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James Harrison

Specialised Subjects

Biochemistry, Biology, Biotechnology, Genetics, Medicine, Neuroscience, Pathology, Pharmacology, Sciences, Zoology

I am Life Science professional with post-doctoral research experience from Imperial College London and University of Birmingham. I have a PhD in Microbiology, a Masters as well as a Bachelor in Biotechnology. I have worked for various not-for-profit projects at Birmingham (Guild of Students) and London (PhD to Consulting). During my academic career I have published 17 research papers in international journals like FEMS Microbiology Reviews, Journal of Biological Chemistry and Molecular Microbiology.

A history of tuberculosis

TB has plagued human kind throughout its recorded history and has possibly resulted in more deaths than any other microbial pathogen. The disease is caused by the etiological agent M. tuberculosis (Koch, 1932; Koch, 1952; Koch, 1982), which evolved from East Africa around 3 million years ago and infected early hominids of that time (Gutierrez et al., 2005). The availability of genome sequences of various strains of the M. tuberculosis complex suggest that all modern strains, including M. tuberculosis, Mycobacterium africanum, Mycobacterium canettii as well as Mycobacterium bovis, had a common African ancestor, approximately 35, 000-15, 000 years ago (Table 1.1) (Brosch et al., 2002). On the basis of molecular markers on the Y chromosome, the origin of Asian and Oceania populations has been traced to Africa 35,000 to 89,000 years ago. It is quite possible that these migrants carried diseases with them including TB to other parts of the world.

Physiological changes due to TB in humans have been reported from Egypt (3500-2650 BC), Sweden (3200-2300 BC), the Eastern Mediterranean (7000 BC) (Hershkovitz et al., 2008) and from the first half of the fourth millennium BC in Italy, while written text describing TB are available in India and China from as early as 3300 and 2300 years ago, respectively (Daniel, 2006). TB was well known in classical Greece, where it was called phthisis or consumption. Hippocrates (460-370 BC), the ‘father of medicine’ had clearly described the clinical signs of TB and recommended good food, milk and physical exercise for its treatment. However, it was Aristotle (384-322 BC) who described ‘scrofula’ and believed it to be infectious rather than hereditary, which was a common belief (Garrison, 1913). In the 5th century AD, Caelius Aurelianus, a Roman physician, brilliantly described the diagnosis of a disease with latent fever, coughing with purulent sputum, breathing difficulty, and loss of appetite with few physiological changes in the body (Herzog, 1998). Aretaeus of Capadocia described pulmonary consumption as a disease with chronic sputum with poor prognosis, while Galen (131-201) re-emphasised the contagious nature of the disease (Guthrie, 1945).

For many centuries, there was no further addition to the knowledge of phthisis or consumption probably due to the down-surge of the disease due to unknown reasons. The work of Johannes Gutanberg (Germany, 1398-1468), Girolamo Fracastro (Italy, 1478-1553), and Andreas Vesalius (Holland, 1514-1564), contributed towards the understanding of the disease to some extent (Daniel, 2006). However, it was the era of pathological anatomy, which enhanced the knowledge of the disease considerably. Sylvius de la Boe (Amsterdam, 1617-1655) was the first to describe tubercles as specific characteristics of lungs and its progression into cavities and ulcers. In addition, he also established the correlation between scrofula and consumption, later supported by Richard Morton (London, 1637-1698) (Keers, 1978; Keers, 1982), while Thomas Willis (UK, 1621-1771) and John Jacobus Manget in France shed light on miliary-TB. However, it was the less well-known English physician Benjamin Marten (1690-1751) who suggested the involvement of small living creatures in phthisis. Furthermore, he also shed light on the air-borne infectious nature of that living organism. Ironically, his work got recognition only after 150 years after the discovery of M. tuberculosis by Robert Koch (Koch, 1932).

Invaluable contributions made by Giovanni Battista in Padua (Italy, 1682-1771) and French giants Marie-Francois-Xavier Bichat (1771-1802), Gaspard Laurent Bayle (1774-1816), and Jean Nicolas Corvisart (1755-1821) were followed by Rene Theophile Hycinthe Laennec’s work (1781-1826), which explained TB pathogenesis and gave the concept of pulmonary and extra-pulmonary TB (Laennec, 1962). The field of TB research was revolutionised with the entry of German scientists. Johann Lukas Schonlein of Wurzberg (1793-1864) who had different thoughts regarding scrofula, tubercles and phthisis coined the term ‘tuberculosis’ to describe the affliction with tubercles. In 1840, Jakob Henle (1809-1885) in Gottingen suggested that phthisis could be contagious only under certain circumstances and gave three postulates for categorising a disease as infectious: (1) the causative agent must be found in every case of disease; (2) it must not occur in another disease; (3) its application must always result in the same disease; later re-stated by his pupil Robert Koch which is also known as Henle-Koch postulates in bacteriology (Evans, 1976). Later in 1865, Jean Antonie Villemin (1827-1892) demonstrated the transmission of phthisis from blood or sputum from diseased human and cattle to rabbits and guinea pigs and showed that a specific microorganism causes the disease. Years later in 1877, Theodor Klebs (1834-1913), was able to maintain the causative agent in artificial medium, however he was unable to recognise the true nature of the agent (Herzog, 1998).

