Saturday, December 20, 2014

Meet Krampus



Dear Readers

As I hastily type these words the realization hits me that they may be my last. I can’t help but cast weary glances behind me, as a cold draught claws, persistently at my nape with its chilly clutch. Try as I may, search as I might, its origin remains a mystery in this well insulated house.

I hate to admit but I’ve been naughty this year, quite possibly the reason for this feeling of unholy fear, which deepens as Christmas day draws near.

Night rode in swiftly on that freezing day as my girlfriend and I snuggled into bed hoping for a pleasant and perennial sleep. Silence reigned all through the house; nothing made a sound, not even a mouse. Well nothing except my snoring spouse, and the incessant whirring of the radiator, which by now was nothing more than a lullaby to us. But suddenly I was jarred awake by a faint clamoring coming from downstairs. The noise became louder as I crept down step by step. Approaching the living room; it was now more distinct than ever. I knew the sound to be of chains rattling against each other.

I peered in to see, a figure hunched over our Christmas tree. He sneered and snickered gleefully and pranced towards our Christmas stocking. It was then that I knew this prick, simply couldn’t be jolly Saint Nick. To say I was revolted and wracked with repulsion, wouldn’t be enough of a justification. Here I was trying to reduce my carbon footprint and he was literally stuffing coals in my socks. The Bastard! I would have none of it.

“Oi Asshole” I shouted intrepidly at him, but when he turned around I almost screamed. For in front of me there stood, half man, half goat, a hideous beast in full.


Horns like pikes burgeoned upon his head; jagged yellow teeth in his gums were imbedded.He had no feet but hefty hooves instead, his glowing red eyes stared at me, dead. Stomping emphatically he trimmed the distance between us. He was so close I could smell on him the putrid stench of rotting corpses, leaning in he whispered with foul breath that he was none other than the infamous krampus.

“Who?” I asked for I didn’t know, I had not seen nor heard of this creature before.


He gasped in shock and disbelief, and proceeded to throw a hissy fit. He reminded me of a hip hop artist with a melodramatic flair, failing his chains, barring his teeth and giving me a pretentious glare. Finally exhausted he flopped down onto a chair, and said “Let me tell you who I am”.  “Please sit “he brazenly offered, a seat in my own home, the audacity of this unwelcome monster. I didn’t know then but soon it would dawn, that I had agreed to an interview with this devil spawn.

This beast was apparently a part of European folklore, one of the things he mentioned as he began to pour, not only details but drool on my hardwood floor. I knew what he was getting for Christmas, a big fat bill for this vile mess; I must remember to ask him his address.

There was a catch in his throat as he spoke of Hel, his mother dearest; it would seem that even demons have feelings.  Sorrow soon turned to bitterness, as he was reminded of Saint Nicholas. “You glorify that pudgy oaf lacking of class, when it should be me you celebrate and commercialize, I’m badass”. It was clear by the statement that he desperately sought, to amend his mummy’s disappointment and be adored.

“He pampers prissy children with materialistic gifts, while I teach naughty brats the hardships of life with my stick” He said as he gave his cracked lips a quick lick. Evidently he drags kids to his lair, and does things bordering on pedophilia. With his bells, chains and ruten cane, you could tell this sick freak was into some hardcore S &M, which would put the contents of fifty shades of grey to shame.

He was telling me about Krampusnacht and how Germans were the best, when we heard the sound of another pair of heavy footsteps. In strode my girlfriend clad in her nightly wear.Krampus’tongue lolled out at the sight of a lady with such debonair ,despite her lack of makeup and bedraggled hair.  “She must be on the nice list, it’s only apropos” ,nudging me the beast cackled “Santa does have a weakness for HO, HO, HOES” 

I knew in that instant this wouldn't end good,it was bad enough that he was wagging his tongue not to mention sporting wood, but he crossed a line when he implied my better half was a prostitute. By the horns, Krampus was thrown, out into the snow, in a manner which almost dislocated his hip bone. Not the first such experience he’s had with a woman scorned, I’m sure.
Thus was concluded my interview, with Krampus the indecent and raunchy ghoul.




