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hello it's great to speak at grad count

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this year

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ultimately all of us at this meeting

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have the same goal

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to figure out how inanimate matter

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organized itself

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to form cellular life today i'll try to

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show you how rna could have played a

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pivotal role

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in bridging the worlds of chemistry and

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biology

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we may never accurately retrace the

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steps back to the origin of life

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but looking at life as we know it the

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worlds of chemistry and biology

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must have been bridged by a primitive

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cellular system

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generated by the self-assembly of

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inanimate matter

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that exhibited the emerging properties

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of life

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um such a primitive cell or a protocell

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would minimally be a sack of genes and

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enzymes

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and this is further simplified by the

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fact that both

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genetic and enzymatic functions can be

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embodied

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by rna so considering the potentially

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central role of rna

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in the origin and evolution of early

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life

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i'm trying to develop experimental

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models to demonstrate

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some of the major chemical transitions

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that are only had to go through

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before the emergence of rna-based uh

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cellular

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life of course it all started with a

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chaotic collection of chemicals and then

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we somehow

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ended up with this vast diversity of

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life

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so the question here is what happened in

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between

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uh prebiotic chemistry produced the

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building blocks of rna

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and these building blocks had to be

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chemically activated

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so that they could assemble into longer

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rna molecules

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non-enzymatically we recently discovered

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that two amino imidazole or

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2ai as we call it is a great activating

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group for

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non-enzymatic rna assembly and it is

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probiotically relevant as well

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which makes it quite attractive for us

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so

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when activated these building blocks

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would self-assemble into

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longer rnas which would then when

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sufficiently

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long fold up into complex structures in

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three dimensions and perhaps even show

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catalytic function and this rna assembly

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process would be

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turbocharged when some of these longer

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rna molecules would start

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to behave as rna enzymes or ribozymes

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that would use the building blocks of

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non-enzymatic assembly as substrates

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for enzymatic rna assembly so these

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ribozymes would be evolutionary links

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between

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non-enzymatic and enzymatic rna assembly

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processes

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now it is important to note here that

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for all of this to happen

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these ribozymes needed to be compatible

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with the prebiotic chemistry

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that generated activated rna building

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blocks

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and finally at some point in this

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journey

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rna catalysis would have to be

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compartmentalized where

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ribozymes would take care of early

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metabolism and

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trigger growth and division and perhaps

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even invent

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darwinian evolution in these uh

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protocellular systems

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so for today's talk i will use rna

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ligation

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as a model uh for prebiotic rna assembly

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to describe some of these transitions

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so let's look at the first major

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transition which is

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the emergence of rna enzymes that

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utilize

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the building blocks of non-enzymatic rna

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assembly

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to make longer rnas so we use the

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technique called

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in vitro selection to identify rna

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enzymes that join

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two pieces of rna in this case with the

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second

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piece activated with the two amino

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imidazole group

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in brief we started with a combinatorial

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rna library that contained a billion

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billion

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rna molecules and the first rna piece to

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be joined was

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actually equivalently linked to each of

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the sequences in in the library

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and then we challenged this library with

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a biotin tagged

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two immunomedical activated substrate

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uh sequences that were able to catalyze

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this ligation reaction between these two

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pieces

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would get joined to the biotinylated

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substrate and therefore be tagged

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with the biotin themselves we use

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magnetic beads coated with streptavidin

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to capture these

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sequences because streptavidin binds

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to biotin very strongly so these

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captured rna sequences on the beads

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were reversed transcribed to dna and

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amplified by

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pcr so by repeating this cycle we were

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able to identify

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several distinct classes of ligase

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ribosomes

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this slide summarizes some of the

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properties of these rna enzymes

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so the image on the top left shows you a

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denaturing

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gel which was used to separate the

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the products of this ligation reaction

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that have

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a slower gel mobility which once again

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uh establishes that these ribozymes are

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indeed ligase ribozymes

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ribozymes that join pieces of rna

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together

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and then the image on the top uh center

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shows you how

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uh catalytic activity was enriched

