Call for Papers: “Morphology is the link between genetics and function”: a tribute to Ewald R. Weibel

Often, we take for granted the things we have learned at school or university or from text books and do not ponder how this knowledge was gained, who was involved, and which technologies made a discovery possible. When we read about the conflicting concepts and discussions that took place before a scientific observation on how something is, or works, was accepted and changed the general understanding in the field, it may be difficult to imagine the struggle that scientists at that time had to face to answer a certain research question.

In the early 1950s, only 70 years ago, the question of the composition of the pulmonary air-blood barrier was a matter of dispute. The theories about the nature of the alveolar epithelium involved 1) its complete lack (“naked capillaries”), 2) an initially continuous epithelium that becomes fragmented due to lung expansion during development, or 3) a continuous epithelium. With the advent of transmission electron microscopy, it was discovered that the alveoli are covered by two types of cell forming a continuous epithelium (1). This discovery heralded the beginning of morphological characterization of the mammalian lung by electron microscopy.

Two years after Low’s paper had been published, a young Swiss, the 26-yr-old Ewald Rudolf Weibel, graduated from medical school at the University of Zürich. When Ewald Weibel started as a postdoctoral researcher at the Nobel laureate André F. Cournand’s laboratory at Bellevue hospital in New York, he was asked to “do anything on the structure of the lung that is of interest to physiology.” Despite the semantic simplicity of this request, the task was challenging and contained a whole scientific concept that was the driving force of Weibel’s scientific work. An impressive illustration of this morpho-functional concept is one of Weibel’s last articles written for a special issue in the journal Cell and Tissue Research (2).

Although neither anatomy nor the lung had been his first choice, he became a giant in lung anatomy, physiology, and cell biology (for details of his way into science and pulmonary research see Refs. 3, 4). Ewald Weibel made groundbreaking contributions to the field of lung physiology at various levels, but in particular, by pioneering the comprehensive quantitative analysis of lung architecture within a functional context from the systemic to the subcellular level. Among his seminal works were the electron microscopic demonstration of surfactant as a surface film covering the alveolar epithelium and as tubular myelin in the hypophase of lungs fixed by vascular perfusion (5, 6); the explanation of the non-nucleated plates by studying the ultrastructure of alveolar epithelial type I cells (7); the development of morphometric methods (8, 9); and consequently, the morphometric characterization of the human lung using functionally relevant parameters (9, 10). Long before the term “systems biology” was coined, Ewald Weibel had used a systematic and systemic approach to follow the oxygen molecule from its entry in the lung to its systemic delivery, consumption in the musculature, to its exit via the pulmonary vasculature (11–18). The methodologically comprehensive approach ranged from biochemical analyses to morphology to the measurement and correlation with function. In addition to performing experiments (e.g., see Ref. 19), he made use of the experiments of nature through evolution to characterize diverse adaptations of mammals to their environments and life styles.

After his retirement in 1994, Weibel continued to be involved in lung physiology and cell biology, particularly as new technical developments, which had not been available in his most active years, enabled the extension of our understanding of lung function. One focus was the potential of new imaging methods, alone or in combination with morphometry, at electron microscopic (20) or radiological level (21). Although in his younger years Ewald focused on the collection of data, in later years he was more concerned with their integration and potential in modeling of lung function (22–24).

Ewald was a man of his time. He was a precise electron microscopist and morphologist, a pioneer and critical but fair expert in lung morphometry (25, 26) and a rigorous, classical pulmonary physiologist. His own work ended at what was visible under the electron microscope. Although he had never worked at a genetic or molecular biology level, he was keenly aware of the genetic basis that shapes structures to optimally match their function.

Ewald Weibel’s main disciplines, quantitative morphology and physiology of the respiratory system, remain as important now as these were before. However, the number of experts in these fields has declined. This may have dramatic consequences if critical knowledge is lost that is needed for the meaningful integration of “big data” obtained by new genetic and molecular techniques into a broader structural and functional context at the systemic level. Therefore, it is timely to pay tribute to Ewald Weibel by encouraging research in this direction.

In 2006, Steven Perry organized the “First International Congress on Respiratory Biology” in Bonn, which presented a comprehensive view on respiration. At the gathering on the first evening, a group of us stood together when Ewald said: “Morphology is the link between genetics and function.” This sentence not only summarizes Ewald Weibel’s way of thinking but also serves as his challenge to his successors, similar to the challenge that André Cournand had once given to him.

This Call for Papers, therefore, encourages the submission of manuscripts integrating genetics and/or morphology and function, thus collecting information that is necessary to better understand the basis for how the lung functions. The approach should be based on the highest methodological standards to generate high quality data that will endure—even if their interpretation changes over time. There are hardly any limits to the topic of the manuscripts—the sole evaluation criterion is the question whether a manuscript relates structural assessment at all levels to lung function.

The following nonexclusive list provides examples of the types of paper that are particularly welcome:

• Development of new methods to better analyze lung function. These studies may be submitted to the American Journal of Physiology-Lung Cellular and Molecular Physiology Innovative Methodology category of manuscripts.

• Imaging studies at all scales (from in vivo live microscopy and super resolution light microscopy to electron microscopy) that contain new data on the normal or pathological lung

• Comparative studies utilizing allometric approaches or “experiments of nature” (rare species, adaptation to perinatal life, consequences of aging) that teach us about certain species or developmental states of the lung

• Comprehensive analyses of new genetically modified model organisms that elucidate the respiratory function of a particular molecule

• Studies addressing the challenges of and the solutions for the collection, analysis, and interpretation of systemic (“big”) data on the respiratory system

• Studies addressing pathophysiological pathways and processes in relevant lung disease models or human lung disease

• Studies that identify or characterize the genetic determinants of lung function and lung disease

• Studies applying new methods that help to increase our understanding of the cellular diversity of the lung (e.g., single-cell RNA sequencing)

• Studies using structural and/or functional data as a basis for modeling the behavior of the lung under various conditions.

If your manuscript fits the scope of this Call for Papers, authors must submit to the American Journal of Physiology-Lung Cellular and Molecular Physiology via the eJournalPress portal. During the submission process, under the “Keywords & Special Sections” tab, select the “Category” drop-down menu and select “Call for Papers: Morphology is the link between genetics and function.” Please address any questions related to the Call for Papers to the Editorial Office at abrown@physiology.org. Deadline for submissions: December 31, 2021.

GRANTS

C. Mühlfeld’s work is supported by the BMBF via the German Center for Lung Research and the DFG (MU 3118/8-1). G. Leikauf’s work is supported by NIH U01-ES015675 and R01-HL134653 and Department of Defense (DoD): Defense Threat Reduction Agency (DTRA) FRBAA09-3-2-0296. L.V. Wain is supported by a GSK/British Lung Foundation Chair in Respiratory Research (C17-1). M. Ochs is supported by the Berlin University Alliance.

DISCLOSURES

L.V. Wain receives research funding from GSK. None of the other authors has any conflicts of interest, financial or otherwise, to disclose.

AUTHOR CONTRIBUTIONS

C.M. and M.O. drafted manuscript; C.M., C.C.W.H., G.D.L., S.O., L.V.W., and M.O. edited and revised manuscript; C.M., C.C.W.H., G.D.L., S.O., L.V.W., and M.O. approved final version of manuscript.