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Burrill and the Buck Team Up on Aging with Inaugural Conference

Author: 
Theral Timpson

The study of biology has and continues to turn many long held beliefs on their head.  

From the time of Hippocrates up to the advent of modern medicine, it was thought the body contained four “humors:” black bile, yellow bile, phlegm, and blood.  And that each of these bodily fluids directly influenced our temperament and health.

There’s the more recent narrow example of ulcers.  Until the 1980’s it was widely believed that peptic ulcers formed as a result of stress and poor lifestyle habits.  Now there is clear evidence that 90% of ulcers are associated with the h pylori bacteria.

However, no scientific challenge to our beliefs about biology, including perhaps Darwin’s Theory of Evolution, is comparable to the one we hear about today, that we can turn back the hands of time and reverse aging.

Yes, average life expectancy has doubled in the last hundred years, mostly because scientists answered the dangers of infectious disease with antibiotics and vaccines.  But the  bold hypothesis that we can end aging altogether has been gaining ground in the life science industry.  

What if getting older does not have to equal aging?  If we go after the aging process itself, will we end all disease?

These questions provided the heart and hope of the inaugural Burrill and Buck Aging Conference held earlier this week in Novato, California, a co-production of Burrill and Company and the Buck Institute for Research on Aging.  

The Buck Institute for Research on Aging

The Science

“Why do we think of aging as normal?” asked Brian Kennedy,  CEO of the Buck Institute.  This was a conference devoted to increasing our paradigms on the topic, so no one spoke up with the answer running through all of our minds, “uh . . . is it because everyone around us ages?”

Brian exhibited some dramatic graphs in his slides, such as the one where you see average life expectancy over the last 20,000 years.   It has that long horizontal line running along the bottom all the way to the end: 10,000 BC, 5,000 BC, 100 AD, 1200 AD,  to1900 AD where it begins to shoot straight up. 

Brian’s other slides sport terms like “healthspan vs lifespan,” and “compressed morbidity.”  And he dived into the latest research at the Buck done on mice with rapamycin which showed some pretty awesome results.  This research focuses on "mTORC" pathways which are directly related to driving up the aging process.   

The work of Cynthia Kenyon was understandably cited throughout the conference.  In 1993, her discovery that a gene mutation (Daf-2) could double the lifespan of C. elegans ignited intensive study into the biology of aging.  

Brian acknowledged that going from nematode worms to mice was a big jump, and an even bigger leap of applying the research to humans in clinical trials.  Still he sounded terribly convincing.  His theory goes like this.  Evolution has never been focused on extending our life span.   There have been so many environmental factors which have led to aging and death.  Before now we didn’t really die of aging.  

“Evolution didn’t deal with aging because it didn’t have to.  It’s actually pretty easy,” he said casually, his slide pointer nearly outpacing his reasoning.

Will humans now be able to give evolution a hand with aging as we have with GM crops, insulin, and cloning?  

The Paradigm Shift

Aubrey de Grey says “absolutely.”   

He’s the CSO at the SENS Research Foundation, an organization that funds aging research around the globe, and the poster boy for “radical life extension.”   He’s also the co-author of Ending Aging: The Rejuvenation Breakthroughs that Could Reverse Human Aging in Our Lifetime.  De Grey has become a lightning rod in the industry for his bullish thoughts about defeating aging in the next few decades.  

At a “working lunch” session, I joined the table chaired by Aubrey to hear the radical ideas which have made him such a media darling.   In fact, de Grey sounded very straightforward, and downplayed his radical side.  He addressed an incentive problem with science funding.  Researchers aren’t willing to tackle big problems such as aging, because of the mantra that they must publish often in order to secure continued funding. Aubrey cited a researcher that SENS has been funding who was able to work on one project without publishing for three years.  

Aubrey acknowledged that his main job has been to bring about a paradigm shift in the thinking toward aging, and I asked him how he’d characterize that paradigm.  Is it a scientific paradigm, a philosophical one?

“In fact, it’s been easy to get scientists on board,” said de Grey, habitually twisting the ends of his ever reaching mustache and stroking his long beard.  (Indeed, from his appearance, Aubrey looks as though he’s defied aging himself, coming from the time of Darwin.)  He suggested that he encounters more emotional resistance than scientific, or philosophical.  

A conference goer at the table spoke up about the economic problems that we are already seeing and would become much worse when we are all staying around longer.   

“How will young folks find a job when the older ones aren’t giving their own up?” came the question.  

“Thank you for the question,” replied Aubrey, continuing with his more characteristic acerbic style,  “but is that your real question, because I can answer that in about ten seconds.”  

Most people respond to the idea of radical life extension with all kinds of questions about this or that issue, says de Grey, but mostly it is just to resist opening their minds.  They’re masking a deep emotional response.

Both Brian and Aubrey insist that there should be a re-prioritization in the industry toward funding research on aging itself.  According to Brian, less than 1% of the NIH budget goes to research on aging.  Aubrey says we currently employ a “divide and conquer” strategy with disease, but that our resources would be better spent on the biological causes of aging because aging leads to the many diseases.

Later this week I attended a Big Data conference at Stanford and asked several researchers whether we should reallocate resources toward aging research.   I couldn’t get any opinions on NIH funds, but the consensus was that we should try many different approaches.  

Mike Snyder, the Director of the Stanford Center for Genomics and Personalized Medicine, and a recent guest at Mendelspod, pointed out that most medical breakthroughs such as that of penicillin came about by chance, even accident.

"There's great value in these more open ended projects," he said.

The Healthcare Burden

In his opening address to the meeting, Steve Burrill covered the broader context around aging and what it means for healthcare around the world.  With his carpet bombing of facts and figures, Steve’s talks always build up a terrible impending disaster and end with hope.  He’s an investor and wants to spur entrepreneurs to innovate.  

Most of the numbers had to do with the growth of the aged population and the enormous burden this is putting on healthcare.  

  • In the year 2000, there were 605 million people over the age of 60.  In 2050, there will be 2 billion. 
  • The majority of healthcare spending on a person happens in the last year of life.  
  • In four years the cost of healthcare in the US will almost double.

To help him build his case and pursue ideas for new models, Steve invited Dr. David Lawrence, former CEO at Kaiser Permanente on stage for a discussion.  

“Ten years ago, nobody wanted to be Kaiser.  Now everyone does,” asserted Steve in his introduction of David.  Kaiser has built a successful healthcare business by being both payer and provider, caring for people from the “cradle to the grave.”  

“Our current healthcare model is not working,” the former Kaiser CEO asserted immediately.  “It was created in the nineteenth century for a different world, a world of infectious disease.  And there is too much waste, the most common of which is when patients ping pong through the system.    Fifty cents on every dollar is spent on waste.”  

Steve then pushed the discussion into new ways to take advantage of technologies such as mobile phones and social media that are connecting people like never before.  When asked whether the new “retailization” of healthcare (quick care centers set up at big retail stores such as Walgreens and CVS) would threaten established models such as Kaiser’s, David replied that he didn’t think so.  

“Innovation will not happen at Kaiser.  It’s just too big.  Too many people and levels involved to make any changes,” he said, adding, “and I hope the new retail centers have a chance to innovate before they are eaten up by the big providers.”  

It was mentioned that governments are becoming more active in determining the value of healthcare products, such as pharmaceuticals.  But just how the new models in healthcare were going to solve the problem of the growing aged population was not that clear.  One thing that everyone agreed upon:  let’s raise the age of retirement.

It’s a bold move to produce a conference on the topic of aging.    While many of the other pioneers of the biotech industry have “cashed in” and get together for “look back” sessions, Steve Burrill is keeping his eye on the future.  Steve is sometimes criticized in the industry for being heavy handed.  But this a joint effort on a glaring topic, the first industry conference on aging research that I’ve seen. 

“This is mankind’s greatest moment,” said Steve with a fire in his eyes.  And I think he believes it.

I asked Steve and David to talk about whether healthcare would become increasingly stratified between rich and poor as we solve the science of aging.  And what they thought of the mantra that healthcare is a right.

Steve confirmed right away that healthcare would indeed be stratified, but not in ways we’d expect.  There will be some “playing God” who will be able to dole out healthcare.  But who that will be is not yet known.  “And let’s not be naive and think if we get the science right, it’ll just happen,” he cautioned.

David chose to tell his own cautionary story about how we value our health and what science may or may not solve, what money may or may not buy.  It was a tale he’d heard from a friend recently about an old fellow who owned an olive farm in Greece.  The old guy would sit each day in front of his olive trees in the sun and smoke his cigarettes.  One day a younger man came up and asked the older man why he doesn’t sell his orchard to developers and make a fortune.  The old man replied, because I’m happy sitting here on this rock smoking in front of my olive farm. 

