Transcontinental Diabetes Duel: The Search for a Stem Cell 'Cure'

Paul Laikind

Doug Melton,

One might call it a California-Massachusetts stem cell face-off. The tussle is over a stem cell cure of sorts for diabetes.

The players are Doug Melton of Harvard and Paul Laikind, CEO of ViaCyte in San Diego.  

Recently in separate forums, the men critiqued each other’s approaches to diabetes.

Most recently it was Laikind three days ago on the blog, ipscell.com, of UC Davis researcher Paul Knoepfler. Laikind was responding in a Q&A carried by Knoepfler.

Knoepfler asked about Melton’s comments in the MIT Technology Review last month. Melton was described in an article as being “worried” that ViaCyte’s technology, now in a first stage clinical trial, would not work. The California stem cell agency has invested $55 million in the firm's approach.

Knoepfler continued,

“(Melton) raised concerns more specifically about the Encaptra capsule, for example, functionally becoming fibrotic and mentioned worries about your cells being immature and taking a long time to mature. Any response on capsule and cells? He also has suggested that his beta cells will be a better option.” 

Laikind replied,  

“Dr. Melton’s work on the beta cell is very interesting. As to the cells, we made the choice to use the pancreatic progenitor cells. An important consideration is that when you first put in cells, they are in a hypoxic environment. Beta cells are sensitive to low oxygen levels, which can negatively affect their survival and function. Beta cells typically exist in a mature highly vascularized organ. The pancreatic progenitor cells that we use undergo an organogenesis-like process, more similar to how they behave in nature, and thus we believe they should be better able to handle low oxygen. They also are believed to release angiogenic and other factors to promote vascularization.

“In regards to the capsule, we do expect there to be a foreign body reaction in patients after implantation, which will generate a fibrotic capsule. In fact, we see a thin fibrotic capsule around the device in mice. But in the mouse model this capsule around the device is very well vascularized. The vasculature is right up against the device membrane on the outside, allowing for oxygen and nutrient diffusion to the cells inside.”

Knoepfler also asked about the diabetes effort in Canada involving BetaLogics Venture, a subsidiary of Johnson & Johnson, which also made a $20 million investment in ViaCyte last summer.

Laikind said situation involving Melton and BetaLogic was “healthy competition.”

He continued,

“There’s room in this area for multiple efforts and we aren’t especially concerned with competition. Yet we do feel we are ahead of others and we have substantial intellectual property that they will need to navigate (~50 patents issued in the United States, and a couple hundred pending patent applications, including international). At ViaCyte we view the real competition as the biology rather than with the efforts of others as we seek to cure this devastating disease.” 

Laikin had more to say about his firm’s product and Melton’s comments.  He also discussed ViaCyte’s clinical trial, which now has four patients with a goal of 40. He said the initial evaluation of efficacy could occur by late 2016. Within five years, he hopes to see “success” with the product and “be moving to market.”

Responding to a question about “product placement,” Laikin said the firm is currently inserting its tiny device in the lower back of patients. Laikin said,

“The reason for that placement is that while the device can withstand the impact of a 60 mph baseball (based on cadaver testing), a needle could go right through it, so we want to put it where patients don’t typically inject insulin.” 

Concerning Melton’s views on ViaCyte, the Feb. 12 MIT Technology Review piece said,

“Douglas Melton, a biologist at Harvard University who has two children with type 1 diabetes, worries that the ViaCyte system may not work. He thinks deposits of fibrotic, scarlike tissue will glom onto the capsules, starving the cells inside of oxygen and blocking their ability to sense sugar and release insulin. Melton also thinks it might take immature cells up to three months to become fully functional. And many won’t become beta cells, winding up as other types of pancreatic cells instead.

“Melton says the ‘inefficiency’ of the system means the company ‘would need a device about the size of a DVD player’ to have enough beta cells to effectively treat diabetes. ViaCyte says it thinks 300 million of its cells, or about eight of its capsules, would be enough. (Each capsule holds a volume of cells smaller than one M&M candy.)    Last October, Melton’s group announced it had managed to grow fully mature, functional beta cells in the lab, a scientific first that took more than 10 years of trial-and-error research. Melton thinks implanting mature cells would allow a bioartificial pancreas to start working right away.”

The Web site, diaTribe, last fall carried an analysis of all three approaches.

$28 Million California Search for HIV/AIDS Stem Cell Cure Advancing to Clinical Trial

The California stem cell agency today announced that one of its multimillion dollar efforts to come up with a cure for HIV/AIDS is moving into the first stage of clinical trials involving human beings.

The effort includes the City of Hope in Duarte, Ca., the University of Southern California and Sangamo BioSciences, Inc., of Richmond, Ca.

John Zaia
City of Hope photo 

The $3 billion agency is pumping $5.6 million into the clinical trial. Overall, the agency has awarded the lead scientist in the project, John Zaia of the City of Hope, $28.2 million for work involving HIV/AIDS. 

The agency, formally known as the California Institute for Regenerative Medicine (CIRM), said the FDA had approved the initial trial to determine the safety of the treatment.

CIRM’s press release said that the plan is to “take blood stem cells from HIV infected individuals, then treat them with zinc finger nucleases (ZFNs), a kind of molecular scissors, to disrupt the CCR5 gene in those cells. The hope is that this will make those stem cells, and their progeny, resistant to HIV. The modified cells will then be reintroduced into the patient with the hope that they will create a new, AIDS-resistant immune system.”

The effort is intended to replicate what occurred with the “Berlin Patient,” a man who has apparently been cured of AIDS as the result of a mutation.

