The Problem With Copying

Jenny Poulton

The system successfully demonstrated in the recent PNAS paper “Litters of self-replicating origami cross tiles” is impressive, but it doesn’t address two key challenges with building fully-functional autonomous Darwinian replicators.

Copying is a process ubiquitous in nature, and indeed the accurate transmission of information from the molecular sequence of one  polymer to another is the core process at the heart of the central dogma of molecular biology. Our best understanding of origin-of-life scenarios is that of simple chain molecules  that are able to produce new copies of themselves that carry the same sequence of constituent units: minimal self-replicators. If these molecules  increase in population exponentially, it allows for Darwinian competition and evolution. Synthesising a successful copying process is a non-trivial task problem which many groups, including that of Braun, Schulman and Otto, have come up with interesting solutions to.

The core issue with creating a copying process can be illustrated as follows. In order for an object to be reasonably defined as a copy of a template, it needs to 1) have a sequence that matches, or correlates with, thetemplate and 2) exist separately from the template. In nature, correlations between copy and template are encouraged by bond specificity, with “matching” bonds being much stronger than unmatched bonds. If we consider a simple system, as in figure 1, this allows the settling on the template at stages 1 and 2. However, these same bonds which encourage accuracy in stages 1 and 2, discourage separation in stage 4. It is very difficult to create a system which successfully manages both of these processes.

Professor Seeman’s new paper follows on from the group’s previous work: “Exponential growth and selection in self-replicating materials from DNA origami rafts”. In the earlier paper, the group design rafts of DNA origami, which are highly programmable, meaning that sticky ends can be designed to encourage matching at stages 1 and 2. DNA origami can also be designed to have bonds which are activated via UV light, and in this system, these are used to create the backbone bonds of the dimers; so that at stage 3, the backbone bonds are created irreversibly. Once this process has been designed, stages 1 and 2 can be achieved through cooling, and stage 4 by heating. The heating at stage 4 does not run the risk of blowing apart the dimers, because of the strong UV activated backbone bonds. This somewhat bypasses the major challenge of replication. This system manages a growth factor of 1.7, with each dimer becoming on average 1.7 dimers at the end of a cycle.

The new paper improves on this system by allowing multiple layers of dimers to be formed in one cycle by increasing the number of sticky ends per monomer to two, figure 2 illustrates this difference. With this setup, the system achieves a growth factor of 4-8.

This achievement is very impressive, but let’s consider which interesting questions about copying that this system answers. This system is profoundly non autonomous, with successive cycles of heating, UV activation and cooling rendering human intervention inevitable. One of the most interesting scenarios of self-replication is the origin of life. By bypassing the issue of creating a system which needs to both have accuracy enhancing copy template interactions, and separation of copy and template, this system ignores the question of  the conditions under which spontaneous self-replication could develop without intervention. Speculation on plausible scenarios can be instructive;  heating/cooling or wetting/drying cycles seem plausible, but Seeman’s cycle seems too complex and contrived to occur naturally.  As an example of someone who uses a plausible cycle, the work of Dieter Braun considers a temperature gradient across a capillary, encouraging thermal cycling. Because there is no external creation of an unbreakable backbone bond, the bond strengths and relative temperatures in the gradient need to be extremely finely tuned. The accumulation of polymers in this system is a genuine breakthrough in our understanding of a plausible origin of life scenario, as it gives us important information on the nature of the chemical building blocks of self replicator. We then come to the next, arguably more complex question: how can we create a system driven purely by chemistry, without any changes in the environment needed at all? Our cells do this by means of enzymes, but are there other ways, and how could they have evolved from the semi-autonomous setting with the cyclic background conditions?

Returning to the Seeman’s paper, to what extent can the system developed be truly considered copying? The mechanism is that there are AA and BB dimers which catalyse the formation of each other. An AA dimer can only create a BB dimer and vice versa. It is difficult to see how the system is generalizable to one in which one arbitrary information is propagated.  In this system, while it is possible for this system to fail to create a dimer during a cycle, the propagation of information is reduced whether an object is created or not. In this system there can be no error propagation because in the event that the object is not created, it cannot then duplicate. The fact that the system is creating dimers only means that you can exactly design the origami rafts so that they are both “end pieces”, with no probability that the system could produce polymers of alternative lengths. If the system was successfully producing trimers, like the work of Otto, then there would be a pool of “centre pieces”. Successfully designing a system which accurately incorporated the correct number of “centre pieces” relative to the template would be a much more sophisticated and generalisable information transfer, with the information being transferred being the length of the polymer.

So what questions does this system answer? The major claim of this paper is that the incorporation of the ability to increase the number of offsprings per cycle would make systems of this nature more evolutionarily competitive. While this is true, another vital component of a system’s competitiveness is its ability to self-replicate autonomously in a naturally occurring environment. It should be noted that the more offsprings per cycle, the more difficult the tradeoff between accuracy and separation would become. While the UV activated bond is clever, it allows the authors to sidestep this issue, and therefore ignore many subtleties about the issues with copying.