161 MJM 2006 9(2):161-163 Copyright © 2006 by MJM

FEATURE REVIEW

The three princes of Serendip

David R. Colman*

"The seeds of great discoveries are constantly floating absent-mindedly placed the dish on his cluttered desk.
around us, but they only take root in minds well prepared Some days later, as he was straightening his desk, he
to receive them." noticed to his great surprise that the bacteria in the dish
Joseph Henry, physicist and first director of The had been destroyed. His curiosity was aroused, and
Smithsonian Institution following his nose (so to speak), he worked to isolate
for the first time the "active principle" - lysozyme - the
The word "serendipity" was entered into the lexicon by antibacterial protein found in tears and mucus.
Horace Walpole in 1754. He had become intrigued with Convinced that more potent agents might exist, Fleming
a Persian fairytale in which three princes of Serendip, began searching for other environmental antibacterials,
(now Sri Lanka) traveled the world, "making eventually coming up in 1928 with penicillin, for which
discoveries, by accidents and sagacity, of things they he won the Nobel Prize in 1945. He shared the prize
were not in quest of..." Walpole proposed the new with Florey and Chain, who made the mass
word, but then went on to give rather mundane administration of the drug to humans practical. In his
examples of its meaning. It is only recently that characteristic understated manner (he was after all the
serendipity has acquired its rather grand and mysterious son of a Scottish farmer), Fleming commented,
significance.
The Oxford English Dictionary defines serendipity as "Nature makes penicillin, I just found it; one sometimes
"the faculty of making happy and unexpected finds what one is not looking for." (italics mine).
discoveries by accident." Serendipity plays an
important part in research of all kinds, but it operates At the end of the 19th century and in another field,
only in a special environment; as Pasteur famously Wilhelm Roentgen, while working in his darkened lab
stated, "Chance favors the prepared mind." In research, with a Crooke's (cathode ray) tube, noticed out of the
what serendipity really means in practical terms is that corner of his eye that several feet away, a piece of paper
scientists discover things in the course of their coated with barium cyanoplatinate was faintly glowing.
investigations that they were not looking for. And these He was puzzled, since the only conceivable source of
new findings are often not the products of cold logic. energy in the room was the tube, which was not emitting
Sometimes, great discoveries are made because of a visible light. When subsequently Roentgen found that
serendipitous situation or observation. One excellent sealed photographic plates in his desk had become
example of a serendipitous observation which led to a fogged in the absence of a visible light source, he
great discovery occurred in 1922, when Alexander deduced that a novel form of radiation energy was being
Fleming, suffering from a particularly juicy cold, generated in the Crooke's tube. He termed the new
happened to sneeze into a Petri dish full of bacteria. He radiation X-rays. Within a year after this discovery in
1895, X-rays were being applied in diagnostic
medicine.
*To whom correspondence should be addressed: David R. Colman, During World War I, a youngster named Cyril Astley
Ph.D.
Clarke was sent to the English countryside so as to be
Penfield Professor and Director
The Montreal Neurological Institute out of harm's way. It was there that he acquired what
Vol. 9 No. 2 Princes of Serendip 162

