18:01,940 --> 00:17:59,010 polyesters could be a proto peptide but 449 00:18:03,260 --> 00:18:01,950 then along the way our team member 450 00:18:07,280 --> 00:18:03,270 around christian murphy said well what 451 00:18:09,380 --> 00:18:07,290 about Esther amid exchange so we all 452 00:18:11,630 --> 00:18:09,390 said what and then you know did some of 453 00:18:13,670 --> 00:18:11,640 the initial experiments to try this out 454 00:18:16,790 --> 00:18:13,680 we published a paper last year at on 455 00:18:18,770 --> 00:18:16,800 Covanta cami on this topic in which by 456 00:18:20,420 --> 00:18:18,780 first making polyesters and then adding 457 00:18:24,500 --> 00:18:20,430 amino acids into the system they 458 00:18:26,780 --> 00:18:24,510 exchanged and if we dry and cycle 459 00:18:29,810 --> 00:18:26,790 glycine only we really make nothing with 460 00:18:31,850 --> 00:18:29,820 lactic acid we do make polymers but when 461 00:18:33,250 --> 00:18:31,860 we mix them together we form all of 462 00:18:36,710 --> 00:18:33,260 these different copolymers 463 00:18:38,240 --> 00:18:36,720 moreover over time because the amadon is 464 00:18:44,540 --> 00:18:38,250 more stable we move further and farther 465 00:18:46,250 --> 00:18:44,550 toward peptides and then Shan Shan is 466 00:18:49,040 --> 00:18:46,260 posters talking about a system level 467 00:18:51,920 --> 00:18:49,050 model in which we consider the wet dry 468 00:18:53,990 --> 00:18:51,930 cycling of this mixture of hydroxy and 469 00:18:55,460 --> 00:18:54,000 amino acids and we look at the different 470 00:18:57,590 --> 00:18:55,470 species that are formed there all Quan 471 00:18:59,690 --> 00:18:57,600 nine different species quantitated here 472 00:19:02,420 --> 00:18:59,700 over time at four different temperatures 473 00:19:05,960 --> 00:19:02,430 and he built a kinetic model to describe 474 00:19:08,750 --> 00:19:05,970 based on five parameters a forward 475 00:19:11,240 --> 00:19:08,760 polymerization rate for the polyester is 476 00:19:13,580 --> 00:19:11,250 a hydrolysis rate a strand exchange mass 477 00:19:17,450 --> 00:19:13,590 transfer coefficient we also have 478 00:19:18,920 --> 00:19:17,460 hydrolysis and we're able to get really 479 00:19:21,020 --> 00:19:18,930 remarkable achievement I think between 480 00:19:22,220 --> 00:19:21,030 for all nine of these species and helped 481 00:19:23,869 --> 00:19:22,230 us to understand that this reaction 482 00:19:25,699 --> 00:19:23,879 could be understood in terms of element 483 00:19:27,979 --> 00:19:25,709 tree mass action kinetics and 484 00:19:29,509 --> 00:19:27,989 diffusional mass transfer and from the 485 00:19:32,059 --> 00:19:29,519 model we were able to gain some insights 486 00:19:33,769 --> 00:19:32,069 that it for different temperatures our 487 00:19:35,269 --> 00:19:33,779 rate constants and mass transfer 488 00:19:36,859 --> 00:19:35,279 coefficient really are very Arrhenius 489 00:19:38,749 --> 00:19:36,869 like now this would never be expected 490 00:19:40,969 --> 00:19:38,759 because we're drying the system it's 491 00:19:43,609 --> 00:19:40,979 really not ideal but we can still see 492 00:19:44,809 --> 00:19:43,619 this same Arenas type of behavior and we 493 00:19:47,479 --> 00:19:44,819 were also able to look at the reaction 494 00:19:50,299 --> 00:19:47,489 pathway and to show that compared to 495 00:19:52,609 --> 00:19:50,309 just drying and cycling the amino acids 496 00:19:56,869 --> 00:19:52,619 we were really able to lower the barrier 497 00:19:59,149 --> 00:19:56,879 towards making the peptide bond by 498 00:20:01,789 --> 00:19:59,159 having this two-step reaction using the 499 00:20:04,609 --> 00:20:01,799 hydroxy acids and also that it was 500 00:20:06,439 --> 00:20:04,619 really based on the analysis of the 501 00:20:09,049 --> 00:20:06,449 model that it's an engine of the 502 00:20:10,609 --> 00:20:09,059 entropic barrier and not the enthalpic 503 00:20:15,960 --> 00:20:10,619 barrier may be similar to something that 504 00:20:21,000 --> 00:20:19,570 so some of the insights that we gained 505 00:20:24,610 --> 00:20:21,010 from this particular study is that 506 00:20:27,180 --> 00:20:24,620 hydroxy acids could potentially play the 507 00:20:29,620 --> 00:20:27,190 role of amino acids in a prototype tide 508 00:20:31,990 --> 00:20:29,630 that was the original idea then we had 509 00:20:33,519 --> 00:20:32,000 this kind of turn in the road where now 510 00:20:35,440 --> 00:20:33,529 it turns out the hydroxy acids might be 511 00:20:37,539 --> 00:20:35,450 the catalyst for the amino acid 512 00:20:41,019 --> 00:20:37,549 polymerization through ester and 513 00:20:42,850 --> 00:20:41,029 exchange over time we go from having 514 00:20:45,700 --> 00:20:42,860 these copolymers between hydroxy and 515 00:20:47,500 --> 00:20:45,710 amino acid to peptides but it also may 516 00:20:49,600 --> 00:20:47,510 be that these copolymers also called FC 517 00:20:51,279 --> 00:20:49,610 peptides could actually be important 518 00:20:53,139 --> 00:20:51,289 evolutionary intermediates because they 519 00:20:57,340 --> 00:20:53,149 have greater reversibility through the 520 00:21:04,210 --> 00:20:57,350 ester