Nobel Prizes Medicine

Published on Explorable.com (https://explorable.
com)
Nobel Prizes Medicine
Table of Contents
1 The Visual System
2 Functional Specialization of Cerebral Hemispheres
3 Prostaglandins and Biologically Active Substances
4 Discovery Of Mobile Genetic Elements
5 Discovery of the Function of Ion Channels in Cells
6 Discovery of Reversible Protein Phosphorylation
7 Prion as an Infectious Agent
8 Discovery Of Split Genes
9 Uncovering The Effects Of Nitric Oxide On The Cardiovascular System
10 Role of G-Proteins in Signal Transduction
11 Discovery of Intrinsic Signals in Proteins Governing Transport and Localization
12 Genetic Control Of Embryonic Development
13 Signal Transduction In The Nervous System
14 Cell-Mediated Immune Response
15 Discoveries on the Key Regulators of the Cell Cycle
16 Programmed Cell Death
17 Discoveries on Magnetic Resonance Imaging (MRI)
18 Discovery Of The Odorant Receptor
19 Discovery of Helicobacter Pylori
20 Discovery Of RNA Interference
21 Advances in Embryonic Stem Cells
22 Human Papilloma Viruses (HPV) - Causative Agent of Cervical Cancer
23 Discovery of HIV
24 Telomeres and Enzyme Telomerase
1
Copyright Notice
Copyright © Explorable.com 2014. All rights reserved, including the right of reproduction in
whole or in part in any form. No parts of this book may be reproduced in any form without
written permission of the copyright owner.
Notice of Liability
The author(s) and publisher both used their best efforts in preparing this book and the
instructions contained herein. However, the author(s) and the publisher make no warranties of
any kind, either expressed or implied, with regards to the information contained in this book,
and especially disclaim, without limitation, any implied warranties of merchantability and
fitness for any particular purpose.
In no event shall the author(s) or the publisher be responsible or liable for any loss of profits or
other commercial or personal damages, including but not limited to special incidental,
consequential, or any other damages, in connection with or arising out of furnishing,
performance or use of this book.
Trademarks
Throughout this book, trademarks may be used. Rather than put a trademark symbol in every
occurrence of a trademarked name, we state that we are using the names in an editorial
fashion only and to the benefit of the trademark owner with no intention of infringement of the
trademarks. Thus, copyrights on individual photographic, trademarks and clip art images
reproduced in this book are retained by the respective owner.
Information
Published by Explorable.com.
Cover design by Explorable / Gilli.me.
2
1 The Visual System
1981 Nobel Prize Medicine (Part 1)
David H. Hubel and Torsten N. Wiesel were co-recipients of the 1981 Nobel Prize in
Medicine or Physiology for their discoveries concerning the visual system.
Read about Nobel Prize Medicine 1981, Part 2: Functional Specialization of Cerebral
Hemispheres
Being the most dominant of all our senses, we depend a lot to our visual system when trying
to make sense of our environment. Due to the discoveries of Hubel and Wiesel, we now know
that beneath our visual experiences, there lies are very complicated maze of connections and
integrations that allow us to visually appreciate our environment.
Read about Nobel Prize Medicine 1981, Part 2: Functional Specialization of Cerebral
Hemispheres
Being the most dominant of all our senses, we depend a lot to our visual system when trying
to make sense of our environment. Due to the discoveries of Hubel and Wiesel, we now know
that beneath our visual experiences, there lies are very complicated maze of connections and
integrations that allow us to visually appreciate our environment.
Hubel and Wiesel also showed that visual impulses need to undergo progressive analysis and
integration before other parts of the brain can create emotions and memory relevant to the
visual stimuli.
Background
During the 1950's, very little was known about the complexity of the visual system. Very few
researches were conducted regarding the mechanisms behind our sense of vision. In the
early 1950's, Hartline tried to spark an interest in this field when he discovered that the visual
input received the retina are divided, fine-tuned and sharpened along its pathway towards the
visual cortex.
3
In the following years, Hubel and Wiesel tried to continue on this pioneering research and
were surprised by the degree to which they were able to contribute to the knowledge not only
in the visual system but also to the characteristics of other sensory system and the brain itself.
The Winners
David H. Hubel was born on the 27th of February 1926 in Windsor, Ontario. He enrolled in
Strathcona Academy in Outremont and finished his basic schooling at the age of 18. During
his stay there, his main hobbies were chemistry and electronics. He soon got tired of
electronics since nothing he built ever worked. He then entered McGill College majoring in
mathematics and physics which he finished in 1947.
Despite the lack of knowledge in biology, he applied to a medical school in McGill and was
accepted. After graduation, he finished three years of hospital training, two years of residency
in neurology which sparked his interest in the nervous system. In 1958, he moved to Wilmer
Institute, John Hopkins Hospital to the laboratory of Stephen Kuffler where he started
collaborating with Torsten Wiesel. Their collaboration lasted for more than two decades but
the fruits of it were unrivalled.
Torsten N. Wiesel was born on the 3rd of June 1924 in Uppsala, Sweden. His father was the
chief psychiatrist and head of Beckomberga Hospital and his mother was a housewife. He
enrolled at Whitlockska Samskolan, a private school in their city. During his stay there, he was
a lazy student who was more interested in sports than studies. At the age of 17, he started
focusing more on his studies and did reasonably well in Karolinska Institute medical school,
where he received his M.D. in 1954.
In 1955, Wiesel moved to John Hopkins University under Stephen Kuffler. He underwent
fellowship in ophthalmology and in 1958, he became an assistant professor in the university.
During the same year, David Hubel joined their laboratory and decided to explore the central
visual pathway. This marked the beginning of their twenty five years of collaboration.
The Discovery
Hubel and Wiesel worked with cats and rhesus macaque monkeys as their experimental
systems. They were able to show that after reaching the retina, the visual stimuli travel the
optic nerve and make its way towards the lateral geniculate nucleus or LGN of the thalamus,
the first visual processing center of the brain. From the LGN, the visual stimuli travel towards
the visual cortex in the occipital lobe of the brain. These structures are the foundations of our
current knowledge about the visual system.
Hubel and Wiesel then recorded the electrical impulses of the nerves in the visual cortex in
4
response to various visual stimuli flashed before the eyes. They were able to differentiate two
types of cells in the cortex which they named simple and complex. Simple cells respond to
only one type of visual stimulus while the complex cells respond to multiple and opposite
stimuli.
In another research, Hubel and Wiesel used autoradiography in tracing neuronal connections
in the visual system and they found that the visual impulses from the two eyes remain
separated in their path from the LGN to the visual cortex.
Furthermore, they found that the impulses then branch out creating a pattern of alternating
columns along the grid of cortical cells. The two doctors then called these the ocular
dominance columns. They also found that since the cells are arranged in columns, the
analysis of the visual impulses takes place in an ordered sequence from one nerve cell to
another and every nerve cell is responsible for one particular detail of the image. This means
that the analysis and integration of the visual impulses are additive and progressive.
After forming a complete and coherent visual image in the visual cortex, the information is
passed on to other parts of the brain to produce emotions and memory that are relevant to the
visual image created by the visual cortex.
In their succeeding researches, they were able to show that the cells in the visual cortex have
a critical period of development. They found that monocular deprivation in the first six weeks
of macaque’s life is sufficient to produce a shift in ocular preference. They also found that an
animal with one eye closed for the first three months of life becomes blind in that eye. Their
further examinations found no changes in the retina, no changes in the optic tract and LGN;
therefore, the changes were in the visual cortex. They also found that visual stimuli are not
enough to bring about normal development of the cortex, it was also necessary for the images
to have various patterns and contours.
Clinical Implications
Their discovery gave the scientific community a hint about the plasticity of the brain
immediately after birth. Their findings also emphasized the role of an enriched environment on
the development of the different senses.
Their findings suggest that what we are encountering today and how we perceive the world
today depends greatly on our sensory perception during our early years of development. Their
findings also lead to the development in the treatment of different childhood eye disorders.
How to cite this article:
Explorable.com (Nov 7, 2011). The Visual System. Retrieved from Explorable.com:
5
https://explorable.com/visual-system
6
2 Functional Specialization of Cerebral
Hemispheres
In 1981 Roger Sperry was recognized as a co-recipient of the Nobel Prize in Physiology
or Medicine for his seminal discoveries concerning the functional specialization of
cerebral hemispheres.
The research conducted by Sperry was definitely the most fascinating chapter in the history of
brain research. He was able to provide profound insights into the specialized functions of the
two cerebral hemispheres. Sperry showed that despite the similarities in the anatomic
structures of the two hemispheres, their corresponding functions are very distinct and unique.
His research also demonstrated the great importance of the structure that links the two
Read about Nobel Prize Medicine 1981, Part 1: The Visual System
The research conducted by Sperry was definitely the most fascinating chapter in the history of
brain research. He was able to provide profound insights into the specialized functions of the
two cerebral hemispheres. Sperry showed that despite the similarities in the anatomic
structures of the two hemispheres, their corresponding functions are very distinct and unique.
His research also demonstrated the great importance of the structure that links the two
Read about Nobel Prize Medicine 1981, Part 1: The Visual System
Background
The workings of the human brain have been one of the most fascinating enigmas in the field
of research. Can you imagine how difficult it is to study the functions of the brain? It is the
most protected organ in our body; no other vital organ is completely covered by a set of
protective bones. Its functions are almost limitless. Unlike any other organ in the body, the
brain is responsible for all the processes that take place within an organism.
It was known that the brain is composed of two structurally identical halves or hemispheres.
Scientists also knew that the two hemispheres of the brain perform different tasks despite
7
their structural similarities. These two hemispheres are connected by millions of nervefibers
collectively known as corpus callosum. It is much like a bridge connecting two islands;
allowing traffic from one island to reach the other island; allowing information from the left
hemisphere to reach the right hemisphere and vice versa.
Scientists have not succumbed to the challenges of studying the functional specialization of
cerebral hemispheres. As early as the 1860's, Broca was able to identify a small part in the
left cerebral hemisphere that was responsible for speech. In the 1940's, Penfield and Jasper
introduced the concept of contralateral motor innervations wherein movements of the left side
of the body are controlled by the right cerebral hemisphere and the movements of the right
side of the body are controlled by the left hemisphere.
Because of these discoveries, scientists thought that the left hemisphere is the dominant
hemisphere; the left hemisphere is responsible for speech and since most of us are right-
handed, then the left hemisphere controls our dominant hand. This notion of having a
“dominant” hemisphere changed when Sperry published his findings in his split-brain studies.
The Winner
Roger W. Sperry was born on the 20th of August 1913 in Hartford, Connecticut. His father
was in banking and his mother was trained in business school. He received early schooling
from Elmwood, Connecticut and William Hall High School in West Hartford, Connecticut. He
received a 4-year Amos C. Miller scholarship and attended Oberlin College. He received his
AB in English in 1935 and studied two more years for an MA in Psychology. He then switched
to zoology for his Ph.D. work under Paul Weiss at University of Chicago which he finished in
1941. He then conducted a postdoctoral research as a National Research Council Fellow at
Harvard University under Professor Karl S. Lashley.
The Discovery
Sperry started his work on cerebral functions in the 1950's with experimental studies in
animals. Sperry severed the corpus callosum, the connection between the two cerebral
hemispheres, of monkeys and noticed that the hemispheres retained their ability to learn and
function independently but the two halves could not communicate or access the information
stored in the opposite half. His next step was to test his findings in human subjects, but he
had no volunteers.
He learned that in the 1940's, severe cases of epilepsy were treated by surgically severing the
corpus callosum, a surgical technique called commissurotomy; the corpus callosum is also
referred to as cerebral commissure. Patients who underwent commissurotomy showed
reduced seizure frequency and severity with very little effect on the patient’s behaviour and
8
ability to learn. These patients were the perfect subjects for Sperry’s further investigation on
the functional specialization of cerebral hemispheres and brain function.
Ten commissurotomy patients underwent his split-brain experiment. First, he asked patients
to look at the center of a screen or a piece of paper with one eye at a time. Images or words
are presented to one eye, hence, one hemisphere at a time. If the stimulus is presented to the
left eye, only the right hemisphere can process the stimulus. On the other hand, if the stimulus
is presented to the right eye, only the left hemisphere can process the image.
Sperry found that if a word is presented to the left hemisphere, the patient can easily read the
word but if the same word was presented to the right hemisphere, the patient cannot read the
word but understands the meaning or context of the word. Similarly, if an image of an object
was presented to the left hemisphere, the patient can name the object but if the same image
was presented to the right hemisphere, the patient cannot communicate what the object is but
can select the corresponding object from a set of different objects placed in front of him.
Due to these findings he concluded that the left hemisphere is responsible for reading and
naming object while the right hemisphere is responsible for understanding the meaning and
context of the words and objects.
Furthermore, he also found that the isolated left hemisphere can perform calculations easily
while an isolated right hemisphere can only perform simple addition up to the number 20.
All in all, Sperry found that the left hemisphere is concerned with speech, writing, abstract
thinking, symbolic relationships, temporal relationships, leading hemisphere in control of
nervous system and calculations.
On the other hand, the right hemisphere is responsible for concrete thinking, spatial
relationships, comprehension of complex relationships, word comprehension, facial
recognition, interpreting auditory stimuli, space perception, reproducing three-dimensional
pictures, intuition and higher brain functions. The right brain is essentially mute since it can
only feel, process and understand but cannot communicate those thoughts while the left brain
is the expressive brain capable of communicating with the environment.
Significance
The work of Sperry proved to be an inspiration to many new scientists. His discoveries
sparked a movement in cognitive science and triggered more researches to be conducted
aiming to uncover the higher functions of the brain.
With the advent of more sophisticated brain imaging techniques, it is now easier to localize
brain functions. Scientists used cerebral blood flow to identify regions of the brain responsible
9
for different cognitive tasks. Scientists can now easily monitor the cerebral blood flow in all
parts of the brain. Since we know that after eating a meal, most of our blood is directed to our
GI system and in times of emergencies, our blood is directed to our muscles. This means that
the more work a region of our body does, the more blood is delivered to it.
Applying this same logic to our brain, if a patient is asked to move his right leg, the region of
the brain with a significant increase in blood flow during the course of the movement is
responsible for the control of that movement. By the use of this method, most of our functions
are now localized to a certain region or groups of regions in our brain.
Explorable.com (May 14, 2011). Functional Specialization of Cerebral Hemispheres.

Retrieved from Explorable.com: https://explorable.com/cerebral-hemispheres
10
3 Prostaglandins and Biologically
Active Substances
1982 Nobel Prize Medicine
Sune K. Bergström, Bengt I. Samuelsson and John R. Vane were awarded the Nobel
Prize in Physiology or Medicine of 1982 for their discoveries concerning
prostaglandins and related biologically active substances.
Bergström, Samuelsson and Vane were able to show that prostaglandins are involved in a
diverse range of biochemical functions and processes; for this reason their research opened
up a new arena of medical research and pharmaceutical applications. The research has
significant implications in several clinical areas, particularly in thrombosis, inflammation and
allergy.
Bergström, Samuelsson and Vane were able to show that prostaglandins are involved in a
diverse range of biochemical functions and processes; for this reason their research opened
up a new arena of medical research and pharmaceutical applications. The research has
significant implications in several clinical areas, particularly in thrombosis, inflammation and
allergy.
Background
Prostaglandins were discovered in the 1930's. Ulf von Euler found that seminal fluid and
seminal vesicles from most animals including man contain a substance which causes
contraction of the smooth muscle of the uterus. He named this new substance prostaglandin
since they were originally thought to be secreted by the prostate gland. During those decades,
scientists were unaware of how these substances were produced and how they functioned. It
was only after 20 years that the mysteries covering the new substance prostaglandin were
uncovered by three brilliant scientists.
The Winners
Sune K. Bergström was born on the 10th of January 1916 in Stockholm, Sweden. After
completion of high school, he worked at Karolinska Institute as an assistant to biochemist Erik
Jorpes. Jorpes was impressed with his assistant and gave him a year-long research
11
fellowship in University of London in 1938. Bergström returned to Karolinska Institute in 1942
and received his doctorates in medicine and biochemistry along with his M.D. two years later.
In 1945, Bergström met physiologist Ulf von Euler who was conducting research on
prostaglandins. In 1947, he was appointed professor of physiological chemistry at the
University of Lund where he met Samuelsson as his graduate student. Together, they
conducted research on how prostaglandins are formed.Samuelsson received his doctorate in
medical science in 1960 and his medical degree a year later. In 1961, he went back to
Karolinska Institute to rejoin his former mentor Bergström, where he remained until 1966. He
was then appointed Dean of the Medical Faculty of Karolinska Institutet, Stockholm, Sweden
in July 1, 1978 until June 30, 1983.
John R. Vane was born on the 29th of March 1927 in Tardebigge, Worcester. At the age of
12, he received a chemistry set from his parents and experimentation became his consuming
passion.
Vane's home became his first real laboratory and his chemical experimentation started
expanding into new fields. He received his B.S. in chemistry from Birmingham in 1946 and
went to Oxford University to study pharmacology. He earned his B.S. in pharmacology in 1949
and his doctorate in 1953. It was in the late 1950's when Vane developed an interest in
prostaglandins.
The Discovery
During the 1950's, Bergström made an outstanding discovery and breakthrough in the field of
prostaglandin research. With the use of Lyman Craig’s countercurrent extraction device, he
was able to purify several prostaglandins and with the use of combination gas chromatograph
and mass spectrometer, he was able to deduce the chemical structures of prostaglandins. He
also discovered that prostaglandins are formed by the conversion of unsaturated fatty acids.
In the 1960's, following his successful researches, he teamed-up with Samuelsson in

