A Stem Cell Media Story: The Case of the Missing Mention

Storks and stem cell blessings

California's $3 billion stem cell agency, which is fighting to demonstrate its value proposition, this week received what could be considered some favorable attention in the prestigious journal Nature.

The catch is that the 14-year-old research program was not mentioned by name by Nature.

The question is: How does that work and why it is important?

First things first: It is important because the agency, known formally as the California Institute for Regenerative Medicine (CIRM), is hoping that the voters will bless it with another $5 billion come the November 2020 election.

The agency expects to run out of money for new awards this year and is also trying to raise privately more than $200 million to tide it over until the 2020 election. In both cases, it needs clear successes that demonstrate that it has earned its keep and will do even better in the future. 

Unproven Therapies in Japan

The not-so-odd case from Nature involves an editorial that cited a CIRM-funded clinical trial.  Nature praised it as something to be emulated in Japan as an example of good ethics and good science. 

Nature's editorial zeroed in on how Japan has embarked on "a worrisome approach." The headlines said,  "Japan should put the brakes on stem cell sales. Unproven therapies should not be marketed to patients."

Instead, Nature declared that Japan should focus on the approach taken by Asterias Biotherapeutics, Inc., of Menlo Park, Ca., which arguably owes its existence largely to CIRM. (See here, here and here.)  Nature wrote, 

"Last week, a Californian company called Asterias Biotherapeutics released promising results from a 12-month first phase clinical trial, in which embryonic stem cells are converted into oligodendrocytes — cells of the central nervous system that support neurons and can stimulate their growth — and then injected into the backs of people with a spinal-cord injury. The data show that injected cells do stick around at the injury site, and that most patients (21 out of 22) showed improved movement. 

"But these are still early-stage results. It is not clear yet whether the improvements are the result of the cells, or whether something else, such as the body’s own regenerative capacity, was at work. To find out, the company wants permission to move forward with a randomized, controlled phase II clinical trial. That’s the right way to do things: stepping carefully, slowly and rigorously forward."

It's Not the Stork

The problem for the stem cell agency, of course, is that Nature did not identify CIRM as a player in the Asterias effort, although the agency has pumped more than $20 million into the research. The case of the missing mention is not an unfamiliar situation for the agency, which is often not noticed in news and press releases about the scientific accomplishments that it has backed with tens of millions of dollars. 

Of course, CIRM cannot take full credit for the Asterias work. And federal regulators have rules for clinical trials. But CIRM put up the cash for the research after Asterias' predecessor bailed out.  The agency also partners closely with its grantees and has a clear set of pioneering research standards that it worked out more than a decade ago. 

Obviously, CIRM would have been only a brief note, perhaps only a phrase in the Nature editorial if it had decided to include a mention. But these things add up and are needed by CIRM as it tries to tell California voters that it has been worth $3 billion. Their absence can amount ultimately to a substantial negative. 

One does not have to support more cash for CIRM to recognize that California voters need the full array of information about the agency to make an informed decision in 2020. Currently, however, the traditions and practices of scientific journalism regularly omit significant financial information.

When one reads about scientific advances in the mainstream media as well as journals, it seems as if the research magically materializes without a critical insemination of cash -- much like a baby being brought by the stork.

Perhaps it is time for CIRM, other research funding agencies and patient advocates to have a facts-of-life "talk" with the scientific press about the reality of what it takes to give birth to prodigious medical advances.

(Editor's note: Here is a related item by UC Davis stem cell research Paul Knoepfler on the Japanese program.)

Advancing Science, Avoiding Harm: New Fed Rules to Raise Curtain on Clinical Trial Results

The Wall Street Journal today carried a piece about sweeping, new federal research disclosure rules aimed at beefing up the public accessibility of findings of clinical trials backed by billions in public dollars.

The regulations are targeting what Francis Collins, head of the National Institutes of Health (NIH), has called a "disappointing" record of publishing clinical trial results.  He said that "both real and potential harm can result from failure to fully disclose the results of clinical trials."

The regulations are scheduled to roll out somewhat slowly but have been more than 20 years in the works. The Journal reporters, Daniela Hernandez and Amy Dockser Marcus, wrote online today,

"The new rules are part of a push for greater transparency and accountability for the NIH's huge investment in biomedical research. In the past, many organizations have failed to properly register studies and report their findings, actions that NIH officials say result in misspent funds, potential human harm and a lack of public trust in science. The NIH spends roughly $3 billion annually on clinical trials."

Violation of the rules carries the possibility of fines running up to thousands of dollars a day plus endangerment of future funding from the NIH.

Already at one California university, the requirements have increased the workload. The WSJ reported,

"Stanford University School of Medicine is 'adding five or six full-time employees to our overall infrastructure for human research,' said Mark Cullen, senior associate dean for research.

"Dr. Cullen said many of his researchers are still worried and confused about how the new policies will affect their work; the new hires are meant to add to an existing support system made up of roughly 100 staffers."

The NIH is particularly interested in reporting research that has negative results. The WSJ wrote,

"Under the old rules that required publication in journals, negative results often remained undisclosed because journals prefer to publish positive findings.

"'The release of negative results not only prevents duplication and potential unnecessary risk to human volunteers, it also advances our understanding of the science,' said NIH’s Dr. (Carrie) Wolinetz (NIH's associate director for science policy).

In 2015, Collins and Kathy Hudson, then NIH's deputy director for science, outreach and policy and now executive director of the People-Centered Research Foundation, wrote in JAMA,

"If the clinical research community fails to share what is learned, allowing data to remain unpublished or unreported, researchers are reneging on the promise to clinical trial participants, are wasting time and resources, and are jeopardizing public trust.

"The scientific community has a disappointing track record for dissemination of clinical trial results.

Inside STAP: New Yorker's Long Look at the Flap and its Implications

Over the weekend, the New Yorker published online a bang-up and thorough account of the STAP stem cell scandal of 2014. which stretched across the Pacific from Japan to Boston.

