Ballot Campaign Hype and Erosion of Trust in Science

The matter of trust came up last week in an item on the California Stem Cell Report that dealt with the Proposition 14 campaign and how hype can erode the people's faith in science.

The following comment was sent via email by a person very well-versed in science, research and human behavior who, however, must remain anonymous.

"What would be the rationale behind trusting science any more than trusting Google, a cable news network, or politician? 

"Science is the work product of scientists, who are human beings the last time I looked. Inherently interested and incentivized human beings, as we all are. 

"Sure, they often tout themselves as 'independent' or 'neutral and disinterested' parties in this business. But rest assured that is just marketing. For there is lots and lots of money at stake. Money that directly benefits and influences these neutral arbiters of truth in exactly the same way as it benefits and influences the executives at Facebook.

"I'm not criticizing, only pointing out the reality that economic forces, like gravity, apply to everyone. No profession is exempt. In that sense, science is trustworthy. Having been paid for, the outcome is both predictable and assured."

****

​A new book about the stem cell agency includes a discussion of trust and the California stem cell agency based on comments from the Institute of Medicine, which performed a $700,000 evaluation of the enterprise. Authored by David Jensen, you can buy the book on Amazon:  California's Great Stem Cell Experiment: Inside a $3 Billion Search for Stem Cell Cures. Click here for more information on the author.

Quote of the Day: 'Immunity to Science'

“We’re now in this position where scientific information is treated as something that you believe or don’t believe because of your partisan leanings. We’ve become a society that has developed an immunity to science, that has said, well none of these guys can be believed.”
 -- Lucy Jones, seismologist, in Los Angeles Times

A $59 Million Matter of Fraud and Hubris: The Anversa Stem Cell Story and Its Fallout

Piero Anversa -- NYTimes photo by Annie Tritt

Fabricated stem cell research and its fallout are back in the news this morning with excellent pieces from the New York Times and the Washington Post involving talk of "temptation" and the weakness of prestigious institutions.

First the piece by Gina Kolata in the New York Times,which includes the first substantial interview with Piero Anversa, the former Harvard researcher now identified as having produced more than 30 studies containing falsified or fabricated data dealing with heart research. Kolata wrote,

"Dr. Anversa’s story has laid bare some of the hazards of modern medical research: the temptation to embrace a promising new theory, the reluctance to heed contrary evidence and the institutional barriers to promptly stopping malfeasance. Even after three independent researchers were unable to reproduce his findings in 2004, Harvard hired him in 2007 and his lab continued to churn out studies upholding his theory."

Anversa, 80, is now living in New York. He told Kolata in an interview in his apartment that he did nothing wrong and that he was "betrayed by a rogue colleague who altered data in paper after paper."

Kolata has more from Anversa, but also dives into the history and ramifications of the scandal and its implications involving the culture of science. She described the case as "a particularly acrid cautionary tale of scientific hubris."

A couple of highlights from the piece.

• "'Science at this level is like a battleship, and it’s really hard to turn it around,' said Dr. Jonathan Moreno, a professor of bioethics at the University of Pennsylvania.'People get emotionally invested, financially invested, professionally invested.'" 

• “'This was a perfect storm of ego, wishful thinking and lack of accountability,' said Dr. Jil C. Tardiff, a professor of medicine at the University of Arizona, and a heart-muscle cell researcher."'

 Kolata concluded:

"It did not surprise some in academia that the bold promises of the research persisted despite the contested evidence. 

 "There was an argument in the philosophy of science about whether there is such a thing as a ‘crucial experiment,' said Dr. Moreno, the ethics professor, referring to a study that answers a question once and for all. 

"'It turns out there isn’t. People can see what they want to see.'"

Carolyn Johnson of the Washington Post covered much of the same ground but has more on suspension of a clinical trial related to Anversa's work. Johnson also pointed out that Anversa received $59 million from the federal government for his research. Harvard has since been fined $10 million by the federal government.  

The trial is in the midst of recruiting patients. Johnson wrote,

"The decision to temporarily pause the trial came 'out of an abundance of caution,' said David Goff, director of the Division of Cardiovascular Sciences at the National Heart, Lung and Blood Institute, who said the trial’s scientific rationale is largely based on animal studies not conducted by Anversa.... 

"Goff said the board charged with overseeing the safety and integrity of the trial was convened last week and NIH leadership made the decision to pause the trial, which has enrolled 125 of 144 patients, to allow a thorough review.

"'Our commitment, first and foremost, is to patient safety. We haven’t seen any safety signals related to the cell treatment, but we can’t do any of our research without the partnership of our participants, and we make a commitment to our participants that their safety is our highest priority,' Goff said. The pause will allow the board to examine the trial and 'assure that it continues to meet the highest levels of adherence to participant safety and scientific integrity.'"

