It is with great regret that I am not with you today to say goodbye to a wonderful friend, colleague, and mentor. Norm was all of these to me and to so many of his students, scientific collaborators, and admirers. Norm's death carries with it the inevitable grief that follows from such a loss and from the realization that there is now a void that can no longer be filled. However, the rush of memories that follows from the loss of someone you love and respect helps to ease the pain.
Life is full of random events, some of which lead to great fortune. For me it was the chance occurrence of getting on a bus for a hundred mile ride from Ann Arbor to Gull Lake for a weekend Cancer Center retreat. I sat next to Norm and we soon discovered a mutual scientific interest in lipids. Norm did most of the talking and I was an eager listener. I was immediately captivated by his scientific insights and knowledge of biochemistry and neurochemistry. The bus ride was followed by a weekend of long walks and meals discussing sphingolipids and their importance in human physiology and disease. The subjects were far ranging and at times what might have started as a discussion about the cellular biology of the brain or kidney quickly evolved into a larger debate over economics, politics, or religion. I will remember this as the best and most important two days of my academic career.
A scientific collaboration soon followed, although initially I was less of a co-investigator and more of a student. Norm had almost 50 years of experience studying sphingolipids and had defined many of the pathways that I had only read about in textbooks and review articles. His depth of knowledge was only exceeded by his boundless energy and enthusiasm for the science. Something must have rubbed off since the collaboration was very productive.
One day, about a year after the bus ride, Norm shared with me the “pink sheet” on his NIH grant application. It read in part “this is an excellent proposal from a 70 year old biochemist…” Remarkably, his grant did not receive a fundable score. Rather than feeling bitter Norm said “I think I should close my lab and move into yours. Would that be okay?” It took all of one second to agree. For the better part of the next five years we worked side by side. This was a gift for which I will always be grateful.
Most of our work focused on a hypothesis that Norm proposed in 1971, the use of “synthesis inhibition” to treat a set of diseases in which sphingolipids accumulate in lysosomes. This included at least seven diseases with names such as Gaucher’s disease, Fabry disease, and Tay-Sachs. Norm’s idea, which was very novel at the time, was that instead of replacing the defective enzyme, the use of a drug that would block the synthesis of the accumulating sphingolipid would be more rational.
Norm had made some progress toward this goal with the identification of a compound called “PDMP” a compound that blocked glycolipid synthesis. Ranga Vunnam was an important co-investigator in this early work. Jin-ichi Inokuchi had continued this project as a post-doc and later went on to pursue important studies in cancer and diabetes. Another post-doc, Akira Abe, stayed in Ann Arbor and continues this work even today.
We decided to try to improve the drug making it more active and specific toward its intended target. This work progressed nicely and eventually resulted in a series of related compound that were very potent. After demonstrating that the newer drugs would work in an animal model of a lysosomal storage disease, we were able to license these compounds for clinical development to a biotech company, Genzyme. The drug that has evolved from Norm’s hypothesis is today called eliglustat tartrate and it works precisely in the manner that Norm proposed. Genzyme has pursued Norm’s synthesis inhibition theory with what has been the largest clinical trial for Gaucher disease ever conducted involving patients in thirty countries around the world. Coincidentally, the “pivotal” phase 3 trials demonstrating the clinical benefits of Eliglustat were reported publicly for the first time yesterday. Importantly, this drug appears to work better than current treatments and if approved, it should be substantially less expensive and more convenient. I am grateful that Norm was able to learn that his theory was proven to be true while he was still with us. I only wish that he were around to see this drug make its way through FDA approval and into routine clinical use.
I once asked Norm why he chose to study sphingolipids. He said that it was his goal in life to try to find ways to make people smarter as this would certainly make the world a better place. He went on to say that the basis for intelligence could undoubtedly be understood by figuring out the biochemistry and biology of sphingolipids since it was these compounds that comprised more than 15 percent of the weight of the brain. I challenged this idea by pointing out that there were over 300 different types of glycolipids alone, reflecting an incredible level of chemical complexity. He rebutted my point by reminding me that all of human knowledge could be communicated with only two materials, the cellulose that paper was made of, and the ink with which words were written. For Norm, sphingolipids were the ink and the glycolipids were the calligraphy that nature used to write the words.
Norm's goal of finding ways to make people more intelligent was laudable. Without doubt, if any of us could attain Norm’s level of intelligence, then we would be the better for it. But more important to me would be the ability to attain Norm's level of curiosity about life and his passion in finding the answers to those questions he thought were important. These qualities, as much as his intelligence, were what made Norm such a great scientist and such a remarkable individual.
Norm, I cannot help feeling that at some point we will see each other again. When we do we will plan some new experiments and continue our debates.
Jim Shayman (February 8, 2013)