As we have come to understand in this series, the most devastating diseases plaguing mankind
throughout all of history were caused by microorganisms.
And yet, humans remained clueless as to their existence for more than 99% of that history.
Even when solutions were eventually found, like Jenner’s immunization technique, these
were reached only through trial and error, without any understanding of the etiology
of the disease, meaning that we didn’t actually know what was causing the disease, or precisely
why these techniques worked against them.
There had been speculation for centuries about the possible existence of living beings too
small to be seen by the naked eye.
After all, humans had noticed exceptionally small insects, which are barely visible to
the naked eye, and it does not require a lot of imagination to conceive of the possibility
that even smaller organisms might exist.
However, the definitive proof that these invisible beings existed could only be reached upon
the invention of the microscope.
And in fact, bacteria were first described by an amateur scientist.
In 1674, a Dutch draper, Antonie van Leeuwenhoek, whose hobby was to grind powerful single lenses,
built a rather simple microscope, and using it himself, he described what he referred
to as “animalcules” moving under the lens.
Over the years, he documented in some detail many examples of what we now understand to
be bacteria, protozoa, and fungi.
Surprisingly, this discovery, now hailed as the birth of microbiology, did not make much
of an impact, and the decisive steps toward establishing this new discipline had to wait
for almost two centuries.
As it came to pass, the field of microbiology truly arose not in the context of therapeutic
needs, but rather in response to intense debates focused on the phenomena of fermentation and
spoilage.
There were many scientists, including top chemists of the time like Berzelius and Liebig,
who claimed that these were spontaneous processes deriving from chemical decomposition pathways.
Others thought that invisible organisms could arise spontaneously from grapes or hops and
trigger the process.
Still others proposed, and correctly as it turns out, that fermentation arose because
microorganisms carried through the air settled down onto nutrients such as the sugar in grape
juice, and multiplied.
Their metabolic activity was the cause of the fermentation that we observed, for example
in beer or wine production.
One of the greatest scientists of all time, French chemist Louis Pasteur, is widely acknowledged
as the father of microbiology.
Pasteur had a doctorate in both physics and chemistry, and his contributions to chemistry
and crystallography were unparalleled.
He turned to microbiology to address the wine fermentation problem, because the father of
one of his students, a wine producer, sought his help.
Pasteur devised remarkably simple but conclusive experiments using swan‐necked flasks filled
with fermentation broth.
As a control, he also used broth contained in normal flasks.
When he left the contents of all the flasks exposed to the air, fermentation rapidly occurred
in the normal flasks, but not in the swan-necked flasks.
This experiment suggested that microorganisms from the air, falling into an open flask,
are responsible for the fermentation process.
He also showed that rapid heating of a potential fermentation medium, such as milk, all the
way to its boiling point, followed by rapid cooling, would prevent spoilage.
This simple idea is at the basis of the process called pasteurization, named in his honor.
These results led Pasteur to the idea that microorganisms may also be the cause of human
diseases.
He had lost three of his five children to typhus, and he was particularly interested
in the root cause of this and other diseases.
He then postulated the germ theory of disease, which identifies microorganisms as etiological
agents of many infectious diseases.
This theory was slowly accepted, and it had a profound impact on society.
For example, British surgeon Joseph Lister, once exposed to Pasteur’s ideas, developed
the technique of sterile surgery.
He sprayed his surgical instrument with a substance named carbolic acid, which is now
known as phenol, a substance which Pasteur had proposed as a bactericide.
Furthermore, he used a clean environment for his surgeries, and even applied pads soaked
in carbolic acid directly to wounds.
Prior to this, at the end of the 19th century, surgeons had been operating under very unsanitary
conditions, often wearing dirty operating aprons, because they were going to be stained
with blood anyway.
Even successful surgeries frequently resulted in the death of the patient due to infection.
But with his new techniques, Lister observed a significant decrease in post-operative infections,
and he published his results in 1867 through a series of articles.
However, these ideas were greeted with much skepticism, and even mockery.
In 1873 the prestigious journal The Lancet published an editorial, warning the medical
profession against Lister’s ridiculous practices.
Nevertheless, as Lister perfected his techniques and the field of microbiology developed further,
his approach was slowly accepted, and he is now recognized as the father of modern surgery.
An antiseptic solution named after him, marketed in 1879 as Listerine, is still used today
as mouthwash.
In 1900, Lister was named Surgeon to Queen Victoria, and he was instrumental in saving
the life of her successor, Edward VII.
The new king had a severe case of appendicitis two days before his coronation, and the team
of surgeons assembled for the operation was supervised by Lister.
This operation was often lethal in those days, due to post-operative infections.
But the king was back on his feet for the coronation thanks to Lister’s antiseptic
concepts.
As far as Pasteur goes, he became a legend in his own time.
In his middle age, he was already a French national hero.
A special institute was created for him, the Pasteur Institute, which he supervised until
his death, and where he is now buried in a special vault.
Later in life, he focused on immunization.
He proposed that an etiological agent can be weakened by chemical means and then used
to immunize healthy volunteers.
This was important, because in this way, scientists did not have to rely on a naturally attenuated
version of the microorganism, like Jenner had done with smallpox and cowpox.
This discovery revolutionized the field, and Pasteur was the first to refer to these artificially
weakened microorganisms with the name “vaccines”, in honor of Edward Jenner.