conducting further researches on prostaglandins. Together, they worked on how
prostaglandins are formed and metabolized. They discovered that prostaglandins are formed
from the progressive conversions of arachidonic acid, an unsaturated fatty acid. They also
found that an enzyme called cyclo-oxygenase converts arachidonic acid to unstable cyclic
endoperoxides from which prostaglandins, prostacyclin and thromboxanes are derived.
12
On the other hand, the formation of the leukotrienes from arachidonic acid is initiated by the
action of 5-lipoxygenase producing leukotriene A4. Further hydrolysis of leukotriene A4 results
in the formation of leukotriene B4 and C4, respectively. Because of this discovery, they were
able to develop synthetic methods of producing prostaglandins and made it accessible to the
scientific community.
In the early 1960's, Vane created upgrades in the procedure known as biological assay or
bioassay. Bioassays are used to determine the strength of a substance by comparing its
effects on an organism with a standard substance preparation. His new dynamic bioassay
was used to measure more than one substance in the blood or other body fluids. By the use
of this method, he learned that prostaglandins are produced by many tissues and organs and
not just by the prostate.
In another study conducted in 1969, he found the methods by which aspirin alleviates pain
and reduces inflammation. By the use of lung tissues of guinea pigs, Vane discovered that
aspirin works by inhibiting the production of specific prostaglandins that causes inflammation.
Vane also discovered the existence of prostacyclin which was found to be of great importance
in dissolving blood clots.
Prostaglandins are now currently used in the treatment of ulcers, alleviating pain from
menstruation and gallstones, and stimulating contractions for childbirth. Prostaglandins have
also been used medically to induce abortions.
On the other hand, thromboxanes were found to be involved in the clotting of the blood.
Prostacyclin acts against thromboxanes since they assist in dissolving clots. This is of great
medical importance since it can be used in dissolving blood clots blocking the supply of the
brain or the heart.
It is also useful in keeping blood from clotting during surgeries. Leukotrienes are found to be
involved with asthma and in anaphylaxis which are characterized by contractions of the
brochi. With this much knowledge in hand, medical researchers were geared towards the
development of drugs and medical interventions that will exploit the use of these discovered
substances.
Explorable.com (May 6, 2011). Prostaglandins and Biologically Active Substances. Retrieved

from Explorable.com: https://explorable.com/prostaglandins
13
4 Discovery Of Mobile Genetic
Elements
Barbara McClintock was awarded the Nobel Prize in Physiology of Medicine of 1983 for
her discovery of mobile genetic elements. She discovered that genes could be
unstable; that there are certain regions of our genome that are capable of switching
positions; and that this gene movement occurs more frequently than the rate at which
mutations in the genome occur.
McClintock's discoveries were not appreciated by the scientific community in the late 1930's to
the early 1950's. The reason behind this was that her discoveries were far ahead than their
current bio-molecular and genetic knowledge. Nevertheless, a great appreciation of her work
began with the development of molecular biology only in the late 1960's.
McClintock's discoveries were not appreciated by the scientific community in the late 1930's to
the early 1950's. The reason behind this was that her discoveries were far ahead than their
current bio-molecular and genetic knowledge. Nevertheless, a great appreciation of her work
began with the development of molecular biology only in the late 1960's.
Background
During the late 1940's and early 1950's, the genetic code and the structure of the DNA double
helix were not yet known. The only known fact during those times was that the DNA molecule
stores the genetic information in its structure. Then McClintock pointed out that there exist
mobile genetic elements in the genome of plants and probably in our own genome too. She
suggested that certain parts of our DNA are capable of changing positions, thus, causing a
change in the functions of our genes.
It was not surprising that a lot of geneticists were not prepared to accept this concept of
“jumping genes.” It took decades of developments in the fields of molecular biology and
genetics before it became apparent that the concept of jumping genes, if not universal, was
quite common. These developments sparked further research in this field which produced
outstanding discoveries which a|dded on what McClintock has already contributed.
14
The Winner
Barbara McClintock was born on the 16th of June 1902 in Hartford, Connecticut. She received
her B.S. in 1923, earned her M.A. in 1925 and her Ph.D. in 1927 all from Cornell University.
She then became a graduate assistant in the Department of Botany from 1924 to 1927. In
1927, she was awarded the position of Instructor which she held until 1931. She was then
awarded a National Research Council Fellowship in 1931 and spent two years as a fellow at
the California Institute of Technology.
In 1933 McClintock received another fellowship this time from Guggenheim. A year later, she
went home to US and joined the Department of Plant Breeding at Cornell. In 1936, she
accepted an assistant professorship in the Department of Botany at the University of Missouri.
In 1941, she accepted a research offer from the Carnegie Institution of Washington in Cold
Spring Harbor, New York. Here she was free to pursue any research that she thought of.
McClintock remained at Cold Spring Harbor for the rest of her life. She died on September 2,
1992.
During McClintock's lifetime, she received numerous awards from different award-giving
bodies. She received the Kimber Genetics Award, National Academy of Sciences in 1967,
National Medal of Science in 1970, Lewis S. Rosenstiel Award for Distinguished Work in
Basic Medical Research in 1978, The Louis and Bert Freedman Foundation Award for
Research in Biochemistry also in 1978, Salute from the Genetics Society of America on
August 18, 1980, Albert Lasker Basic Medical Research Award in 1981 and Louisa Gross
Horwitz Prize for Biology or Biochemistry in 1982.
The Discovery
Her researches started with an observation that in maize, kernels manifest different coloured
patches. The prevailing answer to this observation was that certain chromosomes were more
fragile than others, causing the genes in the fragile chromosomes to mutate more easily which
causes unusual pigmentation. McClintock studied the structure of the chromosome of the
kernels with the unusual pigmentation. She noted the structure, storage protein, starch
content and the pigments in the individual chromosomes. From the ten pairs of chromosomes,
she became particularly interested with chromosome pair nine.
It was indeed in chromosome pair nine where she found her first mobile genetic element
which causes an interruption in the structure of the chromosome. She discovered that the
chromosome was divided into two by this mobile element that she called dissociation or Ds.
Its transposition along chromosome nine caused an interruption to the usual sequence of
genes in the chromosome causing some genes to be completely turned off. She also found
15
that Ds need a trigger for it to be activated. This trigger was called activator or Ac. Together,
the Ds and Ac were regarded by McClintock as a control mechanism of gene activity.
McClintock also found that these control elements are also present in different chromosomes
but they act as normal genes. It is only after transposition that they cause inactivation of
neighboring genes. She also found that these mobile genetic elements can be a part of
regulatory control system in gene expression. Some elements act by programming
neighboring genes to be activated or inactivated at a later time which may be several
generations later.
Clinical Significance
McClintock’s discovery paved the way to the discovery of the role of mobile genetic elements
in the spreading of resistance to antibiotics from resistant to sensitive strains of bacteria. The
notion of transferable drug resistance in bacteria is a serious problem in the medical field
because drug-resistant bacteria cause infections and disease that are more difficult to treat.
This also entails that we need to develop alternative drugs that can treat the infections caused
by the drug-resistant bacteria.
The discovery of mobile genetic elements also contributed to our knowledge of how
antibodies are formed. Scientists have long been fascinated by the number of antibodies that
our bodies can create considering that our genome has a very limited number of genes. The
possibility of having jumping genes gave them the answer to this mystery. It is much like
having a limited number of letters, but by having the ability to rearrange the letters, you can
form almost an unlimited number of words.
Explorable.com (May 20, 2011). Discovery Of Mobile Genetic Elements. Retrieved from
Explorable.com: https://explorable.com/mobile-genetic-elements
16
5 Discovery of the Function of Ion
Channels in Cells
In the year 1991, Erwin Neher and Bert Sakmann were awarded the Nobel Prize in
Medicine or Physiology for their seminal discovery of the functions and mechanisms
behind an ion channel in cells.
Neher and Sakmann were able to develop a technique that registers very miniscule variations
in electric currents that passes through a single ion channel. This same technology is still
being used today by many scientists in different fields of research.
Neher and Sakmann were able to develop a technique that registers very miniscule variations
in electric currents that passes through a single ion channel. This same technology is still
being used today by many scientists in different fields of research.
Background
Cells are the basic building blocks of a living organism. Our bodies are composed of billions
and billions of cells with varying forms and functions. Cells from the same type cluster
together to form a tissue; tissues with similar function forms an organ; and different organs
acting together in a coordinated manner forms a living organism.
This means that each cell has a designated function that it must accomplish to sustain the life
of the organism. To be able to perform their specific functions, the cells must be capable of
communicating with other cells within the same tissue to execute a coordinated action.
Moreover, cells must also have the capability to communicate with cells from a different type
of tissue to execute a coordinated action in the organ level. Furthermore, cells from an organ
must communicate with cells from another organ to execute a coordinated action of the living
organism.
The question now is how do cells communicate? Each cell is bounded by a membrane that
isolates it from its environment, the extracellular environment. However, the cell membrane
has channels that link the extracellular environment with the interior of the cell. This is the way
by which cells communicate with each other.
17
The Minds Behind the Discovery
Erwin Neher was born on the 20th of March 1944 in Landsberg, Bavaria. In the fall of 1963,
he took up physics at the 'Technische Hochschule' in Munich and finished in 1966. After
finishing physics, he earned a scholarship to study biophysics in the US at the University of
Wisconsin at Madison. In 1967, he went back to Munich to start Ph.D. projects in Biophysics
and he met Dr. Lux who was investigating synaptic mechanisms in motor neurons and ion
currents in snail neurons. During the years when he worked with Dr. Lux, he met Bert
Sakmann who was working on a Ph.D. project in the same laboratory facility. The two
scientists met again in 1973 in Gottingen where they started to work together on a research
project.
Bert Sakmann was born on the 12th of June 1942 in Stuttgart, Swebia. His family initially
thought that he will be an engineer due to his interest in motors and aeroplanes. In the final
years of his early schooling, he learned about cybernetics and its possible application to
biology. He then enrolled at the medical school faculty of Tubingen University. After passing
all his medical exams, he became fascinated with neurological synaptic connections. He was
convinced that he needed more knowledge on cellular physiology to understand synaptic
connections. To gain more knowledge, he joined Dr. Dieter Lux’s laboratory and met Erwin
Neher who taught him voltage clamping. Due to the great similarity between their interests,
Neher and Sakmann decided to venture into a new research study as a pair.
The Discovery
The cell membrane is impermeable to ions, so ionic currents are carried through the
membrane by specialized protein molecules called ion channels that span the membrane.
Upon sensing a chemical stimulus, the ion channels change shape creating a pore in the cell
membrane through which ions can flow. Such an idea of ion channels already existed during
the 1950's especially when Bernard Katz at University College London worked on synaptic
transmission from motor nerve to muscle. By the early 1970's there was enough indirect
evidence about the channels to guess that a current of a few picoamps must flow through
each channel. However, the machines during those days were not capable of measuring such
tiny currents.
The world was stunned when Neher and Sakmann were able to observe the currents through
a single ion channel by means of their new method called patch clamp technique.
The new method allowed them to watch the activity of a single molecule, a technology that
was considered fiction during those times. The method entails touching a micropipette with a
tip diameter of about a thousandth of a millimeter against the external surface of the cell
18
membrane in such a way that a high resistance seal is formed between the glass and the
membrane, thus isolating a very small area of membrane.
When an ion channel opens in this patch of membrane, ions will move through the channel as
an electric current, the current flows up the micropipette and can be measured with a sensitive
ammeter. It was through this technique that the presence of ion channels was confirmed with
sufficient physical evidence and the processes that take place within a single ion channel
were uncovered.
Succeeding Studies
Neher was also able to elucidate the mechanisms behind the secretory process. He showed
that different secretory agents are stored in secretory vesicles within the cell and when the cell
is stimulated, the vesicles move closer to the cell membrane. The membrane of the vesicles
then fuses with the cell membrane to release the secretory agents. He was able to show this
by measuring the changes in the electric property of the cell membrane during its fusion with
the secretory vesicle’s membrane by using a refined patch clamp technique.
The major contribution of this discovery was the enormous use of the patch clamp technique.
This technique was combined with the new methods to study the different parts of the ion
channels in cells. Through this procedure, it has been possible to identify what makes an ion
channel select only one type of ion, or be sensitive to a particular type of chemical transmitter.
Through this technique, our standard research procedures to study ion channels have been
changed and became more efficient, more valid and more specific.
Researches are now being conducted about the participation of ion channels during the
secretion of insulin by the pancreas, when the heart is contracting, or when we think or
remember something. Drugs now are being developed to target specific types of ion channel,
which are of importance in disease like anxiety, cardiovascular disease, epilepsy, and
diabetes.
Explorable.com (Apr 14, 2011). Discovery of the Function of Ion Channels in Cells. Retrieved
from Explorable.com: https://explorable.com/function-of-ion-channels
19
6 Discovery of Reversible Protein
Phosphorylation
Edmond H. Fischer and Edwin G. Krebs were awarded the Nobel Prize in Physiology or
Medicine in 1992 for their seminal discovery of reversible protein phosphorylation and
its importance as a biological regulatory mechanism.
Fisher and Krebs were able to show that reversible protein phosphorylation affects the
structure, shape, function and activity of proteins that are responsible for the regulation of
nearly all aspects of cellular life.
Background
Proteins are one of the most important molecules in our body. Proteins are made of a chain of
amino acids that have a distinct three-dimensional configuration. It is this unique three-
dimensional configuration that dictates the molecular function of a protein.
Fisher and Krebs were able to show that reversible protein phosphorylation affects the
structure, shape, function and activity of proteins that are responsible for the regulation of
nearly all aspects of cellular life.
Background
Proteins are one of the most important molecules in our body. Proteins are made of a chain of
amino acids that have a distinct three-dimensional configuration. It is this unique three-
dimensional configuration that dictates the molecular function of a protein.
Each protein molecule within our bodies has a specific function. Proteins participate in
metabolic processes, DNA replication, gene expression, and even in the cell cycle. Antibodies
that are involved in defending our bodies from antigens are specialized proteins. The actin
and myosin that are responsible for muscle contraction are also proteins. Enzymes that act as
catalysts in our biochemical reactions are also made of proteins.
Some hormones like insulin, the hormone that regulates glucose metabolism, are also
specialized proteins. There are also transport proteins like hemoglobin that carries oxygen
20
through the blood.Another important process that dictates the function of proteins is
phorphorylation. Phosphorylation refers to the addition of a phosphate to one of the amino
acid side chains of a protein. Since it is the three-dimensional configuration of the protein that
dictates its function, the addition of another phosphate molecule to the structure of the protein
alters its function.
This means that if a protein undergoes phosphorylation, it undergoes a structural change via
the addition of a phosphate which gives the phosphorylated protein another function.
The Winners
Edmond H. Fischer was born of the 6th of April 1920 in Shanghai, China. At an early age, he
wanted to become a professional musician but his dreams changed during high school. He
then studied in the University of Geneva and enjoyed chemistry and biology. He then worked
on alpha-amylase for his Ph.D. in organic chemistry under Kurt H. Meyer. After his Ph.D. he
went to University of Washington, Seattle due to an offer of Assistant Professorship in 1953.
Six months after settling in University of Washington, he collaborated with Edwin Krebs on a
research concerning glycogen phosphorylase.
Edwin Gerhard Krebs was born on the 6th of June 1918 in Lansing, Iowa. He attended
Urbana High School and then enrolled at the University of Illinois at Urbana in 1936. During
those years, his projected career path was towards organic chemistry or medicine.
Krebs immediately chose medicine after receiving a scholarship to pursue medicine at

Washington University School of Medicine in St. Louis. After earning his M.D. he studied
biochemistry as a fellow to Carl and Gerty Cori who were working on rabbit muscle
phosphorylase. In 1948, he accepted an offer to be an Assistant Professor of Biochemistry at
the University of Washington, Seattle. Five years later, he collaborated with the new comer
Edmond Fischer on their Nobel Prize winning research.
The Discovery
Together, Krebs and Fischer decided to see whether or not they could determine the
mechanism by which 5'-AMP served as an activator of Phosphorylase B. They were not able
to solve that problem but in the course of trying, they encountered another astounding
discovery. They discovered the molecular mechanism by which interconversion of the two
forms of phosphorylase takes place which they called reversible protein phosphorylation.
21
Phosphorylase is the protein responsible for the breakdown of glycogen, our body’s storage
form of sugar and energy. If phosphorylases are activated, glycogen in our liver and muscles
are broken down to glucose, the immediate energy supply of our muscles.
Fischer and Krebs found the mechanism by which phosphorylase is converted from an
inactive form to an active form. They found that phosphorylase is activated by the addition of a
phosphate group from an ATP which is an energy-rich compound, a form of phosphorylation.
They also showed that this process is catalyzed by an enzyme called protein kinase. In
addition, they also found the mechanism by which an active phosphorylase is converted to its
inactive form. This process requires the elimination of the phosphate group and is catalyzed
by the enzyme phosphatase, a complete reversal of phosphorylation. The discovery of these
processes lead to the concept of reversible protein phosphorylation.
They also found that many of the proteins that are phosphorylated upon reception of a signal
are protein kinases as well. This means that some proteins, after phosphorylation, acts as a
protein kinase that will catalyze the phosphorylation of other proteins creating a
phosphorylation cascade. They also noted that phosphorylation and reverse phosphorylation
are regulated by a tightly guarded balance between phosphatases and kinases.
Importance of Reversible Protein Phosphorylation

The advantages of using reversible protein phosphorylation as a control mechanism in many
cellular processes are:
Reversibility – this means that the proteins and their functions can be regulated in both
directions.
Amplification – rapid and wide-spread protein action can be achieved via the
phosphorylation cascade.
22
Conservation – the reversibility of this process entails that the cell does not need to
create new proteins or degrade existing proteins since their functions can be altered via
phosphorylation or dephosphorylation.
Regulation - through the use of phosphorylation cycles and cascades, the cell is able to
regulate a diverse set of processes, including cellular movement, reproduction and
metabolism.
It is the simplicity, reversibility and flexibility of phosphorylation that explains why it has been
adopted as the most general control mechanism of the cell.
Explorable.com (Jul 9, 2011). Discovery of Reversible Protein Phosphorylation. Retrieved

from Explorable.com: https://explorable.com/reversible-protein-phosphorylation
23
7 Prion as an Infectious Agent
Stanley B. Prusiner was awarded the Nobel Prize in Medicine or Physiology of 1997 for
his discovery of Prion as an infectious agent. In his elegant series of experiments, he
was able to identify Prions as the cause behind some of the common neurologic
dysfunctions in animals and in humans.
Prions are protein; they have no genetic material and it is normally found in most of the cells
in our body. Every person in the planet has Prions, but does that mean we are all infected by
a neurologic dysfunction?
Scientific Context of the 1970s and 80s

The well known infectious agents in the 1970's and 1980's are only bacteria, viruses, fungi
and parasites. All the well-known infectious agents during that time have genetic materials
that enable them to propagate and infest the body. The genetic material of these agents were
considered foreign to human bodies and that is the reason why human immune defense
mechanisms act against these agents. Researchers conducted by Prusiner added another
agent into the infectious agent category in the form of prions.
Who is Stanley Prusiner?

