I Prefer My Bacon Crispy: Why I Don’t Think CRISPR is Really That Big of a Deal

Sultan Meghji

With all the recent news around CRISPR my reaction is “meh” (coincidentally, the same reaction I’m having to the current US presidential election noise). We are a wee bit early for both.

Is Jurassic Park – and now Jurassic World real? No.

“Cutting and pasting” of genetic material is a well-used mechanism. It replaced the (ahem) ever so accurate and useful “shoot a bb gun into a petri dish” model a while back. Restriction enzymes have been out there for well over 20 years. The focus on T cells in the blood streams and the usage of electroporation is interesting. Of course, not blowing up the cells would be useful, and there is a non-zero chance of that happening currently.

The net result would be the ability to perform genetic dialysis of the bloodstream to counter disease or inherited traits (and gene therapy).

Let’s push the hype meter down a few notches.

This isn’t a massive leap that will be available in market next week. Like most technologies in this space, you are looking at 10+ years of research validation prior to market entrance. Let’s also remember that the first market entrance will be focused on people deep in sickness, where their wallets will pay anything to ward off death.

My hypothesis is that the first commercial (or end person usable nature) would be in places where modification of existing blood stream traits would be useful – cancer, certainly. Other possibilities are other blood related indications such as diabetes, heart disease, and more. Surely some company will raise $10m and more designing a genetic dialysis, zero-effort weight loss, or hair loss reversal pill. Cialis or Viagra 2.0 is an equal possibility.

The recently announced $120m fund raised by Editas Medicine was a private sector step forward outside of the public view. It will be five or more years before anything actionable comes out of it. Then, of course, the company will face what could be massive and uncharted regulatory issues.

There’s a larger trend here that is worth noting: just because we’ve added a tool to the toolbox doesn’t mean that it is available or useful. Just because we have a better hammer doesn’t mean we can build a flying car.

And this is me: the futurist, idealist, and massive proponent of all things genetic talking!

Where is Oxford Nanopore by the way?

Sultan Meghji is the founder and Managing Partner of Virtova.  This post was orignially published at

The Genomics Grinch

Theral Timpson

One of the handy tools a journalist can use is a sharp pin.  It’s quite helpful when encountering over inflated balloons, such as the politican’s ego,  a financial bubble, or the hype around going to war.   When the pin is used at the right time, and on the right target, there is no question that the resulting “pop” is heard by everyone.  

However, when there is no over inflated balloon to pop, and a journalist still pulls out his pin, he just comes across as a nasty grinch.  This was the case with a piece in BuzzFeed last week by the science journalist, David Dobbs.

“We live in an age of hype,” writes Dobbs, questioning the value of genomics research and the money we are spending on it.   "It is as if they [geneticists] cracked a safe they knew was packed with cash and found almost nothing." 

That there is hype around genomics, I’ll concede.  But Dobbs is way too soon to say the strides we're making in precision medicine are almost nothing.  It’s akin to Senator Jim Inhofe bringing the snowball into the senate floor as proof against global warming.  Or citing the one scientist out of a hundred who questions whether the planet is heating up as a result of increased amounts of CO2 in the atmosphere.

Shouldn’t we err on the side of caution with the future of our planet?  And shouldn’t we be willing to put up with some natural hype ( a scientist overselling their discovery, a journalist adding some lustre, a businessman jumping in on a hot IPO) about what are some remarkable accomplishments in biotechnology and keep our gaze on the long view?

I know what hype is.  I go to the same conferences as Dobbs where we hear of new studies that promise to show this or that.  We hear about new technologies that will “impact patient outcomes.”   I’ll never forget the first time I interviewed someone in Silicon Valley who told me that we could achieve eternal life by reversing aging.   I had an extra beer that night for sure.

Unfortunately, Dobbs confuses capitalism, genuine hope on the part of patients, and the power of the human will to survive and learn with hype.  

“It would be responsible, however, for researchers to temper their hype — though this seems unlikely, because hype pays.”

And . . .?  That particular version of hype is called capitalism.  It funds science.

Dobbs says that the hype around genomics warps the expectations of patients and the incentives of scientists.  