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across these different rounds of

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selection uh

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from us our selection protocol and then

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we observed

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uh about a thousand fold rate

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accelerations

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uh by these selected uh ribozymes which

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is of course

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great we also confirmed that uh this

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catalytic ligation reaction required

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a template which could be either rna or

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dna

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and a two amino imidazole activation on

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the substrate this was important uh

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since the

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two millimeters was activation on the

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substrate was an essential feature of

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this reaction

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the next obvious question is how did

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these

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activated on early earth now an

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interesting chemistry is suggested by

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john sutherland's

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group in the uk has used isocyanide

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aldehyde

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and two amino amino dissolve to activate

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nucleoside

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monophosphates so we thought that we

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could use this chemistry to activate

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oligomeric rna and more importantly

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we wanted to test if uh these ligase

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ribozymes could still

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function under uh the conditions of

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probiotic rna activation

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now before we went into our main

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experiments we wanted

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uh activation and

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ribozymatic ligation to happen

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in one part right so since unactivated

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substrates in the reaction would

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bind to the template and therefore

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inhibit ligation we wanted to first

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maximize

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uh the activation yields so we optimized

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each of the three components in this

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activation reaction

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and collectively we got about 50 percent

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activated substrate which we thought

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would be sufficient

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uh to drive this reaction uh so this is

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the experiment

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we added unactivated substrate to the

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ribozyme

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and template under activation conditions

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and then

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we observed catalytic ligation which

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means that these

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unactivated rnas got activated

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in situ in the same part and then these

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could now act as substrates

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for ribozymatic ligation so this

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preliminary result

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shows that probiotic chemistry and rna

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catalyzed rna assembly

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can work together which is how it would

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have happened on earlier

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so with rna enzymes available that can

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stitch together pieces of rna

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activated with this prebiotically

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relevant two-amino imidazole group

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we are now ready to take the next step

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which is

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to model the emergence of

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compartmentalized

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rna catalyzed rna assembly

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so first how to make a probiotic

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compartment uh

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some of us know that simple short-chain

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fatty acids which are of course the main

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component of phospholipids are

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attractive candidates for primitive cell

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membranes as

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they can be made biotically and

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interestingly fatty acids

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have also been found in carbonaceous

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chondrites which is

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quite exciting but most importantly

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these

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molecules can self-assemble into

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spherical vesicles

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that can encapsulate rna among other

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molecules

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okay so ribozymes making long rnas

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within fatty acid vesicles appear to be

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an exciting model

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for primitive cells right but the

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seemingly simple

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model has not been realized yet

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because of a nagging problem in the

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field which is that most

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ribozymes need medium to high

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concentrations of magnesium to function

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but fatty acid vesicles start to leak at

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those concentrations so

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the bottom line is you either have

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stable compartments or you have active

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ribozymes

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but it's kind of hard to get both

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together

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so one of the ways by which we solve

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this problem

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is by identifying a ligase or ribozyme

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that worked at sub millimolar magnesium

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right so under these conditions fatty

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acid vesicles would be stable

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ribozymes would also function which

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means that this provides an exciting

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opportunity to constitute the first

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instance of rna catalyzed rna ligation

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within prebiotic fatty acid compartments

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uh but before i show you the results for

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this experiment i

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i would like to play devil's advocate

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here so it's obvious that these these

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unique ribosomes that work at some

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millimolar magnesium would be quite rare

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in the in the rna sequence space so

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perhaps we must look for a more

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general systems based approach

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to solve this magnesium problem so

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according to the chase

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uh i discovered that small molecules

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like ethylene glycol or

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d ribose that would have been present on

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early earth

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and may have even played important roles

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in in probiotic synthesis of rna

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building blocks

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could dramatically stimulate uh

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ligase ribozyme function at one

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millimolar magnesium

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so primitive cells of course would

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contain these molecules within them

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right in addition to rna so we could

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then generate

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these crowded protocells with

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00:10:33,430 --> 00:10:30,079
encapsulated rna

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00:10:36,470 --> 00:10:33,440
and d ribose in this case now