The subhead on the story said,

“Rivalries, intrigue, and fraud in the world of stem-cell research”

The piece was authored by Dana Goodyear, a writer for the New Yorker who also teaches writing at the University of Southern California.

UC Davis stem cell researcher Paul Knoepfler, who carried on his blog early and lengthy pieces on the STAP flap, today said of the article:

“It’s a long, fascinating look inside of STAP, the tangled and ultimately tragic scientific implosion that created and then brought down two Nature papers and some careers.”

Goodyear’s article brought out much fresh material, including a more detailed look at the history of the STAP research than has been previously published. The piece also contained probably enough scientific detail to satisfy the experts in the field.

But Goodyear also included thoughts on the stem field in general, issues related to scientific journals, hyper-competitiveness among researchers, replication of research and more. Here are a couple of excerpts from the article, which we highly recommend:

“The promises of stem-cell research lie at the core of human desires—to understand our origins and to cheat death—and there is a great deal of money and prestige at stake. It is a ruthlessly competitive field, susceptible to fantasy and correspondingly sensitive to bunglers. Human embryonic stem cells were first cultured in 1998; nearly twenty years later, basic assumptions about cell behavior are still routinely overturned. Andrew McMahon, a top researcher at the Broad Center for Regenerative Medicine and Stem Cell Research, at the University of Southern California, told me, “It’s not unusual to see something and not be able to explain it.” In reporting results, researchers must often craft a narrative to make sense of mysterious phenomena. What to ignore and what to privilege—that discernment can be the difference between brilliance and quackery, and between fame and obscurity.”

On the difficulties in replicating research findings:

“Many people believe this is partly the fault of the scientific journals. Along with the influential role that Nature has in shaping the trajectories of ideas, technologies, and careers, it is essentially a commercial enterprise. The editors like big stories, and for the right ones they take risks. Some observers complain that incentives to publish have a distorting effect, causing scientists to oversell data; a cutthroat culture sometimes leads researchers to publish intentionally incomplete or vague protocols. The perceived conflict between good science and prestige has become so pointed that, two years ago, Randy Schekman, a Nobel Prize-winning biologist, announced in the Guardian that he would no longer publish in Nature, Cell, or Science, which, he wrote, ‘aggressively curate their brands, in ways more conducive to selling subscriptions than to stimulating the most important research.’”

Safety, Safety, Safety Should be No. 1 Job in Research Labs

Working in a research lab doesn’t even come close to the risk involved in being a logger, which ranks as the most deadly occupation in America.

Nonetheless, handling a variety of risky substances and chemicals does involve significant hazards. We were reminded of that in the last few days in the wake of a tragic case at UCLA and the anthrax exposure flap at the CDC.

According to a report yesterday, as many as 84 persons were potentially exposed to live anthrax at CDC laboratories in Atlanta.  The details of how the exposure came about are still being investigated, but it is clear that it involved a breach of safety standards.

Anthrax, of course, can cause death.  Along the way, the inhalation form of the disease “progresses rapidly with high fever, severe shortness of breath, rapid breathing, bluish color to the skin, a great deal of sweating, vomiting blood and chest pain that may be so severe as to seem like a heart attack,” according to emedicineheath.com.

Sheri Sangji
Sangji family photo

At UCLA, the case involves the horrible burning death of a lab worker, Sheri Sangji, in 2008. The University of California once said the charges that it was at fault were "outrageous."  It took four years for the University of California to accept responsibility for the conditions that led to her death.  The school has agreed to follow safety procedures and create a $500,000 scholarship in Sangji’s name.

The researcher involved, Patrick Harran, became the first professor in the United States to be

charged with a felony in the death of a worker.  Last Friday a judge approved a deal in which Harran admitted no wrongdoing.  According to an article by Kim Christensen in the Los Angeles Times, he agreed to “develop and teach an organic chemistry course for college-bound inner-city students for five summers, perform 800 hours of non-teaching community service in the UCLA Hospital system, and pay $10,000 to the Grossman Burn Center in lieu of restitution to Sangji's family.”

In return, he will serve no jail time.

Her family was bitter about both settlements.  The family said in a statement,

"This settlement, like the previous one with UCLA, is barely a slap on the wrist for the responsible individual." 

What does all this have to do with stem cell research in California? Thousands of persons work in labs linked to such research in the Golden State. Sometimes they deal with dangerous substances.  It behooves the scientists in charge to ensure that none of their workers suffer because of a failure to adhere to safety standards. Moreover, safety at state-funded labs should be a matter of utmost concern for the folks at the California stem cell agency who have more than $1 billion in experiments under their oversight.  It wouldn’t hurt to remind recipients of state largess of the need for making safety their No. 1 task.

For other pieces and commentary on the UCLA case, see OSHA faults UCLA, pervasive problems in labs, and UCLA response.

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.)

Art Caplan on Fake Stem Cell Research: 'Off-the-Rails Syndrome?'

One of the more prominent bioethicists in the nation, Art Caplan, is asking,

“Why so Much Fake, Unduplicable Stem Cell Research?”

Caplan weighed in on Medscape.com today, citing the STAP flap involving Japanese and American researchers as well as a scandal involving a false but widely accepted – for a time -- claim that a Korean scientist had cloned human embryos.

Caplan said,

“Stem cell research seems again and again to go off the rails when it comes to the ethics of research.”

He continued,

“I think there are a couple of reasons why this particular area has gotten itself in so much hot water. One is that there is a relative shortage of funding. Because of the controversial nature of cloning -- getting stem cells from human embryos -- some avenues of funding have dried up, and it puts pressure on people to come up with other ways to try to make human stem cells. With less funding, there is more pressure. Sometimes people cut corners. I think that can lead to trouble.

“Another problem in the stem cell field is that if you can come up with a way to produce human stem cells without sacrificing or cloning embryos from humans, you are going to find yourself being a hero to the world. That is what happened in Japan.”

