Amita Sehgal is a
molecular biologist
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
and
chronobiologist in the Department of Neuroscience at the
Perelman School of Medicine
The Perelman School of Medicine, commonly known as Penn Med, is the medical school of the University of Pennsylvania, a private research university in Philadelphia, Pennsylvania. Founded in 1765, the Perelman School of Medicine is the oldest medi ...
at the
University of Pennsylvania
The University of Pennsylvania (also known as Penn or UPenn) is a private research university in Philadelphia. It is the fourth-oldest institution of higher education in the United States and is ranked among the highest-regarded universitie ...
.
Sehgal was involved in the discovery of ''Drosophila'' TIM and many other important components of the ''Drosophila'' clock mechanism.
[Pennsylvania scientist played role in research that won 2017 Nobel Prize https://www.pennlive.com/news/2017/10/pennsylvania_scientist_contrib.html] Sehgal also played a pivotal role in the development of ''Drosophila'' as a model for the study of sleep.
Her research continues to be focused on understanding the genetic basis of sleep and also how circadian systems relate to other aspects of physiology.
Education and early career
Sehgal grew up in India, and earned her BSc as an undergraduate at
Delhi University
Delhi University (DU), formally the University of Delhi, is a collegiate university, collegiate Central university (India), central university located in New Delhi, India. It was founded in 1922 by an Act of the Central Legislative Assembly and ...
and her MSc at
Jawaharlal Nehru University
Jawaharlal Nehru University (JNU) is a public major research university located in New Delhi, India. It was established in 1969 and named after Jawaharlal Nehru, India's first Prime Minister. The university is known for leading faculties and r ...
, both in New Delhi, India.
She began pursuing her PhD in cell biology and genetics at
Cornell University
Cornell University is a private statutory land-grant research university based in Ithaca, New York. It is a member of the Ivy League. Founded in 1865 by Ezra Cornell and Andrew Dickson White, Cornell was founded with the intention to teach an ...
in 1983.
It was here, while studying a human neuronal growth factor, that her interest in science truly developed.
In 1988, she began her Postdoctoral Fellowship at
Rockefeller University
The Rockefeller University is a private biomedical research and graduate-only university in New York City, New York. It focuses primarily on the biological and medical sciences and provides doctoral and postdoctoral education. It is classif ...
in the lab of
Michael Young, where she had her first exposure to the study of
circadian rhythm
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...
s, a field in which she has since remained.
Research
Timeline of selected major research contributions
*1994: Discovered the ''timeless'' mutation in fruit flies.
*1995: Cloned the ''timeless'' gene and showed the expression of the ''timeless'' gene has daily cycles.
*1996: Showed pulses of light degrade ''timeless''.
*2000: Developed a ''
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
'' model for sleep.
*2001: Showed ''neurofibromin 1'' plays a role in the circadian pathway in fruit flies.
*2006: Discovered the ''jetlag ''mutation and'' ''showed the JETLAG protein is involved in the degradation of the TIMELESS protein.
*2006: Showed mushroom bodies in fruit flies are important for sleep.
*2008: Discovered the ''sleepless'' gene in fruit flies.
*2014: Mapped neural circuits that link the clock to behavior
*2014: Discovered a function of sleep in early life
*2018: Identified a potential role of sleep in adult flies
*2018: Demonstrated circadian regulation of the blood brain barrier
*2019: Discovered a molecular link between sleep and the immune system
Timeless and Period
Amita Sehgal has contributed tremendously towards the understanding of the biological clock of ''Drosophila melanogaster''. In 1994, Sehgal, Price, Man, and Young, through
forward genetics
Forward genetics is a molecular genetics approach of determining the genetic basis responsible for a phenotype. Forward genetics provides an unbiased approach because it relies heavily on identifying the genes or genetic factors that cause a partic ...
, discovered a mutant of the gene
''timeless'' (TIM) in ''Drosophila melanogaster''.
'' ''In the following year, Sehgal and colleagues cloned TIM through
positional cloning
A genetic screen or mutagenesis screen is an experimental technique used to identify and select individuals who possess a phenotype of interest in a mutagenized population. Hence a genetic screen is a type of phenotypic screen. Genetic screens c ...
and were able to show that TIM and
PER
Per is a Latin preposition which means "through" or "for each", as in per capita.
Per or PER may also refer to:
Places
* IOC country code for Peru
* Pér, a village in Hungary
* Chapman code for Perthshire, historic county in Scotland
Math ...
had similar cycling levels of their mRNA.
The model they proposed, which was confirmed over time, was that PER and TIM interact and accumulate during the day. In the evening, they enter the nucleus to inhibit the transcription of their mRNA. In 1996, Sehgal's laboratory showed that degradation in TIM levels caused by a pulse of light resets the circadian clock. Later, they showed that specific phosphatases control stability of PER and TIM in daily cycles.
Neurofibromin 1
Neurofibromin 1
Neurofibromin 1 (''NF1'') is a gene in humans that is located on chromosome 17. ''NF1'' codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. ''N ...
(NF1) is a
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
known to be dis-regulated in
Neurofibromatosis type 1
Neurofibromatosis (NF) is a group of three conditions in which tumors grow in the nervous system. The three types are neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis. In NF1 symptoms include light brown sp ...
, a disorder which causes tumors along the spine. In 2001, Sehgal and her colleagues learned that some patients with Neurofibromatosis type 1 also experience irregularities in their sleep, and so decided to investigate the circadian rhythms of flies with a nonfunctional NF1 gene.