I’ve interviewed a lot of scientists, and doctors, business leaders, policy experts, and patients.  Yes, my job is to cut through the hype and get to the real story.    I’ll share one such interview that I did with Jay Lake, a sci-fi writer with lung cancer who ended the show thanking and pleading with our audience of researchers:  “Please keep up the great work.   Please continue.”

Jay came on the program back in 2013 to tell about his experience getting his genome sequenced.  Jay’s oncologist was at the end of his rope with known treatments.  But that wasn’t enough for Jay.  Jay wanted to try every possible option, so he and his father, a former US ambassador, spent a great deal of time and energy getting Jay’s genome sequenced and interpreted.   And with this new tool, a new prognosis.  Jay would blog up to four times a day about his journey with cancer, and on our show he was honest about how “painful and difficult” it was getting help from genomic experts.  (It’s much cheaper and more available now.)  Still he persevered to find answers in his genome until the end.   In June of 2014, he died.

Now Dobbs would say I'm providing another example of warped expectations.

No, Dobbs.    You have it the wrong way around.  More than scientists warping the expectations of patients, I’d argue that patients like Jay Lake have been pushing the scientists.

Jay fought long and hard, and in the process compelled his doctors to push the envelope, scientists to make new hypotheses, and translational  researchers to go the next step.  Most of all, Jay showed great heart against the odds.  

This wasn’t hype, David, but the will to live.

What is overlooked in Dobbs' piece is a long view on the incredible achievement that has been made in the study of biology.  The response on Twitter to this article didn’t reveal too many warped expectations on the part of the scientists either.

“We were promised flying cars, all we got was fundamental insight into the nature of human variation,” tweeted a snarky computational human geneticist, Joe Pickerell.

So, no, I don’t question that there are cases at the ready to use in pooh-poohing genomics.  (Dobbs begins with the recent bad news that the one gene therapy drug that has been in use is now showing some limits.)  I poked fun a couple weeks ago at the poor case our industry has made for persons to have their genome sequenced in our comic weekly wrap.  But let’s remember the proverb we heard as kids.  For every two steps forward, we see a step back.   How about the story of Dr. Sidney Farber that was told in the  recent Ken Burns documentary on cancer?  Farber pioneered the first use of chemo therapy.  Kids with leukemia who had death sentences were gaining back health.  There was a lot of hope generated.  Journalists emptied their pens.  Then?  After six months, the revived children succumbed again to their cancer.  Should Farber have given up?  

I mean, just who is David Dobbs to call quits on the genomics revolution anyway?

Beyond the long list of practical genomics based assays being used in the clinic or drug development, from new options in cancer therapy to non-invasive prenatal testing, genomics is one of the greatest scientific stories of the past fifty years.  That humans developed the technology to see our own genetic code -- all 3 billion bases -- ranks with the discoveries of Darwin and Mendel.  It’s perhaps our greatest achievement since the landing on the moon.    Let’s tell that story for many, many more generations!

But no, Dobbs will have none of it, insisting on a sinister reading of history.

“After 110 years of genetics, and 15 years after the $3.8 billion Human Genome Project promised fast cures, after more billions spent and endless hype about results just around the corner, we have few cures,” David provokes. “And we basically know diddly-squat.”

Should we really tell nameless breast cancer patients who’ve had 10 or 20 years added to their lives-- to name just one example -- that it’s just “diddlly-squat?”

Dobbs has made a name for himself by combining a comfortable knowledge of biology with a blunt discourse.   In a New York Times editorial he called Nick Wade’s book about race and genes, “dangerous.”  (I think he was right about that.)  He’s also demonstrated an ambition to mess about with the science of biology itself, as he did with his article at Aeon, Die Selfish Gene, Die.   Here Dobbs was attempting to call it quits on an established scientific meme.  The piece was lambasted by several evolutionary biologists, including Jerry Coyne, who wrote two long pieces about how “Dobbs mucks up evolution.”  Coyne muses about whether it was "ambition or boredom" on Dobbs' part.  Whatever it was, such was the outcry among scientists that Dobbs significanlty revised and republished the article with a toned down version.  