Jeff Sheehy, a longtime CIRM board member and HIV/AIDS advocate, said in the press release,

“This trial is enrolling HIV patients whose immune cells have not returned to normal levels even after success in suppressing the virus with antiretroviral therapy, and even if it doesn’t lead to a cure it could still result in a therapy that offers clinical benefit to patients at risk for opportunistic infections.”

(Here is a link to how Sangamo describes its ZFN pipeline.)

Zaia said,

‘While we have a number of drugs that are effective in holding HIV at bay, we have nothing that cures it. In addition, for many patients, these medications come with significant long-term problems so there is a real need for a therapy that can help eradicate the virus from a patient completely. That is where our work is focused.”  

The agency is also funding a clinical trial involving an alternative approach to HIV/AIDS. That effort includes UCLA and an Arizona company, Calimmune, Inc., co-founded by a former member of the CIRM governing board, David Baltimore. Calimmune also has an address near UCLA in Los Angeles.

CIRM said,

“Calimmune, an HIV gene medicines company focused on developing cell-based therapies for HIV, began its human clinical trial in July 2013 and has already shown that the first group of patients treated did well enough for the company to start treating a second group more intensively.” 

Jonathan Thomas, chairman of the CIRM board, said,

“This kind of work is too important to just try one method at a time and sit back and wait to see if it is effective.”

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."

A Critical Perspective: Klein's $100 Billion Stem Cell/Genomics Plan 'Boggles the Mind'

The San Diego U-T newspaper today reported the first criticism of the $100 billion stem cell/genomics research plan being floated by the former chairman of the California stem cell agency, Bob Klein.

The challenge to the proposal came from John Simpson of Consumer Watchdog of Santa Monica, Ca., in an article by reporter Bradley Fikes.

Simpson, a longtime observer of the agency and once heavily involved in formulation of its intellectual property rules, said the proposal for the international consortium “boggles the mind.”

Fikes reported that Simpson found the international plan flawed on several counts: It would lock money into specific areas of research regardless of the state of the science; it would be cumbersome to run, and it would be expensive because it would use borrowed money.

Fikes wrote,  

"’I don't understand how this could possibly work,’ Simpson said in a Monday interview. ‘The logistics of getting together such a (15 nation) coalition boggles the mind.’”

Simpson said Klein, a real estate investment banker who left the agency in 2011, was peddling illusory benefits. Fikes reported,

"'That's the same premise as he's tried to argue with Prop. 71, and I don't think that's been true at all,’ Simpson said. While the (California stem cell) program has resulted in some major research advances, it hasn't yet generated enough of an economic return and proven treatments to justify it, he said.

"'Pay as you can afford to pay,’ Simpson said. ‘I think that's a better approach to research, generally. That's what democratically elected governments are supposed to do, is come up with appropriate funding for the various things they're faced with. If you had this kind of money to throw at certain problems, it's not entirely clear to me, by any means, that stem cells would have the biggest impact. You might do a hell of a lot more with simple things like malaria eradication.’" 

Fikes wrapped Simpson’s critique into the earlier version of his article on Klein’s plan.

$100 Billion Stem/Genomics Plan: Borrowing on an International Scale

Bob Klein at UC San Diego last week
Bradley Fikes/San Diego U-T photo

More details are emerging on the $100 billion, international stem cell/genomics research proposal being offered up by Bob Klein, the first chairman of California’s stem cell agency.

Klein’s plan was discussed in a piece by Bradley Fikes of the San Diego U-T, the only daily newspaper in California’s second largest city. The article yesterday also carried videos of Klein pitching his plan.

Klein, a real estate investment banker, cited California’s $3 billion stem cell agency as an example to be emulated internationally. It operates on money that the state borrows (bonds), which roughly doubles the cost of the research because of the interest expense.

He said an international research organization could be supported by bonds which are backed by pledges from 15 countries, including the United States.

Fikes quoted Klein, who left the California agency three years ago, as saying,

"Because the borrowing is so much cheaper than anything a country can do, from the surplus funds we raise, which are about 35 percent to 40 percent more than most countries can raise from the same amount of money, we can have an international pool, where we can collaborate and compete through peer review." 

Fikes continued,

“Klein pointed to the International Finance Facility for Immunization as an international public-private partnership as a financial model. Using long-term government pledges as collateral, the agency can raise capital as needed from the bond markets.” 

Neither the Fikes piece nor an earlier article from the San Diego Daily Transcript carried any indication that Klein’s proposal had the support of major research organizations or governmental agencies.  

Neither article also carried any reference to Klein’s earlier proposal for another $5 billion bond issue to continue the operations of the California stem cell agency, which will run out of money in 2020 based on current spending rates.

Klein and U.S. Rep. Scott Peters, D-San Diego, shared an appearance at a cancer conference last week at UC San Diego. Both extolled the power of using patient advocates as the leading edge of lobbying for research funds.

Fikes wrote,

“Peters…said scientists must broaden their political base beyond their traditional bastions if they wish to become more influential. Patient advocates are key.

"'When we're fighting for NIH funding, a lot of the voices for that come from people who are in universities and in areas of science, and a fairly narrow political spectrum,’ Peters said. ‘Frankly, they tend to be people from Boston, and San Francisco and San Diego, who don't always vote the same way that people from West Texas, or Kansas or rural Wisconsin vote. So patient advocates provide a huge imput for folks from all across the country."

“Klein recounted an example of how that coalition succeeded in keeping diabetes research money flowing in 2002 when that funding was threatened with interruption. He said the bill, which required unanimous consent, got through the House with the support of then-House Speaker Denny Hastert, an Illinois Republican, who had a staff member with Type 1 diabetes."

Fikes continued,

"'Oklahoma is not a hotbed of scientific support, but through a weekend effort, JDRF (Juvenile Diabetes Research Foundation) was able to get 25,000 emails generated,' Klein said. ‘But more importantly, the patient advocates working as informed advocates with the scientists from the Type 1 research and clinical areas got to enough chairmen of the boards and board members and CEOS of major corporations in Oklahoma that they shut down the switchboards of Sen. Nickles' offices in Oklahoma and Washington D.C. with calls.’"

