Tuesday, 5 April 2016

Minimal instruction set

On of the tireder metaphors for a genome is to say that it is a blueprint or a computer program . . . for making other genomes.  It's easy to state and falls apart with the least bit of critical evaluation. One of the goals of computer science is to create RISC reduced instruction set computers for elegance and simplicity.  If you plot a) people who have made the most significant contribution to biomedical science vs b) people who have or are going to get a Nobel Prize, then Craig Venter is one who has claim to be furthest from the main diagonal. He's had some brilliant ideas, he's driven some seminal investigative projects, he's galvanised the world to get on with the human genome project . . . he's 1:24 odds for landing a Nobel. But long the way he's pissed off a number of important people. I've written about his work before and report now that he's gorn and done it again.

He's created a functional organism whose genome is smaller than that with the smallest known natural genome, which is the 525 gene bacterium Mycoplasma genitalium. M.genitalium lives on the epithelium of mammalian urinary and genital tracts of mammals, and can flare up to cause purulent discharge <eeeeuw> and painful urination <eeeooow>.  It was also the second complete genome sequenced back in 1995 after pneumonia -nducing Haemophilus influenza.  It was chosen for this honour because, even 20 years ago, Venter & Co were interested in minimal genomes.  What can you discard as optional extras or luxuries?  It was not the ideal choice, because M.genitalium grows really slowly, so later they moved sideways to M. mycoides, which is about the same size but easier to grow in the lab.  They then knocked out the genes in batches and noted whether this prevented the bacteria from growing more or less normally - under lab conditions. The genus Mycobacterium, as obligate parasites, live in a warm rich sheltered environment up the urethra; so they don't need to make their own vitamins and amino acids or mainatain a complex of protective machinery to deal with dessication, acids, competitors and excessive salt. The lab conditions attempt to mimic these easy-living conditions.

You might think that knocking out the genes one-a-time and seeing who thrived was a sufficient answer. But Venter's team realised that there is a lot of redundancy in the living world and that there are pairs of genes of which either one is necessary and sufficient for a particular process. So the one-a-time protocol retains both copies, whereas Venter has shown that you can discard either but not both.  Their syn3.0 [L] construct has only 473 genes and is still functional. That's about 10% of the size of, say, the E.coli genome. Teeny, tiny! Interestingly 149 [30+%] of the genes are of  'unknown function': they are (by definition of Venter's protocol) essential for normal microbial existence - and we have no idea what their function is.  That should induce a certain salutary humility among know-it-all scientists.

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