Stanley Prusiner was born on the 28th of May 1942 in Des Moines. He developed his interest
in scientific papers when he was a high school student in Walnut Hills High School. He then
studied in the University of Pennsylvania where he majored in chemistry. He finished college
a cum laude and earned his A.B. in 1964. He then earned his M.D. in 1968 in the University of
Pennsylvania, School of Medicine. He underwent medical internship in the University of
California from 1968 to 1969. He finished his residency in Neurology from the same university
in 1974.
Prusiner then became professor in multiple fields such as neurology, biochemistry, virology
and biophysics in the University of California. It was during his residency, due to an admitted
patient dying of a “slow virus” infection called Creutzfeldt-Jakob disease, or CJD, when he
developed an interest in identifying the molecular structure of this slow virus.
24
Decades of Research to Identify Prion as an Infectious
Agent
The mystery behind the slow virus that caused the death of his patient gave him the push to
read more about CJD and other related diseases like Kuru in New Guinea and the scrapie
disease of sheep. His first step was to purify a scrapie agent wherein he expected to find
small viruses but he kept finding proteins in his results but no nucleic acid. He conducted
other similar experiments but the results showed only proteins and a persistent absence of
nucleic acids.
The crucial step in the understanding of the novel infectious agent was Prusiner’s isolation of
the protein from the infectious material which he named prion, an acronym for “proteinaceous
infectious particle.” He also found that infectivity of prions are significantly reduced by
chemicals that destroy protein structure, and more importantly, by antibodies to prion proteins.
It was also after the isolation of the prion protein that Prusiner was able to identify the gene
coding for prion protein.
Furthermore, he found that the prion protein mRNA is a product of a single host gene which
he noted to be present even in uninfected brain tissues of animals. He also found that prion
proteins are present in white blood cells and especially abundant in the surface of nerve cells
in the brain. This initially was a very contradicting result since he was able to find the gene
that causes prion infection in an uninfected specimen.
To reconcile the contradicting results, Prusiner hypothesized that the prion proteins can exist
in two different forms: a normal cellular protein, which explains the presence of the prion
gene, mRNA and protein in uninfected specimen, and a pathologic protein form, which
explains the diseases.
Prusiner indeed found that a structural difference exists between the prion proteins in normal
tissue and the prion proteins in infected tissue. He added that for a normal prion protein to
become pathologic, it involves a conformational change whereby the -helical content of the
normal protein diminishes and the -sheet content increases. This means that prions are not
totally infectious agents; prions are also normal proteins present in most of the cells in our
bodies. Prions only become infectious agents if it undergoes the mentioned conformational
changes.
Clinical Relevance
Prion as an infectious agent can be considered as a relatively new development in the field of
medicine. They are considered inevitably fatal due the progressive destruction of the brains of
25
the infected individual.
Normal and healthy prion proteins can be infected if it comes in close contact with an infected
prion protein. The continuous infection of prion proteins forms a thread-like structure of prion
aggregates that ultimately destroys nerve cells. Brain specimens that are infected with prions
have a characteristic porous and spongy appearance due to the continuous death of nerve
cells in the region.
Symptoms associated with a prion infection depend on the area of the brain that is infected by
the agent. If the prion infects the cerebral cortex, memory and learning is impaired. If the
infected region is the cerebellum, the infection manifests as gait and coordination impairment.
If the infected region is the thalamus, arousal and sleep disturbances are observed.
There are three ways by which a person can be infected with a prion disease. First is by
spontaneous mutation of the prion gene that causes the conformational change of harmless
prions into infectious prions. Second is by heredity; mutations in the prion protein gene can be
transmitted to an individual’s offspring. Lastly, infection can be transmitted if prions from an
infected person or animal are ingested. Prions cannot be transmitted through air, touch or
other casual contact.
Explorable.com (Nov 24, 2010). Prion as an Infectious Agent. Retrieved from

Explorable.com: https://explorable.com/prion-as-an-infectious-agent
26
8 Discovery Of Split Genes
Similar to the context of most Nobel Prize winning researches, the discovery of Richard
J. Roberts and Phillip A. Sharp regarding split genes contradicted the widely accepted
scientific norm of the 1970's.
Rob were able to provide evidences that genes in higher organisms do not present as single,
continuous strand in the DNA but rather, the genes present as several, well-separated
segments. For this discovery, Roberts and Sharp were awarded the Nobel Prize in Medicine
or Physiology in 1993. Their discovery led to a deeper understanding in the field of molecular
biology and triggered researches concerning the development of different diseases.
Background
DNA is the hereditary material in humans and almost all living organisms. It is composed of
four bases adenine, guanine, cytosine and thymine. The order of these bases determines the
information that the DNA contains. A gene is a stretch of DNA that contains detailed
instructions on how to build proteins. This instruction is first copied from the DNA to
messenger RNA or mRNA.
The information in the mRNA is then decoded in the ribosome wherein amino acids are
assembled to form proteins. Decoding of the mRNA entails that the individual bases in the
mRNA were read three at a time, each triplet of bases corresponding for a single amino acid.
The gene coding for a specific protein is surrounded by sequences of DNA that tells an
enzyme called RNA polymerase where to begin transcribing the RNA and where to stop. The
signal that tells where to start making RNA is called the promoter.
In the 1970's, molecular biologists believed that genes present in a single, continuous strand
in the DNA. This was challenged by the discoveries of Roberts and Sharp which showed that
genes present in a separated manner.
The Winners
Richard J. Roberts was born on the 6th of September 1943 in Derby, England. As a child, he
initially wanted to become a detective but this immediately changed when he received a
27
chemistry set as a present and knew he wanted to become a chemist. He then enrolled at
Sheffield University due to their excellent chemistry department and graduated in 1965.
Fresh from college and just two years post-doctoral work at Harvard, Roberts was invited by
Jim Watson to join him at Cold Spring Harbor Laboratory, where they worked together for
more than two decades. Earlier in 1972, Roberts attended a seminar at Harvard Medical
School given by Dan Nathans where he learned that an enzyme could cleave DNA into
specific pieces. By the use of this enzyme, he began to map the DNA that lead to his Nobel
Prize winning discovery.
Philip A. Sharp was born on the 6th of June 1944 in Falmouth, Kentucky. His early education
was in McKinneysburg Elementary, Butler Elementary and High School and Pendleton County
High School. He then enrolled at Union College and majored in chemistry and mathematics
and decided that he wanted to continue learning about science, particularly chemistry.
Sharp was offered a fellowship and soon began graduate studies under Victor Bloomfield in
physical chemistry. He completed his Ph.D. in chemistry at the University of Illinois in 1969.
He then worked at the California Institute of Technology until 1971. After Caltech, he studied
gene expression in human cells at the Cold Spring Harbor Laboratory under the mentorship of
Jim Watson.
The Discovery
Roberts and Sharp wanted to know if the promoter sequence, the sequence of DNA that tells
where to start making the RNA, of higher organisms is similar to the promoter sequence in
bacteria which was relatively well-known during that time. They used an upper respiratory
virus that grows in human cells called Adenovirus-2.
Roberts and Sharp began to develop methods whereby they could map the exact start of the
mRNA sequences made from Ad-2 mRNA. They thought that if they could work out the
sequence of the mRNA right to its very start, then they would merely need to locate the
corresponding DNA sequence, identify the DNA sequence that preceded it and they have the
promoter. To accomplish this, they developed a technique that allowed them to catch short
sequences from the very start of the Ad-2 mRNAs.
Considering that there are many different mRNAs that Ad-2 creates, they were expecting to
find 15-20 different promoter sequences which code for the different mRNAs. They were
surprised when they found that there is only one sequence for all the mRNAs and that the
main parts of the mRNA were encoded a long way apart from its very start.
By using electron microscopy, they were able to show that the genes in Ad-2 were indeed split
into pieces. They found that a single mRNA molecule corresponded to no less than four well-
28
separated regions in the DNA molecule. For these discoveries, they concluded that genes
present in multiple, well-separated strands in the DNA molecule, split geneshave been
discovered.
Clinical Correlations
To give you a better picture of what Roberts and Sharp discovered, consider the figures
shown below. The shaded area corresponds to the genes and the white area corresponds to
unrelated DNA strands. In the bacteria, the gene presents as a single, continuous strand in
the DNA molecule. However, in the Adenovirus-2 and in higher organisms including man, they
found that the gene presents in a fragmented manner. A gene thus consists of several
fragments called exons (shaded areas) separated by intervening DNA called introns (white
areas).
The consequence of split gene discovery is that the first RNA product produced by the gene
which still contains both exons and introns, needs to be edited such that the introns are
eliminated from the mRNA and the exons are coupled together to form a shorter mRNA.
Split gene discovery also helped us understand how several diseases arise. An example of
which is a form of anemia called thalassemia. This disease is due to inherited defects in the
genetic material. These genetic defects cause errors in the editing process of the mRNA
causing a formation of an abnormal messenger RNA.
Explorable.com (Mar 6, 2011). Discovery Of Split Genes. Retrieved from Explorable.com:

https://explorable.com/split-genes
29
9 Uncovering The Effects Of Nitric
Oxide On The Cardiovascular System
Robert F. Furchgott, Louis J. Ignarro and Ferid Murad were awarded the Nobel Prize in
Medicine or Physiology of 1998 for their norm-breaking discoveries regarding the
effects of nitric oxide on the cardiovascular system.
In their brilliant series of independent researches and experiments, they were able to show
that nitric oxide acts as a signal molecule to elicit vasodilatation or dilation of the blood
vessels.
Background of Nitric Oxide

Air in our atmosphere is composed of 79% nitrogen. When nitrogen is burned, it produces
nitric oxide. It is also considered one of the most common air pollutants due to its sheer
volume. An example of this is the high nitric oxide content of our car’s exhaust fumes. Nitric
oxide is also considered as an unstable and reactive gas especially in the presence of
oxygen. It changes and reacts to other substances that come close to it. It is so unstable that
is can be converted to nitrate and nitrite in a matter of seconds. It was also known to be
present and produced by lower organisms such as bacteria but it was not expected to be of
great importance to higher organisms.

Robert Furchgott was born on the 4th of June 1916 in Charleston, South California. As a child,
he was an avid shell collector and a bird watcher. Within the first couple of years in high
school, he knew that he wanted to become a scientist. He then entered University at Chapel
Hill as chemistry major. By his senior years, his preference was physical organic chemistry.
He then finished his Ph.D. in Biochemistry at Northwestern University in the year 1940. In
1956, he became acquainted with researches in cardiovascular system when he conducted
experiments on photorelaxation of blood vessels, factors in the contractility of cardiac muscle,
peripheral adrenergic mechanisms and endothelium-dependent relaxation.
Louis Ignarro was born on the 31st of May 1941 in Brooklyn, New York. He entered Central
30
Grade School and Long Beach High School with a strong interest in chemistry. He then
applied to Columbia University in New York to study chemistry and pharmacy. He earned his
B.A. in Pharmacy in 1962. He then finished his Ph.D. in Pharmacology in the University of
Minnesota in the year 1966. He also became a professor of the Department of Pharmacology
of Tulane University, School of Medicine in New Orleans. In 1985, he also became of
professor of the Department of Pharmacology of UCLA School of Medicine in Los Angeles,
California.
Ferid Murad was born on the 14th of September 1936 in Whiting Indiana. At the age of 12, he
knew that he will become a doctor. He earned his undergraduate chemistry degree at
DePauw University and his M.D. and Ph.D. in Pharmacology from Case Western Reserve
University in 1965. He became a professor in the University of Virginia in 1970. He also
served as the vice-president of the Abbott Laboratories in 1988. He also became a professor
and Director Emeritus of The Brown Foundation Institute of Molecular Medicine for the
Prevention of Human Disease. He also holds the John S. Dunn Distinguished Chair in
Physiology and Medicine.
The Discovery
In 1977, Murad tried to analyze how vasodilating drugs act upon the cardiovascular system to
achieve this result. In his experiments, he observed that some drugs, such as nitroglycerin,
caused a release of nitric oxide in the body, which relaxes the smooth muscle cells. He was
then fascinated by this result since gases were not known to regulate such important cellular
functions. But he conducted no succeeding experiments to establish the role of nitric oxide in
smooth muscle relaxation.
Three years after the discovery of Murad, Furchgott also tried to work on the effects of drugs
on blood vessels. Initially, he had contradicting results since he noted that same drugs
sometimes cause vasoconstriction, on another test vasodilatation. He then hypothesized that
the effects of the drugs vary depending on the status of the endothelium. He thought that the
effects of the drugs may vary if the endothelium in the blood vessels were intact or damaged.
This hypothesis was verified in 1980 when he successfully showed that acetylcholine causes
vasodilatation only if the endothelium is intact. He then concluded that the blood vessels dilate
due to the intact endothelium’s production of an unknown signal molecule which he called
endothelium-derived relaxing factor or EDRF.
Due to the paper written by Murad in 1977, Ignarro thought that nitric oxide can be the cause
of vascular smooth muscle relaxing action of nitroglycerin and that cyclic GMP might be its
second messenger. In 1979, he conducted an experiment wherein he injected nitric oxide gas
bubbles into an organ bath containing a preconstricted bovine coronary artery strip. He noted
a significant and rapid relaxation of the coronary artery strip. This vasorelaxant effect was
31
noted to be inhibited by methylene blue which was known to inhibit guanylate cyclase which
causes an increase in cyclic GMP levels.
Due to these results, he was able to prove the effects of nitric oxide on the cardiovascular
system as a vasorelaxant and cyclic GMP was the second messenger. In 1983, he conducted
a study to identify the EDRF that Furchgott discovered and he realized that EDRF and NO
shared similar pharmacological and biochemical properties. EDRF and NO both activated
guanylate cyclase and elevated cyclic GMP. The cyclic GMP levels and the vasorelaxant
effects of both EDRF and NO were inhibited by methylene blue. He then concluded that the
EDRF of Furchgott is NO.
The discovery of the effects of nitric oxide on the cardiovascular system and its role as a
signaling molecule astounded the entire scientific community. Signaling molecules are called
neurotransmitters and NO, as a gas, does not fit into this traditional definition of
neurotransmitters. Neurotransmitters are produced, stored and used when needed but NO is
not produced in advanced or stored. Neurotransmitters, in the traditional way, only affects
nearby neurons but NO, as a gas, diffuses in all directions and is not limited to a local effect.
Clinical Relevance
Ignarro enumerated several applications of nitric oxide on the cardiovascular system and to
other organ systems of the body. Based on these properties of NO, new drugs can be
developed such as vasodilators and antiplatelet agents and antiproliferative agents for the
treatment of hypertension, atherosclerosis, stroke, angina pectoris, heart failure, and vascular
complications of diabetes, gastrointestinal ulcers, impotency and other vascular disorders. An
excellent example of the application of basic information learned about NO has been the
development of sildenafil or Viagra, which has revolutionized the treatment of impotency.
Other novel therapeutic benefits of NO will include the prevention and treatment of
gastrointestinal ulcers, inflammatory bowel disease, and related gastrointestinal disorders as
well as urinary incontinence.
Explorable.com (Nov 17, 2010). Uncovering The Effects Of Nitric Oxide On The
Cardiovascular System. Retrieved from Explorable.com: https://explorable.com/nitric-oxide-in-
cardiovascular-system
32
10 Role of G-Proteins in Signal
Transduction
1994 was a revelation for both Alfred G. Gilman and Martin Rodbell for they were
awarded the Nobel Prize in Medicine or Physiology for their discovery of the function
and role of G-proteins in signal transduction. Their discovery explained how the
information in the chemical signals is transduced by target cells upon the binding of
the chemical signals to their respective receptors.
Gilman and Rodbell showed how a chemical signal that reaches the outside of the cell is
interpreted and activates second messengers that can evoke changes in the inner machinery
of the cell.
Background
A single human organism is composed of billions and billions of cells. For the organism to
survive, all the cells must be able to communicate effectively and act together as a single,
unitary organism. Cells communicate with each other through chemical signals.
Gilman and Rodbell showed how a chemical signal that reaches the outside of the cell is
interpreted and activates second messengers that can evoke changes in the inner machinery
of the cell.
Background
A single human organism is composed of billions and billions of cells. For the organism to
survive, all the cells must be able to communicate effectively and act together as a single,
unitary organism. Cells communicate with each other through chemical signals.
In the 1950's and early 1960's, scientists already know that hormones, neurotransmitters and
other forms of signaling molecules are released from cells. These signaling molecules are
called first messengers. These first messengers then attach to their receptors in the target cell
and the receptors will convert them to a signal that will act inside the cells. These signals are
then called second messengers. They know that the conversion from first messengers to
33
second messengers happen in the cell membrane but they didn’t know any further.
Scientists were still unaware of the exact processes of signal transduction happening after the
binding of the first messengers to their respective receptors in the cell membrane.
The Winners
Alfred Goodman Gilman was born in 1941 in New Haven, Connecticut. His father, Alfred
Gilman, is a musician and could play almost any kind of musical instrument. His mother was a
pianist and gave regular piano lessons.
Despite this rich musical heritage, Alfred G. Gilman chose to become a chemist. This choice
was triggered when his father turned to science and became a faculty of the Department of
Pharmacology at Yale Medical School. His father authored a major book in pharmacology with
his good friend Goodman which was published in 1941, the year Alfred Goodman Gilman was
born. That may be the reason why he was named after the authors of the textbook, Goodman
and Gilman. Gilman earned his B.S. in Biochemistry from Yale in 1962. He then enrolled in a
combined MD/PhD program at Case Western Reserve University School of Medicine in Ohio
where he studied under the mentorship of Theodore Rall. He then became a professor of
pharmacology at the University of Virginia School of Medicine. He also became the chairman
of the Department of Pharmacology at the University of Texas Southwestern Medical Center
at Dallas.
Martin Rodbell was born on the 1st of December 1925 in Baltimore, Maryland. He finished his
early schooling in Baltimore City College and enrolled in John Hopkins University majoring in
Biology. He earned his B.S. in Biology in the year 1949. He then earned his Ph.D. in
Biochemistry in the University of Washington in 1954. In the mid-sixties, he listened to a
lecture given by Earl Sutherland on second-messengers and it caused him to do research on
the cyclic AMP paradigm. In the late sixties and early seventies, he conducted his Nobel Prize
winning research on the role of GTP and magnesium ions in hormone action.
The Discovery
Martin Rodbell was responsible for the entire conceptual framework of the receptor complex.
He showed through a series of elegant experiments in the late 1960's and early 1970's that
signal transduction in the cell membrane of the target cell involves three important structures.
He named the three structures as the receptor, the transducer and the amplifier.
The receptor is the structure responsible for the binding of the chemical signals to the cell
membrane of the target cells. The receptor provides specificity to the receptor complex since
chemical signals need corresponding receptors to ensure proper binding. The amplifier on the
34
other hand is in the intracellular end of the cell membrane. It produces large amounts of
second messengers like cyclic AMP or cAMP that activates different intracellular processes.
Aside from these two structures, Rodbell was responsible for the introduction of the
transducer structure.
The transducer is responsible for linking the receptor to the amplifier. Rodbell found that the
transducer is driven by GTP or guanosine triphosphate, its source of energy.
Alfred G. Gilman, intrigued by the transducer concept of Rodbell, set out to determine the
structure and composition of the transducer. He used mutated leukaemia cells in his
experiments. He noticed that one mutated leukaemia cell with normal receptors and amplifier
structures that generate cAMP as second messengers failed to respond to appropriate
external stimuli. Because of this result, he hypothesized that the mutated leukaemia cells
have dysfunctional transducer structure.
In 1980, Gilman was able to isolate and purify a protein that he thought was the transducer.
He thought of this because when this normal protein was transferred to the cell membrane of
the mutated leukaemia cells with dysfunctional transducers, the function of the receptor
complex was restored. This protein was then named G-protein since it reacts with GTP at its
driving force.
Structure, Function and Role of G-proteins in Signal