“Nickles released his hold on the bill.

"'We had unanimous consent of the U.S. Senate, two hours before the end of the special session, because scientists informed and teamed up with patient advocates ... ' Klein said."

Prodigious Pricing and Stem Cell Treatments: Implications for the California Stem Cell Agency

The most widely read item in the last 10 years on the California Stem Cell Report is one that deals with the cost of a possible stem cell treatment.

Newscom image

The piece contains a $512,000 figure and has chalked up 10,714 page views as of this evening. It deals only with a potential treatment in a fully legal and medically acceptable situation. The item is also nearly two years old. The $512,000 number is likely to have been modified by the researchers involved.

Now comes an item by UC Davis stem cell researcher Paul Knoepfler, who has put together a survey of prices of stem cell “treatments” that are being offered around the world. The costs are for procedures available largely outside established medicine with its accompanying government certification and testing.

Knoepfler reported today on his blog that American clinics – non-FDA approved – run about $10,000 per procedure, with more than one treatment usually described as necessary. Outside of the United States, the procedures run up to $100,000.

Knoepfler wrote,

“Whether inside or outside the US, insurance does not cover the costs of these potentially dangerous, unproven treatments.”

He noted that high profits are associated with the procedures. He said,  

“Part of the way that clinics cut corners to boost their profits is by not following FDA regulations, putting patients in danger. Clinics typically do not do pre-clinical studies to get evidence of safety and efficacy before starting to sell their offerings to patients. Clinics also do not include sufficient follow up in the cost of the treatments. They do not publish their data to get peer review and feedback. They often do not have GMP compliant facilities or devices.”

Knoepfler concluded,

“Of course other costs to patients going to dubious clinics, sometimes not considered, include the price of false hope, potential injury due to dangerous stem cell ‘treatments,’ possibly being excluded from a real clinical trial in the future and injury from deferring other arguably more real treatments.”

The high readership on the 2013 cost item on the California Stem Cell Report is likely due to readers who are considering some sort of stem cell procedure.  Knoepfler will also likely see a similar trend.

The strong interest in stem cell costs is something for the California stem cell agency to consider as it invests in clinical trials. Obviously the expense is of considerable concern to those not ensconced within the stem cell community, where the focus is on a euphemism called "reimbursement," shorthand for making a handsome profit.  Stem cell insiders sometimes shrug off the possibility of a severe, negative kickback on prices. 

But it has already happened in other areas of medicine. A physician protest involving the cost of a particular cancer treatment received national attention in 2013. The article about it in the New York Times received 500 reader comments.  

Obviously no stem cell therapies will reach the marketplace if they do not offer the potential for profit. Nonetheless, if one of the California agency's trials is successful but also carries a prodigious pricetag, California taxpayers who have financed the agency are likely to look askance at the agency’s work.

California's Bob Klein Proposes $100 Billion, International Stem Cell/Genomics Venture

The man some consider the father of the California stem cell agency has come up with another grand research plan – a $100 billion, 14-nation effort plus California, along with creation of a federal research “trust.”

The proposal comes from Robert Klein, who led the 2004 ballot campaign to create the $3 billion state stem cell agency. He was also its first chairman and a figure revered by some.

Katherine Connor of the San Diego Transcript reported today on Klein’s quest for a “new paradigm in funding scientific research.” During remarks at an oncology symposium yesterday at UC San Diego, Klein said his collaborative venture is needed given the current state of federal research funding. 

Connor wrote,

Robert Klein

“Klein is working on spearheading such a collaboration, where 22 different partners -- including 14 nations, the NIH and the state of California -- commit to long-term funding of scientific research on stem cells and genomics via a World Bank bond. The money invested by each partner would be used to fund work by that entity." 

Connor continued,

“He said if Congress would appropriate a long-term commitment to support this international bond, the research community could leverage it up to a $100 billion program with surplus funds around 35 to 40 percent more than what each individual country or partner could raise from the same amount of money.” 

Klein is a California real estate investment banker who works closely with bond financing. He said his proposed research venture “would go a long way in diffusing the ingrained competitive attitude toward funding.”

Connor continued,

“'The fundamental problem here is that, long term, we have difficulty holding these interest groups together,' Klein said. ‘In California, with Prop. 71, the way it approached that was if you have a unitary decision, you’re either for the bond or against the bond. You can’t go and say 'I want my appropriation,' you have a unitary decision -- it brings all those groups together as a coalition, they have to work together.’”

The ViaCyte Diabetes Trial: Clarifying a Patient Matter

The ViaCyte clinical trial is aimed at producing a “virtual” cure for Type 1 diabetes among children, but the first implantation of the device involved an adult man.

That information was reported by the MIT Technology Review and raised a question about whether the article was in error or whether something else was involved.

The California Stem Cell Report queried Paul Laikind, CEO of ViaCyte, which is based in San Diego, about the matter.

Laikind replied,

“This first clinical trial of VC-01, called STEP ONE*, requires patients to be 18 to 55 years old (see https://clinicaltrials.gov/ct2/show/NCT02239354?term=viacyte&rank=1).  Once we have gained experience with VC-01 and assuming that it is shown to be safe and effective in the adult population we would expect a follow up protocol to include children with T1D.”  

The Sagan Effect and Public Support for Research

The media chief at the $3 billion California stem cell agency yesterday put together a first-rate piece that invoked Meryl Streep, Carl Sagan and Lindsay Lohan and said that scientists can learn something from them.  

