California's $40 Million Stem Cell Genomics Center: Its Fate and Outcomes

California's stem cell agency hit something of a milestone six years ago when it approved $40 million to create a genomics center that was aimed at positioning the state as a global leader in stem cell genomics. 

The round triggered complaints about irregularities, unfairness, score manipulation and the role of its then president, Alan Trounson. The $40 million, at the time the largest single research award by the agency, was ultimately divided three ways and now has been spent. 

The California Stem Cell Report queried the agency this week about the award, its status and results. Here is the response in Q&A format.

Q: How was the $40 million shared and with which institutions?
A: The genomics grant was split into three awards: $22.7M to Stanford (GC1R-06673-A), $13.2M to the Salk Institute (GC1R-06673-B), $4M to UC Santa Cruz (GC1R-06673-C). (The application numbers carry links to the progress reports on the CIRM website.) 

Q: Is there any requirement for the grantees to come up with a plan for continued funding? 

A: There was no requirement for the grantees to come up with a plan for continual funding in the concept RFA.  Stanford and Salk provided co-funding to support the centers during the award period.

Q: If not, what prevents the doors from closing at the genomics center(s) in the next couple of years?

A: The Stanford sequencing center established by the genomics awards continues to operate with other sources of funding.  The Stem Cell Data Hub established by UCSC continues to be supported.  UCSC has no plans to shut down the site even though its CIRM award has ended. 

Q: How much time remains on the grant(s)? I See there was at least one extension given, but it is unclear why there was delay.

A: All three genomics grants have ended as of May 31^st.  The sequencing centers at Stanford and the Salk were given six month award extensions to continue supporting projects with technical delays in sequencing activities.  The data hub at UCSC was given a 12 month extension to process data generated by the sequencing centers.

Q: What else do readers need to know about this award? 

A: A number of outputs were generated from genomic center projects, including:

• 60 publications connected to CESCG funding
• 10 data analysis/visualization tools created
• 1 new sequencing technique developed
• 300 new iPSC lines created
• Central online data hub created with standard metadata, analysis pipelines, restricted access
• Data repository of human single cell global transcription in heart, pancreas, blood, brain, brain
• 84TB data generated from sequencing activities across projects

*********

​Read all about California's stem cell agency, including Proposition 14,  in David Jensen's new book. Buy it on Amazon:  California's Great Stem Cell Experiment: Inside a $3 Billion Search for Stem Cell Cures. Click here for more information on the author.

Position of the California Stem Cell Agency on Gene-Edited Babies? No Go.

California's $3 billion stem cell agency may be on the leading edge of regenerative medical research, but it is clearly opposed to the type of work that has led to the international flap over the gene-edited babies in China. 

Its regulations have long barred that sort of experimentation. In 2016, the agency, known formally as the California Institute for Regenerative Medicine (CIRM), convened an international conference to discuss the issues involved.

The session in Los Angeles went on for hours, generating a 223-page transcript touching on the difficulty of regulating gene editing, among a host of other difficult issues. 

One patient advocate in the audience, Adrienne Bell Cors Shapiro, noted that it is nearly impossible to control all that might happen. She said,  

"People are messy. And if you develop this technology, somebody is going to find a way to use it."

Last week the MIT Technology Review published an article about a Stanford University investigation into what two of its researchers knew about the Chinese research. The scientists also have received CIRM funds for research unrelated to the Chinese work. 

Asked for a comment, a spokeswoman for the state stem cell agency said in an email:

"CIRM’s regulations prohibit nuclear genome editing for reproductive purposes. In February 2016, CIRM convened the Scientific and Medical Accountability Standards Working Group (SWG) for a workshop on Human Gene Editing. The SWG subsequently recommended that no changes be made to CIRM’s existing prohibition on nuclear genome editing for reproductive purposes."

In 2016, Hank Greely, a law professor at Stanford who deals with bioethical issues, told the gene editing conference:

"CIRM is in the human embryo experimentation world. It funds research as long as the embryos are not implanted. It funds it with special protections and special review considerations and special informed consent considerations. I don't think CRISPR-cas9 changes that."

The controversial research in China triggered a global uproar in the scientific community. The leading stem cell research organization, the International Society for Stem Cell Research, issued a statement opposing such experimentation. 

He Jiankui, the Chinese scientist who performed the experiment, has lost his job in that country, according to news reports, and may be facing criminal charges. His work has not been confirmed by an independent review. 

Genetically Altered Babies: A Bit of a California Connection

This You Tube video produced by He Jiankui had drawn 19,723 views at the time of this posting along with nearly 300 comments, pro and con.  The number of views jumped about 5,000 during one hour this morning.

The startling news about what is being described as the world's first gene-edited baby has a something of a California tie.