Though Dobbs attempts here to see the age of genomics as an over-inflated balloon and he, the enlightened journalist, standing there with his trusty pin, we never hear the “pop.”  Rather we hear an “ouch” as he retreats to a very narrow view of biomedical history filled with diminishing language.

On the Mendelspod program, we continually hear from our leading geneticists,  “we’re just at the beginning of all this.”  Geneticists like David Schwartz from the University of Wisconsin Madison, who compared today’s biology methods with the first days of tinkering around with televisions.  Perhaps there’s a reason scientists maintain an optimistic view of the future.    It inspires them, and fills us all with wonder. 

This is no balloon.  Just below some surface hype is a hard-wired human drive to know.  What you're really writing about, Dobbs, is the human heart.  And it doesn’t pop.


Mendelspod Back on iTunes

Theral Timpson

Good news!

Mendelspod is back up and running on iTunes. You can access it at our new link:

If you wish to subscribe, click 'View in iTunes' under the Mendelspod logo. This will open iTunes on your desktop. Now click 'Subscribe' below the Mendelspod logo, and the podcast will automatically populate in your iTunes.

To access via your smartphone, first download Apple's 'Podcast' app. Then use the app to search 'Mendelspod' and subscribe. We apologize for the delay. It took several weeks of emails back and forth with Apple.

Enjoy the shows.


Garbage In, Garbage Out: A New Look at Biospecimen Quality

Theral Timpson


If you had told me a year ago that there are no regulated standards as to the quality of the biospecimen samples that are used to conduct biomedical research, I wouldn’t have believed it. Yet that’s been the case.

This was brought to our attention by the indomitable Carolyn Compton, a former pathologist and now the Chief Medical Officer for the National Biomarker Development Alliance (NBDA). Carolyn served at the National Cancer Institute with the express purpose of bringing more awareness to the issue of sample quality. It was there that she came to connect the dots between poor sample collection, handling, and storage and the upward trend of non-reproducible research. Bad sampling is leading to bad science.

We were so struck by her hypothesis that we asked Carolyn to help us put together an entire series on the topic with links to each show posted below.

Jim Vaught started us off with an overview of the topic, giving a stunning example of how bad sampling is not just affecting research, but medicine as well. We then delved into just what can go wrong with sample collection and handling with Scott Jewell of the Van Andel Institute.

Diane Farhi is the Chief Medical Officer at Quintiles, the world’s largest CRO. Diane and her team have to deal with problems in collecting samples for clinical trials on a global scale. Next, we explored the new Biospecimen Science, a new sub-discipline which has emerged to offer training and basic education on the topic--albeit not near where it should be according to David Rimm of Yale. We talked with the director of the biorepository that handles samples for 4 NIH Institutes, Andy Brooks. He says that there are so many variables that are beyond our control that perhaps the best thing would be a score to test the quality of the sample in storage.

Carolyn returned to the program with some good news. Through NBDA she had been able to assemble much of the sampling community, including the head and former head of the College of American Pathologists (CAP), and they agreed on an initial framework for sampling standards. It was an historic event.

The Open Secret about the HER2 Assay with Jim Vaught

Biosampling Basics: Scott Jewel, Van Andel Institute

The Daunting Task of Managing Biospecimens at the World's Largest CRO: Diane Farhi, Quintiles

The Sad State of Biospecimen Science with David Rimm, Yale

"It's Pretty Bad": Andy Brooks on Sample Quality

Historic Consensus Reached on Biospecimen Standards: Carolyn Compton, NBDA

Note:  Thanks to Quintiles and Fluidigm for sponsoring this series.


Why We Are Underwriting 'The Faces of Leadership in Diagnostics’ at Mendelspod

Zachary Helminiak

It’s no secret that the diagnostic industry is changing. Outside pressures like reimbursement and regulation, and internal forces like innovation, have produced tectonic shifts and allowed new landforms to rise from the ocean that is the diagnostic industry.