Sure, let's search for the answer to a longer life, the former Kaiser CEO seemed to suggest, and not forget that happiness still trumps all.

 

Francis Collins Talks about the Sequester on Hardball

Author: 
Theral Timpson

NIH Director, Francis Collins discusses the damaging impact of The Big Bad Sequester on biological research.

"Here we are at the moment when science is moving the fastest it ever has, and the support for that science, because of The Sequester, is under greater threat than it ever has been," Dr. Collins tells Chris Matthews.

Visit NBCNews.com for breaking news, world news, and news about the economy

HT: Genome Web

A Setback for Open Science?

Author: 
Theral Timpson

"Open Science" took a real walloping this week. First, Gina Kolata from the New York Times published an article exposing the increasingly predatory nature of open access journals. Then, Evegeny Mosorov, author of The Net Delusion: The Dark Side of Internet Freedom, published an essay over at The Baffler that quite deconstructs the "open source" movement along with the guy who created it, conference producer Tim O Reilly. And Tuesday, we heard that Mendeley, a portal that opens up access to scientific research is to be bought out by the publishing giant, Reed Elsevier for about $70 million, a move that one commenter compared to "Haliburton buying Green Peace."

I was introduced to the open science movement by Joseph Jackson, organizer of the Open Science Summit. My first question was how would business models even function in an environment of giving things away for free. I’ve always been leary of such offers. Everything comes at a price. “It’s free as in freedom, not free beer,” Joseph was quick to tell me at a the conference pre-reception held at his DIY bio lab in Sunnyvale where he handed out . . . . free beer.

Who can argue with “open?” It’s such a great term, as Mosorov argues in his essay. It's a big tent that can house a large crowd. Going to Jackson’s conferences, I’ve got to know that crowd a bit. The open access movement seems to be at the core of open science, and is certainly not without its appeal. What scientist doesn’t want free access to all the research that exists in a field? In our first video interview, we had Jonathan Eisen to the program just after he won the Benjamin Franklin award for open science. He’s the managing editor of one of the PLoS journals and brother to the co-foudner of the pioneering open access publication, Michael Eisen. When we interviewed Jonathan, he’d just uploaded all his dad’s research papers to Mendeley. Why? So anyone could read them. And for free. To the Eisen brothers, "paywall" is an evil term.

The Mendeley site had just gone live when we began Mendelspod. With a name so close to our own, they must be up to something good, and I signed up for their webinar. Naturally, my question during the training was how do you deal with copyright issues. The answer came back by the host of the event, William Gunn, Head of Academic Outreach for Mendeley. He said that scientists are allowed to post their own papers online without violating any publication agreements. Mendeley had some 90 million papers up. If enough scientists shared their papers, one could find what one was looking for, and best of all, for free. And there were no copyright issues.

Surely, I thought, the major publishing houses won’t sit by and let this happen. I watched for lawsuits. None to my knowledge. This week Elseveir made their move. You know what they say: if you can’t knock ‘em, join ‘em. Or make them join you with a sweet enough prize. Will Elseveir drastically change the model for Mendeley, we are all wondering. They certainly have the power to do so now.

What about the scientists out there who have been using Mendeley to get better access to the research they seek? Mendeley was thought to present a whole new world of possibilities for academic publishing, and excitingly, for exploring alternate ways of measuring a publication's importance--what has become known as altmetrics. Another line Jackson uses: "knowledge wants to be free." It’s a nice thought that reflects the utopianism of the open science movement’s strongest adherents. Personifying knowledge makes it more sympathetic. Makes it somehow part of a moral world. Knowledge should be free as humans are free. There’s a democratic, equality aspect to the movement. It is tempting for scientists--scientia is Latin for knowledge- to believe that the internet can make the world a better place where knowledge is free and convenient. Just search the Twitter hashtag #mendelete and you’ll find tweets by many scientists who have committed to delete their Mendeley accounts and boycott Elsevier.

The open access movement has recently been gaining steam. “This whole thing just is hard to believe given the boycott of Elsevier only a year ago and the White House finally extending open access across all federal agencies,” wrote Jackson in an email last night. He’s speaking of a boycott by over 7,500 researchers of the publishing giant over a year ago. The move by the White House that Jackson mentions and a move later in the year by the UK government to commit 10 million pounds to help universities make their research openly available reveals the scale that open access has achieved.

So is the Mendeley buyout a setback for the movement? William Gunn of Mendeley has been one of the most morally outraged and vocal of the open science folks in the Bay Area. Yet for the past couple days he’s been backpedaling tirelessly, tweeting nonstop to comfort their users. In his blog he coaxes:

“I do think there’s a possibility that we could do some good as part of Elsevier. Having talked with tons of people, from the CEO of Elsevier on down, I am now convinced that they want to be a part of the changes, instead of trying to fight them off like the recording companies did.”

Does his heart bleed beneath the surface? In what really is an apologia, Gunn writes that he’s “not personally getting a pile of money from all this,” and that he’ll be staying on.

Jackson says it was “pretty obvious that Mendeley was going to do whatever it takes to satisfy the investors who backed them and are pressuring for an exit. Since an IPO isn't a realistic option for this kind of start up...acquisition is the only endpoint.”

To understand what’s really at stake here, I recommend Mosorov’s take down of Tim O’Reilly and the "open" meme in an article, The Meme Hustler. This is about as good a deconstruction of the "open" movements (open source in this case) that I’ve read. Mosorov’s approach is to look at the history of language in parallel with the rise of Tim O’Reilly, the philosopher turned entrepreneur, CEO of O’Reilly Media, publisher of books and producer of the popular tech conferences. The other epithet Mosorov uses for the subject of his biting prose is “master of meme-engineering.” O'Reilly's first great meme was that of “open source." Begun originally as a free software movement by Richard Stallman, the movement was hijacked by O’Reilly under the more ambiguous and therefore valuable term, “open source.”

“ . . .“Open” allowed O’Reilly to build the largest possible tent for the movement. The language of economics was less alienating than Stallman’s language of ethics; “openness” was the kind of multipurpose term that allowed one to look political while advancing an agenda that had very little to do with politics. As O’Reilly put it in 2010, “the art of promoting openness is not to make it a moral crusade, but rather to highlight the competitive advantages of openness.” Replace “openness” with any other loaded term—say “human rights”—in this sentence, and it becomes clear that this quest for “openness” was politically toothless from the very outset. What, after all, if your interlocutor doesn’t give a damn about competitive advantages?”

As the director of the movement, O’Reilly stood in the best place to gain from his meme. And by producing books and conferences that are rewriting the history of the internet, he maintains this position. In one example, Mosorov points out that a Wikipedia article on "open source" might be seen as objective. Yet O'Reilly admitted to being the editor of the article. Isn't this something along the lines of “history is written by the victors?” Mosorov finds a promiscuousness at work here where O’Reilly used parts of Stallman's free software movement, which originally cared more about the users having access, to create something that was better for developers, users be damned.

It’s a dark view to think that the founders of Mendeley and other similar companies use “open” in this "promiscuous" way. That they attracted scientists with their open platforms, only to turn around and cash in and leave the users hanging. In this case, "open," is another marketing tool. Mosorov calls O’Reilly a PR and marketing genius. One who--far from naive--began in philosophy and the study of semantics. One who seizes on a meme of value and rebrands it for marketing purposes.

How will Elseveir relate to the “open” meme? So far Mendeley has used a "freemium" model. Is there a way to have your cake and eat it to? To open up and keep the platform as users expect it and still protect copyright profits for Elsevier's shareholders? Jackson again: “Elsevier ... has an atrocious reputation and is more like Microsoft buying up an open competitor to subvert it, which they often did under the doctrine of Embrace, Extend, Extinguish...to use a phrase that came to light from internal documents disclosed during the anti trust case the government successful prosecuted them for back in the "browser wars."”

Another blogger wondered whether the data that comes with a site such as Mendeley will be providing the value for the large corporate overtaker, enough value to enable them to keep the platform as it is. As more and more of our lives are moved online, the value is captured at the back end rather than the front. "The idea of my reading behaviors adding economic value to a company making huge profits by locking scholarship behind increasingly expensive paywalls is, in a word, repugnant", the blogger writes.

I’ve always thought the answer to open science was in the marriage of creative new legal agreements to the opportunities the internet provides for sharing. One of my favorite companies is <a href'"https://www.collaborativedrug.com" target="_blank">Collaborative Drug Discovery which provides a platform for drug developers to share their data in new ways. Through various permissions, users are able to share with each other in a more open, yet precise manner. There is convenience and ease, and most importantly, the company assures, security. In our interview with company CEO, Barry Bunin, he says CDD widens the spectrum between open and closed to the “infinite” possibilities in between.