The scientist behind the work, He Jiankui, worked from 2010 to 2012 in the lab of Stephen Quake at Stanford University, who is participating in a $40 million genomics program backed by California's $3 billion stem cell agency.  

Like many other scientists, He Jiankui was trained in the United States, receiving his Ph.D. from Rice University. 

A statement on the web site of Direct Genomics, a company He Jiankui founded, said,

"He was working on genome sequencing research during his postdoc training in the lab of Stephen Quake at Department of Bioengineering, Stanford University. Dr. He has multidisciplinary research background, such as in physical theory of network evolution, influenza virus, immune repertoire sequencing, single cell genomics and bioinformatics."

Quake's lab is currently dealing with ultra high throughput DNA sequencing. On the lab's web site, a mission statement by Quake said,

"My work in single molecule biophysics led to the first demonstration of single molecule sequencing, and my research in this field has led me to become deeply involved in human genetics, immunology, and the development of new clinical diagnostics."

Quake has not yet responded to a query concerning He Jiankui's work at Stanford.

In the stem cell agency's genomics project, Quake is the lead on a project dealing with cell differentiation.

California's Center for Genetics and Society in Berkeley released a statement on the news about the gene editing. Executive Director Marcy Darnovsky, said, 

“If true, this amounts to unethical and reckless experimentation on human beings, and a grave abuse of human rights. We wish the best for the health of these babies, but strongly condemn the stunt that threatens their safety, and puts the rest of us at risk. Throwing open the door to a society of genetic haves and have-nots undermines our chances for a fair and just future.”

LA Times on California's Stem Cell Agency, Biotech Gold Rush and Genetically Altering Human Embryos

The Los Angeles Times, which largely ignores the $3 billion California stem cell agency in its news columns, is carrying a piece this weekend that says the agency is considering “work so controversial that the federal government won’t pay for it.”

The reference is to the possibility of the state of California financing research that involves the editing of genes in human embryos, which the agency began to explore at some length at a Feb. 4 meeting in Los Angeles.

The Feb. 12 Times story, written by Melody Petersen, is straight news piece that recaps the controversy about the possibility of making heritable changes in human beings through the use of CRISPR technology. She also covered how the agency intends to proceed with its review.

Peterson described how businesses are embracing CRISPR,

“It has set off a biotech gold rush as scientists imagine its commercial uses and found start-up companies that are attracting hundreds of millions of dollars in venture capital.”

Peterson also wrote about the likelihood of heritable changes in embryos, interviewing Marcy Darnovsky, executive director of the Center for Genetics and Society in Berkeley. She quoted Darnovsky as saying,

"This is not safe. It's still way too early to try such an experiment on a human being."

Peterson continued,

“The agency's current regulations say that no money can be used to transfer a genetically modified human embryo to a woman to start a pregnancy. But some experts worry that agency-funded researchers could later turn to other sources to finance the reproductive stage of their work.

"'If you have genetically modified embryos in labs around the state,’ Darnovsky said, ‘what's to stop them from being used to initiate a pregnancy?"

Peterson quoted Kevin McCormack, senior director for communications at the stem cell agency, as saying, "So far we have not funded any research that involves CRISPR, nor have we received any proposals for funding using that technology. But that's probably just a matter of time."

The stem cell agency has longed struggled with a lack of news media attention. It would like to spread the word about what it considers its good works, such as the well over $500 million it has pumped into enterprises in the immediate Los Angeles area. The LA Times is an especially important medium because it is the largest circulation newspaper in the state, has an enormous Internet presence and helps to drive what is covered by other outlets.

But given the state of the media nowadays and the shrinkage in science reporting, about all the agency can really expect for now is coverage when something extraordinary happens or when there is the likelihood of something extraordinary happening such as genetic changes being made in human embryos.

California's Stem Cell Agency to Tackle Host of Touchy Issues on Human Genetic Changes

California's stem cell agency yesterday embarked on what is likely to be an exhaustive review of genetic alteration of human embryos with likely recommendations for changes in the $3 billion research effort.

The 11-year-old agency plans to examine a host of issues ranging from inadvertent, inheritable changes in the human race to informed consent on the part of patients.  The move emerged from a day-long review of the far-reaching subject at a meeting yesterday of the California Institute for Regenerative Medicine (CIRM), as the agency is formally known. 

Responding to a request from the California Stem Cell Report, Kevin McCormack, senior director for communications for CIRM, laid out the scope of the agency's future steps and gave his impressions of the session, which suffered from audio quality issues in its audiocast. (See here and here.)

McCormack said the issues were "too many and too complex" to produce recommendations immediately. He said,

"In the end it was decided that the most productive use of the day was not to limit the discussion at the workshop but to get those present to highlight the issues and questions that were most important and leave it to the (research standard group) to then work through those and develop a series of recommendations that would eventually be presented to the (agency's governing) board."

