ViroBlogy

I have kept out of commenting on what J Craig Venter and others have done recently, given that many others have done so, and done so well – however, there is recurring mention of what “this technology” could do for influenza vaccines specifically, which has both puzzled and intrigued me, given a distinct lack of obviousness.

So I will comment, if only to clarify this issue for me and anyone else who cares.

To give some background, the New Scientist issue of the 29th of May has a guest editorial by J Craig Venter, Clyde Hutchison and Hamilton Smith, where they discuss some of the implications of their having made a totally synthetic and viable Mycoplasma mycoides genome (see also Science, DOI: 10.1126/science.1190719).

So what, exactly, is it they did?  OK, so they spent US$40 million or so constructing a genome, in segments, from sequence information housed in an electronic database, via chemical synthesis of long stretches of DNA.  They then assembled these segments into a singular genome in yeast, and then inserted this into cells of the closely-related Mycoplasma capricolum which had been stripped of their genomes – and incidentally, rendered unable to destroy the incoming genome as “foreign”, by a process which is now proprietary.  These cells then expressed the new DNA, which allowed them to multiply, and to take on all of the characteristics of the synthetic M mycoides, given that all of the original cell constituents from the original bug (proteins, mRNA, membranes, etc) would be turned over in time, and become those specified by the new genomes.

This is a big deal – a really, really big deal – but at the same time, they themselves recognise it is an incremental step in a long series of steps that started with Arthur Kornberg’s lab making the first complete synthetic and viable genome of a virus (phiX174) by in vitro synthesis from virion DNA, polymerase and nucleotides.  In fact they modestly point out that this is not even the first  complete cell genome that has been synthesised; it is the largest, however, and the one that worked.  They were not so modest in missing out a few other landmarks before their own complete synthesis of phiX174 in 2003, however: for example, the first synthesis of a functional plasmid, and the first generation of a RNA virus genome from a cDNA copy, and the complete synthesis of an infectious poliovirus genome, are not mentioned.

So what is it they did not do?

Well, they did not “create life”, however much even relatively respectable publications might claim they did: life is a lot more complex than chemicals, and people have “rebooted” cells before with exogenous genomes; what they did is not really qualitatively different to infecting a cell with a synthetic virus.

They have also not done anything that is immediately useful: their new organism differs from the original only in having a few genes missing, and a long literary message and ownership-encoding “watermark” inserted.

More positively, they have also most emphatically not opened the floodgates for bioterrorists to mail order complete poxvirus or anthrax genomes: as I have noted here previously,

“…There are more than enough nasty agents out there that are relatively easy to obtain, and do simple kitchen-based microbiology with, to keep entire cave complexes and Montana libertarian enclaves busy for years, without resorting to complicated molecular biology”.

Or spending $40 million dollars.  And I will say it again….

So aside from the details, what have they done?  In the NS editorial, Venter et al. say this:

“We now have the means to design and build a cell that will define the minimal set of instructions necessary for life, and to begin the design of cells with commercial potential, such as fuel production from carbon dioxide. We can assemble genome-sized stretches of DNA that can also be used to mix and match natural and synthetic pieces to make genomes with new capabilities.

Synthesising DNA in this way is still expensive, but we expect the cost to fall dramatically. This may make the complete synthesis of genomes competitive with the alteration of natural genomes to add new capabilities to bacterial cells. It should also be practical to synthesise simple eukaryotes, such as yeast, to which it is already possible to add extra chromosomes. The construction of large pieces of synthetic DNA and their introduction into a receptive cytoplasm is no longer a barrier. The limits to progress in synthetic biology are now set by our ability to design genomes with particular properties.”

Right: so what they have done is set the benchmark for what is possible – rather than what should be done.

Because it is a lot easier to do things such as they propose by other ways – as is pointed out in the companion article to the NS editorial.  For that matter, I am sure one could more easily end up with a completely synthetic and much larger cellular genome by incrementally replacing genome chunks by homologous recombination or transposon-mediated insertion / Cre-Lox deletion, and have it cost far less and be less subject to error, than by synthesising it de novo.

Influenza virus - Copyright Russell Kightley Media

And how does any of this relate to influenza vaccines?

The only comment I can find in the NS article that sheds light on this is the comment:

“As soon as next year, the flu vaccine you get could be made synthetically,” he [Venter] says.

Except that this has been possible for years already, after the poliovirus synthesis…?  I think it was rather a badly-chosen example rather than any actual plan; however, there is not a lot of point in making a synthetic influenza virus genome, given that the attenuated originals already work quite well as vaccines – and we don’t yet understand how to specify avirulence in influenza, so any synthetic version would necessarily be a copy of an extant version.

So hype rather than fact for ‘flu; promise rather than substance for carbon dioxide sequestration and biofuels – but still the coolest thing since sequencing your own dog…B-)