MERRY CHRISTMASS everyone

The extra "S" wasn’t an accident

and neither is the weight you put on during the holidays

Cheers!







 Image sources:http://theforgottenfriends.deviantart.com/
                        http://fishmas.deviantart.com/
                        http://www.ghoulishgary.com/krampus/

                                                                              

Sunday, December 7, 2014

Nobel Prize 2014 : Chemistry Front Runners & Winners



Dear Readers 

December is upon us and there is a sense of excitement, a sensation of general electricity in the air and about each and every one of us. Perhaps it’s the rush of serotonin from the expectation of the upcoming Christmas celebrations or better yet the utter thrill of participating in the Feast of Winter Veil. Aahhh the memories, it truly is a time for remembrance, reminiscing and rejoice. 

But apart from the solstice festivities I am reminded of yet another event that is a combination of December, serotonin and remembrance. Yes! The 2014 Nobel Prize ceremonies are just around the corner and I am left with the recapitulation of the Chemistry awards to complete the holy trinity of Nobel prizes, for 2014.

And before you say it I am fully aware that I left out the other two awards , but the sole purpose of this omission is due the fact that I wanted to create some controversy before I started the article, and I daresay …….……………people have better things to worry about.

CHEMISTRY












 Ching W. Tang and Steven Van Slyke: Organic Light emitting 
diode 

 It was truly a “Kodak moment” (a reference I’m sure will be missed by the younger generation) when Ching W. Tang and Steven Van Slyke, whilst working at Eastman Kodak Research laboratories, published a paper unveiling  their experiments using electricity to  activate organic chemicals  so that they  generate light ,in a process that was quite energy efficient.


Praise and citations (over 9000!!!!!!! for their papers released in 1980s) followed suit this revolutionary technology which changed the very landscape of electroluminescence. 

A template of the diode would consist of two layers of different semi conductor organic materials squashed in between two electrodes which emitted light when a small charge was passed through the system. This needed far less power (10V) than previous versions of electroluminescent diodes (100V).

As illustrated in the diagram the first layer would be the cathode, magnesium/silver alloy was originally used by the duo. Next came the luminescent or emissive layer of tris (8-hydroxyquinolato) aluminum (Alq3) which was followed by a conductive layer of a diamine. The Anode layer of indium tin oxide would be last. All the layers are deposited, in very thin films, on a substrate usually glass or plastic. 

The reaction when a current is passed through the diode, instigating freed delocalized electrons of the Alq3 to come into contact with the holes of the diamine layer, is the sole cause of its incandescence. Ching and Steven’s rudimentary version, which had a luminous intensity peak of 550nm, visibly representing green, was improved upon by the use of better organic polymer layers and improved electrodes to host the full scope of the color spectrum. 

The appliance of OLEDs can be seen the world over, from your TV screen, to your mobile display, to your camera and even to your hand held game consoles. The innumerable applications of their invention earn the duo a well deserved nomination as they kick start our list.

Steven Van Slyke (right) and Ching W.Tang (left)
 


Charles T. Kresge, Ryong Ryoo, Galen D. Stucky: Modeling Mesoporous Materials 

There are three types of nanoporous mediums, macro (pore size: 50–1000 nm), meso (pore size: 2–50 nm) and micro (pore size: 0.2–2 nm).  Mesoporous materials are considered bulk materials with large internal surface areas of up to 1000 m2/g. Compounds of silica and alumina are the more common mesoporous materials. Their applications range from catalysis, sorption, ion exchanges, optics, photovoltaics, for use in bio-sensors and as molecular sieves.

Charles Kreger
It was Charles Kreger who first demonstrated that such materials could be fabricated and customized in a laboratory, receiving more than 11,500 citations for his paper in Nature publications. The key to his innovative creation process was the use of surfactants, a compound that reduces surface tension of liquids. It was surrounding the resultant micelle; formed from the inclusion of surfactants in its synthesis, that the aluminum silicates grow. The size of the pores depended upon the molecular structure of the surfactant used. 

Ryong Ryoo
Using this process Kreger synthesized several types of mesoporous materials (MCM-36, MCM-56, MCM-67, MCM-68) the most famous of which is MCM -41(Mobil composition of matter No. 41). 