Matters to be addressed include the following, McCormack said, 

• Possible changes in language used in getting informed consent from donors in light of the ability of Crispr to make relatively easy changes in human changes. Crispr is a new technique that has brought the whole question to international attention. 
• Use of Crispr on previously donated materials/samples where general consent was given without knowing that these technologies could be available 
• Genetic modification of mitochrondial DNA as well as genetic DNA. 
• The possibility that somatic cell gene editing may lead to inadvertent germ line editing 
• Engaging patient advocates and other community groups such as the social justice and equity movements for their views. McCormack said, "After all, we are a taxpayer-created and funded organization so we clearly have some responsibility to the wider California community and not just to researchers and patients." 
• Financing the use of Crispr and other technologies that can modify the human embryo provided those embryos are not going to be implanted in a human uterus. 

Here is the full text of McCormack's summary, which we suspect is going to be turned into an item for the agency's own stem cell blog, The Stem Cellar.

"The meeting began with the hope that it would produce a strong, robust discussion of the issues surrounding the use of CRISPR to edit human embryos and to result in a series of recommendations that the Standards Working Group (SWG) could then forward to the CIRM Board on whether any changes needed to be made to our existing rules and regulations about funding such research.

"It turned out to be a thoroughly fascinating day with some thought-provoking presentations and equally thought provoking questions from the audience, from scientists, social researchers and members of the public.

"It quickly became clear that the discussion was going to be even more robust than we imagined and the issues raised were too many and too complex for us to hope reaching any conclusions or producing any recommendations in one day.

"In the end it was decided that the most productive use of the day was not to limit the discussion at the workshop but to get those present to highlight the issues and questions that were most important and leave it to the SWG to then work through those and develop a series of recommendations that would eventually be presented to the Board.
"The questions to be answered included but are not limited to:
"1) Do we need to reconsider the language used in getting informed consent from donors in light of the ability of CRISPR and other technologies to do things that we previously couldn’t easily do.

"2) Can we use CRISPR on previously donated materials/samples where general consent was given without knowing that these technologies could be available or can we only use it on biomaterials to be collected going forward.

"3) Clarify whether the language we use about genetic modification should also include mitochrondial DNA as well as genetic DNA.

"4) The possibility that somatic cell gene editing may lead to inadvertent germ line editing

"5) How do we engage with patient advocates and other community groups such as the social justice and equity movements to get their input on these topics – do we need to do more outreach and education among the public or specific groups and try to get more input from them (after all we are a taxpayer created and funded organization so we clearly have some responsibility to the wider California community and not just to researchers and patients)

"6) As CIRM already funds human embryo research should we consider funding the use of CRISPR and other technologies that can modify the human embryo provided those embryos are not going to be implanted in a human uterus.

"This was a really detailed dive into a subject that is clearly getting a lot of scientific attention around the world and is no longer an abstract idea but is rapidly becoming a scientific reality. The next step is for a subgroup of the SWG to put together the key issues at stake here and place them in a framework for another discussion with the full SWG at some point in the future.

"Once the SWG has reached consensus their recommendations will then go to the CIRM Board for its consideration. 

"I hope this captures the flavor and essence of what happened today. It really was a fascinating discussion and the issues raised, and their complexity, highlighted why so many different groups around the world are wrestling with the potential, and pitfalls, of this new technology."

World's First Approval of Genetic Changes in Human Embryo; California Eyes the Issue Thursday

The Guardian newspaper in England did not back away from the big science story today. Its article by Haroon Siddique said flatly in the first paragraph,

“Britain’s first genetically modified human embryos could be created within months….”

Siddique's piece dealt with the approval today by the key regulatory body in the United Kingdom for genetic changes in human embryos, a topic of international controversy and concern but with a special connection to California.

The news came as the state’s $3 billion stem cell agency plans a full-day examination Thursday of the issue and its implication for research in the Golden State. Of particular concern is a gene editing tool called Crispr that makes it much easier to alter genes and raises the possibility of permanent changes in the genetic make-up of the human race.

The journal Nature said the UK action was “the world's first endorsement of such research by a national regulatory authority.”

Kevin McCormack, spokesman for the California stem cell agency, told the California Stem Cell Report that the move demonstrated the timeliness of this week’s conference, which could lead to changes in California stem cell research standards.

Eminent scientists internationally have called for a go-slow approach until the issues are examined more closely. Leading that effort is David Baltimore, a Nobel Prize winner and a former member of the state stem cell agency board. He is scheduled to speak at Thursday’s session.

Baltimore was interviewed today by Nicholas Wade for a piece in the New York Times. Wade wrote that Baltimore “said the proposed experiment appeared to be consistent with the principles laid out by the (scientific) academies.