bond than do the amino acids and 521 00:21:06,970 --> 00:21:04,220 peptides and moreover we had kind of a 522 00:21:08,590 --> 00:21:06,980 new view on the water problem which is 523 00:21:11,110 --> 00:21:08,600 that perhaps it's not a problem at all 524 00:21:13,480 --> 00:21:11,120 so our simulation study had indicated 525 00:21:15,820 --> 00:21:13,490 that we really needed this recycling and 526 00:21:18,840 --> 00:21:15,830 reversibility in order to evolve to 527 00:21:21,010 --> 00:21:18,850 generate and sustain diversity and so 528 00:21:23,080 --> 00:21:21,020 perhaps that is why life uses 529 00:21:24,970 --> 00:21:23,090 condensation polymers is that because it 530 00:21:26,620 --> 00:21:24,980 needs to have these bonds that are 531 00:21:29,260 --> 00:21:26,630 reversible that could be broken by water 532 00:21:33,789 --> 00:21:29,270 in order to search sequence base and 533 00:21:35,799 --> 00:21:33,799 evolve and now I'd like to move on to 534 00:21:38,799 --> 00:21:35,809 kind of the third of the three topics 535 00:21:40,389 --> 00:21:38,809 that I wanted to discuss today which is 536 00:21:44,019 --> 00:21:40,399 some recent work of ours on the Strand 537 00:21:45,880 --> 00:21:44,029 inhibition problem and so now this is 538 00:21:47,110 --> 00:21:45,890 more of a nucleic acid viewpoint as 539 00:21:52,360 --> 00:21:47,120 opposed to the previous study that's 540 00:21:55,330 --> 00:21:52,370 more that's a focusing on peptides the 541 00:21:58,120 --> 00:21:55,340 Strand inhibition problem is about 542 00:22:01,210 --> 00:21:58,130 replication really of a generally of a 543 00:22:03,549 --> 00:22:01,220 duplex sort of structure and let's say 544 00:22:06,669 --> 00:22:03,559 you want to make a copy of that red-blue 545 00:22:09,130 --> 00:22:06,679 say maybe DNA or RNA sequence you can 546 00:22:11,470 --> 00:22:09,140 heat not enzymatically or snow enzymes 547 00:22:13,930 --> 00:22:11,480 so you can heat the system and separate 548 00:22:15,549 --> 00:22:13,940 the strands but when you cool the system 549 00:22:18,100 --> 00:22:15,559 instead of making a copy instead of 550 00:22:19,810 --> 00:22:18,110 coding and and doubling the number of 551 00:22:22,570 --> 00:22:19,820 strands in the system when you cool down 552 00:22:24,909 --> 00:22:22,580 you really just go back to because the 553 00:22:28,360 --> 00:22:24,919 duplex reforms that's the thermodynamic 554 00:22:31,480 --> 00:22:28,370 product and so you and 555 00:22:34,000 --> 00:22:31,490 and this was a problem articulated by 556 00:22:35,320 --> 00:22:34,010 Jack szostak in his paper that was 557 00:22:37,360 --> 00:22:35,330 mentioned earlier and they've also 558 00:22:38,560 --> 00:22:37,370 recently published an approach to 559 00:22:40,270 --> 00:22:38,570 solving stranded admission using 560 00:22:41,830 --> 00:22:40,280 arginine and so we have a different 561 00:22:44,770 --> 00:22:41,840 approach that we have been looking at 562 00:22:46,810 --> 00:22:44,780 which is to use viscosity so the 563 00:22:48,730 --> 00:22:46,820 hypothesis is that through Mars through 564 00:22:50,610 --> 00:22:48,740 thermal cycling in a viscous environment 565 00:22:53,440 --> 00:22:50,620 you can overcome strand inhibition and 566 00:22:55,840 --> 00:22:53,450 promote template directed nucleic acid 567 00:22:57,880 --> 00:22:55,850 synthesis so now if we have a viscous 568 00:23:00,100 --> 00:22:57,890 environment we can heat the system and 569 00:23:04,680 --> 00:23:00,110 separate the strands same as the same as 570 00:23:08,230 --> 00:23:04,690 in aqueous buffer but now when we cool 571 00:23:10,780 --> 00:23:08,240 what we thought what our hypothesis the 572 00:23:12,160 --> 00:23:10,790 hypothesis was that when we would cool 573 00:23:14,650 --> 00:23:12,170 the long strands would not move very 574 00:23:16,060 --> 00:23:14,660 fast in the viscous solution the short 575 00:23:18,460 --> 00:23:16,070 strands would move faster and they would 576 00:23:21,430 --> 00:23:18,470 be able to coat this but actually when 577 00:23:22,030 --> 00:23:21,440 we kind of did some numbers work some 578 00:23:23,350 --> 00:23:22,040 numbers 579 00:23:24,850 --> 00:23:23,360 it didn't seem like maybe we were going 580 00:23:26,049 --> 00:23:24,860 to get that much differential mobility 581 00:23:28,630 --> 00:23:26,059 because they're probably going square 582 00:23:31,380 --> 00:23:28,640 root of the length and so but anyway it 583 00:23:33,460 --> 00:23:31,390 was you know something that we want that 584 00:23:36,880 --> 00:23:33,470 hypothesis the Nick had and that we we 585 00:23:38,230 --> 00:23:36,890 tried out and what we found actually was 586 00:23:42,760 --> 00:23:38,240 that we were getting intermolecular 587 00:23:44,710 --> 00:23:42,770 folding and of the long strands and that 588 00:23:46,540 --> 00:23:44,720 was probably also playing a role along 589 00:23:47,799 --> 00:23:46,550 with the differential mobility in order 590 00:23:50,799 --> 00:23:47,809 to keep the long strands from coming 591 00:23:53,620 --> 00:23:50,809 back apart and that would give us a 592 00:23:55,060 --> 00:23:53,630 window of time a kinetic solution to 593 00:23:57,400 --> 