The Nobel
Prize in Physiology or Medicine 2021
The Nobel
Assembly at Karolinska Institutet has
decided to award
the 2021 Nobel Prize in Physiology or
Medicine
jointly to David Julius and Ardem
Patapoutian
for their discoveries of receptors for temperature
and touch
Our ability to sense heat, cold and touch
is essential for survival and underpins our interaction with the world around
us. In our daily lives we take these sensations for granted, but how are nerve
impulses initiated so that temperature and pressure can be perceived? This
question has been solved by this year’s Nobel Prize laureates.
David Julius utilized capsaicin, a pungent
compound from chili peppers that induces a burning sensation, to identify a
sensor in the nerve endings of the skin that responds to heat. Ardem
Patapoutian used pressure-sensitive cells to discover a novel class of sensors
that respond to mechanical stimuli in the skin and internal organs. These
breakthrough discoveries launched intense research activities leading to a
rapid increase in our understanding of how our nervous system senses heat,
cold, and mechanical stimuli. The laureates identified critical missing links
in our understanding of the complex interplay between our senses and the
environment.
How do we
perceive the world?
One of the great mysteries facing humanity
is the question of how we sense our environment. The mechanisms underlying our
senses have triggered our curiosity for thousands of years, for example, how
light is detected by the eyes, how sound waves affect our inner ears, and how
different chemical compounds interact with receptors in our nose and mouth
generating smell and taste. We also have other ways to perceive the world
around us. Imagine walking barefoot across a lawn on a hot summer’s day. You
can feel the heat of the sun, the caress of the wind, and the individual blades
of grass underneath your feet. These impressions of temperature, touch and
movement are essential for our adaptation to the constantly changing
surrounding.
In the 17th century, the philosopher René
Descartes envisioned threads connecting different parts of the skin with the
brain. In this way, a foot touching an open flame would send a mechanical
signal to the brain. Discoveries later revealed the existence of specialized
sensory neurons that register changes in our environment. Joseph Erlanger and
Herbert Gasser received the Nobel Prize in Physiology or Medicine in 1944 for
their discovery of different types of sensory nerve fibers that react to
distinct stimuli, for example, in the responses to painful and non-painful
touch. Since then, it has been demonstrated that nerve cells are highly
specialized for detecting and transducing differing types of stimuli, allowing
a nuanced perception of our surroundings; for example, our capacity to feel
differences in the texture of surfaces through our fingertips, or our ability
to discern both pleasing warmth, and painful heat.
Prior to the discoveries of David Julius
and Ardem Patapoutian, our understanding of how the nervous system senses and
interprets our environment still contained a fundamental unsolved question: how
are temperature and mechanical stimuli converted into electrical impulses in
the nervous system?
The science
heats up!
In the latter part of the 1990’s, David
Julius at the University of California, San Francisco, USA, saw the possibility
for major advances by analyzing how the chemical compound capsaicin causes the
burning sensation we feel when we come into contact with chili peppers.
Capsaicin was already known to activate nerve cells causing pain sensations,
but how this chemical actually exerted this function was an unsolved riddle.
Julius and his co-workers created a library of millions of DNA fragments
corresponding to genes that are expressed in the sensory neurons which can
react to pain, heat, and touch. Julius and colleagues hypothesized that the
library would include a DNA fragment encoding the protein capable of reacting
to capsaicin. They expressed individual genes from this collection in cultured
cells that normally do not react to capsaicin. After a laborious search, a
single gene was identified that was able to make cells capsaicin sensitive. The
gene for capsaicin sensing had been found! Further experiments revealed that
the identified gene encoded a novel ion channel protein and this newly
discovered capsaicin receptor was later named TRPV1. When Julius investigated
the protein’s ability to respond to heat, he realized that he had discovered a
heat-sensing receptor that is activated at temperatures perceived as painful.
The discovery of TRPV1 was a major
breakthrough leading the way to the unravelling of additional
temperature-sensing receptors. Independently of one another, both David Julius
and Ardem Patapoutian used the chemical substance menthol to identify TRPM8, a
receptor that was shown to be activated by cold. Additional ion channels
related to TRPV1 and TRPM8 were identified and found to be activated by a range
of different temperatures. Many laboratories pursued research programs to
investigate the roles of these channels in thermal sensation by using
genetically manipulated mice that lacked these newly discovered genes. David
Julius’ discovery of TRPV1 was the breakthrough that allowed us to understand
how differences in temperature can induce electrical signals in the nervous
system.
Research
under pressure!
While the mechanisms for temperature
sensation were unfolding, it remained unclear how mechanical stimuli could be
converted into our senses of touch and pressure. Researchers had previously
found mechanical sensors in bacteria, but the mechanisms underlying touch in
vertebrates remained unknown. Ardem Patapoutian, working at Scripps Research in
La Jolla, California, USA, wished to identify the elusive receptors that are
activated by mechanical stimuli.
Patapoutian and his collaborators first
identified a cell line that gave off a measurable electric signal when
individual cells were poked with a micropipette. It was assumed that the
receptor activated by mechanical force is an ion channel and in a next step 72
candidate genes encoding possible receptors were identified. These genes were
inactivated one by one to discover the gene responsible for mechanosensitivity
in the studied cells. After an arduous search, Patapoutian and his co-workers
succeeded in identifying a single gene whose silencing rendered the cells
insensitive to poking with the micropipette. A new and entirely unknown
mechanosensitive ion channel had been discovered and was given the name Piezo1,
after the Greek word for pressure (í; píesi). Through its similarity to Piezo1,
a second gene was discovered and named Piezo2. Sensory neurons were found to
express high levels of Piezo2 and further studies firmly established that
Piezo1 and Piezo2 are ion channels that are directly activated by the exertion
of pressure on cell membranes.
The breakthrough by Patapoutian led to a
series of papers from his and other groups, demonstrating that the Piezo2 ion
channel is essential for the sense of touch. Moreover, Piezo2 was shown to play
a key role in the critically important sensing of body position and motion,
known as proprioception. In further work, Piezo1 and Piezo2 channels have been
shown to regulate additional important physiological processes including blood
pressure, respiration and urinary bladder control.
It all
makes sense!
The groundbreaking discoveries of the
TRPV1, TRPM8 and Piezo channels by this year’s Nobel Prize laureates have
allowed us to understand how heat, cold and mechanical force can initiate the
nerve impulses that allow us to perceive and adapt to the world around us. The
TRP channels are central for our ability to perceive temperature. The Piezo2
channel endows us with the sense of touch and the ability to feel the position
and movement of our body parts. TRP and Piezo channels also contribute to
numerous additional physiological functions that depend on sensing temperature
or mechanical stimuli. Intensive ongoing research originating from this year’s
Nobel Prize awarded discoveries focusses on elucidating their functions in a
variety of physiological processes. This knowledge is being used to develop
treatments for a wide range of disease conditions, including chronic pain .
David
Julius was born in 1955 in New York,
USA. He received a Ph.D. in 1984 from University of California, Berkeley and
was a postdoctoral fellow at Columbia University, in New York. David Julius was
recruited to the University of California, San Francisco in 1989 where he is
now Professor.
Ardem
Patapoutian was born in 1967 in Beirut,
Lebanon. In his youth, he moved from a war-torn Beirut to Los Angeles, USA and
received a Ph.D. in 1996 from California Institute of Technology, Pasadena,
USA. He was a postdoctoral fellow at the University of California, San
Francisco. Since 2000, he is a scientist at Scripps Research, La Jolla,
California where he is now Professor. He is a Howard Hughes Medical Institute
Investigator since 2014.
