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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.

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.

I like going to first time conferences.  Like a newborn animal struggling to stand up,  they wobble as they learn who they are.  This opens up unique opportunities.

Last week the SENS Foundation put on the first ever Rejuvenation Biotechnology conference in Santa Clara.  (“Rejuvenation” might be misleading.  This is a conference on aging, not on spa treatments.)  The SENS Foundation operates on the  “belief that a world free of age-related disease is possible,”  and the conference is a way to build a community around that belief.  

This grand vision comes in no small part from the foundation’s Chief Science Officer, Aubrey de Grey, who challenged the world back in 2007 with his book Ending Aging.  Aubrey has been working on the development of what he calls “Strategies for Engineered Negligible Senescence” or SENS (negligible senescence = insignificant aging) for some years now.

“What is aging?” Aubrey asks as the conference gets underway.   “Aging is simply the accumulation of damage as a side effect of being alive.” 

Aubrey groups molecular and cellular damage into seven areas.   And says that SENS is dedicated to finding therapies designed to repair this damage.  The goal of the new conference is to connect SENS and their network of researchers with those in industry.

Dressed in jeans and a plain shirt, Aubrey bounces on and off stage like a teenager, always at the ready with a smart quip.  His speech is rapid fire and rhythmic with a tight British accent.  I run into him at the bar after lunch.  

“You’re ideas are gaining hold,” I observe.

“Yes, I’m not as far out there as I used to be.  Not because I changed, but the community has come to me,” he says, stroking his long beard.

Aubrey has been organizing a biennial SENS conference in Cambridge, England, for some years now that has been more research focused.    Then a couple years ago,  he and others set up a 501(c)(3) here in Mountain View, California where they operate out of 6,000 square feet.  Michael Kope is the President and co-founder of the foundation.   His first question to Aubrey when they made plans for the foundation was what would be the IP strategy.  Michael confirms that the new conference is industrially focused and designed to expand the reach of the foundation into the world of business.  They're after products just like Apple or Tesla.  Aubrey says his main message is that there's plenty of research about the aging process out there waiting for application.

I tell Michael that de Grey strikes me as a philosopher only to be quickly corrected.  Michael says de Grey would much prefer ‘visionary’ in the mold of Peter Diamandis, the co-founder with Craig Venter of Human Longevity Inc.

And Diamandis showed on the final day to give a keynote.  His basic premise is that the pace of change on planet Earth is accelerating at an exponential speed.  Beginning  with a picture of a meadow under cloudy skies, Diamandis says that humans in prehistoric times didn’t have to change much.   As a species we could carry on for many generations without much new going on. Cut to the present time.  Change is happening at hyper speed.   If a company was started in the 1920’s and it was successful, it could expect to be on the S & P for over 70 years.  A company started today isn’t likely to last more than 15 years on the index, Diamandis says.  Disruptive technologies are appearing more frequently.  And there are six D’s we can watch for:

Everything is becoming DIGITIZED.   For the first few years, such as when the digital camera went from 0.01 to 1 megapixels, the progress from the digitalization is DECEPTIVE.  We are unaware until there is a dramatic change.   DISRUPTION happens. Products then become DEMATERIALIZED then DEMONETIZED then DEMOCRATIZED.

After seeing one example after the other of this process, from the digital camera--which Diamandis takes time to note was both developed and then shelved by KODAK--to robotics, to the media, it is hard to disagree with Diamandis.  The speed of change does seem to be going on a curve toward infinity.  

“This is so today,” Diamandis would say with each new technology he referenced.

So what does this all have to do with aging, or slowing it down? 

Enter the Diamandis Effect:  the rush of noticable energy and inspiration that comes over an audience witnessing his presentations.  At this conference, that audience was a motley collection  of stem cell researchers, gerontologists, Alzheimer’s researchers, policy wonks,  entrepreneurs, investors, and students.  After Diamandis’ speech, a panel convened on stage where the moderator instructed the audience to come to the mic with ideas rather than questions.  Lines behind both mics filled up immediately.  

One of the panelists gave a short but excellent presentation on how to go about the challenges of FDA regulation.  However the talk seemed to bring to a screeching halt Diamandis’ rocket-like energy.  (And, indeed, he had showed video of his space flight back in ’04.)   The juxtaposition generated creativity.  Several ideas came up for improving regulation.  One audience member, quick on his feet to the mic, said we should automate regulation.  Interesting.  How would that work?   The idea morphed a few minutes later in the mind of another audience member with the suggestion for a kind of Turbo Tax for FDA regulation.   I can see why some of the top companies are hiring the founder of the X Prize to speak.  

A conference focused on the business of ending aging could easily go off the rails and into La La Land.  But this conference stayed grounded.  Formed mainly around panels, the questions and discussions were specific and practical.  