Fabrication and Stem Cell Research: A Tale of 31 Retractions (Maybe), $63 Million and Heavy News Coverage

Stem cell research fraud was big news this past week. It involved millions of dollars, the reputations of researchers and prestigious institutions, lots of wasted work and damage to the entire field. 

The case, which attracted international attention in the mainstream media, involves a prominent heart researcher, Piero Anversa, formerly of  Harvard, and requests for 31 retractions.  STAT/Retraction Watch broke the story in a piece written by Ivan Oransky and Adam Marcus. The New York Times, the Washington Post and other publications followed. 

As the New York Times summarized, Anversa "fabricated or falsified data in 31 published studies that should be retracted, officials at the institutions have concluded." Harvard has been fined $10 million by the federal government.  

Carolyn Johnson of the Washington Post quoted a California stem cell researcher:

"'This body of work has, for better or worse, been hugely influential,' said Eduardo Marbán, director of the Smidt Heart Institute at Cedars-Sinai Medical Center. 'Despite the fact that several prominent laboratories failed to confirm key findings, c-kit positive heart cells were rapidly translated to clinical testing in heart failure patients. … One can only hope that no patients have been placed at risk in clinical trials based upon fraudulent data.'"

Another California researcher, Benoit Bruneau, was quoted by the New York Times. 

"A couple of papers may be alarming, but 31 additional papers in question is almost unheard-of,' said Benoit Bruneau, associate director of cardiovascular research at the Gladstone Institutes in San Francisco. 'It is a lab’s almost entire body of work, and therefore almost an entire field of research, put into question.'"

Gina Kolata of the New York Times wrote, 

"Despite the troubling questions that had been raised about the stem cell work, the National Heart, Lung and Blood Institute began a clinical trial of injected stem cells for patients with heart failure.... 

"In the past few years, however, skeptical researchers moved on to other prospects for heart treatment. 'The field has backed off a lot,' (Jeffery) Molkentin (a professor at the Howard Hughes Medical Institute) said.

"Some scientists wondered how a questionable line of research persisted for so long. Maybe, Dr. Molkentin said, experts were just too timid to take a stand."

Some researchers have called for suspension of the $63 million clinical trial, including Deepak Srivastava, president of the Gladstone Institutes and president-elect of the International Society for Stem Cell Research.

Here are links to other coverage of the matter, which is been brewing for several years: The Niche, The Scientist, Medscape, Biospace and the  Harvard Crimson.

Stem Cells, Anonymous Commentary and Silence Dogood

What do Benjamin Franklin and Mrs. Silence Dogood have to do with the affairs of the $3 billion California stem cell agency?

Very little -- directly -- is one answer. The other answer is that Ben and the publicly spirited Mrs. Dogood had a lot to do with the publication of strong views that run afoul of the established order.

Ben Franklin, Getty Images

Silence Dogood, you see, was a pen name for Ben early in his career. He used it successfully to get his thoughts into print. It made Franklin, as a writer, anonymous -- thus overcoming the barrier that use of his own name posed.

All of which raises the topic of the day -- publication of anonymous comments concerning articles on the California Stem Cell Report -- more particularly the comment this morning on the ViaCyte item earlier this week.

In advance of today's publication of the comment, ViaCyte was offered, in the spirit of fairness, an opportunity to respond to the anonymous writer. Declining on behalf of the San Diego company was Jessica Yingling, president of Little Dog Communications Inc., of San Diego. She also asked whether “it is normal to have comments like this.”

My email reply to her earlier this week said, yes, it is relatively common to permit anonymous comments on the California Stem Cell Report. As I replied, I thought others were likely to have similar questions. Thus this piece came about.

But first, it is helpful to understand just how anonymous comments work on Blogger, the Google-owned platform for the California Stem Cell Report.

Google allows readers, at the option of the blog publisher, to make comments anonymously. Google controls the method that protects the anonymity of the writer. When I receive an anonymous comment, I do not and cannot know the names of persons who file them. But I do moderate them.

I permit anonymous comments because of the nature of the scientific community, the stem cell agency and the biotech industry. Of particular importance is that the agency is, in fact, a state government body and is spending public money. However, it is not answerable to the governor or the legislature because of the terms of the ballot measure that created it, Prop. 71. That is not the case for nearly all other state agencies. Currently the agency, formally known as the California Institute for Regenerative Medicine (CIRM), also functions almost invisibly with little attention from any media, mainstream or otherwise.

Over the past 13 years of writing about this rather large source of public funding for stem cell research, I have found that many persons in the field are reluctant to comment with complete candor, sometimes because it may appear to others in the field that their comments are unseemly. In other cases, people in the field are simply afraid of possible financial or professional repercussions if they make comments that some may find objectionable, no matter how well founded. If anonymous comments were barred entirely, it would mean a loss of a certain perspective about the agency and sometimes useful information about how the stem cell industry and the agency works. That said, not all anonymous comments satisfy that criteria.

I do not publish all anonymous comments. Some have been libelous. A few have been deranged. Others are nothing more than spam.

