Have you wondered why the Nobel Prize 2021 was awarded to two biochemists/neuroscientists and what impact their discoveries have on physiology and medicine. That’s exactly what we are here for.

October 4, 2021  marked the announcement of the Nobel Prize in Physiology and Medicine to Dr. David Julius and Dr. Ardem Parpoutian. 

This episode goes behind the relevance of their findings and why it is such an important moment for a field that brings together biology, physics, chemistry and medicine. 

Key Reviews to dig into: 

Transcript

Hello, and welcome to SKRAPS. It is yet another episode discussing the stories of the sparks of scientific brilliance that underlie discoveries in science, medicine and innovation. 

I am Arun Sridhar and we have a very special episode today. It is a special episode because it deals with the awarding of the 2021 Nobel Prize in Physiology and Medicine. I know most science nerds like me, look forward to October as it is the month when many seminal discoveries are recognized through the course of history. 

Today was one such moment. And I will tell you why. 

The first time I realised I was excited in my life for the Nobel Prize was when I was a graduate student when one of the most seminal discoveries got recognized. To this date, that to me is the most exciting story that I have ever heard. In 2005, the Nobel Prize in Physiology and Medicine was granted to Dr. Barry Marshall and Dr. RObin Warren, who had some of the most unlikely stories ever known to me. It still boggles my mind the lengths Dr. Barry Marshall went to prove his idea. That is a story for another day, but he quite literally to prove that stomach ulcers could be caused by bacteria, drank a beaker of culture medium with the bacteria and ended up with ulcers. For someone who saw a lot of patients in my tertiary care posting during my undergraduate in the southern town of Madurai in my country in India..knowing that the discoverer of this phenomenon was recognized made me feel as if I won the Nobel. 

 It is in fact, this story that moulded me into believing that if you trust your idea, you must put everything behind it. And that it matters, to lead the way! 

Seven years later, the second moment of excitement came when Dr. Robert Lefkowitz and his former graduate student and now a faculty member at Stanford, Brian Kobilka were awarded the Nobel Prize in Medicine and Physiology for their studies of G-Protein coupled receptors. I had grown to admire so much about the GPCRs through my graduate school and the many targets that I worked on at my role at the pharmaceutical company GlaxoSmithKline and the many safety liabilities that came with non-selective targeting and off-target effect assessment. 

So now, coming to 2021. Nine years later, after the last time I was this excited, you might ask what is so exciting in this year’s announcement. Well, thats what we are going to talk about.

On 4th October, the Nobel prize was awarded to two individuals in recognition for their work and I am going to quote the Nobel committee now – “for their  discoveries that have unlocked one of the secrets of nature by explaining the molecular basis for sensing heat, cold and mechanical force, which is fundamental for our ability to feel, interpret and interact with our internal and external environment.

Why is this exciting to me? Well, let me explain. 

I have all my career looking at excitable tissues like the heart and the nerves. The wonderful thing about these two organs is that they exhibit spontaneous excitability. One to pump blood through the body and other to perform both voluntary and involuntary functions. 

I spent my graduate career studying the cardiac action potential and the underlying currents in health and disease. The heart, much like the nerves rely on proteins for the generation of spontaneous electrical activity and propagation of these impulses. These proteins sit on the cell membrane and are govern the movement of ions like sodium, potassium, calcium can move in and out of the molecular alleys encompassed by these proteins. 

Why is this exciting? Because it brings together two of the basic principles in physics and chemistry together with biology. The two principles that I am talking about is something that most high school students will have an appreciation for – Nernst equation for establishing what the equilibrium potential is for ion movement that many would have studied in chemistry. 

And the second is the most basic principle in electricity, Ohm’s Law where the resistance to the passage of current directly proportional to the voltage and inversely proportional to the current. 

The two equations form the basis for understanding ion movements and many physiological processes in our body.  Nernst Equation determines the potential difference or the voltage for driving ion channel flow in one direction or the other, while ohm’s law determines how efficiently, quickly can that flow occur. 

All of this was exciting times and things to learn as a graduate student. And most processes that I described is controlled by voltage gated ion channels. That means that ions like sodium, potassium and calcium move in response to what the voltage that they perceive are. Depending on the tissue and the configuration of the amino acids, these ion channels open and close at different voltages thus triggering a nerve impulse for which Herbert Gasser and Joseph Erlanger were awarded the Nobel Prize in 1944. Gassser and Erlanger postulated that thickness of the nerve fibre made the impulse travel faster. A decade later, Alan Hodgkin and Andrew hUxley were awarded the Nobel Prize for recording the first nerve action potential in the giant squid axon. 

Then from there on, to understanding that ion channels were responsible, it took another 40 odd years, when Neher and Sakmann were awarded the Nobel Prize for being able to record the individual ion channel activity much like how an electrician tests for current flow in a power outlet. Future prizes for how these ion channels brought the Nobel Prize to Rod McKinnon in the 2000s. 

So the field of electrophysiology and the art of making deductions of how electrical activity is generated in the body is a source of inspiration for answers to many physiological processes. This is what makes this year’s Nobel Prize special. 

So let me take it one step further to see if I can explain it to you. Do you remember the feeling of tasting spicy food? The feeling when you bite into a jalapeno or a really spicy Habanero pepper or Wasabi? Also, how can one differentiate between the spiciness of pepper vs. the smell and taste of garlic, to mint or a lozenge that contains menthol. 

Have you ever wondered, how such differentiation happens? Many foodies like myself will say that the taste of food is as much about the smell and aroma of the food, as it is about the taste. While one bites into a green chilli and feels that their mouth is on fire, it is because the tongue has numerous taste receptors, but more importantly, the taste receptors contains a specific ion channel called TRP channel. These TRP channels much like the sodium, potassium and calcium ion channels on heart muscle cells and nerve cells conduct ions into and out of the cells. But unlike, the voltage gated ion channels like sodium, potassium and calcium, these open in response to something extrinsic binding to the them like the chilli peppers constituent, capsaicin. 

