clinical sequencing

“I think the field has just really come to life over the last five or seven years. We’ve got all this sequence data. We’ve got the population data. We’ve got gene editing. I’ve been at this thirty plus years, and we haven’t had a culmination of technology and data like this before. I think everyone has to be excited in some way or other.”

Lon Cardon has lived through a few ups and downs in our field and remembers well the days when mention of his own area, statistical genetics, was the quickest way to kill a dinner conversation. The hype cycle has come full swing, and his days of pessimism have turned to full on optimism. Theral takes a couple stabs at it, but Lon’s giddiness is hard won.

Surely there are challenges, Theral argues. Have we become drunk on sequencing, as a recent guest commented? And what are the practical challenges Lon faces with big data? Aren’t there real hurdles?

We had some challenges of our own with Theral’s mic malfunctioning. But we're optimistic--the backup mic worked. We come in at around 23 1/2 minutes.

Presenting BioMarin’s new Chief Scientific Officer.

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.)

Before Bobby Sebra became the Director of Technology Development at the Icahn School of Medicine at Mt Sinai in New York he worked at Pacific Biosciences, helping to develop their single molecule, long read (SMRT) sequencing technology.

In today's interview Bobby says he left PacBio to be free to use all of the available sequencing platforms to develop clinical solutions. At the Icahn School, he has been scaling up the facilities to include Illumina, Ion Torrent, PacBio and BioNano Genomics sequencers, as wells as researching some of the newer platforms such as 10X Genomics, and Oxford Nanopore Technologies. Bobby’s work includes matching these various platforms with the right project, often going back and forth between short read and long read technologies to get an adequate result.

Building on his familiarity with the PacBio system, one of Bobby's primary projects at Icahn is to take PacBio’s new long read technology and develop new clinical applications, such as looking at more polymorphic domains in the human genome at high throughput.

What are his big challenges? Bobby says that a single cell approach is the next important step for clinical sequencing, and he looks forward to a platform which integrates single cell analysis into one workflow. He is also pushing sequencing tool providers to be able to work with lower input, or smaller initial samples.

What clinical projects has Bobby excited, and what is his reaction to recent skepticism about the clinical potential for the study of genomics? Join us for a wide ranging discussion on the latest in clinical sequencing.

Actually there was no news this week.  It turns out the whole industry took the week off to watch the stunning Ken Burns documentary on cancer.  

No, that’s not true.  We did find some news.  

How about this?  The Affordable Care Act turned five this past week.  Happy Birthday, ObamaCare!  So we thought we’d share some important numbers about the ACA:

11.7 million:   the number of Americans who have signed up for 2015 coverage.

46%:   the increase in enrollment from 2014 to 2015.

0.3%:  the increase in new patient/doctor visits.  (Remember, one of the criticisms was that there weren’t enough doctors to pull this off.)

5:  the number of Supreme Court Justices it takes to screw it up for the newly insured in the current case against the ACA.

4:  this is the number of words that the case is all about.

828:  This is the number of pages that Congress used to provide a clear context as to what those four words mean.

A decision on the bill’s fate is expected later this year.

Also later this year, on November 21, it's Know Your Genome Day.  It was announced this week that on that day anyone can go to Dallas, Texas, have their whole genome sequenced, and receive a clinical interpretation of it. The event is hosted by Genome Magazine--this is a new magazine out for patients and consumers--and by the sequencing company, Illumina.  But the event sponsors haven’t made it clear yet just why you should have your whole genome sequenced.

So we came up with ten reasons of our own why you should have your genome sequenced:

1.  So you can find out that you married your first cousin.

2.  To prove to your business partner that you’re really only 3% Neanderthal.

3.  To find out there’s a strong possibility that you might die at some point in the future. 

4.  So you'll have definitive proof that your parents really are to blame.

5.  To get Angelina Jolie to leave you alone.

6.  To prove that you really are an alien.

7.  So that the sperm you donated in college can come back and haunt you in the form of your own kid.

8.  To be the star of that dinner party next month.

9.  To make Craig Venter and Francis Collins even more full of themselves.

10.  To ensure the good folks in our industry a job.

Do you have your own reasons?  Please share them with us in the comment section below or on Twitter.

Finally, some humbling news for today’s biomedical researchers.  CBS News reported on a thousand year old remedy for eye infections that works stunningly well.  The remedy was found in a 10th Century medical volume called Bald’s Leechbook.  It’s one of the earliest known medical textbooks.   This is a true story.  The remedy calls for garlic and onion, wine, and bile from a cow’s stomach--wait a minute isn’t this what I have for dinner once a week?  Researchers mixed the recipe together, let it sit for nine days and tried it against the antibiotic resistant MRSA bacteria.  The ancient remedy wiped out the MRSA, killing 99.9% of the bacterial cells.

The “ancient-biotics” team, as they’re calling themselves, plan to continue researching old texts for cures.  

Have a great weekend, everyone.

