Amita SehgalNobel Conference 60

Amita Sehgal

John Herr Musser Professor of Neuroscience, Perelman School of Medicine, University of Pennsylvania

Using a Simple Animal Model to Understand How and Why We Sleep

We’ve got rhythm. Within our cells reside “clocks” that determine the cadence of our daily activities. Rather than gears that turn at regular intervals, oscillations of molecular action govern a roughly 24-hour cycle of physiological and behavioral actions. Rhythmic responses, such as development, growth, feeding, and sleep, have been demonstrated in multicellular organisms such as fungi, plants, and animals, and have been observed even in bacteria. Circadian rhythms are critical for life for at least two reasons. First, they ensure that organisms are active – or inactive – when conditions are right. Second, they coordinate several physiological conditions for more efficient function. In humans, one of those functions is sleep.

Amita Sehgal explores how sleep “works” and the molecular connection(s) between sleep and other physiological and developmental processes. A molecular biologist and chronobiologist, Sehgal explores and describes previously unknown or poorly understood relationships among feeding, sleep, memory, and immune function. sehgal’s research demonstrates that sleep is an active and necessary component of our well-being. She and members of her laboratory recently identified a gene, and its protein connecting sleep and immune function. Nemuri, Japanese for “sleep”, is an antimicrobial molecule that helps to stave off infections. However, Nemuri has another function: it induces sleep. Perhaps the production of Nemuri, in response to infection, directly combats the infecting microbes while also inducing sleep to promote healing. This may help explain why we sleep so much when we are ill. 

Sehgal conducts her research using Drosophila melanogaster, a.k.a. the pomace (fruit) fly, because it is an excellent model system in which to explore questions at their fundamental levels. Flies have similar, although simpler, behaviors governed by circadian rhythms (yes, they sleep!). Pomace flies also have time-keeping proteins (“clock” proteins) that are similar to humans’, but fewer in number and less complex in their interactions. 

Experiments in Sehgal’s laboratory showed that flies who were prevented from sleeping accumulated molecules that, in turn, damaged necessary proteins and caused fats to accumulate in cells. These damaging molecules were cleared only when flies were allowed to sleep. When sleep is disrupted the effects “ripple” through the body, affecting metabolism, cognition, and the immune system. Understanding the connection among these apparently disparate conditions is critical for understanding the value of sleep and the harm caused by sleep disruption. 

Amita Sehgal is the John Herr Musser Professor in the Perelman School of Medicine at the University of Pennsylvania. She earned a PhD in cell biology and genetics from Cornell University. 

Her lecture

Sleep remains a major mystery of biology. Why we spend ~a third of our lives sleeping
and what it is that makes us sleepy are major questions about sleep that lack
satisfactory answers. There is universal agreement that lack of sleep impairs
performance, especially cognitive ability, during waking hours and considerable
evidence supports adverse effects of sleep loss on other physiological parameters as
well. Thus, sleep may be regarded as important for waking function. However, what
happens during sleep to facilitate wake performance and promote health?
Driven by the successful use of Drosophila for deciphering molecular mechanisms of the
circadian clock, we developed a Drosophila model to address molecular and cellular
underpinnings of sleep. Through the use of forward genetic screens, we have identified
genes and tissues that affect sleep amount. Coupled with tests of candidate hypotheses
for sleep function, we are starting to get a handle on cellular functions of sleep that may
be broadly relevant for the brain, and perhaps even the body. In general, we find that
sleep is important for metabolic homeostasis, which includes the clearance of metabolic
waste. Together this work is leading to an understanding of cellular/molecular
processes that underlie sleep.