Transcript Koch’s Postulates and Ehrlich’s ‘Magic Bullet”

Koch’s Postulates and Ehrlich’s
‘Magic Bullet” :
Specific Causation, Treatment and
Prevention- Doctrines of Specificity in
Medicine.
By: Elizabeth Griffiths, MS2
How do we treat disease?
AXIOM: Our interpretation of Causality determines
our therapeutic intervention.
• A brief review of medicine until the mid1600s- older concepts of
causality
• Pasteur and Koch- Early bacteriology and Koch’s Postulates
• Paul Ehrlich- The birth of immunology and the ‘Magic Bullet’
Older Concepts of Disease
• The Magico-religious concept of disease: This interpretation
leads to treatments which depend largely upon exorcisms,
prayer and atonement with the assumption that disease has
been sent as a punishment or curse.
- In Mesopotamia disease was interpreted as the hand of god:
disease was the result of ‘… spirit invasion, sorcery, malice or the breaking
of taboos; sickness was both a judgement and a punishment….’(Porter 46).
- The Egyptians believed one was born healthy and disease
originated from demons or intestinal putrefaction. Herodotus mentions that
three days each month were laid set aside for evacuating the body with
emetics and enemas.
•Aristotle suggested ‘four causes’: 1) The material cause, 2) The
formal cause (or blueprint) 3) The moving or efficient cause (the
agent) 4) the final cause (the purpose or outcome).
-For every disease there must be some origin, changing the concept of
disease and its treatment from a religious to an observational/scientific
endeavor
•The Humoral Doctrine of disease:
-The Hippocratics believed that illness stemmed from an ‘imbalance’
in the bodily humors- black bile, yellow bile, blood, phlegm. Treatments were
thus largely aimed at reestablishing balance- bleeding to eliminate excess
blood, exercise, and purging were all standard therapies.
- Galen seized the Humoral concept of disease and his ideas
dominated medicine for almost a millennium. In 1481 the following medical
curriculum was taught at the University of Tübingen:
First year: Galen’s Ars Medica, Avicenna’s Treatise on Fevers
Second year: Avicenna (Anatomy and physiology), Rhazes Ninth book(local pathology)
Third year: Aphorisms of Hippocrates, Galen
•After 1600 Physicians saw manifestations of disease, but the
cause was still humoral imbalance-In 1694 when an autopsy was performed on Marcello Malpighi who
first demonstrated capillaries post mortem showed hemorrhage into the right
ventricle of the brain- but the cause? ‘… glands in the body had poured into
the blood two humors, which when they reached the brain corroded the artery
and caused the bleeding….’ Giorgio Baglivi(1668-1707) ( from Hudson 104)
•In 1761 Giovanni Batista Morgagni published On the Seats and
Causes of Disease
- This work demonstrated the value of clinico-pathologic correlation,
but more importantly it localized the cause of disease to organs rather than
to the bodily humors- but this really didn’t change the way we TREATED
disease.
•The Paris School and all its developments would continue this
tradition, but observation didn’t really bring about a new method
of dealing with disease in terms of treatment.
Pasteur and Lister
• Before 1860 there were many people who believed that fermentation
and putrefaction were caused by living organisms, but no one had
PROVED that this was the case and there was significant debate.
• Between 1860 and 1870 Pasteur demonstrated that fermentation was
caused by micro-organisms, that there were different organisms which
would cause different types of fermentation, and that these organisms
were UBIQUITOUS.
• In 1865 Joseph Lister heard of Pasteur’s discovery and reasoned that if
fermentation was caused by these animalculae putrefaction of wounds
might also be. This led him to institute the use of carbolic acid as a
disinfectant with stunningly successful results-- a 50% drop in mortality.
• Despite Lister’s results many people remained unconvinced (perhaps
because this might mean acceptance of the germ theory of diseaseSemmelweis’ (ca 1847) reception had already shown how popular this
was.)
Setting the Stage
In the middle of the 1870 microscopy had developed
considerably making it possible to visualize Pasteur’s
micro-organisms, although not their intracellular
structures.
Additionally the German dye industry had produced a
number of compounds which were able to stain both
tissues and micro-organisms with differential affinity.
These innovations would facilitate the work that
Robert Koch was about to begin while working in his
back yard laboratory in Eastern Prussia.
Koch’s Life
• Robert Koch(1843-1910)
• 3rd of 13 children
• Trained with Jacob Henle at the
Göttingen Medical School
• After the Franco-Prussian war he
was assigned the district physician
for Wollstein, a town in Polish
Prussia, there he became intensely
interested in bacteriology and
assembled his own laboratory
• In 1873 he began to investigate
Anthrax, which was especially
rampant in Wollstein.
