Mini Review
The role of Serendipity in biological scientific discoveries
Abstract
The principle point of this mini review is to gain an understanding of serendipity and the
impact it has had on a number of biological scientific discoveries. Serendipity was first
coined in 1754 by Horace Walpole, who got the idea for the word from a children’s fairy tale
‘The Travels and Adventures of the Three Princes of Serendip’. Using the fairy tale, he
explained that serendipity is a chance discovery recognized by one’s wisdom and
understanding to be of significant value. Since the scope of this topic is so broad only
certain biological discoveries were chosen to highlight the important role of serendipity.
These were Fleming and his discovery of penicillin and also of lysozyme, various drug
discoveries, the first culture of Helicobacter pylori and the discovery that the SRA gene in
Trypanosomes is the responsible for the resistance to the normal human serum.
Introduction
Teflon, rubber, X-rays, penicillin, anesthetics, Velcro and dynamite all have something in
common which is that they were all discovered by serendipity. The broad range of items
listed, which are from diverse disciplines of science i.e. the realms of biology, chemistry and
physics, were discovered by accident. These are not the only innovations to have been
discovered by serendipity, the list is endless and many of the serendipitous discoveries
have helped improve everyday life, making it more convenient and enjoyable. There have
been immense developments in the area of health care as a result of serendipity in
particular. Without serendipity none of the items listed in the first sentence may never have
been found, as would be true of all serendipitous discoveries. Therefore, serendipity is vital
to the continued success of scientific research and discoveries. 1
Serendipity plays an important role in all areas of science but for the purpose of this review
the focus will be on biological scientific discoveries. Before the discussion of serendipitous
1 biological scientific discoveries, it is important to have an understanding of what serendipity
is. What does the word actually mean?
It is defined by the Concise Oxford English
Dictionary as ‘The faculty of making happy and unexpected discoveries by accident. Also,
the fact or an instance of such a discovery’.
Everyday dictionary defining it similarly.
3, 4
2
The Collins dictionary and Chambers
However, it has been defined many times by
different people all of whom have given the word a slightly different meaning in comparison
to the original meaning developed by Horace Walpole.
6
This has caused discrepancies
among the scientific community over whether discoveries were or where not discovered
serendipitously.
5, 6
The meaning of the word for the purpose of this essay will incorporate
the sagacity of the person who stumbled upon the accidental discovery, something, which
the named dictionaries forgot to mention. It will be defined as the ability to make a discovery
using a combination of accident and sagacity.
5, 6, 7, 8
Only discoveries that contain the two
elements will be mentioned.
History of the word; serendipity
The word was first coined in 1754 by Horace Walpole
5, 7, 8
who was the son of Sir Robert
Walpole the Prime Minister of England under George II. 7 He coined the word in a letter to
his friend Horace Mann. Walpole was writing to Mann concerning some coat of arms of
which he had found new information on. About the discovery, Walpole wrote ‘…indeed [it] is
almost of the kind of which I call serendipity, a very expressive word…’ He then proceeded
to explain the new word, serendipity, through an explanation rather than just a definition. He
‘once read a silly fairy tale, called the three princes of Serendip: as their Highnesses
travelled, they were always making discoveries, by accidents and sagacity, of things which
they were not in quest of…’
5, 7, 8, 9
The fairy tale ‘The Travels and Adventures of Three
Princes of Serendip,’ is approximately 700 years old and parts of the story could date back
over 1,500 years. In 1557 Christoforo Armeno (Christopher the Armenian) collected and
published several ancient stories, which had their origins in Persia and India. He
concentrated on the tale of the three princes and called the island where the tale was set
‘Serendippo’ after the medieval Arabian name for Ceylon, which is modern day Sri Lanka.
2 Walpole came into contact with the story when he read the French adaption of Armeno’s
Peregrinaggio by Chevalier de Mailly. 6, 7
3 Figure 1: Outline of the History of the word Serendipity from J. H. Austin, Chase, chance,
and creativity: the lucky art of novelty (2003) MIT Press, Cambridge, Mass.; London, Ch.