DNA testing in the consumer market is just one example of a volcanic event shaping the industry. Anne Wojcicki made headlines with 23andme on a regular basis the past year, giving a keynote speech to an eager audience of 20-something techies at South by Southwest. Thanks to Elizabeth Holmes and Theranos, soon you will be able to get lab tests at Walgreens with just one drop of blood. And egg freezing, offered by Ovascience, is now a company benefit at Apple and Google.

The faces of the leaders who are innovating in this space and challenging the healthcare status quo are changing as well. They are younger, and more often than before, they are women.

What does this mean for companies trying to compete in this space? What new demands are placed on your company culture if you want to attract an innovative leader?

Slone Partners embraces this change and is proud to partner with Mendelspod by underwriting a new series engaging some of the new faces of leadership.  

In these interviews, beginning next week, Mendelspod host, Theral Timpson, will talk with three women who are expanding the paradigm of leadership in the diagnostic industry.

We hope you enjoy the series.

ASHG 2014 in Review: Exhibitors Open the Kimono

Stephane Budel

The 64th annual meeting of the American Society of Human Genetics (ASHG) this week in San Diego, CA offered a glimpse into current progress in genetic testing. Not surprisingly, next generation sequencing (NGS) was omnipresent. In this blog entry, I highlight some interesting factoids ascertained while visiting select exhibitor booths.


“PrimeFlow enables researchers to look at up to 3 RNA transcripts and protein expression at the single cell level. There seems to be a lot of interest for infectious diseases applications –especially for HIV and HCV– and for stem cell research. One of the key advantages of branched DNA is that we amplify the signal, not the DNA.“


“Our AriaMx qPCR instrument is generating a lot of interest this year. It has a modular design that enables users to easily switch filter sets, and multiplex up to 6 channels.”


“We have conducted 55K WGS, 75 WES and 60K whole transcriptomes. We have access to 200 sequencers, including many in 2 labs in the U.S. We can match Wuxi’s price [of $1,600 per WGS], although we don’t have access to the X-ten in-house. […] For an extra $30 per sample, we’ll extract the DNA from blood samples, so we really offer end to end solutions.”


“After a year on the market, we’ve installed 25-30 systems to date. Our customers include a mix of basic research and government agencies, as well as a couple of clinical customers. The primary use is for genome scaffolding. The system lists for $295K, and then it’s $1,100 per sample [$900 for the chip and $200 for labelling].”


“We’re very proud of the QX200. It now runs not only TaqMan chemistry, but also EvaGreen. The combined system with the automated droplet generator lists at $135K. That’d be $90K with just the manual droplet generator. […] The QX100 and QX200 have been used in 150 publications combined.”


“We deliver a full WES clinical report in 30 days from date of reception for $3,900. We probably process 50-100 NGS samples per week, including 40 exomes. We continue to see a strong transition to WES.”

EMD Millipore:

“We’re introducing two technologies for functional genomics focused on the emergence of RNA as the next frontier of biomarkers. The first, SmartFlare Live Cell RNA Probes, enables direct detection of native RNA in living cells which can be used for downstream functional experiments and isolation of cell subtypes from heterogeneous populations – particularly useful for single cell genomics applications. SmartRNAPlex is a revolutionary multiplex miRNA profiling technology based on encoded hydrogel particles that can turn any standard benchtop flow cytometer (including the $15k Muse Cell Analyzer) into a genomics workhorse.”


“We released the C1 with programmability back in June. A couple of weeks ago, we released a protocol for single cell WES that complements are single-cell targeted resequencing workflow.   And you know that WGS is going to come next. It’s interesting to see the variety of applications that users want to program their C1 for: RNA-sequencing, bacterial sequencing, epigenetic applications, etc.  We also pre-announced our new Juno System for automated genotyping that combines pre amplification and genotyping into one platform.  It offers a robust workflow to support highly variable quality and quantities of genomic DNA input.  It’s the ideal solution those laboratories looking for more efficient solutions for candidate gene or replication studies or sample QC for their biobank samples.”


In the center of the exhibit hall, Illumina displayed a number of their instruments, including the awaited Neoprep platform (release date: H1 2015). Their dominant position was confirmed in yesterday’s earnings call (updated 2014 revenue growth guidance: 30%!).