What will the future of open science look like? Jackson is the one who sent me the Mosorov article. So I turned it back on him asking whether he has seen O’Reilly as a model for his work. He admitted that in some ways he had, but that not everything translated over to the world of life science as it did in tech. He didn’t say whether he considered the Mendeley buyout a setback for the movement and if he thought the buyout path will be the one taken by others. He did write his response to the New York Times article by Gina Kolata exposing the increasing number of predatory open access journals.

"I don't see it as much of an issue. Imitation is the sincerest form of flattery the expression goes. With success, knock offs always spring up by the dozens. This is a part of the economy...nothing unique to Open Access. Think of all the hype around Edu-Tech and the future of education start ups right now. We had a brief wave of this already in the 1990s, leading to such enterprises as the University of Phoenix, which is a bit of a scam. Well, as a "proud" Harvard grad, I can tell you Harvard is also a scam in some ways. It isn't the end of the world (to have crappy online degrees) and it doesn't threaten the online education or Open Access providers who are creating real new value. There are always a lot of low quality imitators in any sector you look at."

I'll wrap up with some tweets: @neuromusic wrote: “Dear #mendelete-ers, did you forget that the "if not paying for it, you're the product" mantra applies to COMPANIES like Mendeley, too?” A tweet the other night from John Wilbanks @wilbanks, a popular speaker at open science events who headed up the open access petition to the White House, read: “I do use twitter, FB, the goog, etc. but I fully expect them to screw me if it's in their interest. That's the deal. Eyes open, people.” Another Wilbanks tweet: “Companies don't exist for social benefit. If their managers don't maximize shareholder value they get replaced.” Wilbank’s tweets sound bitter for one who has taken it on himself to get all government agencies publishing the research they fund in open access. He didn’t sound so cold when he was tweeting about the petition. Wilbanks also began in philosophy. Does his heart not bleed a little too?

I remember when Huff Post sold to AOL, the backlash and lawsuits that came from many of the bloggers. They had given their articles free and wanted some kind of remuneration if the site was going to go the direction of large corporate profits. We see in the "open" movements the conflicting currents of "free enterprise" on the one hand and "freedom for all" on the other. That Tim O'Reilly has used the promise of the latter to build up the former is Mosorov's argument. Last year, we produced a series of programs where open science is seen as the solution to problems facing the life science industry, from various big pharma companies sharing data to the speeding up of research through greater access. In one interview, Mendeley's own Mr. Gunn shares his vision for the future of publishing to be one where "there are as many journals as there are researchers." In the interview he sounds hopeful and excited to be disrupting the old print technology. I looked forward to another interview with Gunn on the new field of altmetrics. Will the Mendeley team remain innovative?

It does seem right to say congratulations to Gunn and the founders of Mendeley. They seized opportunity. They built the business from nothing up to a nice payout. But, did they sell out?

Is Big Science Worth It? Debating the Brain Activity Mappping Project

Author: 
Theral Timpson

The bad boy columnist for the life sciences is at it again. Bill Frezza is an unabashed libertarian venture capitalist based in Boston who pens a regular column over at Bio-IT World called the Skeptical Outsider. Though he’s invested in our industry, he’s undeterred from disparaging things the industry holds sacred, such as the War on Cancer or the Human Genome Project. He is emboldened by two major influences. First, he had some success in the IT industry and sees important lessons there for the life sciences. Second, his son is the CEO at a new life science startup who feeds him the latest from the front lines.

Most of Bill’s gripe has to do with government spending, and last week he took on Obama and the Brain Mapping Project in his article: From Junk DNA to Junk Economics: Beware the Inexorable Sovietization of Big Science. Bill’s a regular guest at Mendelspod. I’m happy to have my basic assumptions challenged regularly by others. It's my job to question. And I give Bio-IT World and their editor-in-chief, Kevin Davies, two thumbs up for encouraging and publishing Bill’s skeptic voice. It’s no surprise to hear a libertarian harping on government spending, but it’s rare from someone inside an industry which has clearly benefited from government largess. Or has it?

When politicians like Sarah Palin question the value of studying the fruit fly “of all things,” we can chalk it up to her ignorance. She isn’t aware of how the study of genetics has unfolded. But when a venture capitalist from our industry questions the NIH, the Human Genome Project, and the War on Cancer, I take a second glance. Recently, when two researchers who are funded by NIH came on the program and denounced big science projects in general, I had Bill’s arguments echoing in my mind.

“The burden of proof for proposed mega-projects should be high, because for every research team working on a billion-dollar, centrally planned National Institutes of Health program, there are hundreds of independent scientists who will go begging. This is a tragedy, as the bulk of our scientific progress—especially in the life sciences—comes not from sclerotic bureaucracies following 10-year plans, but from the genius of independent scientists challenging the status quo,” Frezza writes.

With the ENCODE project, Bill has some room in his argument. The project has come under deep criticism for their claims--even more exaggerated in the mainstream press--about the amount of the genome that is “functional.” There have been some pissed off researchers who feel the money could have been better spent on smaller projects. Bill does not acknowledge, though, that there are a great many researchers who value the data generated by the project. Even Michael Eisen, co-founder of PLoS who warned of the sovietization of science in his interview here at Mendelspod, acknowledged the importance of the data generated. Bill doesn’t acknowledge either the response from Ross Hardison, an ENCODE collaborator. In our interview, Hardison said he is an independent researcher living off IRB’s just as Eisen and Graur, the author of the most biting critique. According to Hardison, it doesn’t matter whether you call it Big or Small Science. Either way it funds his basic research.

To fortify his attack on Big Science, Frezza goes after the big meat and questions Obama’s SOTU assertion that the HGP generated $141 for every $1 spent. Digging up the Battelle Institute’s report, Economic Impact of the Human Genome Project,” Frezza takes aim with claims such as those that the HGP created 310,000 jobs and led to the commercialization of important drugs.

“... [T]he private money invested in genomics-related projects might have been spent anyway, or directed to something else equally or more productive, had HGP not come along. Crediting all of this “economic activity” to a single act of wise government science “investing” is worthy of Cypriot bankers, not serious scientists.”

I’ll go with Bill and question the objectivity of the Battelle report which was funded after all by Life Technologies. I even read the economics essay by the nineteenth century French economist (have you ever heard of Frederic Bastiat?) that Bill recommends in his article. But this game of let’s question the worth of the HGP is a high wire act. Bill is unable to offer any competing studies or claims to the contrary. Questions are easier to come by here than facts.

(This, by the way, is also the weakness of the antiquated sounding French essay. Saying that any tax dollar (or franc) spent by a government is a dollar not spent by the tax payer is banal. It’s not difficult to understand that the government, with a bigger war chest, can tackle larger projects than private industry. Nor are all projects equal. The simple hypothetical case repeated in Bastiat’s essay of taxpayers spending a franc on shoes rather than taxes does little to address the question of whether private investment can have the same long term vision that national projects can. It’s an oversimplification that the essay never surpasses. I have other problems with the essay, but I’ll save them for another day.)

I admit that I was a bit chagrined when Obama touted the $141 to $1 figure. But not for the reason Frezza cites. I ask Frezza: does he believe the HGP was unprofitable? Let’s say the Battelle report was outlandish and the number is half that good. Or one third. Francis Collins uses a more conservative claim that every $1 spent at the NIH generates $2.21 in economic output within one year.

I understand why Obama mentioned these numbers. He’s appealing to Republicans and economic conservatives. Through money. And similar arguments have been made about other projects, such as the clear link between NASA’s early space missions and the development of the integrated circuit and indirectly to the personal computer revolution. But is it not viable to ask about the non-monetary value of large projects such as landing a man on the moon or sequencing the human genome? When Obama goes down the economic return road, is he shorting the project? When Mary Lasker, the health philanthropist teamed up with an oncologist, Dr. Farber, back in the 60’s and 70’s and lobbied to get the National Cancer Act passed, it wasn’t through monetary arguments alone. When Nixon signed the Act, he did so with some caution, “[w]e would not want to raise false hopes by simply the signing of an Act.” There was an obvious understanding that we don’t know for sure where such an investment will lead, but it’s worth the try.

I wasn’t around when Neil Armstrong took his small step and giant leap. I can imagine, though, the faces of the kids who watched it on television. How can you measure the worth of that in dollars? When the Human Genome Project was completed, Science Magazine printed the entire genome in an insert. I took it out and hung it on my wall. My genome looked something like that. I like the title of the recent book about sequencing by Misha Angrist, Here Is a Human Being. Here. Right here on my wall is a real picture of what it is to be human. Do we yet know where such a map will lead? Do we know how to evaluate the profound existential confirmation such a physical readout lends to humanity’s current generation? Not to mention the promise of finding difficult answers to disease, overpopulation, and a damaged planet? Some things are more important than buying shoes.