MCM 41’s most notable predicted application is as a drug delivery system for a cytotoxin to attack cancer cells. 

Enter Ryoo, not the Hadouken hurling Japanese street fighter but rather the award winning Korean chemistry professor. His research at KAIST University focused on mesoporous carbon, specifically on a hard templating synthesis strategy where mesoporous silica were used as scaffolding around which were built carbon based structures. The silica template was later removed leaving a framework of 3nm carbon mesotubes or mesopores (which was later found out to be tunable to twice that size). 
Galen D Stucky

Mesoporous carbon has several applications especially in the area of fuel cell engineering serving as a catalyst support for platinum nanoparticles, used to enhance the rate of half reactions in a fuel cell. 

Additionally the fabrication process itself offers a smart new synthesis strategy applicable to other nanoporous materials. 

Dr. Galen D. Stucky of the infamous Stucky group demonstrated how hexagonal mesostructures with 7nm -30nm pores could be fabricated. Thus was born the Santa Barbara Amophorous No.15 named after the University of California. SBA 15 is used as a drug delivery system especially for poorly water soluble drugs and it is also used as a biosensor.

 For their contributions to the fabrication, customization and improving of the functionality of mesoporous materials, not to mention their future implications and applications, these gentlemen are more than worthy of the illustrious Nobel.

 
Graeme Moad,Ezio Rizzardo and San H. Thang: RAFT Polymerization


From paints to plastics to plates to cups to carbon fiber to rubber to adhesives, Polymers are core components of most of the current technology we see around us.  As such their synthesis, known as polymerization, has become a vital part of modern industry.   Polymer use and synthesis date back to over 70 years; however in the 1990s three chemists working at the Commonwealth Scientific and Industrial Research Organization (CSIRO) centre in Clayton, Melbourne in the land down under, blew previous polymerization techniques asunder. 

Their work particularly revolved around solving the controllability issue of the radical polymerization process which was used to produce polymers such as polyacrylate, polyacrylonitrile, polystyrene, and polyvinyl acetate. This was one of the more direct techniques and involved using a free radical molecule to initiate a repetitive chain reaction between monomers so that they bind together to form a polymer. Alas this repetitive chain reaction’s termination was unpredictable and the entire polymerization process, if not monitored, was found to be extremely hazardous. 

After much research Graeme, Ezio (not from Assassin’s creed) and San discovered that they could control the radical polymerization by introducing a transfer agent in the form of a thiocarbonylthio compound that offered versatility to the process. This transfer agent allowed the control and manipulation of the generated molecular weight and the dispersity of the polymer. It also enabled reversibility. This is due to the fragmentation reaction that occurs resulting in either the starting polymeric species or a radical and a polymeric transfer agent from which the radical or the polymer species can be removed to essentially reverse the process.  Hence the trio named the process “Reversible Addition-Fragmentation chain Transfer” or RAFT. 

San H Thang (left), Ezzio Rizzardo (middle) and Graeme Moad (right)
RAFT polymerization made way for the synthesis of a variety of polymer types with complex architectures, controlled molecular weight and low dispersity. The flexibility it offers allowed the meshing of a wide blend of monomers to make co-polymers and also enabled the process to be conducted in a range of solvents without any temperature restrictions. 

For their development upon the radical polymerization process by introducing, to the world, the RAFT synthesis system these gentlemen earn a laudable nomination to join the ranks of the Nobel laureates. 

Kenichi Honda and Akira Fujishima: Water photolysis

Photolysis refers to the breaking down of a compound with the use of photons; this is most commonly seen in photosynthesis as water is oxygenated to form two hydrogen atoms and a diatomic oxygen molecule which is released into the air. Plants, thylakoids of cyanobacteria and the chloroplasts of green algae naturally use photolysis in the process of creating chemical energy. 

However the recreation of the water photolysis process proved to be difficult as just shining a light did nothing to water. 

It was in 1972 that Akira Fujishima and his mentor, the late, Kenichi Honda devised a simple method to artificially reconstruct this process. They would spilt H2O by incorporating Titanium dioxide as a catalyst and subjecting it to UV light. This process is known as Photocatalysis.