Reasonable people can and do differ about the use of anonymous comments on blogs or in the mainstream media, which are very different animals. During my decades of covering and editing news as well as directing coverage, use of anonymous sources has always been a matter of debate and controversy. I acknowledge that some, perhaps many, anonymous writers may be grinding a particular axe. On the other hand, the targets of such comments are not always forthright. It is not necessarily in their interests to disclose bad news. The media can also be easily manipulated by "official" sources, something I have seen occur widely over the past five decades.

Indeed, the backers of Prop. 71 in 2004 were less than forthright during ballot campaign that created the stem cell agency. But such is the nature of such political activities.

Ben Franklin was an adroit politician as well as a clever writer and advocate. He also hid his identity under many pen names during his life in the 18th century. Today I have no doubt that Silence Dogood would have no difficulties with our judicious posting of anonymous comments on the California Stem Cell Report.

For those of you would like to comment on this topic, please feel free. Just click on the word “comments” at the end of this item. Perhaps we will hear from some of Mrs. Dogood’s descendants.

California's Consumer Watchdog Loses U.S. Supreme Court Challege to WARF Stem Cell Patents

The U.S. Supreme Court yesterday appeared to have put an end to a California’s group nine-year effort to overturn patents on human embryonic stem cells held by the Wisconsin Alumni Research Foundation (WARF).

The court refused to hear the case that was brought by Consumer Watchdog of Santa Monica, Ca., and Jeanne Loring, head of the stem cell program at Scripps. The court issued its decision with no comment.

An article by Lisa Shuchman in The Litigation Daily said,

“The high court's denial leaves in place a ruling last year by the U.S. Court of Appeals for the Federal Circuit, which found that Consumer Watchdog lacked standing to appeal the findings of the PTO's (Patent and Trademark Office) administrative patent review board.” 

While today’s ruling involved relatively technical legal matters, the heart of the challenge to WARF’s patents involves who profits from stem cell research along with whether its patents have or will stifle scientific research.

Royalties from WARF patents in California alone generated an estimated $200 million in 2006 for the foundation. Executives of biotech firms in California have complained that WARF’s restrictions have posed a significant barrier to private investment. 

Asked for comment, Loring said,

"This doesn't mean they believe that human cells can or cannot be patented, but only that they decided that we had not been sufficiently harmed by the patent for them to become involved.

"Even without a Supreme Court decision, we have succeeded.  WARF wanted their patents to include iPS cells as well as ES cells, but they had to narrow their claims as a result of our challenge, and they cannot claim ownership of iPSCs."  

Doing the legal lifting in the WARF challenge was Dan Ravicher, executive director of the Public Patent Foundation of New York. Shuchman carried a comment from Ravicher on yesterday’s ruling. She wrote, 

“Ravicher said Monday that the Supreme Court's decision could impact many would-be patent challengers. ‘This case could have severe consequences for other third parties that challenge patents with IPRs or the other proceedings created under the America Invents Act,’ Ravicher said. ‘Now they will have no right to appeal an adverse decision.’

“But he also said the decision wouldn't preclude individuals who can claim direct harm, such as stem cell research scientists, from challenging WARF's patent—much the same way doctors successfully challenged the Myriad patents.

“Under the America Invents Act, third parties, such as nonprofits, public interest groups and industry organizations, have the right to challenge patents at the PTAB (Patent Trial and Appeal Board). But under the Federal Circuit’s ruling that now stands, they don't have the right to appeal a PTAB decision.”

Shuchman also recounted briefly some unusual history on the federal appellate ruling that declared Consumer Watchdog had no standing to sue. A more detailed account of that hearing can be found here.

The California Stem Cell Report has asked Consumer Watchdog and WARF for comments. We will carry them when we receive them. Here is the full text of what Loring had to say.

"Being involved for nearly 9 years in the challenge of WARF's patent on human ES cells has given me a fascinating glimpse into our legal system. I hoped that the Supreme Court would decide on the patentability of human embryonic stem cells. But ultimately, the Court decided not to take our case.  This doesn't mean they believe that human cells can or cannot be patented, but only that they decided that we had not been sufficiently harmed by the patent for them to become involved. Even without a Supreme Court decision, we have succeeded.  WARF wanted their patents to include iPS cells as well as ES cells, but they had to narrow their claims as a result of our challenge, and they cannot claim ownership of iPSCs.  

"I've learned that the law is every bit as complex as scientific research, and have gained great admiration for people like our attorney, Dan Ravicher, who relentlessly pursue the question of patent ethics - what should and should not be patented in the public interest.  Dan brought the issue of patenting the human genome to the Court, and won (the Myriad Genetics case).  Working on this challenge with Dan and John Simpson (of Consumer Watchdog) has been a joy, and if they ever want my help in the future, I'd agree in a second."