Frezza tends to be provocative just for the sake of provoking. This undermines his more valid points. For example, he asks whether because we put money into cleaning up after Hurricane Sandy “destruction wrought by Sandy can’t count as a return on our investment in global warming?!” He also takes aim at Harvard biologist George Church, doubting the successful researcher’s credentials for being involved in the BAM poject. Frezza has valid questions that are not advanced by furthering the recent misrepresentation of Church’s interview with Der Spiegel that he is “advocating the cloning of Neanderthals.” Church has made clear his point that cloning Neanderthals will be scientifically possible soon, and that he has no grant in at the NIH to fund such a project.

Modern PI’s such as Church of Harvard, Ron Davis of Stanford, and former UDub professor, now founder of ISB, Lee Hood, are examples of how government funding has propelled the profitable commercialization of research and the advancement of an industry. There are few life science companies not directly affected by their work. (Xconomy biotech editor, Luke Timmerman, stopped by Church’s office last week and and offers another view about why Church is involved in the BAM project.) I unabashedly admit I drink Dr. Collin’s KoolAid when he says this is the century of biology. Of all government dollars to bet against, and the NIH fraction is minute, do we really want to be shorting these precious coins?

Three Bioinformaticians Raise Tough Questions about Genomic Medicine

Author: 
Theral Timpson

Today we launch our series on bioinformatics, and I thought I’d jot down a few thoughts that have come from the interviews.  Three bioinformaticians have influenced my thinking and the interviews this year.

Christophe Lambert, Golden Helix

Christophe Lambert is the CEO of Golden Helix, a bioinformatics company based in Boseman, Montana.  Montana?  Yes, Montana. The closest thing Christophe has to a neighbor in our field is Lee Hood when he’s at his ranch.  Lambert is Canadian who ended up doing his under graduate schooling in Bozeman. Going to Duke for his Ph D, Lambert returned to this unlikely place for biotech and formed his own company, becoming one of the first bioinformatician entrepreneurs.  Golden Helix was founded in 1998, the same year that Ingenuity got its start as a spinout from Stanford.  Lambert says he started the company writing code in his bedroom and talking about it out loud to his wife, who nodded in approval knowing nothing of the content.

I came across Lambert this year by reading one of his excellent blog posts, which was reposted here at Mendelspod.  (If you have a blog you’d like published at Mendelspod, please contact me.)  I was currently interviewing for our series on NGS, and had been looking for a bioinformatician to comment on the sequencing tools space.  With Lambert, I found much more.  He’s thought systematically about the future and the business of genomic medicine. In another of his blogs I noticed that Lambert used the thinking tools of the business management guru, Eli Goldratt, the same tools that my partner Ayanna and I have used to build up Mendelspod and produce our shows.

Lambert writes about Goldratt’s work on supply chain theory and how it influenced his thinking about his own business and the adoption of genomic medicine into the clinic.  “As long as the end consumer has not bought, nobody has sold,” Lambert quotes Goldratt.  This truth struck Lambert forcefully.   The end consumer of genomic medicine isn’t buying, except in very special cases.   So, as a bioinformatics company doing the work of analyzing and interpreting human genomes, was Golden Helix really selling?  Lambert laments the commoditization of bioinformatics at a stage when it’s still the bottleneck, and still in its infancy. In today’s interview, he talks about how small the bioinformatics market really is into the research space.  A small market?  I thought bioinformatics was a booming space.

Lambert is a big picture guy and I highly recommend his blogs. Perhaps working in Montana has forced him to do more thinking for himself.

So what is keeping the adoption of genomic medicine from happening in the clinic?  What is keeping the end user from buying?

Nathan Pearson, Ingenuity Systems

Last week we were at Ingenuity interviewing the newest member of their team.  Going by the new title, Principal Genome Scientist, Nathan Pearson moved to Silicon Valley away from the leader in the genomic interpretation space, Knome.  Nathan is known for sharing the stage for a TED talk with Ozzy and Sharon Osbourne after Nathan and the team at Knome analyzed the rock star’s genome.  Calling itself the Human Genome Interpretation Company, Knome was one of the first in the space, offering detailed analysis of genome sequences back when they were available only to the rich and famous.  What does the move to Ingenuity mean, I ask Nathan in our upcoming interview.  In essence--not directly--he tells me that the science is not ready for Knome to achieve its vision.  And why isn't the science there yet? What needs to be done? To make the biggest difference, Pearson says he had to go upstream where Ingenuity is making headway in better curation and analysis software.   

Judging by the way Pearson has voted with his feet, we are still early in the research phase of genomic medicine.  The accounts of patients being diagnosed and treated with information got from their genome are few and far between, such as the story of Lilly Grossman presented at the recent Future of Genomic Medicine Conference.  In our upcoming interview with Pearson, he talks of the work he thinks needs to take place at Ingenuity and other settings before companies such as Knome or the new companies on the block (Personalis, Omicia, or SV Bio) are able to make a difference.

Sultan Meghji, Appistry

So the science isn’t there yet.  But is there more holding back this revolution in medicine?  Sultan Meghji thinks so.  A regular guest at Mendelspod, Sultan has been advising us on the bioinformatics shows we produce.   He says that the culture around medicine is holding us back as well.   Meghji is the VP of Product Strategy at Appistry, a big data company that recently licensed the Broad’s GATK software for commercial release.

Sultan is also a big picture guy. Sultan suggested three questions for each of the series. He’s very much a three point, Ciceronian rhetorician. I’ll list them here, but it’s the first question for the Clinical Genome Series that I want to pursue here.

Infrastructure

  1. What is nanopore based sequencing going to mean for bioinformatics?

  2. What technology is going to allow us to manage data per patient?

  3. What will the next generation of storage/data transfer look like? Are we going to go beyond the cloud?

The Clinical Genome

  1. How do we change the culture in the medical ecosystem toward personal or genomic medicine?

  2. How do we get the medical ecosystem more consumer driven?

  3. How do we bring the cost down 90%?

In an upcoming show, we’ll have Eric Topol on the program to talk about his terrific book published last year, The Creative Destruction of Medicine. In the book, Topol tackles the big data challenges, sequencing everyone’s genomes, wireless sensors data capture and more. But what he and others don't pursue directly is a discussion about the culture of medicine, from a social perspective. Sultan is one of the few who are eager to go there.

“Forty-five percent of Americans don’t even believe in evolution, let alone genomic medicine,” Sultan likes to say. He’s got a point. His impatience with irrational thinking is shared by many working in this industry.

Politically, we read a lot about whether science in general is more accepted on the left than the right. Recently I watched a Canadian program where Michael Shirmer, a well known skeptic, countered this argument. He’s been on a bit of a crusade to say that the left, that progressives have their science denial moments as well as conservatives. He pointed out on the program that many conservatives are willing to accept the science of evolution when it comes to medicine and technology but not when their beliefs are challenged. He points to the fact that conservatives have widely embraced vaccination, even if they want to believe that mankind began in the Garden of Eden.

Is religion holding back the adoption of genomic medicine? Sultan brings up the case of the explosive adoption of prenatal diagnostic testing, (NIPD) and the concerns of Catholics and other religious groups that more parents will choose selective abortions. Here, as with the use of GM foods, the advance of genomic medicine clashes with many of our notions of spirituality. Most of the readers of this blog are scientists, and according to Lee Silver, author of the terrific Challenging Nature: The Clash Between Biotechnology and Sprituality, molecular biologists are the least religious of us all. But it's the average American out there who will be the patient of genomic medicine. How can scientists best sell their discoveries?

(I recommend Silver's book. In dry scientific style, he does his best to first define what is science and what is religion and question again and again the places where the two clash.)

Sultan says he constantly encounters an “irrational resistance to knowledge,” and sees a further segmentation of society along these lines. I can’t help but think that the ethical concerns about NIPD must be dealt with by society as a whole, for it doesn't look like knowledge is going to stop coming any time soon. New technologies such as NIPD do bring up valid ethical concerns that must be considered by us all. (In a recent interview I asked sci-fi author, David Brin, whether we should slow down the progression of science.)

As I said, Sultan is a big picture guy. And these are the questions on his mind as he goes about developing better, more practical bioinformatics tools for the clinic. Lambert says until the end user is buying, bioinformatics companies are not selling. Pearson says the science must improve. And Sultan says we cannot just look at the science. We have to confront the big ethical questions.

Just yesterday I saw articles about three person IVF becoming a reality in England. What will it mean for a child to have three or more parents? Some say that using mitochondrial replacement techniques on humans would violate a widespread international agreement against making changes in human DNA that can be passed down from one generation to the next. Those of us in the industry love to go to conferences such as the Future of Genomic Medicine and hear about the latest story where a genome sequence opened up new possibilities for health. We must also grapple with the larger societal questions that this new technology brings up if we want to see it become a reality.

