Ewald R. Weibel passed away on February 19, aged 89. His remarkable intellect remained intact even as his physical condition worsened. He continued to be fully engaged scientifically at the time of his death, in close professional contact with his longtime associates Connie Hsia (University of Texas, Southwestern Medical Center, Dallas) and Matthias Ochs (Charité, Berlin). It will come as no surprise to those who knew him that he was in preparation of his ultimate research paper, finishing the draft for its Introduction just two weeks before his final hospitalization.

Weibel’s journey from his childhood home in Zurich to membership into the National Academy of Sciences was an interesting one with many unexpected turns. He came from a modest family background; his father was a typewriter mechanic. It was a financial stretch for the family to have their son studying medicine - which he did with a state stipend. When Weibel graduated, he had to find employment as interns then rarely received a salary during their first two years of clinical training. Little would he know that this “outside employment” would set a path on which he would remain for his entire scientific career. His job in pathology was a mandate to study the anastomosing vessels between the bronchiolar and the pulmonary circulation. With an ingenious experiment he could show that the particular structure of these arteries, with longitudinal muscle strands in the intima, could be attributed to the stretch to which these arteries were subjected during ventilation unrelated to their anastomosis function. This work earned him a two year fellowship jointly funded by the Swiss Academy of Medical Sciences and the NIH. His intention was to study the physiology of the collateral circulation in the lung at Andre Cournand’s lab at Columbia University. Cournand had received the Nobel Prize in Physiology just previously in 1956. Newly wed, to his supportive wife Verena, they travelled to New York by ship. After a short stint at Avriell Liebows lab at Yale, and after a successful seminar at Columbia, Weibel could realize his dream and join Andre Cournand’s lab. As one might surmise, Nobel Laurates are outstanding “talent scouts” and Cournand offered him immediately a laboratory and generous resources with only the one requirement: “Do anything on the structure of the lung that is of interest to physiology”.

As Weibel started his work in Cournand’s lab he made a crucial acquaintance. In September 1959 he met Domingo Gomez, a brilliant exiled Cuban biophysicist also working in Cournand’s lab who’s interest was modelling gas exchange in the human lung from first principles. Together they soon realized that to do realistic modelling of gas exchange they must rely on quantitative data on the anatomical structures relevant for gas exchange. As the lung’s surface area is anatomically only accessible on thin sections of lung tissue a serious problem had to be solved: how to make accurate estimates of physiologically relevant structural properties in three dimensions from measurements made on tissue sections in two dimensions. Aspects of this problem had previously been solved for metallurgy and geology but these techniques had not been applied in biology. So together with Hans Elias, Weibel was an early key promoter of a branch of probabilistic geometry later to be named “Stereology” or “Morphometry”. Stereological estimates of some quantitative parameters of the lung and a model of the branching pattern of the alveolar tree let Weibel and Gomez publish a landmark paper on the architecture of the human lung.

However, it became soon clear that the resolution of light microscopy was simply not good enough to resolve the intricate structure of the interface between the air space and the erythrocyte in the lung capillary to realistically model lung diffusion capacity from structural quantities. In 1961 Weibel realized that he needed the resolution power afforded by electron microscopy to obtain the structural estimates needed for physiologically relevant modelling. Fortunately for Weibel, Cournand established contacts with George Palade at Rockefeller. Palade was a pioneer of electron microscopy who went on to receive the Nobel Prize in physiology in 1974 for his contributions in laying the structural foundation for cell biology. Weibel was thus able to learn electron microscopy, the then cutting edge tool of biology, at Palade’s lab. The resolution of electron microscopy allowed for structural measurements of the last step of the oxygen transfer from the air in the alveoli, through the tissue barrier and the plasma space into the red cell as needed for the modelling efforts of Gomez.

While at Rockefeller Weibel came across peculiar tubular structures that he found in endothelial cells of a rat lung but also in endothelia of other tissues. These structures had not been described before and with Palade he published his finding. Today these structures are known as ubiquitous markers of endothelial cells under the name of “Weibel-Palade bodies”. Much later, in 1982, it became known that the Weibel-Palade bodies contain amongst other things the von-Willebrand factor a key component of coagulation.

By 1962 Weibel, his student visa expired, was forced to return to Switzerland. The University of Zürich offered him an Assistant Professorship with the task to set-up the first electron microscopy unit. It was not long before Swiss Universities were competing for Weibel’s skills and intellect and in 1964, at the age of 35, he accepted an offer to become the Director at the Department of Anatomy of the University of Bern. With considerable financial support of the canton of Bern, Ewald Weibel was tasked to establish a cutting edge institution for quantitative structural research. This gamble by the University of Bern paid off big time as this institute became the reference lab for quantitative structural analyses on the microscopic and electron microscopic level world-wide and known as the nurturing ground for the development of stereology. Weibel’s love for stereology had much to do with the fact that stereological measurement techniques are derived from first principles and when done correctly, allow for obtaining unbiased estimates for volumes, surfaces, lengths and numbers of structures or compartments in biological samples. Both the basic and especially clinical impact of these measurements to this day are, arguably, not possible with any other technique used in biology.

