Friedrich Bonhoeffer, one of the great developmental neuroscientists of the past decades, has left us. Known as ‘Bonni’ or ‘FB’ in the Institute, Friedrich Bonhoeffer was Director at the legendary Max Planck Institute for Developmental Biology in the Spemannstrasse in Tübingen. In the 1980s and 1990s he led the neuroscience community in Tübingen and far beyond, fundamentally advancing research in the field of developmental neurobiology with a number of seminal discoveries, bringing him worldwide recognition and making Tübingen an admired hub for developmental neurobiology.
FB studied physics in Göttingen and wrote his doctoral thesis with Arnold Flammersfeld; he obtained his doctorate in 1958 at the age of 26. During his postdoctoral time at the University of California in Berkeley he studied the physical properties of nucleic acids and nucleoprotein complexes. From there he was drawn to Tübingen, where he stayed for the rest of his highly successful scientific career.
In Tübingen, he first investigated questions of DNA replication and, together with his colleague and long-time friend Baldomero Olivera, demonstrated the necessity of DNA polymerase I for the replication of prokaryotic genomes (Olivera and Bonhoeffer, 1974). This discovery succeeded thanks to the development of an ingenious new in vitro assay, a characteristic also of his later work on axonal guidance.
In the 1970s, enabled by the great academic freedom that the Max Planck Society accords its leaders, FB changed his scientific focus and started to explore the development of the nervous system, thereby (co-)founding the field of axon guidance that a few decades later would be ultimately linked to his name. This new and exciting, but uncharted, topic explored the question of how axons originating in one place search out their often distant target nerve cells to connect with them specifically, as a first step in circuit formation. Again using innovative new in vitro assays his work opened this field towards a cellular and molecular understanding of the mechanisms of axon guidance.
FB chose the retino-tectal projection in the visual system as his experimental subject, where axons originating in the eye specifically project to the optic tectum, the part of the brain in which visual information is initially processed. This connection between the retina and the tectum is topographically organized: neighboring cells in the retina are connected to neighboring cells in the tectum, leading to a continuously organized point-to-point connection, and with that to a ‘map’ of the outside world in the tectum. Groundbreaking discoveries to understand the principles of retino-tectal map development go back to experiments by the Nobel laureate Roger Sperry in the 1940s, who showed that precise nerve connections are first established not by neural activity, but by ‘cytochemical tags’, i.e. cell surface molecules. His findings were formally laid down later in the famous ‘chemoaffinity hypothesis’ (Sperry, 1963).
FB continued this line of research, carrying out his pioneering work on chicken embryos, for whose production in the early years a chicken farm with free-range chickens was established behind the Max Planck Institute. His quest for a detailed understanding of axon guidance involved the development of several in vitro assays (Bonhoeffer and Huf, 1980, 1985). Ultimately, it was the ‘stripe assay’ that led to epoch-making breakthroughs in the understanding of the emergence of neural connections (Walter et al., 1987b). In this stripe assay, explants from the retina are placed on a surface prepared so that the (re-)growing axons are given a choice between two alternating substrates consisting of cell membranes from different parts of the tectum which were arranged in stripes. FB, together with his long-time assistant Julita Huf, demonstrated that retinal axons ‘choose’ to grow on the ‘correct’ membranes – that is, membranes derived from the region of the tectum that was also their natural target in vivo (Walter et al., 1987b).
The significance of this groundbreaking finding relates back to Roger Sperry's findings of ‘cytochemical’ (molecular) tags (Sperry, 1963). But before the 1980s, suitable assays did not exist to prove experimentally the existence of these molecules. The development of the stripe assay demonstrated that such tags do indeed exist to guide axons differentially to their correct destination. Furthermore, it provided avenues to better understand the mechanisms of axon guidance and, crucially, a route to track down and actually identify the underlying molecules.
An important breakthrough was the realization that the retinal axons made their ‘choice’ not because they were attracted to membranes from appropriate regions of the tectum, but because they were repelled from growing on membranes from inappropriate regions (Walter et al., 1987a). This finding came at a time when the general dogma stated that axonal steering can be explained only by attraction and differential adhesion. FB's discovery of a repulsive steering mechanism resulted in a far-reaching paradigm shift in the field of developmental neurobiology.
