The Lasker Foundation of New York has announced its annual awards for the year 2013 a few days ago. The award for clinical medical research has gone to a trio “for the development of the modern cochlear implant — a device that bestows hearing to individuals with profound deafness,” with the statement that this device has for the first time substantially restored a human sense with a medical intervention. The Public Service Award goes to the philanthropic couple Bill and Melinda Gates of Microsoft “for leading a historic transformation in the way we view the globe’s most pressing health concerns, and improving the lives of millions of the world’s most vulnerable”. The couple has so far donated as much as $26 billion (more than the total worth of Mr Mukesh Ambani) towards this noble task. And the award for basic medical research goes to Drs Richard Scheller (of Genentech) and Thomas Sudhof (of Stanford) “for discoveries concerning the molecular machinery and regulatory mechanisms that underlie the rapid release of neurotransmitters.”
We focus on the basic medical research award here since the winners have explained the molecular basis of brain activity, in other words the mechanisms behind how we feel sensations. Neurotransmitters are molecules that are ferried across from one nerve cell (called neuron) to the next, transmitting signals of pain, pleasure and such other sensations. Opium has one such molecule, alcohol another and caffeine a third. What Scheller and Sudhof showed is how such signal molecules are taken across nerve cells and regulated. Each of them worked independently but complementarily for over 25 years and identified the proteins and cellular machinery involved.
Of the over 200 types of cells that our body is made of, nerve cells which are responsible for sensations are unique in their architecture and function. A neuron has a globular body with a head that looks like a flower with hundreds of petals. Each of them is called dendrite. At the other end, it has a long stem called the axon, occasionally over a metre long (for example the nerve cells in your foot), fanning out in the end into hundreds (over a thousand) of branches. In effect a neuron resembles a bonsai palm tree, but with a longer stem, its leaves as dendrites and roots as axon terminals.
Like an electric circuit
Neurons connect with one another like in a complex electrical circuit; each axon terminal connects with the dendrite of the next neuron. Given the multiplicity of dendrites at one end and axon terminals at the other, one neuron can actually connect with hundreds of others. Given this, one can imagine the complexity of inter-neuron connections that make even the tiniest of brains.
This inter-neuron junction point is called the synapse (literally a connection point). Here is where the action is. The synapse is made of sacs or bags containing neurotransmitter molecules that help in transmitting information or the signal from the axon of the “pre-synaptic” neuron to the dendrite of the “post-synaptic” neuron. How this is done, how the neurotransmitter is released and regulated has been the work of Scheller and Sudhof.
Neurotransmission is thus a combination of electrical signal and chemical transport. It starts out with an electric pulse that runs down a nerve cells axon. When it reaches the terminal tip, calcium ions enter the cell. Responding to this, the cell triggers the synaptic sac containing neurotransmitter molecules to burst open, much like a long needle bursting a water-filled balloon. The neurotransmitter molecule then attaches itself to specialised receptors on the surface of the dendrite of the next neuron, with a lock and key specificity. Signal is thus passed on downstream. The task is to identify the molecules involved in these processes.
Sudhof isolated a set of proteins (e. g, synaptotagmin) which are activated upon calcium signalling and help in capturing and bringing together the synaptic balloon to the membrane of the pre-synaptic neuron terminal while Scheller isolated and showed another set of proteins (named syntaxin, VAMP, SNAP) involved in the synaptic fusion apparatus. By now we know as many as 60 members of this family synaptic cell adhesion proteins involved in neurotransmitter release and uptake.
As Scheller pointed out, there were a lot of little Eureka moments during these two decades of work that gave rise to the big picture. But what they showed is the fundamental mechanism of membrane fusion by all organisms, for inter-cellular communication.
This is in health. What happens when this protein-mediated pathway is blocked? This is what happened when a snake or even the microbe tetanus inject their toxins into our body. They go to block the protein mediated pathway causing neural inaction. Illnesses such as depression or schizophrenia too are defects in the fusion process described above. As the Lasker review states: “Thus, the work by Scheller and Sudhof has revealed the elaborate orchestration that lies at the crux of our most simple and sophisticated neurobiological activities.”