Dear Readers
Firstly I apologise for the extensive delay. My grandmother
took ill and was hospitalized due to a pulmonary embolism. She’s recovering
now, so all’s well that ends well I suppose, if you can call a brush with death
being well.
Modern Medicine saved her life and I felt I needed to pay homage, give thanks
and acknowledge its journey of continuous improvement and innovation. What more
appropriate way is there to achieve this than to recognize the men and women
whose unyielding efforts lead to the breakthroughs that improve the overall
health of humankind.
These are but a few such vanguards who are worthy of the
Nobel Prize for
Medicine and Physiology
Stephen W. Scherer,
Charles Lee and Michael
H. Wigler: Copy Number variations
We are all familiar with the layman phrase told to us when
we were but budding children, “Everyone is unique”.
However in the scientific
community this was assumed to be further from the truth than the planet Tatooine,
believing the genome difference between two humans to be 1%.
Amusing how it was
the scientific community that was proved wrong.
The force was weak with this presumption as it was blown to
bits in 2004 by the Professorial duo Stephen W. Scherer and Charles Lee and by
Professor
Michael H. Wigler, independently, with the publishing of a paper
bringing to light the large scale differences between human genomes.
Dubbed “copy
number variations” (CNVs) they accounted for a significant 12- 13% of the
genome. In the basic sense the variations are duplications, deletions,
inversions and translocations of a structural nature.
These CNVs are usually hereditary,
but they can occur spontaneously or “de novo” as it is uncommonly referred to
as in the non scientific community. These differences even extend to identical twins,
the scientific dipstick of uniformity.
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| Professor Micheal H.Wigler |
This struck a resounding and resonating chord in the domain
of genetics and evolutionary biology, specifically
around gene evolution, functionality
and traits. One such trait, that bore significant worth, was the susceptibility
to disease.
Quite akin to the infamous miss Taylor swift, who while not
being umm..loose is linked with several bad apples of the media’s eye; the CNVs
aren’t necessarily related to disease but are associated with some of the
notorious illnesses that are of great interest and consequence.Specifically
speaking Harry styles, John Mayer….oh dear wrong list.
The diseases related to
Copy Number Variations of the genome are schizophrenia, HIV, cancers, systemic
lupus erythematosus and a spectrum of autistic diseases. It is this relationship that offers
exciting implications, particularly in the field of genetic engineering, to
possibly increase our resistance to disease and even achieving complete
immunization and eradication of these afflictions.
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| Professor Charles Lee (right) and Professor Stephen W. Scherer (left) |
Although genetics is a subject rampant with controversy and
ethical conundrums the ramifications of the finding earn these outstanding
gentlemen their nomination.
James E. Darnell Jr., Robert G. Roeder and Robert Tjian: Gene
Transcription
A fundamental question that drove the
advancement of science is, “How?” It is this simple yet key scientific
questioning that led Professor Darnell, Roeder and Tjian to uncover the mystery
behind genetic programming.
Darnell, whilst in the midst of
examining RNA processing of cells of mammals, presented the first question.
“How does a lone cell develop into a complex life form with several
differentiated cells with different functionalities?”
The answer in one word,
“transcription”. The DNA present in the nucleus transcribes its genetic coding
into a strand of RNA known as the primary transcript.
This RNA strand is
designated as a messenger (mRNA) and undergoes several stages of maturation before
finally leaving the nucleus (although some do stay on). Once leaving the nucleus the mRNA binds to the
ribosome which decodes its transcript to synthesize proteins in a process known
as “translation”.
This brought Darnell to his next
question “how does our lone cell choose what genetic information to transcribe into
RNA?”
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| Professor James E. Darnell |
With the use of a model system Darnell observed that specific
protein synthesis was triggered inside a cell due to different interferon present
outside the cell. The cell’s receptors identified the interferon and released specialized
molecules which attached to the DNA and essentially chose the relevant genetic
code for transcription.
Ergo these
molecules were named Signal Transducers and Activators of Transcription (STATs)
and in Darnell’s model system he discovered 40 different signals and 7 STATs.
