Paul J. Leibson 1952–2007

The scientific community is deeply saddened by the loss of Paul J. Leibson, M.D., Ph.D., who passed away last August at the age of 55 after a very short battle with a rare form of cancer. For more than 20 years, Paul has been an international leader in the area of NK cell biology and lymphocyte signaling. Through his studies, we have come to appreciate more fully the molecular mechanisms by which distinct activating and inhibitory receptors regulate the development of cell-mediated killing and cytokine secretion by this unique lymphocyte subpopulation.Paul was born to Ruth and Benton Leibson and grew up in the greater Chicago area with his brothers Marc and David. Paul attended the University of Illinois Urbana-Champaign and graduated magna cum laude with a B.S. in 1974. He subsequently attended the University of Chicago as an M.D., Ph.D. candidate, and there he trained with Dr. Hans Schreiber in immunology. After obtaining his M.D., Ph.D. degree in 1981 with honors, Paul pursued a pediatric internship at the University of Colorado Health Science Center in Denver, CO, and in 1984 began a fellowship in allergy and immunology with Anthony Hayward at the National Jewish Hospital and Research Center in Denver, CO. In 1986, Paul joined the Department of Immunology at the Mayo Clinic Rochester, MN, and began his independent research career. During the next 21 years, he would rise through the ranks to Professor of Immunology. During his time at Mayo, Paul also committed himself to teaching and was Dean of the Mayo Graduate School for 5 years. He was recognized as “Teacher of the Year” by the immunology graduate students, was a Mayo Distinguished Educator, and earned the Rose M. and Morris Eisenberg Professorship for his dedication to research and teaching. As an enthusiastic teacher and clear speaker, Paul was a great motivator of young scientists. He trained several medical fellows, postdoctoral fellows, and graduate students, many of whom have since succeeded as productive independent investigators.A long-standing interest of Paul's was to understand how NK cells kill. Starting in the late 1980s, he began exploring the effector molecules involved in the process, by investigating the roles of TNF, lymphotoxin, and Fas ligand, as well as the cellular machinery involved in degranulation of cytotoxic cell. Over his career, Paul contributed to the characterization of numerous signaling pathways in NK cells that could both positively and negatively regulate cell-mediated killing. Even prior to the identification of the activating and inhibitory receptors that control NK cell responses, his own work laid some of the foundations for subsequent research on signaling for activation and inhibition in NK cells. He established that NK cell cytotoxicity could be triggered by different receptors through distinct signaling pathways. Early on, he showed that NK cell contact with MHC class I-positive, resistant target cells resulted in a block of intracellular release of free Ca2+. Inhibition upstream of Ca2+ flux implied that negative signaling had to occur at a very proximal step, within a minute or so. Much of the subsequent work in the field of NK cell regulation has been guided by basic principles laid out in Paul's pioneering work.In the mid-1970s to early 1980s, a lymphocyte subpopulation that could kill certain malignant and virus-infected cells without prior sensitization or MHC restriction was described. Antiviral activity by these cells provided a major early immune defense against viruses in vivo. The early work on NK cells, including Paul's work with Anthony Hayward, required the isolation of mononuclear cells and either enrichment or depletion techniques to isolate or remove NK cell populations from the mononuclear cell preparations. Although these studies were useful in defining the innate immune characteristics of this new subpopulation of cells, more in-depth biochemical characterization of the signaling pathways activated in response to either tumor cells or virus-infected cells was not possible. Unlike the availability of human T cell lines and reagents for the T cell receptor (TCR), no human transformed NK cell line was available, and knowledge on NK cell-activating receptors was limited, aside from the FcγRIII receptor (CD16). Although Paul was convinced that shared signaling pathways might be utilized during the activation of T cells and NK cells, he realized that in order to understand the molecular mechanisms regulating NK cell-mediated cytotoxicity and to perform the kind of biochemical experiments that he was interested in, he needed to obtain larger and homogenous populations of NK cells, preferably nontransformed. Paul succeeded in developing a protocol to isolate