14, 63-69
The tale is about three princes who have been sent travelling by their father to experience
the world. On their travels, a camel driver approached them asking had they seen his lost
camel. Although they had not in reality seen the camel on their travels they had observed
numerous clues, which indicated the existence of the lost camel. They asked the camel
driver these three subsequent questions: Was the camel blind in one eye? Was one of its
teeth absent? And was it lame? The camel driver answered yes to the three questions and
playing a joke on him they said that it had passed them not too long ago and by now must
have journeyed a great distance. As a result, the camel driver travelled far in pursuit of his
lost camel but failed to find it. He met the three princes again a few days later and was filled
with anger that the princes led him on a futile pursuit. He then accused them of stealing his
camel and selling it so he had them thrown in jail. The princes then confessed that they had
not actually seen the camel and quickly explained how they were able to infer the account
through careful observation. One brother noticed that only on one side of the road was the
grass eaten even though the grass on the other side was of better quality. The second
brother witnessed a trail of chewed grass left behind as if it had fallen out of the camel’s
mouth through a gap between the teeth, signifying that a tooth might be missing. The third
had observed the camel’s footprints and seen it was dragging one foot indicating that it
must have be lame. The princes were basing their observations on a careful and intuitive
use of deduction, similar to what is used by detectives trying to solve a case. They
stumbled upon the episode by accident and through sagacity where able to gather the
facts, which in brief is what serendipity is as Walpole illustrated it. 5, 7, 8, 10 It can be seen that
Walpole’s meaning of the word is slightly different to that of the dictionaries mentioned.
They don’t include the important use of sagacity. It was not just by a happy accident that
the princes were able to infer so much about the lost camel. Intuition was just as important
as the accident. Therefore, the dictionaries are lacking the key meaning of the word,
serendipity. To just chance discover something is not enough.
5
As Louis Pasteur put it
‘Chance favours only the prepared mind’.
4 Types of serendipity
There are three types of serendipity that scientific discoveries can be categorized as
according to Robert Friedel, 2011. These three types are sometimes referred to as
Columbian, Archimedean and Galilean serendipity respectively, after their most noteworthy
historical connection. Columbian serendipity occurs when one is looking for one thing but
obtains another that is of greater value and that value is recognized. The example of
Columbus whose intention was to find a new and improved route to the Indies is
unfortunately more ambiguous than one might wish for, for explaining this type of
serendipity. 5 This is because Columbus didn’t fully understand just what he had discovered
and still believed that he found a new route to the Indies. Nevertheless, he is credited for
discovering the European awareness of the New World and his name is given to this type of
serendipity as a result.
1, 5
Archimedean serendipity arises when what is being sought is
found but in an unanticipated and different way than was previously conceived.
Archimedean was given the task of calculating the volume of an irregular solid, a crown.
When taking a bath, he noticed the amount of water that his body displaced and concluded
that the quantity of water displaced must be equal to his body’s volume. Naturally, he did
not intent to solve his task by taking a bath but through his uncanny wit the solution to the
much sought after task was found in an unintentional manner, by accident.
1, 5
Galilean
serendipity is discovering something that one was not in pursue of. When Galileo made his
improvements to the telescope and aimed it towards the sky what he saw was extensively
grander than what he could have envisaged. He detected the shadows of the moon’s
mountains and later recognized the moons of Jupiter. His intelligence to develop something
so intricate, know how to use it and identify what he found, led to his unpredicted discovery,
without this he may never have discovered anything. 5 There is a very fine line between the
three types of serendipity; therefore some discoveries can be classified as two of the types
of serendipity depending on what way one interprets the discovery and the history leading
up to it. Royston M. Roberts identified a different way of distinguishing between different
types of serendipity. He said that true serendipity was finding something that was not
sought for by pure luck and then coined the term pseudo-serendipity for discoveries that
were sought for but discovered in an unexpected way for example the discovery of
5 penicillin.
1
The altered ways for classifying serendipity depict the discrepancies in the
literature among scientists to identify what is and what is not a serendipitous discovery.
Fleming’s discovery of penicillin and its impact
Now that there is an established understanding of what serendipity means i.e. an
unexpected discovery found by accident but realized through sagacity, it is necessary to
mention examples of such discoveries. One of the most known and significant
serendipitous discovery was Alexander Fleming’s discovery of penicillin in 1928.
11, 12, 13
This discovery revolutionized medicine and has saved millions of lives since its introduction
in the 1940s.
12, 14
Humans have been battling deadly infectious diseases for thousands of
years. Uncontrolled and untreated bacterial infectious epidemics have been a contributing
cause to the destruction of a number of ancient civilizations among them the Roman Empire
which suffered from several episodes of the plague, the Byzantine Empire whose decline
was sparked by the bubonic plague pandemic in 542 A.D and Medieval Europe which also
suffered a disastrous population loss as a result of the bubonic plague in the 14th century. If
penicillin had of been discovered during these times considerable numbers of lives could
have been saved and the history of the world might have been written very differently as a
result. 15
Before the launch of penicillin, infectious diseases were the primary cause of death
throughout the course of history. Few therapeutic agents were available for the treatment of
these diseases.
