An interview with Manuel F. and Ann F. Varela: Who was the “Mother of Microbiology”? Angelina Fanny Hesse

Jan 16, 2022 by

Angelina Fanny Hesse

Thus did a modest housewife perform a service to science and to humanity. When [Hesse] died in 1934, few bacteriologists knew of her death, few perhaps that she had ever lived.”

—Arthur Parker Hitchens and Morris C. Leikind, 1939

Michael F. Shaughnessy

1) Many have considered Angelina Fanny Hesse the “mother of microbiology.” When and where was she born, and where did she go to school?

Angelina Fanny Eilshemius Hesse is well known as the woman who made modern microbiology possible as she was responsible for developing agar for use in culturing microbes. Thanks to Hesse’s efforts, microbiologists and many other scientists worldwide have been employing agar for studying microbial life.

Little documentation of her early life exists, but we know that Angelina Fanny Eilshemius was born in 1850 in New York City. Her father, Gottfried Eilshemius, was a wealthy import merchant who emigrated to the United States in 1842, and his wife, Ceclie Elis, came from a French-Swiss family in Lugano. Ceclie’s family is of Dutch descent, originating near Emden, Frisia. Eilshemius was the oldest surviving child of ten children. Regrettably, five of her siblings died early on in their lives. Her father’s business dealings were quite profitable, allowing him to retire in his forties. He purchased a superb plot of land and raised his children at Laurel Hill Manor in North Arlington, New Jersey. Eilshemius and her sisters learned about culinary arts and housekeeping from their mother from an early age. At 15, she traveled to Switzerland to study French and home economics at finishing school.

In 1872, Eilshemius met her future husband, Walther Hesse, then working as a ship’s surgeon on a German passenger liner. The couple married on May 16, 1874, and Hesse moved to Dresden, Germany, to make her home with Walther.

Walther was, in fact, a country doctor who was passionate about hygiene, sanitation, and the well-being of public laborers, chiefly the working environments of workers in the regional mines. He took a sabbatical in 1881 to study in the Berlin labs of Robert Koch, the ‘father of bacteriology,’ to investigate airborne microorganisms.

In addition to her responsibilities of running the household and overseeing the education of their three sons, Hesse voluntarily assisted him in the lab, similar to a modern-day medical technologist. There, she drew strikingly realistic illustrations of what they viewed in the microscope, prepared bacterial growth media (typically beef broth), cleaned and purified equipment, and used her extensive artistic abilities to fabricate striking watercolor illustrations for his periodicals.

On one auspicious day in 1881, during their luncheon, Walther inquired about the jellies and puddings that Hesse made and how they succeeded in remaining in a gelled state despite the warm temperatures. Hesse replied that she learned about agar-agar’s seaweed product in New York City from a Dutch neighbor when Hesse was young. Her neighbor had emigrated from Indonesia, where the local custom fused agar in their cuisine. Hesse suggested that they attempt to replicate this methodology in their laboratory.

Agar proved to be an idyllic gelatinous-like medium that remained firm despite the incubator’s high temperatures and could not be processed by any bacterial enzymes. Walther Hesse notified Koch of this new technique, and he directly added agar to his nutrient broths. This notification influenced Koch to use agar for cultivating the bacteria that cause tuberculosis.

2) Hesse worked with her husband Walther, a medical scientist, for many years—what exactly did she do and learn?

Angelina Hesse learned to apply her artistic skills to scientific illustration and her cooking skills to alter the course of scientific history. Hesse’s husband had become a medical bacteriologist. Married to 24-year-old Angelina in 1874, Walther had been a physician-scientist who practiced medicine in Saxony tending to patients with lung cancer, an endemic condition in an area where uranium mines were nearby. Walther had developed an interest in improving the miners’ working conditions and focused his attention on environmental hygiene and later on public health conditions in the homes and schools. Walther’s first experience with microbiological aspects involved mandatory smallpox vaccinations in school children, a practice that became widespread and ultimately led to the eradication of smallpox in the mid-1970s. In the early 1880s, Walther spent a sabbatical stint under the famous Robert Koch studying bacteriology, using his expertise to measure bacterial growth in water samples.

