NGS


When an Exome Test Is Part of the Therapy and Not a Diagnostic: John West on Personalis and Personalized Cancer Vaccines

About six years ago there was a wave of genome interpretation startups getting their first rounds of funding. One of them was Personalis, a company founded by a well known group of Stanford geneticists and bioinformaticians.

John West is the CEO of Personalis, and he joins us today to talk about how the company is participating in the dramatic shift in drug development toward immuno oncology drugs. Our listeners might remember John from his days at Solexa where he served as CEO and presided over the sale of the company to Illumina.

At the same time Personalis came on the scene, the first drug that would harness the immune system to fight cancer was being approved by the FDA, Yervoy by Bristol-Myers Squibb. This was the first of four drugs known as checkpoint inhibitor drugs. These four drugs have had spectacular success and together generate revenue of over 6 billion per year, a level which has doubled in the past year.

John and Personalis are working with biotech companies on a new generation of immuno therapies known as personalized cancer vaccines. These new drugs are actually custom synthesized for each patient after an “immunogram” or genetic workup of the tumor has been done. We know today that tumor growth is driven mostly by neoantigens, or new antigens which arise from mutations that happen after the cancer first appears, says John. So an immunogram done by Personalis must look at all the genes (over 20,000) and not just the original driver mutations. An immunogram could only be done in the last few years with the latest developments in next gen sequencing and algorithm creation.

How far along are these new personalized cancer vaccines? And what is the commercialization challenge for Personalis?

“We are essentially an integral part of the therapy,” says John. "So we don’t think of it as a diagnostic test. We think about it as the initial part of the manufacturing of the therapy."

How to Scale Cancer Genomics, with Marco Marra, UBC

Back in 2009 at the annual AGBT meeting for sequencing, Marco Marra presented one of the first cases of cancer treatment using whole genome sequencing.

We caught up with Marco at his office at the University of British Columbia where he heads the Department of Medical Genetics. Marco also directs the Genome Sciences Center which is part of a very special organization called the BC Cancer Agency.

In 2012 Marco and his team began a pilot project at the agency to scale up their work from just a one off case to more routine treatment. While doing whole genome and whole transcriptome testing is not yet “standard of care” for cancer patients, the scientists and researchers at the agency have the opportunity to sit down with oncologists on a weekly basis and explore its use with several patients at a time.

What are the major questions and challenges Marco has encountered in scaling? How is the regulatory environment for genomic testing in Canada? And which camp does Marco adhere to when it comes to whole genome sequencing: quantity or quality?

Join us as we talk to the number two cited scientist in all of Canada.

October 2016 with Nathan and Laura

Today’s show was recorded on Halloween, which now feels so yesterday. Forgive us for some spookiness.

What doesn’t feel so yesterday is the launch this past month of Helix, a company spun out of Illumina that aims to add exomes to the lineup of direct-to-consumer testing. Nathan points out their model for delivering data incrementally through various apps. Laura questions how Helix will vet the apps.

This month the genomics community gathered in Vancouver for the annual American Society for Human Genetics conference. The commentators give their highlights. Then we double back on a genetic counseling conference from last month and a big topic that we missed in our last show: population screening for BRCA.

It’s a bird, it’s a plane, it’s a turducken gone crazy. . . . . No, actually, says Nathan, “it’s a virus inside a spider costume for Halloween inside a bacterium inside a fly!"

FDA’s Liz Mansfield on New NGS Guidances

On July 6th, as part of the President’s Precision Medicine Initiative, the FDA issued two new draft guidances for the oversight of next gen sequencing (NGS) tests. The first guidance is for using NGS testing to diagnose germline diseases. In the second, the FDA lists guidelines for building and using genetic variant databases.

To help us understand just what the guidance is and what led to its release, we’re joined by Liz Mansfield, the Deputy Office Director for Personalized Medicine at the FDA.

It’s unusual for the FDA to issue guidance around a single technology, but Liz says that NGS is “transformative” and is eclipsing so many of the older technologies. The biggest challenge is that NGS is a technology used for discovery and has the power to test for so many things at once.

How does the new NGS guidance relate to the much talked about guidance on LDTs that came out a couple years ago? And does the new guidance represent a more incremental, step by step approach for the FDA in dealing with the explosion of today’s molecular testing field?

“No, it’s not an attempt to break down into smaller bites the issue on LDTs. It’s to address this particular technology, regardless of who the developer is,” says Liz.

The two guidances are for very specific purposes and Liz anticipates further NGS guidances to be issued in the future. For example, guidelines for dealing with somatic mutations rather than germline mutations.

Human Genome Turns 15: Mike Hunkapiller

We’re all familiar with the announcement in the year 2000 by US President, Bill Clinton, and the UK’s Prime Minister, Tony Blair, that scientists had completed the first draft of the human genome. It was a big deal. But the actual publications didn’t happen until the next year, February of 2001. Which means that this February is the fifteenth anniversary of the publication of the first human genome. For our commemorative show we’re joined by Mike Hunkapiller, the CEO of Pacific Biosciences.

Mike and his team at PacBio are coming off a great year. Their stock is up. Their long read sequencing technology is used for over a thousand scientific publications. And last year they launched a new better, faster, cheaper instrument, the Sequel, which are sold out through the first half of this year. PacBio is cool again.

How much were tool makers in the driving seat of the genomic revolution? And how much further can sequencing improve? Before asking Mike this, we explore some of his memories of those wild days when sequencing the human genome got presidents and prime ministers on the phone with their speech writers.

