Tag Archive for: Vilain

zika virus

Researcher to decipher how viruses affect the developing brain with nearly $1M NIH award

zika virus

Zika virus in blood with red blood cells, a virus which causes Zika fever found in Brazil and other tropical countries.

The National Institutes of Health (NIH) awarded Children’s National Hospital nearly $1M of research support toward uncovering the specific cellular response that happens inside a developing brain once it is infected with a virus, including how the neuron gets infected, and how it dies or survives. The research is expected to gather critical information that can inform prenatal neuro-precision therapies to prevent or attenuate the effects of endemic and pandemic viruses in the future.

“We need to use all of the information we have from ongoing and past pandemics to prevent tomorrow’s public health crisis,” said Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National. “There is still here a whole lot to learn and discover. We could eventually — and this is the vision that’s inspiring us — prevent neurodevelopmental disorders before a baby is born by understanding more about the interaction between the virus, mother, fetus, and environment, among other factors.”

Different viruses, including HIV, CMV, Zika and rubella, injure the developing brain in very similar ways. This line of work was fostered first by the clinical research team led by Adre du Plessis, M.B.Ch.B., and Sarah Mulkey, M.D., supported by Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National.

The clinical research findings then led to the NIH support, which then inspired more basic science research. Fast forward to now, Kousa will study how Zika affects the human brain and extrapolate what is learned and discovered for a broader understanding of neurovirology.

The research program is supported by senior scientists and advisors, including Tarik Haydar, Ph.D., and Eric Vilain, M.D., Ph.D., both at Children’s National and Avindra Nath, M.D., at NIH, as well as other leading researchers at various U.S. centers.

“This is a team effort;” added Kousa, “I’m thankful to have a group of pioneering and seasoned researchers engaged with me throughout this process to provide invaluable guidance.”

Many viruses can harm the developing brain when they replicate in the absence of host defenses, including the gene regulatory networks responsible for the neuronal response. As a result, viral infections can lead to brain injury and neurodevelopmental delays and disorders such as intellectual disability, seizures that are difficult to treat, and vision or hearing loss.

The big picture

Youssef Kousa

Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National.

The translational research supported by NIH with this award synergistically complements nationally recognized clinical research programs and ongoing prospective cohort studies at Children’s National to identify the full spectrum of neurodevelopmental clinical outcomes after prenatal Zika and other viral infections led by Dr. Mulkey and Roberta DeBiasi, M.D., M.S..

The award also builds upon strengths at the Children’s National Research & Innovation Campus, which is in proximity to federal science agencies. Children’s National experts from the Center for Genetic Medicine Research, known for pediatric genomic and precision medicine, joined forces with the Center of Neuroscience Research and the NIH-NINDS intramural research program to focus on examining prenatal and childhood neurological disorders.

Kousa received this competitive career development award from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number K08NS119882. The research content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The hold-up in the field

Many neurodevelopmental disorders are caused by endemic viruses, such as CMV, and by viral pandemics, including rubella as seen in the 1960s and Zika since 2015. By studying Zika and other prenatal viral infections, Kousa and team hope to gain deeper biological understanding of the viral effects toward developing therapies for anticipating, treating and preventing virally induced prenatal brain injury in the long-term future.

To date, little is known about how viruses affect developing neurons and, as a result, prenatal brain injury is not yet treatable. To bridge the gap towards prenatal neuro-precision therapies, the research explores how genes regulate neuronal developmental and viral clearance by innovatively integrating three systems:

  • Cerebral organoids, which illuminate how a neuron reacts to a viral infection
  • Pre-clinical models that link prenatal brain injury to postnatal neurodevelopmental outcomes
  • Populational genomics to identify human genetic risk or protective factors for prenatal brain injury

Given the scope and complexity of this issue, the international Zika Genetics Consortium, founded in 2015 by Kousa and a team of leading investigators across the world, provides critical samples and resources for the third arm of the research by performing comprehensive genomic analyses using sequencing data collected from diverse human populations throughout Central and South America, which are not as heavily sequenced as Western populations. Through partnerships with the Centers for Disease Control and Prevention and NIH, the consortium’s database and biorepository houses thousands of patient records and biospecimens for research studies to better understand how viruses affect the developing human brain.

“It is inspiring to imagine that, in the longer term, we could recognize early on the level of brain-injury risk faced by a developing fetus and have the tools to mitigate ensuing complications,” said Kousa. “What is driving this research is the vision that one day, brain injury could be prevented from happening before a baby is born.”

Dr. Matthew Bramble, Vincent Kambale, and Neerja Vashist

Gut microbiome may impact susceptibility to konzo

Dr. Matthew Bramble, Vincent Kambale, and Neerja Vashist

From left to right: Dr. Matthew Bramble, Vincent Kambale, and Neerja Vashist. Here, the team is processing samples in the field collected from the study cohort prior to storage in liquid nitrogen. Bramble et al. Nature Communications (2021).

Differences between gut flora and genes from konzo-prone regions of the Democratic Republic of Congo (DRC) may affect the release of cyanide after poorly processed cassava is consumed, according to a study with 180 children. Cassava is a food security crop for over half a billion people in the developing world. Children living in high-risk konzo areas have high glucosidase (linamarase) microbes and low rhodanese microbes in their gut, which could mean more susceptibility and less protection against the disease, suggest Children’s National Hospital researchers who led the study published in Nature Communications.

Konzo is a severe, irreversible neurologic disease that results in paralysis. It occurs after consuming poorly processed cassava — a manioc root and essential crop for DRC and other low-income nations. Poorly processed cassava contains linamarin, a cyanogenic compound. While enzymes with glucosidase activity convert starch to simple sugars, they also break down linamarin, which then releases cyanide into the body.

Neerja Vashist learning how to make fufu

Neerja Vashist is learning how to make fufu. Fufu is a traditional food made from cassava flour, and the cassava flour used in the making of the fufu here has gone through the wetting method to further remove toxins from the cassava flour prior to consumption. Bramble et al. Nature Communications (2021).