00:23:55,070 this thermodynamic problem of strand 594 00:23:59,440 --> 00:23:57,410 inhibition in which we could coat the 595 00:24:01,510 --> 00:23:59,450 long strands maybe using kind of a 596 00:24:03,669 --> 00:24:01,520 toehold mechanism to open up the strands 597 00:24:05,680 --> 00:24:03,679 with these short oligomers coat them 598 00:24:08,850 --> 00:24:05,690 ligate them before we actually got to 599 00:24:13,180 --> 00:24:08,860 the thermodynamic duplex Reformation and 600 00:24:15,760 --> 00:24:13,190 then we could go around again so this 601 00:24:17,440 --> 00:24:15,770 was a paper that was published this year 602 00:24:20,650 --> 00:24:17,450 is online in Nature Chemistry and should 603 00:24:22,660 --> 00:24:20,660 come out 2017 at some point in a in an 604 00:24:24,669 --> 00:24:22,670 actual issue so a one thing that we 605 00:24:27,040 --> 00:24:24,679 needed to do is to choose the viscous 606 00:24:28,750 --> 00:24:27,050 solvent the work I'll show you today is 607 00:24:31,120 --> 00:24:28,760 using like choline which is a mixture of 608 00:24:33,190 --> 00:24:31,130 glycerol and choline chloride also known 609 00:24:37,630 --> 00:24:33,200 as a eutectic solvent or a deep eutectic 610 00:24:39,850 --> 00:24:37,640 solvent and this is a system that also 611 00:24:41,860 --> 00:24:39,860 arena had been looking at previously for 612 00:24:44,760 --> 00:24:41,870 a nucleic acid 613 00:24:48,400 --> 00:24:44,770 Assembly G quadruplex in particular and 614 00:24:50,260 --> 00:24:48,410 what they have found in a group in the 615 00:24:52,240 --> 00:24:50,270 past is that within this particular 616 00:24:55,840 --> 00:24:52,250 mixture of glycol E and the B form of 617 00:24:57,640 --> 00:24:55,850 DNA was retained and so that's kind of I 618 00:24:59,380 --> 00:24:57,650 don't know interesting and and notable I 619 00:25:02,770 --> 00:24:59,390 think that DNA would take its native 620 00:25:04,510 --> 00:25:02,780 form and these solvents are also 621 00:25:06,910 --> 00:25:04,520 miscible with water and so we could have 622 00:25:09,040 --> 00:25:06,920 a cycle with these non aqueous solvents 623 00:25:13,420 --> 00:25:09,050 with water some periods of time and then 624 00:25:15,820 --> 00:25:13,430 dehydrated other periods of time and the 625 00:25:18,160 --> 00:25:15,830 the melting temperature of DNA is also 626 00:25:19,270 --> 00:25:18,170 it's suppressed it's lowered in these 627 00:25:21,340 --> 00:25:19,280 solvents and that turned out to be just 628 00:25:23,020 --> 00:25:21,350 helpful from a practical point of view 629 00:25:24,760 --> 00:25:23,030 in the experiment that we could we could 630 00:25:29,799 --> 00:25:24,770 separate our straight and long very long 631 00:25:32,240 --> 00:25:29,809 strands under reasonable temperatures 632 00:25:34,580 --> 00:25:32,250 and so these are just going to show you 633 00:25:38,930 --> 00:25:34,590 a few of the results this slide shows 634 00:25:40,910 --> 00:25:38,940 how we were able to just look at do that 635 00:25:42,680 --> 00:25:40,920 separating the duplex and then cooling 636 00:25:45,140 --> 00:25:42,690 it back down and we had a window of time 637 00:25:46,850 --> 00:25:45,150 and this glyco leaned in which we could 638 00:25:47,930 --> 00:25:46,860 get the single-stranded DNA so you can 639 00:25:49,730 --> 00:25:47,940 look you look at the gel at the top 640 00:25:52,340 --> 00:25:49,740 there's the top bands is the double 641 00:25:53,990 --> 00:25:52,350 double duplex DNA and the lower one is a 642 00:25:56,960 --> 00:25:54,000 single strand so and glyco lean we would 643 00:25:59,030 --> 00:25:56,970 have a period of time in which we would 644 00:26:01,190 --> 00:25:59,040 have single strand before it really old 645 00:26:04,669 --> 00:26:01,200 where as an aqueous buffer it would 646 00:26:06,560 --> 00:26:04,679 really pretty much immediately Rhea Neil 647 00:26:08,450 --> 00:26:06,570 unless we had an extremely high cooling 648 00:26:10,130 --> 00:26:08,460 rate something like 40 degrees C per 649 00:26:13,810 --> 00:26:10,140 minute which probably is not prebiotic 650 00:26:17,419 --> 00:26:13,820 ly plausible and then we were able to 651 00:26:20,210 --> 00:26:17,429 show that we could lie date assemble 652 00:26:22,100 --> 00:26:20,220 nucleotides on those long pieces during 653 00:26:24,470 --> 00:26:22,110 that window of time and so that's really 654 00:26:27,260 --> 00:26:24,480 what this particular slide shows we 655 00:26:31,010 --> 00:26:27,270 looked at eleven-thirty tumors adjacent 656 00:26:34,640 --> 00:26:31,020 along a three Killa base template and we 657 00:26:36,440 --> 00:26:34,650 could make the full-length product in 658 00:26:41,180 --> 00:26:36,450 glycol in whereas we would not be able 659 00:26:43,340 --> 00:26:41,190 to make it in aqueous buffer and so 660 00:26:45,740 --> 00:26:43,350 again I wanted to describe the 661 00:26:48,590 --> 00:26:45,750 progression of ideas that got us to this 662 00:26:52,820 --> 00:26:48,600 point there's actually this earlier idea 663 00:26:54,049 --> 00:26:52,830 notice again image on/off 2010 on using 664 00:26:57,380 --> 00:26:54,059 non aqueous solvents to drive 665 00:26:58,490 --> 