Walther Flemming: The Pioneer Who Uncovered the Process of Mitosis
- 演化之聲
- 3 days ago
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By the 1870s, the cell theory had established that plants and animals were composed of cells, and some researchers already knew that cells could multiply by division. Yet there was still no reliable account of how a cell completed this process. The theory of "free-cell formation" had not entirely disappeared from scientific thought, and some scholars continued to believe that new cells might arise directly from an unidentified substance between existing cells. Against this background, Walther Flemming combined observations of living cells with fixation, staining and sequential drawings to record how thread-like structures appeared inside the nucleus, became arranged, separated and finally gave rise to two daughter nuclei. Through these studies, he gradually established a coherent chronology of cell division.
Flemming was born in 1843 in Sachsenberg, Mecklenburg, Germany. As a young man, he was especially interested in literature and philology, although he eventually chose to study medicine. He attended the universities of Göttingen, Tübingen, Berlin and Rostock, and studied histological and zoological preparations under the guidance of Franz Eilhard Schulze. Schulze taught him microscopy, but he also instilled habits that would become central to Flemming's later scientific work: cautious interpretation, repeated use of controls and avoidance of speculation that went beyond the available evidence. Flemming was also influenced by scholars such as Rudolf Virchow and gradually adopted the view that the cell was the fundamental unit of life.
Flemming had an exceptional talent for drawing. He could accurately reproduce the faint and short-lived structures he saw under the microscope, both on the blackboard and in his publications. In 1872, he moved to the Charles-Ferdinand University in Prague, where he began his detailed investigations of cell division. At the time, growing national tensions in Prague were causing many German professors to leave the city. In 1876, Flemming accepted the Chair of Anatomy at the University of Kiel. The conditions there were difficult: the institute was too small, funding was limited and there were too few microscopes. At first, he had no assistant and was personally responsible for all lectures, seminars and practical courses. While struggling with the university administration to obtain better resources, he continued observing cells with the limited equipment available to him.
Friedrich Schneider had already drawn several important stages of cell division in 1873. He showed that rod-like structures appeared in the nucleus, assembled near the centre of the cell and later separated into two groups. Schneider, however, interpreted these events mainly as a deformation of the nucleus. Between 1874 and 1876, Flemming followed the process in greater detail. He found that the scaffold and network of the resting nucleus gradually transformed into threads. These threads then separated into two groups, each group formed a skein, and from these skeins two daughter nuclei were re-established. The nucleus did not simply split into two halves. It passed through a regulated series of internal reorganizations.
Much of this analysis came from Flemming's observations of epidermal cells in salamander larvae. He drew the successive appearances of the same type of cell at different times, producing something close to a hand-drawn film. Fine threads appeared inside the nucleus, became thicker, loosened and assumed a star-like arrangement. They then gathered near the centre of the cell, separated into two groups and finally formed new nuclei at opposite ends. Observations of living cells provided the temporal sequence, while fixed and stained preparations made the finer structures easier to see. By comparing the two kinds of material, Flemming reduced the risk of mistaking artifacts produced during specimen preparation for genuine cellular structures.
A major difficulty was that reliable methods for histological fixation and staining had not yet been fully developed. Acids, alcohol and other fixatives could damage cells, and they could also produce fibrous structures that had not existed in the living specimen. Flemming therefore spent considerable time testing different methods of preparation in an effort to preserve the details he had seen in living cells. He experimented with several acids and eventually adopted a mixture of chromic acid, osmic acid and glacial acetic acid, later known as Flemming's fluid. He also compared stains such as haematoxylin and tested very low concentrations of picric acid, formic acid and acetic acid to determine which conditions best revealed the nuclear scaffold and the finer organization of the cytoplasm. For Flemming, improving the method was itself part of the investigation. Only after the effects of fixation and staining had been carefully assessed could an image seen through the microscope be accepted as evidence.
In 1878 and 1879, Flemming published two important studies in which he described the process as "indirect nuclear division." The term emphasized that the nucleus did not divide by simply splitting down the middle. Instead, it first underwent a conspicuous structural transformation. Flemming identified a fibrous nuclear substance that stained readily and named it chromatin. Structures that remained unstained were termed achromatin. In 1882, he brought together years of observations in his major book, Zellsubstanz, Kern und Zelltheilung—Cell Substance, Nucleus and Cell Division. Drawing on the Greek word μίτος (mitos), meaning "thread," he used thread-related terminology for the transformations occurring inside the nucleus, giving rise to the modern term mitosis. The thread-like bodies themselves were not named chromosomes until 1888, when Heinrich Wilhelm Waldeyer introduced the term.
In Flemming's account, cell division proceeded in a clear direction. He called the sequence in which threads appeared in the mother-cell nucleus, thickened, assumed a star-like configuration and became arranged in the centre of the cell the "progressive phase." The "regressive phase" began when the threads separated into two groups, moved toward opposite sides and re-formed the daughter nuclei. His classification did not correspond exactly to the modern stages of prophase, metaphase, anaphase and telophase, but it captured one of the most important features of mitosis: its continuity. Flemming also established that the nuclear threads split longitudinally and proposed that one half of each divided thread entered one daughter cell, while the other half entered the second. Later chromosome research confirmed that this interpretation pointed toward the principle by which hereditary material is distributed equally between daughter cells.
His research was nevertheless constrained by the technology of his time. Microscope illumination depended heavily on daylight, the objective lenses suffered from substantial chromatic aberration, and small structures were often surrounded by coloured halos. Advanced condenser systems were not yet available. Although Flemming observed paired chromosomes during sperm development, he did not recognize the fundamental difference between ordinary somatic cell division and the meiotic divisions involved in gamete formation. His interpretation of some filamentous structures in the cytoplasm also became controversial. Later work suggested that at least part of what he described as cytoplasmic filaments was related to the structures that would eventually be defined as mitochondria.
In his late forties, Flemming developed a severe neurological illness that progressively worsened. He retired around the turn of the century and died in Kiel in 1905 at the age of sixty-two. By the later years of his career, the anatomical institute he directed at the University of Kiel had become an important centre for histology, cytology, comparative anatomy and the study of mitosis. Modern researchers can now follow chromosome movements using fluorescent proteins, electron microscopy and high-speed imaging. The origins of that work can be traced back to an anatomist who, under unstable daylight and through imperfect lenses, patiently drew each transformation inside the nucleus until the hidden sequence of cell division became visible.
Author: Shui-Ye You
References:
McIntosh JR and Hays T. (2016). A Brief History of Research on Mitotic Mechanisms. Biology.
Paweletz M. (2001). Walther Flemming: pioneer of mitosis research. Nature.
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