In early 2014, controversy erupted when two papers in Nature indicated that exposing ordinary cells to stress—an acid bath or mechanical stress—could quickly and efficiently turn them into pluripotent stem cells, capable of developing into virtually all the tissues in the body.
The technique, called “stimulus-triggered acquisition of pluripotency,” or STAP, was lauded for its simplicity compared to other methods like nuclear transfer into egg cells or cellular reprogramming with a set of transcription factors.
The 20th century saw great strides in curing childhood cancer, thanks primarily to the discovery that broadly toxic chemotherapy agents could kill malignant cells. Once virtually incurable, pediatric cancer now has an overall long-term survival rate topping 80 percent.
Gastroesophageal reflux disease (GERD), in which stomach acids back up into the esophagus, is increasingly diagnosed in children. One study based on insurance-claims data found that GERD diagnoses in infants more than tripled between 2000 and 2005 (from 3.4 to 12.3 percent). In addition to heartburn and chest pain, GERD has been implicated in cough, wheezing and pneumonia.
To reduce such acid-related symptoms, doctors increasingly prescribe acid suppression medications such as proton pump inhibitors (PPIs). They’re among the most-prescribed drug classes in the U.S. But clinicians in the Aerodigestive Program at Boston Children’s Hospital noticed that a large number of their GERD patients had lung cultures positive for bacteria, and that a strong predictor was the amount of non-acid reflux the child had.
“We then had to ask the question, ‘are acid suppression medications, which are being prescribed to treat respiratory symptoms, actually worsening the problem?’” says program director Rachel Rosen, MD, MPH. “What are these medications doing to change the bacteria composition in children?”
The twists and turns of Stephen Friend’s career are both dizzying and thrilling. In the early days, Stephen Friend, MD, PhD, CEO and co-founder of Sage Bionetworks, spent many a late night as a resident in the emergency room at Children’s Hospital of Philadelphia with Gary Fleischer, MD, current pediatrician-in-chief at Boston Children’s Hospital.
Friend later wound up at Boston Children’s as well, where he did his pediatric hematology-oncology fellowship and later, as part of the faculty, helped co-lead the team that identified the first tumor suppressor at Boston Children’s. A few years later, Friend left academia to pursue his passion in a startup and later engineered a landing at Sage Bionetworks, a nonprofit focused on patient engagement and open science in the research process. The Resilience Project, one of Sage’s research initiatives, analyzes DNA from healthy volunteers to discover rare mutations that protect resilient people from serious childhood illnesses.
Prospects are looking up for patients who have no explanation for their symptoms despite extensive investigations and testing. There’s a growing revolution in DNA diagnostics (see yesterday’s example) and ongoing work to bring clarity and meaning to sequencing data. Patients with similar symptoms can find each other like never before, and are increasingly empowered to lead in research and discovery.
Another small but important development was announced yesterday by the National Institutes of Health. The NIH’s Undiagnosed Diseases Network (UDN) has opened up a one-stop online portal called the UDN Gateway where patients and families can apply for access to expert team analysis and testing. (A referral letter from a provider is required.)
Some 7,500 rare disorders are known to be caused by single-gene mutations. Most of these disorders first appear at birth or in childhood, and for about half, the responsible gene has been identified. Yet, on average, families with rare disorders spend 12 years searching before getting a correct diagnosis.
Jackie Smith, a 35-year-old mother of two, searched for 32 years for the cause of her muscular weakness. Her parents knew something was wrong soon after she was born. At first, because her ankles turned in, they thought she was bow-legged.
Recent clinical trials for patients with advanced melanoma have found that a new class of drugs—anti-PD-1 antibodies—can elicit an unprecedented response rate. In the last year, the FDA gave accelerated approval to two anti-PD-1 antibodies, nivolumab and pembrolizumab, for patients with advanced melanoma (including Jimmy Carter) who are no longer responding to other drugs. And there’s growing evidence that this class of drugs may be effective in treating other forms of cancer.
Anti-PD-1 antibodies target a receptor on activated T cells, known as the programmed cell death 1 (PD-1) receptor. Tumor cells stimulate this inhibitory receptor to dodge immune attack, whereas anti-PD-1 antibodies block the same pathway, “waking up” the immune cells so they can attack the cancer. The drugs have been hailed as one of the first cancer immunotherapy success stories.
“It’s all about the patients,” says Katherine Janeway, MD, when asked about the motivations behind her efforts to bring precision medicine to pediatric oncology. But it’s more than that; the drive to combine science and care is in her blood. A solid tumor specialist and cancer genomics researcher at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Janeway is the sixth generation of her family to choose a scientific or medical path—not just as a career, but also as a form of service.
For children with complex medical needs, care coordination across medical specialties is a major pain point, as is communication across multiple provider systems. And patients aren’t the only ones feeling the burden. Consider these startling statistics:
$25-$45 billion is wasted annually in the U.S. due to poor communication in health care.
$45 billion has been invested in tools that record and bill for care, but don’t manage care.
The CLARITY Undiagnosed Challenge is heating up. Biomedical teams from seven countries are racing to interpret DNA sequences from five families affected with undiagnosed illnesses—some with gravely ill children, some already bereaved, all desperate for answers.
In July, the 26 competing teams received whole-genome and whole-exome sequence data from each patient and close family members, along with clinical notes and patient videos. Their reports, due September 21, will be judged by an independent panel based on:
the methods used to analyze and interpret the sequence data
the ability to synthesize the information
clinical usefulness, care recommendations and “next steps.”