Caplan said,

“There is a lesson here: Until somebody replicates and until somebody can show that they can also do what has been alleged, there isn't a breakthrough. There is only confirmation and then breakthroughs. I think we have to be a lot more careful -- both in science and in media coverage -- before we start saying, 'Aha -- here is a single study, a single report, a presentation. Now we have shown that something can be done.'”

Caplan said,

“Another major problem in the stem cell field is that the number of people doing research in this area has shrunk. It is obviously of keen interest to come up with regenerative medicine solutions to all kinds of healthcare problems. I think a lot of post-docs and graduate students are saying, "I am not sure that I want to set my career track into a field that is sometimes controversial and where funding may be dipping." That may mean that there are fewer people to watch one another. It is not a big field, so maybe part of the reason that it keeps getting in trouble is less ability to do peer review.”

Our thoughts: There is no doubt some spectacular fraud has surfaced in stem cell research. But the problem of replication within stem cell research may not be entirely out of line with problems elsewhere in science. Los Angeles Times columnist Michael Hiltzik wrote last fall about a study by Amgen that 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 said.

Additionally, as Caplan notes, the stem cell community is small and the hype is grand. With stupendous expectations come the likelihood that every missed shot – fraudulent or not – becomes an equally stupendous failure that is colored by suspicions of scientific misdeeds. Plus there are truly bogus practitioners at work, charging desperate people large sums for untested and potentially harmful treatments.

The mavens of science, those who control the medical schools and set the standards, may have some responsibility for some of the problems with replication. Writing May 8 on the blog of the Global Biological Standards Institute, scientist Beth Schachter touched on this in a post headlined, 

“What are science trainees learning about reproducibility?”

She asked one Ph.D. student at UC San Francisco what sort of training are he and his fellow students receiving on reproducibility and standards. The response?

“None.”

'Paradigm Shift' -- Researchers as Patient Advocates?

It is not easy for a stem cell scientist to break into “print” in that bastion of American capitalism, Forbes magazine. Much less one from that perceived antithesis of free enterprise, Reed College.

But researcher Paul Knoepfler of UC Davis has done just that.

John Farrell of Forbes wrote about Knoepfler on Friday in the wake of the announcement Knoepfler will be honored with a “national advocacy” award by the Genetics Policy Institute.

Paul Knoepfler -- Advocate for a "new ethos"
UC Davis photo

Knoepfler, who received a degree in English literature from Reed in 1989, is being recognized for his activities as a stem cell blogger since 2009.

Farrell quoted Knoepfler as saying in an email,

“With many stumbles, face plants, land mines, and even a few threats of litigation and career retaliation along the way for the last three and half a years, I turned my crazy idea into a reality.”

Farrell continued,

“But it was only possible, (Knoepfler) added, with guidance from many patient advocates and bloggers in other fields who generously helped him learn the ropes of blogging.

“'I see this award as a validation of the notion that advocacy by scientists has become a valued part of the stem cell field,' he said.

“'My hope is to catalyze a continuing paradigm shift whereby stem cell scientists and biomedical scientists more generally have a new ethos that not just accepts, but also deeply values advocacy.'”

Reader Says Open Grant Reviews to Public

An anonymous reader this afternoon filed a comment on the “Prieto on Disclosure" item. Here is an excerpt from the comment from the reader, who has obviously been following the stem cell agency for some years,

“Confidential peer review is just an excuse for secrecy. Any CIRM observer has seen that scientists are more than willing to discuss and argue about their grants before the ICOC (stem cell board) if they think that will get them funded.”

You can read the entire comment by clicking on the word “comment” at the end of the Prieto item.   

A Singular Scientific Story: Duchenne's Disease, a Family and the California Stem Cell Agency

Unusual and personal conditions, including a tie to the $3 billion California stem cell agency, surround a promising scientific development reported today by a husband and wife research team at UCLA. 

Their research involves Duchenne muscular dystrophy (DMD), an inherited disease that afflicts about one in 3,600 boys and results in muscle degeneration and, eventually, death.

Carrie Miceli
UCLA photo

The researchers, Stan Nelson and Carrie Miceli, said they have discovered a promising FDA-approved drug that could advance the fight against the affliction.

Miceli and Nelson have an 11-year-old son, Dylan, with the disease. They have been studying the affliction for some time, but their most recent and ambitious research plan was rejected earlier this year by stem cell agency grant reviewers, a process that normally kills an application. Undaunted, Miceli and Nelson appealed to the full stem cell agency board last July. Backed by an emotional presentation involving patient advocates, they won approval of a $6 million grant.

Adding to all this, their appeal used a process known as an “extraordinary petition,” which the Institute of Medicine (IOM) last week said should be abandoned because it undermines the integrity of the CIRM grant review process.

Stan Nelson
UCLA photo

Even prior to the IOM recommendation, the CIRM board was moving to restrict its free-wheeling appeals procedures.

As for the $6 million CIRM grant, it will carry the important burden of advancing the findings that were published in the journal Science Translational Medicine. However, the money was not used in the study reported today.

The research showed that dantrolene, the FDA-approved drug, “provides a powerful boost to the (Duchenne) therapy currently being tested in clinical trials,” according to a UCLA press release.

The news release said,

“(The researchers) hope this one-two punch used in combination will overcome the genetic mutations that cause DMD, restore a missing protein needed for proper muscle function and allow those affected by the disease to lead relatively normal lives.”

“Their youngest son, Dylan, 11, was diagnosed with DMD in 2004. While he’s still ambulatory – many DMD patients require the use of wheelchairs by about age 10 – Dylan can no longer run or climb stairs and he can’t shoot a basketball over his head like other boys his age.  Despite these challenges, Miceli said Dylan remains a happy, funny and engaged boy, full of life and passion.

“'We entered into this field because of the diagnosis of our son, but we hope our research can help many others,' she said. 'There are drugs that can help manage the symptoms of the disease, but nothing that changes its course dramatically. We’re trying to correct the defect that causes DMD with highly personalized genetic medicine.'” 

