October 29, 2018

Some of the brightest minds in neuroscience recently converged on the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital for its fourth biennial symposium and workshop, in partnership with Baylor College of Medicine.

The special two-day event brought together nearly 300 physicians, scientists, patients, patient advocacy groups, pharmaceutical industry experts and leaders from the National Institutes of Health (NIH), the National Institute of Neurological Disorders and Stroke, and the National Institute for Mental Health, to address key issues in the field of neuropsychiatry, an intersectional branch of medicine that deals with mental illnesses caused by organic disorders of the nervous system.

Neuropsychiatric disorders are a leading cause of disability and take a tremendous toll on society. In the United States alone, one out of five adults lives with mental illness. The spectrum of mental illnesses is vast, ranging from the extremely rare to more well-known conditions such as depression, anxiety, schizophrenia, ADHD, addiction and sleep disorders. Symptoms and their severity can vary widely from patient to patient, which makes them difficult to physiologically measure. For these reasons, neuropsychiatric disorders are some of the least understood – and some of the most difficult to treat.

“These disorders are a major health issue all over the world, however, therapeutic interventions remain limited,” said NRI/Baylor investigator and child neurologist Dr. Hsiao-Tuan Chao. “There is a growing need to understand the organic factors behind mental illness to facilitate a better understanding of the brain, as well as to develop more effective treatment strategies.”

The symposium opened with a welcome address from Dr. Huda Zoghbi, director of the NRI, and this year’s co-organizer, Dr. Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. The pair stressed the importance of identifying new research paths in order to develop targeted therapies that could not only help treat neuropsychiatric symptoms, but could also help mitigate or eliminate side effects and toxicities that far too many patients experience.

Over the course of the first day, presentations from leading experts addressed hot topics in neuropsychiatry. These included a discussion on how genetic mutations contribute to neuropsychiatric disorders; the involvement of neuronal networks in neuropsychiatric phenotypes; the impact of immune cells on these disorders; and a look into how adaptive deep brain stimulation could potentially help specific conditions. Each session gave way to a 20-minute moderated panel discussion on the topic at hand. This feature of the symposium is unique in that it leads to immediate discussion and active participation among the many different types of stakeholders present.

Following a day of stellar research presentations, the investigators split into three working groups that focused on Molecular Bases of Disease and Human studies, Circuits and Neuromodulation, and Young Investigators. The groups discussed not only everything they had heard over the course of the day, but also their vision for the next 20 years in neuropsychiatry, including the obstacles that currently exist and what is needed to overcome them.

The next morning, key points that had emerged from these discussions were shared with the audience. The working groups identified increased access to resources and funding as a major need. But unanimously, all of the young investigators noted the critical importance of building interdisciplinary, multi-institutional collaborations, with a focus on team science and data sharing.

“Building bridges between various disciplines aids in the identification of important areas of neuropsychiatry that require further investigation and therapeutic development,” said Chao. “Neuropsychiatry itself is an interdisciplinary field, and unraveling the causes for these conditions will require continued interdisciplinary collaborations to accelerate the pace of discovery.”

The proceedings will be published as a white paper in Science Translational Medicine, a leading weekly online journal and one of the event sponsors.

October 23, 2018

The New England Journal of Medicine (NEJM), one of the nation’s most respected peer-reviewed medical journals, has released a new study highlighting the groundbreaking work being done by the Undiagnosed Diseases Network (UDN), an National Institutes of Health-funded research consortium that includes the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital, Baylor College of Medicine, Stanford University and other institutions.

Identifying the genes responsible for rare or unknown disorders using traditional approaches is time-consuming work and can take years, or sometimes even decades. And though genetic sequencing is now a routine part of the care people receive for these types of disorders, many patients are still left without a diagnosis. According to the NEJM study, the collaborative UDN model may already be changing that paradigm.

The study reports that the UDN defined 31 entirely new syndromes, and of 382 completed evaluations, 132 patients received diagnoses, a rate of 35 percent – all in just 20 months. The study also found that of the new diagnoses, 37 percent led to non-therapeutic changes in care, such as narrowing of diagnostic testing, and an amazing 21 percent led to changes in therapies for patients.

