Expectations, Ballyhoo and Stem Cell Research

Two seemingly unrelated biotech stories popped up this morning on the news.  One involved an international stem cell research brouhaha. The other involved what could amount to a nearly $2 billion biotech deal for a California firm.  

What brings them together is the diaphanous nature of some of the work in these much ballyhooed fields. But first, let’s look at the latest reports about the STAP stem cell flap concerning research in Japan and Massachusetts that seemed to promise a fast and easy way to make pluripotent stem cells.

After five months and major questions, the journal Nature has decided to retract the STAP paper despite the fact that the journal had it vetted by some of the best scientists in the world. Even with the review, Nature said “extensive” errors have surfaced along with “inexplicable discrepancies.”

It is fair to say that 20 years ago, that paper would still be widely accepted and remain firmly entrenched in Nature’s archive as reliable. What has changed is the Internet and impact of social media on evaluation of research. That has given researchers the unfettered ability to discuss and publish their findings dealing with replication of results and other issues.  At the same time, the speed in which this cyber review takes place is remarkable.  The change from 20 years ago is the equivalent of the move from hand-cranked printing presses to the high-speed presses of today that can spit out thousands of pages an hour.

(We should note that California stem cell researcher Paul Knoepfler of UC Davis played an important role in probing the scientific reliability of the STAP research with responsible reporting and commentary on his blog, ipscell.com.)

Now, about that nearly $2 billion deal, Wall Street Journal columnist Helen Thomas this morning wrote about the acquisition of Seragon Pharmaceutical by Roche, describing it as “disconcerting.” She said it could be a case of shelling   “out vast sums for assets that could quite possibly amount to nothing.”  San Diego-based Seragon “was formed only last year and has one breast cancer drug in early stage trials,” Thomas wrote.

She continued,

“The global pharma sector's forward earnings multiple has expanded to almost 16 times, up from less than 11 times two years' ago, in part because investors believe the (biotech) industry's R&D machine is again producing the goods.”

Thomas noted, however, that only one in 10 potential therapies entering clinical trials reaches the marketplace. “The risks are substantial,” she said. Those same risks apply as well to the 10 clinical trials that the California’s $3 billion stem cell agency has been involved in.

Earlier this year, noted bioethicist Art Caplan wrote about what he called the “off-the-rails syndrome” in stem cell research. The STAP article was his starting point.  Stem cell research is a field that has had more than its share of hype. Well-respected scientists routinely refer to its revolutionary potential. Little public attention is paid to the obstacles and the lengthy and often unsuccessful process of developing a truly usable product.  Expectations of desperate patients are raised. Many of them wind up paying for expensive, untested and perhaps unsafe treatments.

The Seragon-Roche deal is also a reflection of the hype that can arise in biotech/stem cell research. It can be so powerful that the supposedly “rational” economic markets are swept up in the exuberance of a nifty research story.  Ultimately the deal may pan out for Roche, although Roche can afford to take a big loss. But stories are stories.

What does all this mean for the California stem cell agency? Good reasons exist to manage expectations so that the public and potential sources of funding are surprised by successes rather than being surprised by the agency’s failures.  No one wants to see a story like the Solyndra scandal emerge from the California stem cell agency.

Scientific Journals: A Case of 21st Century Dinosaurs?

Out of California's Silicon Valley comes a stout prediction this month that a $10 billion business that feeds off government-financed research has entered its terminal stages.

The forecast was made by Dylan Tweney, editor-in-chief of Venture Beat, a technology news operation that not-so-coincidentally has no print arm.

He wrote on June 6,

“Imagine an industry where a few companies make billions of dollars by exerting strict control over valuable information — while paying the people who produce that information nothing at all.

"That’s the state of academic, scientific publishing today. And it’s about to be blown wide open by much more open, Internet-based publishers.”

He said that the leading companies in the field, Elsevier and Springer, have margins in excess of 35 percent. They subsist off research that is almost totally financed by public money while, at the same time, they do not pay scientists to review the research prior to publication.

Tweney noted that the industry's relatively new competitors, including Plos, Academia and Arxiv, offer free access compared to pricey journal subscriptions that cost Harvard University $3.75 million in 2012.