•Koch was largely responsible for the scientific establishment of
bacteriology
-In April of 1876 traveled to Breslau where he demonstrated
his Anthrax research: Using a method of his own invention Koch was
able to conclusively demonstrate the existence of anthrax spores and
to trace the complete life cycle of the organism-- no one had done
this for any other bacterium. At this demonstration J.F. Cohnheim
declared, ‘There is nothing left to prove. I regard it as the greatest
discovery ever made with micro-organisms.’(Carter xiv)
•Emphasized that PURE cultures were necessary
•A CONSUMATE technician
-He photographed his bacteria, a great improvement over the
contemporary practice of hand drawn sketches.
-in 1881 he presented his development of the poured
bacterial medium(agar, a seaweed byproduct), as well as a number of
other technical innovations- Pasteur himself is said to have rushed
forward saying ‘C’est un grand progrès!’ (Carter xiv).
•Formalized procedures for establishing disease causation
(Koch’s Postulates)
•Began his investigations of tuberculosis in 1881 and in 1882
announced his initial results, he had indeed identified the
causative agent in tuberculosis, (He received the Nobel prize for
this work in 1908).
•Eventually with the help of his colleagues he was able to
identify the causative agents of infected wound diseases,
tuberculosis, cholera, typhoid, and diphtheria.
•His reputation was irrevocably damaged in 1890 when he
announced tuberculin, that was believed to inhibit the growth of
the tubercule bacilli. It was later proven that tuberculin,
although excellent for diagnosis was not useful therapeutically.
•It was further damaged in 1893 when he, then 50 fell in love
with a 21 year old actress and divorced his wife.
Koch’s Postulates
1) The Parasit occurs in every case of the disease.
2) The Parasit does not occur in other diseases or nonpathogenically
3) After being fully isolated from a diseased animal and
repeatedly grown in pure culture, the Parasit can induce
the disease by being introduced into a healthy animal.
Weaknesses of the Postulates
A) There are many diseases for which even Koch himself could not
satisfy all three postulates.
B) Asymptomatic infections (Carriers) were known even in Koch’s
time.
C) Many viral diseases do not fulfil these postulates- e.g.:Epstein-Barr virus
and its association with Burkitt’s Lymphoma, Hodgkin’s disease, and nasopharyngeal
carcinoma.
D) Many viral infections lead to the same illness- Rhinovirus, adenovirus,
RSV, coronavirus.
E) Prion diseases are not ‘culturable’ since they aren’t alive. i.e. mad
cow disease, Kuru, sheep scrapies.
F)Some infectious diseases take many years to produce symptoms.
Weaknesses Cont.
G) Multiple factors may contribute to the development of disease:
- nutrition, diabetes, genetics, concurrent viral illness, immune status, etc.
H) Immune reactions were not addressed by Koch
- mitral stenosis, acute glomerulonephritis following streptococcal
infection.
I) The proximate insult may be far less damaging than collateral
/side effects which may develop later.
- subacute sclerosing panencephalitis, post-polio syndrome.
J) The power of the mind over the body?
K) ‘Essential’ or ‘idiopathic conditions?
Ehrlich’s Life
• Born in 1854 to working class
parents
• Enrolled at Breslau University, but
transferred to the University of
Strasbourg where he became
fascinated with chemistry--he is
quoted as having said, ‘I…believe that
my real natural endowment lies in
chemistry… the benzene rings and
structural formulae…disport themselves
in space before my mind’s eye’ (Wick)
• After the appropriate premedical
education he returned to Breslau to
pursue his medical education where
he pursued research involving the
interaction of aniline dyes with
human tissues.
Ehrlich’s Accomplishments
• Ehrlich’s thesis for his MD was entitled ‘Contributions to the Theory
and Practice of Histological Staining’ during his research he
described a new cell type in human tissues which contained numerous
basophilic granules- he proposed that it be called a ‘mast’ cell.
•After medical school he worked at the Charité Hospital in Berlin.
Under the direction of Freidrich von Freirich, who recognized his
genius Ehrlich was responsible for analysis of all inpatient blood
smears, a task which pleased him and which allowed him to develop a
consummate expertise in morphologic hematology. He later published
a comprehensive text on the differential staining qualities of blood
cells. Additionally during this period he developed the precursor to
the current acid-fast mycobacterial stain and the ‘Ehrlich method’ for
urobilinogen quantitation, all of this before he was 30.
Ehrlich’s Accomplishments Cont.
•When von Freirich died in 1885 he was replaced by Karl Gerhardt, described by
Wick as an, ‘…autocratic, narrow-minded, and professionally deficient man…[who]
interfered in Ehrlich’s research, making it progressively more difficult for him to think
creatively…’(330).
