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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.