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Sepsis in Scientific American, Updating Genetic Tests, Prenatal Gene Editing, Nature Magazine, Type 1.5 Diabetes

Published on October 19, 2018 in Cornerstone Blog · Last updated 3 months 4 weeks ago


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Our breakthrough research at Children’s Hospital of Philadelphia Research Institute made headlines in both popular science media outlets and prominent scientific journals alike, from advances in detecting sepsis, to pioneering work in prenatal gene editing, to the future of genomic medicine. Read on to learn more about how our scientists stay at the cutting-edge of their fields by approaching pediatric medicine inventively, whether it’s by developing the most effective alerts in emergency medicine, modernizing genetic testing models to keep up with an accelerating pace of discovery, and beyond. 

Scientific American Features Pediatric Sepsis Program Research

By combining electronic alerts with a clinician’s judgment, the Pediatric Sepsis Program at CHOP has increased detection rates for sepsis, the leading cause of intensive care unit deaths worldwide, from 86 percent to over 99 percent. This week, Scientific American featured that breakthrough in an article about the value of “the physician’s touch”, the idea that while patients benefit from advances in medical technology, a doctor’s opinion still holds much weight in the outcome.

The story references novel research led by Fran Balamuth, MD, PhD, an emergency medicine physician at CHOP, showing that a two-step sepsis trigger tool successfully reduced missed sepsis diagnoses in children by 76 percent. The protocol consists of both an electronic alert and a “sepsis huddle” in which an emergency medicine physician and nurse evaluate the child at the bedside. Scientific American highlights the fact that though electronic alerts alone helped detect a higher number of serious infections, without a sepsis huddle, it also raised false alarms.

“The [CHOP] teams were able to weed out the algorithm’s false alarms with high accuracy, and in addition find cases the computer missed, bringing their detection rate of deadly infections from 86.2 percent by the algorithm alone, to 99.4 percent by the algorithm in combination with human perception,” writes the article’s author. 

Read the full Scientific American story.

Prenatal Gene Editing Shows Proof-of-Concept in Treating Congenital Disease Before Birth

In a landmark study published last week in Nature Medicine, researchers from the Center for Fetal Diagnosis and Treatment at CHOP and the Perelman School of Medicine described the successful use of gene-editing tools to prevent a lethal metabolic disorder in utero in laboratory mice. The discovery suggests that similar tactics may eventually be used to treat human congenital diseases before birth. For the very first time, the breakthrough provides proof-of-concept for prenatal use of a sophisticated, low-toxicity tool that can efficiently edit DNA building blocks in disease-causing genes.

“Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy,” said study co-leader William Peranteau, MD, a pediatric and fetal surgeon in the Center for Fetal Diagnosis and Treatment. “We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants.”

Dr. Peranteau and his colleagues used CRISPR-Cas9 and base editor 3 gene-editing tools to target a gene that regulates cholesterol levels and reduce those levels in healthy mice treated in utero. Additionally, they used gene editing to improve liver function and prevent newborn death in mice that had been engineered with a mutation causing hereditary tyrosinemia type 1 (HT1), a lethal liver disease. In humans, HT1 appears during infancy, and though it is treatable, patients are at risk for liver failure or liver cancer when those treatments fail.

Genomics Scientist Proposes New Model to Continuously Update Genetic Test Results

As genetic testing continues to help countless patients and their families learn their risk for various health conditions, scientists are constantly unearthing new findings about the associations between diseases and different gene variants. To keep up with this rapid pace of discovery, Mahdi Sarmady, PhD, a genome informatics scientist and director of Bioinformatics in our Division of Genomic Diagnostics, proposed an innovative model that continuously updates genetic test results to remain relevant with new evidence.

In a JAMA Pediatrics Viewpoint article published earlier this month, Dr. Sarmady and Ahmad Abou Tayoun, PhD, a former CHOP geneticist, described the model, which generates ongoing automated updates and enables genetic counselors and clinicians to communicate information to patients both when test results are reported and for years afterwards. The approach differs from traditional methods in that it employs automated algorithms to collect new evidence from scientific literature and notifies a clinician if a previously discovered variant could be pathogenic. Meanwhile, clinicians can use the platform to either order reanalysis of a patient’s variant or enter phenotypic information that would help other researchers and clinicians.