In
addition to having a key role in the function of the immune system, STATs are
responsible for gene regulation, specifically in the facets pertaining to the
growth, survival and differentiation of cells.
Roeder joined the quest to understand gene transcription by
coming up with the brilliant idea to harvest separate cellular components
and then combine them
in a test tube to observe, with clarity, the
transcription process in a cell free system.
 |
| Professor Robert G. Roeder |
His research enabled him to classify RNA
polymerase responsible for transcribing DNA, into three groups. Roeder also
found out that apart from the STATs which were responsible for general
transcription there was the presence of gene-specific activators that bind to
the start of a particular gene in order to recruit said STATs which in turn
unzip the double helix of DNA by discharging RNA polymerase enzymes, acting as
a promoters of gene transcription.
 |
| Professor Robert Tjian |
At the same time Tjian was also working on gene-specific activators
in a cell free system. Both men observed that whilst these gene-specific
activators exponentially promoted RNA synthesis in crude cell-free extracts,
they proved flaccid in more purified cell free systems.
It was Tjian who noted
that the large co-activator complexes that were present acted as mediators between
general transcription activators and specific activators. These co-activators bound
themselves to activators to help calm histones covering tightly coiled DNA so
that the helix can unwind easily thus unfurling genes for further transcription.
Transcription research takes us to the core reasoning behind
cell processing and its implications are mind boggling. However one of the most
significant aspects of Transcription factors is that their mutations and
disorders are directly related to certain diseases, for which drugs can be
created to directly target them. For example the mutation of oncogenes and the
failure of anti-oncogenes are cancer causing and 10% of the drugs prescribed
target these transcription factors.
Darnell, Roeder and Tijan have only scratched the surface of
vast repository of knowledge about genetic programming but their research provided
us with tools of its fundamentalism using which we can dig further into fully
understanding and utilizing the coding of life.
Alfred Knudson: Tumor
suppressing gene and the Two hit hypothesis
Tumor suppressor genes serve as the stalwart wall between us
and cancer however much like the fortress of Helms Deep if the wall is
compromised then true to the analogy we are truly caught between a rock and a
hard place.
However Professor Alfred Knudson discovered that it took
more than one mutation of a cell’s DNA to cause cancer.
It was in 1944 whilst
researching the causes of hereditary retinoblastoma, a type of retinal cancer
that children are afflicted by, that he came upon his discovery.
He observed that the
onset of non-inherited retinoblastoma was triggered by a biallelic mutation, in
other words the mutation of both alleles/alternative forms of a gene, ergo the
“two hit” hypothesis.
The basis of this was that if only one allele of a gene
was damaged, the remainder would still be able to synthesize the necessary protein
to suppress tumors.
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| Professor Alfred Knudson |
Sadly the children suffering from hereditary retinoblastoma
inherited the mutated gene.
After assessing and analyzing his
findings, in 1971, he finally established the cause of retinoblastoma to be a
mutation in the first ever discovered tumor suppressing gene, he dubbed RB1.
But Knudsen soon found out that not all cancers share the
same pathogenesis. This was because the oncogenes responsible for such cancers
only need a single mutation.
Additionally there are some other tumor suppressor
genes that also are exceptions to the two hit hypothesis.
For his contributions ranging from the discovery of the first ever anti-oncogene;
which led to us to better comprehend tumor suppressing genes, their clinical
implications and also to find more of its kind, to improved detection of specific
cancer, to the establishment of a new pathogenesis paradigm, Professor Alfred
Knudsen is another well deserving contender.
Huda Zoghbi: Rett Syndrome , Spinocerebellar ataxias and Atonal homolog 1
Rett Syndrome is rare genetic postnatal neurological disorder that
affects the grey matter of the brain. It is almost exclusive to females and
onsets during the first two years of their lives.
It was in 1983 when Professor Huda had just shifted her pediatric residency
to embrace a neurological one that she received a very unusual case. A week after
reading what would be the first ever report of Rett syndrome she came across another
patient who shared similar complications, which included motor control
disorders, language deficiencies, seizures, imbalance problems, and other
autistic associated impediments.