“I think one of the most exciting recent development for us is the new 250 bp paired-end chemistry that will launched by the end of the year on the X-ten. Besides that, we’re excited to see continued growth in BaseSpace, which now has more than 50 apps available.”


“We sequence 220 genes at 450x coverage and only report what our customers want to know. It’s $1,500 whether you want 2 genes or 30 genes with appropriate clinical indication. Our test menu will expand in the coming year.”


“We released v3.1 of knoSYS this week. We continue to believe that many clinical customers do not want their data on the cloud, so having an appliance that can store data behind their firewall is important. We hear a lot of customers being interested in in silico panels.”

Life Technologies:

“We’re proud to announce the launch of the PGM Dx at ASHG. […] We’ve also received great reception of the Ion Chef. We’ve placed more than 10 [Chefs] in the San Diego area alone in the last 6 months. At $50K, it’s a relatively affordable instrument, but many researchers are waiting for the next round of funding to purchase it. […] The P II chip should be released in early 2015, and deliver about ~50 Gb of data.”


“We’ve put a strong focus on translational research, and done a good job at bringing the research conducted on our platforms into the clinic.”


“I expect us to launch the GeneReader in late 2015. There is really no point in us releasing the instrument before it is fully integrated with our end to end solutions, and the CLC and Ingenuity integration take time. Our NGS products have proven their medals in research settings, and we expect to do well as we move to diagnostics.”


“We don’t offer WGS, although unlike many other [smaller] CROs, we would have the infrastructure to support it. There are plenty of companies that you could get WGS from at an affordable price. About 70%+ of our genomics customers are biopharma customers; others are institutional.”


“My customers are going to miss the GS Junior. Many of them are asking me: ‘what are you going to get rid off next?’ But I think we have a very smart team of people working on the next generation of NGS instruments.”

Oxford Nanopore:

“Well, you’ll have to talk to [blank] about this. We want to let our MinION Access Programme (MAP) customers tell the story of what the technology can do.”

Pathway genomics:

“We’re proud of our weightloss test. It sells for $399 and genotypes thousands of SNPs”


“We’ve installed the Thunderstorm at more than 50 customer sites. Myriad has been using it for all of its myRisk tests very successfully. You just don’t get better amplification uniformity than with our systems.”


“We offer our services mostly to pharmaceutical customers. We charge about $1,600 per genome for high volume customers.”

Note:  This article was orginially posted at

Are We Insane? How Can We Expect Great Biomarkers and Therapies when There Is Poor Sampling?

Theral Timpson

When the former deputy director of the NCI, Anna Barker, suggested we start this year’s Biomarker Development Series with a show on biospecimen quality, I admit: I wondered how I was going to make it interesting.  

Biosampling?  What is there to talk about?

Then I met Carolyn Compton, a former pathologist and now the Chief Medical and Science Officer for the Naitonal Biomarker Development Alliance. Carolyn has a provocative message:  sampling issues are becoming one of the core problems in biomedical research. 

Today, I’m happy to announce the upcoming series, Back to Basics: Improving Biospecimens.  This series of five interviews will give us a chance to explore how big of a problem we have with sampling issues and what can be done about it. Quintiles is one of the largest CROs in the world who deals with sampling issues on a massive scale.  They’ve agreed to underwrite the series to bring more awareness to a topic that is too often overlooked. 

And just why should we talk about sampling?

Let’s start with the issue of non-reproducible research.  According to a study by Amgen in 2012 (Nature 483, 531-533, 2012), only 11% of 53 seminal publications on drug targets or toxicity could be reproduced by their team.  Let's add to that a fact that ASU’s George Poste points out in a Nature article of 2011 (Poste G. Nature-469, 156-157, Jan 2011) that out of over 150,000 biomarkers that have been written about in scientific and medical literature, only about 100 have been commercialized.  Why the stunning lack of success?  

“Garbage in, garbage out,” Carolyn says, borrowing a phrase from the big data folks.

The samples are not procured correctly, they’re mishandled, and they degrade.  It's critical that the industry works to improve standards.

