Interview with Dr. Andrew Ellington at Keystone Symposia’s Precision Genome Engineering and Synthetic Biology: Designing Genomes and Pathways
Parts, Circuits, and Systems
So in directed evolution, what you’re generally trying to do is to optimize function. And that can mean a lot of different things. But if we keep within the synthetic biology paradigm, we always talk about parts, and circuits, and systems. So you can think about the directed evolution of parts, and circuits, and systems. And so for parts, the parts could be of many different sorts. If you want a new or better repressor, you can go and find one in nature, or you can take one you already have, mutagenize it, select for better repressor function, or better activation, or activation by a slightly different type of effector, and eventually get a new part that works the way you want it to.
For circuits, you put various parts together, and then you optimize the function of a circuit. Probably the easiest example would be an operon. If you had an operon, and a way to select for that operon. For example, a biosynthetic operon that made an amino acid. You could optimize the whole operon at once by mutagenizing all the genes, and saying, hey, operon, which variant of you is going to make me the most, or the best amount, of an amino acid.
And finally, at the level of the organism itself, there’s all sorts of interesting properties to optimize. In the long run, one would like to be able to optimize any sort of organismal system.
That’s sort of what Darwin found out, right? That you can use directed evolution, breeding, to make all manner of dogs, and horses that run faster. And that’s a relatively slow process. It is possible, into the future, that using some of the techniques that are coming out of synthetic biology, that we’ll be able to do directed evolution of agriculture products at a much faster rate than is currently possible.
But again, it will be, what are you selecting for? How are you selecting for it? What are you trying to achieve? So those are just some examples of how one can use directed evolution in the synthetic biology mindset. I’ve been around the community for awhile, and I’ve usually been somewhat of a critic of the community, because the community started with this notion that it was going to be just engineers coming to biology and showing us the way.
That parts, and circuits, and systems would finally allow us to do real bioengineering. And, in fact, bioengineering has been around as a discipline for a long time. And synthetic biology is just the newest instantiation of it. The only thing really new about synthetic biology is the ability to make lots and lots of DNA. And that’s a great enabler, but it doesn’t change what people have done in the past. You could make protein overexpression vectors then, you can make protein overexpression vectors now. But I think that what’s impressed me is that many of the folks who work in, sort of what I consider, the doctrinaire aspects of synthetic biology, the idea that you can make parts, circuits, and systems that come together, and can function in a way in which they were designed to work, have mollified their original stances, are now moving towards sort of a systems biology approach. But nonetheless, have made designed circuits that work very well.
Stepping Up the Circuitry
I’m incredibly impressed with what Chris Boyd and Ron Weiss have done, because both of them have now made very complex circuits. They work very well, and they clearly pave the way towards much more useful circuits into the future. And it’s been a long, hard haul, but they’ve earned the right to promote this version of synthetic biology with reality. And not just, we hope this will work someday, but they’ve really begun to make it work.
Now, I think other people won’t find that as fascinating as I do, because they were already in the mindset, of course this is going to work. For me, it was never clear that it was going to work. And the fact that Chris, and Ron, and others have made this work is really quite remarkable. That said, I do think that what they’re learning, and what we’ve seen at several talks at this conference, is that context matters, the system matters, the background matters. Which is all about how things are going interact inside of an organism. It’s not just an isolated pathway, it’s a pathway inside an organism.
And so really we’re coming around from pure design to design in the context of the system, which is more systems biology. And so something I’ve thought for a long time is that we’ll eventually all get to the point where all synthetic biology is, in essence, systems biology. Now my colleagues may not agree with me, because they’re still going to say, look, we’re going to engineer new parts, and engineering new circuits, and engineer organisms to do things the way we want them to.
And so really we’re coming around from pure design to design in the context of the system, which is more systems biology.
But because organisms are so complex, and because these parts work differentially in different backgrounds, and because circuits have idiosyncrasies, I think that more, and more, and more, to make things that really work, that people can use, we’re going to have to move more towards a complete understanding of the organism, or of the system. So I’m very impressed with what my peers have accomplished, but I’m also impressed that they’ve come around, so to speak, to seeing that the parts in a context are very important, and that the systems biology of the whole is probably going to be what leads us into the future. But that’s just my perspective. In many ways, I think other people will shrug and say, well, of course it was going to work out like that.