Transduction
G-proteins are composed of three different proteins consisting of an alpha, beta and gamma
subunits. The interaction between the receptor and the G-protein causes a transfer of a
guanosine trisphosphate or GTP for a guanosine diphosphate GDP on the alpha subunit. This
means that when the receptor-G-protein complex is not activated, GDP is bound to the alpha
subunit and during activation, GTP replaces the GDP. The GTP then activates the alpha
subunit which causes the beta and gamma subunit complex to undergo a conformational
change which allows them to separate from the alpha subunit. The beta-gamma subunit
complex then interacts with another structure in the cell called adenylate cyclase. The
interaction between the adenylate cyclase and the beta-gamma complex activates the
adenylate cyclase to produce cyclic AMP or cAMP, the second messenger. The alpha subunit
then hydrolyzes the GTP back to GDP which causes the beta-gamma complex to rebind with
the alpha subunit. The G-protein is inactivated once again waiting for another wave of
chemical signals.
Explorable.com (Jan 12, 2011). Role of G-Proteins in Signal Transduction. Retrieved from
35
Explorable.com: https://explorable.com/g-proteins
36
11 Discovery of Intrinsic Signals in
Proteins Governing Transport and
Localization
Günter Blobel was awarded the Nobel Prize in Physiology or Medicine in 1999 for his
discovery of intrinsic signals in proteins that govern their transport and localization in
the cell.
The research conducted by Blobel was able to answer several questions that bothered
scientists and molecular biologists during the 1970's. Blobel was particularly able to answer
the question regarding the mechanisms behind the coordinated and properly directed flow of
proteins within the different compartments of the cell and even the mechanisms by which
proteins are transported out of the cell.
Background On Cellular and Protein Function

Proteins are building blocks of life. Approximately 100,000 billion cells make up a human
being. Each cell in a human body contains approximately one billion protein molecules. Each
cell in our body also consists of functionally different parts. Cells have nucleus, endoplasmic
reticulum, mitochondria, ribosomes and a lot more organelles which are lined by different
membranes.
Each protein molecule must be able to learn how to navigate through the maze of organelles
and membranes within a cell just to be able to perform its function. Prior to Blobel’s discovery,
we have little idea on how these billions and billions of protein molecules in our body are
coordinated in such a way that they perform their specific functions properly.
Proteins are made up of 100 to 10,000 amino acids assemble into a chain that folds in itself to
create a three dimensional distinct shape that is determined by the sequence of the amino
acids. Proteins perform a variety of functions in the human body. It can be used as a building
block or part of the different cellular membranes, it can be integrated into the myofibrils of our
muscles and it can also act as an enzyme catalyzing the different reactions that are taking
place within our body. An understanding of how these proteins are directed is vital to our
37
wider understanding of life processes.
Günter Blobel
Günter Blobel was born on the 21st of May 1936 in Germany. He received his M.D. in 1960
from the Univeristy of Tübingen. He then earned his Ph.D. degree in Oncology from the
University of Wisconsin when he worked with Van R. Potter in cancer research. He did his
postdoctoral fellowship with Dr. Palade at the Rockefeller University. He rose from assistant
professor to associate professor to professor in The Rockefeller University and in 1992; he
was named John D. Rockefeller Jr. Professor. During his career, he earned numerous
awards, some of which are US Steel Award in Molecular Biology, The Waterford Bio-Medical
Science Award, The Warburg Medal of the German Biochemical Society and Albert Lasker
Basic Medical Research Award.
Intrinsic Signals in Proteins

The research of Günter Blobel was focused on how a newly made protein, destined to be
transported out of the cell, it targeted to an intracellular membrane system, the endoplasmic
reticulum. His first working hypothesis was named “signal hypothesis” wherein he postulated
that proteins that are bound to exit the cell have intrinsic signals that direct their movements to
and across membranes.
In the experiments that he conducted, he found that proteins that are destined to be exported
out of the cell are synthesized by ribosomes that are attached to the endoplasmic reticulum.
The information provided by the mRNA determines the composition of amino acids that will
make up the protein. He also noted that a signal peptide is formed as a part of the protein that
is being assembled. The signal peptide then binds to the signal-recognition particle or SRP.
The SRP-ribosome complex then docks to the SRP-receptor and channel. The growing
protein chain penetrates the channel and the SRP dissociates from the receptor. The
completed polypeptide chain is released into the lumen of the endoplasmic reticulum and is
subsequently delivered out of the cell.
In succeeding experiments, Blobel was also able to show that similar intrinsic signals in
proteins are responsible for the transport of proteins to other intracellular organelles. He then
concluded that each protein contains in its structure the information needed to direct its proper
location in the cell. Furthermore, he postulated that specific amino acid sequences or
topogenic signals determine the fate of the protein may it be bound for export out of the cell or
become integrated into the membranes of the cell.
38
Clinical Correlation
Our knowledge about the intrinsic signals in proteins also known as topogenic signals has
increased our understanding of several medically important mechanisms. It also helped us
understand the basis of some human hereditary disease associated with errors in these
signals and transport mechanisms. One example is the hereditary disease primary
hyperoxaluria, which causes kidney stones at a very young age. Another disease is
hypercholesterolemia which is a very high level of cholesterol in the blood. This disease was
found to be due to deficient transport signals. Other hereditary diseases like cystic fibrosis are
caused by the fact that proteins do not reach their proper destinations.
Explorable.com (Mar 20, 2010). Discovery of Intrinsic Signals in Proteins Governing Transport
and Localization. Retrieved from Explorable.com: https://explorable.com/intrinsic-signals-in-
proteins
39
12 Genetic Control Of Embryonic
Development
Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus were named the
1995 Nobel Laureates in Physiology or Medicine for their discovery concerning the
genetic control of embryonic development.
Lewis, Nüsslein-Volhart and Wieschaus were able to identify, localize and classify a small
group of genes responsible for the control of early embryonic development of the fruit fly,
Drosophila melanogaster. This small group of genes was shown to be responsible in
determining the body plan and the formation of body segments in the embryonic fruit fly.
Lewis, Nüsslein-Volhart and Wieschaus were able to identify, localize and classify a small
group of genes responsible for the control of early embryonic development of the fruit fly,
Drosophila melanogaster. This small group of genes was shown to be responsible in
determining the body plan and the formation of body segments in the embryonic fruit fly.
The Winners
Edward B. Lewis was born on the 20th of May 1918 in Wilkes-Barre, Pennsylvania. He
finished his early schooling in Meyers High School. He then received his B.A. degree in
Biostatistics from the University of Minnesota in 1939 and his Ph.D. from the California
Institute of Technology in 1942. He served the United States Army Air Force for three years
as a meteorologist and oceanographer.
Lewis joined the Caltech faculty in 1946, appointed professor of Biology in 1956, and named
Thomas Hunt Morgan professor of Biology in 1966. He received multiple awards including
Gairdner Foundation International award in 1987, Wolf Foundation prize in medicine in 1989,
Rosenstiel award in 1990, Albert Lasker Basic Medical Research Award in 1991, and Louisa
Gross Horwitz prize in 1992. Most of his famous researches contributed a lot to the field of
developmental genetics. He died on the 21st of July 2004.
Christiane Nüsslein-Volhard was born on the 20th of October 1942 in Magdeburg, Germany.
She earned multiple degrees: biology, physics, and chemistry from Johann Wolfgang Goethe
University in 1964. She then received her diploma in biochemistry from Eberhard Karls
40
University in 1968.
In 1973 Nüsslein-Volhard earned her Ph.D. in biology and genetics from the University of
Tübingen. She then received her first independent research position at the European
Molecular Biology Laboratory in Heidelberg, Germany. She got acquainted with Eric F.
Wieschaus who was also finishing his training. Because of their common interest in
Drosophila, Nüsslein-Volhard and Wieschaus decided to work together to find out the
mechanisms behind genetic control of embryonic development, such a challenging task for
two newcomers in the field of developmental genetics. Eric F. Wieschaus was born on the 8th
of June 1947 in South Bend, Indiana. He then enrolled at the University of Notre Dame for
college. In his sophomore year at Notre Dame, he needed money and found a job preparing
fly food in a Drosophila laboratory run by Professor Harvey Bender. In Bender's lab, he
encountered his first fruit flies and learned basic genetics. He graduated magna cum laude
with his bachelor's degree in biology from the University of Notre Dame in 1969 and his
doctorate from Yale in 1974. His doctoral dissertation involved using genetic methods to label
the progeny of single cells in fly embryos.
In 1978, Wieschaus moved to his first independent job at the European Molecular Biology
Laboratory in Heidelberg. This gave him a chance to work with Christiane (Janni) Nüsslein-
Volhard on the embryologic development of fruit flies. He then became an assistant professor
of biology in Princeton University in 1981, associate professor of biology in 1983 and a
professor in Princeton University in the year 1987.
The Discovery
Nüsslein-Volhard and Wieschaus started their research in the late 1970's. The pair wanted to
find out how the newly fertilized Drosophila egg developed into a segmented embryo. They
opted to use the fruit fly Drosophila melanogaster as their experimental system due to its
extremely rapid embryologic development. The fruit fly only needs nine days to undergo
complete development and they only have one set of genes that control development
compared to the four sets that humans possess.Their main goal was to isolate specific genes
that are responsible for the embryo’s early development. Their first step was to damage the
male flies’ DNA. Then, they “knocked out” one gene from the fly and bred generations of fruit
flies without this particular gene. By the use of this method, they were able to isolate particular
genes and observe its effects on future mating. After which, these male flies mated with
normal female flies which often produced dead and mutated fly embryos.
After testing approximately 20000 fly genes, they found 150 genes that were essential in the
genetic control of embryonic development. Out of that 150, they found 15 genes that, if
mutated, would cause defects in fruit fly segmentation. They even went further, classifying
these genes into groups based on their effects on segmentation. First, gap genes control the
41
body plan along the head-tail axis. Loss of gap gene results in a reduced number of body
segments. Second, pair rule genes affect every second body segment. Loss of this gene
known as "even-skipped" will result in an embryo consisting only of odd numbered segments.
Lastly, segment polarity genes affect the head-to-tail polarity of individual segments.
On a completely separate laboratory, Lewis was conducting an independent research on the

reasons behind the most common mutation in Drosophila, the development of an extra pair of
wings instead of halters, the fruit fly’s organ of balance. By mutating fly embryos so that the
flies developed extra pairs of wings, Lewis found that it was not only the wings that were
duplicated in the mutated flies, but the whole body segment that contained the wings.
Lewis found that the gene responsible for this development belong to a family of genes known
as bithorax-complex that controls the segmentation of the fly along the longitudinal axis. He
also found that the genes at the beginning of the gene complex controlled the development of
an anterior body segment and the genes are the end of the gene complex controlled the
development of a more posterior body part. This is the foundation of the colinearity principle.
He also found that the body regions controlled by genes overlapped. This means that if a
gene was knocked out, the genes that are proximal to it might take over its controlled region.
The reason why this discovery had great impact in medicine was the fact that the genes
discovered by Lewis, Nüsslein-Volhart and Wieschaus have their counterparts in higher
organisms, especially in the genome of human. These counterpart genes in men performed
similar functions during development. This discovery could help other scientists find genes
that could explain birth defects in humans.
The applications of their research extend to in vitro fertilization, identifying congenital birth
defects, and increased knowledge of substances that can endanger early stages of
pregnancy. Because of our knowledge on the genetic control of embryonic development, we
can also develop ways to treat patients with high risks of giving birth to babies with congenital
defects.
Explorable.com (Nov 20, 2011). Genetic Control Of Embryonic Development. Retrieved from
Explorable.com: https://explorable.com/embryonic-development
42
13 Signal Transduction In The Nervous
System
Carlsson, Greengard and Kandel received the Nobel Prize in Medicine or Physiology in
2000 for their discoveries concerning the signal transduction in nervous system.
Arvid Carlsson was awarded the Nobel Prize for his discovery of the neurotransmitter
dopamine and its clinical relevance to a condition known as Parkinson’s disease. Paul
Greengard was awarded the Nobel Prize for his contributions on the mechanism of action of
dopamine and other neurotransmitters. Lastly, Eric Kandel was rewarded for his discovery of
the molecular mechanisms in the formation of short-term and long-term memory.
Basics of Signal Transduction in Nervous System

