Last night I received an interesting query via twitter:
Many patients in nephrology present with 50-60% of normal kidney function. Even if we can stop the insult that produced this much loss of kidney, at this point the vicious cycle of progression occurs. The kidney tries to adapt to its losses with processes that cause more loss of tissue. In trying to get back to normal, the kidney commits suicide. Over the years, we have discovered ways to slow this process, but we cannot stop it. This is particularly unfortunate, because most people have no symptoms of kidney failure with minimal medication at half of normal function. If we could halt the process at that point, most adults would have relatively normal lives without needing dialysis or transplant! (Since we cannot do this yet, I do not yet know if we could get children to grow and develop acceptably at half of normal function.)
Thus, my answer:
Of course, this is a really broad answer that is likely more clinically oriented than whatever spawned the question. Kidney researchers have been working on progression for as long as I can remember, resulting in our current strategies that slow it down; however, we still do not fully understand the process despite at least two decades of research! And, while I can identify this as a really clinically important area of inquiry, I HAVE NO IDEA WHERE THE BIG BREAKTHROUGH WILL ULTIMATELY COME FROM. If more incremental work in the existing areas will do it, then we may get there in a few years. I suspect the real breakthrough will come out of left field, from completely unexpected directions.
You know, the risky, out-there research that will have more trouble getting funded right now.
It may also come from studies of other organ systems! Other diseases! Other organisms!
I believe this is true for most clinical problems facing us today. We really cannot know what particular basic science piece will lead to therapeutic insights and cures. Who would have thought that studying cilia would help us understand polycystic kidney disease?
That's the real tragedy of the current funding climate. As paylines drop, funding tends to get more conservative with projects having the best chance of "success," defined as fulfilling their hypothesis. This can result in incremental studies which may be valuable, but rarely shift paradigms. Those weird, unexpected results that can impact other fields may be missed completely.
Patch-clamping fruit fly neurons may sound like a ridiculous waste of money to the general public (and congress), but from a basic science standpoint it could be quite important. If we want cures for diseases, we have to support scientific inquiry, not just clinically-directed research. Our current "best treatments" for the problem of progression arose from studies of South American vipers; I would guess that those investigators had no idea that there would be such practical outcomes from their research.
Let's put it this way: I am a physician-scientist with more than 20 years of experience in the field, and I have no idea what specific basic science questions may lead to the next big breakthrough. Our best hope is to fund as much as we can, all of it if possible. We then need to keep scientists and clinicians engaged, so those random sparks of imagination come together.
The process is messy and disorganized and unpredictable. You cannot script discovery.