“This is a major accomplishment in genomic medicine and a giant step forward for these patients and their families,” said Dr. Huda Zoghbi, director of the NRI.

The UDN was established in 2014 with the mission of providing answers for the millions of patients and their families affected by mysterious and rare conditions, but who, after years of extensive testing, still hadn’t received a diagnosis.

The NRI and Baylor have been at the forefront of discovery in the UDN since its inception, jointly serving as one of seven original clinical sites, where doctors and health care providers, ranging from neurologists, immunologists, nephrologists, endocrinologists and geneticists, come together to help find the cause of participants’ symptoms. Baylor, one of the UDN’s two original sequencing cores, currently acts as the network’s sole DNA sequencing site. The NRI and Baylor were also selected to serve as the UDN’s first Model Organism Screening Center (MOSC), which was spearheaded by NRI investigators Drs. Hugo Bellen, Shinya Yamamoto and Michael Wangler.

“The UDN recognized that the resources we had in place and our high throughput made us the ideal candidate to serve as a MOSC site,” Bellen said. “Because of our success with model organisms and the appreciation physicians have for our work, there will likely be a proliferation of MOSC sites in the future.”

In-depth fruit fly studies at the MOSC have helped physicians and scientists identify genes responsible for rare and undiagnosed disorders, leading to the diagnosis of some of the UDN’s most difficult cases. This collaborative effort, which also includes the University of Oregon, has already directly influenced how clinicians care for patients – patients like Avery Reilly.

At only a few months old, Avery began showing signs of a neurologic condition. She could not sit until age 3 or crawl until age 5, and today she cannot walk or speak. An appointment with Texas Children’s neurologist Dr. Timothy Lotze revealed Avery had poor muscle tone, which was delaying milestones. That initial appointment led to years of doctor visits and countless tests, all of which failed to reveal the cause of Avery’s developmental and speech delays.

Then in 2014, the Reillys heard about the NRI’s involvement with the UDN and submitted Avery’s case. For the first time in years, the family had hope. Using exome sequencing, researchers discovered Avery had a new type of genetic mutation. Then a team at the MOSC, led by Wangler, studied the mutation in a fruit fly model to see how the genes were affected. At long last, the Reillys had a diagnosis. What’s more, the discovery of Avery’s mutation led to a change in her medications, which could help slow the progression of her disease.

“The fact that we are able to help the UDN accelerate science to find actionable changes in therapies is very exciting,” said Zoghbi. “Helping people, and working to solve severe medical problems through basic research, and through unfettered collaboration, is what our work is all about.”

The NEJM study is the first to provide a detailed description of the inner workings of the UDN. It presents an in-depth analysis of the referral and acceptance patterns, diagnoses, impact rates and follow-up scientific investigations of 1,519 cases that were referred to the UDN in the last two years.

As the study points out, the most unique feature, and perhaps the biggest contributor toward UDN’s success, is its model of multi-institutional collaborations. Teams of researchers and physicians from participating institutions all over the nation leverage their multidisciplinary expertise and resources to quickly find specific diagnoses for patients with extremely challenging clinical cases, with no additional cost to the patients.

In addition to the original clinical sites and sequencing cores, the UDN also included a coordinating center as part of its phase I deployment. In 2015, a web-based portal, the UDN Gateway, was launched for patients and families to participate in UDN. The network recently expanded its footprint from seven to 12 clinical sites and also added a central biorepository, a metabolomics core and a new MOSC site.

Though the UDN’s larger focus is currently gene discovery, it’s the work being done at the NRI and Baylor that will set up the network’s next evolution.

“Once a gene is discovered, it’s natural that the focus should shift to finding out what the genes do, what the molecular mechanisms are, if they’re linked to other diseases, or if they can be manipulated with drugs,” Bellen said. “That’s what we’re doing at the NRI and Baylor now, and that will be instrumental in the next phase for the UDN. When that time comes, we’ll be ahead of the curve.”

Learn more about the recent research breakthroughs and patient success stories from the UDN and MOSC.