These
encounters shocked her enough to make inquiries and arrange to have patients
suffering from similar symptoms sent to her clinic. “It is a disease
that impacts the whole central nervous system” she describes, needless to say
the discovery of the affliction only served to motivate her as she decided to seek
its root cause.
The presumption that the disease
was a result of a genetic mutation coupled with having a geneticist as a mentor
influenced Professor Huda to start her search by scanning the X chromosome
(female) for genetic
disorders.Despite
the fact that in 1985 they lacked the technology needed to inspect the bulk of data,
which they didn’t even possess, Professor Huda remained undeterred as she
sought to oust the vile mutation from hiding, in the vast space which was the X
chromosome.
Thankfully Professor Huda didn’t limit herself to Rett syndrome alone. Roughly around the same time she also worked
on a collaborative research with geneticist Harry Orr on spinocerebellar
type 1 (SCA1) a hereditary neurological
disorder that slowly led to the degeneration of the patient’s motor system.
Their collaboration proved to be a success as in 1993 they both simultaneously found
the mutated SCA1 gene
known as ATXN1.
Given her rugged begins it is no
wonder that Professor Huda doesn’t let herself be restricted with limitations.
It is admirable that whilst continuing her work on SCA1 she initiated another
research on developmental neurobiology, after her lab discovered the atonal
homolog 1 gene (Atoh1). Along with several other researchers she labored for 15
years to uncover the gene’s vital role in many of the body’s functions, ranging
from hearing to breathing to balance and to its mutation which would cause
medulloblastoma, a malignant tumor in the brain which would afflict children
However the
other projects and successes she had didn’t displace or dull her devotion to the
pursuit of the root cause of Rett syndrome.
She joined forces with geneticist Uta Francke to pool together the gene
sequencing data they collected which they scrutinized one by one using a brute
force strategy
as they sought out the
causal gene. Yet this seemed a herculean task as they had only amassed a region
of 10 million base pairs out of over 100 million. However in August 1999 Professor
Huda received a call from a post-doctoral colleague of hers, Ruthie Amir, and
it boded well. She too had been sequencing genes of many Rett syndrome patients
trying to locate mutations. Her phone call relayed that she thought she had found
the mutation and asked if Professor Huda would offer a second opinion.
The gene data she reviewed was conclusive
proof. At last the long sought after causal gene was found.
 |
| Professor Huda Zoghbi |
Named MECP2, the gene
was a key component of essentially every brain cell and played a significant
role in the functioning of the central nervous system. Its discovery allowed the
recreation of Rett syndrome in mice which enabled scientists to test
therapeutic mediation methods. However while Rett can be reversed in mice, a
cure for humans is yet to be found.
But for her
contributions to neurobiology and for offering the first stepping stone in the
journey to seek a cure for Rett syndrome Professor Huda Zoghbi is a more than exemplary
nominee.
David Julius: Molecular Pain
game
Professor David Julius must’ve bit one extremely hot stray
chilli pepper for him to shift his focus from the happy go lucky serotonin receptors
to the dark side of the spectrum, pain receptors.
He dropped his research on devising
methods to identify and clone serotonin receptors and delved into understanding
the molecular mechanisms behind peripheral pain sensations.
The research revolved mainly around the natural found pain
inducers such as capsaicin found in chilli peppers and menthol found in mint
leaves which elicits heat and cold sensations, respectively.
Using these agents
he examined the activation of molecular pathways for different pain sensation
processing. In one test Professor David observed the sensory response routes and
channels in dorsal root ganglion cells of the exposure to capsaicin which led him
to discover its responsive gene expressions. He experimented with emulating these
expressions in cells that don’t usually respond to the capsaicin by inserting
genes that did. Thus he created the first ever member of transient receptor
potential of the vallinoid subfamily (TrpV1) or more derivatively termed as the
capsaicin receptor.
These cloned receptors not only responded to capsaicin but
to temperatures above 43.25 ⁰C, which were perceived as harmful. Although other
TRPs have been discovered TrpV1 remains the major focus in the field of pain
management. This is due to the fact that the tissue damage releases inflammatory
chemicals that lower the threshold for TrpV1 activation rendering even the
slightest increase in temperature or the lightest contact with capsaicin
extremely painful.
