Paul Kleihues (1936–2022), neuropathology innovator and entrepreneur

Paul Kleihues passed away on the March 17, 2022 at the age of 85. He was a remarkable physician‐scientist, an innovator in the field of brain tumor diagnostics, an entrepreneur in scientific publishing, and most important of all, a mentor for an entire generation of neuropathologists. He will be deeply missed by the neuropathology community.

Paul started his career at the Max Planck Institute for Brain Research in Cologne (Germany), became a professor for neuropathology first in Freiburg (Germany) and then in Zürich (Switzerland) before he was appointed director of the Agency For Research On Cancer (IARC) of the World Health Organization (WHO) in Lyon (France). Following his activities at IARC, he became the founding director of the Comprehensive Cancer Center at the University Hospital Freiburg (Germany), was a fellow at the Institute for Advanced Study in Berlin, and a visiting scientist at the Center for Cancer Research of the United States National Cancer Institute. He concluded his extraordinary career as an emeritus professor of neuropathology at the University of Zürich.

Paul's earlier scientific work focused on chemical carcinogenesis of brain tumors, and he published important papers in this area [4]. He then reinvented his science by taking a sabbatical at Columbia University in the early 1990s, where he learned molecular biology. He returned to Zürich reinvigorated and started several new avenues of research, including early studies of genetic changes in gliomas such as TP53 mutations. He took this work with him when he became director of IARC in Lyon. His group there popularized the notion that primary and secondary glioblastomas were genetically different from one another, an idea that had been germinated by some of the present authors (AvD, DNL). Paul's detailed studies, including population‐based findings, pushed the concepts further and set the stage for the discovery of the IDH genes to paint a clearer picture of glioblastoma variation [5]. In total, Paul published well over 300 peer‐reviewed articles and some of his contributions are among the best‐cited papers in the field. Most importantly, his contributions have had a real impact and are what we would call “textbook knowledge.”

Another pioneering step during Paul's later years in Freiburg was his decision to establish the German Brain Tumor Reference Center for the neuropathological diagnosis of CNS tumors in 1980. Initially opposed by a prominent group of distinguished clinical neuropathologists who felt that a rather young and unusually dynamic colleague with a strong focus on experimental research would never qualify for such an enterprise, Paul and colleagues also turned this project into a big and long‐lasting success. An elegant political move was to affiliate this unit with the Germany Society for Neuropathology and Neuroanatomy, which never really interfered in the early days. It matured in Zürich and subsequently moved to Germany where it was taken over and further developed by Paul's former team members. Today this reference center under the leadership of Torsten Pietsch in Bonn and Guido Reifenberger in Düsseldorf serves as a highly recognized consultant platform.

At Freiburg and even more in Zürich, Paul attracted many young aspiring neuropathologists. Very special in his departments was a high degree of scientific freedom. For instance, Paul allowed projects that he was critical of and the spirited discussions included everyone from novice to department head, with Paul creating the feeling that we were participating in a mission of transforming neuropathology into a modern discipline. Paul's spirited leadership thus enabled a breeding ground for a whole generation of neuropathologists who wanted to change the field.

Paul was also a magnet for esteemed colleagues worldwide, which in turn benefitted his young team. Many neuropathologists took sabbaticals in his exciting department in beautiful Zürich, exposing the fledgling trainees to alternate approaches to diagnostics, sometimes quite different from the one pursued by Paul. Sometimes Paul, as a man of decision, would say that his ultimate diagnosis was based on his unique hearing talents (“the tumor talks to me”), whereas one or another sabbatical professor advised the trainees to rely more on our eyes.

Paul was the primary editor for the 1993 and 2000 WHO classifications of CNS tumors and was heavily involved in the 2007 classification [3]. The first and subsequent versions of the classifications were drafted in his office by Paul and colleagues visiting from all parts of the world. While the role of the trainees was focused on serving drinks, it was a great opportunity to see classification in the making. Evidence was cherished but was relatively sparse at that time, providing ample room for eminence. Inevitably discussion on nearly all topics became locked, and Paul would cut the Gordian knots with his charisma and the words: “I will take care of this later, trust me.” And indeed, he succeeded in finding a solution acceptable to all.

Each classification also involved in‐person consensus meetings with expert neuropathologists. He was a master at leading the discussions decisively and typically in a direction that resulted in the answer that he wanted. It has been said that “diplomacy is the art of having someone else have your way” and Paul followed this old adage—essentially always getting his way in the end. Fortunately, his way was usually the sensible one most supported by the data in the literature and by people's experiences as diagnostic pathologists. For example, at the meeting that guided the 2000 classification, Paul asked the group if anyone had ever made a diagnosis of polar spongioblastoma. When no one raised a hand, he said, “Very well, if none of the experienced neuropathologists here has ever made that diagnosis, we will delete it from the classification.” At that point, a senior neuropathologist raised his hand rather frantically to object since he was fond of the historical term. Paul simply looked at him, put on his charming smile, said “No, we have decided this,” turned his head away, and went on to the next question. The group followed.

Paul was also expert at creating the content of the books, and of putting together the chapters and pictures in creative ways. He had an inherent sense of design, of how to draw up plans for a journal or a book to improve its ability to communicate ideas. In fact, the current format of the WHO “Blue Books” were his brainchild, his design. He innovated this for the 4th‐edition books and the format has carried on into the 5th edition, which is a tribute to Paul's vision and his understanding of journal and textbook layout design [1].

For the 2016 CNS WHO classification, Paul was not an active expert editor but rather served as the “publisher”—mostly deciding on the layout of the book and acting as an intermediary with IARC/WHO. Nonetheless, in his characteristic manner, he wanted a say in every decision, even the neuropathological and molecular ones. In the final proofing stages, three of the editors (including DNL) were in Zürich working with Paul and a copy editor. When Paul returned from a long lunch, after the rest of us had pressed on, Paul said something in German to the copy editor and none of the three editors knew much German. When one of us (DNL) said to Paul that he assumed Paul had just asked if we had changed something important, he put on that charming smile and said, “Oh, you know me too well.” Fortunately, he let our changes pass!

One of us (MG) is Editor in Chief at Brain Pathology, the very journal Paul Kleihues founded in 1990. His entrepreneurial activities in the early days of the journal were key to its success. During “packaging parties,” all medical residents of the Institute were recruited to envelop issues of the journal for shipment, motivated by subsequent pizza and beer. Paul turned out to be a “marketing specialist,” promoting and selling the journal around the globe at neuropathology conventions. Thanks to Paul Kleihues, Brain Pathology has never left the first quartile of journals with the highest Impact Factors in the category of clinical neurology and pathology [2]. The spirit of the journal set forth by Paul Kleihues continues, as does the minimalistic cover design ("black is colorful enough") promoted by him.

As the above reminiscences indicate, Paul was a larger‐than‐life individual. Nothing stopped him from achieving his professional goals, and he did so in creative and insightful ways. All of us will miss his charm, his smile, and his consistent encouragement to achieve our own professional goals.

CONFLICT OF INTEREST

None.

Aguzzi A, von Deimling A, Glatzel M, Louis DN, Wiestler OD. Paul Kleihues (1936–2022), neuropathology innovator and entrepreneur. Brain Pathology. 2022;32:e13073. 10.1111/bpa.13073

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.