Thursday, 6 October 2016

Replication, Replication, Replication II

Here I discuss two recent experimental papers that are related to the challenge of replication or copying, following on from the discussion in "Replication, Replication, Replication I". My take on these papers is heavily couched in terms of that discussion.

Semenov et al.: Autocatalytic, bistable oscillatory networks of biologically relevant reactions
Nature 537, 656–660 (2016)
A catalyst accelerates chemical involving a substrate. For example, amylase accelerates the interconversion of starch and sugars, helping us to digest food. As we learnt at school, a key feature of catalysts is that they are not consumed by the reaction - a single amylase can digest many starch molecules. This fact should remind us of the replication/copy process discussed above, in which it is important that a new copy separates from its template so that the template is not be consumed by the copy process, and can go on to produce many more copies. Indeed, templates for copying/replication must be catalysts. In the specific case of replication, the process is autocatalytic, meaning that a molecule is a catalyst for the production of identical molecules. Simple autocatalytic systems are thus often seen as a bridging point to the full complexity of life.

Semenov et. al. show that a particularly simple set of molecules can exhibit autocatalytic behaviour. Although autocatalysis has been previously demonstrated, the novelty of their approach is the use of such simple organic molecules (which could plausibly have been present on Earth prior to living organisms). Additionally, they are able to show relatively sophisticated behaviour from their system - not just exponential growth of the output molecule (the natural behaviour of autocatalytic systems). When molecules that cause inhibition of autocatalysis and degradation of components are added, for example, the output concentration can be made to oscillate.

Although fascinating, the work of Semenov et al. does not solve the question raised in the blog post above. There are no long polymers in this system, and so the difficulty of separating strongly-interacting copies and templates does not arise. But as a consequence, this autocatalytic mechanism passes on very little information (arguably, none) to the new molecules produced. Autocatalysis alone is not enough  - we are still a long way from processes such as DNA replication, transcription and translation.

Meng et al.: An autonomous molecular assembler for programmable chemical synthesis 
Nature Chemistry 8, 542–548 (2016)
This paper, co-authored by my collaborators in the Turberfield group, takes a completely different approach. The idea is to specify the sequence of a molecular polymer using a DNA-based programme. As I have talked about before, the exquisite selectivity of base-pairing in DNA allows reactions to be programmed into carefully designed single strands, allowing them to self-assemble into a complex patterns when mixed. In this case, the authors mix sets of short DNA strands that are designed to assemble into a long double-stranded structure in a specific order. The selectivity of interactions allows the strands to be programmed to bind one-by one to the end of the structure in the desired sequence.

This process (the hybridisation chain reaction) is not new. The advance is using it to template the sequence of a second (chemically quite different) polymer that can't assemble with a specific sequence on its own - for simplicity, lets call this polymer X (its details aren't important). The authors ingenuously attach building blocks of X to the DNA strands - with each distinct DNA sequence paired with a distinct building block. When a new strand is incorporated via the hybridisation chain reaction, it brings with it the associated building block and adds it to X, which grows simultaneously with the double-stranded DNA construct. The details of this process are a bit fiddly, and due to a technicality a new building block is only added for every second strand incorporated, but the process as a whole allows them to assemble a specific polymer X using DNA-based instructions set by the sequences of the original strands. The authors call this programmed chemical synthesis.

The authors are inspired by the ribosome (see fig, stolen from here), the biological machine that translates an RNA sequence (the red polymer) into a polypeptide sequence (green), which eventually folds into a protein. The ribosome uses RNA base pairing to bring a set of peptide building blocks together in the right order, like the device of Meng et al. uses DNA base-pairing to form polymer X. However, there is a key difference. The information-carrying RNA strand in the figure is not consumed by the process; it acts as a catalyst, as discussed, and the ribosome walks along it until the end and then releases it. The information-carrying components of the system of Meng et al. (the strands that carry the molecular programme) are consumed, being incorporated into a long double-stranded DNA molecule that the authors actually use to analyse the success of the process. Thus although the system allows programmable self-assembly, it doesn't implement catalysis and hence can't perform copying/replication.

Both papers are great pieces of work, but one demonstrates autocatalysis without information transfer, and the other demonstrates the ability to programme polymer assembly without autocatalysis. The challenge to produce chemical systems that copy or replicate is still on.

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