long read sequencing


March 2016 with Nathan and Laura: Genomic Jenga and the Creator, the Anti-Abortion Lobby and Genetic Testing, and Theranos, Again

Which company offers the gold standard of sequencing? Nathan starts us out with a metaphor to compare linked reads with real long reads. Then it’s on to this month’s “knockout paper” that moves us yet further from a deterministic view of genetics. Or is this genomic Jenga part of the “proper design of the Creator”? Laura links a new Indiana law banning abortion due to chromosomal abnormalities such as Down Syndrome to a larger effort by the anti-abortion lobby to go after all genetic testing. Theranos plays the Donald Trump of our industry.

It’s the end of March and time to look back with Nathan Pearson of the New York Genome Center and Laura Hercher of Sarah Laurence College.

How Good are Linked Reads? Serge Saxonov, 10X Genomics

When 10X Genomics launched their GemCode sequencing instrument at last year’s AGBT conference, what they offered seemed too good to be true. 10X was promising researchers a machine that could generate long reads using Illumina’s short read technology at a price lower than what PacBio could offer with their “real” long read instruments. A year earlier, Illumina had announced they were buying Moleculo, a company that promised to offer long read data out of the short reads. But good data with the Moleculo platform failed to materialize.

10X Genomics hasn’t had that problem of Moleculo, and was in fact declared the “winner” at AGBT this year when they presented de novo human data.

Today, for the first time, the CEO of 10X, Serge Saxonov, joins us to talk about their technology and the company’s stellar rise.

The question everyone wants answered from Serge is how well the 10X linked reads stand up to so called “real” long reads. PacBio has spent years co-discovering with their customers applications where their long reads provide significant advantage over short reads, at a price. And even though PacBio released a cheaper-faster-better machine, the Sequel, late last year, some researchers have been wondering whether 10X might come through and "clean house" with their inexpensive system?

“Now you can get the information that people were hoping to access in maybe five or ten years--you can get it now. And in fact you don’t need to make a tremendous new investment and change your workflow radically,” says Serge.

While 10X is enabling Illumina customers to generate long reads, are there still limitations of the short read machines that can’t be overcome?

Serge and 10X have already launched a second system, the Chromium, which offers single cell analysis. How big is the single cell market, and what are Serge’s thoughts on the future of sequencing?

A Home Run on the First Hit: PacBio’s Jonas Korlach

Jonas Korlach is a natural storyteller—a rare trait in a scientist who is more comfortable presenting data than talking of himself. Jonas is the co-inventor of PacBio’s SMRT (single molecule, real time) sequencing, and we wanted to hear from him directly how it all got started, and also when the team realized that they had something big with long reads and close to 100X coverage. How many of us can boast of hitting it out of the park on our first try?

Frontiers of Sequencing: Putting Long Reads and Graph Assemblies to Work

OK, so we get it. Long read sequencing technology is cool. But how cool? Is it another great player on the field, or does it change the game altogether? 

The Mike Schatz lab at Cold Spring Harbor is well know for de novo genome assemblies and their work on structural variation in cancer genomes, so we were curious to hear how long reads have impacted their work. In todays show, lab leader, Mike Schatz, and doctorate student, Maria Nattestad tell of two new projects that include the de novo assembly of a very difficult but important flatworm genome and, secondly, making better variant calls for oncogenes such as HER2.

In the case of the flatworm, Mike says that the move to using PacBio’s long reads improved the assembly by more than a 100 times. That means the difference of looking at a super high resolution picture versus a fuzzy, blurry one, he says. With her work on cancer cell lines, Maria is seeing variants that just weren’t there with short reads. Will her work translate to lower false positive rates for HER2 in clinical diagnostics?

What will be the major headline for sequencing and informatics in 2016?

Mike says we’ll see many more reference genomes done, that the term “reference genome” itself is changing as we go from the one standard reference genome to multiple reference genomes representing the broader population. These new reference genomes are pushing bioinformaticians to come up with new ways to visualize and compare the genomes. Maria details her work into using “graph” assemblies as opposed to the linear approach made popular by the Genome Browser. She says that already a new generation of informaticians are rethinking genome visualization using graph assemblies. (Included below is an image representing her work.)

