NRI-Impact-Report-2019_WEB

Texas Children’s Hospital
Jan and Dan Duncan
Neurological Research Institute ®
2019 Impact Report

“It is our ability to change peoples’
lives for the better that inspires and
motivates us every single day.”
Hsiao-Tuan Chao, M.D., Ph.D.
Investigator at the Duncan NRI

Less than a decade ago, we founded the Jan and Dan Duncan Neurological
Research Institute at Texas Children’s Hospital with a bold vision of understanding
devastating brain diseases that impact one billion people worldwide,
and developing effective treatments. Thanks to the tremendous support of our
community, we are now at the forefront of solving the most complex medical
mysteries that have eluded scientists.
Our progress in 2019 toward uncovering the underlying causes of disease and
developing pathways to life-saving treatments has provided much-needed hope to
patients, families, and the global scientific community. This report highlights some
of the groundbreaking discoveries from the past year.
Duncan NRI in 2019
137 discoveries published in top-tier journals
$21 million in highly-competitive grants
30 faculty investigators
254 trainees
4 clinical trials in development

“At the Duncan NRI, we have experts in cell biology, genetics, molecular biology,
neuroscience, neurophysiology and more. Not only are we all under one roof, which
is so special, but more importantly our leader, Dr. Huda Zoghbi, has cultivated an
incredible culture of generosity.
We are not competing with each other for recognition, because we believe that if
we work together, we can collectively solve more diseases faster to heal the children
who inspire us. It’s simply not like this anywhere else. This makes the translation
of everything we discover at the bench move very quickly to clinical practice.”
Mirjana Maletić-Savatić, M.D., Ph.D.
Investigator at the Duncan NRI
Dr. Huda Zoghbi is the founding director of the Duncan NRI and an internationally renowned
neuroscientist. She has made groundbreaking discoveries in the laboratory and published seminal work
on the genetic bases of Rett syndrome, autism, spinocerebellar ataxia, and late-onset neurodegenerative
diseases including Alzheimer’s disease and Parkinson’s disease.
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2019 MAJOR DISCOVERIES

Tuberous sclerosis
Published in Proceedings of the National Academy of Sciences U.S.A., February 2019
To date, the scientific community has understood mTORC1, a protein complex that regulates cell
metabolism, as the major driving force behind tuberous sclerosis. But according to a newly-published
study led by a team at the Duncan NRI, the development of this rare condition also involves a
second mechanism that is independent of mTORC1. This newly-discovered mechanism results in the
accumulation of glycogen, a main source of energy, which damages cells and results in disease.
This discovery has the potential to lead to new treatments that might benefit patients who only
partially respond to current therapies focused on mTORC1.
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“ Tuberous sclerosis is
devastating. It causes
tumors in the brain,
kidneys, and other organs.
It results in seizures that
can be so debilitating
that children affected
may never speak. We are
hopeful that this new
discovery will lead to a
deeper understanding that
allows the development of
new treatments.”
Marco Sardiello, Ph.D.
Duncan NRI investigator focused on lysosomal storage disorders

Amyotrophic lateral sclerosis (ALS)
Published in Nature Cell Biology, February 2019
ALS, also known as Lou Gehrig’s disease, is a progressive, fatal neuromuscular condition characterized
by an imbalance between the synthesis and degradation of proteins within cells. When this balance
is tipped, excess waste builds up in cells and the disease develops. Researchers at the Duncan NRI
discovered that certain proteins fail to clear the excess waste because the lysosomes are dysfunctional.
When these researchers fed acidic nanoparticles to flies bred to have ALS, clearance of accumulated
waste and the normal flow of the lysosomal process improved. This study suggests potential new
therapeutic strategies.
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“ We are excited by the initial
success of this strategy
in reducing the build-up
of dysfunctional proteins
in flies since it could
potentially be developed
as a novel therapeutic
approach to treat ALS and
frontotemporal dementia.”
Hugo Bellen, D.V.M., Ph.D. and Mumine Senturk, Ph.D.
Duncan NRI investigator and postdoctoral associate respectively,
with focuses on the discovery of unknown neurological diseases

