Obituary: Hans Meinhardt (1938-2016).

Hans Meinhardt, a pioneer in the field of theoretical biology, died on 11 February 2016 in Tübingen. He made numerous important contributions to developmental biology by spearheading the use of mathematical models to investigate the logic of patterning in complex biological systems. His work expanded our understanding of the mechanisms behind diverse biological processes, from the generation of patterns on sea shells to the evolution of the brain. Meinhardt grew up in the German Democratic Republic. His family fled to West Germany before the Wall was built. He studied physics at the University of Cologne and received his PhD in 1966. As a postdoc at the European High Energy Laboratory (CERN) in Geneva he gained expertise in computer-based modeling, but over time became more interested in biological processes and decided to move into the emerging field of molecular biology. In 1969, Meinhardt joined the group of Alfred Gierer at the Max Planck Institute for Virus Research in Tübingen, Germany (which has since become the Max Planck Institute for Developmental Biology). Gierer, a physicist by training, and famous for the demonstration that RNA, not only DNA, could be the genetic material (Gierer and Schramm, 1956), was looking for new challenges in developmental biology. He had started a research group to study the miraculous regenerative capabilities of Hydra, which can self-organize perfect animals even after complete dissociation. Meinhardt’s initial project in Gierer’s department was purely experimental, isolating chromosomal proteins from cow blood cells. Meinhardt was convinced that this could be accomplished without using an ice bucket, arguing as a theoretician that the proteins should be stable at room temperature because they are also stable in living warm-blooded cows. However, discouraged by many wet lab failures, he looked for theoretical rather than experimental challenges. Stimulated after a seminar by Günter Gerisch (a group leader at the newly founded Friedrich Miescher Laboratory) on oscillations and chemotaxis in the slime mold Dictyostelium, Meinhardt considered applying his expertise in computer modeling to simulate the aggregation of Dictyostelium. Gierer was intrigued by the thought of applying computational methods to developmental biology problems, but suggested that Meinhardt instead use this approach to develop a theory explaining the surprising regenerative capabilities ofHydra. This idea was inspired by two major influences. First, Magoroh Maruyama had demonstrated the importance of positive feedback – selfenhancement – that could dramatically amplify small deviations from initial conditions in diverse processes, from morphogenesis to economy (Maruyama, 1963). Second, neurophysiological work in the neighboring Max Planck Institute for Biological Cybernetics showed that contrast enhancement in the visual system is achieved by a local activation from a stimulus together with an inhibitory effect on surrounding areas of the retina, a mechanism termed lateral inhibition (Kirschfeld and Reichardt, 1964). The synthesis of these two concepts of local self-enhancement and lateral inhibition led Meinhardt and Gierer to formulate a theory explaining the emergence of polarity and pattern from near-uniform states. Meinhardt and Gierer hypothesized that patterning could be mediated by a short-range activator with strong self-enhancing capabilities, coupled to an inhibitor of longer range that suppressed the expansion of the activator in the surrounding areas. Meinhardt then performed computer simulations to test whether their hypothesis could explain experimental observations. In the 1970s, no biological institute had a computer, so the numerical simulations had to be done using punch cards on a Hollerith machine at the computer center in the University of Tübingen. Much of the theory was based on Meinhardt’s remarkable intuition, which made the tedious computations feasible. Their famous theory of biological pattern formation was published in Kybernetik (Gierer and Meinhardt, 1972), followed by a paper on applications in the Journal of Cell Science (Meinhardt and Gierer, 1974). Although the theory was driven by the experimental work on Hydra, it also provided an important general recipe for self-organization. Strikingly, even in the absence of specific molecular data these models correctly predicted the behavior of several biological systems (Meinhardt, 1982; Meinhardt and Gierer, 2000). Meinhardt and Gierer’s work is often regarded as equivalent to the earlier work of Alan Turing (Turing, 1952). However, they were not aware of Turing’s paper at the time of submission (Meinhardt, 2006a, 2008; Roth, 2011), and in fact the Meinhardt–Gierer model provided three important advances that were missing in Turing’s work. First, the fundamental concept of local self-enhancement and long-range inhibition, although inherent in Turing’s equations Friedrich Miescher Laboratory of the Max Planck Society, Spemannstraße 35-39, Tübingen D-72076, Germany. Max Planck Institute for Developmental Biology, Spemannstraße 35-39, Tübingen D-72076, Germany.