Eugene Patrick Kennedy, 1919-2011.

E ugene Patrick Kennedy died peacefully at his Cambridge home, age 92 years, on September 22, 2011. He was a giant of 20th century biochemistry, and his pioneering studies of lipid biosynthesis and function were a foundation of modern cell biology. He was also a man of immense intellect and genuine modesty, a devoted teacher who inspired his many students and colleagues, and a loving father, grandfather, and friend. Gene was born September 4, 1919, the fourth of five children of Irish immigrant parents. His early formal education was in the Catholic schools of Chicago, but his real education was from the public library, where he developed an early passion for reading. “While still in grammar school, I happily read my way through a ton of junk,” he later wrote (1). After majoring in chemistry at DePaul University, he enrolled as a full-time PhD student in organic chemistry at the University of Chicago while starting full-time work at Armour & Co., joining a wartime effort to fractionate plasma for the battlefield. Assigned to a new facility in Texas for the industrial-scale fractionation of human plasma, he was joined by his college classmate and coeditor of the student newspaper, Adelaide Mjewski (Fig. 1). They wed on October 27, 1943, and had daughters Lisa (1950), Sheila (1957), and Katherine (1960). With the war’s end, Gene returned to Chicago for doctoral studies in Biochemistry, joining the Lehninger laboratory to study fatty acid oxidation in 1947. There, he made the landmark discovery that the tricarboxylic acid cycle, oxidation of fatty acids, and oxidative phosphorylation all occur in mitochondria. After short postdoctoral studies (with Horace Albert Barker at Berkeley studying β-oxidation of fatty acids and with the legendary Fritz Lipmann at the Massachusetts General Hospital studying the activation of acetate by CoA), he returned to Chicago and joined the faculty of Charles Huggins’ Ben May Laboratories for Cancer Research at the University of Chicago. Kennedy’s new laboratory focused on the formation of the phosphoanhydride bond between choline and phosphatidic acid to yield lecithin. He found, as did Arthur Kornberg, that cell extracts could catalyze this reaction if given high concentrations of ATP. Because the reaction only occurred with some commercial preparations of ATP but not others, Gene reasoned that a contaminant might be responsible, leading to his seminal discovery (2) that CTP and choline formed CDPcholine, the proximal choline donor to phosphatidic acid. This CDP-linked activation of alchohols or diglyceride is the heart of the biosynthetic Kennedy pathway of phosphoglyceride biosynthesis in mammalian cells (Fig. 2) and the similar pathway in bacteria. In 1959, he accepted the Hamilton Kuhn Professorship of Biological Chemistry at Harvard Medical School and embarked on the quest to purify membrane proteins. Gene’s first love in this endeavor was the lactose permease, dubbed the M (membrane) protein. He devised an elegant double-label method to identify the M protein based on the protection of its unique cysteinyl residue from N-ethylmaleimide by bound substrate, thiodigalactoside. It fell to Wilson and others to later isolate the active protein, but a generation of Kennedy laboratory acolytes, purifying more tractable membrane proteins, found that Gene’s response to all reports of promising steps was, “I wonder what that would do for the M protein.” By the mid-1960s, Kennedy’s laboratory at Harvard had hit full stride, with Phyllis Elfman in the office scrutinizing each expenditure with care, Marilyn Rumley in the near laboratory outside the office doing Gene’s experiments and keeping the prized collection of detergents, and a steady flow of graduate students, postdoctoral fellows, and even medical students in the middle and far laboratories. Kennedy taught us all through his simple formulation of questions, an insistence on clear, complete, and simple protocols, looking at the primary data, and maintaining a balanced perspective between the question being addressed and the details of each step. Above all, Gene suffused his laboratory with his devotion to science and his personal kindness to each person. One night, after 24 hours of work purifying phosphatidylserine decarboxylase from the membranes from a 100-lb block of frozen Escherichia coli, I picked the lock on Gene’s office door and lay down on the couch for a catnap, setting a 2-hour windup alarm clock on the floor near my ear. When I awoke, there was sunlight streaming in the window, the clock had gone off hours before, and Gene Fig. 1. Gene and Adelaide Kennedy, Cape Cod (photo courtesy of the Kennedy family).