“Many such experiments are impossible for government-funded researchers in the United States because of the congressional ban (on destruction of embryos in federal research), but ‘luckily, private and state funding sources are available to carry forward such work,’ Dr. Baltimore said.”

The research in the UK is expected to be conducted with embryos donated via an IVF process. The UK rules restrict the length of the experiment to 14 days. None of the embryos will be transplanted to a womb, according to the rules.

In California, the Center for Genetics and Society in Berkeley issued a news release raising questions about the UK action. Marcy Darnovsky, executive director of the center, asked,

“Is today's decision part of a strategy to overturn the widespread agreement that puts genetically modified humans off limits?”

Her statement said, 

“The designer-baby question is a social and political question more than a technical one, and we are at a tipping-point moment on it. Now is the time to ensure that gene editing is not used to create GM babies, and that we stay off the high-tech road to new forms of inequality, and to a consumer-driven form of eugenics.”

Stem cell researcher Paul Knoepfler of UC Davis, author of “GMO Sapiens: The Life-Changing Science of Designer Babies,” wrote on his blog,

“It’s frustrating for us biologists that we still know more about the development of other animals (e.g. mice or fruit flies) than that of our own species. Crispr could change that and I believe it could do it in a big way. So with the appropriate oversight, bioethics training, and transparency, I could support this Crispr work in the UK. I need time to read up on what exactly they have planned….”

Thursday’s conference in Los Angeles will be audiocast live via an 800 number. It is also a public meeting at which anyone can make comments. Directions for the audiocast and the specific location are on the meeting agenda. The California Stem Cell Report will be providing live coverage of the day’s discussions.

$40 Million California Stem Cell Genomics Agreement Signed; A Checkered Past

The California stem cell agency and a Stanford-led consortium have reached agreement on a $40 million stem cell genomics project that triggered complaints about irregularities, unfairness, score manipulation and the role of its then president, Alan Trounson.

The agreement was concluded last month with Stanford, UC Santa Cruz and the Salk Institute in La Jolla, five months after the award was approved by the governing board of the $3 billion agency, which is known as CIRM. The final signature came July 2 when Santa Cruz signed. Salk signed on June 26 and Stanford June 18, according to Kevin McCormack, a spokesman for the agency.

The effort is aimed at paving the way for therapies tailored to a patient’s genetic make-up and positioning California as a world leader in stem cell genomics.

Trounson’s role came under fire when he recommended approval of the Stanford application. The agency’s blue-ribbon grant reviewers, whose advice is rarely rejected by the CIRM board, also recommended funding three competitors. 

The round had a checkered history as a result of a conflict of interest involving scientist Irv Weissman of Stanford and scientist Lee Hood of Seattle, who own a ranch together in Montana. Trounson, who has visited the ranch as Weissman’s guest, recruited Hood to review the applications, including Stanford’s proposal which then specifically included Weissman.

The Stanford application that was ultimately approved did not include Weissman.  Michael Clarke, the No. 2 person in Weissman’s stem cell program at Stanford, was included, however, and was praised by name by Trounson during board consideration of the Stanford application. (See here for discussion of conflicts preceding the board action.)

Seven days after leaving CIRM at the end of June, Trounson was named to the board of directors of StemCells, Inc., of Newark, Ca., which holds $19.4 million in awards from the agency. The firm was co-founded by Weissman, who now sits on its board.  The Trounson appointment surprised the agency and triggered a rash of bad publicity for CIRM. (See here and here.)

The agency’s new president, Randy Mills, banned CIRM employees from communicating with Trounson about StemCells, Inc., matters and announced that he would not accept employment from CIRM grantees until one year after he leaves the agency.

Former CEO of California Stem Cell Agency Named to Board of Firm that Received $19 Million From the Agency

Alan Trounson, the former president of the $3 billion California stem cell agency, today was named to the board of a company that has received $19.4 million from the agency, raising fresh and serious questions about conflicts of interest at the state-funded research program.

Announcement of the appointment came only seven days after Trounson left state employment. Trounson has been dogged for some time with questions about his relationship to the company, StemCells, Inc., of Newark, Ca., and its co-founder, eminent Stanford researcher Irv Weissman, who sits on the company’s six-man board and is chairman of its scientific advisory board.

StemCells, Inc., announced Trounson’s appointment in a press release this morning. The publicly traded firm said it was “thrilled” to have Trounson on its board. The first sentence of its press release noted that he had served as head of “the largest scientific funding body for stem cell research in the world.”

Weissman is director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford. He has received $34.7 million from the agency. Stanford overall has received $281 million from the stem cell agency, formally known as the California Institute for Regenerative Medicine (CIRM). It is the No. 1 recipient of cash from the agency.