Is Illumina Aiming to Compete with its Customers?

Author: 
Christophe Lambert

In a recent GenomeWeb article by Tony Fong, “Sequenom’s CEO ‘Puzzled’ by Illumina’s Buy of Verinata, Lays out 2013 Goals at JP Morgan,” Harry Hixson, Sequenom’s CEO, expresses puzzlement over why its major supplier, Illumina, is acquiring a Sequenom competitor in Non-Invasive Prenatal Testing (NIPT), and thus apparently competing with one of its major customers.

In a JP Morgan interview on January 8, 2013, Illumina CEO Jay Flatley said:

In terms of our market strategy in NIPT: we plan to leverage the Verify test to drive new applications while continuing to supply instruments and reagents to all the NIPT players. In fact, we are working very hard to reinforce our relationships with our existing customers in this field. We plan to partner to help with distribution of the Verify test, and we intend to outlicense the foundational IP broadly and hopefully through that method expand the market more quickly and resolve some of the underlying uncertainty in this marketplace.

Harry Hixson, Chairman & CEO at Sequenom, comments on the Illumina move in his JP Morgan interview:

I get a call from Jay Flatley and he tells me that he is going to acquire Verinata. And so anyway my mind starts thinking about all of the ramifications of that. We’ve met for two, two and a half days now with analysts, investors and everyone asks us the question, “what do you think this means?”, and then they follow it up with “we don’t understand it”. And I would say at this time that Sequenom is puzzled. I would like to read some quotes from Jay’s press release…. And he also says “we are working very hard to reinforce our relationships with our existing customers in this field”. I might add, I’m waiting for the call – the second call.

Illumina’s move appears to be putting Sequenom in an uncomfortable position, a move that is puzzling both its customers and investment analysts. Is there a clear strategy behind what Illumina is doing?

Two explanations come to mind. (I’m curious if anyone has any other theories?) One is that existing products and markets will not enable Illumina to sustain desired growth and so they are entering new markets, including selling to the customers of their customers. The other is that Illumina is deliberately shaking up a conservative diagnostics market in order to drive demand. That is, Illumina is driving quicker adoption of high throughput sequencing for clinical applications by providing both prenatal testing as well as whole genome sequencing services.

Why is this move so interesting (i.e., why do I care)? Many of us in the bioinformatics world feel the competitive pressure of spending large R&D costs to serve a relatively small market of research scientists whose goal units are generally disconnected from revenue generation. If Illumina has a way to break out of the economic limits of the research market, we want to learn from them. Let’s look at the limits to growth in research genetics.

The Genetics Research Market
Various estimates I’ve seen indicate that Illumina has 70-80% of its revenues coming from academic and government research. This may well be higher, as revenue realized from commercial labs may have a substantial fraction of their volume ultimately serving academic research pursuits. Further, Illumina apparently owns an estimated 80% of the NGS sequencing market (though a recent GenomeWeb article says Life Technologies claims it has 60% of the Desktop Sequencing market).

Given NIH provides most of the dollars for US academic and government research and that the days of steady NIH budget increases appear to be on hold for the foreseeable future, the academic and government research market is unlikely to significantly grow over the next several years.

Why is the commercial market such a small proportion of Illumina’s revenue, and must it remain that way? ISI Group, drawing on data from Instrument Business Outlook, shows the total worldwide genetic tools market comprising sequencing, microarrays, PCR, flow cytometry, in-vivo imaging, high content screening and informatics to be an estimated $11B in 2012. This represents about a quarter of the ~$45B life sciences tools industry serving all sectors. According to this same report, 27% of this $45B is academic and government, with 24% biopharma, and the rest made up of hospitals, CROs, and other miscellaneous categories. Sequencers and microarrays make up about 25% of the genetic tools market.

With microarray spend being displaced by sequencing for both DNA and RNA, and with an increasing proportion of PCR being substitutable by Next Generation Sequencing (NGS), it would appear that there is $5B in market share available for Illumina to fight for. However, even with decent market growth, there is no way for Illumina to continue the 83% compound annual growth rate (CAGR) it sustained over the last 10 years.

Given a fixed spend on experimentation in academic/government life sciences research with flat expected growth, fighting to take market share away from other smart competitors (each fighting for their share of that same sandbox) is an uphill battle. It may give short turn returns, but ultimately you will eventually run up against the physics of a limited market. Perhaps this is why Illumina, and most everyone else in the field of genetics research, is eyeing the greener pastures of clinical genetics or diagnostics.

The Diagnostics Market – Greener Pastures
According to Bloomberg, the total diagnostics market today is around $44B, of which $5.6B is genetic testing. However, when a number like $5.6B is reported by healthcare providers, that is the reimbursable charges made by providers to patients and insurers. Many genetic tests are reimbursed at around $3,000, including cytogenetic assays. Consider, however, that for a cytogenetic microarray based test, an equipment and consumables vendor like Illumina might make $50-$300 for the microarray. Whole exome or genome sequencing is more expensive, but for widespread adoption it will likely have to come in line with being profitable for healthcare providers to order tests for around the current $3,000. So even if you are the provider of supplies for the entire $5.6B market, you might bring in revenues less than 10-20% of that or under $1B. So despite 17% annual growth of that market, the question becomes do you want to be the organization receiving $50-300/test by providing equipment and consumables, or the one receiving $3,000/test by providing the one stop solution reimbursable through health insurance?

Illumina’s 2011 annual report says, “the Company is organized in two operating segments for purposes of recording and reporting our financial results: Life Sciences and Diagnostics… The Company will begin reporting in two reportable segments once revenues, operating profit or loss, or assets of the Diagnostics operating segment exceeds 10% of the consolidated amounts.” They appear to be organized to go after diagnostics – it remains to be seen if it is mainly through hardware and consumables or other business models.

Absent some consumer genetics play, for Illumina to do well by its shareholders and grow from a $1B company to a $10B company in the years to come, it almost seems forced to enter the diagnostic testing market as a laboratory service, instead of just providing the equipment and consumables. It thus seems unavoidable that it will more and more come into conflict with its diagnostic laboratory clients who likewise see the potential of that market.

Supplier Becoming a Competitor
So what does it mean for a company like Sequenom to see their supplier becoming their competitor? Or similarly, what does it mean for a core lab that makes its revenues running samples on Illumina HiSeq instruments to see Illumina providing a CLIA sequencing service for whole genome and tumor normal pair sequencing? While Illumina may downplay that they are not in the space of single gene tests or exomes, ultimately it is expected that more and more testing will converge to whole genome coverage, leading to a future collision.

The main fear is that Illumina as the supplier is in a position to out-compete on price. Normally price is a weak competitive advantage among manufacturers, as the time it takes to match a competitor’s price is negligible, and there is the deterrent of a price war in which nobody wins. However, in the case where one competitor cannot manufacture the goods, but must acquire them from the competition, competition on price becomes viable for the manufacturer with the built-in asymmetric advantage. This will lead to the disadvantaged party searching for alternate suppliers, and thus the rise of additional manufacturing competition who are willing to stick to being suppliers and not selling the diagnostics directly. These will be smaller sequencing hardware companies who initially don’t have the growth limitations of Illumina, but who, if they eventually succeed, will be in the same conundrum Illumina is in now. Illumina could alleviate these fears by being the most expensive CLIA service in the market, but that puts them in conflict with increasing the revenues of their diagnostics operating segment.

On the other hand, perhaps they intend to shake the market just enough to get genetic testing labs to start adopting high throughput sequencing en masse to drive demand, then back off and stick to the fundamentals of selling equipment and consumables, licensing their tests and stepping back to let others do distribution.

Perhaps from a scenario planning standpoint they don’t even have to decide at the outset which strategy they ultimately go with – they can probe and test, and will gain regardless. That is, whether they displace their customers and take the market (in which case those customers are not around to complain), or drive a reactive market surge from customers/competitors that lifts all boats and then back off, smooth ruffled feathers, and reap the rewards of a larger market, it seems like they could win either way.

<

p>Like Hixson and investor analysts, I’m also puzzled. What do you think?

This blog was originally posted at Golden Helix's Blog, Our 2 SNPs.

Technologist as Intellectual

Author: 
Theral Timpson

Over the weekend one of our listeners wrote in an email proposing the idea of technologist as intellectual.

I’m assuming that this person has been listening to one of our favorite questions of late. Are scientists and engineers the new world leaders?

My favorite answer to this question came from Chris Mooney, a science journalist and author of The Republican Brain, who came on the show before the last election to talk about science in politics. To the question, Mooney replied:

"If they are, they don’t know it."

