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Andrew Dauber

Andrew Dauber, M.D., MMSc, caps off research success with award and reception

Andrew Dauber

Unfortunately, we’ve been notified that the ENDO2020 conference has been canceled due to concerns of COVID-19. Because of this, we will not be hosting our reception in honor of Andrew Duaber, M.D., on Sunday, March 29.

We hope to see you at a future Endocrinology or Pediatric Endocrinology event.

Children’s National Hospital is incredibly proud of the work Dr. Dauber has done in the endocinology community.

Andrew Dauber, M.D., MMSc, division chief of Endocrinology at Children’s National Hospital, will be awarded the 2020 Richard E. Weitzman Outstanding Early Career Investigator Award at ENDO 2020. The prestigious award will be presented at the annual meeting of the Endocrine Society in recognition of Dauber’s work in understanding the regulation of growth and puberty, and applying innovative genetic technologies to studying pediatric endocrinology. Dauber credits many collaborators throughout the world, as well as the team at Children’s National for the award.

With a five-year grant from the National Institutes of Health (NIH), Dauber and colleagues from the Cincinnati Children’s Hospital Medical Center, Boston Children’s Hospital and the Children’s Hospital of Philadelphia are using electronic health records to identify children who likely have rare genetic growth disorders. Using cutting-edge DNA sequencing technologies, including whole exome sequencing, the researchers are aiming to identify novel genetic causes of severe growth disorders. The first paper describing genetic findings in patients with high IGF-1 levels was published in Hormone Research in Paediatrics in December 2019.

Dauber and researchers at Cincinnati Children’s Hospital Medical Center are exploring how to treat patients with mutations in the PAPPA2 gene. In 2016, the group described the first patients with mutations in this gene who had decreased the bioavailability of IGF-1, stunting their growth and development. In their current phase of research, findings are emphasizing the importance of this gene in regulating IGF-1 bioavailability throughout childhood. The ultimate aim is to create therapies to increase IGF-1 bioavailability, thereby supporting healthy growth and development in children. Their first study to track PAPPA2 and intact IBGBP-3 concentrations throughout childhood was published in the European Journal of Endocrinology in January 2020.

Dauber is particularly interested in studying children with dominantly inherited forms of short stature. Along with collaborators in Cincinnati, he currently has an ongoing treatment trial using growth hormone in patients with Aggrecan gene mutations.  Dauber hopes to announce soon a new clinical trial for children with all forms of dominantly inherited short stature.

Study upon study has shown us that there are many factors that affect an individual’s height and growth. As these studies and the conversation around how to identify and address genomic anomalies become more prevalent, the team at Children’s National is increasingly interested in engaging with other centers around the country. In the coming months, the Children’s National Research & Innovation Campus will open on the grounds of the former Walter Reed Army Medical Center, which will serve as a one-of-a-kind pediatric research and innovation hub. A critical component to this campus is the co-location of Children’s National research with key partners and incubator space.

little girl drinking milk

Children allergic to cow’s milk smaller and lighter

little girl drinking milk

Children allergic to cow’s milk are smaller and weigh less, according to the first published study to characterize growth trajectories from early childhood to adolescence in children with persistent food allergies.

Children who are allergic to cow’s milk are smaller and weigh less than peers who have allergies to peanuts or tree nuts, and these findings persist into early adolescence. The results from the longitudinal study – believed to be the first to characterize growth patterns from early childhood to adolescence in children with persistent food allergies – was published online in The Journal of Allergy and Clinical Immunology.

“Published data about growth trajectories for kids with ongoing food allergies is scarce,” says Karen A. Robbins, M.D.,* lead study author and an allergist in the Division of Allergy and Immunology at Children’s National Hospital when the study was conducted. “It remains unclear how these growth trends ultimately influence how tall these children will become and how much they’ll weigh as adults. However, our findings align with recent research that suggests young adults with persistent cow’s milk allergy may not reach their full growth potential,” Dr. Robbins says.

According to the Centers for Disease Control and Prevention, 1 in 13 U.S. children has a food allergy with milk, eggs, fish, shellfish, wheat, soy, peanuts and tree nuts accounting for the most serious allergic reactions. Because there is no cure and such allergies can be life-threatening, most people eliminate one or more major allergen from their diets.

The multi-institutional research team reviewed the charts of pediatric patients diagnosed with persistent immunoglobulin E-mediated allergy to cow’s milk, peanuts or tree nuts based on their clinical symptoms, food-specific immunoglobulin levels, skin prick tests and food challenges. To be included in the study, the children had to have at least one clinical visit during three defined time frames from the time they were age 2 to age 12. During those visits, their height and weight had to be measured with complete data from their visit available to the research team. The children allergic to cow’s milk had to eliminate it completely from their diets, even extensively heated milk.