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00:10:39,269 --> 00:10:36,480
what we saw was this again helped uh

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00:10:40,230 --> 00:10:39,279
to constitute rna catalyzed rna ligation

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00:10:42,790 --> 00:10:40,240
within these

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00:10:44,310 --> 00:10:42,800
fatty acid vesicles and in addition to

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00:10:47,030 --> 00:10:44,320
helping catalysis

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00:10:49,750 --> 00:10:47,040
we found that ribose stabilized these

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00:10:52,710 --> 00:10:49,760
fatty acid compartments and minimized

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rna leakage even in the presence of

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magnesium as you can see

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even after three hours in the presence

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00:11:01,269 --> 00:10:57,600
of three millimolar magnesium

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there's almost no leakage from these

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fatty acid vesicles if you have d ribose

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00:11:08,710 --> 00:11:05,519
within them

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okay so with that here are these

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00:11:13,670 --> 00:11:11,600
vesicles with fluorescent labeled rna

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00:11:15,829 --> 00:11:13,680
in them healthy and handsome in the

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presence of three millimolar magnesium

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even after three hours uh so we put our

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00:11:23,430 --> 00:11:20,399
ligase ribozyme

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template and the activated substrate

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00:11:27,750 --> 00:11:25,600
within these vesicles and then we added

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magnesium to the outside to initiate

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this

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00:11:32,550 --> 00:11:30,399
reaction and then we broke open these

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vesicles at various time points

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uh to analyze the contents and to our

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00:11:37,910 --> 00:11:36,160
delight

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we observed ligation within these

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00:11:40,710 --> 00:11:39,600
compartments with eels that were

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00:11:44,230 --> 00:11:40,720
comparable

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00:11:47,230 --> 00:11:44,240
to ligation in solution so this is a

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00:11:48,389 --> 00:11:47,240
first step toward our goal of developing

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00:11:50,710 --> 00:11:48,399
self-replicating

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00:11:52,470 --> 00:11:50,720
protocells where ribozymes would make

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00:11:55,590 --> 00:11:52,480
copies of themselves

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within prebiotic compartments this of

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00:11:58,069 --> 00:11:57,519
course has profound implications in the

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00:12:00,230 --> 00:11:58,079
field

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00:12:02,310 --> 00:12:00,240
so say you have two protocells that have

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00:12:05,269 --> 00:12:02,320
slightly different ribozymes

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00:12:06,870 --> 00:12:05,279
you know one with the better ribozyme

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will make more rna

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00:12:10,470 --> 00:12:09,120
and then of course grow fat and make

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00:12:12,470 --> 00:12:10,480
more babies faster

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00:12:15,030 --> 00:12:12,480
and ultimately these are the cells that

348
00:12:16,470 --> 00:12:15,040
would take over the entire population

349
00:12:18,069 --> 00:12:16,480
right so this would represent the

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00:12:20,389 --> 00:12:18,079
spontaneous emergence

351
00:12:22,069 --> 00:12:20,399
of a rather primitive version of

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00:12:24,550 --> 00:12:22,079
darwinian evolution

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00:12:25,269 --> 00:12:24,560
in systems put together from non-living

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00:12:27,110 --> 00:12:25,279
matter

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00:12:29,269 --> 00:12:27,120
uh of course we are far from achieving

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00:12:32,150 --> 00:12:29,279
this but meetings such as this

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00:12:33,190 --> 00:12:32,160
make me hopeful uh okay so that's all i

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00:12:35,269 --> 00:12:33,200
have for today

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00:12:37,829 --> 00:12:35,279
uh i'd like to quickly thank the shostak

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00:12:39,750 --> 00:12:37,839
lab um jack of course and especially

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00:12:41,990 --> 00:12:39,760
grad student stephanie jung who i

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00:12:43,350 --> 00:12:42,000
collaborated with for some of the work

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00:12:45,670 --> 00:12:43,360
that i discussed here

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00:12:46,949 --> 00:12:45,680
and thanks a lot for listening i'd be