One California stem cell researcher, who asked to remain anonymous, said in an email,

“This looks like payback to Alan Trounson for all of the money that CIRM paid out to Irv Weissman (founder of StemCells, Inc.) and his friends at Stanford while Alan was president of CIRM.  Many people have pointed out that Alan seemed to be biased toward Stanford in his public and private comments. The facts bear that out: Stanford and StemCells, Inc., have had more than $300,000,000 of CIRM's $3 billion in funds awarded to them in grants.  Are they really more than twice as good as UCSF ($132,650,363), and three times better than USC ($104,858,348) and UC Irvine ($98,591,836)?”

As a member of the board of directors of StemCells, Inc., Trounson is expected to receive compensation including stock in the company. In 2013, members of the board received total compensation, including stock awards, ranging from $60,800 to $99,800, according to a Security and Exchange Commission filing.

StemCells, Inc., Weissman and the stem cell agency did not immediately respond to requests for comment. Trounson, who announced last fall he was leaving the agency to return to Australia, could not be reached. The California Stem Cell Report will carry the full text of their remarks when they are received.

Last year and earlier this year, conflict of interest questions concerning Trounson and Weissman came in a $40 million stem cell genomics award round that was won by a Stanford-led team last January. The round was marked by a conflict of interest connected to Trounson, CIRM grant reviewer Lee Hood of Seattle and Weissman. Hood and Weissman own a Montana ranch where Trounson has been a guest. Trounson recruited Hood to help review the stem cell genomics applications in 2013 in closed door meetings. Hood, however, failed to disclose his relationship with Weissman.  It only came to light after another reviewer pointed out the connections between the two men. The agency had failed to detect the conflict.

As the California Stem Cell Report has previously noted,,

“Prior to the genomics round Trounson had acknowledged he had a conflict-of-interest in connection with another Weissman-related proposal. In 2012 in a round not connected to genomics, Trounson, who has visited the Hood-Weissman ranch as Weissman's guest, recused himself from the board's public discussions of applications from StemCells, Inc., a company founded by Weissman.

“Under CIRM's procedures, Trounson does not vote on applications during the review process. But beginning last year the board gave him and his staff new authority to make recommendations on applications after they were acted on by reviewers.”

Trounson ultimately recommended board approval last January of the genomics application from Stanford after Weissman was removed from the proposal.

During last January’s meeting, Trounson touted the Stanford application and specifically mentioned Michael Clarke, who is the No. 2 person in Weissman’s stem cell institute at Stanford, and who was part of the Stanford application instead of Weissman.

According to the meeting transcript, Trounson said,

“I think he's (Clarke) an extraordinary good researcher, and I think the Stanford people are terrific at that.”

The agency said earlier this year it had begun an examination of the processes in the stem cell genomics round, which was criticized for irregularities,unfairness, score manipulation and Trounson’s role.   No results of that inquiry have been announced.

Since the agency's inception in 2004 questions have been raised about conflicts of interest at the agency, mainly due to the composition of its board. Roughly 90 percent of its grants have gone to institutions that have been linked to members of its board.  The Institute of Medicine, in a $700,000 study commissioned by the agency, said that the board members essentially make proposals to themselves about what should be funded. And in 2008 the journal Nature editorialized about "cronyism" at the agency.

Stanford's $40 Million Stem Cell Genomics Award Still Hanging Fire

More than four months after a Stanford-led consortium won a $40 million stem cell genomics award, the California stem cell agency has not yet concluded a formal contract with the researchers.

The award was approved Jan. 29 by the agency's board following a process that Stanford's competitors said was marred by unfairness, apparent preferential treatment and manipulation of scientific scores.

The award is aimed at creating medical treatments tailored to a patient's genetic makeup and making the state a world leader in stem cell genomics.

In response to a query from the California Stem Cell Report, Kevin McCormack, senior director for communications, said that the contract with the consortium remains unsigned. He said, however, that the agency is hopeful that final details will be worked out soon.

$40 Million Stem Cell Genomics Award: Details Still Being Worked Out

BURLINGAME, Ca. – The California stem cell agency and a Stanford-Salk consortium have yet to come to terms on a final agreement on a $40 million stem cell genomics award.

The governing board of the agency approved the proposal in late January during a process that was marked by controversy, including complaints about irregularities,unfairness, score manipulation and the role of its president, AlanTrounson.

All awards are subject to review by the agency's staff, which works out final details and assures that all terms are met.

Asked about the status of the award, Kevin McCormack, senior director of public communications for CIRM, said this morning that the agency was still talking with the consortium. He did not go into details about what issues are involved.

California's $40 Million Stem Cell Genomics Award Still Hanging Fire

The California stem cell agency's $40 million award to a Stanford-Salk group for stem cell genomics research is not yet a done deal.

