The Emergence of Complexity
Using Chemical Self-replicators

Literature Seminar #2
M1 Yuki Yamanashi
20/05/28(Thu)Overview: networks of organic chemical reactions in biological systems

2

https://www.genome.jp/kegg/pathway/map/map01100.html- Complex behaviors in biological systems are created by chemical reaction networks.
- Chemists have tried to develop artificial chemical network systems which produce
complex behaviors, in order to understand life.
- Chemical self-replicators are key components of such a system.
Kosikova, T.; Philp, D. Chem. Soc. Rev. 2017, 46 (23), 7274–7305.

Contents

1. Introduction- Networks of organic chemical reactions in biological systems- The origin of life
- two approaches- top-down approaches- bottom-up approaches- open-ended evolution and synthetic replicators- oscillation and synthetic replicators- Applications of synthetic replicators
2. The emergence of complexity using chemical self-replicators- The mechanism of chemical self-replicators- Development of chemical self-replicators- Multicyclic network- Oscillation network- Short summary
3. Future directions and challenges
4. Summary

3

Contents1. Introduction- Networks of organic chemical reactions in biological systems- The origin of life
- two approaches- top-down approaches- bottom-up approaches- open-ended evolution and synthetic replicators- oscillation and synthetic replicators- Applications of synthetic replicators
2. The emergence of complexity using chemical self-replicators- The mechanism of chemical self-replicators- Development of chemical self-replicators- Multicyclic network- Oscillation network- Short summary
3. Future directions and challenges
4. Summary

4

The origins of life: two approaches5- There are numerous models and theories trying to explain the origins oflife, generally grouped into two approaches; bottom-up and top-down.
Krishnamurthy, R. Chem. Eur. J. 2018, 24 (63), 16708–16715.

The origins of life: top-down approaches
Central DogmaDNARNA

6RNA World

information
storage

information
storage /informationtransfer

proteinfunctionRNA

RNA- In top-down approaches, the way how present-day biomolecules havearisen on early earth is searched.
- For example, “the RNA World” hypothesis is one of the most plausible
hypothesis in top-down approaches.
- However, it tends to be difficult in top-down approaches to find solutions
in connecting prebiotic chemistry to biological chemistry.
Krishnamurthy, R. Chem. Eur. J. 2018, 24 (63), 16708–16715.
Sutherland, J. D. Angew. Chemie Int. Ed. 2016, 55 (1), 104–121.
Cech, T. R. Cell 2009, 136 (4), 599–602.

The origins of life: bottom-up approaches

7“dilution” and “mixtures”
Self-replication

Mutation

Open-ended
evolution

Self-replication

Selection- In bottom-up approaches, systems that can emerge complexity aredeveloped, and analyzing such systems will provides the requirementsof the emergence of life.
- Development of synthetic replicators is one of them and important insome reasons.
- Self-replication may be a solution of two core problems in the originof life; “dilution” and “mixtures”.
- Synthetic replicators are core elements of more complex systems(e.g. open-ended evolution, oscillation→next page)
Krishnamurthy, R. Chem. Eur. J. 2018, 24 (63), 16708–16715.
Duim, H.; Otto, S. Beilstein J. Org. Chem. 2017, 13, 1189–1203.
Semenov, S. N.; Belding, L. J. Am. Chem. Soc. 2018, 140 (32), 10221–10232.

The origins of life: oscillation and synthetic replicators

8- Self-replicating reaction network is a core element of chemical oscillator
like Belousov-Zhabotinskii-type reaction; one of the most famous oscillator.
Field, R. J.; Koros, E et al. J. Am. Chem. Soc. 1972, 94 (25), 8649–8664.
Field, R. J. J. Chem. Phys. 1975, 63 (6), 2289–2296.

Applications of synthetic replicators

9- Chemical system with complex behaviors (e.g. BZ reaction) can beapplied to the development of functional material.
Yoshida, R.; Ueki, T. NPG Asia Mater. 2014, 6 (6), e107–e107.

Contents

1. Introduction- Networks of organic chemical reactions in biological systems- The origin of life
- two approaches- top-down approaches- bottom-up approaches- open-ended evolution and synthetic replicators- oscillation and synthetic replicators- Applications of synthetic replicators
2. The emergence of complexity using chemical self-replicators- The mechanism of chemical self-replicators- Development of chemical self-replicators- Multicyclic network- Oscillation network- Short summary
3. Future directions and challenges
4. Summary

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The mechanism of chemical self-replicators

11

Bissette, A. J.; Fletcher, S. P. Angew. Chem. Int. Ed. 2013, 52 (49), 12800–12826.