00:26:57,390 condensation polymerization and so 666 00:27:00,980 --> 00:26:58,500 there's the kind of history of that 667 00:27:02,750 --> 00:27:00,990 within the center research and the HUD 668 00:27:04,520 --> 00:27:02,760 lab the original idea for this project 669 00:27:07,580 --> 00:27:04,530 was to add visca jhin's to aqueous 670 00:27:09,230 --> 00:27:07,590 buffer B polysaccharides to slow the REO 671 00:27:10,850 --> 00:27:09,240 kneeling of the duplex to get that 672 00:27:12,169 --> 00:27:10,860 differential mobility that turned out 673 00:27:13,520 --> 00:27:12,179 from a practical point of view to be 674 00:27:14,570 --> 00:27:13,530 sort of difficult we had these sugars 675 00:27:16,430 --> 00:27:14,580 and we were trying to separate our 676 00:27:20,900 --> 00:27:16,440 duplex and we were caramelizing the 677 00:27:22,610 --> 00:27:20,910 sugars and and so so we decided to try 678 00:27:25,450 --> 00:27:22,620 to use it the small molecule non aqueous 679 00:27:27,740 --> 00:27:25,460 viscous solvents instead as a visca j'en 680 00:27:29,450 --> 00:27:27,750 we really didn't need the fact that they 681 00:27:33,350 --> 00:27:29,460 were non aqueous so much but we wanted 682 00:27:35,030 --> 00:27:33,360 the viscous part then we were able to 683 00:27:36,230 --> 00:27:35,040 observe the desired behavior but it 684 00:27:37,669 --> 00:27:36,240 wasn't really for the reason that we 685 00:27:39,740 --> 00:27:37,679 thought it wasn't necessarily so much of 686 00:27:41,450 --> 00:27:39,750 viscosity maybe partly but the 687 00:27:43,110 --> 00:27:41,460 intramolecular folding that happened 688 00:27:45,210 --> 00:27:43,120 while we had this window of time 689 00:27:47,549 --> 00:27:45,220 Stram separation more than the 690 00:27:49,200 --> 00:27:47,559 preferential diffusion but ultimately 691 00:27:50,549 --> 00:27:49,210 this gave us a new insight which is that 692 00:27:54,030 --> 00:27:50,559 viscous environments could help us 693 00:27:56,430 --> 00:27:54,040 select for long strands and folded 694 00:27:58,530 --> 00:27:56,440 structures for function for 695 00:28:00,420 --> 00:27:58,540 catalytically functional nucleic acid 696 00:28:03,480 --> 00:28:00,430 polymers under may be more typical 697 00:28:04,680 --> 00:28:03,490 aqueous buffer conditions the unfolded 698 00:28:07,170 --> 00:28:04,690 structures are actually easier to 699 00:28:09,450 --> 00:28:07,180 replicate and so you're selecting for 700 00:28:10,590 --> 00:28:09,460 lack of function and set up our function 701 00:28:14,310 --> 00:28:10,600 so we think this can actually be a 702 00:28:15,810 --> 00:28:14,320 pretty important idea going forward so 703 00:28:18,180 --> 00:28:15,820 I'll just make a few closing remarks 704 00:28:20,460 --> 00:28:18,190 while the light is still yellow orange 705 00:28:22,110 --> 00:28:20,470 one is that through this estimate 706 00:28:23,730 --> 00:28:22,120 exchange mechanism the peptide World may 707 00:28:25,919 --> 00:28:23,740 actually be more accessible than has 708 00:28:28,110 --> 00:28:25,929 previously been thought challenging the 709 00:28:32,070 --> 00:28:28,120 single dominance of the RNA world 710 00:28:34,020 --> 00:28:32,080 hypothesis perhaps there were multiple 711 00:28:36,200 --> 00:28:34,030 things going on at once that are all 712 00:28:38,310 --> 00:28:36,210 important as well as their interactions 713 00:28:40,290 --> 00:28:38,320 another insight is that in an aqueous 714 00:28:42,240 --> 00:28:40,300 environment condensation polymers may 715 00:28:46,830 --> 00:28:42,250 have been selected in life because they 716 00:28:48,510 --> 00:28:46,840 could evolve we also think that viscous 717 00:28:51,260 --> 00:28:48,520 environments can drive selection for 718 00:28:53,510 --> 00:28:51,270 folding and functions function and that 719 00:28:55,350 --> 00:28:53,520 furthermore that this research 720 00:28:58,740 --> 00:28:55,360 serendipity that we're having these 721 00:29:01,100 --> 00:28:58,750 surprises that are helpful may or may 722 00:29:04,080 --> 00:29:01,110 not suggest that some of these 723 00:29:05,880 --> 00:29:04,090 environments and chemistry's together as 724 00:29:10,740 --> 00:29:05,890 a system could mimic some key features 725 00:29:13,590 --> 00:29:10,750 of the prebiotic world so with that I 726 00:29:15,540 --> 00:29:13,600 just like to acknowledge all the members 727 00:29:18,900 --> 00:29:15,550 of the Center for chemical evolution and 728 00:29:20,010 --> 00:29:18,910 our funding from NSF and NASA also like 729 00:29:22,820 --> 00:29:20,020 to acknowledge some of the key players 730 00:29:24,810 --> 00:29:22,830 in the work I presented today NIC hood 731 00:29:26,669 --> 00:29:24,820 first and foremost and thank him for 732 00:29:28,860 --> 00:29:26,679 inviting me into the center to work on 733 00:29:31,290 --> 00:29:28,870 this exciting area Sarah Walker 734 00:29:33,540 --> 00:29:31,300 qianxiang you Kristine he and arena 735 00:29:34,710 --> 00:29:33,550 ma'am Adama and I believe Chris butch 736 00:29:36,240 --> 00:29:34,720 I did not talk about Chris's work I 737 00:29:40,500 --> 00:29:36,250 think I believe he's the tall one 738 00:29:42,690 --> 00:29:40,510 