Friday, December 4, 2009

The Seductiveness of Crystals

That's one DnaC protein sticking to another DnaC protein . The dotted lines detail the interactions down to .01 Angstroms (1/1000000000000 meters). Never mind the fact that the actual data on which the image was based has a "resolution" of 2.6 Angstroms.

Your typical protein contains several thousand atoms. To generate these images, the coordinates of all these atoms must be known. That information is normally painstakingly acquired by crystallizing the protein in question, followed by X-ray analysis. There's an element of karma/luck/art involved in generating a crystal; crystallographers can regale you with tales of how they worked fruitlessly for years to coax proteins into a repeating structure, with a drop of spilt coffee proving to be the catalyst that finally gets the job done. A recent Nobel prize in chemistry was awarded to an individual, Ada Yonath, who stubbornly devoted more than 20 years to obtaining her crystal.

More than 60,000 protein structures can be found at the Protein Data Bank. Human DNA only codes for a tad more than 20,000 proteins, but a crystallographer need not fear for his career. You can crystallize proteins interacting with other proteins or ligands. You can crystallize various "isoforms" of proteins. You can mutate your protein strand and recrystallize it. Once you've got the atom-by-atom coordinates in hand, your software can zoom, rotate, label, and color the image. You're an artist. And an explorer, flying over and through the ridges and chasms that might be essential to catalysis.

The work can be important. If you've got a high resolution image of a disease-related protein, it's possible to design drugs that clog it up. It's arguable, however, whether "rational drug design" has come anywhere close to living up to its early promise.

But does this sort of work deserve a Nobel? Does it push boundaries and alter paradigms? Are we talking about extraordinary acts of intellect and creativity? Or just perspicacity?

The questions above are personal, believe it or not. It was flattering to have a professor pursue my services, offering financial inducements, and even pointing out my future lab bench, currently unoccupied. I practically begged for reasons to get excited about the work. I was told of the beauty of meticulousness, the wonders of knowing a subject from the bottom up.

But what about "top down?" Synthesis, integration, binding principles, systems, dynamics, interactions?

The research in question involves a bacterial protein, Cry4a, that is presumed to form a channel in mosquito guts, causing deionization (i.e. death); "presumed" because 20 years of research in labs around the world has failed to prove the point. It would be nice, of course, to benefit humanity by wiping out disease-carrying critters, but...

*Assuming we can engineer a deadlier protein, who's to say it won't get rejected by the bacteria after, say, 1000 generations? The assumption seems to be that a deadlier protein confers greater fitness on the bacteria. Quite naive.

*Assuming a competitive population of bacteria, who's to say the mosquito won't develop resistance to our protein?

*Assuming that resistance doesn't evolve, are we clear about the environmental impact of wiping out a species of mosquitos?

These are "top down" questions. Their answers inform us of the odds that the research might actually be of benefit to humanity. I didn't like the odds. It's possible that some world-beating toxinologists could change my mind. It's surprising, however, that a number of highly respected authorities at my own institute couldn't. There are no vendettas or personal gripes being aired here. I simply wonder a bit about the real state of science in institutes around the world.