Mooney doesn’t deny that it may be the case. And he goes on to acknowledge the “immense power they wield” in that science has become the “key to prosperity, the key to industry, and the key to power.” Mooney says that on the other hand, scientists are “highly disorganized and not ready to take the power that could be theirs.”

Since our reader’s email came in, I’ve been thinking about the term, intellectual. What does it mean in the 21st century? We've come a long ways from referring to "men of letters." Reading through the Wiki article on intellectual, I pulled out two key traits that still work for defining one in today’s world. First, an intellectual deals in abstract thought. Think mathematics and physics, or philosophy. Second, intellectuals have a publicness about them in that they typically challenge existing power structures or the status quo. They are different than an academic or expert in that they take their sophisticated ideas to the public.

Perhaps the iconic life science intellectual of today is Richard Dawkins. He came up with his idea of gene-centered evolution and his concept of ‘memes’ in his book The Selfish Gene, recently released in the 30th Anniversary Edition. Dawkin's books are for scientists but also for the lay reader. And he has developed a public persona. He’s become an activist, most notably for atheism.

George Church got caught in a media flap a few weeks ago when he talked openly to the German magazine, Der Spiegel, about the very real possibility of cloning dinosaurs among other trends in biology. Church is not as much of a lightning rod as Dawkins, but he went further than I've seen him go before. The Spiegel interviewers tried pretty hard to nail him down on whether he believes in God or not, which he danced around with the sophistication of a Cirque de Soleil acrobat. But the line I found most telling was,

“I'm not advocating. I'm just saying, this is the pathway that might happen.”

Church is saying that we need to think more about the future of biology. He’s coming out of his lab at Harvard and sharing some of what he knows as a scientist with the public. Perhaps we could call him the reluctant intellectual.

And what about the technologist? Church is every bit as much a technologist as scientist. In our interview last year with him, he said when he was young, his interest was in computers and biology. And he brought the two together. Strictly speaking, a technologist uses science or technology to solve practical problems. But these days, quite often, a scientist is also a technologist. Both George Church and Institute for Systems Biology founder, Lee Hood, built their careers bringing science and technology together. Science advances and spawns new technology. New technologies, like the DNA synthesizer and sequencers that Church and Hood worked on, then enable and speed up science. The two are inextricably linked.

What names could we come up with for pure technologists who are intellectuals? Is Bill Gates an intellectual, or just a rich philanthropist? What about Steve Jobs? Was he more than a brilliant entrepreneur? Did he promote an ideology?

In our reader’s email, he put forth the name of Richard Stallman who worked on the first free operating system which became Linux. Stallman has been an activist for free software. I read that he was able to get a state in India to dump Windows on all their computers and install free software. That sounds like something an intellectual would do.

What about the folks over at Google? Former CEO, Eric Schmidt made a trip to North Korea recently with politician Bill Richardson. And he’s invested in some hobbies like journalism and space robotics mining, following in the steps of Richard Branson. He’s even rumored to have wanted to be a talk show host, but this hardly qualifies him as an intellectual.

Google's Serge Brin and his wife Anne Wojcicki jumped into the spotlight with Facebook's Mark Zuckerberg and his wife Priscilla Chan and others last week at UCSF for the establishment of a Breakthrough Prize in Life Sciences. A sort of American Nobel Prize, the awards will be ongoing and this year honored the likes of Titia de Lange and Eric Lander for their achievements. In a post today, Xconomy's Luke Timmerman lauds Zuckerberg particularly for the message this gives to young people. Timmerman acknowledges Zuckerberg's "intellectual gifts" and "business acumen" in bringing a billion sets of eyes to his brainchild site. But he also insists that Zuckerberg's age enables him to make a greater impression on young people. Here's a quote from Zuckerberg at the awards ceremony:

"The reason I’m excited about this is that I think our society needs more heroes that are scientists and researchers and engineers. You are doing all this amazing work. The thing we can do from the sidelines is build institutions that celebrate and reward and recognize all of the real work you guys are doing to cure diseases, to expand our understanding of humanity, and to improve people’s lives in all these ways.

“A lot of this isn’t about even you guys here today. A lot of what we’re doing here is about the next generation of folks. The students, the college students, and grad students who are in labs today, trying to figure out what they should work on and research. And younger kids who are trying to figure out what they want to be when they grow up. Hopefully, what we’re doing here today can help create something that will be really inspirational to folks, to encourage more people to do the important work you’re taking on."

Is the Facebook founder becoming a new kind of intellectual in a hoody?

Use Google to do a search for 'technologist as intellectual' and you’ll be buried with a list of discussions of intellectual property relating to tech. Yes, technologists are good at coming up with intellectual realty, but are they intellectuals? Coming up with powerful algorithms requires some brilliance in abstract thinking, but to what end?

When I think back on the guests we've had on the show in the past year, a few fellows come to mind as intellectuals. I mentioned Church, but I might add sci-fi writers, Stan Robinson and David Brin, Open Science Activist, Joseph Jackson, and Innothink's Bernard Munos. Brin, who is also a scientist, is more of a provocative public figure than Robinson. Jackson is a philosopher who loves to rant about open science, the perils of the patent system, and the waste of talent spent writing meaningless apps. Munos was a late bloomer. Once he had his retirement secure from Eli Lilly, he went public with his gospel about the pharma industry in crisis. But unlike many other pharma leaders, Munos talks not just of economic, but moral and leadership crisis.

The concept of intellectual is different today than a couple hundred years ago when the majority of the population was illiterate. Should we add 'writing code' to the list of abstract thinking? Humanities departments at universities around the globe have been shrinking, crowded out by science and technology. In this year's SOTU, the president said we should have even more science and technology in education.

Richard Feynman said "Philosophy of science is as useful to scientists as ornithology is to birds." And I've been provoking our guests with Stephen Hawking's statement at a Google conference last year that "philosophy is dead." What does the intellectual of 2013 look like?

I end with a line from our reader's email:

"Thus it is not philosophy that is irrelevant but that society is being influenced by science and technology in such intimate and fundamental ways that philosophical questions of relevance require technical sophistication to reason about correctly."

Nicely put.

Your thoughts?

The Age of the Engaged Patient: A New Series

Author: 
Theral Timpson

Last year when we recruited Steve Burrill as an advisor to Mendelspod, I asked him for his thoughts on where we should take the program. He replied without hesitation that we should always connect the stories to the end goal, that of improving the lives and health of people around the world. I found it good advise worthy of Steve’s experience and vision.

This year we’ll be producing a special series about the ‘Engaged Patient’ and later another series done entirely with physicians as guests. Yesterday we began planning the patient series with Ryan Witt, a new associate producer at Mendelspod. Ryan is a young man in his mid twenties who started a non profit to advocate for patients after being deeply affected by his grandfather’s death from cancer. He’s a big thinker for his age, desirous to make an impact in healthcare. I’m looking forward to working with him on the patient series and other projects.

I thought I’d jot down a few notes from our session and put them out there so that we might get some feedback in developing this series.

Patient Stories

Everyone has their own stories about being a patient. Ryan has his story about his attempt to find new medications and ongoing clinical trials that might have saved his granddad. He feels convinced that some combination therapy might have gone a long ways to beat back his grandfather’s cancer, and has joined several discussion panels at the FDA to urge more openness to new treatments for terminally ill patients.

I have my own story. Like most others, I took my health for granted. Until it was threatened. I didn’t see doctors in my youth. Why should I? I shook off the occasional flu bug and ankle sprain until in my late twenties I didn’t recover from a virus. A pressure in my head went on for weeks and months until finally I asked a friend what to do and he referred me to his doctor. I saw the doctor. And one after him, and another and another. I went four years seeing specialists, having brain scans, CT scans, taking way too many courses of antibiotics--and all to no avail. Then I happened almost randomly on to a doctor who finally gave me a correct diagnosis. I suffered from a ‘status migraine.’ What? A migraine that caused pressure in my sinuses and congestion and malaise? A migraine that had gone on four years? Indeed.

I got lucky. It turns out my doctor was somewhat of a specialist on headaches, having studied them in a special program with NASA. Migraines can mask themselves in many forms, one of them being the symptoms of sinusitis. I was started on medication, and in a week I’d improved 75%. It was a tremendous relief. This doctor was my hero. She made me believe in my life again. With the help of some medication, a referral to an excellent headache clinic in Mountain View, CA, she gave me a new life. And I’ll always have a special place in my heart for her. I do believe in good doctors. And in Western medicine.

My business partner, Ayanna, has had many surgeries and lived a good deal of her early twenties in a hospital. Ayanna brings a European outlook on healthcare. The difference between her experience and Ryan’s and mine is not insignificant. Ayanna seems to believe more in doctors. She sees them more as partners, and I sense that she’s had a better experience with healthcare than Ryan or I.

