IEEE PULSE presents

Tuberculosis, Cholera, Anthrax: Dreadful Culprits

Retrospectroscope March/April 2020

Dreadful culprits from the minuscule world, indeed, but … what about poverty, war, and terrorism in the macroscopic nowadays world?

This article aims at describing the sagas painfully trodden by researchers to uncover the origins and possible therapeutical means to fight and prevent the fearful culprits mentioned in the title. Moreover, some side historical comments are also included, a few based on misconceptions and sheer ignorance of the past. Mention is made, too, of great epidemics that devastated humanity. Romantic fashionable ideas of those days are also recalled with a condescending smile.

Tuberculosis (TB)

Heinrich Hermann Robert Koch (1843–1910), German physician and microbiologist, founder of modern bacteriology, identified the specific causative agents of TB, cholera, and anthrax and gave experimental support for the concept of infectious disease basing such discoveries on animal and human experimentation (Figure 1). His research led to the creation of Koch’s postulates, a series of four generalized principles linking specific microorganisms to specific diseases that remain today the gold standard in medical microbiology. For his research on TB, Koch received the Nobel Prize in Physiology or Medicine in 1905. The Robert Koch Institute is named in his honor [1].

Figure 1. Robert Koch

TB is a bacterial infection caused by Mycobacterium tuberculosis that primarily affects the lungs, although other organs and tissues may be involved. It is not easy to become infected with TB as most infected people have it in the so-called latent form, meaning they just carry the germs, but their immune system protects them from becoming sick and, therefore, they are not contagious. TB can almost always be treated and cured if proper therapeutics is applied. Unfortunately, there are forms of TB that are drug resistant. When a person with TB in their lungs or throat coughs, laughs, sneezes, sings, or even talks, the germs may spread through the air, thus they are airborne. If another person breathes in these germs, there is a chance of becoming infected. It is important to understand that there is a difference between being infected with TB (latent TB) and getting the disease in its active form [2].

Figure 2. Sambhu Nath De

TB is the disease of poverty along with malnutrition and lack of education. Worldwide, it is the leading cause of death from a single infectious disease. Since 2000, the World Health Organization (WHO) has produced annual TB estimates for all countries. In 2017, an estimated 10 million cases of TB and 1.57 million TB deaths occurred, representing 1.8% and 3.9% declines, respectively, from 2016. Numbers of TB cases and disease incidence were highest in the South-east Asia and Africa regions. Overall progress in global TB elimination was modest in 2017. Intensified efforts to improve TB diagnosis, treatment, and prevention are required to meet global targets for the future [3].

Cholera

The cholera toxin is a protein complex secreted by the bacterium Vibrio cholerae. It is responsible for massive watery diarrhea and belongs to an enterotoxin family. Cholera toxin was discovered rather recently, in 1959, by the Indian microbiologist Sambhu Nath De (Figure 2). He made significant contributions to the understanding of cholera and related diarrheal diseases. Followed by the discovery of Vibrio cholerae in 1884 by Robert Koch, many works have been carried out all over the world to answer many questions related with its pathogenesis and mode of transmission. The seminal works by De, in Calcutta, India, during 1950–1960, breached several doubts pertaining to the enteric toxin produced by bacteria, including V.cholerae and Escherichia coli. Three of his works used the ligated intestinal loop method, which was a reinvention of Violle and Crendiropoulo method in 1915. However, De was unaware of this work; his was an independent discovery for studying cholera in a rabbit model demonstrating the association of some strains of E. coli with diarrhea. Thus, in 1953, De reinvented de novo the ligated intestinal loop of Violle and Crendiropoulo’s short article that appeared in the proceedings of the French Société de Biologie. The article rapidly sunk into obscurity. It came to De’s notice only eight years later, when he happened to read an abstract of it in the Tropical Diseases Bulletin.

Lastly, but most important, is De’s discovery of cholera toxin in 1959 in the cell-free culture filtrate of V. cholerae that stimulates a specific cellular response. It must be recalled that Vibrio cholerae was first described by the Italian anatomist Filippo Pacini (1812–1883) in 1854 [4]. He also first discovered in 1854, that is, 30 years before Koch, the causative agent of cholera, and firmly believed that the disease was contagious. That same year, the British physician John Snow showed that the disease is waterborne. Thirty years later, Koch found the characteristic comma-shaped bacterium in the intestinal tissue of Egyptian patients who died after developing cholera. Later that year, Koch cultured the bacterium in Calcutta and was credited with the discovery of V. cholerae (nicknamed as “the comma bacillus”).

