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Rady Children’s Institute sets Guinness world record

A pediatric genetics nonprofit in San Diego recently proved it could sequence a whole genome in a world record time of 19.5 hours.

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It took 13 years to build the first full set of genetic blueprints for the human race by sequencing the DNA inside our cells that governs everything from eye color to risk of debilitating disease.

But a team at Rady Children’s Institute for Genomic Medicine, working closely with homegrown sequencing sensation Illumina Inc., just proved it’s possible to get the job done in just 19.5 hours.

On Feb. 3, the Guinness Book of World Records documented the technological feat, which could provide quicker diagnoses for kids with puzzling and immediately life-threatening illnesses and hasten the inevitable moment when genetic analysis enters the mainstream.

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“I think the speed they were able to achieve was a ground-breaking moment for genomics,” said Ramlah Nehring, vice president of clinical and science affairs at San Diego’s NAVICAN Genomics.

Nehring, who holds a doctorate in molecular biology, was one of several unaffiliated genetic experts Guinness required Rady to invite to the record-breaking session to observe and make sure the results produced by the Institute’s process were medically and scientifically valid.

The achievement will be announced at a pair of widely-attended genomics conferences in San Francisco and Orlando this week.

It’s the second high-speed, whole-genome sequencing world record for Rady’s Dr. Stephen Kingsmore. He led the research team at Children’s Mercy Hospital in Kansas City, Mo., that set the previous record of 26 hours in 2015 before coming west to serve as the new Rady institute’s first chief executive.

A team of local researchers was able to lop 6.5 hours off the record by using San Diego-based Illumina’s NovaSeq 6000 Sequencing System, which cuts the time it takes to identify all 3 billion pairs of molecules in a patient’s DNA to about 15 hours.

Working directly with Illumina engineers, the Institute was able to use a new generation of high-density flow cells, which hold snippets of DNA while they’re scanned with a laser so that they can be reassembled in digital form for analysis.

“They are on-site here or we are on-site there literally every day of the week. It has become a really good partnership,” Kingsmore said.

Though Rady ended up getting the plaque for setting the sequencing world record, Kingsmore said most of the credit goes to Illumina, which also helped his team in Kansas City with the record-breaking attempt in 2015.

But it wasn’t just Illumina. Cutting-edge tools from a handful of other innovative companies were critical in reducing the overall amount of time it takes to do sequencing and make a diagnosis from the resulting data files.

The 19.5-hour achievement is considered a proof of concept and will need further refinement before it’s ready to be used clinically. At the moment, the fastest the institute’s sequencing lab can go is 37 hours.

But that’s still the fastest turnaround for genetic diagnosis in pediatric medicine. It’s common for this kind of work to take weeks, but Kingsmore has been pushing for years to decrease turnaround times, especially for babies whose conditions are particularly dire.

Last year, he shared news of a child suffering from severe liver disease and whose genetic workup showed a different diagnosis than the one the child was about to be operated on for, and a frantic call to the child’s doctor prevented an unnecessary surgery.

Since then, Rady has performed genetic analysis for 339 children and has expanded its universe of potential patients to children’s hospitals in Orange County, Colorado, Minnesota and Florida.

Thus far, sequencing has provided a genetic diagnosis for 111 of the children whose genomes have been sequenced and, for 69 percent of those, Kingsmore said, the diagnosis has caused a change in treatment.

A few dozen have been of the emergency type where quick action was likely life-saving.

One child was recently admitted at Rady Children’s Hospital with severe seizures that were flat-lining the 8-day-old’s brain activity. The seizures were traced to a pair of genetic mutations causing a rare condition called pyridoxine-dependent epilepsy, which is treatable with a form of vitamin B6. Within 36 hours of treating the newborn with the right vitamin, seizures stopped.

Without genetic testing, doctors would likely have had to play a weeks-long guessing game, trying one anti-seizure medication after another until they eventually found the right one. Getting to the right treatment with less trial and error, Kingsmore said, likely saved the baby’s life.

While these kinds of examples are dramatic, the reality is that most kids don’t need an extremely-rapid genetic workup. Their conditions are stable enough that taking a few days to get the results back doesn’t cause any setbacks. But, for a small group of kids, time really does matter.

Clinical lab director Shimul Chowdhury, who has a doctorate in interdisciplinary biomedical sciences, has been right in the middle of the diagnosis process since Rady bought its first set of genome sequencers.

He said seizures are the biggest area where time to diagnosis really makes a difference. The longer seizures last, the more damage is done to the brain.

“For these uncontrollable-seizure kiddos, every hour makes a difference, for sure,” he said.

Last year, it was Chowdhury who found himself stopping the surgery of the child with liver disease. Even in that case, he said, being able to arrive at a genetic diagnosis a few hours faster would have been better, even if the speed of the existing process was already fast enough to stop an unneeded surgery.

“We ended up calling them right at the buzzer,” he said. “We would be much more comfortable calling them four hours earlier and let them know what the results were.”

Shortening the time it takes to get a genetic diagnosis to less than one day also, in the macro sense, has the potential to make genetic testing fit better into standard hospital-based medical practice. Typically, doctors order tests in the morning or afternoon and the results are ready the next morning for review during their daily rounds.

“That’s really our dream, that doctors would be able to order genetic analysis with the same routine they use for their other standard labs and get the results back in pretty much the same time frame,” Chowdhury said.

Kingsmore is already working toward this goal. Eventually, he said, he would like to see all newborns get whole-genome sequencing based genetic testing, rather than the limited panel of tests they get now, as a matter of course.

Though the speed record is nice, he said, the geneticist is much more excited by the fact that Illumina’s latest batch of sequencing machines, which cost $1 million each, can process up to 58 DNA samples simultaneously.

That’s the kind of throughput, he said, that can ultimately change the standard of care nationwide.

“For me, the big deal is scalability,” Kingsmore said. “Ultimately, we want to do this for all 4 million babies born in the U.S. every year.”

That milepost remains far on the horizon. It would take a lot more machines than Rady has on hand, but the executive said he believes that the path to the goal is buried within the latest 19.5-hour speed record.

To hit that time, his team used special “natural language processing” software from London-based Clinithink Limited to automatically extract important information from patient’s electronic medical records much more quickly than could be done by hand.

Another software package from Belgium-based Diploid uses artificial intelligence to spot genetic mutations within sequenced genomic data and make a preliminary diagnosis in about four minutes rather than the hour or more it takes a highly-trained pediatric clinical geneticist to do the same work.

Also in the mix is San Diego-based Edico Genome’s DRAGEN processing system that significantly increases the speed of mapping and aligning genomic data once it has been sequenced. Software made by FABRIC Genomics in Oakland was also key in helping find the correct genetic cause of illnesses among many possibilities.

Automation is key, Kingsmore said, in getting to the point where diagnosis can keep up with the throughput of ever-more-productive sequencing technology. There are simply not enough trained geneticists in the world to handle the workload manually. The future, he said, is having these highly-trained experts overseeing the output of sophisticated computer programs rather than doing all of the work themselves.

There is another significant advantage that has allowed the Institute’s sequencing efforts to move with maximum speed. Donations, including a $120 million foundational contribution from San Diego philanthropists Ernest and Evelyn Rady, allow the initiative to move forward without waiting for insurance company approval. For kids not yet able to enroll in the sequencing trials that the Institute is running, just getting insurance approval can take weeks.

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paul.sisson@sduniontribune.com

(619) 293-1850

Twitter: @paulsisson

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