15
Nonetheless, one class of substances, the sulphonamides were used to
treat infectious diseases such as gas gangrene, dysentery and gonorrhea to name but a
few. However, there were certain drawbacks to using these drugs and resistance to these
drugs, especially in relation to gonorrhea, was beginning to show at this time. Prolonged
exposure to sulphonamides could cause agranulocytosis, a critical condition where a
patient’s leukocytes were killed. This was one of a few deadly side effects for patients
taking these drugs. Another dangerous one was that the drugs could cause crystalline
deposits in the urinary, which led to blockage of it. Sulphapyridine, in particular, could cause
vomiting and nausea in patients when taken orally. So when penicillin was thrown into the
6 market it quickly took over from the sulphonamides. It was effective against sulphonamideresistant gonorrhea and also syphilis which sulphonamides had no effect on. It then
became the preferred choice when treating people with gas gangrene, streptococcal and
staphylococcal infections. It was learned that it was five times more powerful than
sulphathiazole and that it had minimal tissue toxicity. 15 16 Penicillin triggered the golden age
of antibiotics, and it all started with an accident and a man who had the intelligence to
recognize the potential that it had. 15
In September 1928, Fleming who was working at St. Mary’s Hospital Medical School,
London University and was the Director of the Department of Systematic Bacteriology,
under the guidance of Sir Almroth Wright, returned from a holiday with his family and
decided he should clean up the Petri dishes that were cluttering up his lab bench, since he
was complaining about them to his assistant. While fulfilling this task he picked up one of
his Petri dishes at random that has escaped disinfectant from the Lysol, examined it and is
known to have said ‘That’s funny’.
11, 12, 14
What appeared to Fleming to be ‘funny’ was that
a mysterious mould of approximately 20mm in diameter had contaminated the dish of
staphylococci. Around this unidentified mould there was no visible growth of staphylococci
to be found except in a minor number of places, small semi-transparent groups were
detected.
11, 12, 14, 15, 17
Fleming had the knowledge to recognize the significance of the
event; something that other scientists might have ignored and immediately inferred that this
unknown mould had remarkable antibacterial properties. Within a short time, he declared
that he had at long last found the Holy Grail of bacteriology i.e. a substance that did not
harm the host but fought the infectious disease. 14
7 Figure 2: A photograph of Flemming’s culture plate, which displays the Penicillium colony
around which there is no evidence of staphylococci growth from Fleming A., (1929) British
Journal of Experimental Pathology, Vol. X, Iss. 3
However, this discovery has actually deeper serendipitous roots than one might imagine.
Fleming was extraordinarily lucky with the species of penicillin, Penicillium notatum, that
contaminated his Petri dish. This species is extremely rare and has also one of the most
powerful antibacterial properties in comparison to other species of Penicillium mould,
another possessing powerful antibacterial properties being Penicillium chrysogenum.
11, 14,
The probability of this species landing on his Petri dish was unbelievably high. The series
of events that were to follow, after the mould settled on the Petri dish were also against the
odds of ever being found to have occurred. Fleming who had left the Petri dish covered with
bacterial spores while he went on holiday assumed that the bacterial colony had grown
before the mould had landed on his Petri dish and subsequently the mould had
exterminated any staphylococci to be found in its vicinity. Consequently, when Fleming
went to repeat this sequence of procedures he expected to see the same results, but he
didn’t and his experiments were a failure. The Penicillium mould seemed to have lost its
antibacterial effect. He observed that the Penicillium mould could grow right beside the
8 staphylococci and leave them completely unaffected. Eventually, he found that he needed
to reverse the sequence of procedures in order to obtain the result that had first caused him
to murmur ‘That’s funny’. What had actually happened in the hours and days after the
mould landed on the Petri dish was quite unbelievably lucky. Fleming must have covered
the Petri dish with bacterial spores but left it unincubated in his lab before he went on
holidays.
14
According to the weather reports at the Kew Meteorological Office, the weather
was cool. This was very fortuitous for Fleming, as the bacterial colonies did not grow as a
result of the low temperature being unfavourable for their growth. During this period of cool
weather, a spore of the Penicillium notatum settled on the Petri dish. The cool temperature,
which was not an optimal temperature for bacterial growth, was an optimal temperature for
the growth of Penicillium notatum. Thus, the molud grew a healthy colony and started
generating its antibiotic property before the bacteria. According to the weather reports
again, the weather changed and became warmer. The warmer weather stimulated the
growth of the bacterial colonies everywhere on the dish except in the area near the mould
as the penicillin prevented the newly forming staphylococci from creating its cell wall.
