Download The Concepts that Revolutionized the Field of Infectious Diseases

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Journal of The Association of Physicians of India ■ Vol. 63 ■ August 2015
Pioneers in Infectious Diseases
The Concepts that Revolutionized the Field of
Infectious Diseases
Piyush Chaudhari1, Anjali Shetty2, Rajeev Soman3
T
he fields of Microbiology
and Infectious diseases have
developed tremendously in the
19th and the 20th centuries.
Four revolutionary concepts that
evolved during this period form the
cornerstones on which these fields
have developed further.
Louis Pasteur and Germ
Theory of Infectious
Diseases
Louis Pasteur (1822-1895) was a
French chemist and microbiologist
renowned for his discoveries of the
principles of vaccination, microbial
fermentation and pasteurization.
Louis Pasteur was an average
student in his early years, and not
particularly academic, as his interests
were fishing and sketching. He
earned his Bachelor of Arts degree
(1840), Bachelor of Science degree
(1842) and a doctorate (1847) at the
École Normale in Paris.
Professionally he held several
posts of importance in various
universities. During these
appointments he was considered a
strict disciplinarian responsible for
raising the standards of exams and
greater competition. Pasteur often
made a remark: “dans les champs de
l’observation, le hasard ne favorise que
les esprits préparés.” (In the field of
observation, chance favors only the
prepared mind)
fermentation experiment and
crushing the theory of spontaneous
generation of life.
Before Pasteur there existed
the miasma theory of disease
transmission (which held that
diseases such as cholera, chlamydia
or the Black Death were caused by
a miasma, a noxious form of “bad
air”) and the theory of spontaneous
generation.
Following his fermentation
experiments, Pasteur demonstrated
that the skin of grapes was the
natural source of yeasts, and that
sterilized grapes and grape juice
n e ve r f e r m e n t e d . H e r e c e i ve d
a stern criticism from Félix
A r c h i m è d e P o u c h e t , w h o wa s
director of the Rouen Museum
of Natural History. To settle
the debate between the eminent
scientists, the French Academy of
Sciences offered Alhumbert Prize
carrying 2,500 francs to whoever
could experimentally demonstrate
for or against the doctrine.
Pa s t e u r d e m o n s t r a t e d t h a t
fermentation is caused by the
growth of micro-organisms, and
the emergent growth of bacteria in
nutrient broths is due not
to spontaneous generation, but
rather to biogenesis (Omne vivum ex
vivo “all life from life”). In 1856, a
local wine manufacturer sought his
advice on the problems of making
beetroot alcohol and souring after
long storage. In 1857, he developed
his ideas stating that: “I intend
to establish that, just as there is
an alcoholic ferment, the yeast of
beer, which is found everywhere
that sugar is decomposed into
alcohol and carbonic acid, so
also there is a particular ferment,
a l a c t i c ye a s t , a l wa y s p r e s e n t
when sugar becomes lactic
acid.” He demonstrated that yeast
was responsible for fermentation
to produce alcohol from sugar,
a n d t h a t a i r ( o x y g e n ) wa s n o t
required. And that fermentation
could also produce lactic acid (due
to bacterial contamination), which
make wines sour. This is regarded
as the foundation of Pasteur’s
To prove himself correct, Pasteur
exposed boiled broths to air in a
swan-neck flask that contained a
filter to prevent all particles from
passing through to the growth
medium, and even in a flask with
no filt er at all, wit h ai r bei n g
admitted via a long tortuous tube
that would not allow dust particles
to pass. Nothing grew in the broths
u n l e s s t h e f l a s k s we r e b r o k e n
open, showing that the living
organisms that grew in such broths
came from outside, as spores on
dust, rather than spontaneously
generated within the broth. This
was one of the most important
experiments disproving the theory
of spont aneous g enera t i o n f o r
which Pasteur won the Alhumbert
Prize in 1862.
He concluded that: “Never
Fellow in Infectious Diseases, 2Consultant Microbiologist, 3Consultant Physician and Infectious Diseases
Specialist, PD Hinduja National Hospital and MRC, Mumbai, Maharashtra
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Journal of The Association of Physicians of India ■ Vol. 63 ■ August 2015
will the doctrine of spontaneous
generation recover from the mortal
blow of this simple experiment.
There is no known circumstance
in which it can be confirmed that
microscopic beings came into the
world without germs, without
parents similar to themselves.”