Central to ideas of attraction and repulsion in axon guidance is the concept that molecules are present in gradients across tissues in order to guide axons. This idea was not only formulated by Sperry (Sperry, 1963) but also in the theoretical work of FB's great colleague and mentor Alfred Gierer (Gierer, 1983). FB was able to demonstrate, using an earlier in vitro assay, that the repellent activity is indeed expressed in a functional gradient in the target area (Bonhoeffer and Huf, 1982), and thus can give growing axons position and direction information. FB continued to work intensively on this question in his last years of research, as he thought that a study of the behavior of axons and growth cones within gradients would result in an understanding of the core mechanisms of axon guidance. In fact, although he and his lab made important discoveries on this topic (Rosentreter et al., 1998), multiple new questions arose for future generations of scientists.
When I arrived in Tübingen in the early 1990s, the time was ripe for the identification of the molecules responsible for controlling topographic map formation. Armed with the stripe assay results, FB and my own group conducted crucial protein-biochemical and molecular-biological experiments aimed to identify these molecules. In a 1995 publication (Drescher et al., 1995), we described the cloning and functional characterization of the ephrins, a family of molecules that are now considered to be the prime candidates for the cytochemical (molecular) tags described by Sperry.
Indeed, ephrins bind to a corresponding family of Eph receptors on axons, form complementary gradients in the retina and tectum (Cheng et al., 1995) and act via a repulsive mechanism to control growth and branching of axons and ensure that topographically appropriate connections are made in the right place (Weth et al., 2014). In the years that followed, it transpired that the ephrins and Eph receptor families play fundamental roles in a huge range of other biological processes, from axon guidance to brain patterning to formation of blood vessels (angiogenesis) to cell migration in many parts of the body (Klein, 2004).
FB was among a handful of scientists who were most influential in advancing this field and, with the invention of in vitro assays, paving the way for the identification of the respective molecules that allowed an understanding of neural development on a molecular level. In fact, in the late 1980s and early 1990s, there was a real sense of discovery and huge excitement sweeping through this still young field of axon guidance in Europe and the USA, leading to key insights into the pivotal importance of attractive and repulsive molecules in shaping brain wiring, and culminating in the cloning of the now classical axon guidance molecules netrins, semaphorins, slits and ephrins (Tessier-Lavigne and Goodman, 1996).
A special concern of FB was the promotion of young talented scientists. Over the decades, he housed many independent junior groups in his department, including – 40 years ago – groups conducting stem cell research, exemplifying FB's exquisite understanding of important research questions far ahead of their time. In addition, he was also an attentive and benevolent mentor of generations of junior group leaders at the neighboring Friedrich Miescher Institute. Cooperation and the open exchange of information with other working groups was a fundamental quality of FB. Together with his colleague and Nobel laureate Christiane Nüsslein-Volhard, he went on to establish a gigantic – and very successful – zebrafish mutation screen in order to identify mutants that carried defects in the development of the visual system (Baier et al., 1996). The ‘Tübingen screen’, now famous in the field of developmental biology, led not only to the further identification of genes and molecules that wire the visual system, but to the career development and diaspora across the world of leading neuroscientists whose scientific lives started in the orbit of FB.
‘Guidance’ may be a key word to understand the life, personality and scientific achievement of Friedrich Bonhoeffer. He was interested in the guidance and steering of axons, but he also guided the people who surrounded him through his exemplary behavior, in which fairness, kindness, generosity, and willingness to discuss – underlain with a decent amount of humor – were central. Many visiting scholars who came to Tübingen, be it for only a lecture or for a longer sabbatical, found a very hospitable atmosphere, which they still warmly remembered many years later.
FBs' groundbreaking achievements have been recognized in many ways in recent years, including the award of the Gruber Neuroscience Prize during the 50th anniversary of the American Society for Neuroscience (SfN), which he received together with two other authorities of developmental neurobiology, Corey Goodman and Marc Tessier-Lavigne.
FB leaves behind his wife Dorothee and three sons, Tobias, Philip and Sebastian and their families.
With the passing of Friedrich Bonhoeffer, developmental neurobiology has lost one of its greats.
Acknowledgements
I would like to thank colleagues and friends of Friedrich Bonhoeffer for their insightful contribution to this Obituary.