Neither mentioned it, so we ask at the end, what about Oxford Nanopore’s tech?

 

(The spectral karyotype of the Her2-amplified breast cancer cell line SK-BR-3. The original chromosomes are different colors, so this genome is a complex mixture of various chromosomes. The total number of chromosomes has also jumped from 46 to 80, and there is approximately twice as much DNA as in a normal human genome. Maria Nattestad and Mike Schatz are studying this genome to see how oncogenes like Her2 became amplified while all these changes took place in the big picture of the genome.)

Knowing More about What We Don’t Know: John McPherson on Cancer Genomics

More than with any other major disease, the understanding and treatment of cancer is being transformed by genomics. And these are early days.

John McPherson has been involved in sequencing since the original Human Genome Project. He now directs the Genome Technologies Program at the Ontario Institute for Cancer Research. John chaired a panel on cancer genomics at the recent AGBT, or Advances in Genome Biology and Technology conference, and shares his thoughts on this year's meeting.

Like many others, John is excited about the new possibilities gained by long read sequencing, particularly in showing structural variations of various cancers.

We ask John which platforms he likes, and most importantly--in this day with increasing sequencing instrument options--how he decides how much to spend on sequencing to answer a specific question.

"Our goal is to be as accurate as we can," he says. "For single nucleotide variants (SNPs), we see about a 93-95% verification rate. And we’re pretty happy with that. The question becomes how many samples you do, and not what you do to a sample. Depending what question you’re asking, the number of samples affects your power overall.”

John works in Ontario. We ask him about the state of clinical genomics in Canada, a country with a single payer system.

Gene & Tonic: Disruption in Sequencing, Scientist Politicians, Some Cool Synbio

Join Theral for a quick wrap-up of the week's biotech news:

The biggest news this week has been the flow of stories coming from last week’s AGBT conference held in Florida. This is the annual all out party for the all out darling of our industry, the sequencing space. Like a debutante ball, it’s where anybody who’s anybody comes out and does their curtsy to society.

This year’s debut favorite was no doubt 10X Genomics. It turns out they can almost turn water into wine. Well, almost. What they do is turn short reads into long reads, piggybacking on Illumina’s technology. Have you been following our series on the rise of long read sequencing? It turns out that scientists just decided that they want to actually see the whole genome. Hence the use of long reads.

Illumina has reigned king in sequencing for several years, but their platform is based on short reads. We heard from one of our guests on the program this week that Illumina’s dominance is vulnerable. David Smith at the Mayo Clinic says their platform is about maxed out. Instead he looks for some big stuff from BGI.

Huh? BGI? Isn’t that just Illumina’s platform? Well no. He’s talking about Complete Genomics. Remember them? They were at one time a debut darling then got sold to BGI for a song and a dance. (Every debut is followed by a depression, isn’t it?) But we heard this week that Complete’s still got some juice. David Smith says they’ll be coming out with an assembled human genome for $1,000 come June. That’s an assembled genome.

But this is unofficial. BGI/Complete were not saying anything at AGBT. According to all accounts, the biggest presence at the conference was PacBio. They held this workshop with an incredible lineup of scientific superstars. Temporarily the IQ in the state of Florida rose to the national average.

Craig Venter was there. We heard PacBio flew him in on a private jet with a private security detail.

I mean. Wow. Treatment like the President of the United States.

In fact, I’m going to ask why doesn’t Venter just run for president in 2016? Right, why can’t we have a scientist president? Scientists and technologists are basically in control of the planet anyway. Why not get some on Capitol Hill and recognize them for who they already are.

We found out this week that Harold Varmus is stepping down from the NCI. Why doesn’t he run for a higher office? Why do scientists give up at that level?

Did you see the Science Magazine article this week about the one lone physicist in congress. Bill Foster of Illinois. The news was that he is joining the science committee in the House of Representatives. Wait--there is a scientist committee in congress? So who else is on it then? The lone physicist congressman was quoted in the article:

“There are good conversations to be had on both sides of the aisle. But it’s important that those be fact-based.”

D’ya think?

We asked George Church of Harvard why he doesn’t run for the senate. He looks very senatorial, right? He wrote back and said that if he wanted to hang out with a bunch of Neanderthals, he prefer they be of his own make.