13, 14
The true extent of Fleming’s luck and the magnitude that serendipity played can only now
be realized. His discovery of penicillin was built upon a series of chance events, all of which
had an exceptionally low chance of happening. Fleming was hoping that he would one day
find the ‘magic bullet’, the substance that would be able to flight infectious disease without
damaging the host
14
but as the story shows he discovered it in a truly remarkable way that
no one who have be able to predict.
Further research and development into penicillin was conducted mainly at Oxford University
under Howard Florey though with Fleming’s guidance and support, in the following years.
When it was unleashed onto the market, it rapidly emerged as the single most valued
therapeutic advancement in the history of medicine. 11, 12, 14, 15 Fleming earned a Nobel Prize
for his discovery of penicillin in 1945 along with Florey and Ernst B. Chain who both worked
on the isolation and purification of penicillin for mass production.
11, 12, 14, 15
Serendipity is
the reason that penicillin was found and the subsequent global impact that this discovery
has had is enormous. It initiated microbial genetics. Genetic manipulation made immense
progress in production capability and led to a new branch of technology known as ‘strain
improvement’. Mutations of the original strain of penicillin found by Fleming increased the
9 amount of penicillin that was produced to levels high enough for the use of treatment of
infectious diseases globally from 60mg/l to 70g/l.
15
Microbiologists were intrigued by the
straightforwardness of the technique of mutagenesis and by how it achieved “permanent”
change in the microorganisms through mutation. Then in the 1950s, when some strains of
staphylococci were appearing to be becoming resistant to penicillin, it was clear that new
drugs needed to be developed. The penicillins that were in use at this time were highly
active against Gram-positive bacteria but had minimal effect on Gram-negative bacteria.
Two significant advancements led to the development of new penicillin drugs.
15
The first
happened in 1959 when Batchelor and his team isolated the ‘penicillin nucleus’
18
found by
Koichi Kato in Japan.
19
The ‘penicillin nucleus’, which was the compound, 6-amino-
penicillanic acid, (6-APA) was chemically modified to create semi-synthetic varieties of
penicillin. These were resistant to acid, which allowed them to be administrated orally and
not be affected by the body’s stomach acid, an advantage that the other penicillin drugs did
not have. They also had a broad range of antibacterial action. The second occurred when a
hydrophilic type of penicillin was found that was affective against both Gram-positive and
Gram-negative bacteria. Penicillin made a great contribution to further antibiotic research.
Many of these studies were done on derivatives and relatives of the original penicillin such
as the cephalosporins, which are another branch of compounds used to fight bacterial
infections. It also led to the development of the antibiotic industry. The innovative methods
used for the isolation, ‘strain improvement’ and production of penicillin were adaptable to be
used for other antibiotic discoveries and production. The effects of penicillin are still seen in
the 21st century. In 2009, pencillins accounted for 16% of the $42 billion antibacterial market
and drugs derived from penicillin accounted for another 45% of the market.
15
None of this
might ever have happened if it wasn’t for serendipity. The serendipitous event that occurred
85 years ago still has an influence in our world today.
Fleming’s discovery of lysozyme
Fleming was also the centre of another key serendipitous discovery. This was seven years
earlier, in November 1921. Fleming was suffering from a terrible cold and decided to culture
some of his nasal mucus on one of his ever-ready Petri dishes. When he returned to look at
it two weeks later the results were ‘interesting’ as Fleming put it. The plate was covered
10 with golden-yellow coloured colonies except for the area surrounding the spot of mucus
where there was no bacterial growth whatsoever. Beyond this region there was a ring of
bacteria colonies that appeared glassy and translucent and beyond this region again there
was another ring of bacteria colonies that were opaque in appearance. Fleming reasoned
that there was obviously a substance in the nasal mucus that had killed the surrounding
bacteria. He concluded that bodily fluids must contain an antibacterial property and as he
tested his theory he found that tears, saliva, blood serum and an array of other body fluids
all contained this property. What he had discovered was the enzyme lysozyme, (now Nacetylmuramidase).