 

Discovery of Mycobacterium tuberculosis

On 24th March 1881, Robert Koch (1843-1910) delivered a famous lecture entitled ‘Die Ätiologie der Tuberkulose’ to the Physiological Society at the Charité Hospital in Berlin. He used microscopic techniques and identified the causative agent from tuberculous tissue as a rod-shaped bacilli which he called ‘Mycobacterium tuberculosis’ and also verified the Henle-Koch postulates regarding the disease causing microorganism (Koch, 1932). Later, he introduced the concept of primary and secondary infection in guinea pigs (Koch’s phenomenon) and discovered ‘tuberculin’-a glycerin extract of dead tubercle bacilli, which was later utilised for tuberculin skin test. For his contribution, Robert Koch was awarded with the Noble Prize in Medicine or Physiology in 1905.

In 1907, Clemens Freiherr von Pirquet (Austria, 1874-1929) established that ‘tuberculin’ can be injected intra-cutaneously and resulted in an immune response (von Pirquet, 1907). Further, Charles Mantoux (France, 1877 – 1947), invented a more safe cannulated needle and syringe for tuberculin injection and Florence Seibert (USA, 1898-1991) isolated the active substance from tuberculin: Purified Protein Derivative (PPD) which further improved the accuracy of the tuberculin skin test (Seibert, 1926).

Initial attempts of TB treatment

The discovery of M. tuberculosis as the causative agent and the tuberculin skin test marked key milestones in TB research. However, thousands of individuals were dying due to the absence of a treatment. In the absence of antibiotics, the concept of public health came into existence. Hermann Brehmer (Germany, 1826-1889) emphasised the necessity of an immune balance and the concept of sanatoria: an environment with fresh air, good food, and rest and devoid of any known consumptives. In the following years, this regimen was practiced all over the world for the treatment of TB. Initially, recovery was surprising; however, the long-term results were not encouraging. However, it helped in the restriction of TB transmission, as infected patients were confined to certain locations, minimising contact transmission (Daniel, 2006). In patients where bed-rest alone was not sufficient, the localised collapse therapy by artificial pneumothorax, phrenicectomy or thoracoplasty, which consists of introducing clean and filtered air into the pleural space of the lung was introduced (Sharpe, 1931). In 1888, Carlo Forlanini (Italy, 1847-1918) performed the first artificial pneumothorax. While collapse therapy yielded successful results; with closure of cavities, conversion to negative sputa, and low-operative mortality, it also produced numerous complications which included tissue infection, conversion into acute TB, fistula formation and empyma (Gaensler,1982).

Invention of ‘BCG’

The concept of a vaccine was introduced by Edward Jenner (England, 1749-1823) in 1796, when he found that the use of pus from a hand of a milkmaid with cow pox, when administered to healthy individuals provided protection against smallpox (Baxby, 1999). Based on similar experiments, Frenchmen Albert Calmette (1863-1933) and Camille Guerin (1872-1961), an attenuated strain of M. bovis BCG which could induce protective immunity in humans, especially at an early age (Calmette & Guérin, 1924; Calmette, 1928). Soon a worldwide campaign against TB was started with the involvement of WHO, UNICEF and the Red Cross, based on the use of the tuberculin skin test followed by BCG vaccination (Comstock, 1994).

 

Final combat: The discovery of streptomycin and other drugs against TB

Selman Waksman (USA, 1888-1973) and colleagues at the University of California demonstrated that streptomycin, an antibiotic, isolated from cultures of Streptomyces griseus had the ability to inhibit tubercle growth with low toxicity in laboratory animals (Jones et al., 1944). Subsequently, Selman Waksman was awarded the Nobel Prize in Physiology or Medicine in 1952. This success was short-lived due to the appearance of resistant M. tuberculosis mutants. However, the problem of drug resistance could be overcome by using combinations of two or three drugs under a drug regimen. Following the discovery of streptomycin, p-aminosalicylic acid, isoniazid [INH], pyrazinamide, cycloserine, ethambutol [EMB], and rifampin were developed as anti-TB drugs. There was an improvement in the disease condition with the recommended clinical regimen, involving these drugs. However, due to patient compliance and non-adherence to the drug regimen the number of cases has increased and now the situation has led to the emergence of MDR- and XDR-TB (Pablos-Mendez et al., 1998).

 

Drug resistant TB

During mid-1950s, three-drug combination therapies, consisting of isoniazid, rifampin, pyrazinamide, and ethambutol initially for two months, followed by a two-drug phase of isoniazid and rifampin lasting for four months, were introduced (WHO, 2009). The advent of such a program, almost eradicated TB from many countries. However, the occurrence of HIV and the emergence of MDR- and XDR-TB has led to an uncontrollable spurt in TB cases (Snider & La Montagne, 1994). The complex nature and length of therapy, drug supply and the tendency of patients to feel well before completion of the course of treatment has accelerated and promoted MDR- and XDR-TB (Munro et al., 2007). MDR-TB is a form of drug-resistant TB in which M. tuberculosis can no longer be killed by at least two of the front line antibiotics, isoniazid and rifampin, and XDR-TB involves resistance against second-line drugs, including fluoroquinolone, and at least one of the other three injectable anti-TB drugs; amikacin, kanamycin, and capreomycin (WHO, 2009). There is an urgency to come out with new treatments against XDR-TB and few recent developments are in line with the need (Kwon et al., 2014).

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