THE NOBEL PRIZE IN
PHYSIOLOGY OR MEDICINE 2017
The Nobel Assembly at
Karolinska Institutet has today decided to award the 2017 Nobel Prize in Physiology or Medicine
jointly to Jeffrey C. Hall, Michael Rosbash and Michael
W. Young for their discoveries of molecular
mechanisms controlling the circadian rhythm.
Summary
Life
on Earth is adapted to the rotation of our planet. For many years we have known
that living organisms, including humans, have an internal, biological clock
that helps them anticipate and adapt to the regular rhythm of the day. But how
does this clock actually work? Jeffrey C. Hall, Michael Rosbash and Michael W.
Young were able to peek inside our biological clock and elucidate its inner
workings. Their discoveries explain how plants, animals and humans adapt their
biological rhythm so that it is synchronized with the Earth's revolutions.
Using
fruit flies as a model organism, this year's Nobel laureates isolated a gene
that controls the normal daily biological rhythm. They showed that this gene
encodes a protein that accumulates in the cell during the night, and is then
degraded during the day. Subsequently, they identified additional protein
components of this machinery, exposing the mechanism governing the
self-sustaining clockwork inside the cell. We now recognize that biological
clocks function by the same principles in cells of other multicellular
organisms, including humans.
With
exquisite precision, our inner clock adapts our physiology to the dramatically
different phases of the day. The clock regulates critical functions such as
behavior, hormone levels, sleep, body temperature and metabolism. Our wellbeing
is affected when there is a temporary mismatch between our external environment
and this internal biological clock, for example when we travel across several
time zones and experience "jet lag". There are also indications that
chronic misalignment between our lifestyle and the rhythm dictated by our inner
timekeeper is associated with increased risk for various diseases.
Our inner clock
Most
living organisms anticipate and adapt to daily changes in the environment.
During the 18th century, the astronomer Jean Jacques d'Ortous de Mairan studied
mimosa plants, and found that the leaves opened towards the sun during daytime
and closed at dusk. He wondered what would happen if the plant was placed in
constant darkness. He found that independent of daily sunlight the leaves
continued to follow their normal daily oscillation (Figure 1). Plants seemed to
have their own biological clock.
Other
researchers found that not only plants, but also animals and humans, have a
biological clock that helps to prepare our physiology for the fluctuations of
the day. This regular adaptation is referred to as the circadianrhythm,
originating from the Latin words circa meaning "around"
and diesmeaning "day". But just how our internal circadian
biological clock worked remained a mystery.
Figure
1. An internal biological clock. The leaves of the mimosa plant open
towards the sun during day but close at dusk (upper part). Jean Jacques
d'Ortous de Mairan placed the plant in constant darkness (lower part) and found
that the leaves continue to follow their normal daily rhythm, even without any
fluctuations in daily light.
Identification of a clock gene
During
the 1970's, Seymour Benzer and his student Ronald Konopka asked whether it
would be possible to identify genes that control the circadian rhythm in fruit
flies. They demonstrated that mutations in an unknown gene disrupted the
circadian clock of flies. They named this gene period. But how could this
gene influence the circadian rhythm?
This
year's Nobel Laureates, who were also studying fruit flies, aimed to discover
how the clock actually works. In 1984, Jeffrey Hall and Michael Rosbash,
working in close collaboration at Brandeis University in Boston, and Michael
Young at the Rockefeller University in New York, succeeded in isolating
the period gene. Jeffrey Hall and Michael Rosbash then went on to
discover that PER, the protein encoded by period, accumulated during
the night and was degraded during the day. Thus, PER protein levels oscillate
over a 24-hour cycle, in synchrony with the circadian rhythm.
A self-regulating clockwork
mechanism
The
next key goal was to understand how such circadian oscillations could be
generated and sustained. Jeffrey Hall and Michael Rosbash hypothesized that the
PER protein blocked the activity of the period gene. They reasoned
that by an inhibitory feedback loop, PER protein could prevent its own
synthesis and thereby regulate its own level in a continuous, cyclic rhythm (Figure
2A).
Figure
2A. A simplified illustration of the feedback regulation of the periodgene. The
figure shows the sequence of events during a 24h oscillation. When the period gene
is active, period mRNA is made. The mRNA is transported to the cell's
cytoplasm and serves as template for the production of PER protein.
The PER protein accumulates in the cell's nucleus, where the period gene
activity is blocked. This gives rise to the inhibitory feedback mechanism that
underlies a circadian rhythm.
The
model was tantalizing, but a few pieces of the puzzle were missing. To block
the activity of the period gene, PER protein, which is produced in
the cytoplasm, would have to reach the cell nucleus, where the genetic material
is located. Jeffrey Hall and Michael Rosbash had shown that PER protein builds
up in the nucleus during night, but how did it get there? In 1994 Michael Young
discovered a second clock gene, timeless, encoding the TIM protein that
was required for a normal circadian rhythm. In elegant work, he showed that
when TIM bound to PER, the two proteins were able to enter the cell nucleus
where they blocked period gene activity to close the inhibitory
feedback loop (Figure 2B).
Figure
2B. A simplified illustration of the molecular components of the circadian
clock.
Such
a regulatory feedback mechanism explained how this oscillation of cellular
protein levels emerged, but questions lingered. What controlled the frequency
of the oscillations? Michael Young identified yet another gene, doubletime,
encoding the DBT protein that delayed the accumulation of the PER protein. This
provided insight into how an oscillation is adjusted to more closely match a
24-hour cycle.
The
paradigm-shifting discoveries by the laureates established key mechanistic
principles for the biological clock. During the following years other molecular
components of the clockwork mechanism were elucidated, explaining its stability
and function. For example, this year's laureates identified additional proteins
required for the activation of the period gene, as well as for the
mechanism by which light can synchronize the clock.
Keeping time on our human
physiology
The
biological clock is involved in many aspects of our complex physiology. We now
know that all multicellular organisms, including humans, utilize a similar
mechanism to control circadian rhythms. A large proportion of our genes are
regulated by the biological clock and, consequently, a carefully calibrated
circadian rhythm adapts our physiology to the different phases of the day (Figure
3). Since the seminal discoveries by the three laureates, circadian biology has
developed into a vast and highly dynamic research field, with implications for
our health and wellbeing.
Figure
3. The circadian clock anticipates and adapts our physiology to the different
phases of the day. Our biological clock helps to regulate sleep patterns,
feeding behavior, hormone release, blood pressure, and body temperature.