Artificial intelligence tool
Published in Genome Research, April 2019
Like finding a needle in a haystack, identifying genes that are involved in particular diseases can be
an arduous and time-consuming process. Using artificial intelligence, a team of researchers at the Duncan
NRI has developed a new bioinformatics tool that analyzes data and identifies potentially relevant genes
with greater sensitivity and accuracy than previously possible. This cloud-based computing framework
enables lab scientists around the world to better estimate the statistical significance of each gene that
they measure while generating likely candidate targets for therapies in a matter of hours.
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“ We developed this tool with
the objective of helping
thousands of scientists
around the world. They
can now more accurately
and efficiently screen
data that can lead to
transformational medical
discoveries.”
Zhandong Liu, Ph.D.
Duncan NRI investigator focused on developing bioinformatics tools

Eating disorders
Published in eLife, May 2019
A study conducted in Dr. Benjamin Arenkiel’s lab at the Duncan NRI identified novel circuits in the
basal forebrain that perceive and transmit odors from food and the environment to areas in the brain
that directly control eating behaviors. In mice, researchers found that if basal forebrain circuits are
inactive, they overeat and become obese, but if the circuits overactive, the animals stop eating and
starve themselves to the point of death. Investigators at the Duncan NRI are now working to harness
these newly-discovered brain circuits to develop treatments for eating disorders, mood disorders,
and addiction.
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“ This circuit is highly involved
with how our brain perceives
the outside world. We think
this discovery has potential
implications that reach far
beyond eating behaviors
and physiology, and may
translate into therapeutic
approaches for a wide range
of neuropsychiatric diseases.”
Benjamin Arenkiel, Ph.D.
Duncan NRI investigator focused on the formation, function,
and maintenance of neural circuits

Alzheimer’s disease
Multiple Duncan NRI labs have discovered genes that increase
susceptibility to Alzheimer’s disease and identified targets for
therapeutic intervention:
Published in Cell Reports, August 2019:
A new study sheds light on how the CD2AP gene may enhance
Alzheimer’s disease susceptibility. Researchers discovered that
CD2AP affects neuronal communication by regulating the levels of
key proteins present at neuron terminals (synapses). As a part of this
multi-institutional study led by a team at the Duncan NRI, researchers
examined a collection of more than 800 brain autopsies and found
that low CD2AP levels significantly correlated with abnormal loss of
synaptic proteins, and this relationship was enhanced in the setting
of Alzheimer’s disease.
Published in Cell, August 2019:
A collaborative study with Massachusetts General Hospital at Harvard
Medical School reveals that the ATAXIN-1 gene, which is known to
cause the rare neurodegenerative disease called spinocerebellar
ataxia type 1 (SCA1), also can increase the risk of Alzheimer’s
disease. When a team of researchers—including Drs. Jaehong Suh,
Rudolph Tanzi, and Huda Zoghbi—removed the ATAXIN-1 gene in
mice, they found increased amyloid beta peptides and disruption
of both neuronal connectivity and neurogenesis, which may explain
observations of learning and memory problems.
Published in Cell Reports, October 2019:
A study from the Duncan NRI provides evidence for a new molecular
cause for neurodegeneration in Alzheimer’s disease. By integrating data
from human brain autopsy samples and fruit flies, Dr. Joshua Shulman
revealed a novel mechanistic link between alterations in RNA splicing
and neurodegeneration in Alzheimer’s disease. RNA splicing is one
of the important ways by which organs generate different proteins in
the cells, each of which performs specialized functions. This discovery
shows how aggregates of tau protein within neurons—a key marker
of Alzheimer’s disease—interferes with RNA splicing and presents the
possibility of using RNA splicing as a molecular target for Alzheimer’s
disease and other tau-mediated neurodegenerative conditions.
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“ Alzheimer’s disease is devastating,
not only for the millions living
with it, but also for the friends and
family who watch their loved ones
deteriorate without hope. Through
our multidisciplinary, crossspecies
approach, we are tackling
this complex disease differently
at the Duncan NRI. And over the
past year, we’ve made exciting
discoveries that are opening doors
for many promising new treatment
strategies.”
Joshua Shulman, M.D., Ph.D.
Duncan NRI investigator focused on Alzheimer’s disease
and Parkinson’s disease