standing in the back right there in this 739 00:29:45,330 --> 00:29:42,700 picture from the center so anyway of 740 00:29:48,120 --> 00:29:45,340 many many Center members to acknowledge 741 00:29:50,250 --> 00:29:48,130 here and I also just listed three of the 742 00:29:52,320 --> 00:29:50,260 key publications from this work and with 743 00:29:55,340 --> 00:29:52,330 that I'd like to conclude and welcome 744 00:29:55,350 --> 00:30:01,520 [Applause] 745 00:30:10,140 --> 00:30:03,240 hey-ya so we have some time for 746 00:30:12,030 --> 00:30:10,150 questions and discussion hi um I was 747 00:30:15,330 --> 00:30:12,040 very interested by your work at the 748 00:30:18,420 --> 00:30:15,340 beginning with the the polymers and 749 00:30:21,480 --> 00:30:18,430 wondered are you aware of Dave Demers 750 00:30:23,340 --> 00:30:21,490 work on polymerization like around 751 00:30:25,770 --> 00:30:23,350 thermal vents because that also gets rid 752 00:30:28,830 --> 00:30:25,780 of your problem of actually dropping 40 753 00:30:31,380 --> 00:30:28,840 degrees in a minute so you're talking 754 00:30:40,560 --> 00:30:31,390 about the Strand inhibition problem with 755 00:30:44,010 --> 00:30:40,570 the 40 degrees yeah so so you don't well 756 00:30:46,830 --> 00:30:44,020 or even polymerizing or even naturing 757 00:30:48,840 --> 00:30:46,840 and sort of along those lines it seems 758 00:30:51,290 --> 00:30:48,850 to me that your results are going to 759 00:30:54,420 --> 00:30:51,300 depend a lot on the concentration of 760 00:30:56,100 --> 00:30:54,430 your solutes and so presumably you would 761 00:30:57,270 --> 00:30:56,110 not have very much of your double strand 762 00:30:59,760 --> 00:30:57,280 you have much more short 763 00:31:01,560 --> 00:30:59,770 eligos or single nucleotides and 764 00:31:03,990 --> 00:31:01,570 therefore I question whether that 765 00:31:06,090 --> 00:31:04,000 actually is a terrific way to get 766 00:31:09,390 --> 00:31:06,100 variability and you don't actually have 767 00:31:10,740 --> 00:31:09,400 a strand inhibition problem so so 768 00:31:13,020 --> 00:31:10,750 because there's so much more monomer 769 00:31:20,070 --> 00:31:13,030 than polymer that that would help with 770 00:31:22,710 --> 00:31:20,080 strand inhibition so so that would be a 771 00:31:25,290 --> 00:31:22,720 helpful direction I agree with that when 772 00:31:27,420 --> 00:31:25,300 many of our initial experiments in this 773 00:31:30,180 --> 00:31:27,430 case here we have four to one monomer to 774 00:31:31,860 --> 00:31:30,190 polymer or ligament a polymer although 775 00:31:33,720 --> 00:31:31,870 early on we did experiments more with 776 00:31:39,780 --> 00:31:33,730 twenty to one something like that 777 00:31:41,880 --> 00:31:39,790 DNA is remarkably good associating well 778 00:31:43,800 --> 00:31:41,890 you know where I I guess one thing that 779 00:31:47,420 --> 00:31:43,810 I would say is that that we're trying to 780 00:31:51,470 --> 00:31:47,430 design and demonstrate minimal chemical 781 00:31:53,940 --> 00:31:51,480 systems that can evolve and so we're not 782 00:31:55,620 --> 00:31:53,950 saying that this environment is right 783 00:31:57,300 --> 00:31:55,630 and this environment is wrong but we're 784 00:32:01,850 --> 00:31:57,310 focusing on this particular environment 785 00:32:04,820 --> 00:32:01,860 of drawing and rewedding but you know we 786 00:32:07,350 --> 00:32:04,830 look forward to seeing evolving systems 787 00:32:08,460 --> 00:32:07,360 from other environments as well this is 788 00:32:14,279 --> 00:32:08,470 the particular advice 789 00:32:16,620 --> 00:32:14,289 that were that we're considering okay 790 00:32:19,529 --> 00:32:16,630 great thank you very exciting work and 791 00:32:22,080 --> 00:32:19,539 as a planetary scientists have been 792 00:32:24,510 --> 00:32:22,090 always wondering what the environment 793 00:32:26,549 --> 00:32:24,520 was during a time of origin of life and 794 00:32:31,799 --> 00:32:26,559 the artwork is quite interesting in that 795 00:32:35,970 --> 00:32:31,809 science but exactly how viscous that 796 00:32:40,320 --> 00:32:35,980 environment you require you give as an 797 00:32:44,909 --> 00:32:40,330 example an auto code and how frequent 798 00:32:49,440 --> 00:32:44,919 were your environment change some 799 00:32:52,980 --> 00:32:49,450 examples well choline is about a hundred 800 00:32:56,220 --> 00:32:52,990 centipoise viscosity which is about a 801 00:32:59,159 --> 00:32:56,230 similar to motor oil so not as viscous 802 00:33:01,470 --> 00:32:59,169 as honey but significantly more viscous 803 00:33:03,750 --> 00:33:01,480 than water now we've also demonstrated 804 00:33:06,060 --> 00:33:03,760 this approach with this is work for DNA 805 00:33:08,250 --> 00:33:06,070 but we've also done it in RNA and we've 806 00:33:12,990 --> 00:33:08,260 also demonstrated the phenomenon and 807 00:33:18,960 --> 00:33:13,000 glycerol and in raylene a urea choline 808 00:33:21,390 --> 00:33:18,970 chloride so if we also have diluted the 809 00:33:23,340 --> 00:33:21,400 glycol in with water and so we can also 810 00:33:26,940 --> 00:33:23,350 see the effective viscosity just simply 811 