What would a truly synthetic biology look like?

This is the pre-edited version of an article first published in Physics World in July 2010. The published version can be found here (subscription required). Some of the ideas here were developed in a little more technical detail in an article published in the journal Faraday Discussions, Challenges in Soft Nanotechnology (subscription required). This can be found in a preprint version here. See also my earlier piece Will nanotechnology lead to a truly synthetic biology?.

On the corner of Richard Feynman’s blackboard, at his death, was the sentence “What I cannot create, I do not understand”. This slogan has been taken as the inspiration for the emerging field of synthetic biology. Biologists are now unravelling the intricate and complex mechanisms that underlie life, even in its simplest forms. But, can we be said truly to understand biology, until it proves possible to create a synthetic life-form?

Craig Venter’s well-publicised program to replace the DNA in a simple microorganism with a new, synthetic genome has been widely reported as the moment when humans have created a new, synthetic living organism. This achievement was certainly a technical tour-de-force, but many would argue that just replacing the genome of an existing organism isn’t the same as creating a complete organism from the bottom up. Making a truly synthetic biology, in which all the components and mechanisms are designed and made without the use of existing biological materials or parts, is a much more distant and challenging prospect. But it is this, hugely more ambitious, act of creation that would fulfil Feynman’s criterion for truly understanding even the simplest forms of life.

What we have learnt from biology is how similar all life is – when we study biology, we are studying the many diverse branches from a single trunk, huge and baroque variety on one hand, but all variants on a single basic theme based on DNA, RNA and proteins. We’d like to find some general rules, not just about the one particular biology we know about, but about all possible biologies. It is this more general understanding that will help us in one of science’s deepest questions – was the origin of life on earth a random and improbably event, or should we expect to find life all over the universe, perhaps on many of the the exo-planets we’re now discovering? Exo-biology has a practical difficulty, though – even if we can detect the signatures of alien life-forms, distance will make it difficult to study them in detail. So what better way of understanding alien life than trying to build it ourselves?

But we can’t start building life without having an understanding of what life is. The history of attempts to provide a succinct, water-tight definition of life is very long and rather inconclusive. There are some recurring themes, though. Many definitions focus on life’s ability to self-replicate and evolve and the ability of living organisms to maintain themselves by transforming external matter and free energy into their own components. The principle of living things as being autonomous agents – able to sense their environment and choose between actions on the basis of this information – is appealing. But while people may agree on the ingredients of a definition, putting these together to make one which is neither too exclusive nor too inclusive is difficult. (I very much like the discussion of this issue in Pier Luigi Luisi’s excellent book The emergence of life).

An experimental approach to the problem might change the question – instead of asking “what life is” we could ask “what life does”. Rather than asking for a waterproof definition of life itself, we can make progress by asking what sort of things living things do, and then consider how we might execute these functions experimentally. Here we’re thinking explicitly of biology as a series of engineering problems. Given the scale of the basic unit of biology – the cell – what we’re considering is essentially a form of nanotechnology.

But not all nanotechnologies are the same; we’re asking how to make functional machines and devices in an environment dominated by the presence of water, the effects of Brownian motion, and some subtle but important interactions between surfaces. This nanoscale physics – very different to the rules that govern macroscopic engineering – gives rise to some new design principles, much exploited in biological systems. These principles include the idea of self-assembly – molecules that put themselves together under the influence of Brownian motion and surface forces, constructing complex structures whose design is entirely encoded within the molecules themselves. This is one example of the mutability that is so characteristic of soft and biological matter – a shifting balance between weak interactions in the face of subtle changes in external conditions causes changes in the organisation and shape of molecules and assemblies of molecules in response to changes in the environment.

It’s quite difficult to imagine a living organism that doesn’t have some kind of closed compartment to separate the organism from its environment. Cells have membranes and walls of greater or lesser complexity, but at their simplest these are bags made from a double layer of phospholipid molecules, arranged so their hydrophobic tails are sandwiched between two layers of hydrophilic head groups. The synthetic analogue of these membranes are called liposomes; they are easily made and commonly used in cosmetics and drug delivery systems. Polymer chemists make analogues of phospholipids – amphiphilic block copolymers – which make bags called polymersomes which, in some respects, offer much more flexibility of design, often being more robust and allowing precise control of wall thickness. From such synthetic artificial bags, it is a short step to encapsulating systems of chemicals and biochemicals to mimic some kind of metabolism, and in some cases even some level of self-replication. What is more difficult is to be able to control the traffic in and out of the compartment; this ideally would require pores which only allowed certain types of molecules in and out, or that could be opened and closed on certain triggers.

It is this sensitivity to the environment that proves more complex to mimic synthetically. It’s still not generally appreciated how much information processing power is possessed even by the most apparently simple single celled organisms. This is because biological computing is carried out, not by electrons within transistors, but by molecules acting on other molecules. (Dennis Bray’s book Wetware is well worth reading on this subject). The key elements of this chemical logic are enzymes that perform logical operations, reacting the presence or absence of input molecules by synthesising, or not synthesising, output molecules.

Efforts to make synthetic analogues of this molecular logic are only at the earliest stages. What is needed is a molecule that changes shape in the presence of an input molecule, and for this shape change to turn on or off some catalytic activity. In biology, it is proteins that carry out this function; the only synthetic analogues made so far are built from DNA (see my earlier essay Molecular Computing for more details and references).

Given molecular logic elements whose outputs are other molecules, one can start to build networks linking many logic gates. In biology these networks integrate information about the cell’s environment and make decisions about different courses of action the cell can take – to swim towards food, or away from danger, for example.

In order for a bacteria sized object to be able to move – to swim through a fluid or crawl along a surface – it needs to solve some very interesting physics problems. For such a small object, it’s the viscosity of the fluid that dominates resistance to motion, in contrast to the situation at human scales, where it’s the inertia of the fluid that needs to be overcome. In these situations of very low Reynolds number new swimming strategies need to be found. Bacteria often use the beating motion of tiny threads – flagellae or ciliae – to push themselves forward. At Sheffield we’ve been exploring another way of making microscopic swimmers – catalysing a chemical reaction on one half of the particle, producing an asymmetric cloud of reaction products that pushes the particle forward by osmotic pressure (more details here. But even though we can make artificial swimmers, we still don’t know how to control and steer them.

By now it should be obvious that the task of creating a truly synthetic biology remains a very distant goal. The more that biologists discover –particularly now they can use the tools of single molecule biophysics to unravel the mechanisms of the sophisticated molecular machines within even the simplest types of organism – the cruder our efforts to mimic some of the features of cell biology seem. We do have a reasonable understanding of some important principles of nano-scale design – how to design macromolecules to make to self-assembled structures resembling cell membranes, for example. But other areas are still wide open, from the fundamental theoretical issues around how to understand small systems driven far from equilibrium, through the intricacies of mechanisms to achieve accurate self-replication, to the challenge of designing chemical computers. On a practical level, to cope with this level of complexity we’re probably going to have to do what Nature does, and use evolutionary design methods. But if the goal is distant, we’ll learn a great deal from trying. Even to speculate about what a truly synthetic life-form might look like is itself helpful in sharpening our notions of what we might consider to be alive. It is this kind of experimental approach that will help us to find out the physical principles that underlie biology – not just the biology we know about, but all possible biologies.