The award was approved more than two months ago by the agency's board. However, the proposal is now caught up in a staff review of the nitty-gritty of its details.

 Agency employees, as a routine matter, go through all board-approved applications to be sure all matters are in order, ranging from commitments on matching funds to overall considerations concerning the recipient's research budget.

Sometimes changes are made as the result of the staff review. In rare cases, the recipient declines the award. (See here and here for two stories about recipient rejection of the California agency's cash.)

The California Stem Cell Report earlier today inquired about the status of the stem cell genomics award.

Kevin McCormack, senior director of public communications for the agency, said it had not cleared the staff review. Asked whether there were particular issues, McCormack replied,

“No. Some things just take time.”

The stem cell genomics round was marked by complaints about irregularities, unfairness, score manipulation and the role of its president, Alan Trounson.

In the wake of the award, which was approved on a 6-1 vote by the 29-member board, the agency initiated an examination of the grant review process in the genomics round.

Board member voting on the award was limited because of widespread conflicts of interest among the agency's governing board.

The $13 Million Matter of DR3-07201: Allegations of Conflict of Interest at the California Stem Cell Agency

In an unusual move last December, the California stem cell agency removed – with no public explanation – an application for $13 million from consideration by its governing board.

That application is now back before the board on Thursday and is almost certain to be rejected.

What is missing, however, are important specifics about the matter. They are cloaked by the agency's rules that conceal most of the CIRM grant review process, including the names of applicants along with the identities of reviewers and their economic and professional interests. Also shrouded are the details of any complaints about conflicts of interest as well as any other appeals.

Nonetheless, since the proposal was listed on the agenda of a public meeting of a state agency, it is known that it involves application DR3-07201. The unidentified applicant, according to a CIRM summary, sought $13 million for research into a treatment for heart failure, a therapy that is labeled by the applicant in all capital letters as “DYNAMIC.”

The agency's scientific reviewers last year recommended rejection of the request for funding. The agency's review summary said,

“The major serious criticism and flaw stems from the fact that the applicant is currently evaluating the same cellular product in a Phase 1/2 trial in a different subgroup of cardiac patients. Since the objectives of the proposed and currently enrolling trials are similar, reviewers agreed that the proposed Phase 1 trial does not add value and should be re-evaluated after completion and analysis of data from the current trial .”

No scientific score was released for the review but it was last on the list of all applications in this particular round. The agency usually lists the applications in order of their scores.

Following the removal of the application from the board agenda, the California Stem Cell Report in December inquired about the reason. Kevin McCormack, senior director of communications, replied via email,

“We received a last-minute appeal based on an alleged conflict of interest.  In order to allow time to review the claim, we deferred action.  We have done this previously, though I don’t have an exact count.”

When the application popped up on the agenda for this week's meeting, we inquired again, seeking more information. That was seven days ago.

The answer came in the form of a posting yesterday on the CIRM Web site of a one-page memo dated March 7 from Gil Sambrano, CIRM's associate director, review. In the note to the CIRM board, Sambrano said a conflict of interest allegation was raised by the applicant on the morning of Dec. 12, 2013, the day on which the application was to be considered. Sambrano said,

“The applicant alleged that the GWG (grant working group) review of the proposed project may have been 'tainted' by the 'perceived lack of objectivity' of one member of the GWG. There was no specific basis to support a financial, professional or personal conflict as defined in the GWG conflict of interest policy.”

Sambrano said the investigation into the complaint determined there was no violation of the agency's conflict of interest rules. He said,

“We found no evidence that the reviewer had any significant influence on the score or the recommendation. The reviewer was not an assigned reviewer and therefore did not contribute a written critique to the panel. Consistent with the recollection of the review chair and CIRM science officers in attendance, the discussion notes suggest that this reviewer did not provide any comment either in favor or against the proposal. The individual score given by the reviewer was very close to the mean score and thus did not contribute to the broad standard deviation.”

Sambrano continued,

“The applicant also submitted a request for reconsideration based on material new information. Although the applicant provided some information that is new, it did not directly address the main concern of reviewers and therefore did not provide adequate grounds for reconsideration. The request was denied.”

Sambrano said the agency took an additional step of seeking the opinion of two new expert reviewers and the chair of the grant review group. He said they did not find the new information “compelling.”

Reviewer Joyce Frey-Vasconcells was barred from participating in the review of the application, according to its CIRM review summary. Other reviewers in the round who could participate in assessing the application included Joy Cavagnaro, Raj Chopra, Derek J. Hei, Hassan Movahhed and Andrew Balber. Their names were listed on review summaries on other applications in the round where they had conflicts of interest, either professional or economic.

The applicant's appeal does not necessarily end with the CIRM staff decision. The applicant can appear before the board in public on Thursday and seek to overturn the action or ask for further investigation. It can also send material to the agency for delivery to all board members. 