and grow clonal populations of NK cells in sufficient quantity for his proposed experiments. This represented a large step forward in his ability to gain a more complete understanding of the signaling pathways activated during the development of cellular cytotoxicity. In fact, NK cell clones would become the mainstay of Paul's research and would afford him and other NK cell researchers the opportunity to dissect the mechanisms by which activating and inhibitory receptors function on NK cells.By using cloned human NK cells, Paul's lab quickly demonstrated the requirement for the generation of second messengers (IP3 and cAMP), as well as activation of the tyrosine kinase Lck, which is a proximal component in TCR signaling, and numerous other signaling molecules (e.g., Syk, PLCγ, PI3-K, and Vav) in the regulation of natural cytotoxicity and FcR-mediated (i.e., antibody-dependent) cellular cytotoxicity. Paul realized that a method of expressing wild-type and dominant-negative proteins in NK cell clones was needed in order to further our understanding of the signaling mechanisms involved in regulating NK cells. Unfortunately, unlike the success T cell biologists were having with transformed T cell lines such as Jurkat, cloned primary human NK cells were virtually resistant to transfection of plasmid DNA. This shortcoming was predominantly overcome by the adoption and development of recombinant vaccinia-virus technology into Paul's lab during the 1990s. This approach launched more in-depth signaling studies because virtually any signaling protein could be evaluated for its contribution to NK cell signaling through the expression of wild-type and dominant-negative proteins. As times for genetic manipulation changed from overexpression studies to RNA interference, Paul met the challenge head on and quickly worked out methods for transfection of small-interfering RNAs into human NK cell clones.Once inhibitory receptors for HLA class I were identified in 1995, Paul was among the first to provide a molecular basis for the balance between the positive and negative signaling pathways. In elegant studies published in Immunity in 1996, he defined a link between Src-family-kinase-mediated phosphorylation of the inhibitory receptor and the subsequent action of SHP-1 on the ITAM-dependent Fc receptor activation pathway. More recently, Paul contributed substantially to our understanding of signaling by the human NKG2D receptor complex, which contributes to natural cytotoxicity by recruiting Grb2 and Vav1. Paul's contributions continue to move the field forward, as attested by his first posthumous paper, published in the September 15 issue of the Journal of Immunology, in which he describes that defects in the SNARE protein syntaxin 11 in familial hemophagocytic lymphohistiocytosis 4 patients impair cytolytic function in NK cells and T cells.Beside his love of science, Paul enjoyed spending time with family and friends, traveling, eating food, drinking wine, and foraging the forests of southern Minnesota in the spring for the elusive morel mushroom, which inevitably resulted in eating more food and drinking more wine. Paul was also one of the most positive and optimistic individuals we have ever met, not to mention humorous. Regardless of the situation, Paul maintained a positive outlook and would always make the best of whatever life tossed his way. Despite his prognosis, Paul continued to guide his students and pursue science. His dedication to his work and optimism are best exemplified by the fact that days before his surgery in June 2007, Paul was working on a revised version of his NIH grant that he had had for the past 19 years. He submitted it the day before surgery.Paul's passion for science constantly kept him at the forefront of NK cell biology and signaling. To those working on similar questions, he was a generous and supportive colleague, more interested in advancing the field than in competing toward short-term goals. Discussions with him were open, informative, and enjoyable. His qualities as a kind and thoughtful person always came through, no matter what the scientific argument might have been. He was a wonderful host, known to prepare dinners for appreciative visitors and share special wines from his own collection. A regret shared by many of us is to have not taken more time to know him better on a personal level. We have all enjoyed Paul's work and benefited from his important contributions to science. Although his life ended too soon, Paul's excitement for science will live on with his trainees and colleagues who knew him well. His legacy will surely stand the test of time.Paul finds the “Mother of all Morels” in the spring of 2006.View Large Image | View Hi-Res Image | Download PowerPoint Slide