• In 1888 Ehrlich contracted tuberculosis and left the Charité for Egypt, before he
went, however he submitted to a course of Koch’s ‘tuberculin treatment’ and it is this
which first interested him in immunology
•Ehrlich developed a method to titer the antibody strength in any given serum. This
development stemmed from the work of his colleague Emil von Behring who was
trying to develop antidiphtheria toxin for clinical use. Ehrlich’s contribution allowed
the standardization of the antibody and calculation of a reproducible dose. Von
Behring later cheated Ehrlich out of the profits from the sale of diphtheria antitoxin.
Ehrlich would bitterly criticize him for the rest of his life.
• In 1899 Ehrlich was appointed director of the Prussian State Antitoxin Institute in
Steglitz.
• From 1890-1899 Ehrlich began to formulate his ‘key-in-lock
model for antibody/antigen binding. His theory proposed a
stereospecific interaction based upon covalent, rather than ionic
bonds.
--debate over this raged for years. Ehrlich was right about
stereospecificity, but wrong about the irreversible covalent bonds.
• Ehrlich postulated that there existed a third factor (besides
antibody and antigen) which bound to a part of the antibody
distinct from the antigen binding site
-- Today we recognize complement and know that it binds antibody on
the Fc portion of the antibody. Ehrlich was incorrect, however in proposing that
there were several distinct complements one for each antibody subclass and also
that complement bound antibody independently of its interaction with antigen.
Ehrlich’s ‘Magic Bullet’
•At 45 Ehrlich changed directions again, this time to focus on pharmacology. This
work was actually an extension of his immunological work he proposed that foreign
microbes might posses biochemically unique binding sites whose blockade could
result in targeted destruction of the invading microbe without harm to healthy
tissues. Here was his ‘magic bullet’ concept, still the inspiration for many of
today’s therapies.
• In 1909 Ehrlich and his colleague Sachahiro Hata became intrigued by the
arsenical 606 which was found to be highly effective against yaws and relapsing
fever-- syphilis. At last he had achieved the ‘magic bullet’ for this disease.
• However, the development resulted in a surprising backlash which would
ultimately cause the end of Ehrlich’s career.
-- “He became the object of vituperation, denouncement and discredit. ‘The pox’
was seen as the deserved punishment for promiscuity. In response to a possible cure the
church, politicians and even some scientists responded by reviling 606 and its creators as the
devil’s pawn” (Wick 332). This response seems to have damaged Ehrlich. He ceased to
participate in scientific research and died of a CVA in 1915.
The ‘Magic Bullet,’ an Illusive
Goal
Although Ehrlich never succeeded in producing a single dose
which would be lethal to the parasite while sparing the host,
his ideas fostered a search for ‘magic bullets’ which would be
effective for other bacteria.
The first of these would be the sulfonamides, followed by
penicillin and many others.
However, as we examine illness today it is clear that a single
‘magic bullet’ will not be effective. Most obviously with
tuberculosis, and recently with HIV disease we have found that
several ‘bullets’ are more effective than just one. Moreover
these bullets are invariably more damaging than we would like
them to be.
What are we left with?
It is clear that the ideals for definition and treatment of disease
presented by Koch and Ehrlich at the turn of the century are of limited
direct application. This does not mean that they are not and have not
provided a valid conceptual framework.
As Ruy Perez-Tamayo, MD states in his Epilogue to Mechanisms of
Disease:
“… after all these centuries of recorded history, and many
more preceding our short and ridiculous attempt at keeping track of
all human frailties and greatness, it has emerged that disease, as all
other manifestations of living beings, is life itself, and nothing more.”
References:
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individualized pharmacotherapy. BioEssays. 20:683-685 (1998).
3. Evans, A.S.. Causation and Disease: The Henle-Koch Postulates Revisited. Yale J Biol Med. 49:175-195 (1976).
4. Hudson, R.P.. Disease and Its Control: The Shaping of Modern Thought. New York: Praeger, 1983.
5. Metchnikoff, E.. The Founders of Modern Medicine: Pasteur, Koch, Lister. New York: Walden, 1939.
6. Perez-Tamayo MD, R.. Mechanisms of Disease: An Introduction to Pathology. Philadelphia: WB Saunders, 1961.
7. Porter, R.. The Greatest Benefit to Mankind: A medical history of humanity. New York: WW Norton, 1997.
8. Silverstein, A.M.. Paul Ehrlich’s Passion: The Origins of his Receptor Immunology. Cell Imunol. 194:213-221
(1999).
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(1988).