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

Author: 
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?

Author: 
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

Author: 
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 . . .

Author: 
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!

This Is So Today: SENS Foundation Kicks Off New Conference on Aging

Author: 
Theral Timpson

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.

Aubrey de Grey at Rejuvenation Biotechnology 2014

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.

Peter Diamandis at Rejuvenation Biotechnology 2014

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 speaking at Rejuvenation Biotechnology 2014

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.

New Yorker Takedown of Leading Anti-GMO Activist

Author: 
Theral Timpson

Michael Specter has written an excellent comprehensive piece on the GMO debate over at the New Yorker this morning.

Structured loosely around following Vandana Shiva, a popular anti-GMO activist from India, on tour to Italy, Specter dedicates the first half of his article to fully hearing out the arguments against using genetically modified crops. This is a long article, but don't be deterred. It does appear at first that Specter is in awe of Shiva and her "nature against biotech" rhetoric. I almost stopped the article midway and tweeted my disappointment in the New Yorker for sounding too much like chef and organic movement activist, Alice Waters.

It's only after giving voice to Shiva and telling her story at length--she trained as a physicist before becoming one of the most popular anti-GMO activists, particularly in the West--that Specter begins to question her.  And then he takes off the "kid gloves," and line by line discredits her claims.  For example, most of Shiva's book jackets refer to her as one of the leading physicists in India.  When Spector asked her if she'd ever worked as a physicist, she told him to Google her.  He found nothing.  The more he questioned, the less answers she had.  Finally she stopped talking with him at all.

“It is absolutely remarkable to me how Vandana Shiva is able to get away with saying whatever people want to hear,” Gordon Conway, author of "One Billion Hungry: Can We Feed the World, tells Specter.  “Shiva is lionized, particularly in the West, because she presents the romantic view of the farm,” Conway continues. “Truth be damned. People in the rich world love to dabble in a past they were lucky enough to avoid—you know, a couple of chickens running around with the children in the back yard. But farming is bloody tough, as anyone who does it knows. It is like those people who romanticize villages in the developing world. Nobody who ever lived in one would do that.”

Specter interviews some other notables in the article, including Mark Lynas, the British environmentalist who recently turned an about face of 180 degrees on the question of GMOs, apologizing to the Oxford Farming Conference for "demonizing an important technological option which can be used to benefit the environment.” 

And Specter makes it to St. Louis to talk to Monsanto chairman, Hugh Grant, to ask him how he deals with the backlash.  Grant confesses to Specter that in 2002, after commissioning a study to explore the idea of changing the company's name, he decided against it.  

“It was my call, and it was a big mistake," says Grant.

It's great to see the New Yorker taking a firm, pro-science stance on this topic.

 

FDA Makes Big Move on LDTs and an Industry Reacts

Author: 
Theral Timpson

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.

 

How to Create Your Very Own Silicon Valley

Author: 
Theral Timpson

It’s a question everyone is asking.  How can we get some of that "stuff" going on in Silicon Valley over in our own neck of the woods?  The thriving innovation, the entrepreneurship, the technology, the money.  

For starters, I recommend you watch a presentation by a fellow well known around Silicon Valley, but new to me:  Steve Blank and his talk, The Secret History of Silicon Valley.

Last month I attended the yearly BIO convention in San Diego, an international confab for those in life science.  This is a conference short on science,  long on business.    This is the conference where states jockey for notice, where countries make their simple pitch:  our place is good for biotech.  Politicians are flown in to make this pitch directly. 

It’s also a convention for lawyers and tech transfer specialists.  They all want to duplicate Silicon Valley.   Every university today has an eye on Stanford and its tech transfer office.

“We’re small and we’re underfunded, we’re nothing like Stanford,” said a woman from the tech transfer office at Carnegie Mellon University.  We were standing in line to board an aircraft carrier for the opening night reception. (We Americans love to show off our might to the world.)

“But you want to be . . .”  I guessed.

