Dr. Vinodh Narayanan, Medical Director for TGen’s Center for Rare Childhood Disorders, uses the latest in genomic technologies to diagnose and manage children with rare (neurological) disorders.
Picture your child suffering from a disease so rare it doesn’t have a name. The heartache of seeing their pain, coupled with the agony of not knowing its cause, creates a sense of deep despair. Even this hypothetical can feel unbearable.
One parent, Aseem, described years of searching for a diagnosis for his son as moving through a dark cave, feeling the way forward inch-by-inch, child on his hip.
Parents often refer to this as the “diagnostic odyssey,” a process of fumbling in the dark through misdiagnosis and confusion for years on end. The advocacy group Global Genes estimates that rare disease patients spend, on average, seven years searching for answers: visiting eight or more specialists and receiving at least three misdiagnoses.
That is a long time to be underground in the dark.
“At the Center, we’re able to diagnose about 40 percent of our patients,” explains Vinodh Narayanan, M.D., Medical Director for TGen’s Center for Rare Childhood Disorders, who has spent much of his professional career guiding parents through such darkness. The Center uses the latest in genomic technologies to diagnose and manage children with rare (neurological) disorders.
“Even though it might not lead immediately to treatment, there’s a lot of power in attaching a name to a child’s disorder. Many families spend years in search of an answer, going from specialist to specialist without ever gaining an understanding of what is happening to their child,” he says. Following diagnosis, the focus shifts to understanding the biology behind the disorder and searching for specific treatments.
Narayanan began a clinical research partnership with TGen in 2005. At the time, he worked at St. Joseph’s Hospital in Phoenix, where his Neurogenetics Clinic was based.
“I wanted to create a neurogenetics collaboration to probe the real nature of the pediatric neurological disorders at the genetic level, and it eventually morphed into TGen’s Center for Rare Childhood Disorders,” he says, which TGen launched in 2012 with Narayanan as its founding medical director.
Narayanan moved his research lab to TGen in the summer of 2014.
Since its inception, the center has enrolled more than 2000 participants and analyzed the genetics or genomics of more than 700 families.
“To be the first one to describe a disease is very, very hard, but after the first one is discovered, the second and the third are easier,” he says. “There are tools available now that facilitate connection with clinicians and scientists around the world, sharing information, to allow us to recognize these new diagnoses”.
That moves a lot of patients, parents, and families out of the darkness.
Pioneering Work in the Genomics Revolution
While identifying a disease can provide peace of mind for parents and empower patients and their families, the longer-term benefits lie in the possibilities for treatment. As many as 30 percent of children with rare disorders do not live to age 5.
Using gene editing technologies or identifying so-called orphan drugs—drugs intended to treat diseases so rare that sponsors are reluctant to develop them—may help provide interventions that represent frontiers beyond gene identification.
“Genomic sequencing revolutionized our approach to disease diagnosis,” Narayanan says, “but being able not only to identify but repair pieces of the genome creates untold possibilities. The technology and progress made is truly amazing. When I started my career, the idea that we could repair genes to treat disease was not even on our horizon.”
Gene therapy involves targeting a disease-causing gene by delivering a healthy copy to replace the damaged one, or editing the existing copy to treat or stop the disease.
When Narayanan started his career, he was interested in neither neurology nor genetics. “Life is convoluted,” he says with a smile. “The path we take to get somewhere. My father was a developmental neuroscientist and my mother was a classical geneticist, and they encouraged us to pursue medicine as a career. I used to help in my father’s lab when asked—mainly counting wing or beak movements in developing chick embryos—but this was not my focus in college. I started in engineering but was soon completely engrossed with mathematics and modern physics. That changed gradually as I developed a strong interest in neuroscience. The transition from that point to pursuing training in clinical child neurology was easy – guided by great teachers and mentors.”
Years later, as a resident trainee in pediatric neurology, a mentor suggested he read a recently published paper on Rett syndrome. “He was guiding me about a patient I was seeing, but the real message was that I should constantly be studying the literature and applying this knowledge to my patients,” Narayanan explains. The paper was the first written manuscript in English to describe Rett syndrome.
Rett syndrome is a rare genetic neurological disorder that affects brain development, causing a progressive loss of motor skills and language—primarily in women. While driven by a mutation in the gene, Rett is rarely inherited, which made it a particularly challenging genetic mystery to solve.
Reading the paper lit a fire that inspired Narayanan and became a driving force in his career.
“I want to understand down to the level of the molecular pathway. What is the genetic problem? If it is a genetic problem, and even if it is not, what is the pathway that leads to the disease process, and how can we intervene?” he surmises.
Library of the Future
“Imagine a library of gene therapies,” he says, “where you can take solutions off a shelf to fix a broken gene. We know the exact disease or disorder down to the cellular level, we can pinpoint the exact location we need to change, and—in the future, I am imagining now, we can intervene without drugs or surgery. The future pharmacy may include thousands of gene therapy vectors, each one targeting a specific group of mutations in a specific gene.”
This, Narayanan believes, is the future of research, where these treatments are not just possible but readily available.
At TGen, Narayanan now works with an entire “army of scientists” to make this vision possible: including genomic researchers, drug developers, bioinformaticians and genetic counselors. They are able to take a team approach to tackle the same issue from different angles. “That is the true gift of these collaborative partnerships within TGen. To have so many experts in so many disciplines working together.”
Narayanan balances a clinician–scientist role with equal doses of curiosity and compassion. While the complicated puzzle work of science motivates him, he never loses sight of the families at the center of these mysteries and their real struggles. The photographs of patient families he has worked with over the years that cover his walls serve as daily reminders.
“I am the luckiest pediatrician in the world,” he announces. “I learn something new every day.”