Angelina worked with Walther as his journal article illustrator. Angelina Hesse prepared drawings of magnified bacteriological cultures on Petri dishes during their various growth phases. Hesse then used water coloring to illustrate the bacteria for publication. In particular, Hesse had prepared so-called chromolithographs, which were watercolor-based paintings that her husband used to publish the results of the bacterial content in the air. Her illustrations were published in 1884 in the second volume of her husband’s article published in an official report in “Contributions from the Health Department,” on the quantitative determination of the number of microorganisms found in the air. However, soon after Koch experimented with the newly developed photography technique, the watercolor drawings of Hesse were soon replaced by photographic images in journals.

Angelina and Walther Hesse worked together in their home with an attached research laboratory. Angelina learned to be a medical technologist in their home-based laboratory. One of Angelina’s duties in the research laboratory was preparing broth medium, a liquid consisting of bouillon used to cultivate bacteria sampled from water and the atmospheric air. Hesse prepared test tubes lined with gelatin to study the bacteria from the air. The air samples were aspirated in these gelatin-lined glass tubes, and airborne bacteria would land on the gelatin, forming colonies harboring anywhere between hundreds of thousands to several million cells of bacteria per colony. See Figure 80.

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Figure 80. Pseudomonas aeruginosa, Enterococcus faecalis, and Staphylococcus aureus on Tryptic Soy Agar.

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Once the bacterial colonies formed in the gelatin-lined tubes, the quantities of the bacterial contents could be estimated, with each colony representing a single bacterial cell having undergone clonal growth. When the pigmentation of the bacterial colonies was observed, the types of microbes could be determined. However, a persistent problem often described as “maddening” involved a premature melting process called liquefaction. The gelatin melted, taking the distinctive colonies with them as the liquefied gels dispersed, destroying the enumeration process along with it. The gelatin melting situation prevented acquiring bacteriological data of air and water, and the Hesse laboratory was stymied in their attempts to study bacteria using temperatures at which the pathogens grew the fastest. Temperatures above or below the optimal one typically do not permit microorganisms to reproduce maximally—pathogens cultured most well at higher temperatures than could be tolerated in gelatin.

At room temperature, roughly 22 to 25 °C, gelatin, the same material enjoyed by millions as “Jello,” took a solid form, a perfect condition for bacterial colony discernment and numerical characterization. Excellent bacteriological data, ripe for experimental publication, could be obtained with the colony formation at room temperatures. Unfortunately, at temperatures where pathogens grow optimally, that is, the so-called “blood heat” temperature at about 37 °C, where the gelatin “maddeningly” liquefied! Thus, the Hesses would have to find a more suitable solid culture medium. Here, Angelina Hesse’s efforts would culminate in a historic scientific event—the use of agar to culture microorganisms. In short, agar changed everything about the history of microbiology.

3) Keyword—agar—what exactly is it, and why is it important? Moreover, what role did it play?

Agar provides a solid substrate upon which microbes can grow into uniform colonies that can then be isolated, picked, and cultured in pure form, producing clones of identical microbes for analysis. Agar had been known colloquially as a soup- and jelly-thickening agent of the Japanese seaweed species called Gelidium corneum. Thanks to Angelina Hesse and her agar, microbiologists have enjoyed unprecedented breakthroughs in microbiology, leading to advances in molecular and cellular biology. Modern uses of agar revolutionized biotechnology, making significant strides in vaccine production, medicines, laboratory tests for diagnosis, and the like.

Before using Angelina Hesse’s revolutionary agar, early efforts to study bacteria dated back to the time of Antonie van Leeuwenhoek, the “father of microbiology” who had discovered the microbes using his handmade microscopes. Since Leeuwenhoek’s time, during the 1670s, when he first reported the observation of his “little animals” to the Royal Society, the microorganisms were studied in their original locales, natural environments such as water, soil, and the like.