“Knowing who is more at risk could result in targeted interventions to process cassava better or try to diversify the diet,” said Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research at Children’s National. “An alternative intervention is to modify the microbiome to increase the level of protection. This is, however, a difficult task which may have unintended consequences and other side effects.”

The exact biological mechanisms underlying konzo disease susceptibility and severity remained poorly understood until now. This is the first study to shed light on the gut microbiome of populations that rely on toxic cassava as their primary food source.

“While the gut microbiome is not the sole cause of disease given that environment and malnourishment play a role, it is a required modulator,” said Matthew S. Bramble, Ph.D., staff scientist at Children’s National. “Simply stated, without gut microbes, linamarin and other cyanogenic glucosides would pose little to no risk to humans.”

To understand the influence of a detrimental subsistence on the gut flora and its relationship to this debilitating multifactorial neurological disease, the researchers compared the gut microbiome profiles in 180 children from the DRC using shotgun metagenomic sequencing. This approach evaluates bacterial diversity and detects the abundance of microbes and microbial genes in various environments.

The samples were collected in Kinshasa, an urban area with diversified diet and without konzo; Masi-Manimba, a rural area with predominant cassava diet and low prevalence of konzo; and Kahemba, a region with predominant cassava diet and high prevalence of konzo.

Dr. Nicole Mashukano and Dr. Matthew Bramble wetting cassava flour

From left to right: Dr. Nicole Mashukano and Dr. Matthew Bramble. Dr. Mashukano leads the efforts in Kahemba to teach the wetting method to individuals in different health zones. The wetting method is used as an additional step to further detoxify toxins from cassava flour prior to consumption. Here, Dr. Mashukano and Dr. Bramble are spreading out the wet mixture of cassava flour and water into a thin layer on a tarp for drying in the sun, which allows cyanogen breakdown and release in the form of hydrogen cyanide gas. Bramble et al. Nature Communications (2021).

“This study overcame many challenges of doing research in low-resource settings,” said Desire Tshala-Katumbay, M.D., M.P.H., Ph.D., FANA, co-senior author and expert scientist at Institut National de Recherche Biomédicale in Kinshasa, DRC, and professor of neurology at Oregon Health & Science University. “It will open novel avenues to prevent konzo, a devastating disease for many children in Sub-Saharan Africa.”

For next steps, the researchers will study sibling pairs from konzo-prone regions of Kahemba where only one sibling is affected with the disease.

“Studying siblings will help us control for factors that cannot be controlled otherwise, such as the cassava preparation in the household,” said Neerja Vashist, Ph.D. candidate and research trainee at Children’s National. “In this work, each sample had approximately 5 million DNA reads each, so for our follow-up, we plan to increase that to greater than 40 million reads per sample and the overall study cohort size. This study design will allow us to confirm that the trends we observed hold on a larger scale, while enhancing our ability to comprehensively characterize the gut microbiome.”

Dr. Eric Vilain and researcher in a lab

Children’s National Hospital joins the Mendelian Genomics Research Consortium, receiving $12.8 million

Dr. Eric Vilain and researcher in a lab

Dr. Eric Vilain accompanied by a fellow researcher at the new Research & Innovation Campus.

Children’s National Hospital announces a $12.8 million award from the National Institutes of Health’s National Human Genome Research Institute (NHGRI) to establish the only Pediatric Mendelian Genomics Research Center (PMGRC) as part of a new Mendelian Genomics Research Consortium. Researchers at Children’s National and Invitae — a leading medical genetics company — will identify novel causes of rare inherited diseases, investigate the mechanisms of undiagnosed conditions, enhance data sharing, and generally interrogate Mendelian phenotypes, which are conditions that run in families.

“Our overall approach provides an efficient and direct path for pediatric patients affected with undiagnosed inherited conditions through a combination of innovative approaches, allowing individuals, families and health care providers to improve the management of the disease,” says Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research at Children’s National.

To accelerate gene discovery for Mendelian phenotypes and the clinical implementation of diagnosis, the consortium will leverage the broad pediatric clinical and research expertise of the Children’s National Research Institute and laboratories in partnership with Invitae. The Molecular Diagnostics Laboratory at Children’s National will provide genetic testing for patients in the Washington, D.C., metropolitan area. Invitae will provide genetic testing for patients from elsewhere in the U.S., giving the project a national reach and allowing researchers to leverage more robust data. Integrative analyses will be performed jointly with scientists at Children’s National and Invitae.

“Some patients have genetic test results that are ‘negative,’ meaning the results do not explain their condition. When a patient receives a negative result, it is challenging for parents and doctors to know what to do next,” says Meghan Delaney, D.O., M.P.H., chief of the Division of Pathology and Laboratory Medicine and Molecular Diagnostics Laboratory at Children’s National. “The project will provide an avenue to possibly find an explanation of their child’s condition. Besides filling an important clinical gap, the results will add new knowledge for future patients and the scientific community.”

“Too often parents of children suffering from a rare condition find themselves in a protracted diagnostic odyssey when early intervention could mean better overall outcomes,” says Robert Nussbaum, M.D., chief medical officer of Invitae. “We are proud to partner with Children’s National Research Institute on this important effort to identify the genetic cause of these rare conditions earlier and improve the chances that children with such conditions can receive the appropriate treatments and live healthier lives.”

Deciphering Mendelian conditions will help diagnose more of the estimated 7,000 rare inherited diseases and predict the tremendous variability of clinical presentations in both rare and common conditions caused by the same gene.

There is also a need to establish a new standard of care to bridge the gap in the use of genomic information from diagnosis to improved outcomes. The consortium will establish best practices for obtaining a genetic diagnosis, offering an explanation for the condition to affected patients, and is likely to provide additional explanations for basic biological mechanisms, increasing the knowledge of physiopathology and possibly leading to better condition management.

The PMGRC will enroll an average of 2,600 participants per year with suspected Mendelian phenotypes and previously non-diagnostic tests and their family members. The integration of multiple genomic technologies, including short and long read genome sequencing, optical genome mapping and RNA-sequencing, will enable these discoveries. To disambiguate uncertain variants and candidate genes, the PMGRC will use whole transcriptome analysis, RNA-sequencing, CRE-sequencing and functional modeling.

