Howard Jacob on Why Whole Genome Sequencing is Best for Medicine

CORRECTION: An earlier version of this article misrepresented Nic Volker's health status. His epilepsy is not currently controlled. 

By Ryan Cross 

April 13, 2016 | Rare diseases are a huge problem. Howard Jacob wants to change that.

“It sounds kind of silly, right? Rare disease sounds rare,” Jacob said during his keynote speech at the Bio-IT World Conference & Expo in Boston last week. Yet 5-10% of the U.S. population lives with a rare, undiagnosed disease. Jacob believes that bringing whole genome sequencing to the clinic is the most accurate and economical option for these patients. And he has experience doing it.

Jacob is currently Executive Vice President for Genomic Medicine at the HudsonAlpha Institute for Biotechnology and CEO of Envision Genomics, both in Huntsville, Alabama. He previously pioneered patient-focused genome sequencing as the Director of the Human and Molecular Genetics Center at the Medical College of Wisconsin. It was there that he solved the pediatric case of Nic Volker.

“Imagine going from doctor to doctor and being told I don’t know what’s wrong with your child,” Jacob said. That’s what happened to the Volker family.

From the age of two to four, Nic went in and out of hospitals, but his disease remained undiagnosed. “Surprisingly, medicine pays for trial and error,” Jacob said. Nic was dying when he came to Jacob. Following whole exome sequencing, Jacob probed through 18,000 genetic variants and identified a mutation in the XIAP gene that led him to suggest a core blood transplant for gut disease. It worked, and Nic got better.

 “You are all a big data problem for your physician,” Jacob said. A major challenge that clinicians face is deciding what tests to order. “I’m just going to argue one simple test is a lot easier to figure out than doing each individual test,” he said.

Although Nic’s genome-based diagnosis succeeded, it wasn’t easy to get published. Jacob had to go to seven journals. “Why? Because we were cowboys and irresponsible for using a research-only tool,” he said.

Nic was a single case, but Jacob estimates that 20 million Americans need whole genome sequencing for a clinical diagnosis. His move to HudsonAlpha was partly motivated by their new HiSeq X Ten, which he said was a $40 million investment to sequence 15,000 full human genomes per year.

Coverage Question

Whole exome sequencing covers approximately 1.5% of the genome, corresponding to gene-coding DNA. For many years, some researchers thought the rest of the genome was essentially “junk DNA” with no purpose. But the ENCODE project now shows that 80% of the genome is biochemically functional. This is why Jacob advocates for the use of whole genome sequencing, which he says results in a diagnosis 25% more often than whole exome sequencing. That percentage will rise as more genomic data is collected.

Jacob presented a study where 9 out of 22 instances of whole genome sequencing provided a diagnosis. Whole exome sequencing would have missed 3 out of those 9 diagnoses.

But there is a problem. “Insurance companies don’t pay for this, it is a major issue,” Jacob said.

Blue Cross Blue Shield of Alabama says that whole genome sequencing does not meet medical criteria and is considered investigative. Cigna covers whole exome sequencing, but not whole genome sequencing, saying it is not clinically validated.

Jacob’s response: “Are you kidding me? It is the same technology.” He said that some researchers would be shocked to find that their papers comparing whole genome and whole exome sequencing are being used by insurance companies to prevent paying for the tests. He added, when “we quibble about research and accuracy and utility…that gets put into policy.”

“What we are doing in our research world and how we are publishing this is having an impact on my care for our kids,” Jacob said, referring to his pediatric rare disease patients.

Nic recovered from his gut disease, but later developed epilepsy. He's since had whole genome sequencing and his doctors are searching for a treatment. “I am going to argue that whole genome sequencing is the only test that can be done once from a wet lab perspective, and be used for a lifetime,” Jacob said.

“Whole genome sequencing adds value over time. It is something that is incredibly unusual in medicine,” Jacob said. Every human genome that is sequenced can provide benefits to the patient, their family, and society as a whole.

Clinical validation of whole genome sequencing costs $6,500 at HudsonAlpha. Jacob said that doing whole genome sequencing on Nic Volker earlier would have saved his family from $7 million of debt. There is a myth that whole genome sequencing increases costs, Jacob said. Those costs are already spent on trial and error medicine.

“For me, it is really all about care,” he said.  “We simply have to do better. At some point we have to quit arguing about this and do it.”

Near the end of his speech, Jacob showed a picture of a pediatric patient named Jack. “I went to Jack’s funeral a year ago,” he said. “We read his genome. We didn’t find out what was wrong with him. And you know why this is a problem? Because Jack has a brother, and we don’t know what’s wrong with him. This is not esoteric. This is people in need.”

Even though whole genome sequencing doesn’t always provide the answers, Jacob said that it is a blueprint that can help. Every day physicians are pressed to make diagnoses whether they have the data or not. Jacob concluded, “I’m simply going to say if we give them the blueprint, I think they can practice better medicine.”

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