“Who doesn’t?” came the immediate reply.

If America has a “shining city on a hill” these days, it’s the group of towns known collectively as Silicon Valley.  And their resident university shines brightest.  

In a New York Times article that ran just a few weeks before the BIO convention, a headline called Harvard “the Stanford of the East”-- a reversal hard to argue with.  

“Stanford’s reputation is far more than buzz . . . it’s sparkling facilities and entrepreneurial culture are widely envied.  But in particular, it basks in its image as the hub of Silicon Valley, alma mater to a string of technology moguls and incubator of giants like Google, Yahoo and Cisco," the article said.

We could add a list of biotech companies whose technology was spun out of Stanford, the crown being Genentech and the Boyer-Cohen patent that started biotechnology.  The inventor of the PCR based HIV test, Mark Holodniy, was also a Stanford professor.

How did it happen?  What made Silicon Valley what it is today?  Why is the New York Times calling Stanford America’s “it” school?

This is a question I’ve been pursuing since we began Mendelspod.  We’ve interviewed enterpreneurs whose companies are Stanford spin-offs, and I’ve asked them, what’s in the water over there?

A good part of the answer came from a meeting I had at BIO.  

Steve Blank is the creator of the Lean Launchpad, a class he developed at Stanford for entrepreneurs.  Steve started eight companies himself, four of which went public.  He’s now been contracted by the NIH to help them make better entrepreneurs.  (See our upcoming interview on the NIH I-Corp Training Program.)  Steve was hanging out at the NIH booth at BIO.  

After about two minutes into my chat with Steve, I knew that I was talking with someone intimately familiar with the story and success of Silicon Valley, and that I had to interview him.  

Had he read the recent article by Jill Lepore of the New Yorker that questioned the “innovation economy” and the “disrupt” concept championed by Harvard business professor, Clayton Christensen?  

“Yes,  And the only thing she got right was her name,” came his reply.

We set up an interview with Steve, and over the past couple weeks I've enjoyed getting to know him in preparation.   Steve’s blog is a treasure trove of ideas that are generously given.  In the blog I found a link to his “The Secret History of Silicon Valley.”

As he begins the talk, Steve jokes about those who might think Silicon Valley started when Zuckerberg came to town and built Facebook.  Or “that guy who recently died--what’s his name--oh yeah, Steve Jobs.”  

In fact the roots of Silicon Valley are in World War II.  And two men can be called the fathers of Sillicon Valley.

I already knew one of them,  William Shockley, the nobel prize winning physicist who co-invented the transister.   He’s the founder of Shockley Semiconductor Lab, the first establishment to work on silicon semiconductors in what came to be known as Silicon Valley.  Over the course of twenty years, eight of Shockley’s former employees started sixty-five new enterprises.  Two of those were Bob Noyce and Gordon Moore, founders of Intel.

This is the story we’ve all seen on PBS.

But the other father was a Stanford man.   Fred Terman was Dean of Engineering and later Provost at Stanford.  We’re introduced to him thirty minutes into Steve’s talk after a lengthy lesson on World War II, the first electronic war.  Because only east coast universities were give any real money to help the military during the war, Terman was pulled to Cambridge to oversee the Harvard Radio Lab.  This lab ran all electronic warfare during WWII.

After the war, Terman came back to Palo Alto, determined that Stanford would “never be screwed out of government dollars again.”  He succeeded.    Steve points out that we all know two of his grad students, Bill Hewlett and Dave Packard.  Terman helped them start their company, invested in it, and sat on their board.  There were many others.  As soon as was possible, Terman insisted that new technology be spun out and commercialized so the University could stay focused on new research.  Other companies he personally invested in were Litton Industries and Varian.     With his leadership, Stanford became an “outward leaning” university.  

On Friday we made it to Steve’s ranch up the California coast directly west of the valley for the interview.  We jumped right into history. 

