“Think Microscopically” – The Birth of Cell Theory.

Posted on | April 8, 2025 | 2 Comments

Mike Magee

If there was an All-Star team for 20th Century Medicine, two members of the roster would likely be William Welch and William Osler, two of the “Big Four” founders of the Johns Hopkins School of Medicine. (The other two were surgeon William Stewart Halsted and obstetrician Howard Atwood Kelly.) Welch served as the first Dean of the school and Osler, born and bred in Canada, arrived at Johns Hopkins at the age of 40, and birthed the first residency training program at the school.

Prior to their arrival in Baltimore, the two shared a common medical origin story. They both were trained in pathology and cell theory by the famed German physician, Rudolph Virchow. He encouraged them both to embrace “attention to detail” by “thinking microscopically.”

Virchow is remembered for a famous phrase – “omnis cellula e cellula” (every cell stems from another cell). That may not sound too radical today. But back in 1855, it was revolutionary. Cells, as an entity, had been around for awhile. Two centuries earlier, in 1665, English scientist Robert Hooke, while observing a dead specimen of cork under a microscope, noted that the repetitive compartments reminded him of monk’s rows of rooms or cellula in a monastery. When he published that impression in Micrographia that year, the label “cell” was born.

He was not the first to use a microscope. That honor remains contested. But it is known that the first use of a compound microscope (an instrument which married an eye piece with an objective lens positioned near the specimen) dates to at least 1619. A half century later, in 1674, Anton van Leeuwenhoek, the Dutch scientist, first described a living algae and bacteria cells.

Over the next two centuries, cells were seen here, there, and everywhere, without many conclusions drawn. But in 1838, two German scientists – zoologist Theodor Schwann and botanist Matthias Schleiden – noted the similarities of plant and animal cells in a wide range of observed tissues. A year later, Schwann published a book claiming that: 1) The cell is the fundamental unit of structure and function in living things, and 2) All organisms are made up of one or more cells. In pushing his third insight, that new cells emerged through a process of “spontaneous generation” like crystal formation from an original cell, he found himself “a bit over his skies.” But Virchow happily corrected him 17 years later in 1855 with his “omnis cellula e cellula.”

With this insight, Virchow launched the field of cellular pathology. How exactly cells manage to divide and create identical copies of themselves remained to be determined. Bit he did figure out, before nearly all other scientists, that diseases must involve distortions or changes in cells. From this he deduced that diagnosis and ultimately treatment could now be guided not simply by symptoms or external findings, but by cellular pathologic changes as well. And this was more than theory. In fact, Virchow is credited with first describing the microscopic findings of leukemia way back in 1847.

The first description of a cell nucleus was made by a Scottish botanist, Robert Brown in 1833. Over the next half-century, cell scientists busily described various cell organelles without a clear understanding of what they did. What was clear with light microscopy was that cells were bounded by a cellular membrane.

Most of the attention in the second half of the 19th century was on the nucleus and its division and cell replication. In 1874, German biologist, Walther Flemming first described mitosis in detail. But it wasn’t until 1924 that German biologist Robert Feulgen, “following experiments using basic stains such as haematoxylin, defined chromatin as ‘the substance in the cell nucleus which takes up color during nuclear staining’”. To this day, the Feulgen reaction “still exerts an important influence in current histochemical studies.”

Watson & Crick’s description of the DNA double helix was still far in the distance. But in the mean time, other cell organelles were visualized and named like the Golgi apparatus named in 1898 after Italian biologist Camillo Golgi who also used heavy metal stains (silver nitrate or osmium tetroxide) to aid visualization. Mitochondria, like the Golgi apparatus, stretched the limits of light microscopic visualization. But even without visualization, scientists by the 1930’s were beginning to deduce the functions of organelles they could barely see, and a few (like lysosomes) that they had never seen but knew had to be there.

The electron microscope popularization (if not its discovery) is generally credited to two German PhD students, Max Knoll and Ernst Ruska, who used two magnetic lenses to generate a beam of electrons and achieve much higher magnifications in 1931. For their efforts they received the 1986 Nobel Prize in Physics. Breakthroughs began to roll out almost immediately. High resolution pictures of mitochondria appeared in 1952, followed by the Golgi apparatus in 1954. The inner workings of the cells displayed movement of vesicles across the membrane and from nucleus to cytoplasm, with structures constantly being constructed and deconstructed. And visualization only got better in 1965 when the first scanning electron microscope went commercial.

Cells vary enormously in size. The smallest free-living cellular organism is the mycoplasma bacterium. It lacks a cell wall (important since many antibiotics work against bacteria by disrupting their cell walls) and is 400,000 times smaller than a human cell. A full-grown human organism includes some 30 trillion cells. Each cell is remarkably complex, holding about 10,000 different proteins, but possessing enough directions within its DNA manual to produce up to 100,000 protein varieties. The extra 90,000 are only employed in “specialized cells.” Order is maintained inside the cell by membrane sub-compartmentalization. Specialization is reflected in the choice of macromolecules that are allied by function.

Keeping individual 30 trillion cell human collections alive was part of my learning curve as a surgical resident at the University of North Carolinas from 1973 to 1978. Our Chief of the Trauma Department was a Vietnam veteran, Dr. Herb Proctor. As the Level 1 trauma facility, the sound of helicopters overhead was a constant. And victims arriving often needed fluids fast. One of the intravenous fluids of choice was “Ringers lactate,” a substance that included sodium chloride, potassium chloride, calcium chloride and sodium bicarbonate.

The life saving formula was created by a British physician named Sydney Ringer in 1882. He came up with the formula for Ringer’s Lactate while experimenting on how to keep a frog heart (removed from the frog) beating while suspended in solution. Three years later, a budding German embryologist, Wilhelm Roux, who was fixated on “showing Darwinian processes on a cellular level,” was able to keep cells he had extracted from a chicken embryo alive for 13 days. With that, the discipline called cell culture or tissue culture was off and running.

In modern usage, the term refers to growing cells from a multicellular organism outside the body, or in vitro. Bathed in special culture medium, naturally or scientifically mutated cells, can grow and continue to divide indefinitely, creating an immortalized cell line. In the early years, these cell lines were often contaminated by other types of cells, or more commonly by infectious organisms. The discovery of antibiotics by Alexander Fleming in 1928 greatly improved the reliability of the use of these cell lines for scientific experimentation.

With the introduction of living cell cultures, and the use of the electron microscope, the inner workings of the cell were revealed. Simultaneously, the field of biochemistry matured, alongside the miracle of genetics. Side by side, in direct view, fertilization, embryonic development, multi-potential stem cells with timed specialization, organ development, and ultimately Watson and Crick’s description (building on the work of Rosalind Franklin and Maurice Wilkins) of the DNA double helix in 1953 opened the doors a half century later to the sequencing of the human cell genome in 2003 after a 13 year race to the finish line by competitors, then collaborators, NIH lead Francis Collins and the Celera Corporation CEO J. Craig Venter.

As importantly, the continued mining of cell theory and evolution of tissue culture exploded progress in cancer research and unlocked the mysteries of immunology, the workings of virology, the creation of a range of life saving vaccines from polio to mRNA cures for Covid, and much, much more.

Comments

2 Responses to ““Think Microscopically” – The Birth of Cell Theory.”

Michael O. McKinney
April 9th, 2025 @ 3:45 am

A fascinating and seamless journey through the milestones of cell theory and modern medicine, rich with historical insight and personal perspective.
Mike Magee
April 9th, 2025 @ 9:36 am

Thanks, Michael.

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“Think Microscopically” – The Birth of Cell Theory.

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