Early microbiologists like Joseph Lister, Edwin Klebs, and Carl Salomonsen were somewhat able, but with great effort, to use liquid broth to transfer minute amounts of highly diluted quantities of bacterial samples to new broth media and then grow relatively pure cultures of the bacteria. However, the bacteria were invariably contaminated with undesirable microbes, and investigators could never be entirely sure that the bacteria were pure enough to connect them with their specific physiological behaviors. Liquid media was unsatisfactory for the study of microbial physiology in pure cultures. Suitable solid media was lacking and badly needed.

The first tangible, solid medium to be used in the laboratory was known unceremoniously as “bloody bread.” For centuries, people had been terrified to find so-called “blood spots” in foods or communion wafers. Before Leeuwenhoek, appearances of “blood” in foods were viewed with awe, if not outright miracles, such as the case of the Mass of Bolsena. According to legend, a priest celebrating Holy communion during a mass held up a wafer, only to observe blood in it! The incident triggered an extensive study, and the episode was deemed an official miracle. Rafael commemorated the miracle in his fresco called the Mass at Bolsena. See Figure 81. However, much of these “blood in foods” incidents were non-scientific. In dealing with microbes found as contaminants in foods, most were unaware of the potential pathological consequences inherent in their presence. No one yet knew that microbes could be agents of illness.

Furthermore, in the laboratory, where attempts were made to purify these and other microbes from foods, inanimate objects, soils, and water, investigators were largely dependent on the use of liquid media, a problematic method to conduct, even under precise laboratory conditions. A solid form of culture media was needed to study the biological functions of the microbes.

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Figure 81. Rafael’s fresco Misa de Bolsena. 1512–1514, Vatican City.

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In the 1850s, attempts were made to isolate individual types of bacteria, to classify them and connect individual species to specific microbial activities, such as fermentation, a known physiological process, and in the case of Robert Koch, to test the notion that specific bacteria were responsible for illnesses, as had been predicted earlier by Louis Pasteur. Professor Pasteur, one of the most outstanding scientists who has ever lived, had postulated that microbes could cause disease, a notion known as the germ theory of disease. While Pasteur and others studied specific physiological properties like lactic acid fermentation of sugars and amino acids, no such studies of the germ theory would be forthcoming from the Pasteur laboratory. The hold-up was the unavailability of a solid culture medium that did not melt in the high temperatures required by pathogens.

In the early 1870s, Joseph Schroeter, a student working under the famous Professor Ferdinand Cohn, a botanist, and naturalist who was noted for his discoveries on bacterial endospores, used potato slices, starch paste, meats, and coagulated egg whites, as rudimentary solid substrates upon which to cultivate specific so-called chromogenic microbes. Schroeter and Cohn showed that individual colonies formed on these early solid media arose from individual cells of microbes that reproduced into more significant numbers, each virtually identical in their species types. Schroeter and Cohn could transfer colonies from the original substrate to a fresh substrate, continually maintaining their living presence in the laboratory. Their difficulties, however, with meat, egg, potatoes, and starch media arose from the presence of non-chromogenic microbes, i.e., those without a colorful phenotype upon which to further characterize and perhaps even identify. Much of the microbial identification at the time was based on their distinctive colors.

The use of gelatin by Koch in the early 1880s solved the problem produced by the non-chromogenic phenomenon encountered by Schroeter and Cohn. Like the meats, egg white, and potatoes used earlier by investigators, gelatin was solid naturally. Importantly, gelatin had a transparent character, providing the opportunity to visualize both chromogenic and non-chromogenic microbes alike. Using gelatin, Koch developed the so-called colony-based microbial isolation method, in which individual colonies that presumably contained clones of identical microbes could be manipulated, isolated, and cultivated in pure species form. However, as mentioned above, and like Pasteur before him, Koch had been thwarted in his desire to study pathogens, which required the blood heat, a condition dictated by standard body temperature, 37 °C. Gelatin proved worthless as a solid substance to study pathogens—it dissolved under the blood heat restriction.

The liquefaction problem of gelatin, a protein, was considerable. We know today that specific microbes produce an enzyme called gelatinase that hydrolyzes gelatin into its free amino acids, eliciting a worthless liquified state of the medium. Here, Angelina Hesse would alter the course of infectious disease history and earn Koch and many others a Nobel Prize.