“So if Stanford got the electronics contracts in the fifites, what happened to Berkeley?”  Steve threw out as I got comfortable on his couch.  

I got lucky with my answer.  “Well, Oppenheimer of atom bomb history was at Berkeley,” I volunteered.

“That’s right.  Berkeley got the nuclear program.  And it had to be kept secret.  Whereas Stanford could be this outward facing school with electronics.”

With an impressive command of the history, Steve leaves little doubt that Terman's leadership at Stanford led directly to the tech powerhouse that came to be known as Silicon Valley.   

So, what does this mean for those wanting to duplicate this success in their own corner of the world?   

There is a coda to this blog.  This week I also interviewed a young enterpreneur from Menlo Park, Brian Frezza, co-founder of Emerald Therapeutics.  Brian and his company have just launched the Emerald Cloud Lab, a robotic lab that life science researchers can access via the cloud. Brian and his co-founder, D. J. Kleinbaum, both came from Carnegie Mellon, a university in Pittsburgh started as Carnegie Technical Schools by the well known industrialist.  Brian had worked with the very tech transfer office at Carnegie Mellon represented by the woman I met at BIO.  So how did Brian end up in Silicon Valley?  

It turns out that Brian and D.J. came to Stanford to do their PhDs.  Then they were going to head back to Pittsburg where they were promised free lab space.     However, just before moving back,  the pair of entrepreneurs were wooed to stay in Silicon Valley by Peter Thiel with money from his Founders' Fund. 

Obviously other universities and places will have to do more than be good at tech transfer to compete with Silicon Valley today.  There’s more going on here in the land of Google, Genentech, and Gilead than the Stanford tech transfer office.   There’s now an ecosystem of available money, mentors, and workforce.   But Stanford's history with tech transfer is a good place to start.

The events we hear about in Steve’s talk can seem random accidents of history.  But the story of Fred Terman and his determination to build a tech community is one that can be studied and emulated.

Editor’s Note:  This article has been updated.  "Inventor of PCR" has been changed to "inventor of the PCR based HIV test."

A Year Later: Indie Scientist, Ethan Perlstein

Author: 
Theral Timpson

Social media sites are all the fad.  But how much are they really impacting life science?

Ask Ethan Perlstein that question, and he’ll tell you “a lot.”  

We featured Ethan last July in an interview, Life Scientist Goes Indie.  Moving to the Bay Area and living on his savings, Ethan was sharing some big ideas over social media sites, his blog, and with any reporter who would listen.  He talked of moon shots and breaking into the rare disease area with an entirely new kind of drug development, what he calls evolutionary pharmacology.    And he wouldn't be going the typical academic route.  He was done with academia and grants from the NIH.  He would try other funding routes.  He was going indie and encouraging his fellow scientists to do the same.

So we followed up with Ethan to see how that has worked for him.   Were his ideas doable, or were they just the understandable rebound of an ego that had been hurt by the system?    In short, does going indie really work?

The answer is looking pretty good.   Ethan is now operating in a new lab at QB3@953 in San Francisco.  He has raised somewhere north of one million dollars and is joined by a team of five and cadre of top tier advisors.  Indie science is taking shape.

Video clips from our interview with Ethan

Let’s back up a bit.  Ethan ran a lab as a postdoc at Princeton where he got an independent research fellowship to work on validating a new evolutionary, yeast-based approach to studying how drugs work.  Then the fellowship ran out.  He was out on the street as so many postdocs are today.  Ethan applied around the country at thirty universities where he might continue his career.  None of them accepted him.

"Just hang in there and keep trying," he was told.  "This is typical for young scientists today."

Or he could have joined industry.  

Neither appealed to Ethan.   He decided to go rogue.

And the timing was right.  No sooner did he take to Twitter and blogging, then the world spoke back to him, saying, tell us more.  He became a media favorite with a vision of breaking out of the academic system-what he calls  the “postdocalyse.”   He gave crowd funding a shot--and succeeded.    Soon the Wall Street Journal was writing about him.  