00:33:29,490 --> 00:33:26,950 through dilution so you know this seems 812 00:33:32,600 --> 00:33:29,500 to be a general physical principle and 813 00:33:35,490 --> 00:33:32,610 phenomenon that's not specific only to 814 00:33:40,470 --> 00:33:35,500 glycol Ian in this particular viscosity 815 00:33:43,620 --> 00:33:40,480 but you do need to have enough slowing 816 00:33:45,210 --> 00:33:43,630 of a movement so that you can get this 817 00:33:47,730 --> 00:33:45,220 intramolecular folding but it seems to 818 00:33:52,760 --> 00:33:47,740 have a pretty broad window but these are 819 00:33:58,260 --> 00:33:52,770 for motor oil the the temperature here 820 00:34:00,630 --> 00:33:58,270 so we needed to separate the two strands 821 00:34:03,149 --> 00:34:00,640 and so in order to do that we needed to 822 00:34:05,299 --> 00:34:03,159 get above the melting temperature so in 823 00:34:08,520 --> 00:34:05,309 glycol eeen that's about fifty degrees 824 00:34:11,820 --> 00:34:08,530 and so so we needed to separate the 825 00:34:14,159 --> 00:34:11,830 strands and then we cool down to ambient 826 00:34:16,829 --> 00:34:14,169 temperature room temperature at a 827 00:34:19,349 --> 00:34:16,839 variety of different rates so I went 828 00:34:20,909 --> 00:34:19,359 through this fairly quickly but you can 829 00:34:22,120 --> 00:34:20,919 see here we tried a number of different 830 00:34:24,820 --> 00:34:22,130 rates from four degrees 831 00:34:26,620 --> 00:34:24,830 see per minute up to 40 degrees c per 832 00:34:30,850 --> 00:34:26,630 minute and and then compared the aqueous 833 00:34:35,830 --> 00:34:30,860 buffer to the glycol een so really this 834 00:34:37,450 --> 00:34:35,840 is a proof of principle so exactly what 835 00:34:40,270 --> 00:34:37,460 these numbers would be would depend on 836 00:34:43,090 --> 00:34:40,280 your viscosity would depend on the 837 00:34:45,250 --> 00:34:43,100 particular nucleic acid polymer that 838 00:34:47,470 --> 00:34:45,260 you're looking at so the we're looking 839 00:34:49,000 --> 00:34:47,480 at glycol één which is glycerol and 840 00:34:51,010 --> 00:34:49,010 choline chloride so glycerol would be 841 00:34:53,950 --> 00:34:51,020 considered prebiotic lea plausible the 842 00:34:55,990 --> 00:34:53,960 core choline chloride is the choline is 843 00:34:57,910 --> 00:34:56,000 questionable you know maybe you could 844 00:35:00,160 --> 00:34:57,920 argue and it's been mentioned in 845 00:35:02,320 --> 00:35:00,170 prebiotic literature but we're really 846 00:35:04,510 --> 00:35:02,330 using this as a proof of principle more 847 00:35:13,630 --> 00:35:04,520 than that this particular solvent would 848 00:35:18,359 --> 00:35:16,210 and thank you very much I've got 849 00:35:23,829 --> 00:35:18,369 interested in earning enough your 850 00:35:27,700 --> 00:35:23,839 hypothesis that their hydroxy acid can 851 00:35:29,609 --> 00:35:27,710 work as a catalyst for amino acid for 852 00:35:33,999 --> 00:35:29,619 meditation 853 00:35:39,849 --> 00:35:34,009 why did you conclude in that way I just 854 00:35:44,140 --> 00:35:39,859 asking the hydroxy acid has some 855 00:35:47,920 --> 00:35:44,150 specificity for selective amino acid 856 00:35:50,620 --> 00:35:47,930 sequence or you have the general 857 00:35:56,859 --> 00:35:50,630 catalyst reaction for any types of I 858 00:35:58,450 --> 00:35:56,869 mean so so if we look at the the figures 859 00:36:00,579 --> 00:35:58,460 on the right there you can see that the 860 00:36:03,759 --> 00:36:00,589 amino acids and the hydroxy acids have 861 00:36:07,269 --> 00:36:03,769 their analog so glycine and glycolic 862 00:36:09,370 --> 00:36:07,279 acid alanine and lactic acid so they 863 00:36:11,680 --> 00:36:09,380 differ only by the amine group versus 864 00:36:13,720 --> 00:36:11,690 the O H group so so they're very similar 865 00:36:15,579 --> 00:36:13,730 to amino acids and that was what led 866 00:36:17,259 --> 00:36:15,589 Nick I don't know eight years ago to 867 00:36:18,999 --> 00:36:17,269 come to my office and say look you got 868 00:36:22,749 --> 00:36:19,009 to read this paper about glycolic acid 869 00:36:25,239 --> 00:36:22,759 and an or gal had had talked about its 870 00:36:27,249 --> 00:36:25,249 importance but this ester Hammad 871 00:36:29,499 --> 00:36:27,259 exchange is not so much about the 872 00:36:32,940 --> 00:36:29,509 similarity between these molecules it's 873 00:36:35,620 --> 00:36:32,950 a stramit exchange is a well known 874 00:36:38,680 --> 00:36:35,630 chemical reaction and in elementary 875 00:36:41,650 --> 00:36:38,690 textbooks but it just had not been 876 00:36:43,479 --> 00:36:41,660 applied to these polymers or in an 877 00:36:45,479 --> 00:36:43,489 origins context actually these deficits 878 00:36:47,769 --> 00:36:45,489 peptides are documented in terms of 879 00:36:52,180 --> 00:36:47,779 biomedical applications in the 880 00:36:55,769 --> 00:36:52,190 literature and so it was sort of right 881 00:36:59,079 --> 00:36:55,779 there hiding in plain sight I think 882 00:37:05,170 --> 00:36:59,089 couldn't find it any selectivity for 883 00:37:06,940 --> 00:37:05,180 each or so we tried we have tried this 884 00:37:09,430 --> 