According to scientific lore, Angelina Hesse had proposed the novel solution that agar should be used as a solid medium to cultivate living microbes in the laboratory. The story is told that Hesse had been using the agar for years in her home kitchen to thicken jellies and jams. According to a descendant of Angelina’s, she learned of the substance in New York, where a Dutch neighbor who had immigrated from Java had taught the family about agar. Hesse would use agar as an adult as a food thickening agent in the kitchen.

Angelina Hesse proposed using agar in the laboratory. The fortuitous nature of the agar as a solution to the liquefaction dilemma was that agar mixed easily with known culture media and that once it turned to a solid, it was no longer susceptible to the confounding liquifying predicament. Once agar solidified, it stayed solid, even at the temperature levels of the blood heat! In the incubator at 37 °C, agar stayed solid! This non-liquifying nature of agar provided the first opportunity in the history of science to study pathogens.

In a letter dispatched by the Hesses in early 1881, Angelina’s agar solution was brought to the attention of Professor Koch himself, who was sufficiently impressed to adopt the new solid substance for culturing microbes in the laboratory. With the new agar medium, the Hesses and Koch could now examine bacteria that grew at higher temperatures, incubating the agar plates in their ovens without fear of the dreaded liquefaction, a notorious laboratory problem that had been plaguing microbiologists for hundreds of years.

The Koch laboratory soon employed the colony purification method to isolate candidate microbes that could cause disease and experimentally test Pasteur’s germ theory of disease for the first time in history. Colonies that arose on a so-called streak plate, Figure 82, could be picked from the plates and transferred to new fresh broth or another agar plate and cultivated for cloning and physiological analysis.

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Figure 82. Four-way streak-plate inoculation.

https://commons.wikimedia.org/wiki/File:FINAL_mmg_301_honors_option.jpg (Figure description was omitted.)

In modern times, Petri dishes with Hesse’s agar are still widely employed in microbiological and molecular biological laboratories throughout the planet. See Figure 83. Petri plates with agar in the culture media are used to grow, isolate, clone, identify, and study microbial species’ biochemistry, physiology, and cellular properties. Thanks to the use of Hesse’s agar, scientific investigators have discovered the pathogenic mechanisms of microbes that cause infectious diseases. Antimicrobial agents were discovered using agar in Petri dishes, such as the famous penicillin, when Alexander Fleming serendipitously observed a growth inhibition zone around the contaminating mold on an agar plate containing the Staphylococcus aureus bacterium. Indeed, the agar of Hesse altered scientific history.

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Figure 83. Stacks of Petri plates with Hesse’s agar.

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4) Hesse did some work in “Airborne bacteria.” What were her contributions there?

Throughout the 1880s, Angelina Hesse performed laboratory analyses of airborne microbes. The lab head, Walther, collaborated with Percy Faraday Frankland, conducting a series of studies on so-called “aerobiological particles.” In 1881 Walther Hesse had published an article as sole author describing the airborne microbes, which consisted mainly of bacteria and fungi. The airborne microbes were sampled by aspirating atmospheric air through glass tubes, which measured about two and one half feet in length and half an inch in diameter. Inside the glass tubes, the internal surfaces were lined with a coating of gelatin (spelled “gelatine” in Hesse’s papers) and peptone nutrients, which consisted of proteins and amino acids—food for the microbes caught in the tube taken from the air. It is widely believed that Angelina Hesse participated in the preparation of these gelatin-peptone-coated collection vessels to study airborne microbes. This device became known as “Hesse’s apparatus,” and others would adopt it, like Frankland, to continue their study of the biological particles of the air, such as those present in the gardens near Natural History museums throughout England’s countrysides.

After the air was aspirated through the Hesse apparatus, the microbes trapped within would use the nutrients provided to multiply their numbers, forming distinctive colonies. These newly formed colonies could be enumerated, indicating the microbial numbers floating in the air samples. It was found that air tested outdoors harbored, in their case, more microbes than the indoor air samples.