UCLA said the grant from CIRM will be used for “longer term studies of their drug combination therapy in mouse models to ensure it can restore dystrophin levels to normal or near normal levels. They also will explore whether DMD patients with other mutations can benefit from the combination therapy.”

Asked for comment, Kevin McCormack, a spokesman for the stem cell agency, said today's findings "are certainly very encouraging." He continued,

"Clearly there is still a long way to go before we know if this approach will work in people but we're delighted that funding from the stem cell agency is helping  the researchers move their work forward....This is what voters set out to do when they approved Proposition 71 to create the stem cell agency."

Stem Cell Orthodoxy and Peer Review

Going against the grain can be difficult as UC Davis stem cell scientist Paul Knoepfler learned again in connection with his research that dealt with similarities between cancer and iPS cells.

His “unsettling” findings troubled some scientists who reviewed his paper prior to its publication in September in Stem Cells and Development. (See here and here.)

As many readers know, iPS or reprogrammed adult cells are currently a hot research avenue in stem cell research because they avoid many of the ticklish ethical and political problems connected with human embryonic stem cells.

Knoepfler shared his thoughts on the publication and peer review process on his blog last week. He wrote,

“Not surprisingly...there are certain members of the stem cell field who would rather focus away from the ideas that iPS cells are similar in some respects to cancer.”

Knoepfler, whose research was financed in part by the California stem cell agency, wrote,

“Once we had a manuscript together comparing iPS cells to cancer cells, we sent it to several high profile journals without much luck. We thought that the fact that our data indicated that iPS cells are similar to cancer cells might make reviewers and editors excited. We thought that the paper was novel and thought provoking in a number of ways. At the same time I realized the theme of the paper would be controversial. 

“I would say two general things about the review process at the two journals that turned down the paper. First, the reviewers at these journals were enormously helpful with their suggestions and helped us improve the paper substantially. Second, they were clearly very uncomfortable with the notion that iPS cells are related in some ways to cancer so unsettled in fact that I believe it influenced their reviews.”

At one journal, a reviewer said the findings were either “not sufficiently novel” or “trivial.” “Little useful insights” said another. And a third said, “many unsettling results....”

Knoepfler commented on this blog,

“Yeah, it may be unsettling that iPS cells share traits with cancer cells, but if that is the reality, isn’t it important that people know that and think about it, talk about it, and address the issue with eyes open?”

Knoepfler's item and similar comments from other researchers that can found elsewhere on the Internet indirectly raise questions about the California stem cell agency's process of peer review of applications for hundreds of millions of dollars in funding, especially in the wake of this summer's unprecedented rash of appeals of decisions by grant reviewers.

The key question is whether the agency's closed-door process reinforces orthodoxy or, in fact, is all but controlled by what amounts to scientific conventional wisdom. Obviously, no researcher likes to see a paper rejected or a grant denied. But the record number of appeals at CIRM and other private complaints could well indicate that potentially profitable proposals are receiving a less than welcome reception behind closed doors from agency reviewers.

The agency's board itself is hard-pressed to make such determinations. It is hamstrung by procedures that do not permit it to expand an application directly – only a staff-written summary. Names of applicants and institutions are censored, although the board is required by law to discuss in public most aspects of a research proposal. Exceptions are permitted for proprietary information. Additionally, a handful of the 29 members of the governing board do participate in the reviews, which come before final action by the board. 

Currently the agency is pushing hard to commercialize stem cell research and fulfill at least some of the promises to voters that were made in 2004. To do that, the agency may well have to step outside of the normal comfort zone of the good burghers of stem cell science.

Stem Cell Scientist Says 'Blog or Be Blogged'

Paul Knoepfler
Knoepfler Lab Photo

California stem cell researcher Paul Knoepfler today published a piece in Nature about his nearly two years as a stem cell blogger – a period that included a bout with both cancer and "negative feedback," including insistence that he shut down his blog.

Knoepfler is an associate professor at the School of Medicine at UC Davis. He may well be the only stem-cell faculty scientist in the world who produces a regularly updated blog on stem cell issues.

Knoepfler writes on subjects ranging from basic science and public policy to peer review and stem cell tourism. He also brings a patient advocate point of view to the subject, which has troubled some researchers.

In his Nature piece, Knoepfler offers tips to beginngers and seeks out other stem cell researchers who may be bloggers.

Concerning his unsuccessful search for scientists who blog on stem cells, Knoepfler wrote,

"Why is this? Other scientists in academia tell me they worry that blogging would damage their careers. Specifically, they fear that colleagues would view them as amateurs, 'wasting time' on blogging, which could reduce their chances of achieving tenure. They fear the wrath of others in the field should they post the 'wrong' thing on their blog, and they worry about payback in negative grant and paper reviews. Some are concerned about attracting unruly and insulting readers' comments."

Knoepfler continued,

"There has been some negative feedback, usually expressed privately rather than on the blog itself. Some critics cautioned that I might anger 'the wrong people' in academia or at funding agencies. Others were more direct with their disapproval of some of my most popular posts — usually those that mentioned specific funding agencies or companies by name — with the implied threat that I would see papers or grant applications rejected. Some who disliked my outspokenness insisted I shut down the blog. But don't let this put you off — the threats came from a very small number of people and have (so far) been toothless. My lab is fine in terms of funding and publishing, and I recently got tenure."

Knoepfler concluded,

"Savvy scientists must increasingly engage with blogs and social media. A new generation of young researchers has grown up with an ever-present Internet. Publishers have been quicker than academics to react to this new world, but scientists must catch up. Even if you choose not to blog, you can certainly expect that your papers and ideas will increasingly be blogged about. So there it is — blog or be blogged. "

Our take: Knoepfler produces a useful and interesting blog. It is a credit to the field and to UC Davis. Ultimately, it and hopefully others like it will help to create greater understanding of some of the issues involved in stem cell research.

