For children with GI motility conditions, finding the right treatment – or cure – often takes years of trial and error. At Children’s Hospital of Philadelphia, motility experts are actively researching ways to shorten that wait time – and precision medicine is the key.

Robert O. Heuckeroth, MD, PhD, Research Director and Norman and Irma Braman Endowed Chair of the Suzi and Scott Lustgarten Center for GI Motility, offers an insider’s view of how CHOP’s clinical and research teams are actively employing personalized medicine techniques for children with GI motility conditions – and how this type of precision medicine can help sick kids return to just being kids.

What is precision medicine?

Precision medicine is based on the idea that human disease symptoms often have dozens of potential causes. We strive to determine exactly what is causing your child’s symptoms because once the mechanisms are understood, we may tailor therapies based on the disease mechanism to help your child feel better. In many cases, existing diagnostic tools and treatments work well, but for some diseases we still need to learn more. That’s why we pursue research along with clinical care to develop new diagnostic and treatment strategies.

What does precision medicine mean for motility?

The human bowel has a difficult job: digesting and absorbing food, eliminating waste, and maintaining a protective barrier to keep people safe. Every inch of the bowel needs to constantly monitor the local gastrointestinal (GI) environment and decide how to coordinate contraction/relaxation, so individuals are comfortable and well nourished.

In adults, the bowel is about 30 feet long and takes many twists and turns, so movement of food, liquid, and air through the bowel needs to be elegantly controlled. To sense nutrients and physical factors – like distension – and use this information to manage motility, the bowel has its own intrinsic nervous system called the enteric nervous system (ENS). The ENS has about as many neurons as the spinal cord and controls most aspects of bowel function. One role of the ENS is control of bowel smooth muscle and bowel pacemaker function, which enable efficient digestion of food, absorption of nutrients and expelling waste.

In addition to the ENS, there are many connections between the bowel and the brain. Hormonal, dietary factors and gut microbes (the type of bacteria in the gut) also alter bowel motility. When any of these mechanisms are not working properly, bowel dysfunction can cause debilitating symptoms.

Precision medicine means determining which bowel regions are not working properly, which cells in those regions are defective (e.g., nerves, muscles, pacemaker cells or others), and – ideally – which precise molecules in these cells are causing the problems. In some cases, bowel motility problems are caused by genetic disorders. Others occur when the baby’s body does not form properly before birth. And sometimes, motility problems result from infectious or immune-mediated injury. Some medicines can also affect bowel motility; and in some cases, social or emotional factors (e.g., anxiety, depression, bullying) can impact bowel motility and pain sensation from the bowel. Defining precisely what causes disease in your child gives us the best hope of restoring health.

What’s the role of precision medicine in motility treatment?

When you and your child come to the Suzi and Scott Lustgarten Center for GI Motility at CHOP, we listen to you carefully, then work with you to define your child’s disease mechanisms and restore their health. The details you and your child provide – coupled with a physical exam of your child – allow us to define affected bowel regions, and possible causes of symptoms.

Symptoms may arise from defects within the bowel (muscle, pacemaker cells, neurons or other cells) or may be due to problems in any other organ. For example, vomiting can be caused by problems in the bowel, brain, heart, liver, kidney, gallbladder, or pancreas (to name a few), or may be due to hormonal problems related to the adrenal gland, or medications your child is taking. In addition, emotional distress can often cause vomiting; while the reverse is also true, vomiting may cause emotional distress.

“We have a vision for the future that will provide new cures, new approaches to diagnosis, and new treatments through precision medicine.” – Robert O. Heuckeroth, MD, PhD

To precisely determine the origin of symptoms you or your child describe, we use blood tests, urine tests, imaging, breath tests, and specialized manometry tests typically only performed at a GI Motility Center. Manometry measures the patterns of contraction and relaxation in specific bowel regions, allowing us to say, “This region is causing your problems.” In some cases, we also perform biopsies – by taking a small group of cells from the region that control motility – and examining them under a microscope.