would be a lifelong fascination with butterflies. In fact, species, and placing them in the same dish to coalesce
although he became a physician, he kept up his interest as combinatorial new species. To his extreme
in inheritance of butterfly wing patterns, and made disappointment, the cells from each distinct species
several original observations in this field. A friend of his only sought each other out to aggregate with, and
suggested that he might also examine human blood Wilson was unable to induce any chimeras to form. He
groups from a genetic standpoint, and this serendipitous wrote:
suggestion ultimately led Clarke to an understanding of "1 shall here briefly record some experiments which gave
blood group inheritance in humans, and to the only negative results... These experiments were based on
development of an injectable antibody inhibitor the assumption that if the dissociated cells of a species will
(Rhogam) for Rh disease in newborns. recombine to form a regenerative mass and eventually a
More recently, the multi-billion dollar biotechnology new sponge, the dissociated cells of two different species
industry in great measure found its origins in a may be made to combine and thus form a composite mass
spontaneous, serendipitous detour: bearing potentially the two sets of species-
characteristics..." (italics mine).
"It would sound reasonable if I were to say that the
research work...began as a result of a grand design, with a It was only later that other scientists, most notably
vision of the goals in mind. Unfortunately, this would not Ernest Everett Just, an African-American who was one
be true. This work began the day I took a detour through of the great biologists of the last century, recognized the
Yellowstone National Park on my way to Seattle." extraordinary implication of Wilson's "failure." Just, in
(Thomas Brock) reading Wilson's report, correctly concluded that
sponge cell surfaces must display precise determinants
On his first visit to Yellowstone, Brock became that only allow aggregation between cells derived from
intrigued with the multi-coloured algae mats in the hot the identical species. Hence, the cell surface is not
springs, and on a whim, took some samples back to "lifeless," as textbooks of Wilson's time stated, but
analyze in his laboratory. In 1969, Brock and Freeze rather,
reported the discovery of Thermus aquaticus; this
bacterium became one early source from which the "The cell membrane stands not simply as a barrier of the
heat-stable enzymes were purified - the key tools in cell against the outside world; it is also the medium of
recombinant DNA technologies. exchange between the cytoplasm and the environment. It
And the pharmaceutical industry has benefited many is the first cell region to receive impressions from the
times from serendipitous observations. Perhaps the outside world; through its delicacy of adjustment and
best-known contemporary case is that of Viagra, which fineness of reaction, it constitutes the first link in the chain
was originally tested as a treatment for angina. It was of cytoplasmic reactions and sets the path for the orderly
almost immediately found to be less effective than succession of events comprising the course in the
nitroglycerine for coronary artery dilatation, but then differentiation of development." (E.E. Just, The Biology of
the patients in the first clinical trial reported an unusual, the Cell Surface)
not at all undesirable and now well-known side effect.
It is no wonder that the patients became depressed when Competitors may be annoying recipients of the
the first clinical trials were brought to an end, and it was serendipitous insight. In 1887, Santiago Ramon y Cajal
requested that the unused pills be returned to Pfizer. The visited Dr. Luis Simarro Lacabra, a psychiatrist friend
company noted that never had so many unused clinical of his who had a histological laboratory in his cellar
trial pills been reported as lost, misplaced, or (medical students harken - his hobby was histology!).
accidentally flushed down the toilet... Cajal had been formulating the principles of the neuron
But sometimes the serendipitous insight eludes the doctrine, an extension of the cell theory of Schleiden
original experimenter, and alights instead on the reader and Schwann, but had not as yet found a way to verify
of the experimental report, or (how embarrassing!) on a his hypothesis that each neuron was a self-contained
competitor. A well-reported published experiment may entity. Simarro took Cajal to his cellar laboratory, and
reveal to "prepared" readers a serendipitous discovery showed him some brain slices prepared by the "black
that might have been made at the time, but was missed reaction" method of Camillo Golgi, an eminent scientist
by the original investigators. The fascinating of the time who was an ardent proponent of the
experiments with sponge cells performed by H.V. opposing reticular theory - that neurons are connected
Wilson in the early part of the 20th century fall in this to each other via protoplasmic continuities that
category, and in a stunning way. Wilson set out to create essentially make the brain a large syncytium. Cajal
chimeric sponges by dissociating cells of three sponge recalled that he was "thunderstruck" on his first look
163 McGill Journal of Medicine 2006

through the microscope at the Golgi preparations, and uttered a word to each other.
he recognized in an instant that those slides would show Serendipity still plays a major role in discovery and
the error in the reticularist's position, and demonstrate invention. It is the manifestation of inspiration, and of
the validity of the neuron doctrine: being in the right place at the right time. To some, it has
a certain magic about it that suggests predetermination
"[Individual nerve cells appeared] coloured brownish or intervention by the supernatural, or as Shakespeare
black even to their finest branchlets, standing out with wrote:
unsurpassable clarity upon a transparent yellow
background. All was sharp as a sketch with Chinese ink... "There is a tide in the affairs of men, which, taken at the
ideas boiled up and jostled each other in my mind..." flood, leads on to fortune..." (Brutus to Cassius, in Julius
(Cajal, "Recuerdos di ma Vida") Caesar)

Golgi had had the data right in front of him, but was In the end, though, probably the best way to sum up the
unable to interpret it correctly. Later Cajal would write phenomenon was most thoughtfully stated by Julius
of Golgi that he was "hermetically sealed" against new Comroe:
ideas. Golgi would not accept Cajal's conclusions, even
though Cajal had used Golgi's own techniques to clearly "Serendipity is jumping into a haystack to search for a
prove Golgi wrong. The two shared the Nobel Prize in needle, and coming up with the farmer's daughter."
1906, were on the same stage in Stockholm, but never

Dr. David R. Colman is the Director of the Montreal Neurological Institute. A native of New York City, Dr. Colman
received his B.S. in Biology from New York University, and his Ph.D. in Neurosciences from the State University of New
York, Health Sciences Center, Brooklyn, NY. He became an Assistance Professor of Cell Biology at NYU School of
Medicine and joined the faculty of The Columbia College of Physicians and Surgeons as an Associate Professor of Cell
Biology in 1987, where he received several prestigious awards, including an Irma T. Hirschl Career Development Award,
the Harold and Golden Lamport Award, the Basmajian Award for Teaching and Research, as well as a Jacob K. Javits
Neuroscience Award from the National Institute of Neurological Diseases and Stroke. He was subsequent the Annenberg
Professor of Molecular Biology and Neuroscience at the Mont Sinai School of Medicine in New York City and the Vice-
Chairman for Research in the Department of Neurology and the Scientific Director of The Corinne Goldsmith Dickinson
Center for Multiple Sclerosis of The Mount Sinai School of Medicine. He began his tenure as Director of the MNI in
September 2002. He holds the Penfield Chair in Neuroscience and a Tier I Canada Research Chair. Dr. Colman's research
focuses on problems related to myelination and on nerve cell development with particular emphasis on synaptogenesis.