San Francisco Business Times: CIRM 2.0 is 'Business-Friendly,' 'All-Out Charge' for Stem Cell Cures

Official approval yesterday of the California stem cell agency’s new, $50 million fast-track research effort has generated a lengthy piece in the San Francisco Business Times, a weekly newspaper that circulates widely in an area known for its biotech enterprises.

Ron Leuty authored the article, which could be considered an anniversary overview of the agency as much as anything else. The springboard was the CIRM board action yesterday on CIRM 2.0. Kathy Robertson of the Sacramento Business Journal also had a piece albeit briefer.

Leuty described the plan as “business friendly” and critical to the agency’s future if it is to secure funding beyond 2020.  He wrote,  

“CIRM leaders always stressed that the road from research to the clinic would is unavoidably long and winding. But now, as they talk of seeking another round of cash — possibly asking taxpayers for $5 billion to make its mission permanent — they realize that a high-profile medical victory in the next 24 months may be the only realistic way to make their case.”

Leuty said that Randy Mills, who has served as president of CIRM only since May, “is leading an all-out charge to make the agency more responsive with its remaining six years of cash — and to show the results that could convince others that CIRM must continue to be a long-term stem cell research player.”

Leuty continued,

“Plans for a warp-speed CIRM is not without its critics. 

“Some researchers think the agency should be investing more in basic stem-cell research that may provide the progress that could give private investors confidence. They include people like Dr. Arnold Kriegstein, director of the stem cell program at the University of California, San Francisco.

 "'A modest investment in basic science will pay greater dividends,’ Kriegstein said.

 "A speed-focused CIRM may also not be best for taxpayers, said John Simpson, an advocate with Consumer Watchdog and a frequent CIRM critic.

 "’I understand that they want to be more efficient,’ Simpson said. ‘I question whether they can do it with the necessary and thorough vetting of proposals.’" 

Leuty also had this from Kriegstein: 

"Even in pharma, with all the experience and depth, the likelihood of success is relatively small. The stem cell pathway is less certain. There's bound to be more risk." 

The California Stem Cell Report would like to note that the California stem cell community has been all but silent on the Mills’ CIRM 2.0 plan. The agency has had four hearings on the matter since September. The number of persons from the research community commenting at those sessions has numbered less than 10, perhaps less than five. Kriegstein was not on the scene nor was Simpson.

We should also note that researchers, with a few notable exceptions, have rarely appeared before the the CIRM board over the last 10 years as it has set its priorities and established the rules for the funding that have had a major impact already on hundreds of California scientists.

The California stem cell agency offers a valuable opportunity for researchers to influence decision-making and priorities. They should take advantage of it. Coming before the board after the fact and complaining about this or that flaw in CIRM processes is far too late.

Researcher Takahashi Honored as Stem Cell Person of the Year

Riken photo

Masayo Takahashi, the scientist in Japan who is leading the first clinical trial involving reprogrammed adult stem cells, today was named the stem cell person of the year.

The announcement was made by Paul Knoepfler, the UC Davis stem cell researcher who sponsors the award and personally funds its $2,000 prize.

Knoepfler said,

“In an astonishing feat, Takahashi's team transplanted its first macular degeneration patient recently on September 12, only 7 years after human IPSCs (induced pluripotent stem cells) were first ever published.”

The development of IPS cells, which also originated in Japan, has been hailed because they remove the moral objections that some persons have concerning the use of human embryonic stem cells. Many scientists, however, continue to consider the human cells as the gold standard.

Takahashi is a physician-scientist and a faculty member and project leader at the Laboratory of Retinal Regeneration at the Center for Developmental Biology at RIKEN.

Last December, Takahashi said she was wary of the high economic expectations surrounding potential stem cell therapies. In an article in the Financial Times by Jonathan Soble, she said, 

“Start-up companies are already involved and the road to commercialization is there, but to assume that the concept of iPSCs and regenerative medicine will yield a lot of money is naïve. Only parts of the field will become industries. It’s dangerous to think that all of regenerative medicine will.”

Takahashi was introduced to the field of stem science in 1995 when she followed her husband to the Salk Institute in the San Diego area in California.

Soble wrote,

“Paradoxically, because she had chosen clinical research, academia’s mix of glass-ceiling sexism and disdain for applied science worked in her favor. ‘I could do what I wanted because I was a woman,’ she says. ‘I didn’t think about career advancement.’”

She said barriers to women in science have largely disappeared in Japan although the comment was made before the STAP scandal that involved Riken. A key figure in the STAP research was a woman scientist, and persons prejudiced against women in science may well to use it to justify their biases.

Takahashi did say last year that traditional cultural values remain a problem in Japan. She said,

“'Japanese women don’t want to stand out, they don’t want to be leaders. They don’t think, ‘I want to have my own lab and reach the top in my field.’ I certainly didn’t until Salk.’ But Dr. Takahashi believes things are changing, in part because of the growing number of role models such as herself. ‘Sometimes,’ she says, ‘I meet young women who tell me, ‘You’re cool.’”