“Taken together, these online publishers represent a significant threat to traditional journal publishers like Elsevier because they reach more people and cost nothing. The only remaining value that traditional publishers offer is the imprimatur they provide: The articles they publish have been peer-reviewed and are thus presumably more reliable.

“But even that imprimatur is under attack. The 'reproducibility crisis' in academic publishing refers to the fact that a huge proportion of published research, particularly in medical fields, is based on results that cannot be reproduced by other researchers. In one study, a tiny 6 percent of scientific findings in cancer research were reproducible.”

Scientific publishing has also lured the California stem cell agency, which financed to the tune of $600,000 the start-up of a journal in North Carolina.

As Tweney alludes, the situation is not much different than that of the newspaper and magazine industries a few years back. For the most part, those businesses blundered along in a very profitable mode, ignoring the Internet until it was too late to do anything other than scramble for survival. It is possible that the academic journal business can find a new model. But given organizational inertia and the unwillingness to cannibalize an existing and still profitable business, it is unlikely.

(Disclosure: Tweney is this writer's son-in-law. He did not consult me prior to writing his June 6 piece.)

California Stem Cell Agency Fires Up New Print/Online Endeavor

California's $3 billion stem cell research program this month launched the “Proceedings of the California Stem Cell Agency” in partnership with a scientific journal that it spawned in 2011.

The journal is Stem Cells Translational Medicine, which was initiated at the behest of the Golden State's stem cell agency. The California Institute for Regenerative Medicine or CIRM, as the agency is known, subsidized the new journal for three years with $600,000 paid to AlphaMed of Durham, N.C. (See here, here, here and here.)

The move by the state agency came as reliance on traditional scientific journals for publication of research findings has encountered heavy criticism in recent years for wasting billions of dollars and costing lives.

Ellen Feigal, CIRM photo

Ellen Feigal, senior vice president for research and development for the California agency, and Natalie DeWitt, CIRM's special projects officer, wrote in the latest edition of the journal that the “Proceedings” would consist of a “monthly series (in the journal) of commentaries, articles, interviews, webinars, forums, and concise reviews on a wide range of topics in regenerative medicine.”

The agency executives said,

“Under our direction as series co-editors, the Proceedings will create a dynamic forum for the broad international community of scientists, policymakers, and stakeholders engaged in stem cell research.”

Natalie DeWitt, CIRM photo

The kickoff article dealt with the sharing of clinical trial data, which, Feigal and DeWitt wrote, is “a thorny issue that continues to spur worldwide debate and one for which the regenerative medicine community can shape the discussion at an early stage.”

They said,

“Forthcoming Proceedings will include articles such as policy and scientific considerations surrounding the creation of induced pluripotent stem cell (iPSC) banks; the global regulatory environment for developing stem cell-based therapies; and reports from various focused workshops, such as on bottlenecks in research on Parkinson's disease and ocular disorders, as well as progress in research to generate blood and liver tissues.”

The Proceedings' first offering was authored by Feigal and DeWitt along with CIRM staffers Geoff Lomax and Maria Millan. It said that more information sharing would speed research among scientists but that sharing would need to be “de-risked” by developing standards that protect proprietary information.

The article also discussed, in two dense paragraphs, a need to provide some provide some sort of cash incentive for sharing data. The authors wrote,

“Consideration should be given to mechanisms for rewarding the deposit of data. For example, performance metrics for monetizing the deposit of high-quality data should be considered. Like an investigator's publication record, such a system could be weighted in peer review and progress reporting. Monetization should also be evaluated from the perspective of system quality and sustainability. If quality data can serve to reduce sponsor costs, then reasonable fees or royalties may be appropriate.

“Contract research organizations have ex tensive experience and expertise in data generation, analysis, and management, but funding constraints may not allow them to participate in data sharing. Again, reimbursement mechanisms may bridge this gap.”

The journal provides free online access to individuals but institutional subscriptions can exceed $1,000 a year.

Strangling Science: Antiquated System Wastes Billions, Costs Lives

The scientific community in California and the nation is fraught with worry about declining financial support for academic research. At the same time, however, as scientists wring their hands about the lack of funding, they are going along with the waste of more than $10 billion that could be used to help relieve the cash shortage.