Intellectual disability
Published in the American Journal of Human Genetics, October 2019
Led by the Duncan NRI’s Dr. Hugo Bellen, a group of international scientists—spanning seven countries
and 13 institutions—discovered a new intellectual disability syndrome. By genetically modifying fruit
flies, they discovered that mutations in the IQSEC1 gene cause this novel disease. Collaborators at the
University of Geneva identified five affected individuals from Pakistan and Saudi Arabia with mutations
in gene IQSEC1 who all exhibit similar symptoms, including intellectual disability, developmental delay,
short stature, and low muscle tone. This is a promising first step toward developing diagnostic tests and,
possibly, targeted treatments.
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“ Intellectual disability
is the most common
developmental disability,
affecting nearly 200 million
people globally. However,
many genes and molecular
pathways involved in these
conditions remain to be
uncovered and fruit flies
help us to unravel these
mysteries.”
Hugo Bellen, D.V.M., Ph.D. and Hyunglok Chung, Ph.D.
Duncan NRI investigator and postdoctoral associate respectively,
with focuses on the discovery of unknown neurological diseases

Microcepahly and Zika virus
Published in Developmental Cell and Cell, November 2019
A new study using fruit flies has uncovered a novel genetic pathway that causes microcephaly, a birth
defect in which a newborn has a small and under-developed brain. This pathway affects asymmetric
division of stem cells, a process that is essential to generating brain cells during development. When
this pathway is disrupted, it leads to neuronal loss and microcephaly. Dr. Nichole Link in the Bellen lab
at the Duncan NRI discovered how a Zika virus protein disrupts this pathway, providing insights into
how Zika causes small brains and presenting possibilities for promising targets for therapies.
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“ For decades, researchers
were at an impasse.
We knew that Zika was
linked to microcephaly—
but we didn’t know how.
With this new discovery,
we are excited about the
possibility of developing
a new drug that can stop
Zika’s devastating effects.”
Nichole Link, Ph.D.
Duncan NRI postdoctoral associate in the Bellen Lab,
with a focus on the structure of the nucleus