Los Angeles Times: California Stem Cell Agency Rife with Conflicts and Unrealistic Expectations

The Los Angeles Times, California’s largest circulation newspaper, is carrying a piece this weekend about “cronyism,” conflicts of interest and “inflated expectations” at the state’s $3 billion stem cell agency.

The column by Pulitzer Prize-winning writer and author Michael Hiltzik used this month’s Trounson Affair as a starting point to dissect the situation at the California Institute for Regenerative Medicine (CIRM), as the agency is formally known.

Trounson was appointed to the board of StemCells, Inc., of Newark, Ca., on July 7, just seven days after leaving the agency. StemCells, Inc., holds a $19.4 million award from the agency.  CIRM has ordered a full review of the situation and barred its staff from communicating about StemCells, Inc., matters with Trounson. 

But even before Trounson’s appointment, there were issues involving StemCells, Inc.(See here and here.)  Hiltzik said,

 “The relationship already reeked of cronyism.”

Hiltzik wrote,

“Trounson's move comes as CIRM must begin looking to the future, but any discussions about extending the agency's life span will have to address the flaws created by Proposition 71 (the ballot initiative that created the agency in 2004). Among them is the program's very structure, and even its scientific goals.”

Hiltzik continued,

“How bad are the conflicts? When the board considered a proposal earlier this year to spend $16 million to attract three star scientists to California, so many members had to recuse themselves that only nine were left to vote. (Six ended up voting in favor.)

“When conflicts of interest are so rife that only one-third of your board can weigh in on a major policy issue, that's tantamount to not having any board at all.”

Some of the issues at the agency have to do with the ballot campaign that created it in 2004, an election in which California voters were led to believe that miraculous stem cell therapies were imminent.

Hiltzik wrote,

“Programs like CIRM are always susceptible to inflated expectations.

"”Since Big Science needs great public support it thrives on publicity,’ the physicist Alvin Weinberg, a veteran of the Manhattan Project, wrote in a famous 1961 article in "Science" about the drawbacks of big-money scientific research. He added: ‘The inevitable result is the injection of a journalistic flavor into Big Science which is fundamentally in conflict with the scientific method.... The spectacular rather than the perceptive becomes the scientific standard.’"

Hiltzik acknowledged the contributions that CIRM has made to stem cell science.

“CIRM-funded labs have produced genuine achievements. But the agency tends to delineate its progress in buildings built, papers published, and big-name scientists lured to California. But the specific cures promised by the Proposition 71 campaign haven't materialized, which doesn't surprise anyone steeped in the realities of the scientific method.”

Hiltzik concluded,

“Even if one believes the need for California to devote $3 billion to a narrow, extremely speculative field of science, the Trounson case and other CIRM administrative missteps have made clear that Proposition 71 created the wrong framework to manage a complex research effort. The initiative left the public with no way to tell if its money has been well spent, and no accountability if it hasn't.

“Moreover, the program deprived potentially more promising research efforts of resources and contributed to the general impoverishment of California's entire higher-education system. If its sponsors have the audacity to ask taxpayers for even more money under the same terms as Proposition 71, the reply should be a resounding ‘no.’ If the voters are gullible enough to repeat the same mistake they made in 2004, there's no cure for them.”

The Hiltzik column appeared online last night. It is scheduled to appear in the Sunday print edition of the Times, which says it has a combined print and online reach of 4 million readers. 

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.

California Biotech Guru Steven Burrill in 'Deep Yogurt'

Steve Burrill is perhaps the leading maven on biotech in California as well as nationally. 

He has raised more than $1 billion for life sciences financing via his investment banking firm. He publishes an annual state-of-the-industry study that is something of a bible.

He is an omnipresent speaker at major biotech conferences. In 2006, his firm organized a stem cell conference that was partly a celebration of the California stem cell agency. Next week he is scheduled to be a keynote speaker at the huge BIO2014 industry conference in San Diego, which is expected to be attended by 16,000 persons.

Today, however, the Web site for his investment firm is shut down. The headlines about him on the Internet are less than pleasant. To use an expression that Burrill sometimes utters, he is in “deep yogurt.”

Nathan Vardi broke the story yesterday on Forbes. The piece was headlined 

"Steven Burrill Removed From Control Of Venture Fund For Unauthorized Payments”

Other stories used terms like “disbelief,” “fraud allegations,” “ousted” and "dumped."

Vardi’s snynopsis of the allegations said,

"G. Steven Burrill, the CEO and founder of Burrill & Co., a San Francisco financial firm specializing in biotechnology and life sciences investing, was ousted from control of a $283 million venture capital fund earlier this year by big institutional investors that cited willful or reckless misconduct related to unauthorized payments, according to documents recently filed in California State court in San Francisco." 

Alex Nash at Xconomy wrote,

“Burrill, known for his natty suits and pink shirts, is being sued for fraud by a former colleague for allegedly taking cash meant for investment and diverting it to his own 'designees and affiliates.'”