George Church gave the opening keynote.  Using the strategy of understatement and a presentation of some of his current work, George has his own way of moving a crowd.  He stuck to two promising technologies.  The first was in-situ flouresence-based sequencing, or looking at RNA molecules in a three dimensional environment.  George claims that work done so far in this area is giving much more relevant data than the standard two dimensional sequencing.    

Will we now see a rush in the world of NGS to this three dimensional approach?

The other technology George is obviously great guns over is the new CRISPR/Cas9 DNA editing technique.  George said that he is involved in several research projects to use CRISPR as a viral therapeutic.  He showed a slide with a list of protective gene variants for a number of age related diseases, including Alzheimer’s, cancer, Type 2 diabetes, and coronary disease, among others.

“I’d like to sign up to have my genome edited to include these protective genes,” he provoked the audience.

George urged the researchers in the crowd to look at the outliers in their data, the far ends of the bell curve.  There one finds a small number of genes which have much more effect on phenotype than the genes at the center of the curve.

Stem cell therapy was a major theme at the conference.  Jeff Carp was there from Harvard Medical School offering a summary of his work.  He says that we’ll be using stem cells in four ways:

1. To fill vacancies 
2. To replace damaged cells
3. To change tissues
4. To create new niches

Stephen Minger is the Chief Scientist of Cellular Sciences at GE. 

“GE is now a cell therapy company,” he said, reiterating how far the field has come.  According to Stephen, there are currently over 4,000 listed clinical trials for regenerative medicine.  

The conference was not only grounded in real science and real discussions about gaining regulatory approval and wooing investors.  There were also ethical questions about the expanding socio-economic gap that new treatments are bringing.  As a society how are we going to increase access to elite medicine for more than just the very rich?

Caleb Finch is a researcher at USC.  He’s thought about the implications of lifespan continuing to increase, particularly in regards to mental health.  

“If we reach ninety, the majority of us will be demented,” he said.  “And so we must prioritize Alzheimer’s research.” 

After 60 years old, dementia doubles every five years compared to aging, which doubles every eight years, Finch says.  We will go crazy faster than we will age.

For his book When I’m 164, science journalist, David Ewing Duncan, surveyed over 30,000  people in many diverse audiences and found that a majority of people don’t want  to live longer. 

Absent from the talks I attended was any mention of happiness.   Except for the keynote by Diamandis.  He says that he’s launched a new prize to come up with a device to measure our happiness.   Would this device change the majority's opinion about living longer?

As with all futurist conferences, there was lots of talk of change.  Diamandis presented change as inevitable, and left out any discussion of humans as a species directing or controlling the pace of change. I asked Diamandis if he’d thought much about how we know when to change or not to change.   Surely we do have some control.  Isn’t that what regulation is about? 

Still, can we speed up our ability to decide whether a change is good or not in order to better handle the accelerating pace of change? 

“It’s a good question.  And one I don’t have the answer to,” Diamandis said.

To regulate, or not to regulate--that has been the question with LDTs, or laboratory developed tests.

Last Thursday, July 31, the FDA gave their answer when they notified Congress that in the next 60 days draft guidance on LDTs would be given.  The bell has been rung.  The other foot has dropped.  The “Anticipated Details”  can be seen here.  

Regulation has been an important topic here at Mendelspod.   Later this week, we’ve booked an interview with Liz Mansfield from the FDA to explain their recent move, and just how she expects it to play out.  In the meantime, I’ve reached out to, or followed, some of the guests we’ve had on the show who have argued both for and against the regulation of LDTs.

In her blog on Thursday, “FDA Releases the Kraken”, Mya Thomae, CEO of the regulatory consultancy, Myraqa (recently acquired by Illumina), admits she had become quite pessimistic that the guidance would ever make its way into the light.  After the FDA sent 23andMe a letter last November, Mya told me on the program that she’d become hesitant about the issue because she “lost several bets on when the FDA will regulate LDTs.”   

“I was a naysayer on this recently and FDA has shown my pessimism to be premature. And I'm very happy to be wrong this time. . . .  I’m still working through the document, but at first and second read, it appears FDA has had ample time to prepare themselves for the arguments against regulating LDTs.  Those opposed to regulation will need to step up their game.” Mya writes.  

It’s been common gossip in the industry that the FDA had the guidance written up for some time, awaiting the go ahead from the Obama administration. Just last month, five Democratic senators wrote a letter to the Office of Management and Budget urging that the guidance be released.  

The folks at Roche have long been calling for the FDA to increase regulations of LDTs and thereby create a “more level playing field” in the industry.  Roche has spent big time resources gaining FDA approval for their tests only to be challenged in the market with  LDTs that are not standardized and have not undergone a similar level of analytical and clinical validation.

Walter Koch is VP of Research at Roche Molecular Systems and has argued for more regulation here at Mendelspod.  I expected to find Walter with an open bottle of Champagne on Thursday, but instead found him cautious.  