I pulled the studies mentioned above from a talk Carolyn gave on these issues at a recent skin cancer conference in Scotland.  It’s a terrific introduction to the topic and is embedded at the end of this post.  

We’re going to unroll the series in the following format:

Our first show will be an overview.  We talk with Jim Vaught, President-elect of the International Society for Biological and Environmental Repositories (ISBER).  In his interview, Jim gives a shocking example of where poor sampling is causing an issue.  He says there is such variability between various labs and their assays for doing the Her2 testing for breast cancer.  Jim says that about 20% of the Her2 testing generates a false positive and about 20% generates a false negative.  This means that too many women with breast cancer are treated with the companion therapy, Herceptin, that is not making any difference.  And too many are not treated with Herceptin when they could be.  Jim ties this back to lack of standards in handling the biospecimens.

In our second show we’ll be looking at just what is involved in procuring, handling, and storing a sample.

With the third show, we talk to the Medical Director of Quintiles, Diane Fahri, about the issues she sees in sampling for clinical trials.  Diane has made it a priority to ensure that there is “harmonization” in procuring and shipping samples.  

One country may have a holiday and their shipping lines close.  This can affect the samples, Diane says.   There’s a myriad of issues when it comes to working with samples from such diverse labs around the world.

Fortunately, a new science of sampling has been emerging.  There are new programs, particularly in Europe which are offering training, even a Ph D in handling biospecimens  Our fourth show will be devoted to understanding better this new science.

To finish up, we’ll again have Carolyn Compton to the program to talk about the work she’s doing to improve standards.  So far SOPs have varied largely from institution to institution.  Carolyn is hosting a special conference in early December with many of the key opinion leaders to come up with some basic standards which can then be adopted by the professional organizations, such as the College of American Pathologists or CAP.

Nonreproducible science has become one of the worst plagues of our industry.  Better standards in sample collection, handling, and storage will go a long ways toward improving research and clinical efforts to bring great diagnostics and therapies to patients.

Whoa! Did You See the '60 Minutes' Piece on Drug Pricing?

Theral Timpson

60 Minutes has just produced a piece that is a must watch for anyone in the industry.  And where is big pharma?  

The details of the story are familiar.  60 Minutes caught up with two doctors who in 2012 told drug makers, “enough.”  

In October of 2012, these doctors wrote an op-ed in the New York Times explaining why their hospital, Memorial Sloan Kettering, would not cover one of the new cancer drugs, Zaltrap.  Their reasoning was straightforward:

“The drug, Zaltrap, has proved to be no better than a similar medicine we already have for advanced colorectal cancer, while its price - at $11,063 on average for a month of treatment - is more that twice as high,” they wrote

Drug pricing has been a hot topic this year with much of the pressure being put on Gilead for their breakthrough HCV drug, Sovaldi. 

But yesterday's 60 Minutes piece put the focus back on Sanofi, the company that makes Zaltrap.   They tell the story that after Dr.'s Salz and Bach wrote their op-ed in the New York Times, Sanofi actually dropped the price of Zaltrap by half.  But not to the patients, the doctors explain to the reporter, Leslie Stahl.  Rather than drop the price across the board, Sanofi made a special deal for doctors who would get  the difference in kickbacks for prescribing the drug.  This works because Medicare and the other insurance companies are still billed at the original price of $11K.

OK, so that's the story of two doctors.  How about the other side that we expect from a program like 60 Minutes?  

Unfortunately, no one from Sanofi would talk to the news program about why Zaltrap was twice as expensive as Avastin for the same indication, or why Sanofi made the deal with doctors rather than pass the savings to patients.    Novartis, too, will not comment about Gleevec and why its price has tripled since 2001 from $24K to $93K.  The only one to defend pharma to 60 Minutes is John Castellani, the CEO of the industry group, PhRMA.  And he gets a bit trapped up.

“I can’t comment on specific drugs,” he dead pans.

After a popular journalism piece like this, the image of pharma in the eyes of the American people is likely to get only worse, if it could.  Which is sad.  These are life extending drugs, and they are created by some of the greatest heroes of our time.  