Since many Mendelian conditions first appear prenatally or during infancy, Children’s National will have a unique bed-to-bench-to-bed symbiosis. Patients eligible for the study will come from across the multiple specialty divisions of Children’s National, including the Children’s National Rare Disease Institute, and nationally through the partnership with Invitae. From there, experts from the Children’s National Center for Genetic Medicine Research will enroll patients and integrate the initial clinical test results with broad-based genomic interrogation, leading to new diagnoses and novel discoveries. Finally, the results will be verified and returned to clinicians, which will help inform targeted therapies.

Typically, the patients eligible for this study jump from specialist to specialist without an answer, have a condition that appears in other family members or they have symptoms involving more than one affected organ, which suggests a complex developmental condition. The PMGRC at Children’s National will help find answers to the causes of many puzzling pediatric conditions, providing faster clinical diagnoses and opening up pathways to potentially better treatments.

Dr. Vilain’s work will be based at the Children’s National Research & Innovation Campus on the grounds of the former Walter Reed Army Medical Center in Washington, D.C. The campus is also home to the Children’s National Rare Disease institute — one of the largest clinical genetics program in the United State that provides care to more than 8,500 rare disease patients.

coronavirus molecules with DNA

Novel SARS-CoV-2 spike variant found in a newborn in Washington, D.C.

coronavirus molecules with DNA

Researchers at Children’s National Hospital found a new SARS-CoV-2 spike variant in a neonatal patient, according to a study that genetically sequenced the virus in 27 pediatric patients. The newborn presented with a viral load of 50,000 times more particles than the average patient, which led to identifying the N679S spike protein variant — the earliest known sample of this coronavirus lineage in the U.S. mid-Atlantic region.

While the paper is posted to the preprint server medRxiv and has not been peer-reviewed, it represents an early step towards establishing better surveillance of the COVID-19 pandemic. The new variant helps understand the process of viral adaptation, potentially informing treatment development and vaccine design for any viral variants in the future.

All genomes change and evolve. Additional viral variants are expected to emerge as more patients are infected. The data analysis recognized eight other cases in Washington, D.C., with the N679S variant, pointing toward a European origin due to the genetic similarity between of SARS-CoV-2 strains in the U.S. and United Kingdom.

“We need to sequence more cases to identify variants and stay ahead of the virus,” said Drew Michael, Ph.D., molecular geneticist at Children’s National and senior author of the study. “The United States sequences a tiny fraction of all cases, and because we are not sequencing enough, we are not aware of the variants in SARS-CoV-2 that may be spreading in our community.”

“Novel SARS-CoV-2 spike variant identified through viral genome sequencing of the pediatric Washington D.C. COVID-19 outbreak,” was published on the preprint server medRxiv. Additional authors include Jonathan LoTempio, Erik Billings, Kyah Draper, Christal Ralph, Mahdi Moshgriz, Nhat Duong, Jennifer Dien Bard, Xiaowu Gai, David Wessel, M.D., Roberta L. DeBiasi, M.D., M.S., Joseph M. Campos, Ph.D., Eric Vilain, M.D., Ph.D. and Meghan Delaney, D.O., M.P.H.

You can read the full preprint on medRxiv.

global connectedness concept illustration

Research partnerships and capacity building in the time of COVID-19

global connectedness concept illustration

“COVID infection anywhere in the world is COVID infection everywhere in the world,” said John Nkengasong, M.Sc., Ph.D., director of the Africa Centers for Disease Control (Africa CDC), during his remarks on the importance of shared science, innovation and diplomacy. Leading experts in global health met virtually on November 13, 2020, to discuss updates in the COVID-19 crisis and lessons learned in Africa. Children’s National Hospital, along with the George Washington University (GW) Institute for Africa Studies and the CNRS-EpiDaPo Lab, sponsored the half-day conference that captured the interest of international attendees committed to examining how best to expand strong and enduring partnerships between U.S. and African scientists, health professionals and research institutes to meet global challenges.

Trust, transparency and communication were common themes of expert panelists that included Elizabeth Bukusi, Ph.D., M.P.H., Kenya Medical Research Institute; Maryam DeLoffre, Ph.D., GW Humanitarian Action Initiative; Peter Kilmarx, M.D., National Institutes of Health (NIH) Fogarty International Center; Enock Motavu, Ph.D., Makerere University in Uganda; Jennifer Troyer, Ph.D., Human Health and Heredity in Africa Program (H3Africa) at NIH; Désiré Tshala-Katumbay, M.D., Ph.D., National Institute of Biomedical Research in Kinshasa; Eric Vilain, M.D., Ph.D., Center for Genetic Medicine Research at Children’s National, with Institute for African Studies Director Jennifer Cooke, and Jonathan LoTempio Jr and D’Andre Spencer of Children’s National as moderators and co-conveners. Read more about the panelists.

The keynote speaker, Nkengasong, updated the group on the massive efforts in bending the COVID-19 disease curve on the African continent which at present has two million cases and 46,000 deaths. This is fewer than many other regions, and Nkengasong attributes this in part to health systems strengthening and capacity building that already occurred with past pandemics like Ebola. He stressed the importance of focusing on the “4 Ps” — population, pathogen, politics and policy — in fighting the pandemic, and the need to ensure that citizens trust their leaders and the public health measures they advance. New endeavors by the Africa CDC include the Pathogen Genomic Initiative, which will help inform research and responses to COVID-19 and other emergent disease threats, and the African COVID-19 Vaccine Development and Access Strategy, which aims to ensure widespread access, delivery and uptake of effective vaccines across Africa. Africa CDC is surging to hotspots as lockdowns ease or shift, and is empowering universities to invest in proactive and, which has helped with the active response success. “Rising tides raise all boats in the sea,” said Nkengasong. He went on to say that there is great power in coordination and cooperation, and science diplomacy and technology are critical to winning the novel coronavirus war.