“Instead of a one-time test result, there would be continuous, systematic interaction between the clinic and the genetic testing lab, and reanalysis of changing data,” said Dr. Sarmady in a press release. “This could enable clinicians to provide better diagnoses and change treatment plans for their patients as new information becomes available, and help advance the promise of precision medicine.”

Read more in the press release.

Nature Features Top CHOP Genomics Scientists

If you’ve thumbed through the latest issue of Nature magazine, one of the scientific community’s most prominent journals, you may have noticed some familiar CHOP faces appearing in an article titled “The Clinical Code-Breakers.” Multiple researchers from our Roberts Individualized Medical Genetics Center and the Division of Genomics Diagnostics were interviewed for the feature, which highlights how technological breakthroughs in DNA and whole-genome sequencing have allowed scientists to pinpoint the genetic variations responsible for a wide variety of diseases.

Some of our experts featured include Nancy Spinner, PhD, chief of the Division of Genomic Diagnostics; Livija Medne, senior genetic counselor and co-director of the IMGC; and Marilyn Li, MD, vice chief of the division of Genomic Diagnostics and director of Cancer Genomic Diagnostics, who discussed the advances and challenges of sequencing. The article also highlights the rapid and impactful growth of our Division of Genomics Diagnostics, in tandem with the increasing number of children who undergo rapid genome sequencing. “CHOP has already sequenced 300 exomes this year — and that is nearly twice as many as it sequenced in the whole of 2015,” writes Michael Eisenstein, author of the piece.

Read the full Nature story online.

Genome-Wide Association Study Analysis Reveals New Insights Into Type 1.5 Diabetes

A new study co-led by scientists in our Division of Human Genetics is shedding light on the genetic influences that may underlie latent autoimmune diabetes in adults (LADA), also known informally as type 1.5 diabetes. The findings, published recently in the journal Diabetes Care, may help clinicians make more accurate diagnoses of LADA and pinpoint more appropriate treatments. The international collaboration marks the first genome-wide association study of LADA.

Through a primary analysis comparing LADA cases with control subjects and a secondary analysis comparing cases of LADA with those of type 1 diabetes (T1D) and with type 2 diabetes (T2D), the scientists discovered genetic signals linking LADA with both T1D, the autoimmune form of diabetes that often presents in childhood, and T2D, the metabolic type that usually appears first in adults.

“Further study of underlying genetic interactions in LADA may reveal better biomarkers of the disease,” said Rajashree Mishra, a co-first author of the study, from CHOP’s Division of Human Genetics, in a press release. “Currently, as high as five to 10 percent of patients diagnosed as adults with type 2 diabetes may actually be misdiagnosed, and in fact have a late-onset form of autoimmune diabetes. More accurate diagnosis may guide better clinical management. For instance, patients with LADA may require close monitoring, to detect the optimal point at which they require insulin.”

Learn more about the study in the press release.


Recently on Cornerstone, we published our first explainer describing the science behind gene therapy, recognized Ignacio Tapia, MD, for his receipt of the inaugural Carole L. Marcus Outstanding Achievement Award from the American Thoracic Society, and shared highlights from the 25th Silver Lecture for Pediatric HIV/Aids Research presented by Steven D. Douglas, MD.

Catch up on our headlines from our Oct. 5 edition of In the News:

  • Steven D. Douglas, MD, Named Twenty-fifth Silver Award Recipient
  • CHOP Investigator Awarded Five-Year Grant for Outcomes Research
  • Hyundai Hope On Wheels Awards Drive Pediatric Cancer Research Forward
  • New PolicyLab Webinar Discusses Impact of PA Home Visiting Programs

Keep up with our news, stories, and updates in real time by following us on Twitter, Facebook, LinkedIn, or Instagram. Or subscribe to our newsletter to get an email sent every other Friday by signing up here.