The item by Kevin McCormack, senior director of communications for the stem cell agency, dealt with telling the story of the facts and the romance of science. Not to be too crass about it, but his item piece also dealt with generating the public enthusiasm that will lead to more cash for researchers’ labs. Maybe even do some public good.

McCormack, who has labored both in public relations and in the grimy trenches of journalism, wrote about the American Association for the Advancement of Science conference last week in San Jose on science communications. The session explored ways to get the public to both understand and care more about science and technology and to get scientists to do a better job of explaining both to them.

A number of problems have plagued science communications for decades. One is that science is sometimes difficult for the general public and reporters to understand. It is also difficult to find researchers who can “speak English” – explain what they are doing and why it is important in ways that resonate with the media and their readers and viewers.

Another problem is that sometimes scientists who are good at explaining are dismissed by their colleagues as less than professional or as not really good scientists.

One rendering of invidia at work

McCormack said there is a risk. He wrote,

“Some scientists reported facing a backlash from colleagues who felt they were trying to hog the limelight. They fell victim to what is called the ‘Carl Sagan’ effect, which holds that if someone is spending that much time and effort communicating science to the public they must not be a very good scientist to start with.” 

From what I have seen over the last decade of watching the stem cell agency, such a reaction also often seems a case of invidia at work. Seeing another researcher’s name in print can trigger a serious case of irritation.

McCormack quoted Stanford’s Noah Diffenbaugh on reasons for taking his science to the public.

“I feel it is my responsibility to answer questions from the public when asked, because my research group is publicly funded by taxpayer dollars through agencies like the NSF. And as a public citizen I feel responsible that if we are having a public dialogue about climate change that I should be part of that dialogue.” 

McCormack’s piece on the stem cell agency’s blog, The Stem Cellar, is a good reminder that the science community cannot take for granted public support for science and research funding. Most people are heavily focused on other matters that they believe are more relevant to their lives, such as their jobs and getting their children off to school.

It is up to researchers to make building support and educating the public and the media about the benefits of their efforts a regular part of their profession. Perhaps the stem cell agency could even encourage it by adding a communications component to their awards.

As for Meryl Streep and Lindsay Lohan, it is best to go directly to McCormack’s piece to see how their communication works. It could be inspirational.

ViaCyte's hESC Diabetes Effort Examined, Critiqued in MIT Publication

The ViaCyte device -- photo San Diego U-T

The state of California has invested $55 million in a San Diego firm that last week attracted some East Coast attention for its efforts to develop a “virtual” cure involving Type 1 diabetes.

The firm is Viacyte, which is in a stage one clinical trial involving its therapy. The MIT Technology Review looked at the potential product on Feb. 12.

In a piece headlined “A Pancreas in a Capsule,” writer Brian Alexander said,

“In October, a San Diego man had two pouches of lab-grown pancreas cells, derived from human embryonic stem cells, inserted into his body through incisions in his back. Two other patients have since received the stand-in pancreas, engineered by a small San Diego company called ViaCyte.

“It’s a significant step, partly because the ViaCyte study is only the third in the United States of any treatment based on embryonic stem cells.” 

All three of those trials involve California. A spinal cord injury treatment is being tested by Asterias Biotherapeutics of Menlo Park, Ca. It has received $14.3 million from the California stem cell agency. The other trial is for macular degeneration and is being conducted at UCLA by Steven Schwartz for Ocata Therapeutics of Massachusetts, formerly known as Advanced Cell Technology. The firm applied multiple times for California funding but was rejected.

Viacyte, which has received more funding from the stem cell agency than any other company, began its efforts optimistically years ago. Alexander wrote,  

“'When I first came to ViaCyte 12 years ago, cell replacement through stem cells was so obvious. We all said, ‘Oh, that’s the low-hanging fruit,’” says Kevin D’Amour, the company’s chief scientific officer. 'But it turned out to be a coconut, not an apple.'” 

 (Robert Henry at UC San Diego is conducting the  trial on behalf of ViaCyte.)

  

Alexander continued, 

“Douglas Melton, a biologist at Harvard University who has two children with type 1 diabetes, worries that the ViaCyte system may not work. He thinks deposits of fibrotic, scarlike tissue will glom onto the capsules, starving the cells inside of oxygen and blocking their ability to sense sugar and release insulin. Melton also thinks it might take immature cells up to three months to become fully functional. And many won’t become beta cells, winding up as other types of pancreatic cells instead. 

Doug Melton -- Harvard photo

“Melton says the ‘inefficiency’ of the system means the company ‘would need a device about the size of a DVD player’ to have enough beta cells to effectively treat diabetes. ViaCyte says it thinks 300 million of its cells, or about eight of its capsules, would be enough. (Each capsule holds a volume of cells smaller than one M&M candy.)  Last October, Melton’s group announced it had managed to grow fully mature, functional beta cells in the lab, a scientific first that took more than 10 years of trial-and-error research. Melton thinks implanting mature cells would allow a bioartificial pancreas to start working right away.”

The piece in the MIT Technology Review is a plus for the California stem cell agency, which is seeking to raise its profile.  The agency's president, Randy Mills, is making a push to draw interest from non-California enterprises that might find funding from California attractive even with restrictions that it be used in the Golden State.

Stem Cell Ethics: An Overview from UC Davis Event

Alison Sorkin -- Knoepfler photo

California scientist Paul Knoepfler yesterday posted a synopsis of the recent stem cell ethics session at UC Davis that touched on topics ranging from Right to Try laws to hype about hype in stem cell research. 

Writing on his blog, Knoepfler estimated the attendance at 70 to 80 persons including patient advocates as well as scientists, attorneys and institutional compliance officers.