Burrill has not yet responded to requests for comments from the media covering the situation. And it is not clear whether he will still appear for his scheduled 90-minute talk next Tuesday in San Diego.

All of this involves allegations and contentions in lawsuits. But the perception is not good. Burrill himself knows the importance of perceptions. A few years back he spoke to a group at Stanford about making money in biotech and said,

 “Perceived value is more important than real value.”

 (See embedded video at the top of this article.)

And in February in comments to the Tampa Bay Business Journal about California’s success in life sciences, he said,

“Culture is a big part of it. People want to be part of a culture that tolerates failure.”

Chasing the Sun and Stem Cells From San Diego

The San Diego U-T this morning carried a profile of stem cell researcher Jeanne Loring of Scripps, describing her as a “stem cell evangelist” and a believer in scientific collaboration as opposed to the solitary work her geologist father pursued.

Bradley Fikes, who covers biotech for the San Diego newspaper, wrote the piece about Loring, who is director of the Center for Regenerative Medicine at Scripps.

The article was unusual for the mainstream media, which generally focus its profiles on persons who are more in the public limelight – not scientists.

Fikes noted Loring's early career in biotech businesses in the San Francisco Bay Area in addition to the San Diego, both of which are biotech hot spots. He wrote,

“Unlike the 'pure' academic who regards partnerships with businesses as compromising science, Loring said ties with industry can be rewarding. Businesses can take basic research discoveries and turn them into drugs and other therapies, she said, and that 'translational' arrangement is hard to replicate in a walled-off academic setting.”

The article also touched on Loring's life away from the lab including a pursuit -- eclipses of the sun --that has taken her to Zambia, Libya and Bolivia.

“'The eclipse vacations are the perfect thing for us,' Loring said. 'You can always work, but the eclipse is going to happen at a certain time and a certain place, and you have to be there when it happens.'”  

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.

Sunlight, Stem Cells and Feathers

California stem cell researcher​/blogger Paul Knoepfler is reporting that he has ruffled some elite feathers in the stem cell community.

In a post last week, the UC Davis scientist said that his heavy coverage of the STAP stem cell flap appears to have offended some. He wrote,

“It seems (the) concept of not talking about bad news is well-entrenched in the stem cell field.... I’ve been informed that I’ve ruffled the feathers of a couple elite VIPs of the stem cell world by covering the STAP stem cell story on my blog and doing the stem cell crowdsourcing experiment. 

“Would they really prefer that we all just skip along merrily singing kumbaya? 

“The reality is that the STAP stem cell situation is a serious threat to the stem cell field. As someone who is a big fan of stem cells and advocates actively for stem cell research, I wasn’t going to turn a blind eye.”

Earlier, Knoepfler also defended his blogging on the subject after stem cell scientist George Daley of Harvard expressed “concern” about the use of social media to discuss the subject. I wrote about that situation on March 7, noting the value of social media as a communications tool.

To get another perspective on the subject, I asked Deborah Blum, the Helen Firstbrook Franklin Professor in the School of Journalism and Mass Communication at the University of Wisconsin, Pulitzer Prize winner and author of five books, for her thoughts. She replied,

“I like social media as a tool for transparency, Dave. It gets criticized for being overwrought, or witch-hunting in nature. But I didn't see that in Paul's post. This may explain, though, why he contacted me on Twitter about a post I wrote a while back called "The Trouble With Scientists" that is a defense of bloggers and smart scientist bloggers. Think of Rosie Redfield's blog post on the so-called arsenic-based life report that helped show the flaws. Or the blog Retraction Watch, by Ivan Oransky, who's both an MD and a journalist. The kind of thoughtful online discussion that I think you saw in Paul's piece adds to efforts to make research more open and more accessible. And acknowledging its flaws is just as important in the process as praising its successes. 

“And I do NOT believe a scientist should be punished for writing responsibly about issues in research. I think it's praiseworthy.”

Knoepfler has added this note to his ruffled feathers item,

“It’s important to point out here that I don’t think this STAP situation, even if it gets even worse, can derail the positive momentum of our field overall, but it can slow things down. Also, the stem cell field needs public trust. When I am out there communicating with the public about stem cells and answering their questions, sadly they often spontaneously mention 'scandals' and 'controversy.' Many folks seem to associate these with the stem cell field already.”

Our take: Trying to bury dubious matters and hide questionable activities has led to the downfall of many organizations and individuals. If the stem cell field is to prosper, especially in age of lightning communications, its leaders should be forthright, open and transparent, whether the matter involves replication of research or conflicts of interest. As the late U.S. Supreme Court Justice Louis Brandeis has been famously quoted, 

“Sunlight is said to be the best of disinfectants."

Flawed Research, Cursory Peer Review, Perverse Incentives

“Billions of dollars worth of wrong” is how the situation in life science research is described in the Los Angeles Times this week.

