It's engineering, Jim, but not as we know it

29 April 2008

When synthetic biologists talk about what they are doing, they often point to the analogies between their work and what happens in engineering, particularly electronics engineering. You can point to some processes in living cells and describe them in the same terms as digital logic or oscillators - the kind of functions you find in a lot of electronic circuits.

The analogies don't stop there: the aim of synthetic biology is to develop a kit of parts from which you can build organic systems able to make fuels, drugs and chemical sensors. What are the parts? Professor Richard Kitney of Imperial College, London says: "We mean encoded biological functions: usually we mean modified bacterial DNA."

That modified DNA is injected into bacteria which has the machinery already in place to do the next bit, which is to make the parts work together to create simple circuits and, ultimately, create a system that does something. The annual iGEM competition, where undergraduate teams cook up modified bacteria to do unusual things, shows what can be done even at this stage.

You can have bacteria that smell differently based on whether their cultures are growing or have run out of room. The MIT team that did that put the genes for wintergreen - for a minty smell - and the chemical that gives bananas their characteristic scent in the bacterial chromosome and wired them to built-in sensors. The result was a rudimentary computer that looked at the state of the bacteria and reported what it found as smell.

From this, it sounds as though science is well along the road to being able to design biosystems. The relationship between parts of the bacterial genome seem so well understood that people have started to build tools to assemble the designer sequences: CAD for the genome.

It turns out that the technology to generate genetic sequences is outpacing bioengineers' ability to define them. Patrick Cai of the Virginia Bioinformatics Institute said at the BioSysBio conference last week: “We have more or less followed Moore’s Law for DNA sequencing.”

The technology has reached the point where sequencing company Blue Heron Biotechnology was able to produce a series of DNA chains that were combined to form a genome of 580,000 nucleic acids (bases) for the ‘artificial’ bacterium developed by the J Craig Venter Institute. However, this genome is based on a naturally occurring sequence.

The problem is that the ability to design novel sequences has failed to keep pace. Cai pointed to a competition run by Blue Heron, which would have provided the winner with $250,000 of sequencing in the form of a 40,000 base-long string of DNA. The company, apparently, did not receive a single entry.

The Virginia group has come up with Genocad: a tool that checks artificial gene sequences to see if they obey the 'grammar' of bacterial genetics. Jean Peccoud, associate professor at the institute wants to go further and build a computer language for defining DNA: "We would like to have something like the C programming language or Visual Basic," he says. You would define switches, oscillators, and AND and or OR gates using functions that look like this:

switch (ligand x, ligand y, reporter g)

A compiler would then take all those statements and compile them into a DNA sequence that would, when inserted into a cell, start to perform all the functions you defined. This language, which Peccoud calls XDL, is a long way from reality: "What I showed is only one part of what such a language would look like."

It will probably look less like C than the electronics hardware descriptions in use today, as they handle concurrency, which C certainly doesn't in its native form. Peccoud says: "We are looking at Verilog and VHDL, as used in electronics. We are looking with people who have an EE background to see if they are suitable."

However, this is where the analogies between electronics and IT begin to break down. If you look at a circuit diagram, you have lots of things like AND gates scattered around. In biology, as it stands today, you only get to use one. If you want to have two AND gates in the same biosystem, you need to find another gene that performs the same job but in a different way.

The one thing that electronics has over biology is the ability to define connections between parts. In bacterial cells, at least, you don't get that. Everything happens in what is effectively a little bag of soup in which proteins and molecules only get together by bumping into each other. And just because they bump into each other, it doesn't mean anything will happen: all the processes are statistical. It turns out that electronics is getting a lot more statistical, but it's a convenient abstraction to think as the processes as being deterministic.

Now, a biolanguage compiler could deal with a lot of that, simply picking compatible parts from a big list, such as the MIT Registry of chunks of DNA. However, as you add more genes into a system, you start to introduce odd little dependencies which means, in most cases, the thing doesn't work. There seem to be ways around this. One is to simplify the bacterial DNA chassis to the bare minimum. Another is to focus on doing more design downstream of the gene - it seems that nature makes a lot of use of what are called protein scaffolds. With these, you bring a bunch of functions together in one protein or design the proteins in such a way that only when certain proteins stick together does something happen.

Some insight into this has come from a group that focuses not on turning bacteria into factories but trying to work out why evolution has produced certain things. This is what is happening at the University of California at San Francisco.

"It turns out that signalling proteins are highly structurally modular," said Caleb Bashor, who is based at UCSF, at a meeting on synthetic biology late last year in Cambridge. Some protein enzymes in natural cells sit on a scaffold. Simply replacing and rearranging elements on one scaffold can ‘reprogram’ the protein. "It suggests that the complexity of networks is due to the interactions [between elements on a scaffold].

"Scaffolds appear to provide a powerful platform for exploring the plasticity of [cell] pathway signal processing: a tool for understanding circuit-design rules. Using them, we could rewire cells with new or modified behaviours," Bashor claims.

The problem that faces the synthetic biology community is working out just how concepts such as modularity fit into the discipline. It may be that engineers can only design these systems with a lot of computer support - with statistical tools working out what the potential interactions are between genes and other parts of the cell. It will be very different to what most people think of engineering. But the concentration on statistics might have other spinoff benefits - the inability to deal with random, infrequent events is so often what brings IT to its knees.

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