One presenter was Alison Sorkin, deputy general counsel for University of Colorado Health, who dealt with her state’s Right to Try law. Knoepfler wrote that she said that the law is actually quite limited. Knoepfler wrote,

“She also discussed problematic issues with the specifics of the law such as that patients would be responsible for paying for all of their own healthcare for 6 months after treatment under Right To Try as insurers would be exempt from having to provide ANY coverage. There seems to be a growing sense that Right To Try in Colorado may not actually lead to any patients getting non-FDA approved drugs.” 

Tim Caulfield, a professor, Faculty of Law and School of Public Health at the University of Alberta, dealt with hype. Knoepfler wrote,

“Tim focused on hype in the stem cell field and in particular hype involving scientific publications. He even talked about hype about hype. In the current environment there are strong pressures for scientists to hype their work, including in particular in abstracts. What is the relationship between hype in science articles and in the media?” 

The session was the second annual such event for UC Davis, which will presumably stage another next year.

Stem Cell Researchers Face Tighter Scrutiny in Quest for California Millions

Attention stem cell scientists: Want to know who is going to be scrutinizing your budget in your next application for financing from the $3 billion California stem cell agency?

The California Institute for Regenerative Medicine (CIRM), the formal name for the agency, is hiring outside firms to examine the budgets currently being submitted in a $50 million clinical stage award round.  

The two firms that are  being considered have a host of other clients, some of whom might be competitors with California scientists applying for state funding.  CIRM plans to require the experts to self-report any conflicts of interest, basically excusing themselves if such a situation occurs during their work.

It is all part of CIRM 2.0, a radical and ambitious plan to speed funds to researchers and improve quality of applications.  The budget review is a new and critical step for researchers. If their financial plans, including a new financing contingency requirement, do not pass muster, the applications will not even be sent to the agency’s blue-ribbon reviewers.

Here is what the agency says about the budget review,

“An external team of budget professionals will review the proposed budget to provide information to CIRM regarding how the proposed costs compare with established market rates for similar activities (or how well the costs are justified when market rates are not established).

 “When a proposed budget differs significantly from market rates, adjustments to the budget will be required by CIRM prior to further review of the application. Applicants will be notified of the specific discrepancies and applications will not be forwarded for scientific review until an amended budget has been submitted and approved by CIRM.” 

Last month the agency posted a 37-page request for proposals on its Web site. It contained details of how the work is to be performed, budget templates and much more material that offers insights into the agency’s new, CIRM 2.0 thinking. 

The firms that responded to the RFP are Amarex Clinical Research of Germantown, Md., and Integrium Clinical Research of Tustin, Ca.

Integrium said in its proposal,

“Integrium does not have experience in providing the type of service required in the RFP. However, we have many years of experience in which we have internally reviewed budgets that we prepared for our clients.”

 It appears to have offered to review each application’s budget for $2,740 each.­­­­­­­­­

Amarex said,

“Amarex has experience in conducting budget negotiations for services across all types of clinical sites, and knows what appropriate market rates are.  Our clients are both privately funded, and government funded, so we are also aware of the difference in budgeting requirements for both types of clients.”

The Amarex proposal appears to have a cost of $703 for each budget, with expenses such as travel billed to CIRM plus a 10 percent fee.

The agency’s RFP said,

“CIRM anticipates selecting multiple budget review firms pursuant to this RFP and will alternate work among them based on relative expertise in specific areas, timelines, and the avoidance of potential conflicts of interest.”

Both of the firms are well-established organizations and have a considerable history of work with a variety of clinical trials. Their clients are not identified but could be competitors with the organizations that apply for California funding.

The RFP does not speak directly to those sorts of conflicts although it is more specific about financial ties with CIRM employees.  Regarding the budget review consultants, the proposed CIRM contract said,

“The (budget review) firm must be free from actual conflicts of interest not only at the time of selection, but also throughout the term of the contract.”

The agency has a substantial number of outside contractors. On at least one occasion, a conflict has arisen in public. The case was first reported by the California Stem Cell Report in 2012 and involved a “special advisor” to CIRM who was elected to the board of directors of Sangamo, Inc. At the time, Sangamo was the recipient of $5.4 million from the agency as a co-participant on an award. In 2013, the Richmond, Ca., firm received another $6.4 million directly from CIRM. (See here and here for details.)  In January 2014, the firm’s president told CIRM,

“We wouldn't be where we are today without you.” 

The RFP requires that the firms sign a contract that states, 

“The consultant affirms that to the best of his/her knowledge there exists no actual or potential conflict between the consultant's family, business or financial interest and the services provided under this Agreement, and in the event of change in either private interests or service under this Agreement, any question regarding possible conflict of interest which may arise as a result of such change will be raised with CIRM.”

The RFP also states that the firms may be required to “execute” a form 700, a state document that is aimed at disclosing financial conflicts of interest. However, the form is most commonly filed by individuals -- not commercial interests -- and has major limitations in providing full disclosure.

The RFP does not make it clear whether the form 700s would be publicly disclosed or simply held privately by CIRM. However, the agency has never disclosed any reports involving conflicts of interests of its consultants.

Here are the proposals, which are public records, from the two companies.

   Amarex CIRM Budget Prep Proposal January 2015

  

   Integrium Budget Review Proposal for CIRM January 2015

Update on the Search for New Execs at the California Stem Cell Agency

California’s $3 billion stem agency no longer lists on the Internet job openings for a director of medical affairs and director of administration but reports that the positions remain vacant.

The new, top level posts were created in a reorganization of the enterprise, which has less than 60 employees, by its president Randy Mills, who took over last May. He made the move as part of his CIRM 2.0 effort.

In the initial postings last month, the agency said the positions would remain open until they were filled. Three other openings for directors in the areas of blood and cancer, neuro/ocular and organ systems continue to remain up on the CIRM Web site.