About the New England Journal of Medicine
For over 200 years, the New England Journal of Medicine has rigorously vetted and compiled the latest medical research in support of physicians and their patients. From the first uses of anesthesia to the most recent cardiology and cancer treatments, the New England Journal of Medicine has helped generations of clinicians enhance their knowledge and improve patient care.

Today, with rigorously peer-reviewed research, topical reviews, interactive clinical content and cases, the New England Journal of Medicine is the trusted source for essential findings in medicine.

June 19, 2018

Dr. Zhandong Liu, assistant professor at Baylor College of Medicine and researcher at the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s has received a distinguished service award from the International Association for Intelligent Biology and Medicine (IAIBM).

As a non-profit organization, the IAIBM’s mission is to promote bioinformatics, systems biology and intelligent computing among scientists of diverse backgrounds through discussion, network communication, collaborations and education.

The Liu laboratory has developed many new software tools (e.g. MARRVEL and CRISPRcloud) that have helped biomedical scientists analyze complex bioinformatics data faster and with ease. In addition, Liu’s collaborations with neuroscientists have led to many important biological discoveries that have far-reaching implications for various neurological and neurodegenerative diseases.

Dr. Mingshan Xue, assistant professor of neuroscience at Baylor College of Medicine and a researcher with the NRI at Texas Children’s has been awarded the prestigious 2018 McKnight Scholar Award.

The McKnight Scholar Awards are granted to young scientists who are in the early stages of establishing their own independent laboratories and research careers and who have demonstrated a commitment to neuroscience.

Out of 64 applicants, Xue was one of six awardees. The recipients were chosen for their creativity, technological, precise and rigorous new approaches to overcome barriers in answering long-standing neuroscience questions.

The McKnight Endowment Fund for Neuroscience is an independent organization funded solely by the McKnight Foundation of Minneapolis, Minn., and led by a board of prominent neuroscientists from around the country. Each of the six McKnight Scholar Award recipients receives $75,000 per year for three years.

Dr. Hsiao-Tuan Chao, a child neurologist and postdoctoral researcher at the NRI, has been awarded the highly-competitive 2018 Burroughs Wellcome Fund Career Award for Medical Scientists.

The Burroughs Wellcome Fund is an independent private foundation dedicated to advancing the biomedical sciences by supporting research and other scientific and educational activities. The main goals of this fund are to help early-stage scientists develop into independent scientists and to advance undervalued areas of basic biomedical research. To fulfill that mission, the Career Award for Medical Scientists provides $700,000 of research funding spread over five years to physician-scientists who are currently receiving advanced postdoctoral/fellowship training. This award is intended to help physician-scientists embark on independent academic careers.

Chao, who is also an instructor in the department of pediatrics at Baylor College of Medicine, associate program director of the child neurology residency program and clinical child neurologist, is one of the 13 physician-scientists from leading academic institutions in the US to receive this honor in 2018. This award will help Chao establish an independent research program to understand the mechanisms underlying transcriptional dysregulation of inhibitory signaling pathways in childhood neurodevelopmental disorders.

June 12, 2018

As Texas Children’s continues to expand its physical footprint as a leader in pediatric care, Texas Children’s Neurology Program is growing by leaps and bounds. As one of the largest pediatric neurology service providers in the nation, more than 30,000 patient encounters occur each year at Texas Children’s Neuroscience Center.

Ranked No. 4 nationally in neurology and neurosurgery by U.S. News & World Report, patients are treated for a number of neurological conditions in our 13 specialty clinics including epilepsy, cerebral palsy, Rett syndrome, Batten disease and movement disorders. Many patient families are referred to Texas Children’s for our integrated expertise and multidisciplinary team approach in diagnosing and treating childhood neurological disorders. Recently, the Neurology division expanded its services with the opening of the Angleman Syndrome Clinic to treat children with this very rare, neurogenetic disorder.

“Over the last decade, our neuroscience programs have experienced phenomenal growth,” said Chief of Neurology and Developmental Neuroscience Dr. Gary Clark. “In 2004, the division had 5,000 patient encounters per year. Since then, we have more than quadrupled our patient encounters to 31,500 in 2017. More than half of these patients are seen in the community, allowing for greater access to care.”