“I expect there will be some resistance to this,” he said with characteristic understatement.  

When we talked, he was about halfway through the inch thick stack of guidance.  Walter says the path is anything but straight forward.  The action plan outlined in the guidance would take nearly a decade to fully implement.  The FDA says they’ll be moving forward based on risk, but won’t even have the definitions for the three classes of risk for 18 months after the guidance is finalized.  

Why wasn’t Walter more ebullient about the fact that labs around the country won’t be able to offer high risk tests, such as HER2 and BRAF without FDA approval?  

“We're happy to see some movement on this.  But it’s very complicated,” Walter said.  He doubts that labs which offer LDTs competing with FDA approved tests will stop offering them until forced to do so. 

Furthermore, there is still much up in the air about how the FDA should handle panels, or groups of tests, let alone a whole genome test.  

“What about the Foundation Medicine test?”  he wondered aloud.

Foundation Medicine’s Foundation One test has become popular with oncologists because rather than test one marker at a time, such as the KRAS gene, the test analyzes 200 of the most common molecular abnormalities in tumor samples and can help doctors in choosing treatment.  

In his post announcing the FDA action, Forbes writer, Matthew Herper, felt the news significant enough to warn Illumina investors to “watch closely, as its machines are now used by virtually all players who are doing this type of work.”  

Illumina declined comment.

The complexity of the task ahead for the FDA has been pointed out by those opposed to regulation of LDTs.  We recently featured a geneticist from ARUP Laboratories in Salt Lake City  and president of AMP, or the Association for Molecular Pathology, Elaine Lyon, on the program where she argued that, actually, what her lab offers is more of a service than tests and should be called LDPs, or Laboratory Developed Processes, not LDTs.

I reached out to Elaine on Thursday and she wrote back the following:

“If the proposed guidance stands, it certainly has the potential to limit the access of medically necessary procedures which is why AMP is talking with the FDA to educate them on the distinction between LDPs and in vitro diagnostics, which are tests manufactured and shipped to customer laboratories.”

As for how this action by the FDA might impact their business at ARUP, Elaine told me that the affect is unknown yet, “but it could limit the number of new or improved tests that we develop and offer.  It may also be a disincentive to improve an FDA cleared assay (i.e. perform off-label) for our patient population.”

Another group not happy about the new guidance is ACLA, or the American Clinical Laboratory Association.   Their president, Alan Mertz, has been on the program arguing that LDTs are regulated by CLIA and this is sufficient.  In a statement released within hours of the FDA’s notice, Alan wrote:

“To the extent that stakeholders have concerns about possible regulatory gaps under CLIA, ACLA has long supported enhancing the CLIA regulatory framework, rather than impose an additional layer of regulation based upon a different statute designed for manufactured products rather than laboratory testing.”

There will be much more written over the coming weeks as more attorneys and experts parse their way through the documents.  I heard one industry executive on Friday say that he was waiting for a translation of the guidance from his attorney, but was happy the FDA had “chosen not to include DTC testing.”

However, the language in the guidance on DTCs is not that clear.  In a post at the Genomics Law Report, Jennifer Wagner takes issue with DTC comment in the document after pointing out that it was buried in a footnote.  It reads:

“FDA generally does not exercise enforcement discretion for direct-to-consumer (DTC) tests regardless of whether they meet the definition of an LDT provided in this guidance. Therefore, the enforcement policies in this guidance do not apply to DTC tests, and the FDA’s usual enforcement policies apply to DTC tests."

Jennifer reminds us that “exercise enforcement discretion” is FDA jargon for choosing not to regulate something that the FDA has authority to regulate.  

“So the FDA is saying here--hold on for a jarring double negative--that it does not choose not to regulate DTC tests, and that consequently, DTC tests fall under “usual enforcement policies”?  The FDA asserting authority over DTC tests and reconsidering its enforcement discretion is one thing, but rewriting the regulatory history is quite another,” she writes.

Finally, I chatted with Cliff Reid, the CEO of Complete Genomics, which is now owned by the Chinese genomics powerhouse, BGI.  As a guest here at Mendelspod Cliff has asserted that genomic medicine could very well take off overseas before it does in the U.S.  FedEx and the internet are available everywhere around the world, he points out, and it’s very easy to order tests abroad.  

“The FDA must be careful here.  In today’s global economy, by over regulating, the FDA might end up deregulating,” he said.

It’s an ongoing story, and one we will be covering closely.  Congress went on recess beginning August 1 (was guidance released the day before the recess on purpose?) until after Labor Day.  Support and resistance to the guidance are expected to fall roughly down political lines with Democrats favoring and Republicans opposed.

 Stay tuned for our interview with Liz Mansfield later this week.  And please send in your own comments to the news via email or the comment section below.