Health: Nationwide Children's leads the way in genome research

TC Brown
The Institute for Genomic Medicine's research team at Nationwide Children's Hospital includes, clockwise from left rear: Richard Wilson, Peter White, Elaine Mardis, Dr. John A. Barnard and Julie M. Gastier-Foster.

Every day, in a glass-walled building on the northwest corner of Livingston and Parsons avenues, investigators sift through mountains of information in pristine, sun-splashed laboratories, probing deeply into complex data sequences, seeking answers to an array of puzzling, life-changing mysteries.

Here, at Nationwide Children's Hospital in Columbus, is one of the first ventures into pediatric personalized genomic medicine for children's hospitals anywhere in the world. The work, executed by scientific sleuths at the hospital's Institute for Genomic Medicine (IGM), is both critical and cutting edge. The hospital's lab-to-bedside approach involves genetic researchers who are helping physicians diagnose and track down treatment for perplexing diseases that beset their young patients.

These medical detectives examine, analyze and compare 3 billion data points in a patient's genome, the genetic blueprint that makes an individual unique. (A genome is the complete set of a person's DNA, including all of the genes. Each genome is like an operating system in a computer—it includes all of the information needed to build and maintain the system.)

Gaining access to this raw material of life can reveal root causes for many childhood diseases; thus, physicians, scientists and clinical geneticists in the IGM search exhaustively for the invisible-to-the-naked-eye markers that might lead to answers.

“Nationwide Children's is all about family-centered care and cancer and other diseases that affect the whole family,” says Dr. Julie Gastier-Foster, the senior director of the IGM and vice chair of laboratory genetics in the Department of Pathology and Laboratory Medicine. “We're moving toward a time when all cancer samples will be [studied for their genomic make-up], but for now it is limited to those with recurrence or who aren't responding to therapy or treatment.”

“I believe genomics can impact nearly every treatment for kids and their families,” says Dr. Richard Wilson, the executive director of the IGM. “You are starting to see patients given new treatment opportunities, with fewer side effects and more effective [care], and that is making a difference.”

The hospital opened the IGM after bringing on board Wilson and another internationally renowned genomic researcher in 2016, Elaine Mardis, IGM's co-executive director. Like Wilson, Mardis came from Washington University-St. Louis. Both researchers worked on the groundbreaking Human Genome Project, which finished mapping the entire human genome in 2003.

“Genomics is a single word, but it embodies a multitude of different areas of expertise to really make it happen, and that is one thing that attracted us here,” Mardis says. “This is really team science. We sensed all members of the team we needed were basically here, and they were very supportive of bringing genomics into the realm of diagnostic medicine.”

The result is a team of researchers and physicians that is opening new pathways for medical diagnosis, helping to advance care in ways that could allow for precise, individualized treatment for all patients. “The challenge is analyzing the massive amounts of information that come from genetic sequencing, and that is basically an IT challenge,” says Dr. John Barnard, president of the hospital's Research Institute. “The key is in our ability to be innovative.”

Today, Nationwide Children's is the leading innovator for genomic pediatric healthcare.

Mapping Human Genes

Genomic research has accelerated since teams of international scientists finished mapping out the entire human genome almost 15 years ago, but exploration of this medical frontier is still wide open. In the lab, scientists run a process called sequencing—think of it as the reverse engineering of a genome—in which they labor to identify the precise order of the nucleotides within a DNA molecule.

Investigators are searching for any alterations in the four building blocks of a gene, known as As, Cs, Gs or Ts, the chemical subunits that make up a patient's DNA. Those findings are compared against the model human genome plotted out in 2003. Finding mutations leads to the discovery of the causes of diseases, which in turn can lead to potential treatments. This is no easy task. It's like trying to align the entire text of two encyclopedias.

Dr. Peter White, senior director of the genome informatics group, and his team developed computational technology that they named Churchill, with a nod to White's British heritage. This relatively new technology can efficiently analyze a person's genome, seeking disease-causing variants, in less than two hours at a cost of about $2,000.

This research has come a long way. Consider that prior to 2003, it took 20 labs, 15 years and about $1 billion to sequence the first human genome.

Churchill, using complex algorithms, gathers the massive data and efficiently distributes it across multiple computers. “When you get multiple computers to work on chunks of data analysis simultaneously, you can get answers much faster,” says White.

Although Churchill is now standard technology at the IGM, it was tested and used in research prior to this year. In 2015, Nationwide Children's used this technology, along with its comprehensive team of scientists, physicians and genetic clinicians, to claim victory in the international CLARITY Undiagnosed Challenge. The Manton Center for Orphan Disease Research at Boston Children's Hospital and the Department of Biomedical Informatics at Harvard Medical School hosted the challenge.

The competition involved 26 leading genomics teams from seven countries. Teams were charged with interpreting DNA sequences for five different families whose medical conditions could not be diagnosed, despite numerous visits to doctors, an array of tests and other genetic studies. Nationwide Children's, unanimously chosen as the winner by a panel of independent judges, was the only team from a pediatric hospital.

“This validated what we were doing and that we were using the right approaches to do this by bringing together clinicians and researchers to tackle these medical challenges,” White says.

Churchill was patented and is now licensed, with software and a web-based platform that allows any lab to upload data and run genome analysis, White says.

Unlocking Diseases

Every day, the researchers at Nationwide Children's inch closer to finding answers that may result in big medical advances for pediatric care around the world. Their work may eventually result in the successful treatment of a variety of diseases.

