Publication of the Venter Institute's synthetic bacterial chromosome

Craig Venter and his crew have just published a paper in Science demonstrating synthesis of a complete bacterial chromosome.  Venter let the cat out of the bag late last year in an interview with The Guardian, which I wrote about a few weeks ago, here: "Updated Longest Synthetic DNA Plot".

As a technical achievement, the paper, by Gibson, et al., is actually quite nice.  The authors ordered ~5kB gene cassettes from Blue Heron, DNA 2.0, and GENEART, and then used a parallel method to assemble those cassettes into the ~580kB full genome in just a few steps.  They contrast their method, which may be generalizable to any sequence, with previous research:

All [the previous] methods used sequential stepwise addition of segments to reconstruct a donor genome within a recipient bacterium. The sequential nature of these constructions makes such methods slower than the purely hierarchical scheme that we employed.

The Itaya and Holt groups found that the bacterial recipient strains were unable to tolerate some portions of the donor genome to be cloned, for example ribosomal RNA operons. In contrast, we found that the M. genitalium ribosomal RNA genes could be stably cloned in E. coli BACs. We were able to clone the entire M. genitalium genome, and also to assemble the four quarter genomes in a single step, using yeast as a recipient host. However, we do not yet know how generally useful yeast will be as a recipient for bacterial genome sequences.

The team was evidently unable to successfully use the synthetic chromosome to boot up a new organism.  It turns out that one of the techniques they developed in fact gets in the way of finishing this final step.  There is an interesting note, added in proof, at the end of the paper:

While this paper was in press, we realized that the TARBAC vector in our sMgTARBAC37 clone interrupts the gene for the RNA subunit of RNase P (rnpB). This confirms our speculation that the vector might not be at a suitable site for subsequent transplantation experiments.

So, Gibson, et al., made really interesting technical progress in developing a method to assemble large, (seemingly) arbitrary sequences.  However, their goal of booting up a synthetic chromosome using the assembly technique is presently stymied by one of the technologies they are relying on to propagate the large construct in yeast.  As for the goal of "synthetic life" as defined by constructing a working genome from raw materials, they are close, but not quite there.  Given the many different wasy of manipulating large pieces of DNA within microbes, it won't be long until the Venter Institute team gets there.

Andrew Pollack of the NYT quotes Venter as saying, “What we are doing with the synthetic chromosome is going to be the design process of the future."  This is a bit of a stretch, because no one in their right mind is going to synthesize an entire microbial genome for a real engineering project, with real costs, anytime soon.  Any design process that involves writing whole genomes is going to be WAY in the future.  As I wrote in the "Longest Synthetic DNA" post:

The more interesting numbers are, say, 10-50 genes and 10,00-50,000 bases.  This is the size of a genetic program or circuit that will have interesting economic value for many decades to come.  But while assembling synthetic constructs (plasmids) this size is still not trivial, it is definitely old news.  The question is how will the cost for constructs of this size fall, and when can I have that DNA in days or hours instead of weeks?  And how soon before I can have a desktop box that prints synthetic DNA of this length?  As I have previously noted in this space, there is clear demand for this sort of box, which means that it will happen sooner or later.  Probably sooner.

The Gibson, et al, Science paper doesn't say how many person-hours the project took, nor does it say exactly how much they spent on their synthetic construct (presumably they got a nice volume discount).  The fact that the project isn't actually finished demonstrates that this is hardly a practical engineering challenge that will find a role in the economy anytime soon.

That said, I could certainly be wrong about this assertion, particularly if other technical approaches crop up, as may well happen.  In the NYT story Venter is quoted as saying that, "I will be equally surprised and disappointed if we can’t do it in 2008.”  And they probably will, but what is the real impact of that success? 

The NYT story, by Andrew Pollack, carries the unfortunate title, "Scientists Take New Step Toward Man-Made Life".  Not so much.  Even if Venter and colleagues do get their chromosome working, they will have demonstrated not "man-made" life, but rather a synthetic instruction set running in a pre-existing soup of proteins and metabolites in a pre-existing cell.  It's really no different than getting a synthetic viral genome working in cell culture, which is old news.  Show me a bacterial cell, or something else obviously alive, from an updated Miller-Urey experiment and then I will be really impressed.  Thus the Gibson paper represents a nice technical advance, and a good recipe for doing more science, but not much in the way of a philosophical earthquake.

Without the ability to easily -- very easily -- print genomes and get them into host cells at high efficiency and low cost, building synthetic genomes will remain just interesting science.