They found that these flies also have disrupted circadian rhythms, and these rhythms could be restored by inserting NF1
transgene
A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
s, thus proving that NF1 is involved in the circadian pathway. They showed that in flies, NF1 functions through the
MAP kinase
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses ...
pathway, which is the same pathway implicated in Neurofibromatosis type 1 in humans.
Jetlag
In 2006, Sehgal and her colleagues discovered a mutant fly which takes an abnormally long time to adjust to new light-dark cycles. They named the underlying mutated gene ''jetlag'' (jet). This gene codes for an
F-box protein
F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the 26S proteasome.
Core c ...
called JET, a
ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
that facilitates resetting the drosophila clock. Sequencing of the gene revealed two
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
s of ''jetlag:'' the "c" allele (common) and the "r" allele (rare). In the presence of
CRYPTOCHROME
Cryptochromes (from the Greek κρυπτός χρώμα, "hidden colour") are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields i ...
(CRY), JET plays a major role in the degradation of
TIMELESS (TIM) protein in response to light, which is necessary for the clock to entrain to external light cues.
Mushroom bodies
Mushroom bodies
The mushroom bodies or ''corpora pedunculata'' are a pair of structures in the brain of insects, other arthropods, and some annelids (notably the ragworm ''Platynereis dumerilii''). They are known to play a role in olfactory learning and memory ...
are located in the brains of ''Drosophila'' and are known to play a role in learning, memory, olfaction, and locomotion. In 2006, Sehgal and her colleagues discovered that mushroom bodies also play a major role in regulating sleep in flies. By using a steroid called
RU-486 (Mifepristone) to regulate protein kinase A (
PKA), they were able to upregulate and downregulate the expression of genes in specific areas like the mushroom bodies, and found that this structure is critical for fly sleep. While the specific pathway through which these mushroom bodies regulate sleep is currently unknown, it may be that they are involved in inhibiting processing of sensory information, allowing flies to fall asleep.
Sleepless
In 2008, Sehgal ''et al.'' discovered the ''sleepless ''gene in fruit flies through
insertional mutagenesis In molecular biology, insertional mutagenesis is the creation of mutations of DNA by addition of one or more base pairs. Such insertional mutations can occur naturally, mediated by viruses or transposons, or can be artificially created for researc ...
. Mutations in the ''sleepless'' gene caused the flies to sleep 80% less than normal flies, and live half as long as normal flies. Sehgal ''et al.'' discovered that the SLEEPLESS protein regulates the voltage-gated potassium channel, Shaker, and also nicotinic acetylcholine receptors, specifically one called redeye that they discovered through another genetic screen.
Sehgal ''et al.'' also found increased stem cell activity within the testes of male flies with mutations in ''sleepless''.
Functions of sleep
All species, including humans, sleep a lot in early life. Sehgal et al discovered what keeps sleep at high levels in young fruit flies. They also found that when sleep is disrupted in early life, mating behavior is perturbed in adults. Thus, sleep may be required to allow brain development for behaviors that promote survival and species propagation. In adult animals, a possible function of sleep is to promote clearance of waste. Sehgal et al found that sleep promotes endocytosis through the blood brain barrier in flies.
Clocks and behavior and the blood brain barrier
The blood brain barrier (BBB) protects the brain from potentially harmful molecules in the periphery, but it can also impede the delivery of drugs to the central nervous system. Sehgal et al found that permeability of the fly BBB changes over the course of the day: night cycle, so an anti-epileptic works better at a specific time of day. They have also mapped circuits that link the clock to behavioral activity.
Sleep and immune function
Seeking to identify molecules that induce sleep, Toda et al conducted a genetic screen of >10,000 of fruit fly strains, and found one that drives sleep. This molecule, which they named nemuri, is an anti-microbial peptide. Its expression is switched on by infection or sleep deprivation, and it promotes survival by killing bacteria and increasing sleep.
Awards and positions
Positions
*Director, Chronobiology and Sleep Institute (CSI), Perelman School of Medicine, Univ of Penn, 2019-pres
*Director of Penn Chronobiology Program, 2014-19
*Howard Hughes Medical Institute Investigator 1997–Present
*John Herr Musser Professor of Neuroscience, Perelman School of Medicine, University of Pennsylvania
*Vice Chair of the Department of Neuroscience
*Co-Director of the Penn Medicine Neuroscience Center 2008-2014
Awards
*Outstanding Scientific Achievement Award, Sleep Research Society
*Michael S. Brown Junior Faculty Research Award
*Stanley Cohen Senior Faculty Research Award
*Elected to the National Academy of Medicine (formerly Institute of Medicine) 2009
*Elected to the American Academy of Arts and Sciences 2011
*Elected Fellow of the American Association for the Advancement of Science 2016
*Elected to the
National Academy of Sciences
The National Academy of Sciences (NAS) is a United States nonprofit, non-governmental organization. NAS is part of the National Academies of Sciences, Engineering, and Medicine, along with the National Academy of Engineering (NAE) and the Nati ...
, 2016
[.]
*Switzer Prize from UCLA 2020
References
{{DEFAULTSORT:Sehgal, Amita
Cornell University alumni
Jawaharlal Nehru University alumni
Living people
Indian molecular biologists
Perelman School of Medicine at the University of Pennsylvania
Delhi University alumni
Indian women molecular biologists
Year of birth missing (living people)
Place of birth missing (living people)
Chronobiologists
Members of the United States National Academy of Sciences
Women scientists from Delhi
Perelman School of Medicine at the University of Pennsylvania faculty
Members of the National Academy of Medicine