Patient Conflicts

What are the big issues for patients in the twenty first century? It’s helpful to define ‘patient.’ Just when do we become a patient? The term has been undergoing some rethinking of late. You’ve probably heard presentations by Steve Burrill and Eric Topol who are talking about health consumers who hire advisors, rather than patients who submit themselves to autocratic doctors. I hear stories every week from folks who say that they know more than their doctor on many topics related to their own health. Should we seek another, more useful term than patient?

Looking at some of the conflicts that a patient encounters is useful. Perhaps the most common one is whether to see a doctor. There are many factors which go into making this decision. We ask ourselves if the situation is that bad. We think about our insurance or the money it will cost. We consider the time it will take.

Another conflict is whether to research the health issue online as we do many other problems in life. Should we turn to the Google doctor. Will we find an answer to our specific problem or be led on a goose chase and just end up bewildered and convinced that we have a life threatening illness? I’m sure you’ve had those nights when you couldn’t sleep, desperate to find answers to health problems, browsing one site after another, becoming more frightened with each one. Yes, I do have those symptoms. Do I have such and such? Or we feel comforted reading stories of others who have had the same symptoms. Often we’re left more confused than when we began.

Perhaps the most important single event for a patient is diagnosis. It was for me. Just knowing what I had made it so much more manageable. I was able to stop going down all those blind allies, laying there at night wondering if there was something seriously wrong with me like a brain tumor.

Help!

In our discussion, we pinpointed a central conflict for patients: whether to be open to new ideas to improve our health or not. This might be going to a doctor in the first place, or it might be firing one doctor and going to another. This might be looking online, or even asking a friend what their experience is. It seems to me that the moment we seek help is the moment we become a patient. Our health problem reaches a certain threshold where we say, “hey, I need help.” That seems to be a pivotal moment, an important psychological transition. We acknowledge that we have a problem that is bigger than our present capacity to deal with.

All of us have limited resources, some more limited than others. Where should we go for help? It takes time and money. How much of our lives should we spend pursuing this help? These questions led the discussion to consider the Quantified Self movement and those individuals who spend a good deal of time on their health. And much of it with the idea of prevention, rather than pursuing answers to a problem after it has occurred.

On the other extreme is the person who takes his/her health for granted, who says, “hey, the goal here is to not have to think about health; there are other more important things in life.” I always return to an interview Charlie Rose did with Christopher Hitchens just before Hitch died of esophageal cancer. Rose asked Hitchens:

“Now that you have this health condition, looking back, would you live differently? Would you not have smoked and drank so much?”

Hitch replied, no, he wouldn’t have lived differently. He told Charlie that he had chosen the life of a writer and this was part of it. That the goal of life wasn’t to live the longest but to pursue your passion. Something like that.

Perhaps Hitchens sounds naive to most of us. Are Quantified Selfers a bit too obsessed? Does focusing on your health that much end up bringing on problems in a self fulfilling kind of way? And what about those who are getting their genome sequenced when they are healthy? Does this bring unhelpful anxiety about diseases one doesn’t have but to which one is prone?

For the series, we’ll have on patients who reflect different ways of going about preventing disease, or recovering from serious health problems. Most importantly we want to hear patient stories. What are your thoughts? What topics do you think are important in exploring what it means to be a patient in our day? Join in.

Highlights of the 5th Personalized Medicine World Conference

Author: 
Theral Timpson

This week the always spectacularly organized Tal Behar and her team put on the 5th annual Personalized Medicine World Conference (#PMWCintl). I want to mention a couple highlights from the conference: prenatal diagnostics and cell profiling.

Prenatal Diagnostics

Prenatal diagnostics, or NIPT, is one of the hottest things going in 2013, if not the hottest. And Tal was able to sign up the three leading companies in the space, Sequnom, Ariosa, and Verinata to speak. It’s stunning to hear about the rapid adoption into the clinic these technologies are receiving. Matthias Ehrich, VP of R & D at Sequenom said they’d saved 500 babies. If you’ve been following these companies in the news, you’ll know that their sales are skyrocketing. This is sequencing technology. In the clinic.

Ira Klein from Aetna, a speaker at the conference and <a href="http://www.mendelspod.com/podcast/dx-from-the-payers-perspective-with-ira-klein-aetna>recent guest on Mendelspod, assured me at the break that the success of these prenatal dx companies lies in their ability to demonstrate strong clinical utility. Mark Trusheim, an economist and speaker, echoed Klein. Mark’s presentation showed the economic dangers of stratification-using diagnostics to target smaller audiences. I asked him a common question from our last series on diagnostics: are they undervalued? “Some are,” he said. “When the diagnostic tells a doctor yes, or no, it’s of value. And perhaps those could be valued higher.” The prenatal testing for chromosomal abnormalities offers just such clear information. I wasn’t aware that so many pregnancies were at risk for chromosomal problems. Sequenom claims that 750,000 women in the U.S. are at high risk.

The three speakers had very different approaches which I think reflects on the difference between the companies. (There is a fourth company, Natera, who offers the tests but was not at the conference.) The companies are all suing each other about patents (which I’ll get to in a moment) so first I noticed how civil and complimentary the speakers were of each other. Ehrich from Sequenom stuck closely to the science of their tests. He made the impressive point that in one study, the non-invasive sequencing technology was more accurate than the invasive amniocentesis.

Though a small man in stature, Ken Song, CEO for Ariosa was the bull in the group. Song put forth the largest market numbers. “If we offer the test to women who are 36 years old, why not to those who are 34 and 32” he asked a room so packed there wasn’t even standing room. Ariosa came across as the most agressive, perhaps because they’ve come in on the coattails of Sequenom. They’re offering a test for $800 for which “the others” are charging close to $3,000.

Verinata was represented by Amy Sehnert. Her approach was a conservative one. She stuck to science and fact, again in a tone complimentary of the other two companies. I wondered if her more reserved talk had to do with the fact that Illumina is currently in the process of scooping up Verinata, which she mentioned in passing at the end of the talk. It’s worth repeating. Illumina is buying this company for $450 million. I reminded the crowd of this pretty interesting number and afterwards a former marketing employee from Complete Genomics whispered loudly in my ear: and BGI offered half that for Complete? It’s a great point. Complete Genomics, just down the highway from Verinata, who has been devoted to sequencing human genomes as a service has received much more notoriety than Verinata.

The best line I’ve read about this growing subindustry comes from Andrew Pollack’s article in the NY Times from last Oct. He quotes Dr. Stephen Brown from the University of Vermont who has no financial stake in the the technology. “It’s a game changer,” says Dr. Brown. “You will have dramatically fewer procedures.”

We’ll be doing our own series on Prenatal Diagnostics this Spring, so stay tuned. We’ll be exploring the differences between the companies: their technology, their pricing, and their approach. Finally, the patent issue. All of this is possible as a result of papers published by a Hong Kong researcher, Dennis Lo. Back in the late ‘90’s, Lo et al established that there is indeed cell free DNA in the mother’s blood, detectable by 5 weeks. Sequenom has licensed Lo’s method and claims the other companies are infringing the patent. Verinata has their own patent based on research from Stanford. In January of last year Sequenom sued Ariosa. In response, Ariosa, Verinata, and Natera along with Stanford sued Sequenom, arguing there are differences among the technologies. Will there be a showdown? All par for the course in this industry.

Cell Profiling

The other cool science I’m going to mention is work being done by Gary Nolan, a professor at Stanford. Nolan is one of the founders of the diagnostics company, Nodality, and has been chipping away over the years at single cell profiling. I’ll be honest and admit that most of his talk was over my head. But I think I got the jist of it. “Looking at the aggregate of one person’s cells is like taking everyone in this room, blending them up, and saying here is the genetic, or biological makeup of one of you,” he started. Nolan showed that individual cells become gateways in functional pathways or networks. A cell says “yes” or “no” to whether something happens downstream. His diagrams remind look more like circuit logic. If this, then this. Each cell has unique functions. This leads to looking at a network of cells because, some are more important than others.

From his note in the program:

...Metabolic elements in networks far from the originating pathology of a cell can act as surrogates of the pathology, reflections of how a drug might be correcting the pathology, or by themselves those surrogates might be modulated en masse to force corrective action upon the pathology. Often, the network is “silent” about the pathology until it is perturbed to reveal how it thinks (much like when you interview a candidate for a job position—you don’t look at their CV alone, you invite them in for questioning).

Science always comes down to the assumptions made by the researcher. These assumptions dictate the outcome. Gary is stepping back saying, hey, there is another premise here. Another foundation upon which biology depends. Gary’s work is being commercialized by DVS sciences, a company offering a ‘mass cytometer” instrument and reagents which were presented at the show by Joseph Victor, CEO of DVS.