The human nervous system is made of billions of receptors, neurons and effectors. The
neuron is basically composed of three parts, the dendrites which receive the incoming
information, the soma or the cell body which processes the received information and the axon
which sends out the information to another neurons or effectors.
The information from one neuron is passed on to another neuron or to an effector through
small special gaps or spaces called synapses.
A neuron can have thousands of such special gaps or synapses with other neurons. These
gaps or synapses are bridged by chemicals known as neurotransmitters. These are chemicals
that are synthesized in the neurons, stored in synaptic vesicles, released in the synapses;
transfer the information by binding to its receptors in the other neuron to start a cascade of
events leading to a specific response.
The Winners
Arvid Carlsson was born on the 25th of January 1923 in Uppsala, Sweden. His family had a
very strong orientation to the humanities but at a young age, he thought that science is more
useful than arts. Because of this line of reasoning, he entered Lund University to take up
medicine in 1941. He earned his M.D. in 1951 due to the effects of WWII. He then became of
43
professor in Lund University and in 1959, a professor in the University of Gothenburg. In
1957, despite the worldwide accepted fact that dopamine was only a precursor of
norepinephrine, he proved the dopamine was a neurotransmitter in itself and not just a
precursor of other neurotransmitters.
Paul Greengard was born on the 11th of 1925 in New York City. It was not a completely
delightful day for their family since his mother died while giving birth to him. Greengard
attended public schools in Brooklyn and Queens. After the Second World War, he attended
Hamilton College in New York and majored in mathematics and physics. He then developed
an interest in Biophysics and participated in a research headed by Detlev W. Bronk who used
electrophysiological techniques to study nerve function. In 1953, he earned his Ph.D. in John
Hopkins University. From 1953-1959 he conducted postdoctoral studies in biochemistry at
University of London, Cambridge University, and National Institute for Medical Research,
England.
Eric Kandel was born on the 7th of November 1929 in Vienna, Austria. He entered Harvard
University and majored in Literature and History. He then became interested in learning and
memory despite the fact that Harvard was dominated by B.F. Skinner, a well-known
Psychologist of that time who pioneered on experimental conditioning. In 1952, he entered
New York University Medical School and his fascination to the human mind became firmer. In
1960, he became a resident in Psychiatry in Harvard Medical School and a staff Psychiatrist
in 1964.
Discovery of Dopamine as a Neurotransmitter and Its

Relevance to Parkinson’s Disease
In the 1950's, scientists thought that dopamine is just a precursor of norepinephrine or
noradrenaline. This line of thinking was completely changed when Arvid Carlsson developed
an assay used to measure the amount of dopamine contained in specific tissue samples. His
research found that dopamine was highly concentrated in an area of the brain called basal
ganglia, especially in substantia nigra. Furthermore, he found that the level of dopamine in
this structure was higher compared to its noradrenaline content. These results led him to a
conclusion that dopamine in itself is a neurotransmitter and not just a precursor other
neurotransmitters.
Basal Ganglia, the part of the brain with high dopamine content, is of particular importance in
the control of fine motor behavior. In his succeeding experiments, he introduced reserpine, a
chemical used to deplete the storage the neurotransmitters including dopamine, to different
animals. He noted that the animals showed inability to perform spontaneous movements,
presumably due to the depletion of dopamine. Carlsson showed that the animals which lost
44
normal motor behavior, if subjected to L-dopa which is a precursor of dopamine, resumed
normal movements which are associated with normal levels of dopamine in the brain. There is
also a human condition characterized by tremors, rigidity and reduced ability for spontaneous
movements, similar to what the animals displayed in the study. This condition is called
Parkinson’s disease. It is caused by the degradation of dopaminergic neurons in the basal
ganglia.
Discovery of Mechanisms Involved in Slow Synaptic

Transmission
There are two types of synaptic transmission: fast synaptic transmission that lasts for a short
duration with an electrical nature and slow synaptic transmission which lasts for a longer
duration with a chemical nature. Slow signal transduction in nervous system involves an
action potential that causes the secretion of a chemical substance called neurotransmitter by
the presynaptic cell. The secreted neurotransmitter then binds to its specific receptor on the
postsynaptic membrane of the other neuron to initiate a cascade of events leading to a
specific response.
Paul Greengard showed that slow synaptic transmission involved phosphorylation of certain
proteins, particularly in synapses. He demonstrated that when dopamine stimulates its
receptor in the postsynaptic membrane, it causes an increase in cyclic AMP or CAMP which is
a secondary messenger. The increase in intracellular CAMP levels causes an increase in
Protein Kinase A levels or PKA. The high intracellular PKA level causes phosphorylation of
certain proteins in the nerve cell. Phosphorylation is a process wherein a phosphate group is
added to the structure of the protein thus changing its shape and function.
Discovery of Model System for Learning

Signal transduction in nervous system is highly dependent on the plasticity of the synapses.
Synaptic plasticity is described as the ability of the synapses to undergo alterations. It involves
restructuring of synapses for long-term changes, and depends partly on phosphorylation of
proteins, especially synapses. In the research conducted by Kandel, he was able to
demonstrate that short-term and long-term memories are located in the synapse and are
mostly governed by synaptic plasticity. He also showed that changes in the shape and
function of the synapse are central to learning and memory.
45
He used the simple protective reflex that protects the gills of a sea slug, Aplysia, to study its
basic learning mechanisms. Kandel noted that some stimuli resulted in the amplification or
strengthening of the protective reflex of the sea slug. He observed that this reflex amplification
endured for days, even weeks after stimulation and was thus considered a form of learning.
Kandel was also able to differentiate the mechanisms behind long-term memory and short-
term memory. He showed that weaker stimuli cause the development of short-term memory.
The mechanism behind the development of short-term memory involves an alteration in the
calcium channels causing an increase in intracellular calcium levels in the presynaptic
membrane. This triggers an increase in the release of neurotransmitters into the synapse
causing an amplification of the reflex. On the other hand, a stronger stimuli cause the
development of long-term memory. Stronger stimuli cause an increase in CAMP levels which
increases intracellular PKA. These signals reach the nucleus of the nerve which leads to an
increase in the synthesis of certain proteins. If the synthesis of these proteins is inhibited, long-
term memory is blocked but short-term memory is not affected.
Clinical Relevance
The discovery regarding signal transduction in nervous system triggered a lot of researches
that led to an understanding of the mechanisms involved in several neurological disorders and
consequently helped in the development of new drugs and therapies for the treatment of
these disorders. Researches targeting the cure of Parkinson’s disease and the loss of
learning or memory are main results of this discovery. So far, there is no absolute cure for
these diseases and any progress made in this area is a significant step forward towards the
amelioration of human sufferings due to these neurological disorders.
Hopefully, future research in this area lead to the development of new drugs and therapies
that can serve as permanent and absolute cure for these diseases.
Explorable.com (Sep 6, 2010). Signal Transduction In The Nervous System. Retrieved from
Explorable.com: https://explorable.com/signal-transduction
46
14 Cell-Mediated Immune Response
Peter Doherty and Rolf Zinkernagel were awarded the 1996 Nobel Prize in Physiology
or Medicine for their discovery of the specificity of the cell-mediated immune response
mounted by our immune systems against viruses. They were particularly able to
identify the mechanism behind the recognition of self molecules against foreign and
harmful organisms.
Doherty and Zinkernagel discovered how white blood cells, especially T-lymphocytes,
recognize and kill virus-infected cells. Their discovery offered a great deal of information to
clinical medicine especially in the field of immunology and virology.
Background
Try to imagine the environment that we live in. We are surrounded by a wide array of
microorganisms that are always present in our environment. Our only defense from these
harmful microorganisms is our immune system.
Our immune system is basically composed of various interdependent cells that act to protect
our body from parasitic, bacterial, viral and fungal infections. Their main purpose is to
eliminate foreign and harmful microorganisms along with infected cells and keep all self-
molecules safe from infection. To be able to perform this task, the immune system must be
able to detect, recognize and differentiate molecules from the harmful microorganism from
normal self molecules. The immune system cannot simply destroy everything in its path
regardless of the nature of the target cells and tissues.
Lymphocytes are one of the primary components of our immune defense. There are two types
of lymphocytes, the B-cells and the T-cells. B-cells are responsible for our humoral immune
response while T-cells are responsible for out cell-mediated immune response. B-cells were
already widely understood during the 1970's. Scientists have already discerned how
antibodies work against foreign bodies such as bacteria. The less understood topic during that
time was cell-mediated immune response and how cellular immune effectors recognize and
kill virus-infected cells without harming normal healthy cells.
47
The Winners
Peter Doherty was born on the 15th of October 1940 in Brisbane, Queensland. He attended
the Indooroopilly State High School. He earned his BVSc (Bachelor in Veterinary Science) in
1962 from the University of Queensland. He also received his MVSc master’s degree in
veterinary science in 1966 from the same university. He then attended University of Edinburgh
in Scotland for his Ph.D. which he finished in 1970. After receiving his Ph.D., he went back to
Australia and conducted research on immunology at John Curtin School of Medical Research
in Canberra.
Rolf Zinkernagel was born on the 6th of January, 1944 in Riehen, a village near Basel,
Switzerland. At an early age, his mind was already set to pursue medicine and become a
doctor. He studied medicine in the University of Basel and earned his M.D. in 1970. He
became a visiting fellow in the Department of Microbiology in John Curtin School of Medical
Research from 1973-1975. It is during this time that he collaborated with Peter Doherty. It was
also due to their scientific interaction that he chose to enroll as a Ph.D. student at the age of
28 at ANU. He received his Ph.D. from Australian National University in 1975.
The Specificity of Cell-Mediated Immune Response

The main goal of the research conducted by Peter Doherty and Rolf Zinkernagel was to study
how the immune system, particularly T-cells which are involved in cellular immune response,
could protect mice from a virus that causes LCM or Lymphocytic Choriomeningitis. Doherty
and Zinkernagel injected LCM-immune T-cells into immunosuppressed, virus-infected
recipients. The T-cells home equally well to lymphoid tissue of mice from the same strain and
mice from another strain. Surprisingly, they found that the T-cells continue to multiply only in
the mice from the same strain. This means that replication is not triggered by the virus, but is
dependent on the thymus-derived lymphocytes exposed to histocompatible, virus-infected
target cells.
In a similar study, they also found that the T-lymphocytes, despite their reactivity with the
virus, were not able to kill the virus-infected cells from a different strain of mice. This means
that being infected with the virus is not the only factor considered by the T-cells for them to
attack the virus-infected cells. The virus-infected cells must also be histocompatible with the T-
cells. This means that T-cells from a strain of mice will not attack virus-infected cells of
another strain of mice because they are not histocompatible.
The next logical question is how does the T-lymphocyte recognize histocompatible virus-
infected cells? The answers to their question were proteins encoded by the Major
Histocompatibility Complex that are expressed on the surface of cells which displays self
48
antigens. This histocompatibility antigen enables the T-cells to recognize self molecules.
Integrating all the results that they were able to gather, they concluded that the cellular
immune response needs to simultaneously recognize both foreign molecules and self
molecules via histocompatibiliy antigens.
Succeeding researches conducted by other scientists showed that if a cell is infected by a

virus, a small part of that virus is displayed bound to the cell’s histocompatibility antigen on the
cell’s surface. The complex formed by the virus and histocompatibility antigen serves as the
signal for the T-cell receptors to recognize the virus-infected cells.
Clinical Relevance
The most immediate impact of this discovery was on the field of research. As mentioned
above, the discovery of the virus-histocompatibility antigen complex was triggered by this
discovery. Our increased knowledge concerning the specificity of cellular immune response
enables us to strengthen beneficial immune reactions. On the other hand, that same
knowledge also enables us to diminish or change unwanted immune reactions towards the
body's own tissue, such as those occurring in rheumatic diseases. This discovery also
triggered the development of new vaccines that will protect us against all these infectious
diseases.
Explorable.com (Jun 2, 2010). Cell-Mediated Immune Response. Retrieved from

Explorable.com: https://explorable.com/cell-mediated-immune-defence
49
15 Discoveries on the Key Regulators
of the Cell Cycle
In 2001 Leland H. Hartwell, R. Timothy Hunt and Paul M. Nurse were awarded the Nobel
Prize for Medicine or Physiology for their discoveries regarding the key regulators of
cell cycle.
During that time, scientists and researchers all know that the cells in our bodies divide via
cellular division but the mechanisms by which cellular division takes place was still unknown.
They had no idea of specific proteins and signaling pathways responsible for the control and
regulation of the cell cycle.
Basics of the Cell Cycle

Scientists estimate that for every gram of tissue in our body, there are one billion cells in it.
Can you imagine how many cells compose a single human adult?
All the cells in our body came from a single cell, the fertilized egg cell. During our physical
growth, the single fertilized egg cell divides continuously until groups of cells finally make up a
tissue, until groups of tissues finally make up an organ, and until a group of organs finally
make up a living human. All these cannot be done if our cells are not capable of cellular
division.
Cell cycle or cell division cycle is the series of events that happens within the cell leading to its
division. The cell cycle consists of several phases.
First is the G1 phase wherein the cell grows bigger until it finally reaches a critical size to
enter the next phase, the S phase. During this phase, the genetic materials are duplicated and
a copy of the chromosomes is formed. Next is the G2 phase wherein the cell checks if the
duplication of the chromosomes is complete and there is further growth in the size of the cell.
Next comes the M phase or mitosis phase wherein the cell divides to produce two identical
daughter cells. Not all cells in the G1 phase automatically proceeds to the S phase, most of
the cells exit the cell cycle and enters a resting phase or G0.
50
The Men Behind the Discovery
Leland Hartwell was born on the 30th of October 1939. During his childhood, he was an avid
collector of bugs, butterflies, lizards, snakes and spiders. His major break was when he took
the entrance exam on California Institute of Technology and he fell in love with the
environment of real sciences. He graduated in 1961 and went to MIT for graduate school and
he decided to work on gene regulation. He then became a professor in University of California
and in the University of Washington.
Timothy Hunt was born on the 19th of February 1943 at Neston near Liverpool. He earned his
B.A. in the University of Cambridge in 1964 and his Ph.D. also in the University of Cambridge.
Sir Paul Nurse was born on the 25 of January 1949. He earned his B.sc. in the University of
Birmingham in 1970 and his Ph.D. in the University of East Anglia three years after. He
became the Director-General of the Imperial Cancer Research Fund in London and became
the head of the cell cycle laboratory.
The Seminal Discovery

Leland Hartwell was the pioneer of studying cell cycle using genetic methods. He made use of
the yeast Saccharomyces cerevisiae as the subject of his experiments. In the year 1970, he
tried to isolate individual gene that he thought were vital in the control of cell cycle.
Successfully, he was able to isolate cells wherein the cell cycle regulator genes were
dysfunctional. By the use of this same method, he was able to isolate more than a hundred
genes that were directly involved in the control of cell cycle. He called these genes CDC gene
which stands for cell division cycle genes. Among the hundreds of CDC genes that he was
able to isolate, he noted CDC28 gene for it was observed to control the first step of the cell
cycle, progression from the G1 phase. For this function he named the gene, “start.” He also
introduced the concept of “checkpoints” wherein the cell cycle stops to check whether the
DNA was perfectly duplicated.
The primary focus of the research of Sir Paul Nurse was to identify rate controlling steps in the
cell cycle. He used a different type of yeast, Schizosaccharomyces pombe, as the subject of
his experiments. In the 1970s, he discovered the CDC2 gene. With the help of his friend
Pierre Thuriaux, they were able to prove that CDC2 gene was a rate limiting step controlling
the onset of M phase.
On another study, he was trying to find a gene that also controls the transition from G1 to S
phase similar to what Hartwell found. As a negative control for this experiment he used CDC2
mutants which he thought would block cell cycle progression from G2 to M phase.
51
Surprisingly, his negative control always gave significant positive responses. He thought that
his experiment was flawed and hypothesized that CDC2 was required twice in the cell cycle,
first in the transition from G1 to S phase and from G2 to M phase. What he thought to be a
faulty experiment turned out to be completely accurate.
Serendipitously, he found that CDC2 gene was also a rate limiting factor for the onset of S
phase and M phase. In 1987, he also isolated the corresponding gene in humans which he
called CDK1. This gene encodes for a protein that is a member of the cyclin dependent kinase
CDK family.
In the early 1980s, Tim Hunt discovered the first cyclin molecule. He made use of another
organism in his experiments, Arbacia, a sea urchin. In his experiments, he found strange
bands with a basic behavior of strange disappearance which turned out to occur about 10
minutes before each cellular division. He called these bands cyclins because the levels of
these proteins vary periodically during the cell cycle. Cyclins are proteins that are formed and
then degraded during each cell cycle. This explains their varying levels.
The cyclins bind to the CDK molecules, thereby regulating the CDK activity and selecting the
proteins to be phosphorylated. Cyclins have no catalytic activity and CDKs are inactive in the
absence of its partner cyclin. When a CDK is activated by its partner cyclin, it activates or
deactivates proteins that in turn control the entry of cells into the next phase of the cell cycle.
This discovery has great impact in cancer research. Chromosome alterations can be caused
by faulty cell cycle control, defective S phase or uncontrolled cyclin-CDK activation. These
chromosomal abnormalities are directly related to the development of cancer cells.
Developments in the field of cancer diagnosis via this discovery include the fact that detecting
increased levels of CDK-molecules and cyclins are sometimes found in human tumors like
breast cancer and brain tumor. In the field of cancer therapy, inhibitors of CDK-molecules are
now being tested for its effects in cancer treatment.
52
16 Programmed Cell Death
The Nobel Prize for Medicine or Physiology of 2002 was awarded to Sydney Brenner, H.
Robert Horvitz and John E. Sulston for their discovery regarding gene regulation of
organ development and programmed cell death or apoptosis.
Using the nematode Caenorhabditis elegans, the three scientists were able to identify genes
that are responsible for regulation of organ development and apoptosis and they were also
able to show that these genes are also present in more complex species like humans.
Basics in Organ Development and Programmed Cell

