Fastcompany has an interesting interview with Nancy Hutson of Pfizer on the failures and success of the the drug discovery process. Its quite a telling article focussing on the managment of pharmaceutical research projects and an interesting piece on how to keep going when ninety odd percent of everythng you do is a probably going to fail…Fastcompany: The thrill of defeat
I’d never really thought about it before but science is built on so many failures compared to success it is strange that anyone even considers it a career – it lacks the certainty, and predictability of most other careers – and perhaps thats why us scientists are such a strange bunch – carved from a mold where progress and success are not the same thing, where the path you set along rarely leads to where you want to go, and where few of us will ever know success as measured by “normal” folk.
a structural study of this mysterious polymerase
Well Khosla’s group have done it again. In this months Nature Structural Biology is the crystal structure of actinorhodin KS-CLF. For most of you this’ll mean absolutely nothing to you but save to say its one of the major enzyme complexes I’ve been investigating as part of my PhD and our groups (particularly Matt Crumps) have been trying to solve the structure as well (Southhampton Katy had Crystals which were diffracting to a low resolution months ago – but then had a car accident which has left most of it shelved whilst she recouperated)
The structure is heterodimeric (NOT a dimer of heterodimer as we’ve predicted in the past based on gel filtration and ultracentrifugation studies) – and it is structurally very similar to the KAS enzymes of type II fatty acid biosynthesis (no surprise there) – it does raise a few difficult questions for my old thesis – and I’ll have to sit down and think about what the paper actually means.
As with all Khosla papers though it throws up a few points which you just have to raise an eyebrow or two at – the obsession with including MCAT in polyketide biosynthesis, the sweeping statement that CLF is NOT responsible for decarboxylation of malonate to acetate (and the subsequent lack of explanation of what they think this 400 odd amino acid enzyme actually does all day) – despite mutagenesis and chemical modifiction data to the contrary, and finally an image of ACP bound to CLF during chain elongation.
From a scientific point of view I’ve always found the development of resistant bacterial strains both interesting and concerning but it wasn’t until about a year and a half ago that it became personal when my granddad pased away in part due to contracting a massive MRSA infection of his kidney’s whilst in hospital after having a stroke.
Now though it seems that MRSA has been taking a few more terrifying steps down evolutions path with the develpment of a highly communicable strain. Unlike standard MRSA, which is only communicable by essentially infection via breaks in skin (and as such has been confined for the most part to hospitals etc) this new strain is capable of transfer with only casual contact.
So how have we got here? there are a number of reasons mainly the overuse and missuse of antibiotics by doctors and patients, the use of antibiotics in agriculture (feed to chicken and cattle) and the widespread use of antibacterial soaps, washing powders, washing up liquid leading to a text book example of natural selection – with only the most resistant, most transferable and quickest replicating bacteria surviving.
With these new strains developing the ability to tranfer by simple contact, added to increased resistance to vancomysin, daptomycin and linezolid, the antibiotics which form our last line of our defence, this poses a very real threat to the health of millions.