Development of chemical self-replicators

12

component
enzymepeptidemicellevesicletoday’s topics

inorganic
molecule

environmentorganic small
molecule

oligonucleotide

complex behavior

stablefeedback loop

oscillation

dynamic

patternformationsystem-level
response

The emergence of complexity using chemical self-replicators

13

Multicyclic networkorganic small
molecule

stablesystem-level
response
Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

Oscillation networkorganic small
molecule

dynamicoscillation
Cafferty, B. J.; Wong, A. S. Y. et al. J. Am. Chem. Soc. 2019, 141 (20), 8289–8295.

The emergence of complexity using chemical self-replicators

14

Multicyclic networkorganic small
molecule

stablesystem-level
response
Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

Oscillation networkorganic small
molecule

dynamicoscillation
Cafferty, B. J.; Wong, A. S. Y. et al. J. Am. Chem. Soc. 2019, 141 (20), 8289–8295.

Research background (1)15tans-31

cis-31- Chemical reaction networks with self-replication activity had been developed.
Vidonne, A.; Philp, D. European J. Org. Chem. 2009, No. 5, 593–610.

Research background (2)16- However, multicyclic networks which can respond to the environmental change(addition of template) was still difficult, because of the different efficiency of each
replicator.
Kassianidis, E.; Pearson, R. J. et al. Faraday Discuss. 2010, 145, 235–254.

Designed multicyclic network

17

Simplified network- Reagents A to D create a network of interdependent replicators.
Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

Components of network

18- Pairwise 1,3-dipolar cycloaddition reactions afforded two self-replicators and two
reciprocal replicators.
- 19F NMR spectroscopy was used to monitor the concentration of products.
Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

Self-replicating behavior of network

experiment

19[A]~[D] = 10 mM
no T (no template)once

Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

The effect of template molecule to network

experiment

20[A]~[D] = 10 mM
no T, R2, T1, T2
once

Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

The multicyclic network responded to the environmental change.

experiment21[A]~[D] = 10 mM
no T, R2, T1
5 times- The composition of network was maintained through sets of serial transfer.
Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

The multicyclic network responded to the environmental change.

[A] = 1 mM
[B]~[D] = 10 mM
no T, R2, T1
5 times[A]~[B] = 5 mM
[C]~[D] = 10 mM
no T, R2, T1
5 timessimulation[A]~[D] = 10 mM
no T, R2, T1
5 times[A]~[D] = 10 mM
no T, R2, T1
5 times2kcat20KaDuplex(R2, T2)

22([R1·R2], [T1·T1], [T2, T2])

- The persistence was observed when the starting condition and the kinetic orthermodynamic properties of the replicators were changed.
→The persistence observed experimentally is a direct result of the network connectivity.
Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

Short summary

23

Multicyclic network

A network of multicyclic replicators can ensure
the compositional stability and diversity.

Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

The emergence of complexity using chemical self-replicators

24

Multicyclic networkorganic small
molecule

stablesystem-level
response
Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

Oscillation networkorganic small
molecule

dynamicoscillation
Cafferty, B. J.; Wong, A. S. Y. et al. J. Am. Chem. Soc. 2019, 141 (20), 8289–8295.

Research background

25

Semenov, S. N.; Kraft, L. J. Nature 2016, 537 (7622), 656–660.

CSTR (continuously stirred tank reactor)

26

Ellman’s reagent(to measure R-SH)
Semenov, S. N.; Kraft, L. J. Nature 2016, 537 (7622), 656–660.

The mechanism of the oscillation network

i Trigger

27

ii Amplification

iii Exhaustion
Semenov, S. N.; Kraft, L. J. et al. Nature 2016, 537 (7622), 656–660.
Cafferty, B. J.; Wong, A. S. Y. et al. J. Am. Chem. Soc. 2019, 141 (20), 8289–8295.

Entrainment of the non-oscillatory components by the oscillatory one

experiment28

Caﬀerty, B. J.; Wong, A. S. Y. et al. J. Am. Chem .Soc. 2019, 141 (20), 8289–8295.

Increased robustness of heterogenous networks

experiment

29

space velocity [min-1]= flow rate / reactor volume- The network with AlaSEt and GlySEt has increased robustness of the range ofspace velocity and the oscillation period than the network with only AlaSEt.
Cafferty, B. J.; Wong, A. S. Y. et al. J. Am. Chem .Soc. 2019, 141 (20), 8289–8295.