To the naysayers: human embryonic stem cell research needs many strong advocates if the field is to continue to advance. For scientists or academcians to turn away from blogging is to surrender the field to opponents. The absence of reliable and well-communicated information means that other, less-well-informed views will fill the void. Not all researchers should be bloggers, but those who are effective communicators should seriously consider emulating Knoepfler's pioneering effort.

WARF Loses Latest Round on Challenge to hESC Patents

Two watchdog groups said today they have scored a “major victory for unfettered scientific research” in a case involving a WARF patent on human embryonic stem cells.

Consumer Watchdog of Santa Monica, Ca., and the Public Patent Foundation of New York City filed the challenges to the WARF patents on work by Jamie Thomson of the University of Wisconsin.

The groups said in a news release that federal patent regulators have “agreed with the groups that the creation of human embryonic stem cell lines was obvious in the light of work that had been done in other species. In order to obtain a patent, work must be both new and non-obvious.”

WARF, which can appeal the decision, released the following statement.

“WARF has been invited by the Board of Patent Appeals to continue prosecution of this application and plans to do so and vigorously pursue these claims with the patent office. This decision regarding ‘913 does not affect the patent office’s 2008 decision to reaffirm WARF’s two most important base stem cell patents for primate and human embryonic stem cells, ‘780 and ‘806. These reaffirmed patents are not eligible for further appeal in this reexamination process.”

Geron Corp., of Menlo Park, Ca., which holds a license on the patent, said the decision will not “impact” the firm's “dominant human embryonic stem cell patent position.”

The 2006 challenge to the WARF patents was supported by Alan Trounson, then connected to Monash University but now president of the California stem cell agency, Douglas Melton and Chad Cowan of Harvard and Jeanne Loring, director of the Center for Regenerative Medicine at Scripps.

Loring said,

“This is great news for medical research. Human embryonic stem cells hold great promise for advancing human health, and no one has the ethical right to own them.”

The challenge involved three patents. Federal officials originally ruled unfavorably.

The Consumer Watchdog news release said,

“Under current patent law only one of the three (earfier) patent rulings could be appealed by the two groups.  That was the patent rejected by the Board of Appeals and Interferences. However, said the groups, the latest ruling by the Board of Appeals is a strong decision that could set a precedent leading to the revocation of the other two patents as well.

“The two public interest groups noted that the original three patent challenges  had already improved the situation for stem cell researchers; shortly after the PTO launched its initial re-examinations in 2006 at the groups’ request,  WARF announced a substantial easing of its licensing requirements.

“'WARF executives were acting like arrogant bullies blinded by dollar signs,' said (John M.)  Simpson (of Consumer Watchdog). 'Our challenges prompted a more co-operative stance towards the stem cell research community on their part.'”

“Both Consumer Watchdog and the Public Patent Foundation stressed that while University of Wisconsin researcher James Thomson deserved acclaim for his research that isolated human stem cells, important scientific accomplishments are not necessarily patentable.  They said one of the main reasons he was able to derive a human stem cell line was because he had access to human embryos and financial support that other researchers did not have.”

Geron issued a news release on the decision. The company said,

"'This is not a final rejection of the patent claims,' noted David J. Earp, J.D., Ph.D., Geron's chief patent counsel and senior vice president of business development. 'We are confident that WARF will make a strong case in support of the patentability of these claims in continued examination.'"

Good Faith, Loopholes and CIRM

SAN FRANCISCO – The $3 billion California stem cell agency says a headline carried last week by the California Stem Cell Report is “damagingly misleading” and would like a correction.

We disagree and will tell you why. But the matter goes beyond a mere eight words. It deals with trust, good faith and more.

The headline in question is: “CIRM Rolls Back Effort to Undercut Affordable Access.”

The subject involves a proposed – but now retracted – major change in CIRM intellectual property regulations. The revision was quietly fast-tracked for what would have been final approval last Thursday by the CIRM board at its two-day meeting here. Fortunately, the loophole was caught the day before the meeting by John M. Simpson, stem cell project director of Consumer Watchdog of Santa Monica, Ca. He wrote a letter challenging the revision. We published an item on his comments along with the text of his letter. As a result, the proposal was pulled back.

Simpson has been deeply involved in the CIRM proceedings that hammered out the IP rules and their provisions for affordable access. The process took place over several years, and CIRM directors have repeatedly reaffirmed their commitment to affordable access to any taxpayer-financed therapies. Affordability is also part of the promise of Prop. 71, the ballot initiative that created CIRM. Simpson has publicly praised the CIRM IP process for its openness and diligence and has expressed great respect for IP Task Force Chairman Ed Penhoet.

On Wednesday, the day after Simpson discovered the loophole, Chairman Robert Klein called Simpson to tell him that the offending provision was being dropped. Klein also mentioned it to us at the meeting here later that day. But loophole did not come before the full board until late in the meeting the next day.

No one at the session disputed Simpson's conclusion that the change in wording was a “tremendous loophole” that would endanger affordable access and also could prove to be a major benefit to the biotech industry.

Rather CIRM's question concerning our headline involves the intent of changing previously agreed upon language. The matter also involves whether CIRM was honoring its principles by advancing the proposed change in a manner that appeared surreptitious, at the least. The revision was buried in 491 lines of prolix regulatory language that was described on the board's agenda as merely a “consolidation” of previous regulations.

The loophole – which involved only a few words – was also proposed at a time when CIRM is aggressively moving to embrace the biotech industry. According to its strategic plan, it will take a leading role – at taxpayer expense – to lobby nationally to remove barriers facing the industry. All with the good intent, we should add, of speeding cures.

When the proposed revision came up during Thursday's board session, Elona Baum, CIRM's new general counsel who joined the agency in April after 12 years with Genentech, said that questions had been been raised about “sublicensing.” She said, “In the interests of clarity, the language was inserted.”

CIRM directors then formally acted to remove the offending language, which will go out for a 15-day public comment period before becoming official.

Shortly after Baum offered her comments, Don Gibbons, chief communications officer, sent me the following email about the headline in question.