The discovery of the photocatalysis of water has several implications and quite a few applications.
The most obvious and central use is that the hydrogen gas that is formulated offers a clean, renewable and inexpensive source of energy and therefore research is being carried out ,feverishly, to develop practical photochemical hydrogen fuel cells for mass consumption and commercialization. 

Akira Fujishima
Catalysts other than titanium dioxide are being tested to find an effective and efficient way of yielding hydrogen gas however due to the fact that an inordinate supply of input energy is required for the process the main source of hydrogen remains to be natural gas. 

Kenichi Hond
Photocatalysis is also used to disinfect water in a process called Solar water disinfection. Although water disinfection can be done without using a catalyst, recent studies have shown that using such an agent like titanium dioxide augmented the effects of solar irradiation. Even though the process isn’t quite efficient photocatalysis disinfection requires no energy input and the materials involved are quite stable thus maintaining its appeal as a viable process, applicable especially in remote areas. 


Akira and Kenichi’s contribution made way for avenues of research in both the invention of a much needed energy source for the future and the equally needed purification of polluted and infected water. Thus it is only just that they receive their rightful acclamation for the Nobel Prize. 

 
Jacqueline K Barton: DNA ET, Metallo DNA Binding probes, DNA electrochemistry 

To Jacqueline Barton the body was a complex machine with DNA representing its molecular wires. This unorthodox outlook stemmed from being an inorganic chemist and it is this perspective that led her to experiment and examine the interactions between metal complexes and DNA. 

Jacqueline pioneered the application of these organo-metal complexes to probe the “pie” stacked double helix structure of DNA. She synthesized two classes of probes, each designed to interact with DNA in a specific manner. Rhodium complexes would photocleave the sugar phosphate backbone of the DNA near its binding site and Ruthenium complexes would illuminate after binding. Unlike Organic complexes they can be manipulated into different modules integrated with recognition elements. These complexes once intercalated allow for DNA sequence recognition. 

Whilst tuning metal complexes for DNA sequence recognition Barton and her team stumbled upon the capability of certain complexes to recognize single base mismatch pairs. Thus was born a third class of organo-metal complexes, christened metalloinsertors. Using Crystallography and Nuclear magnetic resonance spectroscopy (NMR) they were able to examine the binding process of metalloinsertors. The sterically expansive ligand of the metalloinsertor would be inserted into the DNA’s minor groove to eject the mismatched pair into the major groove to allow for access. This would be the first ever observation of a small molecule insertion of DNA.  

The applications of the DNA binding probes range from the early detection of cancer and contribution to chemotherapeutics to hampering the proliferation of mismatch repair deficient cells to drug delivery systems.
However this was but only one of her contributions. The next would be aided by the prior discussed research. 

Jacqueline K Barton along with Bernd Giese and Gary B.Schuster conducted the first research to demonstrate that aside from carrying our valuable genetic information DNA is also responsible for the transfer of electrons, for which they earned a Nobel nomination in 2009. 

Electron transfer (ET), as it was acceptably theorized by Nobel winner R.A Marcus and improved upon by N.S. Hush, referred to the quantum mechanics of the redox process wherein electrons are gained by an acceptor molecule (reduction) and lost by a donor molecule (oxidization).There are three main ways in which the transfer can occur. The electron can travel along an established ligand bridge or transition through temporary bridges or circumvent this process and hop straight to its destination. 

 Numerous biological processes, like photosynthesis, were also found to have ET chains and it was experimentally observed that DNA was quite an exceptional medium for the transfer and transportation of electrons. 

Jacqueline likened the double helix π stacked structure of DNA to a wire, used for long range signaling between proteins in a cell. However DNA frequently gets damaged by the metabolic activity in our bodies and environmental factors such as radiation. In such a scenario signaling will be impaired. These DNA lesions, if you will, are constantly repaired by special proteins synthesized by our cells. Like the late Jedi council the fixer proteins constantly keep in touch through the force (DNA) and actively seek out disturbances (damages) in it. However when repair proteins get corrupted by power and they turn to the dark side entire cells are defiled becoming cancerous. 

Star wars analogy aside this discovery would be a crucial stepping stone to the development of DNA based electrochemistry. 