The piece also brings to light something that perhaps most Americans don't know:  Medicare cannot negotiate pricing, by law.  Payers have to pay whatever price the drug companies come up with.  This is in stark contrast to other countries who, able to negotiate, are paying 50 - 80% less than Americans.  

So why can't Medicare negoiate? It does seem strange that the country which champions capitalism like we do has our hands tied when it comes to negotiating drug prices.  

Where was the representative from Medicare explaining this?  

Our American insurance system is complicated for sure.  In truth, it is unsustainable, including Medicare.  Obamacare didn’t come close to fixing it.  The Brits and the Germans negotiate, and determine whether a drug is worth it at a goverment level.  But in America this negotiation is seen as unethical.  If there’s a drug that will help, then surely it should be covered, no matter the cost.  

We in the industry are all too familiar with the high cost of drug development.  But as Matt Herper over at Forbes writes, industry leaders now carry the onus of explaining why a company like Sanofi can drop the price of a drug by half when the original price was supposedly set based on the development costs.

The Zaltrap vs Avastin case is one of the more simple.  But with widespread media coverage, this simple case could set a precedent and embolden other hospitals, insurance carriers, and perhaps even lawmakers to end the system of pay whatever the drug makers ask.

Interestingly, the drug companies mentioned in the piece, Sanofi, Novartis, and Roche are all European companies benefiting from our American system of pay whatever the drug companies ask.

Will our system change?  Should there be an American government agency whose job is to negotiate pricing like Germany and the U.K. have?  Or is it part of the success of our system, that because we don’t have a government agency bargaining, it’s left to the patients and doctors to ask on their own, is this drug worth it? 

60 Minutes has delivered a powerful punch here.  We'll get some folks to the program to reply.  

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

Theral Timpson

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).

With Illumina, the dominant player in the NGS market, claiming this year that they’ve reached that target with their HiSeq X Ten system, it’s fair to stop and ask just what has been achieved.  What do you get for that $1,000?  And furthermore, where does NGS go from here?

Beginning next week, we're launching a new series, The Rise of Long Read Sequencing.

I first heard “long read” sequencing differentiated from “short read” in an interview with Mike Hunkapiller, CEO of Pacific Biosciences last year.   I had asked him the obvious question about how he expects to compete with Illumina, and he responded saying that “short read technologies” had serious draw backs.  

“Wait a minute,” I remember thinking at the time, “did Mike just dismiss Illumina’s technology out right?  And what are these long reads he’s talking about.”

There’s no doubt that Illumina is a major success story.  In the current edition of Forbes, Matthew Herper crowns Illumina with a glowing article, naming the rapid decrease in the price of sequencing after their CEO, “Flatley’s Law.”  This is no small praise for Illumina’s Jay Flatley, who has led the company from startup who used to offer oligos for $0.15/base to be the dominant player in the sequencing space, and now strongly poised as an upcoming contender in the clinical diagnostics industry.  

But this is the story you’ll hear everywhere.  

What is less known is that of the turnabout of Pacific Biosciences and the rise of long read sequencing.  PacBio had a much touted beginning, raising north of $600 million.  But they disappointed the industry by not delivering on some early hype that they could compete with Illumina on throughput by sequencing a human genome in fifteen minutes.  In fact, PacBio not only didn’t improve on Illumina’s high throughput,  their technology had the unattractive high error rate of 15%.  And to top that, their machine was more expensive.

However, for over a year now, we’ve been following an emerging trend among researchers toward the use of PacBio’s long reads to do not only de novo sequencing, but to probe areas of the human genome that have defied short read technologies.  From better characterization of RNA isoforms to raising the quality of the human reference genome, more and more papers are published touting the new possibilities of PacBio's long reads.  

There’s also now some data coming from Oxford Nanopore’s new minION that is exciting the first round of users.  This is long read data.  In addition, I recently toured  Genia Technologies’ facility in Mountain View and was shown their new sequencer now in alpha testing.    Genia’s CEO, Stefan Roever, says their new chip will read over a million long reads per run.