“Having heard this discussion, I would hope you feel it is appropriate to self correct this damagingly misleading headline. It should have been clear this was never CIRM’s intent.”

The CIRM board, which is the ultimate authority at the stem cell agency, is to be commended for removing the loophole. But how and why the language was inserted is a matter in dispute.

Gibbons is paid $190,00 a year to polish CIRM's image. We understand why he does not care for our wording. However, both Simpson and I have been given to understand that the loophole did not result from merely a lack of legal felicity.

We asked Simpson for a comment on Gibbons' opinion concerning the headline. Here is what Simpson said,

“Either the lawyer responsible for the proposed change in the definition didn’t understand its implications, which implies incompetence or the lawyer completely understood, which implies deliberate intent to make substantive policy changes and subvert the process. Neither choice is pleasant, so I’ll simply celebrate the fact that when the ICOC (the CIRM board), particularly the members of the IP Task Force, was made aware of the situation, it was immediately rectified.”

Last Tuesday, we asked Gibbons for a comment on behalf of CIRM concerning the loophole. He never responded. We are asking him if CIRM has any comments on this item. We will carry any response verbatim.

Stem Cell Star Search: Recruitment, Money and Conflicts

The California stem cell agency's proposed $44 million recruitment plan seems certain to draw some of the shining lights of the stem cell world to the Golden State, but it also opens a door on the high stakes bidding for research stars.

The proposal additionally shines a light on the built-in conflicts of interest on the 29-member CIRM board. At least 12 members of the board have positions at institutions that stand to benefit from the recruitment plan.

In response to a query, James Harrison, outside counsel to CIRM, said all will be allowed to vote this week on the proposal. However, they will not be able to vote next year on specific recruitment grants if their institution applies for a recruitment grant.

The CIRM recruitment packages could run to $4.5 million for six years for perhaps eight scientists, according an example provided by CIRM, but could be less or more. That does not include contributions from the recruiting institutions themselves.

Among other things, CIRM would provide up to $186,000 a year for salaries, $1 million for lab renovations and equipment (with an equal amount from the institutions) and $300,000 annually for lab operations, not including indirect costs.

To your average Californian, the amounts might seem quite generous. But according to one well-informed observer, they are not excessive although they could be construed as “lavish” for public institutions.

To help put the plan in perspective, we queried some folks in the field.

Ann Keissling, who serves on the CIRM research standards group and is director of the Bedford Stem Cell Research Foundation in Massachusetts, said,

“After a brief review, this looks like an excellent plan. The approximately $4 million for a six-year commitment to a good mid-career investigator is appropriate, and will give California institutions with less robust stem cell departments the chance to bring themselves up to a par with other institutions.

“Over reliance on NIH-funding is weakening U. S. science for a number of reasons and those institutions with the greatest NIH-dependency will be forced to develop alternatives. This might be an excellent opportunity for good science to go forward rapidly that might languish waiting for federal funding. This would not only be a boon for California, but for U. S. biomedical science in general. A win for everyone in the long run.”

Dennis Clegg, who runs the stem cell program at UC Santa Barbara, said,

“Since many places have a hiring freeze, including UCSB, CIRM help in recruiting is very welcome. More support would have greater impact, but CIRM has to weigh its various priorities.”

A few years ago, Clegg recruited Jamie Thompson to the campus as an adjunct professor, putting together a $1 million package for him.

One California researcher, however, said anonymously that the size of the CIRM proposal seems to go beyond the current packages being offered or in place. The scientist also expressed concern about fairness towards researchers already in California.

“We should be giving those young researchers who we have been nurturing with CIRM money a chance to blossom rather than bringing in some of those half-tamed Harvard boys.”

CIRM said the program is modeled after the “early career” awards from the Howard Hughes Medical Institute. The Hughes program is monetarily more modest, sprinkling only $4 million among 11 researchers this year.

One commentator said that the CIRM packages could be aimed at recruiting recipients of Hughes awards or other programs that remove their grants when the recipient leaves the original institution.

In terms of specific individuals, stem cell scuttlebutt has it that UC Berkeley is looking for a star and needs financial assistance because of the California state financial crisis. The names of Kevin Eggan and Amy Wagers, both of Harvard, have been mentioned in that regard. Eaggan has also popped up as a possibility at UC San Francisco as well.

Eggan serves on the CIRM standards group. Wagers is on the CIRM grant review group.

While the program helps academia, biotech businesses will be frozen out . Only academic and research institutions and medical centers will be allowed to nominate candidates. No reason was given by CIRM.

The proposal seems certain to have something of inflationary impact on the field and to trigger bidding wars as rival institutions compete. It could also stimulate upward financial pressure from scientists who might not be considered by institutions as meeting the CIRM criteria of being “highly likely to become world leaders in their fields.” They are naturally going to look at the deals and ask for more for themselves.

But the even the brightest stars are lagging behind others in the university firmament. UC Berkeley, UCLA and Stanford are paying much more handsome salaries in another field, $1.9 million, $1.3 million and $1 million respectively to their football coaches.

Montana Lad Speaks Out on Scientists, Stem Cells and Obama

Nature Reports Stem Cells this week carried an interview with the son of some fur traders and junk dealers on the subject of stem cells.

Among other things, he said most scientists don't know what medicine is and then took on President Obama concerning the new NIH rules on stem cell research.

The comments came from Irv Weissman of Stanford in a Q&A with Monya Baker, editor of Nature Reports Stem Cells. The interview keyed on his role as the new president of the International Society for Stem Cell Research.

Here is the section on scientists and medicine.

Baker: "Why is it so hard to move science into medicine?"

Weissman: "First, most scientists don't know what medicine is. They don't know what whole-body physiology or pathology [is]. So they tend to be, at least at the beginning, unrealistic in their expectations. Second, there are not many people trained to do clinical trials.

"And you have to realize that things don't make it into clinical, commercial therapies without a lot of money."

