NGS

A one month old baby is admitted to a hospital with fever. This is cause for serious alarm. The child is put on broad spectrum antibiotics. The infected area is drained and a culture run to try to identify the pathogen. The cultures come back negative, the pathogen not identified.

This is what was happening in a case that our guest David Hong, the VP of Medical Affairs at Karius, talks about at the outset of today’s interview. But because Karius uses the patient’s blood and new testing based on next generation sequencing, they are able to discover cell free remnants of the pathogen and identify the organism causing the baby’s infection. This diagnosis then allowed the doctors to change to a targeted treatment, a more narrow antibiotic.

This story exemplifies the revolution going on in the infectious disease space as a result of new sequencing based tests. The folks at Karius call them liquid biopsies for infections. Today David shares with us the kinds of hard-to-diagnosis cases that are coming to them from hospitals around the country. He also explains how better diagnosis is impacting the main issue on the minds of those in infectious disease today: antibiotic resistance.

How quickly can Karius get a new test out to market? How much discovery do they do for new pathogens? And just what are the possibilities here moving forward into 2019?

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?

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.

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.

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.)

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?

Major outbreaks of deadly viruses, such as the recent spread of Ebola in Northern Africa, are nothing new on planet earth. What is new is the technology that we are using to identify, track, and contain such plagues.

Scientists at Thermo Fisher Scientific developed a special "Ebola Panel" for their Ion Sequencing system, and over the past year teamed up with the University of Cambridge and other international organizations in an effort to curb the further spread of the Ebola. This included air dropping their portable Personal Genome Machine into remote areas and infected zones and dealing with various on the ground challenges.

How have new technologies such as next gen sequencing changed our ability to deal with public health crises such as deadly viruses or microbes, we ask Chris Linthwaite, president of Genetic Sciences at Thermo Fisher. With so many labs around the world equipped with the latest nucleic acid technologies who are also now connected via the cloud, Chris says that our ability to track global public health is dramatically changing.

Last year, pharma giant Roche went on a buying spree, picking up one company after another. In December, when it was announced they had bought out Bina Technologies, many of us were playing catch up. Who is Bina, and how do they fit in the overall bioinformatics space?

Today we hear from Bina's CEO, Narges Bani Asadi. As with many new bioinformatics companies, Bina has changed their service and product since they spun out of Stanford and UC Berkeley four years ago. Narges says that the biggest demand from customers is to provide a comprehensive solution for the entire organization. Often, she says, she encounters brilliant bioinformaticians working at customer organizations who are completely overwhelmed by all of the various informatics tools available. Many of these tools are offered free over the internet, and, she says, it’s creating “open source overload.”

Bina has been a very ambitious company from the start, working to provide NGS users with a comprehensive informatics solution, from beefy, fast infrastructure to an interface for the various kinds of users in an organization, to high powered analytics. And Narges is excited about the Roche buyout, saying that it will speed up their plans. Indeed, just providing bioinformatics solutions to Roche in both their drug and diagnostic divisions is already a huge project.

What was Bina doing so well that attracted Roche, and what will the future NGS informatics ecosystem look like? Join us for an inside look at the world of bioinformatics with one of the space’s most dynamic leaders.

In the second part of our interview with Tim Triche, Director of the Personalized Medicine Center at Children’s Hospital Los Angeles, Tim says that micro arrays are still a vital technology for today’s cancer researcher. Making use of both next-gen sequencing and arrays for his research, Tim confirms that arrays still have advantages in the clinic as well, such as quicker turn around time. 

Tim also weighs in on some ongoing questions about whether poor biospecimen quality is hampering research efforts and whether genomic medicine is paying off for patients. 

Go to Part 1:  Want Answers? Look to the Non-Coding Region of the Genome, Says Cancer Researcher, Tim Triche

Listen to Tim Triche from Children's Hospital Los Angeles for very long and you’ll get excited again about cancer research. I couldn’t stop listening. Which is why his interview is being published in two parts.

Now sure, like other guests we’ve had on the show, Tim calls this the “absolute golden age of biomedical research.” But Tim has a unique story. He has been, and is still - though less so now, he says - an outlier in cancer genomics. Whereas most cancer researchers talk about genes, Tim is more interested in non-coding RNA.

An avid user of microarrays, Tim begins Part 1 of the interview with a reference back to “a very interesting experiment” done at the Affymetrix research lab when the first arrays were being designed. The Affy research team put (nearly) the entire stretch of chromosome 21 onto a wafer, and in a “beautiful Science paper” showed the importance of the non-coding or inter-genic region of the genome.

Using the Affymetrix Exon array that was developed as a result of the experiment, Tim has continually demonstrated that there are indeed useful diagnostic and prognostic cancer biomarkers to be found in the non-coding RNA.

And speaking of technology from the early 2000’s, Tim argues that we should reconsider GWAS studies. Perhaps there are still some simple answers to be found when considering the whole genome and not just genes.

In Part 2, Tim vows the incredible staying power of the array technology in the clinic as well as research. He also responds to recent skepticism over whether the age of genomics is delivering on its promise.

Editor's Note:  In this interview, Tim refers to an older generation Affymetrix array (GeneChip^(R) Exon 1.0 ST Array).  The newest array (GeneChip^(R) Human Transcriptome Array 2.0) is able to measure gene and exon level expression of coding and long non-coding RNA with the ability to detect alternative splicing events.