In 2017, the neurology service received 1,300 new patient referrals each month which is a 30 percent increase from last year. To meet the increased demand for these services and to accommodate the growing patient population, the pediatric neurology division faculty expanded from 9 to 52 neurologists.

While enhancing access to patient care remains a top priority for Texas Children’s, one way the Neurology service is helping to achieve this collaborative milestone is through the implementation of telemedicine, an interactive telecommunications system that uses real-time video technology to link patients with their primary care and specialty providers. Instead of making the trek to the Texas Medical Center, patients can now “see” their neurologist without ever leaving their primary care clinic.

“Through an HRSA grant, we have seen children with epilepsy in one of our medical homes via this new technology and completed more visits than any other grant recipient,” said Brian Cordasco, practice administrator for Neurology. “This successful experiment will serve as a blueprint for future growth of telemedicine at Texas Children’s. Six faculty offices are now equipped with telemedicine capabilities.”

To balance outpatient services with the increasing demand for inpatient care, the Neurology Service has also developed an inpatient service rotation for physicians at Texas Children’s Hospital West Campus. Just like Texas Children’s Medical Center Campus and Texas Children’s Hospital The Woodlands, neurologists and epileptologists take turns working out of clinic to take neurology consults at the hospital.

Partnerships advance clinical research in neurology

The neurology division’s partnership with the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s under the leadership of Dr. Huda Zoghbi also has helped to advance clinical and basic science research leading to the development of new treatments for neuro and developmental disabilities.

Nearly $185 million has been raised to build and partially endow the NRI, and the hospital’s long-time philanthropic partner, The Blue Bird Circle, has raised funds (initial gift $1M for four years) to form and partially endow the Blue Bird Circle Clinical Research Center in which NRI discoveries are realized through clinical trials.

The Blue Bird Circle has been the catalyst for so much of what has happened in pediatric neurology in the past 20 years at Texas Children’s. Clinical research protocols have grown from 9 to 63 over the 8-year existence of the Blue Bird Circle CRC. The Blue Bird Circle has raised in excess of $1.2 million annually to directly fund clinical treatment, training and research in pediatric neurology at Texas Children’s.

Through these collaborative research partnerships, the neurology team has made significant progress:

  • Texas Children’s is one of the few sites in the country that provides therapy to patients with an enzyme deficiency in the form of Batten disease by surgically injecting the synthesized enzyme directly into the brain thereby halting this degenerative form of Batten disease.
  • Texas Children’s treats patients with spinal muscular atrophy, a disease where the spinal cord degenerates due to a defective SMN1 gene. This treatment involves injecting a DNA molecule into the spinal fluid that turns a latent gene into an effective one that makes the deficient protein.

“We are contemplating similar treatments for Angelman and Rhett syndromes,” Clark said. “We are so grateful to Texas Children’s Blue Bird Circle Research Center in collaboration with the Jan and Dan Duncan Neurological Research Institute at Texas Children’s for helping us make these research breakthroughs possible, and I am excited about what the future will hold for pediatric neurology.”

April 24, 2018

Dr. Peter Hotez, director of the Texas Children’s Hospital Center for Vaccine Development, and Dr. Huda Zoghbi, director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, have been elected as the newest members of the American Academy of Arts and Sciences, one of the nation’s most prestigious honorary titles.

“Membership in the Academy is not only an honor, but also an opportunity and a responsibility,” said Jonathan Fanton, president of the American Academy. “Members can be inspired and engaged by connecting with one another and through Academy projects dedicated to the common good. The intellect, creativity and commitment of the 2018 Class will enrich the work of the Academy and the world in which we live.”

The Academy is one of the country’s oldest societies and independent policy research centers. It recognizes exceptional scholars, leaders, artists and innovators and engages them in sharing knowledge and addressing challenges facing the world. This year, Hotez and Zoghbi join more than 200 other individuals from a wide range of disciplines and professions as elected members of the Class of 2018.

