What can Synthetic Biology Teach us About Basic Biology? (Part II: The Origin of Life)

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.

In my last post I asked what synthetic biology can tell us about the suite of potential, though non-existent, organisms. That question presumes that life (as we know it) has already come about. However, I think that synthetic biology has something to contribute to that "ultimate question," the origin of life. In fact I think synthetic biology has far too much to say than could fit into a blog post. However, two areas stand out as particularly interesting, which might be called the minimal cell and the RNA World cell.

An important and not satisfactorily answered question in biology is "What is the minimum set of genes required to sustain life as we know it?" That's the minimal genome. "Life as we know it" means cells encapsulated by lipid bilayers, governed by a DNA genome, carrying out chemical reactions driven by proteins. They also must self replicate by building copies of themselves with only nutrients as input. The eminent J. Craig Venter Institute made the minimal genome one of its major projects. Starting with Mycoplasma genitalium, the bacterium with the smallest known genome that can grow in pure culture, they generated a series of mutants with different genes disabled¹. To do this they used transposons, pieces of DNA that randomly insert themselves into the genome, disrupting other genes in the process. If a transposon inserts itself into a gene, and the cell dies as a result, then that gene was essential.

Eventually the team identified 387 protein-coding genes as essential for M. genitalium. Surprisingly 110 of those have completely unknown functions (at least at the time of print); all we know is they are necessary for survival. Figure 2 of Glass et al. (2006) shows a complete map of the M. genitalium genome (essential vs. nonessential genes marked), including 43 RNA genes that they didn't test, and it looks astounding-certainly worthy for a poster! You can even download a spreadsheet describing each gene. A fair number of the genes don't have known functions, and I long to see them all filled in. We would then have a complete schematic for a living cell. In other words, "Put these genes together and you get life!"

That approach deals only with life "as we know it." It's certainly an important approach, but another intriguing question is "What was life like originally?" or at least "What might life have been like originally?" It clearly wasn't anything like Glass's minimal cell, which is far too complicated to have arisen by a single chance event. We only call it a minimal cell because we are thinking within the constraints of the DNA/RNA/protein form of life that appears ubiquitous today.

You have probably heard of the "RNA World" hypothesis, the rightfully popular idea that the first cells used RNA for both information storage and for catalyzing reactions. Szostak, Bartel, and Luisi (2001) give this subject a thorough, and provocative, theoretical treatment². They suggest that putting a RNA enzyme (ribozyme) that itself makes copies of RNA (a self-replicating replicase) into a lipid membrane is the right place to start. Ribozymes that copy RNA have already been discovered and improved in the lab, but they aren't very efficient. But once we have a more efficient one, adding a second ribozyme that synthesizes the lipid components of the membrane would allow a truly self replicating system to emerge and begin evolving. Natural selection could push mutant RNAs to perform other structural and catalytic functions to increase the fitness of the system. The authors' examples are more efficient RNA replicases, ribozymes that synthesize RNA precursors, and RNAs that are anchored to the membrane. Since we have already discovered a number of ribozymes in nature (the self-splicing hammerhead ribozyme is shown above), these ideas don't seem farfetched.

It's astonishing that we can make these kinds of speculations. RNAs that perform these specialized functions aren't currently known (they have either never existed or are long extinct), but we've been remarkably successful in our quest so far. We will never know exactly how life originated, but we can use synthetic biology to create it ourselves.

"What I cannot create, I do not understand." –Richard Feynman

1. Glass, J. I. et al. Essential Genes of a Minimal Bacterium. PNAS 103, 425–430 (2006).

2. Szostak, J. W., Bartel, D. P, & Luisi, P. L. Synthesizing Life. Nature 409, 387–390 (2001).

For a great introduction to origin of life research, accompanied with short video animations, see http://exploringorigins.org/