What this is all about is the “stranglehold” that scientific journals have on publishing the results of the research paid for almost entirely by taxpayers. That research is the foundation of the journal industry, which is both highly profitable and a powerful lobby in Washington as it seeks to maintain its franchise. The industry is also based on a 400-hundred-year-old system that not only wastes money but costs lives because of its tediously slow mechanisms.

“Tragically insane” and unnecessary is how respected UC Berkeley researcher Michael Eisen describes the whole business, which is nearly invisible to the general public. That is, until one of its members starts to seek publicly financed information that is buried behind expensive paywalls.

Michael Eisen
UCB Alumni Association photo

Scientists are the unpaid workers for journals, submitting their articles for what they hope will be professional prestige and advancement. They do so, Eisen said, “while they acknowledge that their business practices are bad for science and the world.”

Last year, Eisen spoke to the Commonwealth Club in San Francisco about the subject. His speech was carried in a somewhat truncated form in this past winter's issue of the UC Berkeley alumni magazine. One of the headlines on the article asked,

“In the age of the Internet, why is so much research inaccessible?”

What Eisen had to say is worthy of careful thought as the $3 billion California stem cell agency faces financial extinction and the NIH sees its budget under increasing pressure. It seems a dubious proposition for scientists to give away the fruits of their labor and then have to pay for critically necessary access. Here is how Eisen described the situation along with additional excerpts from his speech.

“Every year universities, governments and other organizations spend in excess of $10 billion dollars to buy back access to papers their researchers gave to journals for free, while most teachers, students, health care providers and members of the public are left out in the cold. 

“Even worse, the stranglehold existing journals have on academic publishing has stifled efforts to improve the ways scholars communicate with each other and the public. In an era when anyone can share anything with the entire world at the click of a button, the fact that it takes a typical paper nine months to be published should be a scandal. These delays matter – they slow down progress and in many cases literally cost lives.”

Eisen continued,

“Tonight, I will describe how we got to this ridiculous place. How twenty years of avarice from publishers, conservatism from researchers, fecklessness from universities and funders, and a basic lack of common sense from everyone has made the research community and public miss the manifest opportunities created by the Internet to transform how scholars communicate their ideas and discoveries.”

Eisen decscribed the role of the scientific publications.

“I want you to note just how little the journal actually does here. 

“They didn’t come up with the idea. They didn’t provide the grant. They didn’t do the research. They didn’t write the paper. They didn’t review it. All they did was provide the infrastructure for peer review, oversee the process, and prepare the paper for publication. This is a tangible, albeit minor, contribution, that pales in comparison to the labors of the scientists involved and the support from the funders and sponsors of the research. 

“And yet, for this modest at best role in producing the finished work, publishers are rewarded with ownership of – in the form of copyright – and complete control over the finished, published work, which they turn around and lease back to the same institutions and agencies that sponsored the research in the first place. Thus not only has the scientific community provided all the meaningful intellectual effort and labor to the endeavor, they’re also fully funding the process. 

“Universities are, in essence, giving an incredibly valuable product  – the end result of an investment of more than a hundred billion dollars of public funds every year – to publishers for free, and then they are paying them an additional ten billion dollars a year to lock these papers away where almost nobody can access them.
“It would be funny if it weren’t so tragically insane.”

How does it affect the public, particularly persons with serious diseases? Eisen answered,

“This is most obviously a problem for people facing important medical decisions who have no access to the most up-to-date research on their conditions – research their tax dollars paid for. In a world where patients are increasingly involved in health care decisions, and where all sorts of sketchy medical information is available online, it is criminal that they do not have access to high quality research on whatever ails them and potential ways to treat it. 

“Astonishingly, many physicians and health care providers also lack access to basic medical research. Journal subscriptions in medicine are very expensive, and most doctors have access to only a handful of journals in their specialty. 

“But this lack of access is not just important in the doctor’s office. Scores of talented scientists across the world are blind to the latest advances that could affect their research. And in this country students and teachers at high schools and small colleges are denied access to the latest work in the fields they are studying – driving them to learn from textbooks or Wikipedia rather than the primary research literature. Technology startups often can not afford to access to the basic research they are trying to translate into useful products.”