He spoke about overcoming nontechnical barriers in the stem cell field.

“(G)going from labs to commercial and clinical products, we need to understand how it could be a commercially viable business. Stem cells, unlike drugs or proteins, self-renew and differentiate in a fashion regulated by the body; they regenerate systems for life from a single therapy. If you're going to deliver stem cells for lifetime therapy, the cost of goods and reasonable profit has to be priced with the knowledge it replaces daily therapies like insulin or blood transfusions.

“One of the greatest experiments I know of is being done in California. The California Institute of Regenerative Medicine [CIRM] sent out last year an RFA [request for applications] for disease teams to take stem cells and/or therapies derived from them through preclinical right up to the filing of the first IND [investigational new drug application] with the FDA. That's an area that was formerly funded only by companies. Now universities and other nonprofit institutions need to learn what companies do, including rigorous manufacturing practices [GMP] and FDA-compliant regulatory documents.”

Weissman also answered a question about how he came to be a scientist:

“I was born and brought up in Great Falls, Montana. My father and grandfather were fur traders and junk dealers. I was about to be the first in those generations to get an education. When I was ten years old I read a book called Microbe Hunters, which was about the lives of people like Robert Koch and Louis Pasteur. It was incredibly exciting to me.

“I really looked for a way to do research after that. I should say I was never a straight A student. When I was about 16, I met Ernst Eichwald at the local hospital. Ernst was German, his father was Jewish.

“During the beginnings of WWII Ernst belonged to a student group against the Nazis; somebody in his group was arrested, and without going home he crossed the border. He came to Harvard, he was on faculty there; he came to Utah, was on faculty there for awhile. He got sick of academic politics and decided to run the pathology service at the Montana Deaconess Hospital. Very early he handed me a paper [George Snell's paper on histocompatibility genes] as if I could read it, and I told him that I didn't understand the first word! He spent a whole Saturday with me, and we covered just that one paper.

“I realized that the language of science substitutes Greek and Latin terms for plain English, that it was a way to keep people out of the field. He didn't need to say histocompatibility. He could say "tissue-transplantation compatibility", but I also realized I could understand it. Thanks to the freedom Dr. Eichwald gave me, I began designing my own experiments at 16.”

Comment on Verfaillie Post

A thoughtful and informed comment has been posted on the Verfaillie item from Aug. 11. The anonymous poster raises a question about whether she should be allowed to serve as a CIRM grant reviewer and as well as another question about whether CIRM should increase its vigilance on who sees confidential grant information at CIRM. You can read the comment at the end of original item or by finding it in the “recent comments” column just to the left of this post.

CIRM Grant Reviewer Verfaillie Linked to Investigations in Minnesota

A internationally known stem cell researcher who serves as a grant reviewer for the $3 billion California stem cell agency is at the heart of an inquiry at the University of Minnesota concerning the integrity of some of its stem cell research.

The matter involves Catherine Verfaillie (pictured) and New Scientist magazine, which raised concerns about the research. Verfaille is currently listed on the CIRM Web site as one of the scientists who make de facto decisions on research grant applications for hundreds of millions of dollars from the California Institute of Regenerative Medicine.

We queried CIRM two days ago about Verfaillie but the agency has not responded.

The research inquiries at the University of Minnesota involve scientists who worked in Verfaillie's lab or who were affiliated with her. She is now working at Katholieke Universiteit Leuven in Belgium but is still associated with the University of Minnesota. New Scientist once described her as running “one of highest-profile teams in stem-cell biology.”

Here is how Chris Williams of The Associated Press began his story last week on the research investigation,

“The University of Minnesota has launched its third internal investigation in two years into allegations of research misconduct....”

Jeremy Olson of the St. Paul Pioner Press wrote,

“In a familiar pattern, reporters from New Scientist magazine found images in a published study that appeared questionable and alerted U officials.

“The university already has retracted one stem cell study and corrected two others because of concerns raised by New Scientist. Having to launch yet another inquiry is an embarrassment for a university that has been viewed as a global expert in stem cell research....”

Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania, said that the Minnesota case has implications that go beyond one researcher or institution.

According to reporter Williams,

"'What's unusual here is that you're starting to get other people involved," (Caplan) said. 'It's become a problem of a group, not an individual.'"

Williams continued,

“The Minnesota situation is also unusual, Caplan said, in that its researchers have been getting special scrutiny from New Scientist. He suspects there would be more questions of sloppiness or fraud at other universities if more outsiders were watching.

“There is particular pressure on scientists working in the stem cell field, with its mix of politics, the prestige of breakthroughs and the potential profits from patents.

"'I really can't think of too many areas that are more set up for somebody to cut corners than stem cell work,' he said.”

Peter Aldous and Eugenie Samuel Reich have been investigating the work at the University of Minnesota over several years. Their most recent piece on Aug. 5 said,

“Other stem cell biologists are disturbed that so many problems have been found in papers from a single institution. 'It's pretty discouraging," says Arnold Kriegstein of the University of California, San Francisco. Given the pressure on scientists in such competitive fields, he wonders what might emerge at other research centres if their publications were subjected to similarly close scrutiny.

"'It raises serious issues about how widespread this could be,' he says."

Aldous and Reich's Aug. 5 article has a full rundown on the cases they have investigated.

The Silence of the Scientists

Consumer Watchdog, the Santa Monica, Ca., group that has spent more time and money than any other organization monitoring California stem cell matters, today chastized a trio of major researchers for their failure to speak out on an issue that some contend is holding back not only the science but the industry.

Writing on his organization's blog, John M. Simpson, stem cell project director for the group, discussed the dispute that involves Irv Weissman of Stanford, Fred Gage of the Salk Institute and David Anderson of Caltech and indirectly their institutions.

StemCells Inc. of Palo Alto, Ca., which was founded by the three researchers, is "thwarting noncommercial neural stem cell research" at Children's Hospital of Orange County as part of the company's zealous protection of its patents, Simpson said.