Since then he has turned his ideas into a new reality.  He calls it Indie Science, which he defines as a combination of the good parts of academia and the commercial enterprise.  

“We let the curiosity drive the research as in academia, but insist on deliverables typical of industry,” he says.

The name Ethan has chosen for his enterprise, Perlstein Lab, PBC, reflects this combination of academia and industry.  PBC stands for Public Benefit Corporation, a new class of corporation that allows companies to pursue profit as well as a strong social or environmental mission.  Standard corporations must pursue shareholder value.  But a PBC can also build value for the stakeholders--employees, suppliers, a community, or the environment.  

As we sit in the shared conference room at QB3 and catch up on the last year before we look in on the actual lab, I can’t help but wonder if the name “Perlstein Lab” will become something bigger than one scientist’s independent accumulation of bench and researchers.  Will Perlstein Lab represent a new model of biological research and drug development?

Ethan attributes his success this year in building the Indie Science brand to Twitter, his blog, and the chance to hang out with the team of a start-up.

I know first hand that Ethan is very active on Twitter, but how does that turn into funding, I ask.  He says that if there’s been a conversation happening about rare diseases, he’s usually jumping into the middle of it.  One of the tweets he wrote impressed the CEO of  a drug development company in the rare disease space.  The CEO was also an independent investor.  Now he's Perlstein Lab's top investor.  Other investors came much the same way.  

Ethan says the early partners of the business, such as patient advocacy organizations and advisors have come through his media coverage, most importantly the Wall Street Journal article.

I ask Ethan to tell me more about the Indie Science brand.  What is it?  And is it duplicatable by others?

Team at Perlstein Lab, PBC

Perlstein says that his weekly lab meeting is a lot like those that happen in the university.   He refers to his team as "academic castaways."   The scientists at Perlstein Lab, PBC will be more free, he says, to pursue their own curiosity than those in a typical drug development company.   In addition to the lab meeting, the team gets together each Friday for happy hour where they are all peers. (For more details on indie science culture, see video clips of our interview with Ethan above. And for more on the team members, they're featured nicely at the Perlstein Lab blog.)  

Ethan’s lab is housed at QB3 which is no small part of his success.  This is an incubator space sponsored by Janssen Labs that has been reported on widely and houses some promising startups.  Significantly, Perlstein and his team have saved over a quarter million dollars in capital equipment that is shared among the various labs at the incubator.

Perlstein is doing what he calls evolutionary pharmacology, using simple model organisms such as yeast for research.  These organisms grow faster and therefore potentially offer a quicker timeline. Part of a wave of recent  research into the rare disease space, this new approach has yet to prove itself.  

Still, to get this far, one must acknowledge some success in breaking out from the traditional funding system.  With big pharma being more open to non-traditional partnerships, one can easily see Ethan finding an exit for his assets.  

Doug Crawford oversees the QB3 facility where Perlstein Lab, PBC is located. He recognizes Ethan's trailblazing.

"Ethan has proven that there is a larger and more diverse community of investors interested in early stage life science than we have been accessing," Doug told me. "I think he is out in front of what could become an important trend."

We stroll over to the lab itself. Our chat is immediately cut off by one of the scientists asking Ethan a question.  The team--who would otherwise be looking for academic research positions--has yet to do any real research.  They are busy setting up equipment and validating protocols.   As Ethan poses for some pictures with the team, he continues to fill me in on some of the supplier partnerships, such as that with the virtual lab manager, HappiLabs. Before we leave, he begins to talk of an Institute for Rogue Scientists.   

I can see myself coming back in another year to chat with some of the rogue scientists at Perlstein Lab, PBC.  What work will they have accomplished?  Will the investors be happy?  Will Perlstein Lab, PBC be that different from any another biotech?

Ethan goes by the traditional title of CEO and says he's not able to work at the bench anytime soon himself.  Like any CEO, he has to raise more money.