Death or Apoptosis
Everything starts with the union of the egg cell and the sperm cell to form an embryo. The
fertilized egg will then undergo mitosis which will cause a rapid exponential increase in the
number of cells in the developing embryo. Each cell will develop into a more specialized type
of cell so that it can perform specific functions. An aggregation of cells performing similar
functions is called a tissue. A group of tissues all directed to a common function is called an
organ. Organ development is the process wherein individual cells develop into specific types
of cells for them to be more equipped in performing the functions of their respective organs.
During the process of bodily growth, organ development and continuous cellular division
which are all constructive processes, there is also a co-occurring destructive process called
programmed cell death or apoptosis. Programmed cell death is a regulatory process to
maintain the appropriate number and age of cells present within a tissue. There must always
be a balance between cellular division and cell death to ensure the viability of the species.
The Researchers Who Contributed to the Discovery

Sydney Brenner was born on the 13th of January 1927 in Germiston, South Africa. He
immediately became addicted with chemistry and collected test tubes and other glassware at
home. He then decided to pursue medicine and took courses on Anatomy and Physiology. He
became the director of Medical Research Council Laboratory of Molecular Biology in England.
H. Robert Horvitz was born on the 8th of May 1947. He finished his M.A. and Ph.D. in Biology
53
at Harvard University. He then became a professor of Biology in MIT Cambridge and an
Investigator in Howard Hughes Medical Institute, MIT. He also received numerous awards like
Spencer Award in Neurobiology, U.S. Steel Foundation Award in Molecular Biology and Ciba-
Drew Award for Biomedical Science.
John E Sulston was born on the 27th of March 1942. He is the son of an Anglican priest and a
teacher of English. He got a scholarship to Merchant Taylors and immediately loved the
sciences. He then studied at Cambridge with another scholarship. In 1963, he finished his
B.A. at the University of Cambridge. Three years after, he finished his Ph.D. in the same
university.
Contributions to the Discovery
Sydney Brenner and C. Elegans
Sydney Brenner was the pioneer of the entire series of researches. He was the one who
established Caenorhabditis elegans as the ideal and most suited organism for their
experimental trials. He thought that if he wanted to observe organ development and cell
death, he cannot use unicellular models like yeast and bacteria since it is very difficult to study
organ development and the interplay between different cells in such organisms. Furthermore,
he noted that using mammals in his study will also be difficult since the organism is too
complex and there is enormous number of cells that must be studied. He wanted to limit his
study to a manageable organism and he chose to use the nematode C. Elegans since it is not
too complex or too simple.
The worm is approximately 1mm long, has a short generation time and is transparent allowing
direct viewing of cell division under the microscope. In his studies in the early 1970s, he was
able to show that specific gene mutations can be induced in the genome of the worm by using
the chemical EMS or ethyl methane sulphonate. By the use of this method, he was able to
induce specific gene mutations that caused direct effects on organ development.
John Sulston and C. Elegans Cell Lineage
A few years after the study of Brenner on C. elegans, John Sulston developed techniques to
view the process of cellular division from the fertilized egg of C. elegans to the 959-cell adult
worm. He specifically targeted the development of the nervous system of the worm. He was
able to conclude that the cell lineage is invariant. This means that all the worms he observed
underwent exactly the same process of cell division and differentiation. He also noted that
during the process of cellular differentiation, there is a co-occurring cellular death that is tightly
regulated by the organism. Furthermore, he was able to distinctly identify steps in cellular
death and a gene that participates in programmed cell death, nuc-1 gene. His succeeding
54
studies showed that the nuc-1 gene was responsible for the degradation of the genetic
materials in the dead cell.
Robert Horvitz and a Genetic Program Controlling Death
Robert Horvitz followed up on the discoveries of Brenner and Sulston. He wanted to know if
there is an internal genetic program in every cell that controls programmed cell death or
apoptosis. In his investigations on C. elegans, he found that ced-4 and ced-3 genes
participate in the execution of cellular death. These are the two death genes that he was
searching for. He also found that every cell needs a functional ced-3 and ced-4 to undergo
programmed cell death. Moreover, he also showed that ced-9 gene acts as an inhibitor to the
two death genes. One of his most stellar contributions was proving that there exists a ced-3
like gene in the genome of humans. This entails that the death genes he found in the genome
of C. elegans can possible have counterparts in our own genome.
Clinical Applications
One of the most obvious applications of this discovery is the control of cancer development.
Numerous researches are being conducted to discover ways to control the activities of these
genes. If we can develop a technology that can stimulate death gene activity in cancer cells,
this may provide us a way to cure cancer. If we can also learn how to stimulate ced-9 gene
activity, we can address neurodegenerative problems that are characterized by massive
cellular death.
These technologies or drugs can lead to the survival of cells that are normally destined to die.
Lastly, these discoveries proved to be very important in the field of medical research
especially in the pathogenesis of many diseases.
Explorable.com (Apr 7, 2010). Programmed Cell Death. Retrieved from Explorable.com:

https://explorable.com/programmed-cell-death
55
17 Discoveries on Magnetic Resonance
Imaging (MRI)
Cumulative discoveries in the field of Nuclear Magnetic Resonance paved the way to
the development of the most advanced, safe, and non-invasive method in diagnostic
imaging used in medicine today, the MRI or Magnetic Resonance Imaging.
These developments pioneered by Paul Lauterbur and Peter Mansfield gave them the
recognition of their lifetime, the Nobel Prize in Medicine or Physiology in 2003. Together, they
were able to develop a non-invasive method of visualizing bodily structures without the use of
ionizing radiation.
Prior Advancements in Nuclear Magnetic Resonance

The first successful experiment in Nuclear Magnetic Resonance or NMR was conducted in
1946. Felix Bloch and Edward Mills Purcell showed that the resonance phenomenon is
dependent on the simple relation between the intensity of the magnetic field and the
frequency of the radio waves. Furthermore, they proved that for every type of atomic nucleus
with unpaired protons, there exists a mathematical constant by which it is possible to
determine the wavelength as a function of the strength of the magnetic field. The discovery
was named Nuclear Magnetic Resonance because first, only the nuclei of certain atoms
reacted that way, second, a magnetic field was required and lastly, because of the direct
frequency dependence of the magnetic and radiofrequency fields. For this discovery, they
were awarded the Nobel Prize for Physics in 1952.
During the late 1960s and early 1970s, a physician named Raymond Damadian showed that
an NMR tissue parameter of tumor samples which he called T1 relaxation time, measured in
vitro, was significantly higher compared to normal tissues. He used NMR not as an imaging
technique, but as a method for tissue characterization. His method help differentiate benign
from malignant tumors. He was also the first to apply NMR technology to the field of medicine.
The Inventors and Their Contributions

Paul Lauterbur was born on 1929 in Sydney and during his childhood, he immediately
56
developed a passion for chemistry. He graduated with a BS in Chemistry from Case Institute
of Technology. After graduation, he began to learn about nuclear magnetic resonance from
various visitors and speakers. This gave him the inclination to conduct researches about NMR
technology.
Lauterbur’s groundbreaking discovery was the imaging technique which he called

zeugmatography. This imaging technique joins together a weak magnetic field with a stronger
magnetic field allowing a spatial localization of two test tubes of water, one with ordinary
water, the other with heavy water. He used a back projection method to produce a cross
section image of tubes with ordinary water surrounded by heavy water. This made it possible
to build up two-dimensional pictures of structures that could not be visualized with other
methods. This imaging experiment moved from the single dimension of NMR spectroscopy to
the second dimension of spatial orientation being the foundation of MRI. He then continued
imaging living animals like tiny crabs and in the year 1974, he was able to image the thoracic
cavity of a living mouse.
Sir Peter Mansfield was born on the 9th of October 1933 in London. At the age of 18, he
developed an interest in rocketry. In 1956, he attended Queen Mary College, University of
London and took up Physics. One of the projects assigned to him during those years was to
develop a portable NMR spectrometer to measure the earth’s magnetic field. It was because
of this project that he became acquainted with NMR technology.
Sir Peter Mansfield was initially looking into using NMR to obtain complete structural details of
crystalline materials via a similar field gradient scheme. In 1976, he further developed the use
of field gradients in the magnetic field. He also developed a way to mathematically analyze
the feedback signals and transform the data into an image. He named this extremely rapid
imaging technique echo-planar imaging.
What Do We Know Now About MRI

Magnetic Resonance Imaging or MRI is now considered as the most powerful, most sensitive
and safest method in medical diagnostic imaging. Unlike its predecessor, the CT and X-ray,
MRI does not use ionizing radiation making it perfectly safe for the patients. MRI can image
literally any internal part of the body but it is specifically used to evaluate organs of the chest
and abdomen, the pelvic organs including the reproductive organs, blood vessels and most
especially the human brain and spinal cord.
How does it Work
A great majority of our body is composed of liquids more specifically, water. Each water
molecule if composed to two hydrogen nuclei. When a patient enters the magnetic field of the
MRI, the magnetic moments of the protons in the hydrogen nuclei align with the field. A radio
57
frequency transmitter is then turned on to produce an electromagnetic field. The photons in
this field have resonance frequency to flip the spin of the previously aligned protons. The field
is then turned off to allow the protons to return to their original state and the difference in
energy of the two states of the proton is released as a photon. These photons are then
detected by the scanner. Images are formed because the protons in the various tissues of our
body return to their original states by releasing various amounts of energy at different rates.
MRI’s Immediate Use in the Field of Medicine
Starting from the 1980s, the use of MRIs became widely spread in the field of medicine. In the
year 2002, more than 22, 000 MRI were already in use worldwide and more than 60 million
examinations using the MRI were already performed. This success of the MRI as a diagnostic
imaging technique is attributable to its effectiveness and safety.
MRI has been proven valuable in diagnosing conditions like cancer, heart and vascular
disease, muscular and bone abnormalities and brain/spinal cord abnormalities. It is also an
outstanding preoperative tool since with an MRI; surgeons can already locate the lesion within
the body of the patient even before starting the surgery. It also reduces the discomfort of
patients especially in cases like pancreatic and bile duct abnormalities.
The only downside of the use of MRI is its high cost compared to the much cheaper X-rays
and CT Scans. Also, patients with metal in the body or pacemakers cannot undergo MRI
because of its magnetic nature.
Explorable.com (Sep 9, 2010). Discoveries on Magnetic Resonance Imaging (MRI). Retrieved

from Explorable.com: https://explorable.com/magnetic-resonance-imaging
58
18 Discovery Of The Odorant Receptor
Richard Axel and Linda Buck were the recipients of the 2004 Nobel Prize in Medicine or
Physiology for their study which shed light on odorant receptors and its role on how
our olfactory system works.
The Organization of the Olfactory System

Axel and Buck discovered a large family of genes responsible for the different olfactory
receptors. They also discovered that there is high specificity when it comes to signal
transduction since all receptors from a single family send impulses to a single glomerulus in
the olfactory bulb. Information from the olfactory bulb is then sent to the different parts of the
brain.
The Importance of the Olfactory System

Olfaction is the process by which we identify chemical substances in the environment via the
olfactory receptors in our olfactory epithelium. This process is one of our vital survival
mechanisms since it helps us differentiate harmful and poisonous foods from healthy foods. It
has been shown that our degree of dependence to our sense of smell is also directly
proportional to the number of odorant receptors in a given species. Fishes, which are not
highly dependent to their olfactory system, only have 100 olfactory receptors while mice,
which are highly dependent to their olfactory system, were found to have 1000 olfactory
receptors and humans have less than 1000 receptors, some of which were lost during
evolution.

Richard Axel was born in Brooklyn, the first child in the family of immigrant parents. During his
early years, he immediately fell in love with biology. During the early 60s, he worked as a
glassware washer in a laboratory to support his college education. He was then fascinated by
Molecular Biology and worked as a research assistant in the same laboratory. After college,
he then decided to attend graduate school in genetics. Before he could finish his graduate
studies, a war started and he decided to go to medical school at John Hopkins University
59
School of Medicine.
Linda Buck was born in 1947 in Seattle, Washington. She initially wanted to be a
psychotherapist so she took psychology in her undergraduate years. Her interest then shifted
when she encountered immunology and decided that she wanted to become a biologist. Buck
is only the seventh woman ever to receive the Nobel Prize in Medicine or Physiology.
The Path Towards the Discovery

During the 1980s, Richard Axel developed a fascination in the problem of perception,
especially towards olfaction. He thought that if genes are the links to what we perceive in the
outside world, then the understanding of these genes can provide important insight to the
manner by which we experience perception. During the same time, Linda Buck was also
fascinated by the unknown mechanism underlying odor detection. She first thought that to
solve her problem, she need to know how the odorants are detected by the nose.
In 1988, Axel and Buck together embarked on a research on odorant receptors, the answer to
both of their questions. During that time, the only things that they know about olfactory
receptors were the following: that odorants depolarize and activate olfactory sensory neurons
in the nose and that olfactory transduction involves G-protein linked receptors which causes
increase in cAMP. Their initial step in the research was to establish three assumptions. First,
since the odorants are known to vary in structure, there would also be a variety of related
odorant receptors which can be encoded by a multigene family. Second, the odorant
receptors are also related to the relatively small set of G-protein receptors which were known
during those times. Third, the odorant receptors are expressed in the olfactory epithelium
where the sensory neurons can be found.
Buck’s method employed a micropipette to empty the contents of an olfactory receptor cell
and then shows exactly which odorant receptor gene was expressed in the given cell. After
multiple trials, Linda Buck was able to come up with experimental data showing that there
were 1000 odorant receptor genes in the rat genome, the largest family of genes in the
chromosome and this gave them the solution to the problem of diversity of odor recognition.
They also noted that the 1000 different genes give rise to an equivalent number of olfactory
receptor types. Furthermore, they also discovered that each olfactory receptor cell only has
one odorant receptor type. Each of these receptors can only detect a limited number of
odorant substances. Receptor cells then send information to glomeruli found in the olfactory
bulb. All similar receptor cells send information to a single, complementary glomerulus. The
glomeruli then relay the information to the other parts of the brain.
Current Information about the Olfactory System.
60
Processes Involved in Olfaction
The very first thing that happens prior to scent perception is the binding of the odorants to the
olfactory receptors. Olfactory receptors are responsible for the detection of odor molecules.
The noteworthy characteristic of the receptor-odorant relationship is that the receptors display
affinity for a range of odorants and not just a single odorant. This means that an odorant can
bind to a number of different receptors but with different affinities. The binding of the odorant
causes structural change to the receptor which activates the G-protein linked receptor in the
receptor neuron. The G-protein then activates adenylate cyclase which will then convert ATP
to cAMP. cAMP will then open calcium and sodium channels that will allow extracellular
sodium and calcium to enter the cells. The depolarization of the cell will begin an action
potential which will transmit the information to the different parts of the brain. From the
olfactory bulb, olfactory information will then be relayed to both the cerebral cortex which will
handle conscious thought processing, and to the limbic system which will generate emotional
feelings. This is also the reason why certain feelings and memories are elicited by the scent of
a certain odorants.
The story of the discovery of Buck and Axel is a great example of how molecular biology can
bring light to mysteries concerning the human brain and its sensory processes. We must
remember that both of the authors are not physiologists, but still, they were able to unravel the
basics of the olfactory system by the use of molecular biology.
Explorable.com (Aug 8, 2010). Discovery Of The Odorant Receptor. Retrieved from

Explorable.com: https://explorable.com/odorant-receptors
61
19 Discovery of Helicobacter Pylori
The Nobel Prize in Physiology or Medicine of 2005 was awarded to Barry J. Marshall
and J. Robin Warren for their discovery of bacterium Helicobacter pylori and its role in
the development of Gastritis and Peptic Ulcer Disease in humans.
This remarkable and paradigm-breaking discovery showed that bacterium Helicobacter pylori
causes inflammation of the stomach or gastritis as well as the ulceration of the duodenum or
the first part of the small intestines that is connected to the stomach. This discovery led to a
radical change in the treatment of Peptic Ulcer Disease which now includes eradication of the
bacteria and not just gastric acid control.
The Prevailing Scientific Knowledge Prior to Discovery

During the 1970s and the early 1980s, scientists, physicians and researchers all thought that
the main cause of Peptic Ulcer Disease or PUD and Gastritis are stress and lifestyle
problems. Lifestyle problem especially excessive alcohol intake was considered as the main
reason behind the development of Peptic Ulcer Disease and Gastritis but even during those
times, there were cases wherein the patients with Peptic Ulcer Disease and Gastritis were not
heavy alcohol consumers. Suspicions and further evidences were raised during the 1980s
suggesting that there is another reason behind PUD and Gastritis.
The Culprits of Paradigm Change

Barry Marshall was born in 1951 in Kalgoorlie, east of Perth, Western Australia. As early as
high school, he was known to have exceptional knowledge in Science and Math but he opted
to pursue Medical School. He graduated MBBS Bachelor of Medicine, Bachelor of Surgery.
After which, he became interested in an academic career combining research and clinical
medicine. He became acquainted with J. Robin Warren during one of his clinical research in
his rotation to gastroenterology division.
J. Robin Warren was born on the 11th of June 1937 in North Adelaide, South Australia. He
enjoyed cycling, photography and rifle shooting during his younger years. During the 1970s,
he developed an interest in the new gastric biopsies from patients suffering from PUD. From
then on, his time was devoted to the study of the biopsies and the bacteria that he found in
62
them.
The Discovery of Helicobacter Pylori