The springboard for Simpson's latest commentary was an article about the matter by Michael Hiltzik in the Los Angeles Times. It pointed out that some experts believe that over-protection of IP is hampering stem cell science and even the high tech industry.

Simpson's piece was headlined "A deafening -- and embarassing -- $ilence" and substituted a "$" for the "S" in silence.

Simpson wrote,

"This is a situation that should have been settled easily in a month, if not a week. After a two-year stalemate the silence is deafening."

The three researchers have not responded to requests for comments from Hiltzik nor from earlier ones from the California Stem Cell Report. We are renewing our queries and have promised the men that we will carry their comments verbatim.

You can read our earlier item on the Hiltzik piece here.

Stem Cell Patent Flap Gains Wide Media Exposure

Three of the top names in California stem cell research – not to mention the world – surfaced during the weekend in a piece in the Los Angeles Times about a matter that is at the heart of the field – money.

Michael Hiltzik, a columnist at California's largest newspaper, brought up the scientists in connection with a patent imbroglio in Orange County that reaches into Stanford, the Salk Institute and Caltech via the researchers, who are Irv Weismann, Fred Gage and David Anderson, respectively of the three institutions.

Generally, such disputes put the general public to sleep. But Hiltzik wrote today,

"...(T)he penetration of private investment concerns into what used to be largely academic pastures threatens to hobble, rather than hasten, the march of science. The harvest may be secrecy, delay and the directing of research only toward developments that promise quick financial returns."

The matter pits researcher Philip Schwartz of the Children's Hospital of Orange County against StemCells, Inc., of Palo Alto, Ca., which was founded by Weissman, Gage and Anderson. Schwartz has spent six years providing academic researchers with neural stem cells cultured by a method he helped to invent at Salk, Hiltzik wrote.

But StemCells Inc. has effectively put a halt to Schwartz' distribution. That occurred after the firm wrote a letter to Children's Hospital warning that Schwartz' efforts infringed on its patents in the neural stem cell field and that it wanted to discuss a licensing arrangement.

This all started two years ago, but nothing has been resolved, although little apparent conflict exists between the “core clienteles” of StemCells Inc. and Children's Hospital. Hiltzik said,

"...(I)n the biotech world, where millions or even billions of dollars in profits beckon to those who can assert ownership of important discoveries, good intentions and purely scientific goals don't matter like they used to. Access by basic researchers to the essential building blocks of biomedical advances has been shrinking for years, thanks to a land rush by entrepreneurs wielding patent portfolios."

Hiltzik reported that the conflict between research and business has gone beyond biotech. He noted that Andy Grove, the fabled former CEO of Intel, this month warned of the evil effects of over zealous protection of IP.

The problem has become more serious, however, in stem cell science, according to Gregory Graff, a patent expert at Colorado State University.

According to Hiltzik,

"Graff says this phenomenon is becoming especially pronounced in stem cell science, which is especially dependent on collaboration but is already being cordoned off by commercial entities claiming property rights to essential research. The best solution, he says, may be for academic institutions -- where 45 percent of all stem cell research is performed -- to create collaborative patent pools so they can more freely disseminate information and technology without giving up all their potentially lucrative patent rights."

The issues raised by the Children's Hospital-StemCells, Inc., flap were first publicly reported April 15 by John M. Simpson, stem cell project director of Consumer Watchdog of Santa Monica, Ca. We carried a follow-up on April 16, noting that Harvard business professor and biotech industry consultant Gary Pisano warned in 2006 about the harmful impact of the "monetization of IP" on the biotech business. Our item triggered a robust exchange of comments that are attached at the end of the piece.

We asked Weissman, Gage and Anderson for comment a couple of times over the last several weeks. They did not respond to our queries. Nor they did respond to Hiltzik.

New Stem Cell Patent Ruckus in California

The delicate interface between science and business has come a cropper again.

The latest set-to involves the National Human Neural Stem Cell Resource of Children's Hospital of Orange County Research Institute and Stem Cells Inc. of Palo Alto, Ca.

John M. Simpson, stem cell project director of Consumer Watchdog of Santa Monica, Ca., Wednesday provided a summary of the dispute. He reported that Philip Schwartz, head of the Resource, said his organization's efforts to promote research with human neural stem cells has been effectively blocked by patents held by Stem Cells Inc.

The entire story can be read on Simpson's organization's blog along with a response from Stem Cells, which said it did not control actions by the Resource.

The situation reminds us of a book, "Science Business," by Harvard business professor Gary Pisano, published a couple of years ago. He has studied and consulted with the biotech industry for decades and has written about its consistent lack of profits. He suggests that part of the problem lies in the "monetization of IP" and inappropriate application of high tech industry IP principles in the biotech industry.

In 2006, he said in an interview on the Harvard Business School web site:

"Science and business work differently. They have different cultures, values, and norms. For instance, science holds methods sacred; business cherishes results. Science should be about openness; business is about secrecy. Science demands validity; business requires utility. So, the tensions are deep.

"What has happened is that we have tried to mash these two worlds together in biotech and may not be doing either very well. Science could be suffering and business certainly is suffering. If you try to take something that is science, and then jam it into normal business institutions, it just doesn't work that well for either science or business."

Stem Cells Inc. was founded by scientists Irv Weissman of Stanford, Fred Gage of the Salk Institute and David Anderson of Caltech.

Simpson wrote,

"You would have thought that with academic heavyweights like these involved with the company it would have been a no-brainer to figure out a way for Schwartz to distribute cells he has derived from CHOC patients to qualified researchers.

"The root of the problem is the Bayh-Dole act governing federally funded research. It has turned our universities into commercial entities where scientists rush to patent their discoveries rather than rush to publish and explain them."

We are querying Weissman, Gage and Anderson about their thoughts on the general issues raised by Schwartz along with the specifics.

Simpson's piece was the result of a notice by Schwartz to about 2,700 persons, mostly academics, about the patent issue. Simpson sent out a note to about 75 journalists nationwide about his item.