Strong words, but supported by findings from Amgen and Bayer HealthCare that may be well known in relatively tiny scientific circles but rarely heard in an outlet such as the Times. It is the largest circulation paper in California and says it reaches 8.6 million adults weekly in Los Angeles via print and the Internet -- not to mention its national pull.

The column on “verifiable facts” and science was written by Pulitzer Prize winner and author Michael Hiltzik.

Among other things, he cited a study by Amgen of Thousand Oaks, Ca., which examined 53 “landmark papers” in cancer research and blood biology. Only five could be proved valid, a shocking result, according to Amgen. Similar results were turned up by Bayer in Germany.

Hiltzik continued,

"'The thing that should scare people is that so many of these important published studies turn out to be wrong when they're investigated further,' says Michael Eisen, a biologist at UC Berkeley and the Howard Hughes Medical Institute. The Economist recently estimated spending on biomedical R&D in industrialized countries at $59 billion a year. That's how much could be at risk from faulty fundamental research.

"Eisen says the more important flaw in the publication model is that the drive to land a paper in a top journal — Nature and Science lead the list — encourages researchers to hype their results, especially in the life sciences. Peer review, in which a paper is checked out by eminent scientists before publication, isn't a safeguard. Eisen says the unpaid reviewers seldom have the time or inclination to examine a study enough to unearth errors or flaws.

"'The journals want the papers that make the sexiest claims,' he says. 'And scientists believe that the way you succeed is having splashy papers in Science or Nature — it's not bad for them if a paper turns out to be wrong, if it's gotten a lot of attention.'"

Hiltzik goes on to discuss the flawed nature of peer review and “perverse incentives” in scientific research along with the new PubMed Commons project at the NIH, which Hiltzik said is aimed at substituting “continuing scrutiny” for “ a cursory, one-time peer review.”

Hiltzik's main piece appeared on the Web yesterday. Today he had a follow-up dealing with the late Richard Feynman's “cargo cult science,” the term physicist used for published research that did not prove valid.

Hiltzik's bottom line?

"The demand for sexy results, combined with indifferent follow-up, means that billions of dollars in worldwide resources devoted to finding and developing remedies for the diseases that afflict us all is being thrown down a rathole. NIH and the rest of the scientific community are just now waking up to the realization that science has lost its way, and it may take years to get back on the right path."

Stanford Loses Star Stem Cell Researcher to Montana State University

Renee Reijo Pera, Stanford photo

The California stem cell community today chalked up its second departure of the month with the announcement that Renee Reijo Pera is leaving Stanford to join Montana State University.

The news about Reijo Pera, whose research is recognized internationally, comes only one week after Alan Trounson announced he was leaving his post as the president of the $3 billion California stem cell agency to return to Australia. 

Reijo Pera, 54, will become the new vice president for research, creativity and technology transfer at Montana State in Bozeman beginning Jan. 15. Currently director of Stanford's Center for Human Pluripotent Stem Cell Research and Education, Reijo Pera has won $24.4 million from the California stem cell agency in addition to her federally funded research.

She has been at Stanford since 2007 after leaving UC San Francisco. Prior to her 10 years at UC San Francisco, she was at MIT and the Whitehead Institute for Biomedical Research. (Her resume can be found here.)

Reporter Gale Schontzer of the Bozeman Daily Chronicle wrote anicely detailed story on Reijo Pera's appointment. Schonzter said that MSU research funding dropped 17 percent this year to $94 million, partly because of the loss of some researchers. She quoted a Montana spokesperson as saying that Reijo Pera “has amazing credentials that we think will continue to move our research forward.”

Schontzer reported that Reijo Pera's salary will be $200,000, “making her the third highest-paid administrator on the Bozeman campus.”

Reijo Pera also told the reporter that she “'absolutely loved' Stanford, but felt 'it's kind of time to do the next thing…. There is potential to do more at Montana State.'”

The news article also provided some interesting history on Reijo Pera. Schontzer said, 

“In high school, Reijo Pera said she had no interest in science or college. But after graduating and working as a car dealership bookkeeper, she wanted more. She enrolled at the University of Wisconsin-Superior to major in business. A class in human genetics for non-majors changed her life.”

Not mentioned in the Bozeman Chronicle story was a professional, Montana-Stanford linkage involving stem cell scientist Irv Weissman and Reijo Pera. In 2007, Weissman, director of the Stanford stem cell institute, hailed the hiring of Reijo Pera after playing a role in recruiting her.

Weissman has strong ties to Montana where he grew up and where he has a ranch.

Public Banned from 'Best Stem Cell Meeting in the World'

“The best stem cell meeting in the world” is underway today in San Francisco – conducted at taxpayer expense – but the public is barred from attending.

More than 500 persons are at the meeting at an undisclosed location, including some representatives of biotech firms. And the meeting is even being written about on the internet by a blogger. But the $3 billion California stem cell agency says the public is not allowed in because some of the information is “proprietary.”