What then is a rogue scientist?  I ask.

“One who operates in a more creative space,” he replies.  “We don’t have to live or die by what the gatekeepers say.”

Raising the Standards of Biomarker Development - A New Series

Author: 
Theral Timpson

We talk a lot on this show about the potential of personalized medicine. Never before have we learned at such breakneck speed just how our bodies function. The pace of biological research staggers the mind and hints at a time when we will “crack the code” of the system that is homo sapiens, going from picking the low hanging fruit to a more rational approach. The high tech world has put at the fingertips of biologists just the tools to do it. There is plenty of compute, plenty of storage available to untangle, or decipher the human body. Yet still, we talk of potential.

Chat with anyone heavily involved in the life science industry--be it diagnostics or pharma-- and you’ll quickly hear that we must have better biomarkers.

Next week we launch a series, Raising the Standards of Biomarker Development, where we will pursue the “hotspots” that are haunting those in the field.

The National Biomarker Development Alliance (NBDA) is a non profit organization based at Arizona State University and led by the formidable Anna Barker, former deputy director of the NCI. The aim of the NBDA is to identify problem areas in biomarker development--from the biospecimen and sampling issues to experiment design to bioinformatics challenges--and raise the standards in each area. This series of interviews is based on their approach. We will purse each of these topics with a special guest.

The place to start is with samples. The majority of researchers who are working on biomarker assays don’t give much thought to the “story” of their samples. Yet the quality of their research will never exceed the quality of the samples with which they start--a very scary thought according to Carolyn Compton, a former pathologist, now professor of pathology at ASU and Johns Hopkins. Carolyn worked originally as a clinical pathologist and knows first hand the the issues around sample degradation. She left the clinic when she was recruited to the NCI with the mission of bringing more awareness to the issue of bio specimens. She joins us as our first guest in the series.

That Carolyn has straddled the world of the clinic and the world of research is key to her message. And it's key to this series. As we see an increased push to "translate" research into clinical applications, we find that these two worlds do not work enough together.

Researchers spend a lot of time analyzing data and developing causal relationships from certain biological molecules to a disease. But how often do these researchers consider how the history of a sample might be altering their data?

"Garbage in, garbage out," says Carolyn, who links low quality samples with the abysmal non-reproducable rate of most published research.

Two of our guests in the series have worked on the adaptive iSpy breast cancer trials. These are innovative clinical trials that have been designed to "adapt" to the specific biology of those in the trial. Using the latest advances in genetics, the iSPY trials aim to match experimental drugs with the molecular makeup of tumors most likely to respond to them. And the trials are testing multiple drugs at once.

Don Berry is known for bringing statistics to clinical trials. He designed the iSpy trials and joins us to explain how these new trials work and of the promise of the adaptive design.

Laura Esserman is the director of the breast cancer center at UCSC and has been heavily involved in the implementation of the iSpy trials. Esserman is concerned that "if we keep doing conventional clinical trials, people are going to give up on doing them." An MBA as well as an MD, Esserman brings what she learned about innovation in the high-tech industry to treatment for breast cancer.

From there we turn to the topic of “systems biology” where we will chat with George Poste, a tour de force when it comes to considering all of the various aspects of biology. Anyone who has ever been present for one of George’s presentations has no doubt come away scratching your head wondering if we’ll ever really glimpse the whole system that is a human being. If there is one brain that has seen all the rooms and hallways of our complex system, it’s George Poste.

We’ll finish the series by interviewing David Haussler from UCSC of Genome Browser fame. Recently Haussler has worked extensively on an NCI project, The Cancer Genome Atlas, to bring together data sets and connect cancer researchers around the world. What is the promise and pitfalls David sees with the latest bioinformatics tools?

George Poste says that in the literature we have identified 150,000 biomarkers that have causal linkage to disease. Yet only 100 of these have been commercialized and are used in the clinic. Why is the number so low? We hope to come up with some answers in this series.



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