The germ theory of disease states
that some diseases are caused
by microorganisms. These small
organisms, too small to see without
magnification, invade humans,
animals, and other living hosts.
Their growth and reproduction
within their hosts can cause a
disease.
While Pasteur was not the first to
propose the germ theory (Girolamo
Fracastoro, Agostino
Bassi,Friedrich Henle and others
had suggested it earlier, with an
experimental demonstration by
Francesco Redi in the 17th century).
Pasteur developed it and conducted
experiments that clearly indicated
its correctness and managed to
convince most of Europe that it was
true. Today, he is often regarded as
the father of germ theory.
Robert Heinrich Herman
Koch and his Postulates
addition, Koch created and
improved laboratory technologies
and techniques in the field of
microbiology, and made key
discoveries in public health.
His research led to the creation
of Koch’s postulates, a series of four
general principles linking specific
microorganisms to specific diseases
that remain today the «standard»
in medical microbiology. These
postulates, which not only
outlined a method for linking
cause and effect of an infectious
disease but also established the
significance of laboratory culture
of infectious agents. The postulates
were formulated by Robert
Koch and Friedrich Loeffler in 1884,
based on earlier concepts described
by Jakob Henle. Koch applied the
postulates to describe the etiology
of cholera and tuberculosis, but
they have been generalized to
other diseases.
The postulates are:
1. The organism must always be
present, in every case of the
disease.
2. The organism must be isolated
from a host suffering from the
disease and grown in pure
culture.
3. S a m p l e s o f t h e o r g a n i s m
taken from pure culture must
cause the same disease when
inoculated into a healthy,
susceptible animal in the
laboratory.
4. The organism must be isolated
from the inoculated animal and
must be identified as the same
original organism first isolated
from the originally diseased
host
Robert Koch (1843 – 1910) was
a celebrated German physician
a n d pi o n e e r i n g m ic robiologis t
and is considered the founder
o f mo de r n b a cteriology. H e is
known for his role in identifying
the specific causative agents
of tuberculosis, cholera,
and anthrax and for giving
experimental support for the
concept of infectious diseases. In
Koch’s postulates have played
an important role in microbiology,
yet they have major limitations. For
example, Koch was well aware that
in the case of cholera, the causal
agent, Vibrio cholerae, could be found
in both sick and healthy people,
invalidating his first postulate.
Furthermore, viral diseases were
not yet discovered when Koch
formulated his postulates, and
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there are many viruses that do
not cause illness in all infected
individuals, a requirement of the
first postulate. Additionally, it was
known through experimentation
that H. pylori caused mild
inflammation of the gastric lining
when ingested. It still did not
immediately convince skeptics
that H. pylori was associated with
ulcers. Eventually, skeptics were
silenced when a newly developed
antibiotic treatment eliminated the
bacteria and ultimately cured the
disease. More recently, modern
nucleic acid-based microbial
d e t e c t i o n m e t h o d s h a ve m a d e
Koch’s original postulates even
less relevant. These nucleic acidbased methods make it possible
to identify microbes that are
a ssoci at e d wi t h a d i se a se , b u t
in many cases the microbes are
uncultivable. Also, nucleic acidbased detection methods are very
sensitive, and they can often detect
t h e ve r y l o w l e ve l s o f v i r u s e s
that are found in healthy people
without disease.
K o c h ’ s p o s t u l a t e s h a ve a l s o
influenced scientists who examine
microbial pathogenesis from a
molecular point of view. In the
1980s, a molecular version of Koch’s
postulates was developed to guide
the identification of microbial
genes encoding virulence factors.
Molecular Koch’s postulates are
a set of experimental criteria that
must be satisfied to show that
a gene found in a pathogenic
microorganism encodes a product
that contributes to the disease
caused by the pathogen. The
postulates were formulated by the
microbiologist Stanley Falkow in
1988 and are based on Koch’s
postulates. For many pathogenic
microorganisms, it is not currently
possible to apply molecular Koch’s
postulates to a gene in question.
Paul Ehrlich and the Magic
Bullet
Paul Ehrlich (1854 – 1915) was
a German Jewish physician and
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Journal of The Association of Physicians of India ■ Vol. 63 ■ August 2015
was a Russian biologist, zoologist
and protozoologist, best known
for his pioneering research into
the immune system.
scientist who worked in the fields
of hematology, immunology,
and chemotherapy. His laboratory
discovered arsphenamine
( S a l va r s a n ) , t h e f i r s t e f f e c t i ve
medicinal treatment for syphilis,
thereby initiating and also naming
the concept of chemotherapy.
