My Brief Encounter with the Phosphoinositides and IP3

Abstract

. Before describing thisresearch, however, I should say how that choice came about. While in graduate school at theUniversity of Wisconsin, I had had the good fortune to study under Karl Paul Link, who waswidely renowned for his discovery of dicumarol and the synthesis of related blood anticoagu-lants such as warfarin, work that was recognized with two Lasker Awards (1). On the side,however, Link remained a carbohydrate chemist at heart, a hobby that had grown out of hisstudies on plant polysaccharides and uronic acids while a student and then a young facultymember. In fact, Stanford Moore had completed his doctoral dissertation with Link on amethod for characterizing aldo-monosaccharides as benzimidazole derivatives (2).I arrived at Madison in the fall of 1946, fresh from a stint in the United States Navy, andI found Link’s laboratory bursting at the seams with about 15 ex-GIs, all hard at work tryingto make up for lost time. During earlier investigations on the structure-function relationshipof coumarin anticoagulants, an attempt to synthesize the glucoside of dicumarol had beenfrustrated because the acetylated intermediate was degraded in alkali under conditions usedfor deacetylation (3). Because glycosides are acetals, which are typically acid-labile andalkali-stable, I found the anomaly intriguing and decided to study a variety of syntheticcompounds in an effort to understand the structural basis for alkali sensitivity (4). Thisresearch formed the core of my doctoral dissertation, and although I failed to recognize it at thetime, the chance exposure to carbohydrate chemistry was to have a lasting influence on thedirection my career would take.I continued my indoctrination in sugar chemistry during a postdoctoral year in Edinburgh,Scotland, with E. G. V. Percival in the new Department of Chemistry at Kings Buildingsheaded by Edwin Hirst. This was a time of economic depression in Britain, which was stillsuffering the aftermath of the war, and I discovered that I had left a well equipped laboratoryin Madison to engage an unexpectedly primitive research environment. Wisely I did not letthis change in fortunes discourage me. Instead I undertook a project dealing with the structureof maple sapwood starch and did the best that I could with the available facilities (5). Myefforts were well rewarded because, in the process, I became adept at the uses of analytical andpreparative filter paper and cellulose column chromatography, skills that were to be extremelyvaluable in my later research. The greatest challenge to my ingenuity, however, was toconstruct an electric stirring device from a small board-mounted motor, a couple of woodenpulleys, a piece of string, and a glass rod. The speed of the motor was regulated by adjustinglight bulbs that were wired in series with the power cord to draw off electricity, a crude buteffective method of control. I have always enjoyed working with my hands, so this mundaneproject even took on a certain appeal.Living in a new environment always has its fringe benefits. While in Edinburgh, I developeda special affection for the Scots and a better understanding for the lingering resentment that