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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.

Earlier today Nathan Vardi at Forbes broke the news that one of biotech’s most notable investors, Steve Burrill, was ousted from his own company’s fund and has been sued for fraud by a former managing partner.   The news hit the biotech community like a major earthquake, particularly in the Bay Area where Steve has been advising and funding bitoech companies since the the founding of Cetus and Genentech. 

Reporting from documents just filed with the California State Court in San Francisco, Vardi writes that thirteen investors to Burrill Life Sciences Capital Fund III, including the Treasury of the State of North Carolina, Oregon Investment Fund, Unilever, Monsanto, and Celgene removed Steve as general partner of the fund in March.  

And why?  The investors in Fund III claim that the Glass Ratner Advisory Capital Group audited the fund and reported that nearly $20 million had been paid to “various designees and affiliates” beyond what had been earned in management fees.

Steve Burrill has built up a venerable name in biotech, having participated in getting the first biotech companies off the ground, funding some of the winners over the years, and publishing financial data and other industry news in the The Burrill Report.  

We’ve featured Steve on the program each of the last three years to review his annual State of Biotech book which covers the latest trends in everything from the R & D crisis in big pharma to the new digital health apps.

While I’ve heard various opinions about Steve--most of which go something like “Steve is all about Steve Burrill” and “Steve is a brilliant guy, but too heavy handed”--allegations of fraud and dishonesty have never been among them.  If true, these claims would stain what has been a phenomenal career.

The Forbes scoop has been tweeted right and left today, but with no more comment than:

“Wow.”

“Whoa!”

“Big.”

“Yikes.”

@ArthurKlausner wrote the most in his tweet:  Stunning News about Steve Burrill -- hope there’s an “explanation.”

Alex Lash of Xconomy put out a piece this afternoon with the same details from the Forbes article and a link to the fraud lawsuit against Steve filed by Ann Hanham, former managing partner at Burrill and Co.  

A story like this takes some time to digest.

I emailed Steve this morning for comment, but so far nothing has come back.  

And I’ve reached out to some of our local advisors, but no one wants to go on record yet.

Steve Burrill has been an advisor to Mendelspod, and agreed to an in-depth interview shortly after we got up and running.  (It doesn’t take long to run into the Burrill brand in this industry.)  He’s been very approachable and even  offered up his rolodex, saying he’d reach out to anyone we wanted to get to the program.  We’ve partnered with Burrill and Co.’s media division, attending and reporting on their always high level conferences.  Last year Burrill and Co. partnered with the Buck Institute on a conference on aging that was a first of its kind.  I’ve valued all of my chats with Steve, both formal and informal, over the past few years.  He’s offered great advise and pointed us to key trends.

At Burrill's Personalized Medicine conference last Septemeber, as I reported here, there was quite a break in tone from previous conferences.  After that we couldn’t reach some of our steady contacts in the media division.  On December 3rd, Luke Timmerman, biotech editor at Xconomy wrote a piece, Burrill VC Fund Splits into New Firm, Biomark, after Short Marriage.  Timmerman interviewed Steve and partner David Wetherell for the piece and even probed them to see if there were any “disagreements” over startegy with what was called the Burrill Capital Fund IV.  

“No,” came Wetherell’s answer.

Well, it turns out there were already problems with Fund III.  According to the Forbes piece, Burrill and Co’s managing partner, Ann Hanham “discovered that a substantial portion of the money that had been raised from Fund III limited partners had gone missing.”  Hanham’s number?  About $20 million.  

In what appears to be the most damning evidence against Steve are quotes from an email he himself wrote urging Hanham and her colleagues not to report the missing funds to the investors.

“We can earn our way out of trouble,” Steve wrote.  “What we need is revenue to solve our problems n just timely enough to meet any capital calls which might be needed . . . Each of u are part of the solution.”

I've heard it said around the industry that Steve doesn’t hire anyone who will give him trouble.  Perhaps that all changed with Ann.

So far it’s a "she said" story without the "he said."   But with some big consequences.  The investors of Fund III have heard enough to be convinced that they are done with Steve.

Steve has been using the title, CEO of Burrill Media.  As Timmerman reported back in December, Steve had let go some of the media staff and made contractors out of the rest in what he called a "rightsizing."   For example, Danny Levine has moved on to create his own company, but still produces the weekly podcast for The Burrill Report.  