No, he didn’t really say that. We made that up.

But speaking of synthetic biology projects, one of our guests this week is making color changing flowers. You can see it on video. These flowers literally change to another color while you’re watching them. Isn’t it just amazing what mankind can do when we get bored? Next thing you know, we’ll be bringing back smallpox, polio and the measles to the U.S. Because living in the age of vaccines just hasn’t been fun enough.

And that’s Gene & Tonic for Friday March 6th. Stay tuned next week when we’ll continue our conversation on long reads with a researcher from the Ontario Institute for Cancer Research. We’ll also be talking about arrays in this age of sequencing in an exclusive interview with the CEO of Affymetrix, Frank Witney.

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Test Driving Genomic Medicine: Thomas Quertermous, Stanford

Guest:

Thomas Quertermous, Director of Research, Division of Cardiovascular Medicine, Stanford University Bio and Contact Info

Listen (7:45) Close, but not quite there

Listen (5:34) How good are the commercial bioinformatics providers?

Listen (8:19) The challenge of education

Listen (5:12) Genetics and heart disease

Listen (2:55) Where do you put the price for whole genome interpretation?

Listen (2:32) Are long reads a big deal?

Thomas Quertermous co-chairs a pretty spectacular committee at Stanford. Called the Dean’s Panel on Clinical Genomic Testing, the committee makes the call on which genetic tests are ready for prime time in the clinic. Thomas joins us to launch our new series, Genomic Medicine Today: Where Are We?

The goal of this series is to find out just what practical progress we’ve made in commercializing whole genome sequencing. What are the success cases? How many are there really? What are the obstacles and keys to progress?

TQ, as he's known in the industry, recently co-authored a paper published in the Journal of the American Medical Association (JAMA) that provided a snapshot of just where we’re at today with genomic medicine. The conclusion? We’re close, but not quite there.

The key to clinical whole genome sequencing, he suggests, is to come to it with the question of "what you hope to learn from the adventure."

“I think it’s good if you start with a goal and try to stick to that goal rather than create an all encompassing analysis of the genome," he says in today’s interview.

As for challenges, TQ says that we need better healthcare informatics solutions, and always, better education at the provider level.

What are his thoughts on the leading commercial solutions for whole genome interpretation, and does it really cost $100,000? What does TQ think about the rise of long read sequencing led by PacBio this past year?

Join us as we begin a new series probing the front lines of clinical genomics.

Podcast brought to you by: Omicia - Offering end-to-end genome interpretation and reporting solutions to help diagnostic labs and research institutions unlock the potential of individualized medicine.

The Progress of Clinical Genomics in Sweden with Ulf Gyllensten

Guest:

Ulf Gyllensten, Professor, Department of Immunology, Genetics, and Pathology, Uppsala University, Sweden Bio and Contact Info

Listen (4:24) What are your goals at the National Genomics Infrastructure?

Listen (4:42) PacBio revolutionizing HLA typing

Listen (4:01) Getting the word about long reads out to clinicians

Listen (3:17) What would you like to see from sequencing companies in the future?

Listen (8:03) An update on clinical genomics in Sweden

Listen (5:02) The Road Show

For our final show in the series on long read sequencing, we move to Sweden and talk to Ulf Gyllensten, Co-Director of the National Genomics Infrastructure.

Ulf and his team use all the major sequencing platforms, and one of their jobs at the NGI is to compare the platforms. In today’s interview, he tells of the goals at the NGI and how new long read technology from PacBio is opening up new applications.

Some of these applications are clinical, and Ulf gives an update on clinical genomics in Sweden where regulation and privacy concerns are much more straight forward than they are here in the U.S.

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

Test Driving Illumina's X Ten with Shawn Baker, AllSeq

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."

Has the Race to the $1,000 Genome Proceeded at the Expense of Quality? New Series on The Rise of Long Read Sequencing

According to a 2010 article in Bio-IT World, the term $1,000 Genome has been around since 2001.  The University of Wisconsin’s David Schwartz claims to have coined the term at an NHGRI retreat during a breakout session.  Whatever its origin, the $1,000 Genome soon became the target for the rapid development of next-gen sequencing (NGS).



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