Nobel Prize 2014 : Medicine and Physiology Front Runners & Winners

 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.

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. 

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?”

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. 

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 ataxias 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.