Lipid mass spectrometry: A path traveled for 50 years

In the middle of the 1960s, I began graduate school and at the same time started on the path of using mass spectrometry to gain insight into various aspects of lipid biochemistry. This was not a straight path but one that went from organic geochemistry, to lunar sample analysis, to a pursuit of the structure of an elusive and very active, lipid mediator slow reacting substance of anaphylaxis (SRS-A). The discovery of the structure of SRS-A opened important questions about phospholipid biochemistry and the arachidonate cycle in cells. I have written this reflection to highlight the various advances in mass spectrometry that occurred during this time that had a great impact on our ability to study lipid biochemistry. I specifically applied these new advances to studies of leukotriene biosynthesis in vivo, leukotriene metabolism, and arachidonate-containing phospholipids that are essential in providing arachidonic acid for the 5-lipoxygenase pathway. Along the way, imaging mass spectrometry was shown to be a powerful tool to probe lipids as they exist in tissue slices. We found this as just one of the ways to use the emerging technology of lipidomics to study human pathophysiology. Our studies of neutral lipids and oxidized phospholipids were especially challenging due to the total number of molecular species that could be found in cells. Many challenges remain in using mass spectrometry for lipid studies, and a few are presented.