CIRM President Alan Trounson addressed the meeting earlier this week and declared it was “the best stem cell meeting in the world,” according to UC Davis researcher Paul Knoepfler, who is reporting from the session on his blog.

The attendees consist almost entirely of the recipients of taxpayer-funded grants given by the stem cell agency  although a number of businesses have been brought in.. CIRM, which is paying for the gathering,  says of the annual sessions,

 “The purpose of meeting is to bring together investigators funded by CIRM, to highlight their research, and encourage scientific exchange and collaboration.”

Kevin McCormack, spokesman for the agency, today said the public was barred from the meeting, which ends tomorrow, because “so many presentations/talks (are) using proprietary information.”

That rationale is nothing new in the world of science. But there is no chance of maintaining secrecy about anything that is truly proprietary when hundreds of people have access to it in this sort of forum. No penalties exist for disclosure, plus the whole point of the session is to share information.

Yesterday we wrote briefly about the importance of transparency and openness in government, and make no mistake about it, the stem cell agency is a government operation. We doubt that anything egregious is underway at the session, but closing it to the public is a reminder about where the agency's priorities lie.  

Yamanaka and the Frailty of Peer Review

More than one back story exists on Shinya Yamanaka and his Nobel Prize, but one that has received little attention this week also raises questions about hoary practice of peer review and publication of research – not to mention the awarding of billions of dollars in taxpayer dollars.

The Yamanaka tale goes back to a 2010 article in the New Scientist magazine by Peter Aldous in which the publication examined more than 200 stem cell papers published from “2006 onwards.” The study showed an apparent favoritism towards U.S. scientists. Also specifically reported were long delays in publication of Yamanaka's papers, including in one case 295 days.

Here is part of what Aldous wrote,

“All's fair in love and war, they say, but science is supposed to obey more noble ideals. New findings are submitted for publication, the studies are farmed out to experts for objective 'peer review' and the best research appears promptly in the most prestigious journals. 

“Some stem cell biologists are crying foul, however. Last year(2009), 14 researchers in this notoriously competitive field wrote to leading journals complaining of "unreasonable or obstructive reviews". The result, they claimed, is that 'publication of truly original findings may be delayed or rejected.' 

“Triggered by this protest, New Scientist scrutinised the dynamics of publication in the most exciting and competitive area of stem cell research, in which cells are 'reprogrammed' to acquire the versatility of those of an early-stage embryo. In this fast-moving field, where a Nobel prize is arguably at stake, biologists are racing feverishly to publish their findings in top journals. 

“Our analysis of more than 200 research papers from 2006 onwards reveals that US-based scientists are enjoying a significant advantage, getting their papers published faster and in more prominent journals (find our data, methods and analyses here). 

“More mysterious, given his standing in the field, is why two of Yamanaka's papers were among the 10 with the longest lags. In the most delayed of all, Yamanaka reported that the tumour-suppressing gene p53 inhibits the formation of iPS cells. The paper took 295 days to be accepted. It was eventually published by Nature in August 2009 alongside four similar studies. 'Yamanaka's paper was submitted months before any of the others,' complains Austin Smith at the University of Cambridge, UK, who coordinated the letter sent to leading journals. 

“Yamanaka suggests that editors may be less excited by papers from non-US scientists, but may change their minds when they receive similar work from leading labs in the US. In this case, Hochedlinger submitted a paper similar to Yamanaka's, but nearly six months after him. Ritu Dhand, Nature's chief biology editor, says that each paper is assessed on its own merits. Hochedlinger says he was unaware of Yamanaka's research on p53 before publication.”

Last week, Paul Knoepfler of UC Davis wrote of other issues dealing with peer review, but coincidentally also dealing with iPS cells. What New Scientist and Knoepfler are discussing is not an isolated situation. It is part of a continuum of complaints, both serious and self-interested but exceedingly pervasive. A Google search today on the term “problems with peer review” turned up 10.1 million references.  Writing on Ars Technica last year, Jonathan Gitlin, science policy analyst at the National Human Genome Research Institute,  summarized many of the issues, citing a “published” (our quotation marks) study that said peer review doesn't work “any better than chance.” Gitlin said,

“A common criticism is that peer review is biased towards well-established research groups and the scientific status quo. Reviewers are unwilling to reject papers from big names in their fields out of fear, and they can be hostile to ideas that challenge their own, even if the supporting data is good. Unscrupulous reviewers can reject papers and then quickly publish similar work themselves.” 

At the $3 billion California stem cell agency, peer review is undergoing some modest, indirect examination nowadays. The agency is moving towards tighter scrutiny of budgets proposed by applicants. And, following a record wave of appeals this summer by disgruntled applicants rejected during peer review, it is also moving to bring the appeal process under more control.

As the agency tries to move faster and more successfully towards development of commercial therapies, it may do well to consider also the frailties of its peer review process and the perils of scientific orthodoxy.