No explanation was offered for removal of the medical affairs and administration openings. Kevin McCormack, a spokesman for the agency, said the positions have not been filled.

Here are job posting documents as they originally appeared.

   Director of Administration, California Stem Cell Agency

   Director Medical Affairs, California Stem Cell Agency

Crossing the One-Million Mark: A Decade's Worth of Stem Cell Readership

Google message on page views from last Friday.

The California Stem Cell Report last week chalked up its one millionth page view, a large and fancy readership score that came after more than 10 years of writing about the Golden State’s $3 billion stem cell research program.

Google reported the seven-digit figure at 10:50 a.m. PST on Friday.  No bells rang, however, and no whistles sounded. The tumbler on “dashboard” of the blog just simply and silently clicked over from 999,999.

For those not familiar with Internet terms, a page view is recorded by Google each time a person opens his or her Internet browser on a particular page. It is an industry standard that it is used to help define readership, something akin to circulation numbers for newspaper.

The one-million figure is both large and small. It is tiny in comparison to most general news sites, which may gather millions of page views in a week. It is large in comparison to the potential audience. This writer estimates that no more than 3,000 or 4,000 persons worldwide are deeply interested in stem cells. Considerably fewer are deeply interested in the affairs of the California stem cell agency.

There is also the “so what” question that comes up when evaluating readership. Have any of the more than 4,000 items published since January 2005 had a significant impact? That is always hard to judge, but bumps in readership tend to indicate that certain themes are resonating.  The scope of the audience also indicates that many individuals find frequent value in what is carried here. 

Regular readers of the California Stem Cell Report range from the general public to the folks at the National Institutes of Health. Readers check in from Harvard, UC San Francisco, Stanford, UCLA, UC San Diego, France, Germany, Russia, the United Kingdom and many other locations. Occasionally, a member of the stem cell agency governing board will comment favorably and privately about the value of the blog. Journalists read it, using it as a springboard for their own stories.

The article with the highest views by far deals with the potential cost of stem cell therapies and discussed a report from Japan that contained the figure $512,000.  Earlier today, the item recorded 10,303 page views since it was published less than two years ago. Also today, the article ranked No. 6 out of 2.5 million results in a Google search using the term “stem cell therapy cost.” The piece seems to have attracted a great deal of interest from the public with many onetime hits, probably coming from people who are considering such a treatment.

The second most read item on the California Stem Cell Report is a 2009 item headlined, “Controller Calls for Online Posting of Financial Holdings of CIRM Officials.” It had 2,748 page views. Third is a “pay-for-eggs” item from 2013 that hit 2,487.  That piece involved a commentary in Forbes, which undoubtedly generated abnormally high traffic for the subject.

Our continuing intent has been to delve deeply into a single subject, the California stem cell agency. It is an important experiment in stem cell research funding. Its work has already had a major impact on the field in California. The agency’s success or failure could have major implications for the field and is worthy of considerable attention.

The California Stem Cell Report brings an independent focus to information about the agency. The Report is the only news site devoted exclusively to coverage of the agency and related matters, including analysis and commentary.  The blog provides on-the-scene coverage of the agency's most important public events, either via the Internet or from the sites of the sessions. The blog also explores in more depth California stem cell issues ignored by both the scientific press and the mainstream media. It provides information that can be nowhere else. 

The Internet is well-designed for such a relatively narrowly focused effort as opposed to the mainstream media, which must pursue mass audiences.  Blogs are especially useful in dealing with narrow subjects because of their relatively low production costs, timeliness and lack of space limitations. Newspapers and other mass media, on the other hand, have high costs and extraordinary space limitations as to do all print products. Timeliness can also be issue with some Web sites associated with print.

As for our costs, this blog is produced by one person, David Jensen (yours truly). He is a retired journalist who finances it personally and who has no financial ties to biotech academia or industry,
or the agency. Google does place ads on the site, which generate about $150 every six months or so based on the number of people who click on an ad.

But beginning today this blog is boosting its efforts to cover the costs of the California Stem Cell Report and adding a way to contribute directly to the effort. On this page, you can find a PayPal “donate” button in upper left hand corner. Donate today. It is a way to help keep independent, California stem cell news flowing vigorously. As the California stem cell agency noted last week, “Money matters.”

And thanks to all who are moved to contribute.

A California Stem Cell Plus: Cash Counts on Research Publications

“Money matters,” says the $3 billion California stem cell agency. And it is right.

The agency was commenting yesterday on a study published this week that indicated that the Golden State has “over-performed”in terms of publication of research findings as the result of the agency’s efforts.

The comment appeared on The Stem Cellar, the agency’s blog. Kevin McCormack, senior director of communications, wrote,

“The question the researchers posed was; have the states that fund stem cell research seen an increase in their share of scientific publications in the field? The answer, at least in California’s case, is absolutely yes.” 

The study by Aaron Levine of Georgia Tech said its findings “suggested” that the increase was due to 667 awards totaling $1.9 billion made by the stem cell agency over the last 10 years.

As Levine’s article noted, many other factors need to be examined to determine whether the agency has met the goals of the 2004 ballot campaign that created the stem cell research effort. But for now, the piece by Levine is a significant plus for the California Institute for Regenerative (CIRM), as the agency is formally known. And it comes from an independent source, one that is not financed by the agency, as some other studies have been.

The California Stem Cell Agency and "Over-Performance' -- Study Cites Hefty Publication Record

The trajectory of CIRM-funded research publications in two areas: The blue
line involves U.S. hESC research articles, green represents iPSC. The black
 and grey lines involve non-CIRM funded research from California in cancer
and RNAi. The vertical bars indicate the general date when each of the four
 states studied began their state-funded efforts. Levine chart.

A study by a Georgia Tech researcher today indicated that California state funding has “played an important role” in creating “over-performance” in the Golden State’s stem cell research efforts.