11, 12, 13, 14
As with the case of penicillin there is more to this story in
terms of serendipity than meets the eye. Fleming was incredibly lucky with the antibacterial
agent/ bacteria combination that he happened to be working with. The bacteria that had
occupied the Petri dish were found to be distinctively susceptible to being eradicated by
lysozyme. Likewise, the mucus he used was fresh from his nasal cavity and he later
learned from numerous repeated investigations that freshly collected mucus is the more
potent.
12, 14
Unfortunately, lysozyme was found only to be effective against non-pathogenic
microbes which was a major disappointment for Fleming who though he had found a new
way to fight infectious diseases. 14 Nonetheless, it was still a significant discovery, which led
to a new insight into the evolution of pathogens. Fleming and Wright used lysozyme to
“teach” non-pathogenic bacteria that where cultured through natural selection to gain
resistance to it. This was done to show how non-pathogenic bacteria might have evolved
into dangerous pathogens.
12
Fleming’s career was defined by these two important chance
discoveries both of which may never have been discovered if it was not for a lucky accident
and Fleming’s ‘prepared mind’. 14
Drug discovery
The elusive phenomenon that is serendipity has played an astounding role in the discovery
of many drugs that are in use today. The total number of FDA approved drugs on the
market according to DrugBank is 1437. This total number only includes drugs that are small
molecules and in clinical use. Of these, 84 were acknowledged to have been aided in their
discovery by serendipity, which corresponds to 5.8% of the total number of drugs in use at
11 the present time. Of the 84 drugs, 31 of them were discovered in the laboratory, which is
2.2% of the total number of pharmaceuticals and 116 drugs were derivatives of the 31
discovered in the laboratory. The remaining 53 drugs of the 84 (3.7%) were discovered in a
clinical setting and 147 drugs were derivatives of the 53 discovered in a clinical setting.
Furthermore, 263 of the total (18.3%) are chemical derivatives of the drugs aided in their
discovery by serendipity. Overall, 24.1% (347/1437) of the available drugs on the market
are linked to serendipity. 20
Figure 3: A pie chart presenting the distribution of serendipitous events in relation to the
total number of drugs available on the market at present, where they were discovered
(laboratory or clinical setting) and their respected derivatives (100% = 1437) from HargraveThomas, E., Yu, B. and Reynisson, J. (2012) 'Serendipity in anticancer drug discovery',
World J Clin Oncol, 3(1), 1-6.
Anti-cancer drugs
In relation to anti-cancer drugs there are 88 at present on the market. 31 of which can be
credited to a serendipitous occasion, which is 35.2% of the total. 13 of these treat cancer,
which is 14.8% of the total and the outstanding 18 are their chemical derivatives 20.5% of
the total 88. 20
12 Figure 4: A pie chart representing the distribution of anti-cancer drugs in relation to the ones
that were and were not found by serendipity and also the derivatives of the anti-cancer
drugs found by serendipity (100% = 88) from Hargrave-Thomas, E., Yu, B. and Reynisson,
J. (2012) 'Serendipity in anticancer drug discovery', World J Clin Oncol, 3(1), 1-6.
There are several types of anti-cancer drugs that were aided in their discovery by
serendipity. One was the discovery of cisplatin by Barnett Rosenberg at Michigan State
University in 1964.
20, 21, 22
He was experimenting with cultures of Escherichia Coli (E. coli)
to study the consequences of applying them to an electric current. The results he obtained
showed the peculiar elongation of the E. coli cells and also showed that the cells had not
proliferated. After a succession of repeated experiments to find out what was actually
happening he deduced, somewhat unexpectedly, that the only part the electric current
played was in the creation of electrolysis products. A consequent chemical study was
carried out which found that the new chemical compound accountable for Rosenberg’s
observation was cisplatin or cis-diamminedichloroplatinum (DDP).
Various xenografts
tumours were tested with different configurations of cis and were found to suppress tumour
growth. However, there were problems due to the clinical toxicity of the drug but this was
reduced with the introduction of drugs that had increased solubility such as carboplatin and
oxaliplatin.
21, 22
This chance discovery motivated researchers to find other metal-based
drugs that could be used to treat cancer. 22
13 Figure 5: The chemical structures of the platinum compounds that are in medical use at
present from M. F. Brana and A. Sanchez-Migallon, Clin Transl Oncol, Spain, Editon edn.,
2006, 8, 717-728.
A second one was the unique observation of the anti-cancer properties of nitrogen mustard,
a chemical tool used in warfare.
20
At some point in World War II, General Eisenhower
ordered a supply of mustard gas (or yperite) to be kept at the Front and used in retaliation if
the Nazi army employed the benefit of chemical weapons. The supply was on board the
Liberty Ship, which was docked at Bari harbor. Before the ship set sail it was raided by the
Germans and obliterated, releasing the supply of mustard gas into the atmosphere.