As mentioned previously, the name of the applicant was withheld by the stem cell agency. But it could likely be discerned by a knowledgeable stem cell researcher based on information contained in the review summary. If the applicant would like to send both of its appeals to the California Stem Cell Report, we would be glad to carry their full text and any additional commentary that the applicant would like to make. Other applicants have done so in the past. The agency has no prohibition against such an action and actually has a term for it – self-disclosure.

Our take: The stem cell agency's appeal process ill serves the California public, grant applicants and CIRM itself. The $3 billion agency's reliance on secrecy only raises more questions about cronyism and unfairness, some of which have dogged CIRM since its inception. The recent flap over the $40 million genomics round is only the most recent example. Roughly 90 percent of all the cash handed out by CIRM has gone to institutions that are represented on its governing board, which sets the rules for the grant-making process and determines the nature of the grants. The board's conflicts are built in by Prop. 71, the measure that created the agency in 2004. The only genuine way to ameliorate the issue is with more transparency.

Craig Venter's "Road to the Cure" Stem Cell Venture

Craig Venter aboard his research yacht in 2004.
Sidney Morning Herald/Dallas Kilponen photo

Craig Venter, the international genomics superstar, is staking out a claim on stem cell turf.

The move comes with the formation of Human Longevity, Inc.(HLI), Venter's new company in the La Jolla, Ca., area.

Venter kicked off the enterprise this week with the announcement that it had $70 million in backing. The company press release said the firm is a “a genomics and cell therapy–based diagnostic and therapeutic company focused on extending the healthy, high performance human life span.''

Most of the news coverage concentrated on genomics. But the firm's press release also said,

“The company will be embarking on an ambitious multi-pronged effort utilizing stem cell therapy advances to enhance and improve the healthy life span. HLI's work is premised on the theory that as the human body ages many biological changes occur, including substantial changes and degradation to the genome of the differentiated, specialized cells found in all body tissues. There is also a depletion and degradation of healthy regenerative stem cell populations in the body over time. HLI will monitor the genomic changes which occur during stem cell differentiation, normal aging, and in association with the onset of disease.

"'The global market for healthy human longevity is enormous with total healthcare expenditures in those 65 and older running well over $7 trillion,' said Dr. (Bob) Hariri. 'We believe that HLI's unique science and technology, along with our business leadership, will positively impact the healthcare market with novel diagnostics and therapeutics.'"

Bob Hariri
HLI photo

Hariri. the former CEO of Celgene Cellular Therapeutics, is vice chairman and co-founder of the new firm, which is located on a street called “Road to the Cure.”

Writing on Biopolitical Times, Pete Shanks of the Center for Genetics and Society in Berkeley picked up part of the conference call earlier this week announcing the company. Shanks said, .

"Asked on this conference call if HLI would be in touch with the new Sanford Stem Cell Clinical Center (at UC San Diego), Venter blandly noted that Larry Goldstein, who heads the center, is on the HLI advisory board. (Peter) Diamandis added:

'Stay tuned for more announcements on the stem cell side.'"

Diamandis is a co-founder of the firm and CEO of the X Prize Foundation. The Sanford stem cell center was funded with $100 million last fall from billionaire Denny Sanford. Goldstein has received $21 million in funding from the California stem cell agency. Three other representatives from UC San Diego are on the HLI scientific advisory board including David Brenner, a longtime member of the governing board of the California stem cell agency.

Venter was a featured speaker at a California stem cell agency governing board meeting in 2012. The J. Craig Venter Institute is a partner in the $40 million genomics stem cell award made by the agency to a team led by Stanford in January during a controversial award process.

$40 Million California Genomics Award: Missing Names of Conflicted Reviewers Disclosed

When the governing board of the California stem cell agency last month considered proposals for a $40 million genomics stem cell center, it failed to disclose the names of the grant reviewers who were barred from reviewing the applications because of conflicts of interest.

Normally, the names are reported to the public when the $3 billion agency posts summaries of the reviews of applications – prior to consideration of the proposals by the agency's board.

The departure from the agency's normal grant-making procedures is not the first in the genomics round, which is the subject of an internal examination by the agency that includes the board's outside counsel, James Harrison of Remcho Johansen and Purcell of San Leandro, Ca. Allegations of conflicts of interest and complaints about the role of CIRM President Alan Trounson, score manipulation, irregularities and unfairness have been raised.

It is unlikely that the normal disclosure of conflicted reviewers' names would have affected the outcome of the genomic awards at the governing board meeting Jan. 29. However, if questions had been raised at the public board meeting about the absence of the names, concerns about the closed-door review process may well have been elevated, given the earlier conflict-of-interest violation involving reviewer Lee Hood.  