The Class of 2018 members were elected in 25 categories and are affiliated with 125 institutions from across the globe. They include scientists, scholars, an academy award winner, philanthropists, CEOs, historians, a past U.S. president and a current Supreme Court judge.

See a full list of new members.

The new class will be inducted at a ceremony in October 2018 in Cambridge, Mass., at which the newly elected members will sign the Book of Members, and their signatures will be added to the Academy members who came before them, including Benjamin Franklin (1781) and Alexander Hamilton (elected 1791) in the 18th century; Ralph Waldo Emerson, (1864), Maria Mitchell (1848) and Charles Darwin (1874) in the 19th; and Albert Einstein (1924), Robert Frost (1931), Margaret Mead (1948), Milton Friedman (1959) and Martin Luther King, Jr. (1966) in the 20th.

Hotez

In addition to his responsibilities at Texas Children’s, which include being the Endowed Chair in Tropical Pediatrics, Hotez is professor and dean of the National School of Tropical Medicine at Baylor College of Medicine and is a Fellow in Disease and Poverty for the James A. Baker III Institute for Public Policy at Rice University. He also holds a title of university professor at Baylor University and is founding editor in chief for the open access medical journal PLOS Neglected Tropical Diseases.

Hotez has been recognized for his work in research and advocacy as a world-renowned expert in neglected tropical diseases. He founded the National School of Tropical Medicine at Baylor College of Medicine in 2011. There, he leads an international team of scientists working to develop vaccines to combat some of the world’s most common yet potentially deadly diseases such as hookworm infection, schistosomiasis and other infectious and neglected diseases, including Chagas disease, leishmaniasis and SARS. These diseases affect millions of children and adults worldwide in some of the most poverty stricken areas.

In 2006 at the Clinton Global Initiative he helped to launch a Global Network for NTDs, and 10 years later in 2016, Hotez became known as the thought leader on the Zika epidemic in the Western Hemisphere and globally. He was among the first to predict Zika’s emergence in the U.S. He has been called upon frequently to testify before Congress and served on infectious disease task forces for two consecutive Texas governors.

Zoghbi

Zoghbi, a professor of pediatrics, molecular and human genetics, neurology and neuroscience at Baylor, is the world’s leading expert on Rett syndrome. The disease strikes after about a year of normal development and presents with developmental regression, social withdrawal, loss of hand use and compulsive hand wringing, seizures and a variety of neurobehavioral symptoms.

After encountering girls with Rett syndrome, Zoghbi set out to find the genetic cause of the disease. She and her research team identified mutations in MECP2 as the cause and revealed the importance of MeCP2 for the function of various neuronal subtypes. Her work in mouse models showed just how sensitive the brain is to the levels of MeCP2. Too little MeCP2 causes Rett syndrome; doubling MeCP2 levels causes progressive neurological deficits. The latter disorder is now recognized as MECP2 duplication syndrome.

The discovery of the Rett syndrome gene provided a straightforward diagnostic genetic test, allowing early and accurate diagnosis. It also revealed that mutations in MECP2 can cause a host of other neuropsychiatric features ranging from autism to juvenile onset schizophrenia. Further, it provided evidence that an autism spectrum disorder or an intellectual disability disorder can be genetic even if it is not inherited.

Her discovery opened up a new area of research on the role of epigenetics in neuropsychiatric disorders. Her more recent work has shown that symptoms of adult mice modeling the duplication disorder can be reversed using antisense oligonucleotides that normalize MeCP2 levels. This discovery provides a potential therapeutic strategy for the MECP2 duplication syndrome and inspires similar studies for other duplication disorders.

Zoghbi and collaborators also have made many discoveries toward understanding mechanisms driving adult-onset neurodegenerative disorders and are now focused on identifying potential therapeutics for these disorders.

March 20, 2018

Dr. Huda Zoghbi, director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s, Howard Hughes Medical Institute investigator and professor at Baylor College of Medicine, has been awarded the sixth annual Ross Prize in Molecular Medicine by The Feinstein Institute for Medical Research at Northwell Health.

