Wearing glasses and a plaid shirt, the director of the Shriners Children’s Genomics Institute peers at his computer screen. At the top is a string of capital letters, spelling nothing. Beneath them, lines and bars of varying widths and colors stretch horizontally across the screen. Relaxed yet intent, Kamran Shazand, Ph.D., is looking for patterns. Artificial intelligence has isolated some possibilities for him, but only a person has the knowledge and judgment necessary to make sense of it all. He is analyzing a gene.
Awtum Brashear Lewis, Ph.D., is a bioinformatics specialist at the Shriners Children’s Genomics Institute.
Across the hall, in a smaller room with warmer lighting, Awtum Brashear Lewis, Ph.D., sits before two computer screens, one set up the usual way, the other mounted vertically. Both are filled with lines of code, much like the computers in the Matrix movies – the patterns and the meaning are there if you know how to see them. Trained in biology and computer analytics, the bioinformatics specialist is looking at records from the Shriners Children’s Research Data Warehouse, hoping to make connections that haven’t been made before.
Kamran Shazand, Ph.D., and Anxhela Gustafson, Ph.D., analyze genetic patterns.
The adjoining room is a laboratory with humming machines and good natural light. Wearing a maroon Shriners Children’s shirt, khakis and blue latex gloves, a woman sits at a counter, surrounded by stacks of clear plastic vials. Each contains a 2-milliliter sample of saliva. In front of her is a tray holding a few smaller, open vials. With her long dark hair tucked behind her ears, she is using a tool that seems like a very high-tech turkey baster. Working in a smooth rhythm, she suctions up a drop of liquid, releases it into a small test tube, ejects the used turkey baster tip into the trash, taps a new tip into place and repeats the process. Anxhela Gustafson, Ph.D., is deep in the process of manually extracting DNA from a saliva sample from a Shriners Children’s patient or parent.
Here in the headquarters of the Shriners Children’s Genomics Institute, located on the campus of the University of South Florida in Tampa, all three of them are “doing science.” Together with colleagues around the Shriners Children’s healthcare system, they are doing work that is going to change the world.
It is only a matter of time.
The vision
Shriners Children’s is in a unique position to collect and analyze genetic data related to the conditions we treat. That’s because not only does the healthcare system care for a large number of patients, but we also have a diverse patient population that comes to us from around the world.
The goal of Shriners Children’s genomics research is to discover the genetic causes for diseases and conditions and use the knowledge to create personalized therapies. This genetics-based approach to care is known as precision medicine.
To go from test tubes to treatments for kids is a lengthy process. Just analyzing the genomic samples takes thousands of hours a year. Years of testing occur before clinical trials with patients can begin. Precision medicine is the destination, but working in medical research requires enjoying the journey.
A quick science lesson
Strands of DNA are made of four chemical units, which are identified by the letters A, T, G and C – the capital letters at the top of Shazand’s computer screen. Many of these units strung together make up a gene. A gene gives our cells the instructions to make proteins, and the proteins make it possible for our bodies to function. Our genome is our complete set of DNA, and every person’s is unique.
Sometimes our genetic code makes mistakes. It may mix up the chemical units – placing a T where G should be, for example – or inserting an extra piece where it doesn’t belong (turning a sequence that should be GCT to GCCT, perhaps). Sometimes these errors have little or no consequence to our health. Other times, they cause life-threatening or life-changing conditions. Those are the ones Shriners Children’s research is targeting.
Libbie has arthrogryposis, a rare condition researchers are learning more about through genomics.
Benefits for patients
Work at the Genomics Institute falls into two categories. One is building the database – collecting genetic samples and sequencing them. The other is using the data to investigate genetic causes of specific conditions.
While some conditions are caused by a change in a single spot in the genome, most are not. However, the changes are often found in a similar area, called a pathway. By identifying pathways and correlating them with symptoms, scientists create information clinicians can use.
Take idiopathic scoliosis. A physician may have two patients whose spines look exactly the same yet respond far differently to the same treatment. Genetic researchers are working to identify different pathways associated with scoliosis. In the future, we expect doctors will be able to sequence the two patients’ genes, locate the affected pathways, and select different, appropriate treatments for each based on the cause of their scoliosis. That’s precision medicine.
Shriners Children’s is currently conducting research projects for 10 conditions, including scoliosis, cerebral palsy, arthrogryposis, club foot, and cleft lip and palate, with plans to add more.
Gustafson processes samples in the lab.
How we get there
The healthcare system is working to sequence 15,000 genomes. That means collecting and processing the samples of 15,000 Shriners Children’s patients and parents. Patients give their sample during a visit to their Shriners Children’s location or outreach clinic, providing 2 milliliters of saliva in a sterile vial. Samples are labeled only with the donor’s sex, condition and clinical symptoms and are then sent to the laboratory in Tampa.
There, they go through an elaborate process to extract the DNA and prepare it for sequencing. The lab recently purchased the latest in sequencing technology. Previously, the machine they used could process 48 samples over a period of three days. The new machine can practically double that.
The sequencer is how we get from spit in a cup to a string of 6.4 billion letters. It takes computer analysis, artificial intelligence and human judgment to arrange the data into forms that can yield insights. That’s bioinformatics.
Only then can researchers comb the genes for clues to medical problems. Shazand does the bulk of that, although Gustafson, Brashear Lewis and lead bioinformatician Andrew Quitadamo, Ph.D., who is based in North Carolina, help when they can. When a genetic sequence is identified as a possible link to a disorder, it’s marked for further investigation. It takes a full day’s work to analyze one genome. With 500 more samples to go, there’s a lot of work to be done.
Worth the wait
Shazand has dedicated his career, and his life, to research. At Shriners Children’s, he said, “We want to be part of the international effort in tackling rare pediatric disorders. That is what animates us.”
But what drives him to work so hard, knowing tangible results won’t be seen in his lifetime? His first grandchild was born in June.
“I have the most beautiful mission,” he said. “The father in me is driving this research.”
Perhaps today’s work will benefit his grandchildren, or his grandchildren’s grandchildren?
“I am certain it will,” he said. “It’s just a matter of time.”
To watch a video about the work at the Institute, visit bit.ly/GenomicsVideo.