Increased robustness of heterogenous networks (mechanism)

simulation

30

space velocity [min-1]= flow rate / reactor volume- To maintain oscillation in higher space velocity, higher hydrolysis rate is needed.
- The robustness of the range of space velocity was explained by two factors; (i)[thioester] increases more rapidly at larger space velocities, (ii) GlySEt is moresensitive to [thioester] because of kaml[GlySEt]2.
- The robustness of the oscillation period was because more rapid ethanethiol
formation decreases the oscillation period.
→The heterogenous networks can dynamically compensate for their environmental
changes.
Caﬀerty, B. J.; Wong, A. S. Y. et al. J. Am. Chem .Soc. 2019, 141 (20), 8289–8295.

Oscillation in a mixture of non-oscillatory components (hybridization)

experiment31- The network with GlySEt and AbuSEt oscillated, even though neither GlySEt nor
AbuSEt oscillated as a single component.
→Multiple reactions can act in a complementary way to yield complex behaviors.
Cafferty, B. J.; Wong, A. S. Y. et al. J. Am. Chem .Soc. 2019, 141 (20), 8289–8295.

short summary

32

Multicyclic network

A network of multicyclic replicators can ensure
the persistence of chemical constitutions.

Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

Oscillation network

A heterogenous network of replicators canpromote complex behaviors.

Cafferty, B. J.; Wong, A. S. Y. et al. J. Am. Chem. Soc. 2019, 141 (20), 8289–8295.

short summary

33

Multicyclic network

A network of multicyclic replicators can ensure
the persistence of chemical constitutions.

Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

Oscillation network

A heterogenous network of replicators canpromote complex behaviors.

Cafferty, B. J.; Wong, A. S. Y. et al. J. Am. Chem. Soc. 2019, 141 (20), 8289–8295.

By building synthetic replicators using small organic molecules, we can identify
principles of the emergence of complexity, which is relevant to the origin of life.

Contents

1. Introduction- Networks of organic chemical reactions in biological systems- The origin of life
- two approaches- top-down approaches- bottom-up approaches- open-ended evolution and synthetic replicators- oscillation and synthetic replicators- Applications of synthetic replicators
2. The emergence of complexity using chemical self-replicators- The mechanism of chemical self-replicators- Development of chemical self-replicators- Multicyclic network- Oscillation network- Short summary
3. Future directions and challenges
4. Summary

34

Future directions and challenges

35- Bridging the gap between synthetic replicators and living systems- Shifting away from homogenous and stable condition to heterogenous
and non-equilibrium conditions- Integrating replication with metabolism and compartmentalization→development of artificial replicators that can undergo open-ended evolution-Further applications- Development of replicators with a broad range of substrates- Development of functional material
Kosikova, T.; Philp, D. Chem. Soc. Rev. 2017, 46 (23), 7274–7305.
Semenov, S. N.; Belding, L. et al. J. Am. Chem. Soc. 2018, 140 (32), 10221–10232.
Post, E. A. J.; Fletcher, S. P. J. Org. Chem. 2019, 84 (5), 2741–2755.

Summary- Development of chemical self-replicators is important tounderstand the origin of life and develop more complex systems.
- In addition to their scientific significance, chemical self-replicators
may have potential to other applications.
- By building synthetic replicators using small organic molecules,
we have identified some principles of the emergence ofcomplexity, which is relevant to the origin of life.
- To develop open-ended evolution system, using non-equilibrium
conditions and integrating replication with metabolism andcompartmentalization are needed.
- For further applications, development of replicators with a broad
range may be important.

36

Appendix

Belousov-Zhabotinsky reaction: FKN mechanism

38

process A

process C
process B

Field, R. J.; Koros, E et al. J. Am. Chem. Soc. 1972, 94 (25), 8649–8664.
Field, R. J. J. Chem. Phys. 1975, 63 (6), 2289–2296.

Belousov-Zhabotinsky reaction and functional material

39

Yoshida, R.; Ueki, T. NPG Asia Mater. 2014, 6 (6), e107–e107.

Simple representation of systems mentioned in this seminar

Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

Cafferty, B. J.; Wong, A. S. Y. et al. J. Am. Chem. Soc. 2019, 141 (20), 8289–8295.

Semenov, S. N.; Belding, L. et al. J. Am. Chem. Soc. 2018, 140 (32), 10221–10232.

40

NMR measurement

experiment41

Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

The effect of template molecule to network (concentration-time)

experiment42

Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

The multicyclic network responded to the environmental change.

simulation

43

Huck, J.; Kosikova, T.; Philp, D. J. Am. Chem. Soc. 2019, 141 (35), 13905–13913.

Ellman’s reagent

44detected byabsorption at 412 nm

The origin of robustness(1)simulation- (i) [thioester] increases more rapidly at larger space velocities

45

The origin of robustness (2)simulation- (ii) GlySEt is more sensitive to [thioester] because of kaml[GlySEt]2.

46

The origin of robustness (2)simulation- more rapid ethanethiol formation decreases the oscillation period.

47