Airborne microbes were collected by simply leaving Petri dishes (culture plates) out in the open. The plates contained gelatin and later Angelina Hesse’s agar, supplemented with nutrients. There is no doubt that Angelina had a hand in the preparation of these sorts of nutrient agar plates, as well. It was found that if the air around this nutrient gelatin or agar plates was undisturbed, the accuracy in the microbial numbers was high, and repeated analyses were consistent with newer sampling methods developed later. Throughout the 1880s, several publications emerged from the Hesse laboratory. Interestingly, Angelina Hesse was not included as a co-author of the articles. However, these studies of airborne microorganisms would provide the basis for the analyses of airborne microbes of a pathological nature, namely, those having a role in causing a terrifying disease called “The Consumption,” an ailment known today as tuberculosis or TB.

5) Tuberculosis—another word that strikes fear into our hearts—what was her role in this?

Angelina Hesse would play two critical roles in the study of tuberculosis. One of these had dealt with her influence upon Professor Robert and his use of agar to research TB. The other dealt with agar and its use in developing a culture medium for TB diagnosis.

In his Nobel Prize-winning article, Koch would for the first time mention the term “agar” in his famous discovery that the bacterium Mycobacterium tuberculosis, the tubercle bacillus, was the cause of the terrifying Consumption. Without Hesse’s agar, it would have been quite difficult, if not impossible, to have discovered that the tubercule bacillus caused the dreadful TB. Koch had invoked his well-known postulates using agar to identify the causative microbial agent of TB. In an article published in 1882 dealing with the discovery, Koch is noted to have briefly mentioned using agar to do so, neglecting to cite either of the Hesses.

Furthermore, with Angelina taking part, the Hesse laboratory developed a new culture medium that would be used to diagnose tuberculosis. Agar would be used in the Hesse laboratory to store the Mycobacterium tuberculosis bacteria under long-term conditions needed to culture and store the microbe for bacteriological study. The new nutrient agar medium permitted the Hesse laboratory investigators to observe distinct colonies of the tubercle bacillus on solid agar plates within two to three days after incubation in the laboratory.

In short, had it not been for the astuteness of Angelina Hesse and her agar, the progress of infectious disease research on TB and other clinical pathogens would have been set back years if not decades. Indeed, much of microbiology, bacteriology, mycology, infectious disease medicines, and basic molecular biological studies might have been significantly deferred had it not been for Angelina Hesse.

6) She had outlived her husband by about 23 years—and her contributions were acknowledged—what were they?

Angelina Hesse is now well known for introducing agar, a solidifying substance used by generations of microbiologists, to advance the progress of scientific discoveries. After the death of Angelina’s 64-year-old husband Walther in July of 1911, she took it upon herself to care for his documents and articles dealing with their research investigations. She kept her illustrations, which were passed on to one of her children, Friedrich Hesse, who became a surgeon and provided details about his parents and the circumstances regarding their beloved agar.

In her lifetime, Hesse would not benefit monetarily from her agar discovery. There was no patent in her name. No article was published by the Hesses that dealt explicitly with the importance of agar. It seemed that other microbiological questions, microbes in the air and water, were considered more important.

Today, students of the microbiological sciences use agar on a routine basis, using the history-altering substance in Petri dishes and test tubes in many ways to learn about microbes and other living cells and tissues. Educational arenas dealing with microbiology-, medical- and molecular-based laboratory courses worldwide use agar.

Further, biotechnology firms use agar for developing diagnostic or species identification kits to market. From the beginning of modern microbiological history, vaccine development efforts have all used agar, starting with TB and polio, culminating with many other infectious diseases, including the historic COVID-19 pandemic. Undoubtedly, agar will continue to be employed in a great variety of venues to advance the progress of science well into the future.

7) What have I neglected to ask about this famous female scientist?

Interestingly, the Hesse laboratory at the Technical University in Dresden had been burned down on purpose after the death of Walther because the facility had been deemed “a danger to public health” as the lab was known to contain highly virulent cultures of bacteria.

At 67, Angelina Hesse would sell the family home in Strehlen, Dresden, to live closer to her children. Her childhood home in New Jersey would be sold in 1917, and part of the proceeds would be confiscated as “property of the enemy” during the Great War. As a widow civil servant, Angelina received a small pension in her later years. In 1934 on the first day of December, Angelina passed away at 84.

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