Sequencing in Space: Chris Mason, Cornell

The last time we talked with Chris Mason of Weill Cornell Medical College the Supreme Court had just decided the controversial Myriad gene patent case. How forever ago two years can seem. Since then Chris has swabbed and sequenced the microbiome of New York City and began the project of sequencing in space.

His favorite research this year has been to longitudinally profile the genome, epigenome, transcriptome, metabolome and microbiome of identical twins, one in space and one on earth.

"We see that the gene expression changes dramatically as soon as you get into space, says Chris on today’s show. "What we’re looking for in particular are changes in RNA methylation--which has been related to circadian rhythm--and also RNA processing and stability. Really we’re looking at the epitranscriptomic changes of astronauts.”

Epitranscriptome? What’s that?

The second half of the interview is devoted to Chris’ assessment of the latest sequencing tools. Chris says he’s pleased with Oxford Nanopore’s MinION. Not only has he sequenced what he thinks is the longest continuous read (86 KB) on the MinION, he says the high error rate has come down and the GC bias is much improved. If this geneticist who sees his work as "a duty to the universe" had to choose one sequencer, which would it be?

Going Beyond the $1,000 Genome with Mark Gerstein

Though recent guests at Mendelspod say we're not quite to the $1,000 genome, we're close enough to use that benchmark in genomics discussions. But what are we getting for that almost $1,000?

Mark Gerstein is the co-director of the Yale Computational Biology and Bioinformatics program where he focuses on better annotation of the human genome and better ways to mine big genomics data. He has played a big role in some of the large genomics initiatives since the first human genome project, including ENCODE and the 1,000 Genomes Project.

“I’m very enthusiastic, of course, about the thousand dollar genome, but I don’t think that a true human genome has arrived for a thousand dollars,” Mark says at the outset of today’s interview. "The great excitement of next generation sequencing—which is deserved—has also obscured that there are a lot of very deep technical questions in terms of really assembling the tricky parts of the genome and really being able to conceptualize the more complex bits of human genetic variation that need to be tackled.”

So what are those tricky remaining parts? Mark shares his interest into the importance of structural variation, and says there is much more to learn from the overlooked non-coding portion of the genome. He’s particularly interested in pseudogenes.

We took some audience questions for Mark which lead us into a discussion of how best to query and mine big genomics data. As with several other leading bioinformaticians on the show, Mark agrees that privacy is the big issue for genomics and for society at large.

A Diagnostic Success Story with Alka Chaubey, Greenwood Genetic Center

Diagnostics can be a tough business. The FDA is making a strong push to bring more oversight. Obtaining reimbursement can be outright Sisyphean. And clinicians are slow on the uptake. All of which makes today’s story so good.

Located at 106 Gregor Mendel Circle in Greenwood, SC, the Greenwood Genetic Center became the first lab to partner with Affymetrix to commercialize their recently FDA cleared CytoScan Dx assay. This test is the first-- and so far the only--FDA cleared whole genome test to aid in the post-natal diagnostic evaluation of constitutional disorders, such as developmental delay.

In today’s interview, Alka Chaubey, director of the cytogenetics lab at GGC, explains why this array-based test has become so successful.

With Two New Easy-to-Use Sequencing Instruments, Thermo Readies for Primetime in the Clinic

The race to the $1,000 genome has been full of breathtaking advances, one after the other. But is next gen sequencing reaching maturity? Will there be that many more significant innovations?

Yes, says our first guest in today’s program, Andy Felton, VP of Product Management at Thermo’s Ion Torrent division. Andy presented Thermo’s two new sequencing instruments, the Ion S5 and the Ion S5XL at a press conference today. While their numbers (accuracy, read length, throughput) don’t look that significant an achievement over the stats of their predecessors--the Personal Genome Machine (PGM) and the Ion Proton--the S5 and S5XL perhaps lead the industry now in ease-of-use.

Integrated with Thermo’s new sample prep station launched last year, the Ion Chef, and robust bioinformatics software, the workflow from sample to report is impressively simple and straight forward. Only two pipetting steps are required. The genomics team at Thermo is betting that this attractive simplicity will open a new market. "Genomics for all," they boast.

Does this just catch Thermo up with Illumina, or does it put them in the lead for clinical sequencing, we ask our second guest, Shawn Baker, CSO of AllSeq. (See Shawn's own blog here.)

New York Genome Center’s Nathan Pearson on Public Outreach for Genomics

Nathan Pearson, formerly a genome scientist at Ingenuity and Knome, has been doing public outreach for genomics at the New York Genome Center for about a year now. In today’s interview, Nathan says he always wanted to be able to speak directly to the larger public about the great science he’s been involved in.

“Ever since graduate school, I’ve wanted to take insights from our field to the public more directly. Not just through the ivory tower--the education system that is set up to train scientists—but to help other people out there who won’t be professional scientists. They can benefit from the insights that science brings societally, and can also increasingly contribute to those insights by investing their own data on behalf of science," he says at the outset of today's show.

Nathan offers first an overview of the mission at the NY Genome Center and lists examples of their collaboration projects. Then the interview runs a bit like a review of genomic medicine as of summer 2015.

What are Nathan’s thoughts on the debate over how much of the genome is functional? What is Nathan doing to reach out to the general public? And is he concerned about the ‘hyperbolome,' or the over hyping of genomic discoveries and technologies?



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