by Peter Nollert
August 29, 2009 02:44
When I look at different structural biology labs with their different crystallization processes and equipment they employ I see a wide diversity of techniques used and processes installed. At the extreme end of the spectrum there is the individual investigator working on the structure determination of a single or several related proteins at a time. At the other side are the high-throughput crystallography labs, churning through thousands of constructs and producing hundreds of new X-ray structures. Most labs are somewhere in between and have fine-tuned their operation based as a result of the given resources, expertise and available technology.
At one point in this spectrum there is a peculiar transition, akin to a phase change where interesting things happen. Here the one-investigator-one-target model is replaced by a process-management model. Evidently, the success rates of the high-throughput operations are a lot lower than that of smaller labs. On the other hand, the cost /structure has been continuously driven down by the high-throughput model, making it possible to generate X-ray protein structures at well below $100,000.
Why is there this decline in success rates? One reason is that the 'one-size-fits-all' approach of high-throughput structure determination explicitly accepts failures. Some targets are just not compatible with the particular crystallization regime chosen, the latter of which would be typically varied when handled as a single entity. I suspect though that during the transition to high-throughput, researchers manage processes in a more abstract way and something gets lost. For example they typically don't know precisely what is happening to each individual protein in the pipeline. I think that the intimate knowledge of a protein's characteristics in expression and purification does contribute to success in crystallization.
In addition there may also be a motivational issue. You'd do everything in your capacity to grow better crystals from CLO's (Crystalline Looking Objects) because that's the one target you're focusing on (think back to your days as a PhD student). A process manager however would be more likely to triage a weak hit and instead order a new construct or crank the high-throughput machine a little faster and create more output that way.
I wonder if there's a way to combine the advantages of both regimes. Can we bring back this bond that exists between the person carrying out the crystallization experiment and the target protein? Any ideas?
Cheers,
Peter