Barnard says adding Mardis and Wilson to the hospital's team of genomic researchers was key to the hospital's advances. “Their ideas and our support embodied the IGM, which houses state-of-the-art equipment and the nation's best talent, all together in a seamless community,” Barnard says. “It's unique in a way that other institutions have not yet been able to accomplish.”

“We are sequencing more and more kids, and the speed part is important,” White adds. “When we can isolate DNA from tumors and rapidly do sequencing and analysis with the goal of identifying markers, it can help clinicians determine the best treatment for patients.”

Of course, none of this work would have been possible had scientists not plotted out the entire human genome in 2003, and the work done by Wilson and Mardis. Mardis, who describes herself as a “tech geek,” coordinated and directed small teams of molecular biologists and engineers on the Human Genome Project.

“We couldn't interpret this data today, because of its complexity in size, if we didn't have the human genome reference to lay it on,” Mardis says. “That was the scaffolding. It's the Rosetta Stone of how to interpret now what we call the next generation sequencing data, which is this new technology.”

Even in those early days, it was clear this journey of discovery would be propelled by data, an element no less important today. “We had to have software and mechanical engineers to build things that didn't exist, to manage all of this information. It became the infrastructure,” Wilson recalls.

Big data plays a major role for sure, but the look and action within the laboratories has changed significantly over 15 years. On a recent Monday morning, it was tranquil in one brightly lit lab in Nationwide Children's Research III building. Only a couple of people moved through the aisles, surrounded by shelves stacked with vibrant red, purple and green bins and containers, as well as small machinery and computers.

“In the early days of the genomic project, you would walk into a lab and see all these cool robotics and computer processors and drives, with flashing lights and lots of noises,” Wilson says. “It's pretty chill now. A lot of it has been miniaturized, and now we do everything on the computer cloud, which is a powerful advance.”

Speed has become the norm, too, as researchers examine more DNA at a much faster pace through flow cells, which resemble dark-lined microscope slides. “When Elaine and I first started to do data sequencing, we would sequence about four little pieces of DNA at a time and it took us about a day and a half to get data out of that,” Wilson says. “Now, with the flow cells we use, there are hundreds of millions of little pieces of data, and they are all being sequenced.”

Solving Health Challenges

Because cancer is the “low-hanging fruit of genomics,” Wilson says, the IGM focuses much of its efforts on diagnosing that disease and seeking new treatments. But researchers also are looking at congenital heart disease, the most common type of birth defect, as well as neonatal care and the causes of preterm births.

Since arriving, Mardis and Wilson have zeroed in on brain cancers, because it is a recurring issue and the leading cause of cancer deaths among children.

“Oftentimes even that second reoccurrence [of a tumor] is removed by surgery because there is a chance it can be cured,” Mardis says. “So we can compare and contrast the before and after and learn a lot about the mutations by virtue of having those samples to study.”

Dr. Jeffrey Leonard, Nationwide Children's chief of neurosurgery, who previously worked with Mardis and Wilson at Washington University, says great strides are being made in understanding brain cancer.

“This allows us to diagnose tumors and shrink them if we're able to find FDA-approved drugs specific to the tumors,” Leonard says. “They are translating what they find in the lab into the clinic. We now have the potential to personalize treatments and hopefully improve the prognosis with this life-threatening disorder.”

All of this work requires significant financial resources. “If you want to build a genomic medical program and want it to be great, it ain't cheap,” says Wilson.

The hospital doesn't typically disclose capital investments, but a DNA sequencer costs about $750,000, and the IGM has three.

And because genomic science is still relatively new, insurance companies have been reluctant to commit, Mardis says.

“You need to have the clinical benefit evidence for the insurance companies to really address the question, ‘Why is it this kid who gets this testing better off than the kid who did not?'” Mardis says. “That takes some numbers and evidence. At the end of the day you have to provide the data for them to be convinced of the health economy benefit.”

So, for now, the hospital relies on philanthropy to fund this innovative work. The Nationwide Foundation Pediatric Innovation Fund, which has supported several key clinical and research efforts in heart health, neonatology and injury prevention, has answered the call with $40 million. More than half of that money has been earmarked for genomic medicine, says Chad Jester, president of the Nationwide Foundation.

“We already had a relationship with the hospital and they approached us about an additional investment,” Jester says. “Genomics is going to be a game-changer for medicine in moving forward, starting with the identification of disease or any other type of malady a child may have.”

Dr. Tim Cripe, division chief for Hematology, Oncology and Bone Marrow Transplants, agrees that in the near future, genomic medicine will be essential as “best practice” medicine. He compares the creation of and results coming out of the IGM as someone turning on a light in a previously dark room.

“Before the IGM, when initial therapies for patients failed, any other therapies we might try were essentially shots in the dark,” Cripe says. “Now, for each of these patients we are able to determine if there is a genetic Achilles heel that we can attack to help treat their cancer.”

While much work lies ahead, the IGM opens up new avenues for discovery in understanding how mutated cells work and subvert normal cells, he says.

Scientists are making progress every day, but Wilson says he is not sure if it will ever move fast enough. “For a cancer patient, we can turn around an answer in a few weeks, but we'd like to be able to turn around answers much faster for a new baby in intensive care with difficulties of one type or another that physicians can't get a handle on,” he says. “We'd like to have that answer in 24 hours or less, but the technology is not quite there yet.”