In a panel on research partnerships, speakers Motavu, Tshala-Katumbay, and Vilain emphasized the global benefits of scientific collaborations in Africa. Africa contains more human genetic variation than any other region of the world, and capturing that diversity in global understanding of the human genome — which is still heavily skewed toward individuals of European ancestry — will be a major factor in global medical advances of the future. And research into relatively localized diseases can lead to breakthroughs in broader understanding on connections between climate variation, environment, nutrition and child health. “The simplistic, localized, nationalist, way of doing science is over,” said Tshala-Katumbay, “and there is no way to go back.” The discipline of science diplomacy will take time for people to grasp, he added, “but it will be crucial for the future generation of scientists to go back.”

A recurring conference theme was that collaboration between countries is crucial for development of better care. Kilmarx told the event participants that in 2019, the National Institutes of Health supported some 1,668 collaborations with African research institutions. Investments in capacity building have yielded impressive results, and today some of Africa’s foremost leaders in science research and public health have received NIH training and support, stating: “If you plant acorns over the decades, you have some mighty oaks.” Bukusi, once such NIH trainee, now is engaged in training a new generation of African researchers and U.S. researchers based in Africa and expanding research partnerships at the Kenya Medical Research Institute.

Troyer showed the successes of the Human Heredity and Health in Africa Initiative, a large consortium that supports a pan-continental network of laboratories that aims to determine disease susceptibility and drug responses. Finally, DeLoffre underscored the need for long-term investments and the value of building local capacities to respond to current crises and anticipate future challenges.

Overall, there was optimism that innovative coalitions are a long-term strength in fighting pandemics and promoting reciprocal learning that will last after the crisis. Science can be a neutral platform that, combined with diplomacy and technology, builds bridges between peoples.

The science-policy interface

We can do better: Lessons learned on COVID-19 data sharing can inform future outbreak preparedness

Since COVID-19 emerged late last year, there’s been an enormous amount of research produced on this novel coronavirus disease. But the content publicly available for this data and the format in which it’s presented lack consistency across different countries’ national public health institutes, greatly limiting its usefulness, Children’s National Hospital scientists report in a new study. Their findings and suggestions, published online August 19 in Science & Diplomacy, could eventually help countries optimize their COVID-19-related data — and data for future outbreaks of other diseases — to help further new research, clinical decisions and policy-making around the world.

Recently, explains study senior author Emmanuèle Délot, Ph.D., research faculty at Children’s National Research Institute, she and her colleagues sought data on sex differences between COVID-19 patients around the world for a new study. However, she says, when they checked the information available about different countries, they found a startling lack of consistency, not only for sex-disaggregated data, but also for any type of clinical or demographic information.

“The prospects of finding the same types of formats that would allow us to aggregate information, or even the same types of information across different sites, was pretty dismal,” says Dr. Délot.

To determine how deep this problem ran, she and colleagues at Children’s National, including Eric Vilain, M.D., Ph.D., the James A. Clark Distinguished Professor of Molecular Genetics and the director of the Center for Genetic Medicine Research at Children’s National, and Jonathan LoTempio, a doctoral candidate in a joint program with Children’s National and George Washington University, surveyed and analyzed the data on COVID-19.

The research spanned data reported by public health agencies from highly COVID-19 burdened countries, viral genome sequence data sharing efforts, and data presented in publications and preprints.

PubMed entries with coronavirus

Publications with the term “coronavirus” archived in PubMed over time.

At the time of study, the 15 countries with the highest COVID-19 burden at the time included the US, Spain, Italy, France, Germany, the United Kingdom, Turkey, Iran, China, Russia, Brazil, Belgium, Canada, the Netherlands and Switzerland. Together, these countries represented more than 75% of the reported global cases. The research team combed through COVID-19 data presented on each country’s public health institute website, looking first at the dashboards many provided for a quick glimpse into key data, then did a deeper dive into other data on this disease presented in other ways.

The data content they found, says LoTempio, was extremely heterogeneous. For example, while most countries kept running totals on confirmed cases and deaths, the availability of other types of data — such as the number of tests run, clinical aspects of the disease such as comorbidities, symptoms, or admission to intensive care, or demographic information on patients, such as age or sex — differed widely among countries.

Similarly, the format in which data was presented lacked any consistency among these institutes. Among the 15 countries, data was presented in plain text, HTML or PDF. Eleven offered an interactive web-based data dashboard, and seven had comma-separated data available for download. These formats aren’t compatible with each other, LoTempio explains, and there was little to no documentation about where the data that supplies some formats — such as continually updated web-based dashboards — was archived.

The science-policy interface

Graphic representation of the science-policy interface.

Dr. Vilain says that a robust system is already in place to allow uniform sharing of data on flu genomes — the World Health Organization’s (WHO) Global Initiative on Sharing All Influenza Data (GISAID) — which has been readily adapted for the virus that causes COVID-19 and has already helped advance some types of research. However, he says, countries need to work together to develop a similar system for harmonized sharing other types of data for COVID-19. The study authors recommend that COVID-19 data should be shared among countries using a standardized format and standardized content, informed by the success of GISAID and under the backing of the WHO.

In addition, the authors say, the explosion of research on COVID-19 should be curated by experts who can wade through the thousands of papers published on this disease since the pandemic began to identify research of merit and help merge clinical and basic science.

“Identifying the most useful science and sharing it in a way that’s usable to most researchers, clinicians and policymakers, will not only help us emerge from COVID-19 but could help us prepare for the next pandemic,” Dr. Vilain says.

Other researchers who contributed to this study include D’Andre Spencer, MPH, Rebecca Yarvitz, BA, and Arthur Delot-Vilain.

Vittorio Gallo and Mark Batshaw

Children’s National Research Institute releases annual report

Vittorio Gallo and Marc Batshaw

Children’s National Research Institute directors Vittorio Gallo, Ph.D., and Mark Batshaw, M.D.

The Children’s National Research Institute recently released its 2019-2020 academic annual report, titled 150 Years Stronger Through Discovery and Care to mark the hospital’s 150th birthday. Not only does the annual report give an overview of the institute’s research and education efforts, but it also gives a peek in to how the institute has mobilized to address the coronavirus pandemic.