Ehrlich popularized the concept of
a “magic bullet”.
Ehrlich had postulated that if
a compound could be made that
se l e cti ve l y t a r g e t ed a diseasecausing organism, then a toxin
for that organism could be
delivered along with the agent
of selectivity. Hence, a “magic
bullet” (magische Kugel, his term
for an ideal therapeutic agent)
would be created that killed only
the organism targeted. The concept
of a “magic bullet” was to some
extent realized by the invention
of monoclonal antibodies as they
provide a very specific binding
affinity.
Elie Metchnikoff and
Phagocytosis
Ilya Ilyich Mechnikov (also seen
as Élie Metchnikoff) (1845 –1916)
Mechnikov was born in the village
Ivanovka near Kharkov, Russian
Empire (now near Kharkiv
in Ukraine) the youngest son of
Ilya Mechnikov, a Guards officer.
As a child Mechnikov developed
a passion for natural history as
well as biology and botany. He
w o u l d g i ve l e c t u r e s o n t h e s e s
subjects to his siblings and other
small children. When Charles
Darwin’s The Origin of Species was
published, Mechnikov became
interested in the survival of the
fittest, testing and teaching it.
He attended Kharkiv
University where he studied natural
sciences, completing his four-year
degree in two years. He then
went to Germany to study
marine fauna on the small North
Sea island of Heligoland and then at
the University of Giessen, University
of Göttingen and then at Munich
Academy. While at Giessen, he
discovered, in 1865, intracellular
digestion in one of the flatworms,
a n o b s e r va t i o n w h i c h wa s t o
influence his later discoveries.
M e t c h n i k o v a l s o d e ve l o p e d
a theory that aging is caused
by toxic bacteria in the gut and
that lactic acid could prolong
life. Based on this theory, he
drank sour milk every day. He
wrote three books: Immunity in
Infectious Diseases, The Nature of
Man, and The Prolongation of Life:
Optimistic Studies, the last of which,
along with Metchnikoff’s studies
into the potential life-lengthening
properties of lactic acid bacteria
(Lactobacillus delbrueckii subsp.
bulgaricus), inspired Japanese
scientist Minoru Shirota to begin
investigating a causal relationship
between bacteria and good intestinal
health, which eventually led to the
worldwide marketing of kefir and
other fermented milk drinks,
or probiotics.
References
1.
Seckbach, Joseph (editor) (2004). Origins:
Genesis, Evolution and Diversity of Life.
Dordrecht, The Netherlands: Kluwer
Academic Publishers. p. 20. ISBN 978-14020-1813-8.
2.
Ullmann, Agnes (August 2007). “PasteurKoch: Distinctive Ways of Thinking about
Infectious Diseases”. Microbe (American
Society for Microbiology) 2 (8): 383–7.
Retrieved December 12, 2007.
He discovered phag ocy t osis
after experimenting on the larvae
of starfish. He realized that the
process of digestion in microorganisms was essentially the same
as that carried out by white blood
cells. His theory, that certain white
blood cells could engulf and
destroy harmful bodies such as
bacteria, met with scepticism from
leading specialists including Louis
Pasteur, Behring and others. At the
time most bacteriologists believed
that white blood cells ingested
pathogens and then spread them
further through the body.
3.
Magner, Lois N. (2002). History of the Life
Sciences (3 ed.). New York: Marcel Dekker.
pp. 251–252. ISBN 978-0-2039-1100-6.
4.
Roll-Hansen, Nils. “Experimental
Method and Spontaneous Generation:
The Controversy between Pasteur and
Pouchet, 1859–64”. Journal of the History
of Medicine and Allied Sciences 1979; XXXIV
(3): 273–292.
5.
Farley J; Geison GL (1974). “Science,
politics and spontaneous generation in
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Medicine 48 (2): 161–98. PMID 4617616.
7.
Amsterdamska, Olga. “Bacteriology,
Historical.” International Encyclopedia of
Public Health. 2008. Web.
Mechnikov’s work on
phagocytes won him the Nobel
Prize in 1908. He worked
with Émile Roux on calomel, an
ointment to prevent people from
contracting syphilis, a sexually
transmitted disease.
8.
Karnovsky ML. “Metchnikoff in Messina: a
century of studies on phagocytosis”. N Engl
J Med (US) 1981; 304:1178-80.
6.http://en.wikipedia.org