What can Synthetic Biology Teach us About Basic Biology? (Part I)

In a series of posts I want to explore the interplay between basic biology, which looks at the natural world to learn about how life works, and synthetic biology, which studies what is not found in nature.

When you read about synthetic biology in the news, or even in the literature, most of the work is all about engineering cells do something useful (or at the very least interesting and clever). It's easy to accept that as is, but it isn't necessarily the whole story. Michael Elowitz at Caltech promotes synthetic biology, in part, by drawing attention to the contrast between it and the ‘canonical' scope of biology¹. Historically biology as a whole has focused exclusively on existing organisms that inhabit the planet. We ask questions like: How do we classify the wide collection of diverse organisms? Why do animals behave the way they do? What are the evolutionary relationships between organisms? And more recently, what do particular genes do? Synthetic biology can allow us to answer questions about the vast collection of potential organisms and potential living systems.

It could be that the DNA/protein basis of life that we've come to take for granted has the power to create about any life form imaginable. In some sense it already has; even the mythological creatures imagined by cultures around the world carry at least a modest resemblance to actual creatures, and creatures that defy human imagination are discovered all the time (think depths of the ocean). However we do see patterns and limitations on modern as well as fossilized organisms, because of history. Insects, all similar in a number of ways, are abundant because they are remarkably successful, and their collection of similarities was chanced upon early in the history of animal evolution. However, I think that life as we know it probably does have boundaries of some sort (even excluding obvious cases like cells lacking membranes or energy harvesting machinery). Maybe we can probe this space of potential organisms using a combination of rapid evolution and deliberate manipulation by synthetic biology.

Rapid evolution can be used to answer questions like, "How do cells respond (in an evolutionary sense) to prolonged exposure to a particular toxin?" I'm still not clear what exactly rapid evolution means. Obviously a good first start would be to use a natural organism that reproduces (and therefore evolves) relatively quickly. Bacteria are obviously the frontrunners in that respect, and the biologist Richard Lenski at Michigan State has done just that. In 1988 his research group started growing 12 cultures of E. coli, day in and day out². The bacteria from one day's cultures are used to start the cultures of the next. These 12 lineages of E. coli have been growing ever since (to my knowledge, up to this day).

Every 75 days, which amounts to 500 generations, Lenski's team will freeze down the population of bacteria to create a cryogenic "fossil record." Carl Zimmer gave the subject excellent treatment in his blog³, but to summarize (as of 2008) the bacteria grow 75% faster compared to 1988. More amazingly, one of the lineages evolved the ability to metabolize citrate, a component in the culture media that E. coli is typically not able to metabolize under aerobic conditions. (Apparently this inability to metabolize citrate is practically part of the definition of E. coli. This just goes to show that nature shows no regard for our classifications and definitions). Luckily someone in the lab snapped a couple pictures! The flask with particularly cloudy liquid is the strain that feeds off citrate. Experiments like this might serve as examples for future rapid evolution experiments, again whatever those might be.

Deliberate manipulation, on the other hand, can answer questions like, "Will E. coli still function if I delete gene X?" Experiments of that type aren't anything new; we've been making knockout strains (as they're called) for quite a while now. However, synthetic biology has only recently offered us the opposite tactic. "Will E. coli still function if I insert this useful collection of genes?" I'm faced with that question often in my own research. The ever-pressing question, however, is "Will E. coli function predictably if I insert this useful collection of genes?" Unfortunately, not always. Synthetic biologists have learned, painfully, that context is incredibly important, and that genes aren't as modular as we would like. Roberta Kwok gave this issue good treatment in a Nature article last year⁴.

I'm confident that through more experiments we will understand these issues more thoroughly, and that knowledge will give us further insight into constraints that operate on the DNA/protein scheme of life. I'm very intrigued by this feedback between traditional and synthetic biology. Everything we do in synthetic biology rests on knowledge gained by traditional biology. Using synthetic biology we in turn learn more about the fundamental rules of biology by testing extreme or otherwise noteworthy cases.

Image Credit: E. coli close-up: Erbe, E. and Pooley, C., USDA Agricultural Research Service (via Wikimedia); Lenski lab flasks of E. coli: Baer, B. and Hajela, N. (via Wikimedia)

References:

1. Elowitz, M. and Lim, W. A. Build Life to Understand It. Nature 468, 889–890 (2010).

2. Lenski, R. Overview of the E. coli Long-Term Evolution Experiment

3. Zimmer, C. A New Step in Evolution. The Loom.

4. Kwok, R. Five Hard Truths for Synthetic Biology. Nature 463, 288–290 (2010).