Field of Science

Obligatory synthetic genome post: clearing up some confusion

I wasn't gonna bother writing anything about this, considering that pretty much the entire blogging community has sucked the topic dry and written about it much better than I could've. But one little detail still bugs me enough to fail at keeping my trap shut: the phrases "synthetic cell" and "synthetic bacterium". And the brutal media misrepresentation of the whole thing. Also note there will be bias as I tend to be rather skeptical towards synthetic biology in general, partly because the sheer magnitude of their difficulties are underplayed in the media, and replaced with some naive fantasies about "custom life" or irrational fears of Frankenstein-like creatures taking over the world or something. I think we are faaaaar too behind in our understanding of biology attempts at understanding biology for any of these fantasies and fears to be worth considering.

With the recent hype about the synthesis of a new bacterial chromosome (based on an existing one with a few minor modifications), it seems like media and bloggers alike are confusing 'genome', 'cell' and 'organism', using all three interchangeably. In fact, one does get the feeling that lately the existence of the cell has been largely eclipsed by the genome. As it largely has been outside the field of cell biology, sadly. I think a nice sketch of this majority viewpoint can be represented in this quote from Pharyngula:
"So, if after a period of time, you've got a cell whose DNA was produced by a machine, and whose membranes, enzymes, structural proteins, and metabolic by-products were all produced by that machine-generated DNA or the protein products of that DNA, what makes it a non-synthetic cell?" PZ Myers 22 May 2010
Granted, this was said in defense before some utterly ridiculous claims by crazy people, eg. that this somehow proves creationism. Still, as a biologist, PZ Myers should know better - only the proteins and nucleic acids (incl. ribozymes) have been synthesised by the genome. The membranes and non-protein metabolic products, while influenced by genomic activity, also have a life of their own, having been inherited and modified since the origin of life itself. Furthermore, systems like cellular organisation are also not entirely 'programmed' by the genome, and are also inherited extragenomically.

In the paper, the authors use the word 'control' to describe what the genome does, which I think is also not entirely accurate -- would be close enough for most circumstances, but the topic here has become much too philosophical and thus demands careful semantics. Thus, normally I wouldn't've even noticed the slightly misused term. Strictly speaking, as mentioned before, the genome synthesises proteins and ribozymes which act in symbiosis with membranes and cytoplasm to form the cell, also the fundamental level of selection in most cases (eg. see the discussion near the beginning of Cavalier-Smith 2001 J Mol Evol). Thus, the genome cooperates with the rest of the cell, rather than controlling it. Both the extragenomic and intragenomic elements 'seek' to be propagated further, and are mutually co-dependent to achieve said goal, thereby acting as a unit. The gene-centred view popularised by the likes of Dawkins may well be parly responsible for the dismissal of heritable (and thus, evolvable) elements outside the nucleus. While the gene-centred view lays foundations for many important and useful models, one must not get too carried away with it.

There's also a point made that by inserting the synthetic M.mycoides genome into M.capricolum, the latter was essentially transformed into the former - that is, 'changed species', if you will. First of all, the M.capricolum-now-mycoides cell is quite possibly still not identical to M.mycoides, perhaps retaining some cytoplasmic features unique to M.capricolum - this depends on how truly different the two species were to begin with. Which leads us to the second point: the muck that is our attempt to define a species in prokaryotic (that is, asexual) populations. While I personally think that, philosophically, a case can be made for some form of species concept in prokaryotes -- eg. stable 'islands' in the 'fitness landscape' or 'design space' -- the authors have not provided a clear description of the difference between the species (or strains?) in question, and thus it is difficult to evaluate the claim about 'one species taking over another'.

The insertion of nuclei into foreign cytoplasm is not a novel concept. In fact, some red algae have mastered the technique millions of years ago, long before animal cloning and such (remember Dolly?). And genomic fragments overall often tend to be quite promiscuous and not too choosy about their cytoplasmic environment.

My intent is not at all to underplay the achievements. Creating long stretches of custom modified DNA is kind of nice, and could perhaps someday be helpful in, say, generating complex knockouts or modifying multiple gene expression patterns/fusing stuff to them/etc at once. Perhaps someday people will look upon our small-scale molecular genetics work in much the same way we now [try not to] laugh at people who spent years sequencing one gene by hand. I worry whether we are entirely prepared to handle such an onslaught of data, but perhaps 20 years ago they wondered the same thing about us. Perhaps someday organismal biologists will move from molecular genetics to molecular genomics (and thus it is imperative for us to understand both genomics and the tree of life itself!). Again, our current work was beyond fantasy just some two-three decades ago!

But I don't think Venter's paper signals any sort of new era of biological science just yet, let alone humanity or whatever. The world has not ended yet. Nor has utopia begun. Tomorrow is back to lab as usual!

I'm rather overwhelmed by offline stuff right now, especially in the reading and comprehension (and writing!) department, and thus have no time to read over what everyone has to say about the paper, let alone analyse the results in any particular detail, but here's a few recommended musings on the subject, much better written than mine:

- fellow protistologist who kind of scooped me on several points, grrr! =P
(I also wondered about the use of an obligate intracellular parasite in the search for 'minimal life'. Parasites are known to undergo rather extreme reductions both in genome complexity/size and cell structure, and tend to be obscenely derived.)

Lab Rat - bacteriologist who is also cautious about the findings. She also comments that implanting synthetic genomes into bacteria is unlikely to add much to the terrorist's arsenal at this point. She also points out just how much we have yet to know before attempting to create life, as even when an organism emerges from some deep resting stage, it is still equipped with various non-genetic elements necessary for its survival. For the rest, read it yourself! =P

A Russian science news site,, actually got the title somewhat accurate: "The first living organism with a synthetic genome was created" (rather than "OMG SYNTHETIC LIFE!!1!"), and then goes into a detailed history of the project itself, with some insightful comments - apparently at some point Venter's team had some issues with a random deletion in dnaA, kind of important for DNA replication! While I still disagree with their underappreciation of cytoplasmic inheritance, the article overall is well-written, if you speak Russian.

Completely irrelevant to the discussion, but my [poorly informed] impression of Craig Venter is along the lines of this music video from a slightly overfunded (;-)) Harvard lab.

On an unrelated note, Merry and Elio have compiled a summary of the first half-year of microbial blogging for 2010 at Small Things Considered. Anyone interested in microbiology, both nucleated and non, should read their blog if you don't already!

Ok, I've now exhausted my writing juices for the next little while. Hopefully not for long...


  1. Thanks for the link! And congrats on getting a T-CS reference in there :P I can't wait until exams are over and I can start looking seriously at bacterial membranes and membrane/lipid evolution, it is starting to really interest me.

  2. As a former colleague of Venter's, I followed the press coverage with bemusement. Only Nicholas Wade at the NY Times really got it right, and he obtained some choice quotes from other prominent scientists, such as David Baltimore, pointing out that it really wasn't such a big advance. In fact, the 2007 paper by the same group did almost the same thing: they transplanted on Mycoplasma genome into another. The only real difference is that in the new 2010 paper, the transplanted genome was synthesized in the lab rather than taken from another cell. The synthesis was done by an outside company in 1000-base pieces, and Venter's team developed a protocol (using yeast) to stitch the pieces together.

    And the first demonstration of a synthetic self-replicating organism was by Wimmer et al at Stonybrook, who synthetically created a polio virus and created fully functional polio virus particles. The genome is 100 times smaller, but they published their work in 2002. Nicholas Wade was the only reporter who pointed this out.


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