CONFERENCE CENTER
Center for Global
Collaboration
In fall 2019, the Duncan NRI opened a new state-of-the-art
conference center with the latest technological capabilities
to provide an ideal space for national and international
scientific collaboration and public engagement. It will
be the epicenter of knowledge sharing and partnerships
across more than 30 countries.
The kick-off event in the new conference center was the
Rett Syndrome Symposium, an international gathering
honoring the 20 th anniversary of Dr. Huda Zoghbi’s
momentous discovery of the genetic cause of Rett
syndrome. Dr. Zoghbi opened the two-day conference
by saying, “The hope is that in five years’ time, out of the
work and discussions that happen at this conference,
we will be celebrating new treatments for Rett syndrome.”
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PATIENT SPOTLIGHT
Leo the Superhero
Leo was a happy and healthy child. He reached his developmental
milestones, walking and babbling during his first year. However, after
the age of two, things began to change. Leo became increasingly
unsteady until he could no longer walk or run. His parents consulted
a multitude of specialists—even traveling to Japan—but after many
tests, there was still no diagnosis.
As his parents continued to look for answers, Leo’s motor and verbal
skills rapidly deteriorated. By the time he started preschool, he was in a
wheelchair, his speech was slurred, and he had trouble swallowing food.
“His mom and I are always in awe of his determination and how he
faces every adversity with a smile,” says Leo’s dad, Satoshi. “He’s
always been our superhero! Leo cannot walk, talk, or even eat on his
own, even though he was able to do all of that just a few years back.”
Leo’s mystery condition was finally solved thanks to a collaborative
study that included researchers at the Duncan NRI. They identified
the importance and function of the IRF2BPL gene, a gene that was
mutated in Leo’s DNA, by implementing a multidisciplinary approach
that combined comprehensive clinical tests, exome sequencing,
and studies in fruit flies. This cutting-edge process is akin to finding
a needle in a haystack because the human genome consists of
three billion base pairs, and most people have many genetic variants
in their genome, not all of which are harmful or cause disease.
Eager to learn more about their son’s condition, the family visited
the Duncan NRI and met with Drs. Hugo Bellen, Shinya Yamamoto,
Michael Wangler, and Huda Zoghbi. They were astonished to see how
fruit flies with the same genetic mutation as Leo could be the key to
finding a treatment for his condition.
Satoshi explains, “After years of trying to make sense of Leo’s
condition, my wife and I were elated. We are at the cusp of yet
another long journey to find a treatment for Leo and other children
like him who have IRF2BPL variants. The huge difference this time
around is that we’re not alone. We feel blessed to have the support of
other families and talented teams of physicians and scientists who are
as passionate as we are about finding a treatment for this disorder.”
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SCIENTIST SPOTLIGHT
Roy Sillitoe, Ph.D.
Dr. Roy Sillitoe is a neuroscientist at the Duncan NRI and an associate professor at Baylor College
of Medicine. He has earned international recognition as a leader in the field of cerebellum research,
with a focus on understanding the underlying causes of devastating motor and balance disorders
and improving the quality of life for those affected.
What inspired you to become a neuroscientist?
My interest in the brain started when I was a child living in Zambia. I was fascinated watching my father
piece together all sorts of things—machines as small as broken toasters and as large as the engines of
18-wheeler semi-trucks. I enjoyed helping him with both, especially when I got to drive the semi as a
9-year-old! This interest in repairing things coincided with a realization that there were many kids my own
age growing up without the ability to help their fathers because they suffered from incurable diseases.
I would later become curious about the brain and loved the idea that if I could learn how all the little bits
in the brain are put together, perhaps I could begin thinking about ways of trying to fix them. Since then,
I have had the opportunity to study and work in three countries—Canada (Vancouver and Calgary), the U.K.
(Oxford), and the United States (New York and Houston). What motivated and inspired me, then and now,
is a love for learning and for making medical discoveries that can help people live happier, healthier lives.
Today, I have the privilege of tinkering with the brain in hope of finding ways to repair broken circuits.
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DONOR SPOTLIGHT
The Hamill Foundation
Through the generosity of The Hamill Foundation, Texas Children’s Hospital launched The Breakthrough
Fund to harness the collective support from generous families and foundations in Houston and beyond to
fund transformational research efforts at the Duncan NRI. The Breakthrough Fund addresses a fundamental