“Our inaugural research program in 1947 began with a budget of less than $10,000 for the study of polio — a pressing health problem for Washington’s children at the time and a pandemic that many of us remember from our own childhoods,” says Vittorio Gallo, Ph.D., chief research officer at Children’s National Hospital and scientific director at Children’s National Research Institute. “Today, our research portfolio has grown to more than $75 million, and our 314 research faculty and their staff are dedicated to finding answers to many of the health challenges in childhood.”

Highlights from the Children’s National Research Institute annual report

  • In 2018, Children’s National began construction of its new Research & Innovation Campus (CNRIC) on 12 acres of land transferred by the U.S. Army as part of the decommissioning of the former Walter Reed Army Medical Center campus. In 2020, construction on the CNRIC will be complete, and in 2012, the Children’s National Research Institute will begin to transition to the campus.
  • In late 2019, a team of scientists led by Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research, traveled to the Democratic Republic of Congo to collect samples from 60 individuals that will form the basis of a new reference genome data set. The researchers hope their project will generate better reference genome data for diverse populations, starting with those of Central African descent.
  • A gift of $5.7 million received by the Center for Translational Research’s director, Lisa Guay-Woodford, M.D., will reinforce close collaboration between research and clinical care to improve the care and treatment of children with polycystic kidney disease and other inherited renal disorders.
  • The Center for Neuroscience Research’s integration into the infrastructure of Children’s National Hospital has created a unique set of opportunities for scientists and clinicians to work together on pressing problems in children’s health.
  • Children’s National and the National Institute of Allergy and Infectious Diseases are tackling pediatric research across three main areas of mutual interest: primary immune deficiencies, food allergies and post-Lyme disease syndrome. Their shared goal is to conduct clinical and translational research that improves what we know about those conditions and how we care for children who have them.
  • An immunotherapy trial has allowed a little boy to be a kid again. In the two years since he received cellular immunotherapy, Matthew has shown no signs of a returning tumor — the longest span of time he’s been tumor-free since age 3.
  • In the past 6 years, the 104 device projects that came through the National Capital Consortium for Pediatric Device Innovation accelerator program raised $148,680,256 in follow-on funding.
  • Even though he’s watched more than 500 aspiring physicians pass through the Children’s National pediatric residency program, program director Dewesh Agrawal, M.D., still gets teary at every graduation.

Understanding and treating the novel coronavirus (COVID-19)

In a short period of time, Children’s National Research Institute has mobilized its scientists to address COVID-19, focusing on understanding the virus and advancing solutions to ameliorate the impact today and for future generations. Children’s National Research Institute Director Mark Batshaw, M.D., highlighted some of these efforts in the annual report:

  • Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research, is looking at whether or not the microbiome of bacteria in the human nasal tract acts as a defensive shield against COVID-19.
  • Catherine Bollard, M.D., MBChB, director of the Center for Cancer and Immunology Research, and her team are seeing if they can “train” T cells to attack the invading coronavirus.
  • Sarah Mulkey, M.D., Ph.D., an investigator in the Center for Neuroscience Research and the Fetal Medicine Institute, is studying the effects of, and possible interventions for, coronavirus on the developing brain.

You can view the entire Children’s National Research Institute academic annual report online.

DNA Molecule

Decoding cellular signals linked to hypospadias

DNA Molecule

“By advancing our understanding of the genetic causes and the anatomic differences among patients, the real goal of this research is to generate knowledge that will allow us to take better care of children with hypospadias,” Daniel Casella, M.D. says.

Daniel Casella, M.D., a urologist at Children’s National, was honored with an AUA Mid-Atlantic Section William D. Steers, M.D. Award, which provides two years of dedicated research funding that he will use to better understand the genetic causes for hypospadias.

With over 7,000 new cases a year in the U.S., hypospadias is a common birth defect that occurs when the urethra, the tube that transports urine out of the body, does not form completely in males.

Dr. Casella has identified a unique subset of cells in the developing urethra that have stopped dividing but remain metabolically active and are thought to represent a novel signaling center. He likens them to doing the work of a construction foreman. “If you’re constructing a building, you need to make sure that everyone follows the blueprints.  We believe that these developmentally senescent cells are sending important signals that define how the urethra is formed,” he says.

His project also will help to standardize the characterization of hypospadias. Hypospadias is classically associated with a downward bend to the penis, a urethra that does not extend to the head of the penis and incomplete formation of the foreskin. Still, there is significant variability among patients’ anatomy and to date, no standardized method for documenting hypospadias anatomy.

“Some surgeons take measurements in the operating room, but without a standardized classification system, there is no definitive way to compare measurements among providers or standardize diagnoses from measurements that every surgeon makes,” he adds. “What one surgeon may call ‘distal’ may be called ‘midshaft’ by another.” (With distal hypospadias, the urethra opening is near the penis head; with midshaft hypospadias, the urethra opening occurs along the penis shaft.)

“By advancing our understanding of the genetic causes and the anatomic differences among patients, the real goal of this research is to generate knowledge that will allow us to take better care of children with hypospadias,” he says.

Parents worry about lingering social stigma, since some boys with hypospadias are unable to urinate while standing, and in older children the condition can be associated with difficulties having sex. Surgical correction of hypospadias traditionally is performed when children are between 6 months to 1 year old.

When reviewing treatment options with family, “discussing the surgery and postoperative care is straight forward. The hard part of our discussion is not having good answers to questions about long-term outcomes,” he says.

Dr. Casella’s study hopes to build the framework to enable that basic research to be done.

“Say we wanted to do a study to see how patients are doing 15-20 years after their surgery.  If we go to their charts now, often we can’t accurately describe their anatomy prior to surgery.  By establishing uniform measurement baselines, we can accurately track long-term outcomes since we’ll know what condition that child started with and where they ended up,” he says.