During the 1970s, there was a sudden increase in the incidence of PUD and Gastritis. In the
year 1979, due to his interest in the new gastric biopsies, J. Robin Warren noticed small
curved bacteria growing on the surface of 50% of the gastric biopsies taken. These gastric
biopsies were taken from the antrum of the stomach of the patients. He also noted signs of
inflammation in the area where the bacteria were seen.
Over the next two years, he painstakingly gathered numerous examples of gastric biopsies
with the bacteria and showed that it usually occurs with chronic gastritis. To prove that the
bacteria were in fact the cause of the disease, he wanted to gather negative samples of
gastric biopsies. However, this proved to be difficult since normal gastric biopsies done on the
antrum of the stomach is very rare. But he eventually found 20 samples and none of those
were infected by the bacteria.
Barry Marshall also

intentionally consumed
helicobacter pylori to
support the hypothesis
made. He became infected
with the bacterium,
suffered from symtoms but
was relieved from the
symtoms by use of
antibiotics.
In 1981, Warren met Barry Marshall to talk about the newly found curved bacteria from the
gastric biopsies. This quickly caught the attention of the physician since the study was about
an unreported bacteria thriving in extreme conditions like the extreme acidity of the gastric
environment. After a few meetings, the two gentlemen decided to make a complete
pathological study of the bacteria. Barry Marshall, as a physician, can provide better biopsies,
specimen cultures and endoscopic results of actual patients which will boost the replicability
and reliability of the results that they found. Barry Marshall was successful in cultivating a
hitherto unknown bacterial species from most of the biopsies. Together, the two virologists
found that the bacteria were present in almost all patients with gastritis, duodenal ulcer or
gastric ulcer.
63
What are Helicobacter Pylori?
Helicobacter pylori are gram-negative bacteria that infest the stomach or the duodenum of the
intestines. It is the cause of stomach or duodenal inflammation which is strongly linked to the
development of gastric or duodenal ulcers. H. pylori survive the highly acidic pH of the
stomach by secreting high amounts of urease enzyme which serves as its protective covering.
It is also a highly variable bacterium; even in a single infected patient, all the bacteria are not
identical due to its independent adaptations to the changing conditions in the stomach.
Development of Gastritis and Peptic Ulcer Disease
Colonization of the stomach by Helicobacter pylori is the cause of gastric inflammation or

Gastritis. Gastric and duodenal ulcers occur when the colonization of H. pylori causes
excessive secretion of gastric acids which can then overwhelm the protective mechanisms of
the stomach and intestines.
The type of ulcer depends on the location or site of H. pylori colonization. If the H. pylori
colonize the antrum of the stomach, the inflammatory response of the G cells in the site is to
secrete more gastrin. The increase in gastrin will then trigger the parietal cells in the corpus of
the stomach to produce more gastric acids. Increase in acids damages the duodenum and
ulcerations may occur. On the other hand, if the H. pylori colonize the corpus of the stomach
where the acid secreting cells called parietal cells are located, there will be a marked
decrease in acid production and secretion which will eventually cause atrophy of the stomach
lining which may lead to gastric ulcers.
Diagnosis
The noninvasive methods to test H. pylori colonization are the following: blood antibody test,
stool antigen test and the carbon urea breath test. On the other hand, the more reliable ways
to test H. pylori infection are biopsy during and endoscopic examination with a rapid urease
test, histological examination and microbial culture.
Development in the Treatment of Peptic Ulcer Disease
Previously, the treatments for PUD were antacids, H2-antagonists and proton pump inhibitors.
The discovery of a bacterial cause of PUD triggered an innovation in the treatment of the
disease. The treatment of PUD prior to the discovery of Helicobacter pylori was to inhibit the
secretion of gastric acids but it will usually relapse. This is because the treatment was not
directed to the eradication the cause of the disease; instead, it only solved the consequence
64
of the bacterial infection.
Currently, the treatment for PUD incorporates an antibacterial drug that will eradicate the main
cause of the disease. This is called the first-line therapy which is a one week triple therapy
consisting of a proton pump inhibitor such as omeprazole and antibiotics clarithromycin and
amoxicillin.
Explorable.com (Jul 9, 2010). Discovery of Helicobacter Pylori. Retrieved from

Explorable.com: https://explorable.com/helicobacter-pylori
65
20 Discovery Of RNA Interference
The discoveries of Andrew Z. Fire and Craig C. Mello regarding the control of the flow
of genetic information via RNA interference or RNAi, gene silencing by double-
stranded RNA gave them the honor of being awarded the Nobel Prize for Medicine or
Physiology of 2006.
Their seminal discovery gave the scientific community a glimpse on how to regulate protein
production by the degradation of the mRNA that codes for specific proteins.
The Central Dogma – Dna to mRNA to Protein

The DNA is the nervous system of the cell. It controls all the biological processes that take
place within the cell by the genetic information that it contains. To be able to continuously
regulate the biological mechanisms within the cell, the DNA needs to undergo replication, the
first stage of the central dogma. Replication is the process wherein the genetic information in
the DNA is copied to form another DNA containing exactly the same set of information.
The next stage is transcription wherein an equivalent RNA copy is created from the DNA
sequence. Transcription is the first step in the process of gene expression. The DNA
transcribed into RNA encodes for at least one gene. There are approximately 30,000 genes in
our genome but only a small part of it is active in the cell. The process of transcription controls
which gene is expressed and which genes are keep inactive. If the gene transcribed encodes
66
for a protein, the product of transcription is called messenger RNA or mRNA.
The mRNA then migrates from the nucleus of the cell to the cytoplasm where it will be
decoded to produce proteins via the process called translation. Proteins do not code for the
production of protein, RNA or DNA. They are involved in almost all biological activities like in
enzymes digesting our food, receptors receiving signals in the brain, and as antibodies
defending us against bacteria. The entire process of DNA replication, transcription to produce
RNA and translation to produce proteins was called the central dogma of molecular biology by
the British Nobel Laureate Francis Crick.
The Minds Behind RNAi

Andrew Fire was born on the 27th of April 1959 in Santa Clara County California. He studied
in Hollenbeck Elementary School, Mango Junior High School, and Fremont High School. He
earned his AB degree in Mathematics at University of California at Berkeley in 1978. He then
entered Ph.D. program in Biology at MIT. He then conducted a research on gene regulation
during early development of C. elegans. It is through this research that he got acquainted with
the worm C. elegans and the mechanisms behind gene regulation.
Craig Mello was born on the 18th of October 1960 in New Haven, Connecticut. During his
early years, he never had doubts that he will be a scientist when he grew up. He became an
avid reader of science fiction, an amateur astronomer, and a serious student. He pursued
biochemistry and molecular biology at Brown University. After Brown, he went to Colorado for
graduate school where he was introduced to C. elegans. He then moved to Harvard University
and finished his graduate school there.
Discovery of RNA Interference or RNAi
During the research of Andrew Fire and Craig Mello on gene expression in the worm
Caenorhabditis elegans, they found that injecting mRNA that encodes for muscle protein
production elicited no responses from the worms. Bear in mind that the genetic code in the
mRNA is considered as the sense sequence. They also tried to inject antisense RNA into the
worms which can pair with the sense sequence mRNA but it also elicited no responses from
the worms. Finally, when they tried to inject both the sense and the antisense RNA together,
they noted twitching movements from the worms. These results surprised them since they
know that the same kinds of movements were noted from worms whose genes encoding for
muscle protein were dysfunctional.
To explain the results that they got, Fire and Mello hypothesized that the double-stranded
RNA molecule formed by the binding of the sense and antisense RNA silences the gene
carrying exactly the same code as the RNA molecule. To test their hypothesis, they injected
double-stranded RNA that codes for specific proteins. In all their experiments, they found that
67
the genes carrying exactly the same code as the RNA they injected were silenced.
Their discovery on RNA interference is noteworthy for two reasons. First, with RNAi,
researchers can specifically knockdown the production of any protein in a cell. Second,
initially scientists thought that a portion of the DNA called introns were just junk DNA and they
serve very little purpose, buy now they know that much of these introns code for RNAi
elements.
Mechanisms of RNA Interference or RNAi
Double-stranded RNAs or dsRNA are used to silence the expression of target genes via RNA
interference. After introduction of the dsRNA into an organism, it is processed and broken
down into small interfering RNA or siRNA by an enzyme called Dicer. Then, siRNA bind to
RNA-induced silencing complexes or RISCs. The siRNA strands then guide the RISCs to their
complementary RNA where they cleave the cognate RNA leading to a generalized destruction
of the RNA and cessation of protein synthesis if mRNA was the target.
Clinical Relevance of the Discovery

RNAi is an important process in our defence against viruses. A lot of viruses have double-
stranded RNA in their genome and when such a virus infects a cell, it injects its RNA molecule
which will bind to Dicer which will eventually lead to the degradation of the viral RNA.
Other proposed medical uses of RNAi technology is in the field of disease management and
treatment. If we can create double-stranded RNA that can degrade the mRNA of genes
responsible for chronic diseases like hypertension, diabetes, cancer, cardiovascular diseases
and other medical conditions, we can silence these genes and control these diseases.
The only drawback of this application of RNAi is its safety. RNAi has a potential for off-target
effects in which a gene similar to the target gene can also be silenced. Such potential can
cause adverse effects on the health of the patients.
Explorable.com (Apr 7, 2010). Discovery Of RNA Interference. Retrieved from

Explorable.com: https://explorable.com/rna-interference
68
21 Advances in Embryonic Stem Cells
2007 was a very fruitful year for the field of genetic research. During this year, Mario R.
Capecchi, Martin J. Evans and Oliver Smithies were awarded the Nobel Prize in
Medicine or Physiology.
Capecchi, Evans and Smithies won the Nobel Prize for their discovery regarding the principles
in introducing specific gene modifications in mice by the use of embryonic stem cells.
There were two vital discoveries in their research. First is homologous recombination wherein
DNA sequences are exchanged within two homologous chromosomes, one from the mother
and the other from the father. The second key discovery is the use of embryonic stem cells.
Embryonic stem cells can grow and differentiate into any type of tissue present in the body of
the organism from which it was taken.
The Three Brilliant Minds

Mario Capecchi was born 1937 in Italy. During high school, his primary inclination was sports.
He was varsity of football, soccer and baseball. During college, he initially took political
science but switched to physical science physics and chemistry. He finished his PhD in
Biophysics in 1967 at Harvard University. He then became Howard Hughes Medical Institute
Investigator and Distinguished Professor of Human Genetics and Biology at the University of
Utah.
69
Martin Evans was born on the 1st of January 1941. As early as prep school, he was already
exposed to biology. During middle school, chemistry, physics and biology are his inclinations.
During college in Cambridge, he took up biochemistry, finished his PhD in Anatomy and
Embryology in 1969 in London. He then became Director of the School of Biosciences and
Professor of Mammalian Genetics in Cardiff University.
Oliver Smithies was born prematurely on the 23rd of June 1925 in England. He initially
planned to take up physics in college but ended up in a medical school. He then finished his
PhD in Biochemistry in 1951 in Oxford University and became a professor of pathology and
laboratory medicine in the University of North Carolina at Chapel Hill.
Route to Nobel Prize of 2007

The concept of genetically introducing gene modifications in mice via embryonic stem cells
has a pretty straightforward method: create a targeted gene modification in a chromosome of
the embryonic stem cell and use these cells to grow mice that can transmit the chromosomal
changes to their offspring. This method is highly dependent on two genetic principles: the
exchange of specific chromosomal DNA sequences by homologous recombination, and
development of embryonic stem cells that will allow genetic inheritance.
During the process of fertilization, the haploid sperm cell and the haploid egg cell unites to
form a diploid zygote which has a new pair of chromosomes, one from the egg and one from
the sperm. As the zygote develops, the chromosomes recombine with their homologues
derived from the two parents and this process is called homologous recombination.
Homologous recombination provides continuous genetic variation as the species pass their
gametes to the succeeding generations.
In 1985, Oliver Smithies attempted to introduce DNA sequence from the human beta-globin
locus into an erythroleukemia cell line and he found that specific exchange of the introduced
gene with the homologous sequence in the erythroleukemia cell line is possible. This
experiment of Oliver Smithies proved that targeted recombination of genetic materials is
possible.
During the same time of Smithies discovery, Mario Capecchi was able to devise a method to
introduce DNA directly into the nucleus of the target cell by the use of a glass pipette. The
method developed by Capecchi allowed efficient transfer of genetic materials into random
chromosomal locations which also leads into homologous recombination. This was a key
discovery since Capecchi was able to prove that homologous recombination can occur in
somatic cells. In his succeeding studies, he was able to perfectly rescue a genetically mutant
cell by introducing a functional copy of the dysfunctional gene.
70
The next challenge was to be able to ensure heritability of the genetic modifications so that
the changes can be passed on to future generations. The only solution to this problem was to
use a cell line of embryonic origin. Smithies and Capecchi looked into the work of Martin
Evans for the solution. Martin Evans discovered that embryonic stem cells can be taken
directly from early mouse embryos. His next step was to test whether his embryonic stem
cells can actually contribute to the germ line, thus, allow heritability. He proved this by
injecting blastocysts with cultured embryonic stem cells that were infected with a retrovirus
since retrovirus integrates their genes into the chromosome. He found that the retroviral DNA
was detectable in both somatic and germ-line cells of the developed blastocysts.
The collaboration of the three great minds initially aimed to repair defects in the ‘hprt gene’.
They identified and selected cells that have undergone homologous recombination thereby
eliminating the defective gene. This was then implanted into a surrogate mother who gave rise
to a mice strain that is homozygous to the inert gene which they called aknockout mouse. This
work wherein gene targeting is done by homologous recombination while ensuring heritability
of the genetic changes led to the understanding of the function of the genes present in our
genomes.
This method became a norm in genetic research. A lot of researches were done using this
method to explore the functions of different genes. This development made it possible to
study the function of almost any gene in a living animal. Furthermore, given the high degree of
similarity between the mouse and human genomes, this technology of gene manipulation has
important clinical implications. Considering the success of gene targeting in the genome of
mice and its similarity with our genome, it is reasonable to envision clinical applications of a
similar strategy used in medical settings. Maybe it is possible to genetically modify stem cells
to restore the function of a dysfunctional gene in specific tissues. Maybe we can eliminate
genes which are vital in the development of life-threatening diseases like cancer, diabetes,
heart disease, stroke and a lot more. Maybe this discovery is the key to the ultimate goal of
medicine, the eradication of all human diseases.
Explorable.com (Jun 20, 2010). Advances in Embryonic Stem Cells. Retrieved from
Explorable.com: https://explorable.com/embryonic-stem-cells
71
22 Human Papilloma Viruses (HPV) -
Causative Agent of Cervical Cancer
2008 Nobel Prize Medicine (part 1)
Amidst the prevailing medical beliefs, researches and scientific norms during his time,
Harald zur Hausen, proposed a radically different causative agent of cervical cancer,
the Human Papilloma Virus or HPV.
Zur Hausen discovered and proved, amidst all the scepticisms, that a previously unrecognized
subtype of the HPV, HPV 16 and 18, were consistently found in about 70% of cervical cancer
biopsies throughout the world. This discovery gave him the Nobel Prize in “Medicine or
Physiology” in 2008 together with Françoise Barré-Sinoussi and Luc Montagnier for the
discovery of HIV.
The Scientific Paradigm Prior to the Discovery

In the late 1970s, scientists believed that viruses cannot cause cancers. It was a fact back
then. In the early 1980s, this was challenged by the prevailing topics of research during that
decade. The majority of researches during that decade were about herpes simplex virus type
2 (HSV-2) as the causative agent of cervical cancer. HPV during the 1980’s was only known
to be the cause of genital warts and not of cervical cancer.
Dr. Harald Zur Hausen and His Discovery

As a child born in 1936, Harald zur Hausen already has intensive interest in biology and
during that early age, he already wanted to be become a scientist. Due to his passion for
science, he opted to pursue medicine. Medicine gave him the chance to experience surgery,
internal medicine and obstetrics and gynecology. The last part fascinated him the most. He
then left the field of medicine and pursued Medical Microbiology and Immunology.
72
In 1972, he was appointed chairman of the Institute of Clinical Virology in Erlangen-Nürnberg.
During this time, he received different reports stating that there exists malignant wart
conversion into squamous cell carcinomas, cervical cancer. This then triggered the idea that
the cause of genital warts, Human Papilloma Virus or HPV can be the cause of cervical
cancer.
In 1974, he conducted a pilot study that revealed that there are different types of papilloma
viruses. In the following years, he was able to isolating increasing number of Human
Papilloma Virus novel subtypes. In 1979, his co-researchers Lutz Gissmann and Ethel-
Michele de Villiers were successful in cloning the first DNA from a genital wart, HPV-6.
Following HPV-6, they discovered HPV-11. They used HPV-11 as a probe and one out of 24
cervical cancer biopsies turned out to be positive. In these biopsies, unknown faint bands
became visible suggesting that a different subtype of HPV is related to the cancer. The
unknown bands were asked to be cloned and in 1983 and 1984, they were able to isolate
HPV-16 and HPV-18 respectively.
HPV-16 DNA was found to be present in 50% of all cervical cancer biopsies while HPV-18
was found to be present in 20% of the cases. These figures proved that HPV-16 and 18 play
an important role in cervical cancer development.
Importance of the Discovery