While these “standard tests” provide a lot of information, we believe there is much more we can learn by applying recently invented strategies and by pursuing cutting-edge research. Some new FDA-approved approaches include:

• Exome sequencing, a type of genetic testing that can analyze many genes at once
• Genome-wide SNP arrays, which can help identify genomic alterations associated with a wide variety of disorders
• Mitochondrial DNA analyses, which uses new testing of mitochondrial DNA to find and quantify certain variations and deletions, providing useful information to help guide treatment
• Body Surface Gastric Mapping (BSGM), which offers a more complete understanding of gastric functioning in individual patients
• G-Tech patches, which use a wireless and wearable patch to measure GI motility in the stomach, small intestines and colon non-invasively over multiple days
• EndoFLIP, which provides details about a child’s organ dimensions and pressure to help plan treatments and determine the effectiveness of treatment
• EsoFLIP, which dilates the esophagus and examines it without any radiation
• Translumbosacral anorectal magnetic stimulation (TAMS), which delivers focused magnetic energy through an insulated coil to the lumbo-sacral nerves that regulate anorectal function

The results obtained from these approaches are often complicated, and we often need more information to determine the best way to use the information obtained.

Our CHOP research team is also investigating completely new ways to “view” the cells that control bowel motility and pursuing basic research into disease mechanisms. Patients and families can contribute to this knowledge by participating in research studies and helping us learn new ways to help patients with motility conditions to feel better. Please ask us about research studies you may be able to participate in as we work together to help your child feel better.

What are the benefits of precision medicine for motility?

Many medical strategies treat symptoms of disease. With precision medicine, we strive to treat the causes of disease to eliminate symptoms. Identifying the cause of disease often suggests strategies that would not otherwise be considered. Defining precise disease mechanisms is essential as we work to find new diagnostic strategies, new treatments, and hopefully, new cures. To do this, we pursue basic and translational research (scientific) studies that we hope will help patients heal and feel better.

What is the success rate of precision medicine for motility?

There is no simple answer to this question. In most cases, we can determine which organ defects are causing symptoms, and can often identify dysfunctional cells or cellular networks that underlie the disease. In some cases, a single region is defective and can be removed or treated resulting in a cure. In other cases, intricate interactions between the gut and other organs cause symptoms. For example, we see many children whose symptoms occur because of “Disorders of Gut-Brain Interaction” (DGBI). DGBI are common because there are many gut-brain connections and problems with either organ can cause misfunction in the other. When DGBI are identified, therapies often target both organs to help children’s symptoms improve.

Motility disorders may be defined by:

• Physiology, e.g., how the bowel moves or activity of nerves that carry sensory signals from bowel to brain
• Anatomy or structural problems
• Problems with biochemistry or cellular function

In some cases, genetic defects cause symptoms, and we can pinpoint the problem precisely. Genetics may also alter your risk of disease, but symptoms must be triggered by stress, infection, trauma, emotional responses, medicines, or immune-mediated injury.

The tools of modern genetics provide remarkable information, but in many cases, we can only partially interpret results. For example, it may be difficult to tell if a genetic variant causes disease. Because motility diseases are complex and multifactorial, we work as a team in the Suzi and Scott Lustgarten Center for GI Motility and often in coordination with other specialists at CHOP to help your child feel better.

How does CHOP’s precision medicine differentiate from other centers?

Our GI Motility Center specialists take advantage of CHOP’s enormous infrastructure and wide range of expertise to offer every possible type of clinical testing. We work together – relying on a broad range of specialized knowledge to find ways to restore health and optimize functioning for all patients. We enlist the help of colleagues from around the world to precisely define disease mechanisms and find new treatments and cures. We pursue cutting-edge basic, translational and clinical research, and may ask your family to consider participating in research studies. Most importantly, we have a vision for the future that will provide new cures, new approaches to diagnosis, and new treatments through precision medicine. We integrate these goals with our deep commitment to do what we can to help every child feel well and live a fulfilling and happy life.