In his old age and after his death, Pasteur was widely criticized for being extremely
secretive, presumably for financial reasons.
Indeed, he instructed his family to keep his legendary lab notebooks secret and never to
reveal them to anyone.
They finally became publicly available in 1971 and are now displayed in the French National
Library.
Pasteur also became embroiled in a bitter rivalry with an eminent German physician and
microbiologist, Robert Koch, who is credited as a co-founder of the new discipline.
Koch’s enduring legacy is the formal establishment of microbiology as a science.
He developed the so-called Koch’s postulates, which can be summarized as follows.
One.
To be demonstrated as the etiological agent of a disease, a microorganism has to be isolated
from a sick animal or patient.
Two.
It has to be grown in a lab culture and observed to multiply.
Three.
The microorganism obtained in the lab culture needs to be injected into a healthy animal
and the healthy animal has to develop the disease.
And four.
The original microorganism has to be observed in the sick animal and has to again be isolated
and grown in the lab.
These criteria are still generally applied in microbiology, although with some modifications
given our modern understanding of pathogens and their behavior.
Although Koch worked on several diseases, his best-known research was done on tuberculosis,
which is one of the greatest killers of all time, having caused the death of several billion
humans since the dawn of mankind.
In Koch’s time, it was believed that tuberculosis was a hereditary disease.
Koch proposed instead that the disease was caused by a bacterium, and he was able to
isolate it.
He called it Mycobacterium tuberculosis, and found that this microorganism satisfied all
four of his postulates.
In collaboration with his colleague and friend Paul Ehrlich, he developed a diagnostic test
for the disease, called tuberculin, which is still used to this day.
Initially, this was meant to be a therapy against the bacterium, but it failed to cure
the disease.
For his work, Koch received the Nobel Prize in 1905, and today, the Robert Koch Institute
in Berlin is the primary German center for microbiology.
The contributions of Pasteur and Koch to mankind cannot be overstated.
In the span of about 50 years, humans went from complete ignorance of the etiological
agents of disease to the emergence of two new scientific disciplines, microbiology and
immunology.
The door to finally overcoming the great scourges of mankind was now wide open.
The next step, which was quite obvious but difficult to achieve in practice, was to find
a treatment for these diseases.
We saw in the previous tutorial how quinine was isolated from the bark of a tree and had
become a major strategy to combat malaria even without any knowledge of microbiology.
However, this time scientists took another approach.
Instead of relying on nature, chemists would make the medicine in the lab themselves, via
chemical synthesis.
Now bacteria could be grown in vitro, and therefore chemicals could be tested directly
on the bacteria, and scientists could then determine how effective any chemical might
be in killing these bacteria.
The most promising agents could then be tested in infected animals and finally in human patients
to see whether they could cure the disease.
Though with far greater sophistication, this is essentially how the pharmaceutical industry
still operates.
The father of chemotherapy is the German physician we mentioned a moment ago, Paul Ehrlich, who
worked in Berlin and Frankfurt at the institute which now bears his name.
As a first disease target he chose syphilis, a bacterial infection caused by Treponema
pallidum, and transmitted sexually.
There is still no vaccine against it, and mortality is around 58%, although the progression
can last over thirty years, and the symptoms are devastating.
It is still a significant disease today, with 35 million new cases and 100,000 deaths per
year, mainly in the developing world, though it can now be treated quite easily with antibiotics.
At the beginning of the 20th century, however, it was still treated with mercury salts, which
were ineffective and toxic.
Interested in finding a cure, Ehrlich tested hundreds of synthetic compounds, and he hit
the jackpot with compound 606, named Arsphenamine, then marketed as Salvarsan, an arsenic-containing
molecule with a very unusual structure.
He proceeded to test the substance in vivo, and was successful in curing patients.
In spite of his stunning success, and in spite of having received the Nobel Prize for Medicine
in 1909, Ehrlich suddenly became a controversial scientist.
He was Jewish, and much of the animosity displayed against him may have been motivated by the
anti-Semitism of the times.
He was accused of fueling the moral destruction of the German people by encouraging the sexually
promiscuous behavior which had been kept in check by the fear of the disease.
At the same time, he was accused of unethical behavior, as some of his initial patients
had died from the side effects of the drug, which was indeed quite toxic.
In his famous Frankfurt Lecture of 1910, Paul stated what is still one of the basic concepts
of chemotherapy: In effect, the hope of finding the ideal of modern therapy, i.e. entirely
safe substances for curing bodily ills, seems to me virtually incapable of being realized.
We shall always have to reckon with some degree of toxicity.
But the negative aspects must not constitute a risk that is excessive in relation to the
danger from the disease itself.”
Paul was deeply affected by the many personal attacks, and eventually slipped into a depression,
leading to his premature death.
In his later years, to address the problems of drug side effects, he proposed the idea
that we could develop a “vehicle” which would hit only the desired target, and we
could use this vehicle to deliver very toxic drugs quite selectively, therefore avoiding
damage to the host.
He called this approach “Zauberkugel”, German for “magic bullet”.
Ehrlich failed to develop this magic bullet.
His ideas were 100 years too early, and only now are we beginning to put this concept successfully
into practice.
In any case, the doors to chemotherapy and the treatment of all bacterial diseases were
opened by Paul Ehrlich’s approach.
We will see moving forward how this initial success led to more exciting results against
a number of other diseases.