The Ross Prize is awarded annually by Molecular Medicine to scientists who have made a demonstrable impact in the understanding of human diseases pathogenesis and/or treatment, and who hold significant promise for making even greater contributions to the general field of molecular medicine.

“It is an honor to be recognized by Molecular Medicine and to join the prestigious roster of past Ross Prize recipients,” said Zoghbi, professor in the Departments of Pediatrics, Molecular and Human Genetics, Neurology and Neuroscience at Baylor. “I look forward to discussing my work and furthering a dialog that I hope will encourage young trainees to join the fields of neurobiology and molecular medicine.”

The prize, which includes a $50,000 award, will be presented to Zoghbi on June 5 at the New York Academy of Sciences in New York City, followed by lectures from Zoghbi and other eminent researchers. The Ross Prize is awarded through the Feinstein Institute’s peer-reviewed, open-access journal, Molecular Medicine, and made possible by the generosity of Feinstein Institute board members Robin and Jack Ross.

“Huda Zoghbi’s examination of the genetic causes for neurological diseases, such as spinocerebellar ataxia and Rett syndrome, has led to a better understanding of neurobiology,” said Feinstein Institute President and Chief Executive Officer Dr. Kevin J. Tracey, who also serves as editor emeritus of Molecular Medicine. “It is through her discoveries that researchers are able to identify new, potential therapies for these conditions that currently have no cure.”

Zoghbi’s research focuses on identifying the genetic causes of neurodegenerative and neurodevelopmental diseases and a broader understanding of neurobiology. Her lab, along with Harry Orr’s team at the University of Minnesota, discovered that excessive repeats of the DNA segment, CAG, in the ATAXIN-1 gene causes the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). Over time, SCA1 may cause mental impairment, numbness, tingling or pain in the arms and legs and uncontrolled muscle tensing, wasting and twitches. Understanding the genetic cause for SCA1 has inspired additional research that may identify a therapeutic strategy for this condition that affects coordination and balance, difficulties with speech and swallowing, and weakeness in the muscles that control eye movement.

Zoghbi’s lab also has identified the genetic mutations that cause Rett syndrome. Rett syndrome mostly targets young girls and is a postnatal neurological disorder which causes problems in diverse brain functions ranging from cognitive, sensory, emotional, and motor to autonomic functions. These can affect learning, speech, sensations, mood, movement, breathing, cardiac function and even chewing, swallowing and digestion. Zoghbi’s discoveries provide a framework for understanding this disorder as well as the MECP2 duplication disorder and for charting a path for potential therapeutic interventions.

January 30, 2018

Dr. Huda Zoghbi was awarded the National Order of the Cedar, Knight grade by Lebanese President General Michel Aoun at a ceremony held in January at the Presidential Palace in Baabda.

Zoghbi is the founder and director of the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital and Baylor College of Medicine, a Howard Hughes Medical Institute investigator, and holds the Ralph D. Feigin, MD, Endowed Chair in Pediatrics.

This prestigious honor touches close to home as Zoghbi was born and raised in Beruit, Lebanon’s capital and largest city. She received her Bachelor of Science degree from American University Beirut (AUB).

“It is an honor for AUB and indeed for Lebanon that the President of the Republic of Lebanon has conferred on Huda Zoghbi the Order of the Cedar,” said American University Beirut President Fadlo R. Khuri. “Thus, the greatest and most decorated scientist to have completed her undergraduate education at our university over the last several decades, a woman whose work is transforming the science and medicine of some of the world’s most serious neurological diseases, is now recognized by her native country’s highest award.”

Zoghbi’s hard work and dedication to the medical field spans through Texas Children’s and beyond. The National Order of the Cedar is a public service award and Lebanon’s highest honor.

“I am deeply honored and humbled to receive this great honor,” Zoghbi said. “I owe a lot of gratitude to my family who shaped me and to the institutions that educated me: Makassed and the American University of Beirut. I feel fortunate that I grew up and spent my formative years in Lebanon and I hope the culture that inspired me to seek knowledge will continue to inspire and empower the youth of Lebanon.”