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Today we bring you a story which you probably wouldn’t have heard at last week’s AGBT conference at Marcos Island. While PacBio and 10X Genomics were getting most of the buzz at the annual show on all things sequencing, it could be the new BGI/Complete Genomics platform that steals the show later this year, says David Smith, a cancer researcher at the Mayo Clinic.

In his research, David uses sequencing to analyze the connection between the human papillomavirus (HPV) with oropharyngeall cancer.

“A couple decades ago, the incidence of HPV in oropharyngeal cancer was less than 20%. And now at the Mayo Clinic, 80-90% of these cancers are HPV positive,” he says.

Why? A change in sexual practices, David says.

To find out just how HPV causes cancer and integrates into the genome, David is using ‘long read, mate pair’ sequencing. This is a new technology that essentially converts short reads got from such platforms as Illumina’s into long reads. David acknowledges the nice long reads coming from the PacBio machines, but says the cost is still prohibitive. He’s looking for a price that scales into the clinic, and for this, he's most excited about a product that BGI is rolling out later this year, i.e., an already assembled human genome sequencing for $1,000.

We finish the interview with a discussion about how well clinical genomics is being adopted into practice at Mayo.

Guest:

Eric Schadt, Professor & Chair Genetics and Genomic Sciences, Director Icahn Institute for Genomics and Multiscale Biology Bio and Contact Info

Listen (5:01) Getting buy-in from a few lead doctors

Listen (5:24) Do you see shift toward long read sequencing?

Listen (6:35) Scaling up for the clinic

Listen (6:03) PacBio leading on quality

Listen (4:07) The genome fractal? Using math in biology

Three years ago, Eric Schadt left the sequencing company, Pacific Biosciences, as their CSO to go be guru of genomic medicine at Mt Sinai in New York City. Backed with terrific funding and leadership, Eric has the resources to be in the vanguard of translating our latest understanding of genomics into real world benefits for patients.

Today he updates us on his work at Mt Sinai, detailing his strategy and the obstacles that he faces. He then weighs in on the rising importance of long read sequencing, not just for microbial research, but for practical human genomics. Eric comments here on the journey of PacBio from a company that was overhyped and under delivering to one that is setting the mark for quality in human genome sequencing today.

“It’s very exciting to see the quality of the PacBio data,” he says. “The utility is just beyond compare, whether you're assembling a bacterial genome de novo, or looking at structural features in the fragile X region of the [human] genome, or looking at methylation simultaneously. ”

Eric has a Ph D in biomathematics. We end by discussing how math will help in deciphering biology.

“We don’t know the language yet of biology. So we’re trying to learn how to write the book without really understanding all the words or knowing how to string the words together into sentences," he says at the conclusion of the interview.

Podcast brought to you by: Pacific Biosciences - providers of long read sequencing solutions based on their Single Molecule Real Time technology.

Guest:

Dan Geraghty, Researcher, Fred Hutchinson Cancer Center; CEO, Scisco Genetics Bio and Contact Info

Listen (4:43) Unable so far to find causal linkages in MHC region of the genome

Listen (4:43) Illumina vs. PacBio

Listen (9:27) Major sequencing projects should be done with long reads

Listen (9:32) Is the message about long reads getting out there?

Listen (3:15) What projects will you pursue with long read technology?

Dan Geraghty has a message for anyone looking for genetic causes of disease.

A researcher at the Fred Hutchinson Cancer Center, Dan has been working at characterizing the difficult region of the genome known as MHC, or major histocompatibility complex. This region controls a major part of the immune system and is linked with many common diseases. Until now, Dan says, researchers have so far been unable to find causal linkages to common diseases, such as diabetes, celiac disease, and rheumatoid arthritis in the MHC region because they haven't been able to look at long enough pieces of DNA.

Unlike with Mendelian diseases where a single mutation is linked directly to the disease, the regions in the MHC that are linked to disease often include long "flanking" sequences which play a part. Until now, to get a complete look at a long genetic region, researchers have used Illumina's short read technology and then had a lot of data analysis and finishing work to do. First of all, that finishing takes hours and hours. And secondly it doesn't give an accurate picture.

"The finishing is really prohibitive for a modest research effort," says Dan.

Enter new long read technology. Recently Dan worked with PacBio where he was able to get 40kb read lengths. Contrast that with the 300bp reads of the Illumina technology. There's just no comparison, he says. And the error rate for the long reads: one in a million.

"This is really high quality data," Dan says of the PacBio reads. "This is the kind of zero error rate where you can compare your cases and controls and easily validate them and have high confidence that what you're seeing is accurate."

What does this mean for genomic research going forward? Take the 1,000 Genome Project of the NHGRI. Shouldn't researchers be using long reads to get the most accurate data possible?

And just what projects is Dan pursuing with what he calls the "breakthrough" technology?

"We're hot on the trail," he says. "We basically can see the entire picture. We're not looking under a lamppost for the keys. It's daylight, and we can see the whole neighborhood. So we're gonna find the keys."