More than 500,000 women per year are affected by Cervical Cancer. More than 5% of all
cancers worldwide are caused by a persistent infection of the Human Papilloma Virus or HPV.
There are already more than 100 HPV types that are known to men and 40 of these infect the
genital tract, out of the 40, 15 HPV types put women at high risk for cervical cancer. HPV as
noted to be seen in 99.7% of all cervical cancers in the world. The discovery of Harald zur
Hausen gave us the knowledge about HPV-16 and 18. This discovery paved the way to a
greater understanding of cervical cancer. Furthermore, it led to the development of vaccines
that are now found to be more than 95% effective in protecting women from HPV acquisition.
Cervical Cancer
Vaccines
There are two available vaccines in the market today, Cervarix by GlaxoSmithKline and
Gardasil by Merck. Both of these vaccines protect against the infection of both HPV-16 and
18. But Gardasil also protects against HPV-6 and 11 which causes genital warts. These
vaccines are recommended to 11 and 12 year-old girls and also to 13-26 year-old females.
Both vaccines are delivered 3 times over six months and it is recommended that you take the
73
same brand for the three doses. The vaccines provide little benefits if you are already infected
with HPV. It also has no therapeutic effects on existing HPV infections.
Signs and Symptoms
Most people with HPV infections do not manifest symptoms. In more than 90% of infections,
the virus is naturally clear from the body within two years. But sometimes, HPV can cause
genital warts or worse, cervical cancer. Note that the type of HPV that causes genital warts is
different from the type of HPV that causes cervical cancer. Cervical cancers usually do not
have symptoms unless it is in the advanced stages. This is the reason why women are
advised to get regular cervical cancer screening to detect the cancer during its early stages.
Treatment
There are no treatments available for the virus; treatments are only available for the health
problems that it can cause. Cervical cancer, like all the types of cancer is most treatable
during its early stages so early diagnosis is the key. Women should get routine cervical
cancer screening to detect the cancer even before it develops. The message is prevention is
always better than treatment.
Explorable.com (May 13, 2010). Human Papilloma Viruses (HPV) - Causative Agent of
Cervical Cancer. Retrieved from Explorable.com: https://explorable.com/human-papilloma-
viruses
74
23 Discovery of HIV
Human Immunodeficiency Virus or what is commonly known as HIV was discovered by

Françoise Barré-Sinoussi and Luc Montagnier.
Barré-Sinoussi and Montagnier were awarded the Nobel Prize in “Medicine or Physiology” of
2008 for this discovery together with Harald zur Hausen for the discovery of human papilloma
viruses causing cervical cancer.
Barré-Sinoussi and Montagnier were awarded the Nobel Prize in “Medicine or Physiology” of
2008 for this discovery together with Harald zur Hausen for the discovery of human papilloma
viruses causing cervical cancer.
HIV is the cause of the Acquired Immunodeficiency Syndrome or AIDS that was declared to
be a pandemic by the WHO. The major effect of HIV is the impairment of the immune system
of the infected patient making him prone to other infections. HIV is usually not the direct cause
of the death of the patient with AIDS; the other infections brought by the impaired immune
system are usually the cause of death.
Human Immunodeficiency Virus or HIV and AIDS are the major concerns of most healthcare
oriented research today. From its discovery in the early 1980s to 2006, AIDS already caused
25 million deaths. In 2005, AIDS caused the death of more than 3 million lives and an
estimated 20% of which were children. Moreover, HIV was found to have infected more than
0.6% of the world’s population exclusive of the unreported cases.
Scientific Context Prior to the Discovery

During the late 1970s to the early 1980s, there was a sudden increase in patients, mostly
homosexuals, suffering from an unknown disease. Willy Rozenbaum was one of the first
clinicians in France to observe the alarming new disease and reported it to the Center of
Disease Control. The initial hypothesis about the cause of the new disease was HTLV. HTLV
is Human T-Lymphotropic Virus which is the only retrovirus known during the time. This virus
is known to cause secondary immune depression which is one of the symptoms of their
unknown disease. This hypothesis was proven wrong by the studies of Françoise Barré-
Sinoussi and Luc Montagnier.
75
The Enlightened
Françoise Barré-Sinoussi was born in 1947 in France. She has a PhD in virology and served
as a professor and director of Regulation of Retroviral Infections Unit, Virology Department,
Institut Pasteur in Paris. During the early years of his career, she served only as a volunteer in
a laboratory of a research group led by Jean-Claude Chermann at the Institut Pasteur. Very
quickly after being a part of the group, she was offered a PhD project about the use of a
synthetic molecule which inhibited the reverse transcriptase to control leukaemia.
The other Nobel Prize recipient is Luc Montagnier, born in 1932 also in France. He also has a
PhD in virology and is Professor emeritus and Director of the World Foundation for AIDS
Research and Prevention in Paris. He had major contributions in the field of Viral Oncology,
the ultimate goal of which was the detection of viruses involved in cancer.
Discovery of the Human Immunodeficiency Virus Hiv

The clinical observations pertaining to the new disease suggested that the disease attacked
the immune cells of the patients. The virus causes strong depletion of CD4 lymphocytes that
greatly hindered the isolation of the virus with full-blown AIDS. The way around this problem
was to take sample from a patient with the early signs of HIV infection which is
lymphadenopathy.
During the late 1982, Françoise Brun-Vézinet, a former student of Luc Montagnier, who was
working with Willy Rozenbaum contacted Luc Montagnier, her professor, about this new
disease. Luc Montagnier then organized a research group for the putative retrovirus from the
patient presenting with early signs of the disease, lymphadenopathy. The patient was a young
homosexual who travelled to USA and was consulting Dr. Willy Rozenbaum for swollen lymph
nodes in the neck.
76
The biopsy from the lymph nodes of the patient arrived on January 3, 1983. The lymphocytes
were dissociated from the lymph nodes, T-cell growth factors were added and Montagnier
observed that the T cells grew well. His associates Françoise Barré-Sinoussi and Jean-
Claude Chermann measured the reverse transcriptase or RT activity in the culture medium
every 3 days. During the first week, the samples did not show any RT activity but during the
second with, Françoise detected a weak enzymatic activity which increased significantly
during the next days. Subsequently, the RT activity dropped dramatically as the T
lymphocytes in the culture were dying. To save the culture, they decided to add T
lymphocytes from a blood donor. Successfully, the virus infected the new lymphocytes and
there was a significant increase in RT activity again. The virus was initially names
Lymphadenopathy Associated Virus LAV.
Immediately after the isolation of the virus, amplification and characterization rapidly ensued.
The collective studies and efforts of the virologists, the physicians and the researchers
brought a convincing evidence for the scientific community that the LAV, which will later be
named Human Immunodeficiency Virus HIV, is the causative agent of AIDS.
What Do We Know About Aids
Acquired Immunodeficiency Syndrome or AIDS is characterized by the failure of the immune

system to acts against opportunistic infections. This condition enables other infective agents
to successfully infect the patient with AIDS. Human Immunodeficiency Virus, or HIV, is the
causative agent of AIDS. HIV infects vital cells in the immune system like CD4 T cells causing
a decrease in CD4 T cell levels.
Hiv Transmission
HIV Transmission occurs via blood, semen, vaginal fluid, pre-ejaculate and breast milk. The
major causes of HIV transmission is unsafe sex, use of contaminated needles, breast milk
and the transmission of the virus from the mother to the child during birth. Generally, if an
open wound comes in contact with HIV infected blood, HIV may be transmitted. A correct and
consistent use of condoms can lessen the risk of HIV transmission by around 85%. 12-14% of
babies who breastfeed from infected mothers may acquire HIV. HIV is also found in urine,
saliva and tears but the amount is negligible. It is not possible for mosquitoes to transmit HIV.
Human Immunodeficiency Virus Hiv Diagnosis
HIV testing consists of an initial screening with the use of ELISA to detect antibodies.
Specimens with nonreactive ELISA are reported HIV negative. If the specimens were reactive
77
to ELISA, it will be retested. Specimens that were found to be repeatedly reactive to ELISA
will be subjected to a more sensitive test like Western Blot or IFA. Specimens that are
repeatedly reactive to ELISA and positive by IFA or reactive to Western Blot are considered
HIV positive which is indicative of HIV infection.
Signs and Symptoms
A progressive decrease in CD4 T cell level is associated with HIV infection. The stage of the
infection is characterized by the levels of CD4 T cells and the level of HIV in the blood. The
first stage of infection is the incubation period wherein no symptoms are manifested by the
patient. This stage usually lasts between two to four weeks. The second stage is the acute
infection which includes symptoms like fever, lymphadenopathy or swollen lymph nodes,
pharyngitis or sore throat, rashes and muscle pains. The third stage is the latency stage which
also has no symptoms. The last stage is AIDS with symptoms that are consistent with the
symptoms of the other infections that have already infected the patient. For children, the
primary symptom associated with HIV infection is growth retardation, recurring diarrhea and
lung infection.
Treatment
Currently, there are no vaccines or cure for HIV infection or AIDS. However, an antiretroviral
treatment given immediately after exposure to the virus, which is known as post-exposure
prophylaxis, is found to reduce the risk of HIV infection. The treatment available today is the
Highly Active Antiretroviral Therapy or HAART. The only reliable means to escape infection is
to avoid exposure to the virus. Prevention is always better that cure.
Explorable.com (Mar 23, 2010). Discovery of HIV. Retrieved from Explorable.com:

https://explorable.com/human-immunodeficiency-virus
78
24 Telomeres and Enzyme Telomerase
Telomeres are short fragments of DNA found at the ends of eukaryotic chromosomes.
It caps the ends of chromosomes to protect them during cellular division.
Telomere... a Fountain of Youth?

Multi-awarded scientist Elizabeth Blackburn, her student Carol W. Greider and fellow scientist
Jack Szostak grabbed the 2009 Nobel Prize in Physiology or Medicine for their discovery of
telomeres and the enzyme telomerase.
Telomere... a Fountain of Youth?

Multi-awarded scientist Elizabeth Blackburn, her student Carol W. Greider and fellow scientist
Jack Szostak grabbed the 2009 Nobel Prize in Physiology or Medicine for their discovery of
telomeres and the enzyme telomerase.
Scientific Context Prior to the Discovery

Most if not all the processes that take place in our body is controlled by our genes. The
collection of all our genes is called our genome. This genome is contained in our
chromosomes which are made up of different DNA molecules. During the 1930s, Nobel Prize
winners Hermann Muller and Barbara McClintock observed that chromosomes are prevented
from attaching to each other by a structure found at the ends of the chromosomes, the so-
called telomeres. They thought that the telomeres have protective roles in the chromosome
but its manner of action was still unknown.
79
In the 1950s, when scientists started to learn how genes are copied, a lot more questions
were raised concerning the existence of the so-called telomere. During the process of DNA
replication, all the bases that make up the DNA are copied one by one to create an exact DNA
duplicate. But at the end of the chromosomes, the very end of the strands is not copied. In
1973, the Soviet scientist Alexey Olovnikov then predicted the existence of telomere
shortening. This mechanism states that the very end of the chromosomes, the so-called
telomere, is the one that is not copied during cell division. This means that the telomere
shortens progressively during cellular division.
Multiple Studies Leading to a Nobel Prize

Dr. Elizabeth Blackburn is a professor of Physiology and Biology in the Department of
Biochemistry at the University of California. She was the president of American Society for
Cell Biology in 1998. She was also a fellow of the American Academy of Arts and Sciences in
1991; fellow of the Royal Society of London in 1992; fellow of American Academy of
Microbiology in 1993 and the American Association for the Advancement of Science in 2000.
In Dr. Blackburn’s research, she identified a DNA sequence that was repeated several times
at the very end of the chromosome of the unicellular organism Tetrahymena. During the same
time, unaware of the research of their fellow scientists, Jack Szostak observed that a DNA
molecule which is a type of minichromosome is quickly degraded when introduced into yeast
cells. Jack Szostak made pioneering contributions in genetics especially in the field of
chromosomal recombination.
In 1980, Blackburn presented the results of her research regarding Tetrahymena at a

conference which Jack Szostak also attended. Together, they launched another ground
breaking experiment that crossed the boundaries between two distant species. Blackburn
isolated her DNA sequence from Tetrahymena, they coupled it with the minichromosomes of
Szostak and introduced them into the yeast cells. Surprisingly, the minichromosomes were
80
not degraded by the yeast cells due to the DNA sequence from Tetrahymena. This result
showed a fundamental mechanism involving telomeres that were previously unrecognized.
Carol Greider, a graduate student, along with her supervisor Blackburn initiated a pioneer
study to find out if the formation of telomeres is due to an enzyme. In December 1984, Greider
and Blackburn were able to purify the enzyme that can extend the length of telomeres and
they named it telomerase.
What Do We Know About Telomeres

Telomeres are short, dense fragments of DNA that can be found at the end of the
chromosomes. Telomeres do not contain genes. Their main function is to form a protective
molecular cap that will serve as the defence of the chromosomes during cellular division. You
must keep in mind that during cellular division, genetic materials are replicated so that the
same sets of genetic materials are present in the resulting daughter cells. This process entails
division and replication of chromosomes, and this is where the protective mechanism of the
telomeres comes into play.
During repeated cellular division, the length of the telomeres shortens progressively. This
mechanism is known as telomere shortening. The problem arises when the length of the
telomere becomes too short for further cellular divisions. In such a case, cellular division is
inhibited and senescence or cellular death takes place.
Telomerase... Cure to Cellular Senescence

Thanks to the advent of the enzyme telomerase, telomere shortening can now be inhibited.
Telomerase is an enzyme made of protein that protects against telomere shortening by
forming telomere caps at the ends of the chromosomes. Telomerase allows for replacement
of the short bits of telomeres which are progressively shortened by a continuous cellular
division. Without telomerase, chromosomes will eventually reach a limit inhibiting it from
further cellular division but with telomerase, the lost telomeres can be replaced and the cells
can divide limitlessly.
Aging
According to some scientists, aging comes with progressive telomere shortening. This is due
to the concept that if telomeres reach their limit which inhibits them from dividing, cellular
death ensues. And due to the discovery of telomerase, a lot of studies are now being
conducted on the possibility of preventing the process of aging with the use of the enzyme
81
telomerase. But a problem arises due to telomerase’s tumorogenetic properties. It can cause
growth of cancer cells, which instead of delaying aging; can cause the death of an organism.
Cancer
Cancer cells are considered immortal due to their telomerase activity. Since telomerase
promotes cellular division, it can be the mechanism behind cancer cells. Due to this
mechanism, a telomerase-inhibiting treatment was proposed as an answer to cancer.
Experimental, telomerase-targeted drugs are now being developed to be potential cures to
cancer.
Explorable.com (Feb 14, 2010). Telomeres and Enzyme Telomerase. Retrieved from
Explorable.com: https://explorable.com/telomeres-and-enzyme-telomerase
Thanks for reading!

Explorable.com Team
Explorable.com - Copyright © 2008-2015 All Rights Reserved.
82

Nobel Prizes Medicine

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Nobel Prizes Medicine

Uploaded by

Copyright:

Available Formats

Published on Explorable.com (https://explorable.

Nobel Prizes Medicine

Cover design by Explorable / Gilli.me.

How to cite this article:

Explorable.com (Nov 7, 2011). The Visual System. Retrieved from Explorable.com:

How to cite this article:

Explorable.com (May 14, 2011). Functional Specialization of Cerebral Hemispheres.

In the 1960's, following his successful researches, he teamed-up with Samuelsson in

How to cite this article:

Explorable.com (May 6, 2011). Prostaglandins and Biologically Active Substances. Retrieved

How to cite this article:

How to cite this article:

Krebs immediately chose medicine after receiving a scholarship to pursue medicine at

Importance of Reversible Protein Phosphorylation

How to cite this article:

Explorable.com (Jul 9, 2011). Discovery of Reversible Protein Phosphorylation. Retrieved

Scientific Context of the 1970s and 80s

Who is Stanley Prusiner?

How to cite this article:

Explorable.com (Nov 24, 2010). Prion as an Infectious Agent. Retrieved from

How to cite this article:

Explorable.com (Mar 6, 2011). Discovery Of Split Genes. Retrieved from Explorable.com:

Background of Nitric Oxide

The Minds Behind the Discovery

How to cite this article:

Structure, Function and Role of G-proteins in Signal

How to cite this article:

Background On Cellular and Protein Function

Intrinsic Signals in Proteins

How to cite this article:

On a completely separate laboratory, Lewis was conducting an independent research on the

How to cite this article:

Basics of Signal Transduction in Nervous System

Discovery of Dopamine as a Neurotransmitter and Its

Discovery of Mechanisms Involved in Slow Synaptic

Discovery of Model System for Learning

How to cite this article:

The Specificity of Cell-Mediated Immune Response

Succeeding researches conducted by other scientists showed that if a cell is infected by a

How to cite this article:

Explorable.com (Jun 2, 2010). Cell-Mediated Immune Response. Retrieved from

Basics of the Cell Cycle

The Seminal Discovery

Basics in Organ Development and Programmed Cell

The Researchers Who Contributed to the Discovery

Contributions to the Discovery

Sydney Brenner and C. Elegans

John Sulston and C. Elegans Cell Lineage

Robert Horvitz and a Genetic Program Controlling Death

How to cite this article:

Explorable.com (Apr 7, 2010). Programmed Cell Death. Retrieved from Explorable.com:

Prior Advancements in Nuclear Magnetic Resonance

The Inventors and Their Contributions

Lauterbur’s groundbreaking discovery was the imaging technique which he called

What Do We Know Now About MRI

How does it Work

MRI’s Immediate Use in the Field of Medicine

How to cite this article:

Explorable.com (Sep 9, 2010). Discoveries on Magnetic Resonance Imaging (MRI). Retrieved

The Organization of the Olfactory System

The Importance of the Olfactory System

The Minds Behind the Discovery

The Path Towards the Discovery