Dr. Snow (1813–1858) [5], an obstetrician with an interest in many aspects of medical science, had long believed that water contaminated by sewage was the cause of cholera. Snow published an article in 1849 outlining his theory, but doctors and scientists thought he was on the wrong track and stuck with the popular belief of the time that cholera was caused by breathing vapors or a miasma in the atmosphere. Snow is considered to be the father of modern epidemiology.

Having isolated the organism from cholera patients and grown it in culture, Koch had fulfilled two of his famous postulates for proving causality, but he had yet to fulfill the third, i.e., to show that pure cultures of the comma bacillus obtained from cholera victims could cause the disease in an animal model. This third postulate remained undemonstrated for the next 75 years, until the toxin that caused cholera was discovered by De in Calcutta in 1959. De, in effect, also proved Koch’s third postulate by reproducing the disease in an animal model. The full significance of De’s discovery is highlighted by the fact that it took Koch just under eight months to discover the more elusive and fastidious etiologic agent of TB, which he did in March 1882, including replicating the disease in a guinea pig model. It was the availability of an animal model for TB that enabled Koch to discover the pathogen. However, in the case of cholera, success eluded him because there was no animal model to provide proof that the comma bacillus could cause the disease. In 1959, when De reported the discovery of the cholera toxin, another group in Bombay, India, led by Nirmal Kumar Dutta (1913–1982) reported the development of an infant rabbit model for cholera and demonstrated that the symptoms of the disease were caused by a toxin [6].

Between 1951 and 1959, De, born in 1915 near Calcutta, added significant discoveries on the pathogenesis of cholera that radically changed the understanding of the disease. The pioneering 1953 article of De and Chatterje is a classic [7]. It was the first in a series of articles that examined the action of V.  cholerae on the intestinal mucous membrane and that culminated in the discovery of cholera toxin. Prior to the above work, almost all research had consisted of administering the stools of cholera patients or various toxic preparations derived from V. cholerae to different animals by various routes using a multiplicity of techniques to check for potential systemic or lethal effects, all giving conflicting results. In the simple experiments that led to the article, living V. cholerae cultures were first introduced into the intraperitoneal cavity of a rabbit and later into the lumen of the rabbit’s ligated intestine. So it was demonstrated that V. cholerae alters the permeability of the intestinal mucosa and thereby causes fluid secretion.

The prodigious work of De and Chatterje was followed by the demonstration that the pathogenicity of some strains of Escherichia coli was very similar to that of V. cholerae, and such strains were what today is known as enterotoxigenic E. coli. The discovery of the cholera enterotoxin and its effect on intestinal permeability, the demonstration that bacteria-free culture filtrates of V. cholerae are enterotoxic and the development of a reproducible animal model for cholera are milestones in the history of the fight against the disease.

Seven cholera pandemics have occurred in the past 200 years, with the seventh pandemic originating in Indonesia in 1961. Additionally, there have been many documented outbreaks, such as a 1991–1994 one in South America and, more recently, the 2016–2019 Yemen cholera outbreak.

Not much is known about the mechanisms behind the spread of cholera, for example, what makes the disease happen in some places and not others. Lack of treatment of human feces and lack of treatment of drinking water greatly facilitate its spread. Bodies of water have been found to serve as a reservoir, and seafood shipped long distances can spread the disease. The first cholera pandemic occurred in the Bengal region of India, near Calcutta starting in 1817 through 1824. The disease dispersed from India to Southeast Asia, the Middle East, Europe, and Eastern Africa through trade routes. The second pandemic lasted from 1826 to 1837 and particularly affected North America and Europe due to the result of advancements in transportation and global trade, and increased human migration, including soldiers. The third pandemic erupted in 1846, persisted until 1860, extended to North Africa, and reached South America, for the first time specifically affecting Brazil. The fourth pandemic lasted from 1863 to 1875 and spread from India to Naples and Spain. The fifth pandemic took place from 1881 to 1896 and started in India and spread to Europe, Asia, and South America. The sixth pandemic started in India and happened from 1899 to 1923. Egypt, the Arabian Peninsula, Persia, India, and the Philippines were hit hardest during these epidemics, while other areas, like Germany in 1892 and Naples in 1910/1911, also experienced severe outbreaks. The seventh pandemic originated in 1961 in Indonesia and is marked by the emergence of a new strain, nicknamed El Tor, which still persists (as of 2019) in developing countries. Cholera did not occur in the Americas for most of the 20th century after the early 1900s in New York City. It reappeared in the Caribbean toward the end of that century. Deaths in India between 1817 and 1860, in the first three pandemics of the 19th century, are estimated to have exceeded 15 million people. Another 23 million died between 1865 and 1917, during the next three pandemics. Cholera deaths in the Russian Empire during a similar time period exceeded 2 million [8].