00:37:06,950 reaction for many different hydroxy 885 00:37:11,859 --> 00:37:09,440 acids and many different amino acids and 886 00:37:13,839 --> 00:37:11,869 some have more reactivity than others 887 00:37:16,299 --> 00:37:13,849 but it is a general phenomenon it's not 888 00:37:21,130 --> 00:37:16,309 specific to particular amino acid and we 889 00:37:22,660 --> 00:37:21,140 have made sequences copolymer sequences 890 00:37:24,880 --> 00:37:22,670 with different amino acids different 891 00:37:27,249 --> 00:37:24,890 hydroxy acids so it's a it's a it's a 892 00:37:27,640 --> 00:37:27,259 just a general reaction that just has no 893 00:37:30,690 --> 00:37:27,650 differ 894 00:37:34,690 --> 00:37:30,700 so rates depending on the particular 895 00:37:40,360 --> 00:37:34,700 hydroxy acid or amino acid but it seems 896 00:37:43,360 --> 00:37:40,370 to be very robust so I'm just wondering 897 00:37:45,610 --> 00:37:43,370 about the geochemical settings of the 898 00:37:51,040 --> 00:37:45,620 dry/wet cycles or any kind of cycles 899 00:37:53,590 --> 00:37:51,050 like that so it is really interesting to 900 00:37:55,120 --> 00:37:53,600 have like these polymers clusters and 901 00:37:57,400 --> 00:37:55,130 everything but these kind of settings 902 00:37:59,980 --> 00:37:57,410 should don't you like also take it to 903 00:38:03,910 --> 00:37:59,990 account the fact that well you will have 904 00:38:05,950 --> 00:38:03,920 salts in the in the water and since you 905 00:38:07,960 --> 00:38:05,960 have salt it will be like a evaporite 906 00:38:09,220 --> 00:38:07,970 basin or whatever so you will have to 907 00:38:12,250 --> 00:38:09,230 take into account the fact that you have 908 00:38:15,310 --> 00:38:12,260 at least one more of any salt the salt 909 00:38:18,070 --> 00:38:15,320 there so after you have your brine is it 910 00:38:22,360 --> 00:38:18,080 reversible do you expect that you will 911 00:38:26,650 --> 00:38:22,370 have the same kind of result yes 912 00:38:28,630 --> 00:38:26,660 certainly adding other species will add 913 00:38:29,950 --> 00:38:28,640 complexity to the reactions and 914 00:38:33,550 --> 00:38:29,960 potentially change the events we have 915 00:38:35,380 --> 00:38:33,560 been focusing more on pH dependence one 916 00:38:37,690 --> 00:38:35,390 point that I did not make here but that 917 00:38:39,100 --> 00:38:37,700 is important for the estimated exchange 918 00:38:43,990 --> 00:38:39,110 reactions is that because we have 919 00:38:46,180 --> 00:38:44,000 hydroxy acids they're acidic so that 920 00:38:50,200 --> 00:38:46,190 drives forward and acid catalyzed 921 00:38:52,390 --> 00:38:50,210 polymerization of the polyesters and 922 00:38:53,800 --> 00:38:52,400 then when we dry its might start out not 923 00:38:55,690 --> 00:38:53,810 as acidic then we dry down then it 924 00:38:56,920 --> 00:38:55,700 becomes acidic so there's a lot going on 925 00:38:58,810 --> 00:38:56,930 that we've been looking at in terms of 926 00:39:00,460 --> 00:38:58,820 the pH dynamics of the system not that 927 00:39:02,410 --> 00:39:00,470 we're imposing but that just sort of 928 00:39:05,860 --> 00:39:02,420 naturally emerge from the lactic acid 929 00:39:08,170 --> 00:39:05,870 presence of the the hydroxy acid so we 930 00:39:09,580 --> 00:39:08,180 also have talked about the presence of 931 00:39:11,650 --> 00:39:09,590 salt and the addition of salt and that's 932 00:39:13,330 --> 00:39:11,660 something that you know of course will 933 00:39:17,220 --> 00:39:13,340 have impact on the system but I don't 934 00:39:19,480 --> 00:39:17,230 think it's a show stopper in any way 935 00:39:21,700 --> 00:39:19,490 we've we've talked about it actually in 936 00:39:23,740 --> 00:39:21,710 some of the other projects and kind of 937 00:39:26,020 --> 00:39:23,750 the micro environments direction that I 938 00:39:28,180 --> 00:39:26,030 did not talk about today but certainly 939 00:39:34,390 --> 00:39:28,190 I'm salt we would be present and we play 940 00:39:36,970 --> 00:39:34,400 a role when you refer to the monomers in 941 00:39:39,220 --> 00:39:36,980 taste are you assuming that these thin 942 00:39:41,170 --> 00:39:39,230 stages are actually like short polymers 943 00:39:43,359 --> 00:39:41,180 of either peptide 944 00:39:46,569 --> 00:39:43,369 you know lactic has always worried it 945 00:39:49,030 --> 00:39:46,579 can actually drive the chemical reaction 946 00:39:51,220 --> 00:39:49,040 and throughout the metabolic yes so the 947 00:39:53,020 --> 00:39:51,230 idea in those simulations is that we 948 00:39:55,240 --> 00:39:53,030 have a fixed amount of mass in the 949 00:39:57,370 --> 00:39:55,250 system the simulation is closed to mass 950 00:39:59,049 --> 00:39:57,380 and that it's a scarce resource and the 951 00:40:01,930 --> 00:39:59,059 different polymers are competing for it 952 00:40:04,780 --> 00:40:01,940 and so that if a polymer could make more 953 00:40:05,890 --> 00:40:04,790 than especially that's co-localize you 954 00:40:08,559 --> 00:40:05,900 know then it would have a great 955 00:40:09,910 --> 00:40:08,569 advantage in terms of replication but 956 00:40:12,640 --> 00:40:09,920 yeah the assumption is that there