Euan Ashley 2016-12-03T06:23:56+00:00

profile_eashleyAdvancing Clinical Sequencing is Close to His Heart

Euan Ashley, MRCP, DPhil, FAHA, FACC

Director of Clinical Genomics Service, Stanford University

For Euan Ashley, a cardiologist and Director of the Stanford Clinical Genomics Service, there is no question that the era of genomic medicine has arrived. “It’s happening every day. It’s routine now,” he says. By this he means that clinics around the world, including his, are using the exomes and genomes of patients to guide disease diagnosis and treatment. And it’s working.

In addition to his clinical responsibilities, Ashley’s lab works on researching inherited heart disease – conditions like hypertrophic cardiomyopathy, familial dilated cardiomyopathy, and long QT syndrome – that can cause sudden death. He’s also been part of a pioneering group of researchers at Stanford who are interested in the broader application of whole genome sequencing to medicine.

“We realized very early on that genome sequencing was dropping in price, and in medicine we needed to be ready for what was coming,” Ashley explains.

“Someday soon a patient was going to walk in with his or her whole genome on a hard drive, and what were we going to do?”

In 2009, Ashley was in the office of his colleague Stephen Quake, a bioengineering professor at Stanford who had made headlines a few months before for sequencing his own genome in 5 days for $40,000 (a five fold reduction in price). “He was showing me his data and pointed to a gene that I happen to know very well, and said he had a variant in it. As it turns out, this gene can be associated with sudden death. He proceeded to tell me that a family member had recently passed away in a sudden death, and that his family has a history of heart disease. We agreed he would become a patient in my clinic,” Ashley says.

It was at this point that point Ashley realized his clinic would be the first in the world, in that previously imagined scenario, where someone would walk in with their data from a whole genome analysis and seek medical advice. He called a couple of colleagues at Stanford including, Russ Altman and Atul Butte. They were both in a great position to help, according to Ashley, because Altman had been running the PharmGKB database for about eight years, and Butte had been putting together a database of known common variants called Varimed. Together with Ashley’s experience studying Mendelian and rare disease and heart conditions, they put together a pipeline for analyzing genomes.

In 2010, the group published their work in The Lancet. At that time, another person close to the genomics industry was taking a pioneering step forward in the new era of personal genomes. John West, former CEO of Solexa, a gene sequencing company acquired by Illumina, had his family of four sequenced. “After seeing the paper in The Lancet, West got in contact with us,” explains Ashley. “His kids had already started analyzing it on their own!” In fact, West’s daughter actually joined their team as they took on the analysis project. The team scaled up what they had done for Quake’s genome, which involved developing new algorithms to put the analysis in a family context. At the time, West was particularly interested in his history of pulmonary embolism. Though he’d gone on warfarin, he had a second episode, “which is extremely uncommon,” says Ashley. “He wanted to know if he passed his predisposition to clotting on to his kids, and whether his condition was resistant to warfarin.”

The team expanded, adding other notable Stanford researchers such as Michael Snyder and Carlos Bustamante, and a series of patents and algorithms came out of their work.

“We then started getting a lot of requests for genome analyzing, and we realized this was something we should develop commercially. It quickly came together through a couple of meetings,” Ashley says.

Four of the team members were interested in co-founding the company, and West had the CEO experience and interest to lead the team.

“One of the major obstacles in our way and challenges we had to overcome was data quality,” explains Ashley.

“In a sense, getting back to the level of quality we demanded in a prior era with Sanger sequencing, when we would not report clinical diagnostic results for a gene unless every single base was called. These days (with next-gen sequencing) clinical labs will report on these genes as long as 90 percent is covered at 10x or more, without any reference to the quality of that coverage. That’s one area that Personalis is focused on.”

In standard exome sequencing services coverage tends to be extremely variable, even for genes that are known to be important in health and disease. “We’re given median numbers of coverage, but that median completely belies the enormous variation across genes,” Ashley explains. “The median might be 60 or 80 fold, but certain regions might be covered at 150 fold, which may be much more than you need, and unfortunately other regions will be covered at close to zero, which means large portions of single genes aren’t there.”

This can be a matter of life or death, says Ashley.

“For example, if you had a strong history of sudden death and close member of your family has long QT syndrome or hypertrophic cardiomyopathy, whether or not you get a defibrillator implanted depends, among other things, on whether you carry the family variant. If we are going to start using this genomic information for a real clinical test and making decisions for individuals with it – I think we want to be quite sure that we have it right,” Ashley continues.

“That’s what we mean about clinical grade, and there are many elements to it.

The vision of Personalis is to embrace all of them.

I think most groups are just focusing on the informatics part, and there are a lot of challenges in the informatics part that can be improved. But if you only look at the informatics aspect then you can only do so well because you’re limited by the input,” Ashley says.” That’s what moved us to look earlier in the process – to the DNA sequencing chemistry to DNA preparation – to what information you are going to feed those algorithms, then we can do better with the algorithms.”

Most of these algorithms were developed during the era of the 1000 Genomes Project or genome wide association studies and were focused on SNPs. “In many ways this is the type of variation least likely to cause a clinical effect because it’s the smallest change. In clinical genetics, we come from the other end where you might be trying to detect a whole additional chromosome or a large structural re-arrangement” Ashley says.

“We need to have our algorithms for structural variation and indels as good as our algorithms for SNPs.”

Whole-genome sequencing and exome sequencing continue to be used in research studies outside of the clinic as well, like Ashley’s recently initiated study looking at the genetics of the fittest people in the world. Not only will the results of this study help society better understand the biology of human performance, but Ashley hopes it will provide clues that can unlock a rich gold mine of targets for use in potential therapeutics.

The recent development of “super statin” PCSK9 inhibitors is a precedent for this approach. By sequencing people with either extremely high or extremely low LDL cholesterol levels the PSK9 gene was discovered as a target for this new class of drugs that inhibits a protein that reduces the liver’s ability to remove bad cholesterol from the blood.

“We’ve done extremely well using this technology to date, there have been phenomenal advances in using the genome in medicine,”

says Ashley.

He acknowledges there is still a ways to go, but says “we are at the end of the beginning.”

“This technology should be an integral part of medicine,” says Ashley. “It could literally affect every individual in the health care system.”