The frustrating part is trying to produce good crystals. We figured out how to make a lot of the protein--we produced a lot in bacteria--but then the frustrating part is screening an enormously large set of conditions to find out which conditions would give us crystals of sufficient quality to solve the structure. Membrane proteins can take a very long time--many, many years--and we managed to solve this problem in about two years. But it was two years where we worked very hard indeed; many members of the lab worked hard on this problem, talented scientists like Declan Doyle, Jo¿o Morais Cabral, worked for maybe two years; Alice Lee, Anling Kuo, Richard Pfuetzner, all of the authors on the paper worked hard over that two years. So in terms of person-years, it was many, many more than two years. We were all very excited about the problem, and we guessed that if we could see this structure, we could understand a lot more than we ever could without seeing it. So that's what drove us through this enormous set of conditions, and then many trips to the synchrotron--a great source of x-radiation that we used to study the crystals in order to deduce the structure.
SA: So studying the structure once you have got the crystals, is that a fairly straightforward process?
RM: Yes, fairly straightforward, although there still are challenges. The hardest part in this whole process is obtaining the crystal that's of sufficient quality. Once you have obtained that, it's fairly straightforward, but it can still take quite a bit of time. We had the crystals that were good enough to solve the structure almost nine months before we completed the structure, and it took us about that time.
SA: I think the structure you came up with revolutionized the whole field. Do you think it has applications to medicine?
RM: Yes, I do. People ask, "Well, now can you immediately cure a disease with this?" and the answer to that is, no. It has applications to medicine in the way that it's laying the foundations for understanding an important class of molecules. So I can't say you can take the structure and immediately predict a drug that could then work on our own potassium channels, for example. That would be wrong to say.
But we need to consider what potassium channels do--they make the electrical signals in our hearts, in our brains; they aid our movements and our thoughts; they control the smooth muscle on the lining of our arteries, so they control blood pressure, and they also control the smooth muscles in our airways, so they can affect asthma. Because they play such a central role in many physiological processes in us, to understand the basic molecules that do this is merely a beginning to laying the foundation for eventual development of drugs that can affect some conditions.
There are certain diseases related to ion channels, but I would predict that the utility of drugs, of pharmaceutical agents acting on ion channels, won't be so much to take an abnormal ion channel and make it normal. I think it's more going to be to slightly affect the behavior of an already known ion channel, to basically correct a condition that's abnormal but not primarily related to the ion channel. So, for example, compounds that can affect the electrical activity of our nervous system eventually can be used as anti-seizure agents or anti-arrhythmics for the abnormal electrical activity in our hearts. Also there is potential for anti-hypertensives--blood pressure medications.