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Creating the creators: nanomachine mimics protein synthesis

The idea of artificially created life has always had the power to inspire both hopes and fears, and synthetic biology is the modern-day incarnation of this age-old endeavour. At the centre of a convergence of chemistry, biology and engineering, this emerging field aims to design and build artificial components to work with biological systems.  Promising areas currently include biosensing chips and nanoparticles for drug delivery.

Some aim to push the boundaries further. In January 2013, a team of synthetic biologists led by David Leigh at the University of Manchester published a paper in the journal Science[1] describing the small-molecule machine they had created which attempted to mimic the function of a cell’s ribosomes. This was a remarkable claim — though it did not receive the usual media hype and attention that usually greets advances in ‘synthetic life’, perhaps because not enough journalists or editors understood what it meant. But it was significant nonetheless.

Ribosome

Diagrammatic representation of a ribosome

The ribosome is the behemoth of the cellular world, comprised of a huge complex of protein and nucleotide subunits. It has a central function: to read the cell’s genetic instructions and construct the proteins that our DNA codes for. These proteins include structural components, enzymes, signalling molecules, and hormones.

To see ribosomes in action, if we could, would be an astonishing sight: the mRNA being read in; each amino acid recruited in the correct order then positioned and connected with atomic precision; the peptide chain starting to form, folding into its complex three-dimensional protein structure even as it emerges from the factory. Replicating this artificially was never going to be straightforward.

A tiny nanoscale machine, the synthetic ‘ribosome’ consists of a ring-shaped molecule called a rotaxane, which moves along an axle on which amino acids have been loaded. This molecule has a side chain called a ‘reactive arm’ which picks up each amino acid in turn and adds it to the end of a sequence attached to the rotaxane itself, hence building up the peptide chain. Rotaxane nanomachines have been developed before[2], but never one that can be programmed to perform sequential actions like this.

The results presented in Science show that the machine was used to successfully synthesise milligram quantities of the peptide— which may not sound much, but in fact it is a respectable amount, the sort of quantity that might be useful for biochemical analysis. This feat was achieved with an incredible 1018 rotaxane nanobots working in parallel.

This number gives us a clue as to how efficient —or not — the nanomachine is at this job compared to the real ribosome. It takes hours rather than milliseconds to add each amino acid, hence the need to make use of massive economies of scale to produce any meaningful amount of peptide. It’s surprising then that Professor Leigh suggests this approach might someday be a new and efficient way to replace the current methods of making peptides for use in medicine or industry, which he describes as ‘laborious’.

Currently we have two ways of making peptides. One involves chemical reactions in the organic synthesis lab, building up the molecule from its basic chemistry —only practical for the smallest and simplest peptides. The other makes use of biological organisms such as yeast and bacteria to grow the peptides or proteins for us. The ribosome-like machine falls somewhere in between the two approaches, and aims to do better than either. That is an ambitious target.

It also raises a question, both on practical and philosophical grounds: is attempting to mimic Nature the best approach? Natural biology at times seems overly complex and inefficient; biological systems tend to come with a lot of baggage accumulated along the way in their evolutionary history. But sorting out what exactly is baggage, and what is essential but we just don’t know it yet, that is not straightforward —as geneticists are finding with so-called ‘junk’ DNA, much of which is turning out to have an important role after all.

The ribosome is no different: its size and complexity is likely that way for a reason. It is not the static bulk it might once have seemed, but dynamic. Recent research uncovered a network of interactions between the subunits, a flow of energy and communication, but there is still much that is not understood.

Sometimes it is better to take a different route. For example, computational approaches to creating artificial intelligence generally work better than attempts to simulate an actual brain. In trying to copy Nature, we risk always being left trying to play catch-up, when we are evolutionarily millennia behind.

Is this what will happen with the ribosome and its synthetic counterpart? That remains to be seen. But if this can work — this creation of the creator at the heart of our biology, only ‘not limited by the building blocks of nature’ (as Professor Leigh hopes) —  it will be a true breakthrough. And, like many great advances in biological engineering, as simultaneously unnerving as it is inspiring.

 

References

  1. Lewandowski B, De Bo G, Ward JW, et al. (2013), Sequence-Specific Peptide Synthesis by an Artificial Small-Molecule Machine. Science 339 (6116), 189-193. http://www.sciencemag.org/content/339/6116/189.abstract
  2.  Yang, W, Li, Y, Liu, H, et al. (2012), Design and Assembly of Rotaxane-Based Molecular Switches and Machines. Small, 8: 504–516. http://onlinelibrary.wiley.com/doi/10.1002/smll.201101738/abstract

This post was written by:

Sarah Byrne Sarah Byrne

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