From November 1994 to March 2015, 191 children were enrolled in the study, 111 with cow’s milk allergies and 80 with nut allergies. All told, they had 1,186 clinical visits between the ages of 2 to 12. Sixty-one percent of children with cow’s milk allergies were boys, while 51.3% of children with peanut/tree nut allergies were boys.

In addition to children allergic to cow’s milk being shorter, the height discrepancy was more pronounced by ages 5 to 8 and ages 9 to 12. And, for the 53 teens who had clinical data gathered after age 13, differences in their weight and height were even more notable.

“As these children often have multiple food allergies and other conditions, such as asthma, there are likely factors besides simply avoiding cow’s milk that may contribute to these findings. These children also tend to restrict foods beyond cow’s milk,” she adds.

The way such food allergies are handled continues to evolve with more previously allergic children now introducing cow’s milk via baked goods, a wider selection of allergen-free foods being available, and an improving understanding of the nutritional concerns related to food allergy.

Dr. Robbins cautions that while most children outgrow cow’s milk allergies in early childhood, children who do not may be at risk for growth discrepancies. Future research should focus on improving understanding of this phenomenon.

In addition to Dr. Robbins, the research team includes co-author Robert A. Wood, M.D., and senior author Corinne A. Keet, M.D., Ph.D., both of Johns Hopkins University School of Medicine.

*Dec. 18, 2019 update: After leaving full-time employment at Children’s National Hospital, Dr. Robbins became an AstraZeneca employee, working on immuno-oncology safety.

Andrew Dauber

Andrew Dauber, M.D., MMSc, awarded prestigious laureate award

Andrew Dauber

Unfortunately, we’ve been notified that the ENDO2020 conference has been canceled due to concerns of COVID-19. Because of this, we will not be hosting our reception in honor of Andrew Duaber, M.D., on Sunday, March 29.

We hope to see you at a future Endocrinology or Pediatric Endocrinology event.

Children’s National Hospital is incredibly proud of the work Dr. Dauber has done in the endocinology community.

Andrew Dauber, M.D., MMSc, division chief of Endocrinology at Children’s National Hospital, will receive the 2020 Richard E. Weitzman Outstanding Early Career Investigator Award from The Endocrine Society. Given annually, the award was established in 1982 and honors the memory of the late Richard E. Weitzman, who had a brief but outstanding career studying neurohypophyseal hormone and cardiovascular-endocrine physiology – two seminal areas of modern endocrinology.

Dr. Dauber was selected as a recipient for the prestigious award for his contributions to understanding the regulation of growth and puberty, and his success at applying innovative genetic technologies to studying pediatric endocrinology.

“I feel extremely honored and humbled to be the recipient of the Richard E. Weitzman Outstanding Early Career Investigator Award from the Endocrine Society,” says Dr. Dauber. “I am so grateful to my many collaborators throughout the world as well as to my entire research team whose hard work and friendship are the basis for this award. I am excited to continue our work at Children’s National, an institution dedicated to innovation and team science.”

Dr. Dauber joined Children’s National in 2018 and specializes in studying and treating growth disorders. He has published over 75 studies examining genetic clues to endocrine disorders, with a focus on short stature and growth disorders.

The award will be presented at ENDO 2020, The Endocrine Society’s annual meeting, March 28-31, 2020, in San Francisco, California.

tube labeled "CRISPR"

$2M from NIH to extract meaningful data from CRISPR screens

tube labeled "CRISPR"

Protein-coding genes comprise a mere 1% of DNA. While the other 99% of DNA was once derided as “junk,” it has become increasingly apparent that some non-coding genes enable essential cellular functions.

Wei Li, Ph.D., a principal investigator in the Center for Genetic Medicine Research at Children’s National in Washington, D.C., proposes to develop statistical and computational methods that sidestep existing hurdles that currently complicate genome-wide CRISPR/Cas9 screening. The National Institutes of Health has granted him $2.23 million in funding over five years to facilitate the systematic study of genes, non-coding elements and genetic interactions in various biological systems and disease types.

Right now, a large volume of screening data resides in the public domain, however it is difficult to compare data that is stored in one library with data stored at a different library. Over the course of the five-year project, Li aims to:

  • Improve functional gene identification from CRISPR screens.
  • Develop new analyses algorithms for screens targeting non-coding elements.
  • Study genetic interactions from CRISPR screens targeting gene pairs.

Ultimately, Li’s work will examine a range of disease types. Take cancer.

“There is abundant information already available in the public domain, like the Project Achilles  from the Broad Institute. However, no one is looking to see what is going in inside these tumors,” Li says. “Cancer is a disease of uncontrolled cell growth that makes tumors grow faster.”

Li and colleagues are going to ask which genes control this process by looking at genes that hit the brakes on cell growth as well as genes that pump the gas.

“You knock out one gene and then look: Does the cell grow faster or does it grow more slowly? If the cell grows more slowly, you know you are knocking out a gene that has the potential to stop tumor growth. If cells are growing faster, you know that you’re hitting genes that suppress cancer cell growth.”