It was evident that the use of ET as a reporting and signaling system to locate DNA damage and lesions was vital for the operation of DNA repair; however its function is assumed to extend beyond that of the DNA repair process. Transcription factors such as SoxR oxidative stress regulator and p53 related to tumor regulator cells are also believed to use the ET system. 

The Barton Group residing in Caltech are using DNA’s ET system to develop a highly sensitive mode of detecting DNA binding proteins and mRNAs. 

An electrochemical approach they are focusing on is depositing a self assembled monolayer of Thiol modified DNA, inserted with a redox- activate probe, onto a gold surface. The reduction of the redox probe within the DNA enables the analyzing of the DNA’s structure in the section between the gold surface and the probe, to uncover DNA lesions, mismatches and even protein based interactions like DNA base flipping. 

Research is being conducted into incorporating new redox probes and surface passivation strategies to make this a feasible analytic procedure for the detection of protein and mRNA. The development of a gold multiplex chip to conduct several DNA analysis simultaneously with the least amount of sample preparation holds great promise in the field of pathology detection, especially for exposing cancer transcription factors. 

Jacqueline K Barton


For her continous efforts and contributions, which are products of her daring outlook and ideals on DNA, Prof.Jacqueline Barton deserves approbation and acclamation and a nomination for the Nobel Prize. 


The winners of 2014 Nobel Prize in Chemistry 

Eric Betzig, Stefan W. Hell and William E. Moerner: super-resolved fluorescence microscopy

“For a long time optical microscopy was held back by a presumed limitation: that it would never obtain a better resolution than half the wavelength of light. Helped by fluorescent molecules the Nobel Laureates in Chemistry 2014 ingeniously circumvented this limitation. Their ground-breaking work has brought optical microscopy into the nanodimension” ~NobelPrize.org

This beyond revolutionary advancement ushered in the age of observable, optical nanoscopy sending shockwaves throughout the fields of biology.  

The journey began with Prof.Stefan Hell who upon the finishing his Ph D embarked on a quest to prove the infamous Abbe wrong. No, it wasn’t the 16th president of the United States that he wanted to challenge but Professor Ernst Abbe, who in 1973, set in stone, the law of limited resolution. It stated that the observation of objects smaller than 0.2 micrometers (half the wave length of light) was pure ludicrous. However after watching the Ten commandments we all know what happens to laws written in stone. 


Stefan Hell
But as all rebels do, he was met with harsh admonishment, cold discouragement and many an obstacle, which made him finally decide to leave Germany. So it was that the ambitious young Stefan Hell found himself in Turku where he was taken in by a scientist, working on fluorescence microscopy, and asked to join his research team. Whilst laboring in the library of the University of Turku, he stumbled upon a tome titled “Quantum Optics” and in it he would find his first guiding muse “stimulated emission”

Fluorescence microscopy involved using fluorescent molecules (e.g. antibodies) to join with cellular components (DNA) for imaging purposes. This enables scientists to see where the component is located however its resolution, or lack thereof, prevented clear observation of small molecules.

After reading about stimulated emission he noted that in a state of population inversion, it could optically amplify the incoming light due to its ability to reduce the energy of excited molecules thus creating photons with the same phase, frequency, polarization, and direction of travel as its source incident wave.

It dawned on Stefan Hell that incorporating stimulated emission into fluorescence microscopy would essentially provide the answer he sought.

One light to fluoresese them all
Another to quench them
Two lights to find them all
and in the darkness clarify them

In 1994 he published a paper proposing a method where two light pulses were to be used, one to excite all molecules and then the second to extinguish fluorescence in all molecules but the ones left in a nanometer sized gap in the middle which would be imaged. By carefully scanning the sample, nanometer by nanometer, a detailed image can be modeled. Its significance was that the resolution depended on the amount of fluorescence registered at a given point thus rendering resolution essentially limitless.   

He dubbed his method Stimulated Emission Depletion (STED) and in the wake of Y2K managed to successfully image an E.Coli Bacterium with resolution unattainable by a regular microscope.  However, unbeknownst to Stefan Hell, other forces were at work trying to achieve the same goal; although in a quite a different manner. 