I interviewed Steve just last month to go over his annual book (which came out on time), and Steve carried on pretty much as usual.  I noticed in his email signature that his address had changed from the 27th floor of the prestigious One Embarcadero Center building to a “Suite 120” in The Presidio.  A fire engine siren sounded during the interview.  With the address change, I obvserved to Steve that he must be down on the ground floor now.

“Yes.  I’m very grounded now,” he replied.

Insiders to genomics are looking around and, generally over a tasty adult beverage, bemoan the lack of forward progress on the clinical side of adoption. Why haven clinical adoption rates gone up faster? What’s making this hard? I’ve become frustrated over the last few years, raising a significant amount of money across a number of companies, all trying to speed up the scale of adoption in the non-sick population. Looking back, looking around and seeing how the current landscape of startups and new activities in clinical genetics are being run, I’ve come to the following conclusions.

1.      Why should I (the patient) care about my genetics?

It’s expensive. It’s confusing. It doesn’t give me any actionable information. We’ve seen how quickly the alpha consumers are taking up activity trackers and other actions-oriented technologies; the lack of an equal demand in clinical genetics is a clear indication.  The general population just doesn't see the point in utilizing clinical genetics and are not asking for it.

2.     The case hasn’t been made to the physicians

The vast majority of front line caregivers acknowledge the technological advances but just aren’t convinced that genetics would make a useful differentiation in healthcare. The current environment has placed an onerous burden to change the standard of care, with the exception of a new pill to replace the old one, usually at a pricing premium. Not too long ago I was talking to the #2 at a major regional medical center (an oncologist by training and practice) and the quote from him I took away was, “..clinical genetics doesn’t matter to me in my practice. There is no proven utility to the vast majority of our patients.” 

3.     The front line caregivers need to be (re)educated

Given that most front line caregivers do not have an education around molecular biology, the entire dialogue around genetic information needs to start at scratch and there isn’t a common platform to do that.  Any easy way to discover this is to ask your primary care physician if (a) they took molecular biology in college and (b) how many molecular tests they’ve ordered this year. For far too many the answers are “no” and “zero”. 

4.     The hospitals, clinics and labs which the physicians have access to don’t offer full service, cost effective solutions

Another interesting question to ask your PCP is what tests are actually available now. Is there a test that they can order right off the menu from their office/lab/hospital/clinic? Again, for the vast majority of doctors, even if they had an educated and motivated patient and an educated, motivated and willing doctor, the local infrastructure doesn't support this. The one shining light of hope is for people with chronic or specific issues, especially around cancer. 

There is a tremendous amount of effort being put into “4” and the other supporting systems, but until 1, 2, and 3 are resolved we’ll never see the broader impact we hope for.  There are a few interesting movements out there, but right now change can be measured generationally. A ray of hope comes from the current pain in the public educational system where k-12 is using resources like the Khan Academy, which has a nice introductory set of content on genetics.

In an environment where most PCP’s are between the ages of 50-55 (AMA), coupled with the increasing age of the general population, we find ourselves in a situation where most people inside the medical ecosystem do not understand genetics.  This is true both on the patient and the provider side.  The ecosystem is currently focused on financially oriented activities (ACA, playing nicely with Medicare/Medicaid and the health insurance providers) vs. actually integrating new useful technologies.  

Inside the industry, we still talk about the lack of adoption as a scientific or techincal issue, when actually this "last mile" issue is with doctors and the average person just not seeing the value. We need to do a much better job of educating the general populace as to the value of genetics in their daily lives. 

With Silicon Valley blazing on as number one hot spot for high tech and the Bay Area claiming the same for biotech, it makes sense that Stanford, sitting there mid-peninsula basking in all that brilliance, should command a leading role in bioinformatics.

Today, Stanford’s Big Data in Biomedicine Conference kicked off with a star lineup and even a whiff of glamour.  The conference room at the Li Ka Shing Center was packed with attendees looking up on a stage lit with colored lighting, backed by giant screens, and filled with elegant white leather chairs.  Cameras and lights filled the lobby, with interviews being done on the side.  The conference is being tweeted (#bigdatamed) like a presidential election!   

Along with a contingent from Oxford University, speakers included representatives from the White House, NIH, and the FDA.  Stanford  is well connected with the national funders and policy makers.   Though beginning with some of the hype from last year (the first time is always the most exciting), by the end of the first morning the conference had settled down in a somewhat grounded pace when some good questions were addressed:  whether there is enough "science" in data science.  Questions of privacy and quality were lightly touched on.  