Supporters of the journal industry argue that it is necessary because it provides for peer review of research results, thus ensuring the integrity of the science. Eisen said, however, that current peer review “poisons science.”

“Peer review is the closest thing science has to a religious doctrine. Scientists believe that peer review is essential to maintaining the integrity of the scientific literature, that it is the only way to filter through millions of papers to identify those one should read, and that we need peer reviewed journals to evaluate the contribution of individual scientists for hiring, funding and promotion.

“Attempts to upend, reform or even tinker with peer review are regarded as apostasies. But the truth is that peer review as practiced in the 21st century poisons science. It is conservative, cumbersome, capricious and intrusive. It encourages group think, slows down the communication of new ideas and discoveries, and has ceded undue power to a handful of journals who stand as gatekeepers to success in the field.

“Each round of reviews takes a month or more, and it is rare for papers to be accepted without demanding additional experiments, analyses and rewrites, which take months or sometimes years to accomplish.

“And this time matters. The scientific enterprise is all about building on the results of others – but this can’t be done if the results of others are languishing in peer review. There can be little doubt that this delay slows down scientific progress and often costs lives.”

Eisen continued,

“So, while it is a nice idea to imagine peer review as defender of scientific integrity – it isn’t. Flaws in a paper are far more often uncovered after the paper is published than in peer review. And yet, because we have a system that places so much emphasis on where a paper is published, we have no effective way to annotate previously published papers that turn out to be wrong.”

Flawed stem cell research has made international headlines in recent months. They came in the case of a peer-reviewed paper published in the world's most prestigious journal, Nature. Hundreds, if not thousands, of other examples exist that are chronicled on a Web site called Retraction Watch.

High Priests vs. Open Access to Research

The high priests of the newspaper business – otherwise known as editors and publishers -- have learned about the power of the Internet the hard way. Their business is turning remorselessly downward as advertisers shift their dollars to chase readers who have abandoned print.

Now comes the turn of the high priests of scientific journals. And the forces at work are something that the California stem cell agency will have to confront as it deals increasingly with public access to publicly funded research findings and how quickly that access becomes available.

Merrill Goozner, director of the Integrity in Science project for the Center for Science in the Public Interest, wrote recently that both houses of Congress have approved legislation that would provide free public access to all published articles from NIH-funded research. The measure was opposed by publishers who say that their ability to support independent peer review requires exclusive copyrights.

Goozner cites an article in The Scientist that points out that there may be a link to profits, which in turn are linked to salaries, for example, at the American Chemical Society, which generates $500 million a year from its 36 journals. Several top executives at the society earn more than $750,000 a year.

Any researcher working for a private company knows that he who pays the piper calls the tune. The fact is that taxpayers finance this research. At the heart, they own it just as much as a bank owns a mortgaged house or shareholders own a company.

The Internet is like a tidal force. Resisting its imperative may appear to be possible in the short term, but over the long term the high priests will be sweep out to sea. The alternative is come up with a better business plan and to find a way to ride the tide instead fighting it.

CIRM's Research Standards -- A Look at Their Principles and Reasoning

If you looking for a good overview of the rationale and background for the research standards enacted by the California stem cell agency, check out an article on PLoS Medicine by three men deeply involved in the subject.

The piece is called "Responsible Oversight of Human Stem Cell Research: The California Institute for Regenerative Medicine's Medical and Ethical Standards." It was written by Geoffrey P. Lomax, Zach W. Hall and Bernard Lo.

Hall is the former president of CIRM. Lomax deals with the institute's research standards development. Lo is with UC San Francisco, where he deals with medical ethics. He also serves as co-chair of CIRM's standards working group.

The ESC regulations developed by CIRM broke new ground in some areas and were the most refined in the nation at the time they were promulgated.

The article notes:

"Because other states and jurisdictions may also be developing standards for hESC research, consideration of the principles that guided the CIRM efforts and the innovative measures that it enacted may be useful to others."

One of the excellent attributes of the piece is that it is not hidden behind a private Web site that costs hundreds of dollars to access. It can be found gratis at the www.plosmedicine.org.