Chronic leucopenia, which is a decrease in the number of leukocytes,
20
21
was the outcome
for any survivor that was subjected to the fumes of the gas. When a scientist named Gilman
heard about the poisonous effect of the gas he recognized the potential it could have in
treating lymphosarcoma. He experimented with one of the known gas weapons, nitrogen
mustard, and used it to treat mice with lymphosarcoma. This observation was the dawn of
cancer chemotherapy and led to the advancement of the alkylation agents, the first one
being mechloerethamine. 20, 21
14 Figure 6: A number of derivatives from nitrogen mustard, yperite illustrating the
advancement of the alkylation agents from Brana, M. F. and Sanchez-Migallon, A. 2006
'Anticancer drug discovery and pharmaceutical chemistry: a history', Clin Transl Oncol, 8,
717-28.
Another type of anti-cancer drug founded by serendipity was the drug ametantrene. This
was first developed as ink for a ballpoint pen but when sent for cell culture tests it was
found to possess a promising ability to prevent cell proliferation. This chemical led to the
related structure antracyclines to be synthesized and was the cause of the formation of
mitoxantrone, a molecule that positions itself in between the base pairs of DNA and binds to
the DNA double helix. This is an intercalator and is used clinical to treat cancer. 21
Psycopharmacology
The pharmacological treatment of psychiatric illnesses has been majorly advanced because
of the contribution of serendipity.
23
A distinct example of this was the detection of
anticonvulsant properties of valproic acid. Valproic acid was originally synthesized as an
organic solvent equivalent of valeric acid in 1881 by Beverly S. Burton. Valproic acid was a
common organic solvent used by the industries of Western countries in the middle of the
20th century. As a result, the pharmaceutical industry started to use it too as an organic
solvent. In 1963 in Laboratoire Berthier, Grenoble, Georg Carraz, a researcher was
15 investigating several different compounds of khelline for anticonvulsant properties. As was
the norm at this time, he dissolved the khelline compounds in valproic acid. Employing the
pentylenetetrazole model, which identifies pharmaceuticals that might combat and reduce
the incidents of convulsions, he accidently discovered that regardless of what compound of
khelline investigated, any that were dissolved in valproic acid were found to have
anticonvulsant properties. He concluded that valproic acid was the substance that had the
sought after properties. Carraz later synthesized the derivative of valproic acid, valpromide
which he hoped would be more liposoluble and able to cross the blood-brain barrier more
effortlessly. He did a number of clinical trials in patients who suffered from epilepsy with the
help of psychiatrists Sergio Borselli and Pierre A. Lambert in Hôpital Psychiatrique of
Bassens (Rhône-Alpes). When valpromide was given to patients along with the further antiepileptic drugs known at that time it was found to have a predominately sedative effect. On
the other hand, when valpromide and valproate were given separately, it was noticed quite
by accident that the patients had acknowledged improvement in both neurological function
and mood stability. In 1967 valproate was approved as an anti-epileptic in France and in
1993 as an anti-manic substance in the United States. 24
Another example is the discovery of the antidepressant imipramine by Roland Kuhn, a
psychiatrist in the United States in 1956. Kuhn was looking for new antipsychotic drugs
after the satisfying triumph of the introduction chlorpromazine in 1952. He was carrying out
a clinical study with the substance G-22355, later called imipramine that had the identical
side chain as chlorpromazine to see if it would have a similar antipsychotic effect. This was
not the case at all, as it was found to have a deteriorating effect on patients formerly treated
with chlorpromazine. In spite of this, three patients diagnosed with depression were noted
to having experienced an improved mental state in a short space of time. From this, Khun
inferred that imipramine could be used to treat depressive patients. Further studies were
conducted with more patients suffering from depression and the results were successful,
proving the anti-depressive properties of the drug. The discovery of the antidepressant
activity of imipramine was utterly unexpected and accidental. Khun had the aptitude to
identify the antidepressant even though he wasn’t looking for it. 23, 24
Other drugs that were assisted in their discovery by serendipity include the antidepressant
Iproniazid, a drug originally developed to treat tuberculosis but when administrated patients
16 where observed to be euphoric and overexcited. The antianxiety drug, meprobamate which
was developed from mephenesin a chemical that was anticipated would prevent the
enzymatic destruction of penicillin but was found during laboratory tests on rats to have
tranquilizing effects and cause muscle relaxation. 23, 25
Also, Chlorpromazine, which was mentioned above has it’s own serendipitous links. It was
synthesized in 1950 in the hope that it would calm patients suffering from anxiety and have
anesthetic properties. When clinical trials were prepared to investigate the effects of this
drug it was found that the drug did not instigate a loss of consciousness or mental activity
as was hoped but instead produced an inclination to sleep and patients were indifferent as
to where they were. The drug is now used to treat schizophrenia and bipolar disorder. 23, 25
Finally, one serendipitous drug that has transformed the modern era is Sildenafil. Sildenafil
is a selective inhibitor of 5-phosphodiesterase, which by acting on cyclic-GMP relaxes
cardiac vessels. Therefore, it was thought that it would be a suitable treatment of angina
pectoris. When Pfizer, a leading American pharmaceutical company carried out the clinical
trials the outcome was incredibly different to what was predicted. Sildenafil did not alleviate
anginal pain but in some male patients it stimulated penile erections to their surprise.