In a nutshell, CRISPR (clustered regularly interspaced short palindromic repeats) screens knock out different genes and monitor changes in corresponding cell populations. When CRISPR first became popular, Li decided he wanted to do something with the technology. So, as a Postdoc at Harvard, he developed comprehensive computational algorithms for functional screens using CRISPR/Cas9.

To reach as many people as possible, he offered that MAGeCK/MAGeCK-VISPR software free to as many researchers as possible, providing source code and offering internet tutorials.

“So far, I think there are quite a lot of people using this. There have been more than 40,000 software downloads,” he adds. “It’s really exciting and revolutionary technology and, eventually, we hope the outcomes also will be exciting. We hope to find something really helpful for cancer patients.”

Research reported in this publication was supported by the National Human Genome Research Institute of the National Institutes of Health under award number R01HG010753.

DNA

International collaboration discovers new cause for dwarfism

DNA

An international collaboration resulted in the identification of a new cause of dwarfism: mutations in a gene known as DNMT3A.

Beyond diabetes, short stature is the most common reason for children in the U.S. to visit an endocrinologist. For the vast majority of children with short stature, the cause remains unknown – even though many of these conditions stem from an as-yet unidentified genetic cause, says Andrew Dauber, M.D., M.M.Sc., division chief of Endocrinology at Children’s National Health System.

“Parents are concerned about why their child isn’t growing and if there are other complications or health problems they’ll need to watch out for,” he says. “Without a diagnosis, it’s very hard to answer those questions.”

Dauber’s research focuses on using cutting-edge genetic techniques to unravel the minute differences in DNA that limit growth. This research recently led him and his colleagues to identify a new cause of dwarfism: mutations in a gene known as DNMT3A. The discovery, which the team published in the January 2019 Nature Genetics, didn’t happen in isolation – it required a rich collaboration of labs spread across the world in Scotland, Spain, France and New Zealand, in addition to Dauber’s lab in the U.S.

The journey that brought Dauber into this group effort got its start with a young patient in Spain. The boy, then four years old, was at less than 0.1 percentile on the growth curve for height with a very small head circumference and severe developmental delays. This condition, known as microcephalic dwarfism, is incredibly rare and could stem from one of several different genetic causes. But his doctors didn’t know the reason for this child’s specific syndrome.

To better understand this condition, Dauber used a technique known as whole exome sequencing, a method that sequences all the protein-coding regions in an individual’s entire genome. He found a mutation in DNMT3A – a change known as a de novo missense mutation, meaning that the mutation happened in a single letter of the boy’s genetic code in a way that hadn’t been inherited from his parents. But although this mutation was clear, its meaning wasn’t. The only clue that Dauber had as to DNMT3A’s function was that he’d read about overgrowth syndromes in which the function of this gene is lost, leading to large individuals with large heads, the exact opposite of this patient’s condition.

To gather more information, Dauber reached out to Andrew Jackson, Ph.D., a researcher who studies human genes for growth at the University of Edinburgh in Scotland. Coincidentally, Jackson had already started studying this gene after two patients with a shared mutation in a neighboring letter in the genetic code – who also had short stature and other related problems – were referred to him.

Dauber and his colleagues sent the results from their genetic analysis back across the Atlantic to Jackson’s Edinburgh lab, and the doctors from Spain sent more information to Jackson’s lab, including the patient’s clinical information, blood samples and skin biopsy samples. Then the whole team of collaborators from around the globe set to work to discover the processes influencing short stature in each of these three patients.

Their results showed that these mutations appear to cause a gain of function in DNMT3A. This gene codes for a type of enzyme known as a methyltransferse, which places methyl groups on other genes and on the protein spools called histones that DNA wraps around. Each of these functions changes how cells read the instructions encoded in DNA. While the mutations that cause the overgrowth syndromes appear to allow stem cells to keep dividing long past when they should taper off and differentiate into different cell types – both normal processes in development – the gain of function that appears to be happening in these three patients prompts the opposite situation: Stem cells that should be dividing for a long time during development stop dividing and differentiate earlier, leading to smaller individuals with far fewer cells overall.

The researchers confirmed their findings by inserting one of the gain-of-function human DNMT3A mutations into a mouse, leading to short animals with small heads.

Eventually, says Dauber, these findings could help lead to new treatments for this and other types of dwarfism that act on these genetic pathways and steer them toward normal growth. These and other scientific discoveries hinge on the type of international collaboration that he and his colleagues engaged in here, he adds – particularly for the types of rare genetic syndromes that affect the patients that he and his colleagues study. With only a handful of individuals carrying mutations in certain genes, it’s increasingly necessary to combine the power of many labs to better understand the effects of these differences and how doctors might eventually intervene.

“The expertise for all aspects of any single research project is rarely centered in one institution, one city, or even one country,” Dauber says. “Often, you really need to reach out to people with different areas of expertise around the world to make these types of new discoveries that can have pivotal impacts on human health.”