Some ill considered comments on the protein structure initiative.

The PSI must be considered from three perspectives: (1) its impact on science, (2) its policy implications, and (3) its effects on funding structural biology. In terms of its scientific impact, I have some deep concerns, chiefly related to the objectives and the focus of the program, which have, it appears to me, not been consistent and clear. Initially, PSI had, I vaguely recall, the stated purpose of solving the structures comprising the human proteome. Swiftly abandoning that too ambitious idea, PSI was then going to fill protein folding space with carefully selected (by bioinformatics miracles) gene products. This all proved too demanding, so various organisms were chosen by different PSI centers, and everyone started off in all directions. Then some centers dropped the idea entirely of solving proteomes of anything and focused on proteins that might serve the needs of drug designers and pharmaceutical development. Some turned to address specific classes of enzymes, while others continued to churn out whatever it was that crystallized. Any coherent theme vanished, and to this observer, it has yet to be found again or reconstructed. A major problem with the current PSI is that its objectives have become so scrambled that coherence has disappeared from the program. Perhaps my vision is simply blurred, but that's the picture I have of it right now.I am further concerned that I hear increasingly that the greatest, or principal benefits of PSI will be the technology development and technology spin-offs. Now I appreciate new technology as much as anyone, but this spin-off motive has a familiar and ominous ring. I was a participant on NASA advisory committees for nearly 15 years. The chief topic of most meetings was the development of microgravity and life science programs for the US Space Station. Initially, NASA announced that (what later became) the International Space Station was purely for science. It would be a platform for science, and science would be its sole objective. When that failed to materialize, its continued importance rested on it serving as a vehicle to inspire closer relations between countries, principally the United States and Russia. Then it was to be a platform for the commercial development of space, then a vehicle for inspiring and educating America's eager young minds, and then a platform for the development of engineering techniques. Finally, NASA abandoned the pretense that it was good for anything and justified its continued existence by touting all the advanced technology spin-offs. OK, call me a cynic, but the PSI is looking more like a space station all the time. When your major successes are the spin-offs and not the stated objectives, Houston, you have a problem.One might conclude from this dark vision that I favor abandoning PSI completely—that would be wrong. I believe that PSI could yet be an enormous success if it could just re-establish its focus, regain coherence and purpose, redefine its objectives, and get its act together. It could succeed if it could make it evident to everyone (well, no, you can never please everyone) what the program was trying to achieve and what progress it had made in doing so.The second and third perspectives, policy and funding, are of course intertwined. It appears to this observer that the NIH, by creating various kinds of PSI mega- and minicenters, has placed an excessive amount of otherwise scarce resources in the hands of a chosen few, and has somehow expected most of the worker bees out there to cluster around the queens and be productive. They have created dukes and barons to oversee and dispense the riches of the realm. This may be good administrative logic, as I am sure it is easier to manage a dozen or so 20–50 million dollar projects than to manage several hundred smaller enterprises. But is it good science policy to do that? Is it good funding policy? Is the scientific return on the former greater than would be that of the latter? I'm afraid I have my misgivings.The funding of R01 grants and other grants to individual investigators by NIH has fallen precipitously in recent years, almost in parallel with the growth of the PSI. Perhaps that is simply coincidence, but it is hard not to draw the obvious conclusion that the structural biology community is sacrificing and suffering for the PSI. This has produced the inevitable jealousies and hard feelings among researchers. They may have always been there, but hard times, which are what most researchers are experiencing right now, makes them more pronounced. Perhaps PSI is getting a bad rap here. Maybe PSI is actually a huge add-on for structural biology, but if that is so, it is not evident.This has been a rather negative review to this point, I realize. Were this a study section review, PSI would be triaged out on the first pass, no score, no support, go away, and, indeed, I must admit to a certain gloominess regarding future prospects. That is unfortunate, however, because the PSI does, in fact, have some remarkable, and I think unexpected achievements to boast about. The PSI centers are currently contributing a large portion of new PDB entries, and a greater proportion of their structures represent truly novel structures and unique folds. By most measures PSI structures appear to be of greater precision and to contain fewer errors than structures from outside the PSI. The PSI structures are better determined, Rfrees are lower, resolutions higher, and costs lower. Quality overall appears excellent and beyond most observers expectations. New technologies are indeed emerging by the day—technologies that will be broadly useful. The centers have been conscientious in reporting structures and allowing access, they have been open with their operations, and willing to share expertise and technology, and one would be hard-pressed to criticize the commitment and honest effort of the scientists involved in PSI research. I wish my lab worked as well, but then, I also wish my lab had their funding.