The bumpy road to molecular imaging

November 13, 2007

We have begun a marvelous new journey, we’re told, that will bring us personalized medicine. Therapies and the underlying causes of disease will come together like pieces of a puzzle. Imaging technologies, molecular imaging technologies to be exact, are the key to seeing how these pieces fit together. Last week I discovered just how tough it will be to connect basic research and patient care.

We have begun a marvelous new journey, we're told, that will bring us personalized medicine. Therapies and the underlying causes of disease will come together like pieces of a puzzle. Imaging technologies, molecular imaging technologies to be exact, are the key to seeing how these pieces fit together. Last week I discovered just how tough it will be to connect basic research and patient care.

Researchers at Ohio State University Medical Center reported that they had found the reason cardiac cells die after coronary arteries are reperfused. This paradox is of enormous consequence for the more than one million in the U.S. who suffer heart attacks each year.

Data explaining this paradox were uncovered in cells from rats using a novel imaging technique called dual-wavelength excitation spectrophotofluorometry. I was intrigued. If anything was molecular imaging, this was it. What I learned about the research published in the October issue of the Journal of Molecular and Cellular Cardiology, however, gave me pause.

Described in the article were answers that might lead to the means for managing patients in the throes of a heart attack. They explained why the rush of oxygen-rich blood following the placement of a stent killed rather than saved oxygen-starved cells.

The Ohio State researchers discovered that mitochondria, the microscopic power plants of cardiac cells whose source of fuel is pinched nearly shut by coronary stenosis, held the key. Molecular probes using dual-wavelength excitation spectrophotofluorometry allowed the scientists to watch how mitochondria responded when first deprived of oxygen and then provided all the oxygen they could want.

The results involved a world populated by biochemicals, such as substances that reacted with thiobarbituric acid, and measures of intramitochondrial ionized calcium concentration. Relying on little more than a fading concept of the Krebs cycle and a homegrown version of metaphorical science, I concluded that a protease inhibitor cocktail consisting of leupeptin, phenylmethanesulfonyl fluoride, pepstatin A, and aprotinin followed by the appearance of the cytochrome c protein was bad news, coming as they did during and then after hypoxia.

The real calamity to a cardiac cell, however, comes at the hands of calcium in a biochemical event equivalent of a quench to a superconducting magnet. A torrent of calcium, spurred by reperfusion, triggers the release of an enzyme that produces free radical nitric oxide, which overwhelms the mitochondria, and bang!-- down goes the cell.

The Ohio State researchers can't figure out what causes this rush of calcium, but in pegging the enzyme--mitochondrial nitric oxide synthase--they know what they need to stop in order to keep the cell alive. Or so they think. Future research may tell, but that isn't the point. What I learned about broken mitochondria during this brief encounter with molecular medicine pales in comparison to my newfound appreciation for the magnitude of what one day may be molecular imaging.

Up until now, we have been repackaging nuclear medicine the way competing corporations treat soft drinks. Will molecular imaging give us the same clinical results as nuclear medicine, but with a new look? Or do we go further and delve into basic science? If we do, how far do we go?

Do we follow biochemists into the microscopic recesses of the cell, into the inner workings of mitochondria, accounting for calcium flow and the generation of enzymes? In uncovering fundamental new truths, how do we reveal them visually in the body in ways that make clinical sense?

Thirty years ago, at the height of the supercomputer revolution, pharmacologists beamed that the day of intelligent drug design had dawned. Today, we wring our hands over an antibiotic-resistant staph infection and reach for vancomycin, a drug fast-tracked for FDA approval in 1958.

It is all too easy to be satisfied that we have entered a new era of medicine and to accept potential as accomplishment enough. The challenge of molecular imaging is not to demonstrate possibilities and then delight in what might be, but to define what we can achieve and then do it.