TrpV1 is associated
with many painful sensations including the pain felt with,
Multiple sclerosis, amputation,
depression, anxiety
, use of chemotherapy, etc.
The two major approaches to treatment for pain are either desensitization
with the use of agonists (capsaicin) or the use of antagonists (drugs used to
block the activation of TrpV1). Antagonists however had a major problem.
The
use of TrpV1 antagonists resulted in hyperthermia or the exponential increase
in the body’s temperature thus leading to the discovery that TrpV1was also
associated with temperature modulation. Since the application of antagonists
will be quite beneficial, research is being conducted to find a pain blocker that
does not cause hyperthermia.
The discovery of another TRP family alone deserves
recognition but the implications and applications of TrpV1 in both pain and
temperature modulation earns Professor David Julius a well deserved nomination.
The winners of 2014 Nobel Prize in Medicine and Physiology
John O'Keefe,
May-Britt Moser and Edvard I. Moser: Inner
positioning system
“How do we know where we are? How can
we find the way from one place to another? And how can we store this
information in such a way that we can immediately find the way the next time we
trace the same path? This year's Nobel Laureates have discovered a positioning
system, an "inner GPS" in the brain that makes it possible to orient
ourselves in space, demonstrating a cellular basis for higher cognitive
function.”~NobelPrize.org
Knowing where we are and where other things are is a
fundamental reason for our survival. Scientists, Philosophers and the like have
all questioned the rudiments and reasoning behind our sense of positioning.
Over two centuries
ago, German philosopher Immanuel Kant in his literature “The Critique of Pure
Reason” contended that some of our cognitive abilities were preset in our
brains and not formed of experience particularly referring to our concept of
space as prior knowledge through which the world is perceived.
In the mid nineteen hundreds behavioral psychologist Edward
Tolman conducted an experiment to examine how rats traversed through a maze. He
observed that the rats learnt how to navigate, showing signs of the
establishment of a cognitive map.
It was around 1967 that neuroscientist John O Keefe started
his post doctoral research focused around
cells”
concluding that the collective activation of some of these cells represented a
cognitive map as predicted by Edward Tolman and that different activity
combinations meant different maps.
spatial memory. He experimented with recording
signals of individual nerve cells in the hippocampus of a rat scurrying about in
a room.
The Hippocampus besides being a lovable mythical pet of Poseidon is
also the part of our brain responsible for converting short term memory into
long term memory. Professor Keefe noted activity in specific cells were linked
to the position of the rat in the room. He labeled these as “place
May-Britt and Edvard I. Moser’s contributions came more than thirty years
later as they came across something quite unusual.
Whilst mapping out the
hippocampal connections of a rat’s movement the Mosers noticed cell activation
in a part of the brain called the entorhinal cortex. It was observed that
certain cells in the entorhinal cortex were activated when the rat moved over
several places situated in a hexagonal grid.
Further examination revealed that
these “Grid cells” combined to create coordinate and directional systems and were
activated in a distinctive spatial pattern that enabled spatial navigation.
The integration of these grid cells and place cells presents a
comprehensive positioning and mapping system in our brains.
The discovery gives us an insight into how such neural circuits carry out
advanced cognitive processes and helps us better understand neurological disorders,
such as Alzheimer’s disease , which in early stages often leads to the progressive degeneration of the
hippocampus and entorhinal cortex resulting in the loss of spatial memory.
Although
the implications don’t offer pharmacological or clinical solutions as of yet,
I’d like to dream of a world where cell transcription and nanotechnology enable
us to possess an actual inner GPS.
I congratulate the trio on their Nobel Prize.
Bandits stalked the
roads preying, on merchants, traders and carriages of all sort, at gunpoint. Protection
became a desperate necessity for all voyages. The only solution present to the
common folk was to fight fire with fire, or in this case buckshot with buckshot.
By the late 19th century every station wagon carrying precious cargo
had a guard, armed with a 12 gauge shotgun. Thus was coined the expression “Shotgun
messenger”. The responsibilities and risk that comes with assuming this highly
hazardous position next to the driver will make most of us think twice before
squabbling over it again. 