Dr. Casella’s research project will be conducted at Children’s National under the mentorship of Eric Vilain, M.D., Ph.D., an international expert in sex and genitalia development; Dolores J. Lamb, Ph.D., HCLD, an established leader in urology based at Weill Cornell Medicine; and Marius George Linguraru, DPhil, MA, MSc, an expert in image processing and artificial intelligence.

little girl being examined by doctor

First Washington-based Turner syndrome clinic opens Jan. 28

little girl being examined by doctor

Endocrinologists at Children’s National work with a team of cardiologists, gynecologists, geneticists, psychologists and other clinicians to provide comprehensive and personalized care for girls with Turner syndrome.

Starting Monday, Jan. 28, 2018 girls with Turner syndrome will be able to receive comprehensive and personalized treatment at Children’s National Health System for the rare chromosomal condition that affects about one in 2,500 female births.

Many girls with Turner syndrome often work with a pediatric endocrinologist to address poor growth and delayed puberty, which may be treated with human growth hormone and estrogen replacement therapy. They may also need specialty care to screen for and treat heart defects, frequent ear infections, hearing loss, vision problems and challenges with non-verbal learning.

Roopa Kanakatti Shankar, M.D., M.S., a pediatric endocrinologist at Children’s National, aims to consolidate this treatment with a comprehensive Turner syndrome clinic.

“We’re creating a place that girls with Turner syndrome can come to receive specialized and personalized treatment, while feeling supported,” says Dr. Shankar.

Patients can now schedule visits and meet with multiple specialists in one clinic location:

The multispecialty referral team includes neuropsychologists, otolaryngologists (ear, nose and throat doctors), orthopedics, urology and dentistry to address unique medical needs. Families can also schedule appointments with audiology and get labs and other studies on the same day.

As girls with Turner syndrome age, they are at increased risk for diabetes, an underactive thyroid and osteoporosis, which is one reason Dr. Shankar wants to educate and increase awareness early on.

“There is something special about girls with Turner syndrome,” says Dr. Shankar. “They are very inspiring and endearing to work with,” she adds, reflecting on her past research and future goals with the clinic. “Their perseverance in the face of challenges is one of the things that inspires me to work in this field.”

The Turner syndrome clinic at Children’s National meets the criteria for a level 2 clinic designation by the Turner Syndrome Global Alliance by providing coordinated medical care, same-day visits with multiple specialists and connecting patients with advocacy groups.

Within the next two years, Dr. Shankar looks forward to meeting level 4 criteria, the designation for a regional resource center, by adding multi-institutional research partners, mentoring programs and organizing a patient-family advisory council.

“As we start out, we aim to provide excellent clinical care and create a database while forming these partnerships, and over time, we hope this information will influence future research studies and foster a greater depth of tailored care,” says Dr. Shankar. “Our ultimate goal is to treat, support and empower girls with Turner syndrome to achieve their full potential.”

To learn more about the Turner syndrome clinic, available on the fourth Monday of every month, visit ChildrensNational.org/endocrinology.

Groundbreaking at Research and Innovation Campus

Children’s National breaks ground on research and innovation hub

Groundbreaking at Research and Innovation Campus

Pictured, from left to right: Mike Williams, board chair of Children’s National, Mark Batshaw, M.D., chief academic officer and physician-in-chief at Children’s National, Kurt Newman, M.D., president and CEO of Children’s National, Ward 4 Councilman Brandon Todd, Norvell Coots, M.D., president and CEO of Holy Cross Health, and Sarosh Olpadwala, director of real estate, Office of the Deputy Mayor for Planning and Economic Development.

On November 28, 2018, Children’s National Health System marked the official start of construction on its pediatric research and innovation campus with a groundbreaking event. The campus will be distinct nationally as a freestanding research and innovation complex focused on pediatric medicine.

“We had this vision to create a one-of-a-kind pediatric and research innovation campus, which is also a first for Washington, D.C.,” said Kurt Newman, M.D., president and CEO of Children’s National. “If we’re going to help children grow up stronger, then it’s not enough to just provide excellent medical care. We have to work on the research and innovation, which drives discoveries and improves the care for our next generation.”

Children’s National is renovating four existing buildings on a nearly 12-acre portion of the former Walter Reed Army Medical Center campus. This includes a research and innovation building, an outpatient care center, which will include comprehensive primary care services for the community and a conference theatre.

With 160,000 sq. ft. of research and innovation space – and room for expansion – Children’s National will be able to expand its efforts in the high-impact opportunities in pediatric genomic and precision medicine. Developing treatments that can target an individual’s disease more precisely can produce better outcomes with fewer side effects. This focus on personalized research will also improve access at the main hospital by freeing up space for the high-demand critical care services that Children’s National provides.

These efforts will be anchored by three areas of strength at Children’s National: the Center for Genetic Medicine Research, headed by Eric Vilain, M.D., Ph.D., the clinical molecular genetics laboratory directed by Meghan Delaney, DO, MPH, and the Rare Disease Institute headed by Marshall Summar, M.D.

A critical component of the new campus’ success is its proximity to key partners, such as industry, universities, academic medical centers, federal agencies and start-up companies. By working together with these partners, Children’s National hopes to create an ecosystem for nurturing innovation from laboratory discovery all the way through to commercialization.

The new pediatric research and innovation center will also provide an economic benefit of $150 million through its completion date of 2020, providing 350 temporary jobs and 110 permanent positions. The long-term growth, based on an independent study by McKinsey and Company, is exponential and could produce up to $6.2 billion in economic benefit by 2030, based on projected tax revenue and 2,100 permanent jobs, pending future research partnerships.

“Medical advances that effectively treat or prevent disease mean that our children will live fuller, more productive lives,” said Mike Williams, board chair of Children’s National. “That is real economic and societal benefit.”

Veronica-Gomez-Lobo

Multidisciplinary care for children with urogenital differences

Veronica-Gomez-Lobo

Veronica Gomez-Lobo, M.D., brought together a multidisciplinary team to form the Positive Reevaluation of Urogenital Differences (PROUD) Clinic.

When a child is born with urogenital differences, the chromosomes, internal organs or external genitalia are considered to be atypical. While these differences were once thought to be rare, they are more common than people realize, with about 1 in 100 newborns affected.