Solomon Snyder and his colleagues at the John Hopkins University explained this result,
externally of Pfizer. They were researching the compound nitric oxide (NO), which dilates
the body’s blood vessels. They speculated that it might be a neurotransmitter and with the
enzyme in charge of the production of NO, NO synthase (NOS), performed
immunochemical experimentation. From this study they found that NOS is confined to the
penis indicating that NO might be the neurotransmitter for erection. This all implied that if
NOS was blocked by inhibitors erections would also be blocked. NO is similar to Sildenafil
in that it is facilitated by cyclic-GMP this explained the secondary effect of penile erection in
the patients who took part in the Pfizer study. Sildenafil, which is marketed as Viagra, is
used today to treat male erectile disorder. 25, 26
There can be no doubt that serendipity has had a huge influence on the drug industry.
However, some would disagree about the true role that serendipity has played which can be
expected giving the confusing quality of this term. For example Jeste et al. belittle the
significance that serendipity has played in their area of study, which is psychiatry. They
dispute the fact that any of the drugs discovered were truly serendipitous.
27
Conversely,
17 Klein disapproves with the actions to increase cost-control is hospital laboratories thinking it
will diminish the creative environment that serendipity thrives on.
28
Lastly, Kubinyi
expresses his view that good science is required for the continued success in drug
discoveries. 29
Helicobacter pylori
The story of how Helicobacter pylori (H. pylori) were first cultured in isolation in the
laboratory has serendipitous links. H. pylori are virulent, microaerophilic bacteria that are
highly motile due to a number of lophotrichous flagella (flagella which are all located on the
same polar end).
30
They are known to cause peptic ulcer disease in the stomach of
humans. They infect the stomach by adhering to the epithelial cells that line the stomach
and so colonize the mucus layer. The stomach responds to the infection with the hormone
gastrin, which intensifies the production of acid so that it is in excess. This over production
of acid causes tissue damage and a peptic ulcer ensues. 31
Figure 7: Image of Helicobacter pylori taken from Prof. Jay Hinton’s second lector for the
BY2209 Infection and Immunity module for Senior Freshmen, 2012, Trinity College Dublin.
Barry Marshall, a medical internist and Robin Warren, a histopathologist in the Royal Perth
Hospital, Western Australia were working with patients with gastritis. Warren had obtained
specimens of a gastric biopsy and observed mucosal bacteria to be present after staining
18 with Warthin-Starry stain. Meanwhile, Marshall was administrating tetracycline to a patient
with gastritis and gastric bacteria, which he noticed alleviated the bacteria infection and
improved the gastritis. Researchers struggled for years to culture these bacteria in isolation
until 1982 when Marshall and Warren accidentally left their culture plates incubated for 5
days over the Easter weekend. What they observed after that weekend were visible
colonies of ‘Campylobacter-like organisms’ later to be called Helicobacter pylori. Marshall
and Warren then realized the connection between these bacteria and peptic ulceration and
that the bacteria might also be linked to gastric adenocarcinoma. Diagnostic techniques that
were dependable for accuracy became available, as did treatments for these gastric
infections as a result of the H. pylori, which caused these infection being cultured in
isolation and studies being carried out on them to find ways to stop them infecting patients.
For their serendipitous discovery they shared the Nobel Prize in Physiology or Medicine in
2005. 31, 32, 33, 34
Trypanosomes; discovery of SRA
This case of serendipity has touched the life of Dr. Derek Nolan, lecturer and researcher in
Trinity College Dublin, who has a prime interest in trypanosomes and is working with them
to investigate how their surface proteins are used in endocytosis and trafficking.