challenge in research: federal support is highly competitive and generally advances a restrictive line of
inquiry. This fund pools resources and directs them quickly and flexibly, enabling researchers to pursue their
most promising and timely experiments to alleviate the suffering of those living with devastating neurological
and psychiatric conditions.
“We have supported Dr. Huda Zoghbi’s research at the Duncan NRI since 2007 and are delighted to
channel our giving through The Breakthrough Fund to maximize its impact. Dr. Zoghbi has continuously
exhibited world-class vision, expertise, and leadership, and we are proud to support her efforts.”
―Tom Brown, Grants Director, The Hamill Foundation
Charlie Read, President, The Hamill Foundation; Mark Wallace, President and CEO, Texas Children’s
Hospital; and Tom Brown, Grants Director, The Hamill Foundation, celebrate the naming of The Hamill
Foundation Board Room in the Duncan NRI Conference Center.
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SELECT AWARDS AND HONORS
Heather Born, Ph.D.
Duncan NRI Zoghbi Scholar Award
This award is presented annually through a special fund established
by Dr. Huda Zoghbi to honor and support the incredible achievements
of trainees at the Duncan NRI and to foster the next generation of
successful scientists.
Hsiao-Tuan Chao, M.D., Ph.D.
McNair Scholar
The McNair Scholar program, supported by The Robert and Janice
McNair Foundation and managed by the McNair Medical Institute,
identifies and recruits influential researchers in neuroscience,
cancer, and juvenile diabetes.
Matthew McGinley, Ph.D.
John S. Dunn Research Collaborative Award
This award provides a seed grant to develop a platform to better
understand mechanisms that integrate audio information with
the brain’s broader cognitive maps and, in the process, improve
technologies like cochlear implants.
Lauren Miterko
Masao Ito Award from the Society for Research on Cerebellum and Ataxias
Marco Sardiello, Ph.D.
The 2019 Michael E. DeBakey M.D. Award for Excellence in Research
These awards are given to a select few Baylor College of Medicine
faculty members for their excellence in published scientific
contributions to clinical or basic science research over the past
three years.
Huda Zoghbi, M.D.
Norman J. Siegel New Member Outstanding Science Award by the
American Pediatrics Society
Award recipients are selected for considerable contribution to the
advancement of pediatric science. Dr. Zoghbi was recognized for
her patient-inspired research that has led to the discovery of genes
responsible for many devastating neurological disorders.
Victor A. McKusick Leadership Award by The American Society of
Human Genetics (ASHG)
This award, named in honor of the late Victor A. McKusick, M.D.,
recognizes individuals whose professional achievements have fostered
and enriched the development of human genetics as well as its
assimilation into the broader context of science, medicine, and health.
Miterko received the award, presented to trainees at the annual
symposium of the Society, for her poster titled, “Sustained benefits
of deep brain stimulation in the Car8wdl mouse model of cerebellar
motor disease: A focus on the ataxia phenotype.”
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Hsiao-Tuan Chao,
M.D., Ph.D.
Dr. Chao is the most recent addition to the faculty of the
Duncan NRI. Working in both the lab and with patients at Texas
Children’s Hospital, she is using a cross-species approach (flies,
mice, and humans) to understand the regulation of neural circuit
development and function in disorders such as intellectual
disability, epilepsy, and autism. Dr. Chao has already earned
numerous prestigious awards, including the National Institutes
of Health Director’s Early Independence Award and a Child
Neurology Foundation grant.
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Faculty
Founding Director
Huda Y. Zoghbi, M.D.
Co-Director
John W. Swann, Ph.D.
Genevera I. Allen, Ph.D.
Anne Anderson, M.D.
Benjamin R. Arenkiel, Ph.D.
Andrea Ballabio, M.D., Ph.D.
Hugo Bellen, D.V.M., Ph.D.
Juan Botas, Ph.D.
Hsiao-Tuan Chao, M.D., Ph.D.
Benjamin Deneen, Ph.D.
Jimmy L. Holder Jr., M.D., Ph.D.
Xiaolong Jiang, Ph.D.
Tiemo Jürgen Klisch, Ph.D.
Hyun Kyoung Lee, Ph.D.
Olivier Lichtarge, M.D., Ph.D.
Zhandong Liu, Ph.D.
Jeffrey C. Magee, Ph.D.
Mirjana Maletić-Savatić, M.D., Ph.D.
Matthew J. McGinley, Ph.D.
David L. Nelson, Ph.D.
Akash J. Patel, M.D.
Rodney C. Samaco, Ph.D.
Marco Sardiello, Ph.D.
Joshua M. Shulman, M.D., Ph.D.
Roy V. Sillitoe, Ph.D.
Ignatia B. Van den Veyver, M.D.
Michael Wangler, M.D.
Mingshan Xue, Ph.D.
Shinya Yamamoto, D.V.M., Ph.D.
Scientific
Advisory Board
Albert-László Barabási, Ph.D.
Nathaniel Heintz, Ph.D.
Story Landis, Ph.D.
S. Lawrence Zipursky, Ph.D.
International
Advisory Board
Ralph Alexander
T. Craig Benson
Albert Chao
Robert Graham
Prisca Marvin
Anthony Petrello
Charif Souki
Michael Wilsey
Philanthropy
Staff
Virginia Tomlinson
Emily Church
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nri.texaschildrens.org/impact
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