would 957 00:40:14,380 --> 00:40:12,650 be a similar small molecule present in 958 00:40:16,480 --> 00:40:14,390 the environment that's similar to the 959 00:40:19,030 --> 00:40:16,490 monomer and this would you know perhaps 960 00:40:20,349 --> 00:40:19,040 you know truncate off some piece or 961 00:40:22,720 --> 00:40:20,359 perform some sort of chemical 962 00:40:24,960 --> 00:40:22,730 modification that would turn it into say 963 00:40:27,220 --> 00:40:24,970 the amino acid and then if you 964 00:40:28,750 --> 00:40:27,230 incorporate the recycling cycle I really 965 00:40:32,109 --> 00:40:28,760 loved that recycling cycle concept 966 00:40:35,079 --> 00:40:32,119 because actually because the sequence of 967 00:40:37,809 --> 00:40:35,089 those polymers in the environment will 968 00:40:40,240 --> 00:40:37,819 be governed by the composition of those 969 00:40:42,160 --> 00:40:40,250 each polymers so actually if they're if 970 00:40:45,099 --> 00:40:42,170 you introduce these monomers in taste 971 00:40:48,280 --> 00:40:45,109 into the system then that will probably 972 00:40:50,049 --> 00:40:48,290 change the composition of the in the 973 00:40:51,549 --> 00:40:50,059 environment which will change the 974 00:40:54,250 --> 00:40:51,559 sequence based kind of kind of shape the 975 00:40:55,390 --> 00:40:54,260 sequence space of the those randomly 976 00:40:56,620 --> 00:40:55,400 yeah that's right and that's what you 977 00:40:59,079 --> 00:40:56,630 can see actually in this middle panel 978 00:41:01,380 --> 00:40:59,089 here where we have a nays I'm we have an 979 00:41:03,730 --> 00:41:01,390 enrichment of the a monomer and then 980 00:41:06,039 --> 00:41:03,740 depletion of the B monomer in this case 981 00:41:07,690 --> 00:41:06,049 though we had all of our polymers we're 982 00:41:09,490 --> 00:41:07,700 assumed to have equal amounts of a and B 983 00:41:10,480 --> 00:41:09,500 different sequences but same composition 984 00:41:12,069 --> 00:41:10,490 so we just didn't introduce that 985 00:41:13,450 --> 00:41:12,079 additional complexity into the 986 00:41:15,430 --> 00:41:13,460 simulation but you're absolutely right 987 00:41:17,799 --> 00:41:15,440 that if we have more a than that would 988 00:41:19,599 --> 00:41:17,809 it be easier for polymers rich in a to 989 00:41:21,069 --> 00:41:19,609 replicate and that would be an 990 00:41:25,290 --> 00:41:21,079 additional effect to include that we did 991 00:41:30,390 --> 00:41:28,920 I can use this one okay so towards the 992 00:41:33,150 --> 00:41:30,400 end you had this very brief comment that 993 00:41:35,670 --> 00:41:33,160 perhaps the biological polymers evolved 994 00:41:37,710 --> 00:41:35,680 because they are good at evolution which 995 00:41:38,700 --> 00:41:37,720 I think sounds very interesting so I was 996 00:41:42,690 --> 00:41:38,710 wondering if you could say a little tiny 997 00:41:48,180 --> 00:41:42,700 bit more about that I think I don't know 998 00:41:49,520 --> 00:41:48,190 I mean I do I like that idea as well and 999 00:41:53,280 --> 00:41:49,530 that's something that Nick and I have 1000 00:41:58,380 --> 00:41:53,290 discussing and that he perhaps really 1001 00:41:59,760 --> 00:41:58,390 articulated but but but I think we think 1002 00:42:05,190 --> 00:41:59,770 was kind of present in this earlier 1003 00:42:07,170 --> 00:42:05,200 modeling study that yeah I guess I guess 1004 00:42:10,620 --> 00:42:07,180 I would like to hear people who disagree 1005 00:42:12,180 --> 00:42:10,630 and for what reasons I think it it makes 1006 00:42:14,610 --> 00:42:12,190 a lot of sense but that we just don't 1007 00:42:16,140 --> 00:42:14,620 want we don't want a system that is too 1008 00:42:18,750 --> 00:42:16,150 stable that's something that we saw very 1009 00:42:20,760 --> 00:42:18,760 clearly in that simulation study was 1010 00:42:24,120 --> 00:42:20,770 that if you have a limited monomer 1011 00:42:25,680 --> 00:42:24,130 resource and you want to explore so many 1012 00:42:27,680 --> 00:42:25,690 sequences you have this combinatorial 1013 00:42:30,900 --> 00:42:27,690 explosion of sequences you just can't 1014 00:42:32,880 --> 00:42:30,910 lock up all of your resources in 1015 00:42:34,860 --> 00:42:32,890 sequences that are probably not 1016 00:42:36,390 --> 00:42:34,870 functional and so this turnover is so 1017 00:42:39,090 --> 00:42:36,400 important so that's what that recycling 1018 00:42:40,860 --> 00:42:39,100 recycling idea is is about is that you 1019 00:42:43,350 --> 00:42:40,870 you need to have that recycling and so 1020 00:42:45,480 --> 00:42:43,360 you know these probably esters that orgo 1021 00:42:49,110 --> 00:42:45,490 had talked about them as being a 1022 00:42:51,030 --> 00:42:49,120 potential proto peptide but they were 1023 00:42:53,220 --> 00:42:51,040 maybe just dismissed because they're 1024 00:42:56,130 --> 00:42:53,230 just not stable enough and that that but 1025 00:43:00,000 --> 00:42:56,140 actually you just can't be too stable 1026 00:43:04,370 --> 00:43:00,010 or you're just not going to get em okay 1027 00:43:08,390 --> 00:43:04,380 well thank you very much for for that 1028 00:43:20,740 --> 00:43:08,400 [Applause]