The article in Cell Stem Cell by Aaron Levine, an associate professor of at Georgia Tech’s School of Public Policy,  was titled "Assessing State Stem Cell Programs in the United States: How Has State Funding Affected Publication Trends?"

It dealt with publication of human embryonic (hESC) and induced pluripotent stem cell (iPSC) research from 2006 to 2013 from four states with stem cell programs. He and his students counted the frequency of articles that cited some funding from each of the state agencies involved.  

Levine wrote,

“In both California and Connecticut, state funding programs appear to have contributed to over-performance in the field.”

 He also said,

“Between 2010 and 2013, approximately 55 % of hESC-related articles published with at least one California author acknowledged state funding, suggesting that this funding program played an important role as California maintained and built upon its early leadership in the field.” 

Levine noted that other measures are important in assessing the impact of the state efforts, including New York and Maryland. In an email, he said,

“There are many possible measures of impact. These could include measures of research output (i.e. publications or patents), research quality (i.e. citations to publications or patents or measures of journal quality), scientist training, scientist recruitment, commercialization of research, etc.  The hope for this article is to provide one data point in an ongoing effort to better understand the impact of CIRM and other state stem cell funding programs.  It's always hard to know how a research program will unfold, but I certainly hope to conduct additional analyses of state funding efforts and contribute to our understanding of the impact these programs have had on the field.” 

Levine examined hESC articles because that area of research was critical to California voter approval of Proposition 71 in 2004. The ballot measure created the $3 billion California Institute for Regenerative Medicine (CIRM), the formal name of the stem cell agency. The initiative was mounted in response to the Bush Administration’s restrictions on hESC research.

The agency says that about 240 of its 667 awards involve human embryonic stem cells. A little more than 100 involve iPSC. CIRM has awarded $1.9 billion so far and is expected to run out of money in 2020 at the current pace.

Aaron Levine
Georgia Tech photo

Levine, who served on the Institute of Medicine panel that evaluated the California agency, also published a piece in 2010 that said through 2009 only 18 percent of California's dollars went for grants that were "clearly" not eligible for federal funding.

Here are some excerpts from Levine’s article today.

“After the California Institute for Regenerative Medicine (CIRM) issued its first grants in April 2006, the share of articles acknowledging California funding increased rapidly from approximately 3% in 2006 to 2007 to more than 20% in 2010 to 2011 and 2012 to 2013. 

“Overall, California state funding was acknowledged in nearly 19% of all hESC-related articles in our data set published between 2006 and 2013, compared with 1.8% of articles in a comparable set of RNAi-related research (t test, p < 0.01). 45% of the hESC-related articles published between 2006 and 2013 in our data set with at least one author from California acknowledged funding from the state.”
 “Our comparative analysis provides some of the first evidence that the distribution of stem-cell-related publications in the United States differs from the distribution of publications in fields not targeted by specific state funding policies, and our analysis of the funding sources acknowledged in many of these articles strongly suggests that state funding is responsible, in part, for these differences.

"The share of hESC-and iPSC-related publications produced in each of the four states examined depends on a variety of considerations, including the size, strengths, and interests of the scientific community and the specifics of the policy itself (i.e., its timing, its size, and its focus). In addition, it depends on the competitive environment within the United States, as over-performance in one state must be balanced by under-performance in others. In both California and Connecticut, state funding programs appear to have contributed to over-performance in the field. In California’s case, the state was already a strong performer in hESC related research before its state funding policy was adopted in 2004, and funding began flowing in 2006. This may reflect a generally supportive state environment or a first-mover advantage, as Geron Corporation, a key funder of early hESC research, is based in the state.

“Following passage of Proposition 71 in November 2004 and the creation of CIRM in the ensuing years, the state’s share of hESC-related research grew from approximately 25% in 2002 to 2003 to more than 40%, and the state maintained this position of strength in both hESC-and iPSC-related research from 2008 through the end of our data in 2013. Between 2010 and 2013, approximately 55% of hESC related articles published with at least one California author acknowledged state funding, suggesting that this funding program played an important role as California maintained and built upon its early leadership in the field." 

“In addition, publications are only one measure of the impact of state science funding programs, and examining other outcomes (e.g., patents awarded, clinical trials initiated, etc.) is an important topic for future investigation. Indeed, more thorough efforts to evaluate these state stem cell programs, ideally drawing on the initial goals of the programs and a wide range of relevant outcomes, would be an important step to help assess their impact on the field and the value of field specific state science funding programs more generally.”

The students listed on the article include Hillary Alberta, Albert Cheng, Emily L. Jackson and Matthew Pjecha.

Trounson Named as Advisor to California Cord Blood Firm

A California cord blood firm yesterday appointed Alan Trounson, the former president of the $3 billion California stem cell agency, to its newly formed scientific advisory board.

Cord Blood Registry of San Bruno, which says it is the largest “family bank” in the world, announced yesterday that Trounson is one of four members of its science board. It said the panel would help expand the scope of therapies that it is developing.

Alan Trounson, UCSD photo

Trounson last year left his post as president of the agency, formally known as the California Institute for Regenerative Medicine(CIRM). Seven days later, he joined the governing board of StemCells, Inc., a firm that had received $19.3 million in funding from CIRM. The move surprised the agency and generated a flap over revolving-door conflicts of interest.

Cord Blood Registry has not received any funding from the stem cell agency. In response to a question, Kevin McCormack, senior director for CIRM communications, said today the firm has “no connections whatsoever” with the agency.

It is not clear whether the firm plans to seek financing from CIRM in the future. Cord Blood announced last month that it is involved in an effort with a CIRM-funded, Cellular Dynamics International of Madison, Wisc., to reprogram cord blood and umbilical tissue into reprogrammed pluripotent cells.