These capsaicin molecules bind to the proteins called TRP channels, where TRP stands for Transient Receptor Potential. So unlike the sodium channel which opens and closes with voltage change, these TRP channels open and close very transiently as long as the chemical binds to it. Molecularly, it is revealed as a little calcium ion puffs that enters the cells to provide the chemical to electrical conversion of the impulse, thereby communicating to the brain or the taste centers that something that you bit into is so hot that your mouth feels like its on fire. 

It is interesting that while in humans, we associate the TRP channels with smell and taste like the hot chilli flavour mediated by TRPV1 or TRPM channels mediating methol flavours etc, it was originally discovered in frutflies where it is crucial for vision. A mutation in the TRP channel gene rendered the fruitflies blind. 

You will be interested to know that the fruitfly experiment was described not in the last two decades but back in 1969 by two scientists called DJ Couzens and Aubrey Manning. 

Now, we know that TRP channels exist in tissues beyond just the taste buds. Let’s go back to Gasser and Erlanger’s nerve impulse Nobel award. They postulated that nerve fiber thickness differences  mean that they conduct impulses faster, called A fibers. So if you understand basic physics, you might have heard a theory in electricity called Cable Theory. So Herbert Gasser and Joseph Erlanger concluded that thicker fibers conduct nerve impulses faster and thinner ones conduct slower. The slower fibers are called B and the smallest diameterand slowest conducting fibers are called C fibers. 

   For examples, many of the nerve fibers that are slow in conducting, so called C fibers contains the TRPV1 channels and are crucial for some of the sensations that we associate the touch and feel sensations, so called somatosensory signals. What is interesting to note and something that I am aware of, is that these TRPV channels of which TRPV1 is a type of channels are present in many tissues and organs of the body. Like for examples, TRPV4 subtypes senses the change in capillary pressure in the lungs and signals to the brain about pulmonary edema in a patient with heart failure and this triggers breathlessness as a physiological signature. So much like how your mouth feels on fire is a protective sensation so that you don’t ingest too much of the hot stuff, TRP channels are ubiquitous. 

TRPC channels are present in vascular tissues like arteries, veins and signals vascular elastance signals in response to stretch. And another more important aspect that was reciognized by the Nobel committee which takes into account the translatability of the scientific discoveries to application. So TRPA channels are closely tied into cytoskeletal proteins and act as sensory mechanism for detection of inflammation, injury and pain. So naturally, blockers of this ion channels are being considered for treating pain, 

Ok, so that was the story of TRP channel and despite many other before David Julius, he was recognized because his laboratory provided critical information for the functional classification and characterization of the ion channels. 

So now, let’s come to the second awardee, Ardem Parpoutian. Dr. Parpoputian’s lab at the Scripps Research Insitute is critical in understanding another type of ion channel that was just coming to be recognized around the time that I completed my PhD. He worked on a channels called Piezo channel, whose name might be similar to a few medical technologies. 

Piezo electric crystals are the mainstay of ultrasound and echocardiography probes and no points for guessing, what Piezo channels do. They recognize the mechanical forces that our body and cells in our body sense. For example, let me give you a classic example where mechanical force can translate to an electrical activity. 

Let us take one of the examples that we routinely hear in daily life or in television programs. A patient gets cardiac arrest and as a result, the heart stops beating. What are the ways in which a first responder tries to resuscitate the heart. It is by what healthcare professionals refer to as CPR or cardiopulmonary resuscitation. The core part of which is check for obstruction of the airway, check for breathing and check for pulse. Once there is no pulse, what ensues is precordial compressions, which is a mechanical attempt to restart. 

It is hoped and known for many years that an appropriately timed chest compressions can maintain the circulation and prevent death. The core to this belief is that chest compression or in some cases, electrical defibrillation using the chest paddles acts to restart the heart. WHat is the the center of this mechano-electrical transduction? The Piezo channels that was worked on, by our second nobel prize awardee for 2021, Ardem Parpoutian. 

Piezo channels are critical components of this type of mechano-transduction processes and therefore critical to many bodily functions. It is also abundantly found in the sensory ganglia that communicate the sensory signals of touch, feel to the spinal cord. You can almost sense the importance of such channels in the pressure sensing regions of the body that communicate to the brain on a beat to beat basis. 

Therefore, together the two awardees have demonstrated the molecular mechanisms for how touch, sense, feel, taste and stretch has impacted not just one organ or disease but many bodily processes in animals and in non-vertebrates. 

Why did we do this episode? Just so that we can provide such anecdotes and facts that might elude you in popular media. We have included a few references for you to look at in the show notes, if you are interested in digging deeper. 

We also did this episode because it ties together the interdisciplinary areas of biology, chemistry and physics and how sensations that are physical in nature are deduced in the human body via conversion of chemical to electrical stimuli in the case of TRP channels or mechanical to electrical signals in the case of PIEZO channels. 

Therefore, the underlying msg is one of approaching a problem that impacts society and science at a holistic level and not in isolation. One can use bespoke techniques but an integrated view is essential. 

We hope that the recognition of Dr. David Julius and Dr. Ardem Parpoutian excites, inspires and engages many of you to know more about how external stimuli are understood by the human body. We have all the people who came before them to thank as well for their contribution and these gentlemen have extended that line of thinking and deduction. 

That’s the end of this episode. If you liked this episode, let us know of your love, by sharing the episode link on social media on twitter, linkedin or other channels. Do tag us and give us your feedback. 

Thanks once again and hope to have the gift of your listening ears soon.