Podcast brought to you by: Pacific Biosciences - providers of long read sequencing solutions based on their Single Molecule Real Time technology.

Guest:

Shawn Baker, CSO, AllSeq Bio and Contact Info

Listen (5:27) Taking the X Ten for a test drive

Listen (6:56) What is the latest price for a whole human genome sequence through Allseq?

Listen (3:05) Illumina's bold move into clinical space

Listen (7:17) NGS story of the year: X Ten or long reads?

Listen (7:24) Latest from Oxford Nanopore and Genia

In January, Illumina made headlines by announcing that their new HiSeq X Ten sequencers now can deliver the $,1000 genome.

“Sort of “. . . says today’s guest, Shawn Baker, the co-founder and CSO of AllSeq. They are an online marketplace connecting providers and users of sequencing. AllSeq offers their users a way to get access to a close to $1,000 genome without having to shell out the big capital.

Recently AllSeq teamed up with one of their providers, the Garvan Institute, an early adopter of the X 10 system, along with the bioinformatics platform, DNAnexus, to do a test drive on the expensive but impressive new devices. They are offering a free look at the data here.

Having Shawn on the program is always a chance to get an overall perspective on the sequencing space. What are his thoughts on the emerging importance of PacBio's long reads? And what's the latest from Oxford Nanopore and Genia Technologies?

Podcast brought to you by: Chempetitive Group - "We love science. We love marketing. We love the idea of combining the two to make great things happen for your marketing communications."

Guest:

Mike Snyder, Director, Center for Genomics & Personalized Medicine, Stanford Bio and Contact Info

Listen (5:44) Current method for figuring out transcriptomes is crazy

Listen (4:18) Long reads necessary to find paternal or maternal alleles

Listen (4:31) Practical applications of the transcriptome

Listen (4:41) Has the race to the $1,000 Genome been at the expense of quality?

Listen (6:33) If price drops for long reads is there a future for short reads?

Today we launch the much anticipated series on The Rise of Long Read Sequencing with Mike Snyder, Chair of Genetics at Stanford. Mike has been working four years on what has become known as the “Snyderome” (or "Narcissome" as his colleagues call affectionately call it), looking at hundreds of thousands of his own molecular biomarkers regularly over time. Lately Mike has been focused particularly on his transcriptome, or RNA molecules.

The transcriptome is studied by looking at individual isoforms. On average, every gene has five or six isoforms or transcripts. Recently Mike has co-authored a couple papers showing that it is difficult to identify full-length transcript isoforms using the current short read sequencing technology.

“The way we figure out transcriptomes now is kind of crazy if you think about it," he says. "We take RNA. We blow it up into little fragments, and then we try to assemble them back together to understand what the transcription looked like in the first place. That’s a horrible way to do this.”

Mike explains how PacBio's long read technology is opening up new possibilities for characterizing the transcriptome and identifies some of the practical applications that might come from his research.

So what does this mean about the future of NGS? If PacBio or one of the emerging nanopore sequencing companies can offer long reads at high throughput, is there any reason why a researcher would use short read technology?

"If the long reads are high quality and cheap, you wouldn't need the short reads. . . [long reads] would take over the market." Mike says.

Reflecting on the rapid changes we've seen in the NGS space from year to year, he says, "next year we'll probably have a whole different conversation."

Guest:

Eliot Forster, Executive Chair, MedCity Bio and Contact Info

Listen (2:54) Cashing in on illustrious life science tradition

Listen (2:56) Culture of collaboration strong in the UK

Listen (5:01) A growing acceptance of GMOs

Listen (4:59) Did you ever think you would see American companies moving to the UK?

Listen (7:49) How goes the shift toward personalized medicine?

From Darwin's seminal work to the discovery of the structure of DNA to the 100K Genomes Project, the U.K. can boast of an illustrious life science tradition. Today, the U.K. government is backing a major push to cash in on that tradition, seeing life science business--from personalized medicine to genetic engineering—as a a major component of their new economy.

MedCity is a non-profit representing the life science community in London, Oxford, and Cambridge. Eliot Forster, Executive Chair of MedCity, joins us to give an update on the U.K.’s bio-economy. With support from the highest offices in government, the life science community there is benefiting from some important trends. Forster says there is a strong culture of collaboration and a regulatory and tax environment that is favoring more innovation.

Forster chuckles at the thought that some American companies are taking advantage of these new trends in England in the form of tax inversions. Thirty years ago, you wouldn't have predicted it, he says.

The commitment to biotech in the U.K. was on full display earlier this year when Prime Minister David Cameron created the new cabinet role of life sciences minister.

“If you’re looking to do work in the life sciences sector--whether a startup or a subsidiary of a major international—come to London, come to Oxford, come to Cambridge,” says Forster. "You’ll be very surprised by what you find, and pleasantly so."

Podcast brought to you by: Chempetitive Group - "We love science. We love marketing. We love the idea of combining the two to make great things happen for your marketing communications."