Trypanosomes
are
responsible
for
African
sleeping
sickness
also
known
35
as
trypanosomiasis in humans. The protozoal parasites are transmitted by the tsetse fly and
the disease is very prominent in sub-Saharan Africa.
36
There are only two types of
trypanosomes that are actually associated with sleeping sickness in humans, which are
Trypanosoma brucei rhodesiense (T.b. rhodesiense) or East African sleeping sickness and
trypanosome brucei gambiense (T.b. gambiense) or West African Sleeping sickness.
The latter accounts for greater than 90% of the current reported cases.
36
36, 37
All other
trypanosomes that enter the body are killed by normal human serum (NHS), which contains
a trypanosome lytic factor, recognized in 1902 by Alphonse Laveran. T.b. rhodesiense and
T.b. gambiense are resistant to this lytic factor and hence cause the disease. 38
19 When T.b. rhodesiense is cultured in other sera it loses its ability to resist NHS. If a
population sensitive to serum (S), is grown in NHS is can become serum-resistant (R).
When these studies were carried out by De Greef and Hamers in Vrije Universiteit Brussels,
they discovered a section of coding DNA exclusive to the R form. This section was called
serum resistance associated (SRA) gene. Its ability to be reversible expressed was
connected to the reversible nature of resistance of NHS. The SRA gene was also found to
code for a protein surprisingly resembling a truncated VSG.
39
In 1996 Etienne Pays in
Université Libre de Bruxelles (ULB) takes over story. He imagined that the R form, the
phenotype resistant to NHS, might be connected to either VSG or expression site switching.
SRA was assumed to be just a VSG pseudogene. However, when Southern blot tests were
carried out it was shown that only a single VSG expression site was chosen, called the RES, and it was the same site every time the parasite came into contact with human serum.
The SRA gene was shown to be contained in the highly truncated R-ES site and this is now
used as a diagnostic tool for sleeping sickness.
40
Unfortunately, the serendipity part of the
story was not published, however Dr. Nolan who had a prime interest in the case was able
to fill me in on the unpublished luck. What happened was that a researcher working on the
project was using S form trypanosomes induced with the SRA gene, which caused them to
become resistant to NHS (this was not known). He/she accidently inoculated him/herself
with these trypanosomes and developed East African sleeping sickness.
41
From this it was
concluded that the SRA gene seemed to trigger full resistance to NHS. It alone was
responsible for converting the harmless non disease-causing organism into a deadly human
pathogen.
40
on humans
This was not published due to ethical reason as it is forbidden to experiment
41
but subsequent experiments were carried out to prove this marvel and the
these results were published in in 1998 by Xong HV et al..
40
(Note: the researcher was
treated and survived 41)
Conclusions
Serendipity is an ambiguous term. Due to differences in the meaning of the term it has
caused disagreements among scientists in the literature. 6
20 Scientists don’t always attribute serendipity to their discoveries as it is felt that it
undermines the good science and years of hard working research that has gone into their
projects. They don’t want it to overshadow the previous years of research that have led to
the discovery like it happened by magic one day.
5, 20
Therefore, there could be numerous
more unpublished incidents of serendipity meaning that it could potentially have a bigger
impact than previously imagined. 20 Another reason why serendipity could go unpublished is
just like the incident with trypanosomes, it could have occurred due to an unethical accident
and it would not be in the best interests of the scientists involved to publish an event like
that.
However, serendipity harbours creativity in scientists, thinking outside the box, when one is
presented with an unexpected result it needs a scientist that will not pass it by but inspect it,
as one can never know, it could be a new breakthrough similar to penicillin during World
War II.
12, 14
If it was not for accidental discoveries the world might be a different place and
life would be very different. 1
It cannot be underestimated that serendipity has in some way contributed to the role of
biological research and will continue to do so into the future. 1, 6
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** Outstanding interest papers
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Roberts R. M., (1989) Serendipity: accidental discoveries in science,
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Friedel R. (2011), Serendipity is no accident, Kenyon Review, 23(2), 36-46 *
21 Good outline of the contribution that serendipity has made to science. It also includes
a good summary of the coinage of the word and the types of serendipity with
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Lopez-Munoz F., Baumeister A. A., Hawkins M. F. and Alamo C. (2012) The role of
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[See also 12 below]
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Taken
from
the
Trinity
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36.
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Nolan D. (2012) Discussion of the serendipity aspects of the discovery of SRA
24