Cellular Dynamics, founded by famed researcher Jamie Thomson, has a a facility in Novato, Ca., and was awarded more than $16 million from CIRM in 2013.

Heather Brown, vice president of scientific and medical affairs at Cord Blood (CBR), said in a press release,

"The (scientific board) will provide strategic guidance on current issues that will contribute greatly to CBR's continued progress in research and clinical development."

The company’s press release said,

“CBR is dedicated to advancing the clinical application of newborn stem cells by partnering with leading research institutions to establish FDA-regulated clinical trials, requiring CBR processed cord blood….” 

The company has been in business since 1992 but yesterday’s announcement marked the formation of its first scientific advisory board. It is headquartered in the San Francisco Bay Area, but it stores its cord blood in an 80,000-square-foot facility in Arizona.

Last month, Geoffrey Crouse, CEO of the firm, told Karen Garloch of the Charlotte Observer that some private cord blood banks have“overstated the state of the research” involving cord blood.

He made the comment in connection with the formation of the national Cord Blood Association. He said that he expects the association to “bring the industry to a higher standard.”

According to an April 25, 2014, article in the Wall Street Journal, the blood cord banking business globally runs about $4 billion a year and has had its share of problems. The piece by Dionne Searcy and Christopher Stewart said,

“A Wall Street Journal analysis of government inspections and a review of lawsuits in the U.S. found problems in the loosely regulated cord-blood-banking business, including dirty storage conditions, leaky blood samples and firms going out of business. 

“Some private cord-blood banks are essentially marketing websites that lure customers, collect fees, then outsource the processing and storage of what is touted as biological life insurance for children.”

California's Stem Cell Agency Receives Two Applications in Kick-off of Fast-track Program

The California stem cell agency said today that its new, $50 million CIRM 2.0 program has attracted two applications from businesses for funding of clinical stage work.

The $3 billion agency refused to reveal any further information about the applications, which are part of a radical overhaul of its grant-making efforts.

The next applications in the round are due on Feb. 27.  End-of-the month, rolling deadlines for applications will continue through the middle of this year. The agency did not expect to see a rush of applicants last month because the new, rolling deadlines allow researchers greater flexibility on when they can seek financing.

The goal of the CIRM 2.0 program, which was devised by Randy Mills, president of the agency, is to fast-track funds to researchers and improve the quality of applications.

If the applications that were filed last Friday are approved, the companies should receive their cash before the beginning of May. That compares to an average of about 22 months under former agency President Alan Trounson.

The agency, formally known as the California Institute for Regenerative Medicine or CIRM, has yet to officially promulgate the rules for the grant rules as well as revised loan policies.

Both items were on tap for last week’s board meeting. They were put off until the March meeting while unspecified revisions are being made. A draft is available for the new grant administrative process.

The agency has declined to disclose the draft of the new loan regulations. The loans have been attractive to businesses in the past because they are forgivable if no commercial product results. It is not clear whether the agency intends to continue with that policy.

The California Stem Cell Report has asked the agency for the amount being sought on each application, the general nature of the research being proposed and which of the three CIRM 2.0 programs the applications address.

Correction

The Stem Cellar item on Saturday said that Anne Holden wrote the piece in question on the CIRM blog. It was actually written by Don Gibbons. The attribution to Holden was based on information on the CIRM blog item that incorrectly indicated she wrote it.

Ethics and Stem Cell Research Symposium Feb. 12: Gordie Howe to Right to Try

The public and other interested parties are invited to a UC Davis bioethics symposium Feb. 12 that is likely to deal with some high profile issues involving stem cell research.

Davis researcher Paul Knoepfler is helping to organize the event which he said will include stem cell tourism (think former hockey great Gordie Howe), Right to Try laws and much more. The panelists include Timothy Caulfield of the University of Alberta and Leigh Turner of the University of Minnesota.

A blogger by the name of HappyAnise wrote on the StemcellPromise blog,

“What it makes this so exciting is that they’re apparently going to be talking about some REAL, GENUINE ethical issues. To wit… what on earth are we going to do about all of those stem cell clinics popping up in various and assorted countries? You know, the ones with the weird, dubious, expensive treatments that the FDA would never approve in a gazillion years? And while we’re on the subject, when is the FDA going to do anything about regulating, say, $10,000 stem cell creams? And what about those “Right to Try” laws? They passed in four states in November, but what is the federal government going to do, if anything? What should they do?”

You can register with at 916-734-6181 or julie.bechtel@ucdmc.ucdavis.edu.

California's New, Fast-Track Stem Cell Program Draws Applications But Details Missing

California’s new and ambitious effort to speed stem cell therapies into widespread use drew “multiple” applications as it closed out its first round on Friday.

January is the first month of what the agency calls a radical move in its grant-making. Its initial foray is a $50 million clinical stage round that will be accepting applications for funding at the end of each month until the middle of the year.

The promise for those filing Friday is to put money in their hands in roughly four to five months. That compares to an average of 22 months under the agency’s previous grant rounds.

Randy Mills, the president of the agency, devised the fast-track effort and dubbed it CIRM 2.0. He told agency directors on Thursday that “multiple applications” had been received. (See here and here for more on CIRM 2.0.)

The California Stem Cell Report on Thursday and Friday asked for the specific number that Mills referred to. The agency, formally known as the California Institute for Regenerative Medicine(CIRM), however, did not provide a figure. 

The requests from the California Stem Cell Report also sought the following, all of which is public information: the total number of applications, the number from academic institutions, number from nonprofits, number from businesses, figures on the amount being sought on each application and the general nature of the research proposed.

Applications were due by 5 p.m. PST Friday. Presumably the agency will have the complete information assembled by early Monday and will provide it then.