The complexities of caring for children with urogenital differences, also known as differences of sex development (DSD), were not fully understood for many years. In the past, if a child was born with DSD, the family would see an endocrinologist for hormone therapy and a urologist for surgical options. Counseling was not part of the standard of care, so there was little support available to help families understand the tremendous psychosocial impacts of DSD.

In the last decade, fundamental changes have occurred in the way physicians care for children affected by DSD, with psychosocial health becoming a prominent focus. Veronica Gomez-Lobo, M.D., a Children’s National pediatric and adolescent gynecologist, was one of the physicians who embraced this focus and sought out a new care paradigm for her patients.

Creating the PROUD Clinic

Dr. Gomez-Lobo brought together a multidisciplinary team – including medical geneticist Eyby Leon Janampa, M.D., geneticist Eric Vilain, M.D., Ph.D., urologist Daniel Casella, M.D., endocrinologist Kim Shimy, M.D., psychiatrist David Call, M.D., and psychologist Elaine Goldberg, Ph.D. – to form the Positive Reevaluation of Urogenital Differences (PROUD) Clinic. It can be very challenging to bring together diverse specialists in a complex area like DSD, but her team possesses a similar philosophy – to care for the whole family by managing both the psychosocial and medical aspects of care in one location.

The team meets before each clinic to discuss the patients they will see that day. Patients vary significantly by the type of DSD and also by age – some patients are still in utero, while others may be newborns, children, adolescents or even occasionally adults.

Families see the entire team during their appointment, which can often last two to three hours to ensure that families receive the full support resources offered by the team.

“Even in difficult cases without a clear answer, we present the facts we know to the families, discussing all possibilities about psychosocial issues, gender identity, sexuality, function and fertility,” says Dr. Gomez-Lobo.

Long after the initial appointment, the PROUD Clinic continues to work closely with families and individual providers, following up as needed for medical diagnosis and care and providing continued psychosocial support with the entire team. Due to the efforts of the PROUD Clinic, patients and their families are now receiving compassionate care that looks at all facets of DSD, from childhood through adulthood.

Increasing DSD knowledge in the medical community

In order to give her patients the most thorough understanding of DSD and to expand the medical community’s knowledge, Dr. Gomez-Lobo’s program also participates in the Disorders of Sex Development Translational Research Network (DSD-TRN), which is led by Dr. Vilain. Supported by the National Institutes of Health (NIH), the DSD-TRN provides physicians across the country with the ability to perform research to advance knowledge regarding these conditions, as well as learn how to improve the care of these individuals and families. The DSD-TRN also provides a forum to seek advice about complex cases and to communicate how to transition patients from pediatric to adult medicine.

The relationship with the DSD-TRN helps the PROUD Clinic team further their goal of creating care for their patients that is current, individualized and compassionate.

 

Javad Nazarian

Advancing pediatric cancer research by easing access to data

Javad Nazarian

“This is a tremendous opportunity for children and families whose lives have been forever altered by pediatric cancers,” says Javad Nazarian, Ph.D., M.S.C., principal investigator in the Center for Genetic Medicine Research and scientific director of the Brain Tumor Institute at Children’s National.

Speeding research into pediatric cancers and other diseases relies not only on collecting good data, but making them accessible to research teams around the world to analyze and build on. Both efforts take time, hard work and a significant amount of financial resources – the latter which can often be difficult to attain.

In a move that could considerably advance the field of pediatric cancer, the National Institutes of Health (NIH), a body that funds biomedical research in the United States, recently awarded a public-private research collective that includes Children’s National Health System up to $14.8 million to launch a data resource center for cancer researchers around the world in order to accelerate the discovery of novel treatments for childhood tumors. Contingent on available funds, five years of funding will be provided by the NIH Common Fund Gabriella Miller Kids First Pediatric Research Program, named after Gabriella Miller, a 10-year-old child treated at Children’s National.

As principal investigators, researchers at Children’s Hospital of Philadelphia will lead the joint effort to build out the “Kids First” Data Resource Center. Children’s National in Washington, D.C., will spearhead specific projects, including the Open DIPG project, and as project ambassador will cultivate additional partnerships with public and private foundations and related research consortia to expand a growing trove of data about pediatric cancers and birth defects.

“This is a tremendous opportunity for children and families whose lives have been forever altered by pediatric cancers,” says Javad Nazarian, Ph.D., M.S.C., principal investigator in the Center for Genetic Medicine Research and scientific director of the Brain Tumor Institute at Children’s National. “From just a dozen samples seven years ago, Children’s National has amassed one of the nation’s largest tumor biorepositories funded, in large part, by small foundations. Meanwhile, research teams have been sequencing data from samples here and around the world. With this infusion of federal funding, we are poised to turn these data into insights and to translate those research findings into effective treatments.”

Today’s NIH grant builds on previous funding that Congress provided to the NIH Common Fund to underwrite research into structural birth defects and pediatric cancers. In the first phase, so-called X01 grantees—including Eric Vilain, M.D., Ph.D., newly named director of the Center for Genetic Medicine Research at Children’s National—received funding to sequence genetic data from thousands of patients and families affected by childhood cancer and structural birth defects.

This new phase of funding is aimed at opening access to those genetic sequences to a broader group of investigators around the globe by making hard-to-access data easily available on the cloud. The first project funded will be Open DIPG, run by Nazarian, a single disease prototype demonstrating how the new data resource center would work for multiple ailments.

DIPG stands for diffuse intrinsic pontine glioma, aggressive pediatric brain tumors that defy treatment and are almost always fatal. Just as crowd sourcing can unleash the collective brainpower of a large group to untangle a problem swiftly, open data sharing could accomplish the same for childhood cancers, including DIPG. In addition to teasing out molecular alterations responsible for making such cancers particularly lethal, pooling data that now sits in silos could help to identify beneficial mutations that allow some children to survive months or years longer than others.

“It’s a question of numbers,” Dr. Vilain says. “The bottom line is that making sense of the genomic information is significantly increased by working through large consortia because they provide access to many more patients with the disease. What is complicated about genetics is we all have genetic variations. The challenge we face is teasing apart regular genetic variations from those genetic variations that actually cause childhood cancers, including DIPG.”