The year was 1989; In an IBM research center in San Jose California, W.E Moerner became the first scientist to measure the light absorption of a single molecule. All chemical experiments were to that point conducted by observing a collection of molecules from which a mean was derived to represent a standard molecule. Moerner’s breakthrough meant that chemists could now use techniques to assess single molecules thus improving our understanding of molecular chemistry. 

As fate would have it Professor Moerner moved to San Diego, in 1997, to join the University of California, right about the time when upcoming Nobel Laureate Roger Tsien was meddling about with his discovery, the Green Fluorescent Protein (GFP) that he extracted from a jellyfish. He was trying to make the protein fluoresce with colours other than green. What was fascinating about GFP was that, when bound to other proteins in a cell, it would make them visible, acting as a marker system with which the location of a bound protein could be observed. 

Moerner was intrigued by this and experimented with GFP. He found a variant of it which could essentially be switched on and off by subjecting it to a specific light wave length. After initial excitation, at 488nm wavelength, it would eventually fade away, but would only be reactivated at the wavelength of 405nm.
In an experiment he scattered these proteins in a gel, at intervals larger than Abbe’s diffraction limit and found that it was indeed possible to observe single molecules that fluoresce through an optical microscope. Moerner likened them to optically controllable little lamps and published his findings in Nature publications, 1997, which landed in the hands of Eric Betzig. 

Eric Betzig had managed to already surpass Abbe’s law by the start of the 1990s. He used a thin tip placed only a few nanometers away from the specimen surface to emit light in a method called near field microscopy.

However near field microscopy could not visualize anything below the sample surface and it was soon evident that it could not be improved further. Depressed he quit his research career at Bell labs, yet Abbe’s diffraction law still haunted his mind.

Perhaps it was the chill of that winter’s day but something sparked a thought in his mind. Whilst working on his near field microscopy, the exploits of other scientists particularly one W.E Moerner had compelled him to observe a fluorescent molecule using his special microscope. A query formed in his mind whether the use of fluorescent molecules of different colors could possibly enable him to circumvent the diffraction law using a regular microscope. 

He formulated an answer by suggesting that fluorescent molecules of different colours, possibly red, green and yellow, be spread out in intervals of distances greater than Abbe’s 0.2 micrometers limit. A microscope would be set to register one image per colour and all images when superimposed would give a high resolution image where single molecules, due to their distance apart and different colours, could be observed. He published his theory in the journal of Optics Letters, but still wasn’t ready to return to the world of research and academia.  

It was during this time that he came across literature about the GFP. It renewed his passion for research since now; the possibility of implementing his theory was within his grasp. However it was in 2005 that the fruition of its implementation grew ever closer, with Betzig’s discovery of a protein,similar to the one Moerner found, that could be optically controlled. This led to the revamping of his hypothesis as it wasn’t necessary for the fluorescent molecules to possess different colours anymore; they just had to fluoresce at different times. 

His 11 year long wait was rewarded in 2006 as he, along with other scientists working with fluorescent proteins, demonstrated the applicability of his theory. They used a weak light pulse to temporarily excite small groups of fluorescent proteins (which were spaced at distances greater than 0.2micrometers) at a time, per image. The superimposition of these images gave them a detailed comprehensive and high resolution image which shattered Abe’s law of diffraction. His victory was final once he published his work in Science publications. 


Our epic trio still continues to tirelessly strive for progress, as they spearhead research in the field of 
nanoscopy. Their contributions resulted in the techniques of nanoscopy used around the globe. Stefan hell himself has seen the inside of a living nerve cell and looked upon brain synapses. W.E. Moerner has examined proteins related to Huntington’s disease. Eric Betzig has witnessed the wonders of cell division inside embryos. This tool they have forged has enabled us to visually observe the most minuscule elements that make up life so that we may better understand it.

Make sure you tune in on the 10th to witness the celebrations as the winners of this year’s prizes officially join the ranks of the Nobel laureates. 

I hope you have a wonderful winter or, if you are in the southern hemisphere, a smashing summer ahead of you 

Cheers.

                                                                             

 



Saturday, November 22, 2014

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.