I was disappointed to see that none of the panel topics for the entire three days--which range from integrating genome scale data to machine learning--included bioethics.  Stanford has some great speakers on bioethics, such as regular Mendelspod guest, Hank Greely.  Big data certainly holds big promise for improving healthcare, but new technology always brings up big unforseen consequences.  Addressing those thorny issues like privacy, equality, and safety head-on would have kept the conference more balanced.

Todd Park is the second CTO ever for the U.S.  And having him come directly from the White House adds some glamour, yes.  But Mr. Park’s keynote was more Easter service than scientific conference, more cathedral than campus.  Using lines like “there has never been a better time to innovate in healthcare than now” and “we are so blessed to be living in . . .”, Mr. Park “god blessed” the crowd of scientists praying that “the force be with you.”  Hm hm.  Bring on the data, please. 

And yes, the next speaker, Colin Mahony, used the term “nirvana,” alluding to that big data heaven that we all dream about.  But from there on the conference came back to earth with slides and graphs of . . . . data.  

Mike Snyder, perhaps the most biologically studied person in history, gave an update on his iPOP, or integrated personal omics profiling project.  He didn't offer much new today other than that he’s had some progress in tracking epigenetic changes--not easy--and some characterization of his microbiome.  Steve Quake and Stanford newcomer, Julia Salzman, rounded out the session leaving plenty of time for a panel discussion with Q & A.

Snyder’s ongoing project of looking at hundreds of thousands of his own biomarkers over time, often referred to as the Snyderome, provoked a great question from panel moderator and bioinformatics super star, Atul Butte.  There’s been lots of progress on the various omes, but isn’t the most challenging one the time-ome (anyone for temporome?), or the ability to continually access samples and build the data set over time, Atul asked.

This is of course the key to Snyder’s project, so he launched into more details of his “longitudinal” study. It was Steve Quake who delivered the provocative line.

“I think of time as my friend,” Steve said.

It’s when you look at the data points over time that you’re able to find an anomoly or a signal, Steve reasoned.

Panelist Colin Mahony chimed in with an excellent observation as well.  When you look at the various slides that the speakers use to present their data, Colin observed, time is usually the only constant.  Time can provide “the best primary key” to work around in building data sets, he concluded.

Julia Salzman delivered what was for me the biggest WOW moment of the morning with her talk on “circular RNA.”  

Apparently scientists have already been aware of RNA molecules that circle back on themselves, biting their own tail.  But these molecules--unlike their linear siblings-- have been dismissed as non-protein coding, and therefore not interesting.  Julia said that by being “willing to look at data that was in the trash”, her team discovered that circular RNA has implications for disease and could be used as a diagnostic tool.  She went so far as to say that with this discovery, biological textbooks are now obsolete.  That sounds like a big deal!

The issue of quality was raised.  But unfortunately the discussion followed a specific instance of sequencing, and the general question of how to clean up huge amounts of data was not addressed.    A recent guest bioinformatician at Mendelspod said her biggest challenge was not with storage or compute power, but in improving the quality of the data.

A small debate broke out between Snyder and Quake over big science vs. small science when the NIH representative speaker, Philip Bourne, asked what the NIH could do more for bioinformatics projects--other than give more money.  Quake said that we have some great data sets out there produced from big consortium projects already. Now money should go to good ideas at the individual research level.  Snyder argued that the ongoing large ENCODE project had been beneficial and proved that big data sharing projects could consist of individual researchers pooling their RO1s (smaller grants) together, sharing their data, and benefiting from more real time interaction.  A hybrid of big and small science.

A top question at Mendelspod this year has been whether with the increased data storage and data mining abilities, research has become more data driven than hypothesis driven.  And is anything lost in that?  I presented this question to the panel.

Mike Snyder asserted, with examples,  that “the biggest discoveries in science were not hypothesis driven.”  

So the question was asked, if there is plenty of data, then what is the "scarcity" for generating better questions.  

Steve Quake couldn't resist sharing a local joke:  "how do you define data scientist?  any statistician who lives in San Francisco.”   Then Quake threw out a serious challenge:

“We have a scarcity of ideas, not data.”  

The big data conference continues through Friday and is being broadcast live at https://bigdata.stanford.edu. 

For Twitter stream, search #bigdatamed.