The main focus of the experimental work at Weibel’s lab continued to be the gas exchange apparatus. He was keenly interested in the potential malleability of the pulmonary gas exchanger with exercise and hypoxia but also understood the value in comparative physiology. He studied the lungs of very small mammals such as the 3g Etruscan Shrew as well as the lungs of humans that were collected post-mortem. In various collaborations he also made his morphometric techniques available for the study of fish gills and the lungs of birds. An important finding of these studies was that in a comparative context, pulmonary diffusing capacity as measured by morphometric techniques scaled in direct proportion to body mass (scaling factor 1) while resting oxygen consumption scaled to body mass with a scaling factor of 0.75 – an apparent discrepancy.

As his pursuits grew, he never lost his interest in the nature of the Weibel-Palade bodies. So on his first sabbatical in 1975 he decided to once again join his old friend Palade and together they used cell biological techniques to unravel the function of the tiny tubular structures in endothelia that carried his name. It turned-out this was one of the few projects that Ewald did not finish with success; a reminder of how failure is an integral part of success. Indeed, this led to a long and productive new direction.

The failure to unravel the secret of the Weibel-Palade Bodies gave Weibel the opportunity to meet C. Richard (“Dick”) Taylor, a Harvard Comparative Physiologist who had a gift for measuring the maximum aerobic capacity (VO2max) in a number of mammalian species of different body size. The two of them decided to join forces to launch an expedition to Kenya with the aim of understanding oxygen uptake, transport and utilization across species. To do this they measured VO2max data on as many wild African species as possible and coupled those data with samples of lung and muscle morphometry from the same animals. This gigantic project was the start of a close friendship between Ewald Weibel and Dick Taylor that lasted until Taylor’s death in 1995. It was also the start of an extremely fruitful collaboration between Taylor’s Lab at the Concorde Field Station of Harvard University and the Department of Anatomy of the University of Bern. The collaboration resulted in more than 25 joint publications. The unique contributions of this research matched the maximal oxygen uptake of animals to their relevant quantitative structural features of the heart, the circulation and the skeletal muscle tissue. This complex study provided countless insights into the design of the entire respiratory cascade in mammals in a coherent quantitative frame and under limiting physiological conditions of VO2max.

One indisputable finding of this long collaboration was the close match between structure and function in the design of the mammalian respiratory system, linking the “upstream” and “downstream” steps of the respiratory cascade. Weibel coined the term of “symmorphosis” to denote that in each step of the cascade was exactly quantitatively tuned to demand, there was enough – but not too much – structure to support oxygen flow. But he also found one apparent exception to his concept of symmorphosis – namely the lung. The analysis indicated that there was seemingly excess lung structure in large animals. This finding continued to bother him for the rest of his career and through all of his retirement. In fact, the last manuscript he was working on dealt with this problem and the potential effect that shorter alveolar duct lengths in small animals could have on the condition of oxygen transfer between the alveolar air space and erythrocytes.

Ewald R. Weibel will long be remembered as an outstanding scientist. His articles and books cover three main areas: lung structure and function, stereology and the design of the respiratory system. For his work, he has received a number of prestigious academic prizes such as the Marcel Benoist Prize, the Anders Retzius Medal and the Purkinje Gold Medal. He also served in many academic functions such as Rector of the University of Bern, President of the Swiss Academy of Medical Sciences, and President of the International Union of Physiological Sciences. Above all, Ewald Weibel was an inspiration for all who had the chance of working with him. He had a piercing mind, he loved the academic battle and he hated any kind of dishonesty. It was important for him to follow and foster the career of his many collaborators. Throughout his career and as a head of the Department of Anatomy he shouldered a full teaching load. He was a brilliant and engaging role model for all medical students and he remained proud of his first academic vocation as a medical doctor. He will be sorely missed. Ewald Weibel leaves his wife Verena behind for whom he had lovingly cared for the final years of his life.

Hans Hoppeler Prof. University of Bern, Switzerland, hoppeler@ana.unibe.ch
Department of Anatomy, Baltzerstrasse 2, CH-3000 Bern, Switzerland.

Stan L. Lindstedt, Northern Arizona University, Flagstaff, USA, stan.lindstedt@nau.edu
Department of Biological Sciences, NAU, South Beaver Street, Flagstaff, AZ 86011-5640