Anthrax (carbunco, in Spanish)

It is a typical animal pathology, mostly gotten from cows and bulls, a very serious disease caused by the bacteria known as Bacillus anthracis, studied by Koch. Farmers and country workers are liable to get it. Although it is rare, people can get sick if they come in contact with infected animals or contaminated animal products. The type of illness a person develops depends on how anthrax enters the body. Typically, anthrax gets into the body through the skin, lungs, or gastrointestinal system. All types of anthrax can eventually spread throughout the body and cause death if they are not treated with antibiotics.

Anthrax is thought to have originated in Egypt and Mesopotamia. Many scholars think that in Moses’ time, during the ten plagues of Egypt, anthrax may have caused what was known as the fifth plague, described as a sickness affecting horses, cattle, sheep, camels, and oxen. Ancient Greece and Rome were also well acquainted with anthrax, and this is illustrated in many of the ancient writings of the most famous scholars from those times.

Vaccines against the livestock and human disease anthrax, caused by the Bacillus anthracis, in modern times, started with Louis Pasteur’s pioneering 19th century work with cattle. Human anthrax vaccines were later developed by the Soviet Union in the 1930s and the United States and U.K. in the 1950s [9].

TB: The romantic disease

Interesting enough, this undoubtedly serious disease had a special attraction for women. It even attained the stature of beauty. The romanticized literary vision of TB flourished among the Europeans as well as the Japanese people from the end of the 18th century, and the disease was endowed with aesthetic images that continued for a long period. Alexandre Dumas, Jr. (1824–1895) was a French author and playwright, best known for the romantic novel La Dame aux Camélias (The Lady of the Camellias), published in 1848, which was adapted into Giuseppe Verdi’s opera La Traviata (The Fallen or The Lost Lady). It was first performed in 1853, in Venice, Italy. Violetta, the main character, had TB and died as its tragic result, leaving Alfredo, her lover, in despair [10].

Discussion and conclusion

There is considerable information in this article, even with added variety, because it goes into scientific aspects, which are the core subject, and also getting into some biographical details where the reader can realize how unfair was the poor recognition Dr. Sambhu Nath De obtained. Not rarely the human being gives too much to some, often undeservedly, and too little to others who selflessly offered their efforts to humankind. Finally, the romantic connotations of TB were remembered; so silly or narrow- minded or blinded can man and women become? Or how dark the human mind sometimes is!

In March 2020, humanity was struck by another unknown pandemic due to the so-called coronavirus, apparently originated in Wuhan, China. Its effects are devastating for the establishment of strict quarantines mostly the world over. The effects, besides health, are economic, social, and psychological. Older people are senselessly discriminated against, transforming them into outcasts under the pretext of “protection,” even threatening with fines. Countries apply such philosophy in different degrees, but all produce negative results. There is news of a possible vaccine, although its actual implementation is still a hope.

References

  1. [Online]. Available: https://en.wikipedia.org/wiki/Robert_Koch
  2. [Online]. Available: https://www.cdc.gov/tb/topic/basics/default.htm
  3. [Online]. Available: https://www.who.int/tb/publications/global_report/en/
  4. A. Shakeri and F. Pacini, “A life of achievement,” JAMA Dermatol., vol. 154, no. 3, p. 300, Mar. 2018, doi: 10.1001/jamadermatol.2017.5356.
  5. [Online]. Available: https://www.ph.ucla.edu/epi/snow.html#YOUTH
  6. [Online]. Available: https://en.wikipedia.org/wiki/Nirmal_Kumar_Dutta
  7. S. N. De and D. N. Chatterje, “An experimental study of the mechanism of action of Vibrio cholerae on the intestinal mucous membrane,” J. Pathol. Bacteriol., vol. 66, no. 2, pp. 559–562, Oct. 1953.
  8. D. Hu et al., “Origins of the current seventh cholera pandemic,” Proc. Nat. Acad. Sci., vol. 113, no. 48, pp. E7730–E7739, Nov. 29, 2016, doi: 10.1073/pnas.1608732113.
  9. [Online]. Available: https://en.wikipedia.org/wiki/Anthrax
  10. [Online]. Available: https://www.operaphila.org/whats-on/on-stage-2015-2016/la-traviata/full-synopsis/

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