Once you have long reads and high throughput, is there any use for short read technology? I asked Stefan.  “Not really,” he confirmed.

To chronicle the rise of long reads, we went to PacBio and asked them if they’d introduce us to some of their users and sponsor a series on the topic. They did. 

Take the story of Gene Myers, for instance.  Gene helped develop the BLAST algorithm for sequence alignment back in the 90’s, working on the Human Genome Project at Celera.   Then he got out of sequencing to pursue “more interesting science.”  He thought that the future of sequencing was pretty straight forward and not that provocative for a scientist.  

“Everything basically went short because that’s where you could get the reduction in cost,” says Myers in our upcoming interview.  “Today everyone does it routinely but I don’t think they should be. . . . They’re using 100 bp reads, and the assemblies are crappy,” Gene says.

Gene is now back into sequencing, working at the Max Planck Institute in Germany.  And he’s very excited about long reads.  He says that for the first time ever it is theoretically possible to get to 100% accuracy with PacBio’s technology.  

Wait a minute.  What about PacBio’s terrible accuracy rate?  

It turns out that that even though the error rate of the PacBio SMRT system was quite high,  the errors were random.  So if you stacked the sequences deep enough, you could greatly improve the accuracy.

We ask Gene how is it that the industry has bought in for so long to the short read technology?

“I think it’s because they weren’t offered anything else.  It’s what you got,” says Myers.

We start off the series with Mike Snyder from Stanford who explains how PacBio’s long read technology has opened up his research into the transcriptome.  Often there are various RNA isoforms that are hard to analyze with Illumina’s short read technology, Mike says.  He’s recently published a couple papers showing that with PacBio’s long reads he is able to completely cover the full-length RNA molecules, thereby characterizing areas that previously have not been annotated.

After that we’ll be talking with the former CSO of PacBio, Eric Schadt, now at the Icahn Institute at Mt. Sinai in New York.  In his current job he’s working to bring sequencing to the clinic and says that the PacBio long reads are very important for getting a better picture of the genome.   From Eric's interview:

“In order to drive the throughput super high, we’ve been ignoring  a lot of the structural features in the genome that are as important as some of the single nucleotide hits, whether its long tandem repeats that vary, or bigger structural variations, or focal variants that are important in cancer--those things are difficult to characterize unambiguously with the current short read technology.    [Short reads] were attuned to certain problems and had certain advantages that enabled this big advance, but they are absolutely not hitting the entire problem like we need hit.”

In addition to improving our understanding of the transcriptome and structural variation of the genome, the long read technology is helping us nail down that troublesome area of the genome known as the HLA region.  This is a region that holds much promise for biomedical research because not only has it defied easy characterization, it just happens to be connected to many of the common diseases we have.  

Dan Geraghty has been sequencing the HLA region for many years.  Some of his work was used in the original Human Genome Project.  Dan says that long read sequencing is a game changer.

“Long reads is the NGS story of the year,” he told me in our pre-interview chat.

For now this long read story is pretty much owned by PacBio.  But all of these researchers say they are platform agnostic and are happy to see new technologies on the horizon that are promising long reads.  There’s Oxford Nanopore and Genia and others, including Nabsys who we’ve profiled here as well.  Illumina offers their Moleculo technology which assembles long reads from shorter reads, but not many have seen the datasets or other details about this technology.  

So what does this mean for the future of NGS?  Do long reads open up vast new territories in genomics that have yet to be discovered or are they just a nice bonus?   We’ll be pursuing these questions with other guests as well, including upcoming chats with Shawn Baker, CSO of the sequencing marketplace, Allseq, and with George Church of Harvard.

Mendelspod Does That One Thing . . .

Theral Timpson

Yesterday, our partner Chempetitive Group challenged us to take the Ice Bucket Challenge to raise awareness for ALS or Lou Gehrig's Disease. So here we are, just under 24 hours accepting the challenge.

And we nominate three more:

Stefan Rover, CEO, Genia Technologies. Jill Hagenkord, CMO, 23andMe, Greg Cruikshank, CEO, Labroots

Let's see those videos folks. You have 24 hours!

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