Nazarian predicts some of the early steps for the research consortium will be deciding nuts-and-bolts questions faced by such a start-up venture, such as the best methods to provide data access, corralling the resources needed to store massive amounts of data, and providing data access and cross correlation.

“One of the major challenges that the data resource center will face is to rapidly establish physical data storage space to store all of the data,” Nazarian says. “We’re talking about several petabytes—1,000 terabytes— of data. The second challenge to address will be data dissemination and, specifically, correlation of data across platforms representing different molecular profiles (genome versus proteome, for example). This is just the beginning, and it is fantastic to see a combination of public and private resources in answering these challenges.”

Eric Vilain explores “Disorders/differences of sex development: A world of uncertainty”

Eric Vilain

In his keynote address at Children’s National’s Research and Education Week, Eric Vilain, M.D., Ph.D., explored the genetics of sex development and sex differences.

After announcing he would be joining Children’s National as the new director of the Center for Genetic Medicine Research late last year, internationally-renowned geneticist Eric Vilain, M.D., Ph.D., gave a keynote address entitled “Disorders/Differences of Sex Development: A World of Uncertainty” during Children’s National’s Research and Education Week.

Dr. Vilain explored the genetics of sex development and sex differences – specifically differences of sex development (DSD), congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical.

“The first step in sex development is looking at genetic sex and how it results in gonadal sex,” Dr. Vilain said. “From a scientific perspective, we are trying to take a step back and assess how cells become more typically male or female.”

He explained that, at conception, the fundamental difference between male and female embryos exists in the sex chromosome complement. Both XX and XY embryos have bipotential gonads capable of differentiating into a testis or an ovary, though embryos are virtually indistinguishable from a gender perspective up until six weeks in utero.

Eric Vilain - sex differences

According to Dr. Vilain, the fundamental difference between male and female embryos exists in the sex chromosome complement, though embryos are virtually indistinguishable until six weeks in utero.

Whether or not a bipotential gonad forms is largely left up to the genetic makeup of the individual. For example, a gene in the Y chromosome (SRY) triggers a cascade of genes that lead to testis development. If there is no Y chromosome, it triggers a series of pro-female genes that lead to ovarian development.

However, genetic mutations can alter the subsequent steps of sex differentiation. Dr. Vilain explained that, depending on the genotype, an individual may experience normal gonadal development, but abnormal development of the genitalia.

He also noted that these genes are critical to determining the differences between men and women in non-gonadal tissues as well.

In addition to exploring the genetics of sex development and sex differences, Dr. Vilain’s research explores the biological bases of sex variations in predisposition to disease. His clinic at Children’s National is completely devoted to caring for patients with a wide array of genetic and endocrine issues, particularly cases dealing with variations of sex development.

For seven years, Children’s National’s Research and Education Week has celebrated the excellence in research, education, innovation and scholarship at Children’s National and around the world. This year, the annual event focused how “Collaboration Leads to Innovation” and celebrated the development of ideas that aim to transform pediatric care.

Eric Vilain, M.D., Ph.D.

Eric Vilain to lead genetic medicine research

Eric Vilain

Eric Vilain, M.D., Ph.D., emphasizes the idea of health and disease as a compound process that will transform children’s health and impact a patient throughout life.

Eric Vilain, M.D., Ph.D., an internationally renowned geneticist well known for groundbreaking studies of gender based biology, will soon lead the Center for Genetic Medicine Research at Children’s National Health System.

Dr. Vilain joins Children’s National from the University of California, Los Angeles (UCLA) where he serves as Professor of Human Genetics, Pediatrics and Urology, Chief of Medical Genetics, and attending physician in the Department of Pediatrics.

As the Director of the Center for Genetic Medicine Research, Dr. Vilain will emphasize the idea of health and disease as a compound process, which he believes “can transform children’s health and help the treatment and prevention of illness, not only in childhood, but throughout a patient’s life.”

The Center for Genetic Medicine Research currently houses a highly interdisciplinary faculty of over 50 scientists and physician investigators and brings together a variety of clinical and scientific disciplines to coordinate scientific and clinical investigations simultaneously from multiple angles. The Center also provides access to the leading edge innovative technologies in genomics, microscopy, proteomics, bioinformatics, pre-clinical drug trials, and multi-site clinical trial networks for faculty within the Children’s Research Institute, the academic arm of Children’s National.

Dr. Vilain’s current laboratory focuses on the genetics of sexual development and sex differences – specifically the molecular mechanisms of gonad development and the genetic variants of brain sexual differentiation. His research also explores the biological bases of sex variations in predisposition to disease. His work crosses several disciplines (genetics, neuroscience, psychology) leading to findings with major societal implications. In addition to scientific investigation, Dr. Vilain created a clinic devoted to caring for patients with a wide array of genetic and endocrine issues, particularly those with variations of sexual development.

He brings nearly 30 years of expertise with him to Children’s National. He has authored seminal articles regarding the field of sexual development, and his research program has continuously been funded by the National Institutes of Health (NIH). Dr. Vilain is a Fellow of the American College of Medical Genetics and a member of numerous professional committees. The recipient of numerous awards, he has been recognized by organizations ranging from the NIH to the Doris Duke Charitable Foundation, March of Dimes, and the Society for Pediatric Research. He has served as an advisor to the International Olympic Committee Medical Commission since 2011 and has been a member of the Board of Scientific Counselors of the National Institute of Child Health and Human Development since 2015.

Mark Batshaw, M.D., Executive Vice President, Physician-in-Chief, and Chief Academic Officer at Children’s National says, “Dr. Vilain’s vision and expertise in the study and use of precision medicine approaches, and the development of novel treatments for diseases of childhood, will lead to drastically different and improved outcomes for some of the most devastating diseases, such as cancer.”

“I am honored to join the world-renowned team at Children’s National, and look forward to continuing to find new, innovative ways to research, diagnose and treat rare and common disorders,” Dr. Vilain adds.