What’s the state of personalized medicine in 2013? Each year at this conference I detect less hype and more specific stories. Of technology, of new science, of new companies. I did miss the higher profile talks in the main room as I was emceeing in Track 2, so perhaps I missed some of the hype.

I’ll make a comment on the format. I heard from speakers in every break that 14 minute talks are not enough time to do them justice. I agree with them. Particularly because there was no time for Q & A. The keynote speaker himself, Lee Hood, told me the night before the conference that he was still trying to cut his presentation down to the 14 minute slot. Tal and her team did a great job booking the best speakers and filling up the show with attendees. There are several personalized medicine conferences each year, and PMWC is one of the best, organized to the “t”. It was truly thrilling to feel the enthusiasm and participation of so many as we see the possibilities for human health become better and more personalized. I hope the format itself will also see improvement. Ideas, especially complex ones, need time and much interaction to develop.

Note: Be sure to check out our current show with a speaker at PMWC, Mike Snyder, of Stanford. We follow up with him on his iPOP study and he shares his view of what health is.

Is Bad Science Undermining Big Science? A Conversation Between Guests and Audience

Author: 
Theral Timpson

One can look at funding for science and break it up into Big and Small Science. Funders of Big Science would be large corporations, foundations, and the government, whereas Small Science relies on VC, startup funds, small businesses and entrepreneurs. Big Science comprises those big projects like the sequencing of the human genome and the war on cancer. But are such big projects yielding results that justify the massive spending?

Bill Frezza, a regular guest at Mendelspod, says not, the massive spending isn't justified. Bill pens a column over at Bio-IT World, The Skeptical Outsider, where he plays provocateur and questions some of the basic assumptions that we in the life science industry hold dear. He thinks NIH funds are badly mismanaged and talks about academic science as a feudal systems with lords (PI’s) and vassals (postdocs). His latest article asserts that “bad science” is threatening Big Science.

“Think about the modern business model of Big Science -- an interconnected set of interests whose tentacles extend into academia, foundations, and major corporations. Advocates of a variety of causes across numerous fields—from health care to agribusiness to energy and the environment—selectively promote scientific results produced by legions of scientists, some of whom are independent and others not. These pronouncements are generally aimed at attracting more public and private research funding, selling more goods and services, or impacting laws and regulations that control the selling of goods and services. Sounds science helps policymakers and consumers make wise choices. Bad science, not so much.” (The Skeptical Outsider, Jan, 2013)

For Frezza, “bad science” is that which is not reproducible. Recently we’ve seen an uptick in non-reproducible findings, and Bill says it’s because of corruption and moral hazard. Examples of corruption he cites are influences that are “buying a predetermined scientific outcome” such as cancer studies funded by the tobacco industry and anti-GMO studies funded by environmental activists. Moral hazard, he says, is a cousin of corruption that is more subtle, such as researchers cherry picking results, fooling not only others but themselves.

His solution: improve the quality of science by publishing in new peer review journals such as GigaScience and eLife where the data behind the findings can be comprehensively logged.

Responses

I sent Bill’s article to a couple industry friends for their take on his assertions. The first is from a scientist at Stanford who has worked in Ron Davis' lab for years.

“I think there is at least a grain of truth in most of the statements.  But it's pretty complex.  One could argue the so-called entitlement programs aren't a culprit for reduced R&D spending at all, that we all pay in our own share, and if politicians weren't trying to fix problems in the Middle East we'd have plenty to go around.

About the science, there is indeed a major problem with spending dropping.  Pharma used to fund billions in R&D but has all but stopped.  Everyone turns to NSF and NIH now, whose budgets have been flat for years meanwhile the lack of private money and the huge increase in biologists being trained, but a total lack of money to pay them or fund their work.  

So there is, in my opinion, greater pressure to get groundbreaking results or perish.  Unfortunately, the increased quantity of scientists being trained doesn't mean their skills are any better (an in fact they're probably on the whole less talented).  So there is a pull towards the "dark side" for some.

NIH is a huge problem.  What we need are breakthroughs and all they fund are conservative, incremental improvements.  So much of the lack of real innovation is based on our fear of trying.  Yet truly innovative science attracts only the very best and brightest, and often is our only hope at solving major problems.  

Much of it is also our desire for quick results.  Yet there is no quick fix to cure cancer or world hunger.  So we see Apple and Samsung in a technology battle that produces new products every few months.  We become fixated on this level or progress.  Curing cancer is a problem that is many orders of magnitude more complex than making a smartphone.  People need to realize that innovation in cancer treatments is a challenge of decades and not months.”<.em> (Keith Anderson, Scientist at Stanford Genome Technology Center)

The second responder, who can always amuse, is the CSO of a small life science reagent company in San Jose:

"To assume that we have loss of faith means that we had faith at the first place. Did we? Science is just like cars: cars get better over time and the more advanced they get, the less we understand or need to know how they function. The better they work, the less we worry about them or getting stranded on the freeway. If they don’t work, we have no idea how to fix them and we need to refer to a specialist that will charge us big bucks to do so. Science is the same: science does a pretty good job for most people so they don’t have to worry about it.

Science as a big lobby: nothing new in Bill’s article. When I did my PhD, the joke was that state scientists look for 5 pm and time to go home. However, if we want to put everybody to college, then one needs this legion of science instructors. Science at school is just a by-product of ‘education.’” (Anonymous Chemist in San Jose)

Recently I interviewed Lee Hood, founder of the Institute for Systems Biology, and used Bill’s skepticism in a question.

Mendelspod: Should we continue the current system of funding when so many tax payer dollars are going toward bad science that cannot be reproduced.

Lee Hood: I think a lot of the bad science that can’t be reproduced is really viewed in the wrong way. The essence of scientific experimentation is to try ideas, test them, and if they work, great. But what’s key is making sure they work in many other people’s hands. . . I don’t think there’s all that much bad science in the sense that it was done with the wrong motivations in mind. I think it’s just part of the scientific process that a lot of science doesn’t end up working out well in the future. How you distinguish between good and bad science--we attempt to do that with the peer review systems that we have now. And frankly I think that the peer review sessions that we have now do just about a job as anyone can do. And if the alternative were to say there was some politician who’s going to decide what’s good and what’s bad science, I think that would be terrible beyond belief. . . This is a draconian suggestion. . . I think we have pretty good systems now and I would hesitate to change that. . . . Big Science done well is absolutely fundamental to attacking big challenging scientific problems.

Dr. Hood set up the Institute for Systems Biology to go after the challenge he calls P4 Medicine that he says needs big funding. He actually calls NIH funding Small Science.

Bill’s response to Lee Hood:

As much as I respect Dr. Hood, he completely dodged your question on how to reduce the amount of bad science. His defense of the existing peer review system as the best of all possible worlds is pathetic. His call for more Big Science funding is entirely self serving. He's right that politicians can't be trusted to do the job, but that's a false alternative. Only transparent and efficient market-like mechanisms that “punish” scientists who continue to spit out unreproducible results will fix the problem. Claiming that the science is too complex to be easily reproduced is excuse making.

I laud Bill for taking on such topics and big interests. From what I’ve seen, there’s not enough of this in the life sciences. Perhaps the industry grew so fast that everyone got drunk on the same kool-aid. Bill questions the war on cancer, and rightly so. Frequently I hear from guests that we’ve hardly moved the needle after 30 years. However, I’d argue that the incredible high speed at which this industry has advanced is an indication of its success. Thirty years ago we were sequencing DNA manually with a gel and PCR was yet to be widespread. Most all of us have our stories how some medication or another developed in this time has made our lives much better.

Bill points to his former industry, the world of IT as an example of "good science." But the IT industry benefited greatly from Big Science projects, the biggest being perhaps the internet. Would Frezza say that the internet was not worth it? Would he say that the sequencing of the human genome wasn’t worth it? Indeed this project is proving to be the platform on which much of today’s research is built. With big fundamental projects, it can be difficult to imagine the impact they have on humanity's direction, let alone that of the country.

I'm happy with Dr. Hood's response. The system of science will always produce bad results. That doesn’t mean the system is broken. It means scientists are willing to try new hypotheses. Dr. Hood may be self serving, but that doesn't mean he's not community serving as well. Still, we must ask ourselves, why the increase in bad science. Bill’s suggestion about open publishing of all the data is a great start. As we’ve reported before, it’s also important that so-called bad or negative results are published as well. But does this answer the fundamental issues?

We’ll be pursuing this subject in several upcoming series of shows where we’ll have Bill on the program with someone who has not lost faith in Big Science. And we’ll try to understand better the causes for the increase in non-reproducible science.

What are your thoughts? Are we losing faith in Big Science? Why the increase in "bad science?"




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