The names of the reviewers with conflicts were added to the review summaries this week following an inquiry Monday by the California Stem Cell Report, which sought to double-check the apparent fact that no reviewers were in conflict since none were listed as recused.

Kevin McCormack, senior director for communications for the agency, replied,

“There were some conflicts of interest with the genomics review but apparently there is a bug in our data system, which is why they aren't showing up. We're going to fix that so thanks for bringing it to our attention.”

Here are the names of the reviewers now listed on the CIRM review summaries as being recused and the four applications involved. The four were recommended for funding by reviewers.

Stanford-Salk's winning application, Richard Gibbs, Maynard Olson; UCLA, Bradley Bernstein, Richard Gibbs, Aarno Palotie, Barry Rosen; Scripps-Illumina, Maynard Olson, Martin Pera, Jared Roach; UC San Francisco–UC Berkeley, none.

Board Counsel at California Stem Cell Agency Engaged in Examination of $40 Million Genomics Award

The California stem cell agency yesterday confirmed that the counsel to its governing board, James Harrison, is involved in the examination of its $40 million genomics round, which has been criticized for irregularities, unfairness,score manipulation and the role of its president, Alan Trounson.

Harrison has been with the board since its inception and wrote parts of Proposition 71, the ballot initiative that created the $3 billion research effort in 2004. Harrison, who is a partner in the Remcho Johansen & Purcell law firm of San Leandro, Ca., also has expertise in conflicts of interest and ethics. He is on contract with the agency and is not an employee.

In response to a question Feb. 8, asking whether Harrison was looking into the grant review process in the genomics round, Kevin McCormack, senior director for communications, confirmed that the agency was examining how the applications were handled. However, he did not reply directly to the question of whether Harrison was involved in the inquiry.

After being asked again yesterday, McCormack said,

“As you know after every review we go back to see what we could have done better and that usually involves several staff members at the agency, including James, who look at what happened and try to identify ways to improve next time.”  

Amid Allegations of Unfairness, California's Stem Cell Agency Begins Examination of $40 Million Genomics Award Round

The California stem cell agency today said it has begun an examination of the grant review process in its $40 million genomics round, which has been criticized for irregularities, unfairness, score manipulation and the role of its president, Alan Trounson.

The agency confirmed the inquiry after the California Stem Cell Report asked last Thursday asked whether the board's counsel, James Harrison, was looking into the matter.

Kevin McCormack, senior director for CIRM communications, replied today in an email,

“There are always ways in which we can improve our performance, and we regularly review our processes to try and ensure we do a better job with each round of funding. We have been looking into the genomics award to identify areas where we can improve the process for future awards.” 

McCormack did not specifically respond to the question of Harrison's involvement. We have queried McCormack again about whether Harrison is involved. (McCormack subsequently confirmed Harrison's participation.)

Harrison, who is with Remcho Johansen and Purcell of San Leandro, Ca., has been outside counsel to the board since its inception. He drafted portions of Proposition 71, which created the $3 billion research effort in 2004. Harrison has expertise in conflict of interest and ethics issues as well as other related public policy matters.

Harrison's role at the agency exceeds that of a simple attorney. His length of service, knowledge and skills give him much wider influence.

CIRM's examination of the genomics round review followed complaints from rejected applicants and others about the process, which has been covered extensively by the California Stem Cell Report.

Trounson has come in for criticism in connection with the review and his subsequent recommendation in favor of the successful Stanford-led bid. One of the critics is Jeanne Loring, head of the stem cell program at the Scripps Research Institute and whose genomic application was rejected by Trounson and the CIRM staff. Her application and two others were recommended for funding by reviewers. Loring has contradicted Trounson's assertion that all applicants were given information that matching funds were part of the review criteria. Her application contained none. Stanford said it had $7 million.

Loring said that Trounson has interfered in CIRM's review processes in favor of Stanford. Trounson has been a guest at a Montana ranch owned by Irv Weissman, head of the Stanford stem cell program. Trounson did recuse himself in an earlier round involving an application linked to Weissman, but did not recuse himself in the genomics round.

Weissman was not listed in the latest Stanford application, but was in its original version. The associate director of Weissman's Stanford stem cell institute, Michael Clarke, was included in the final CIRM-approved version. Trounson lauded Clarke at the governing board's meeting last month in support of the Stanford project.

California's $40 Million Stem Cell Genomics Award: Irregularities, Complaints and Integrity

A number of firsts were recorded last month as the California stem cell agency gave $40 million to a Stanford-led consortium to put California in the global forefront of stem cell genomics.

Not all of those firsts necessarily enhanced the reputation of the California Institute of Regenerative Medicine (CIRM), as the $3 billion agency is formally known.

The unusual events and irregularities surrounding the award, CIRM's largest research grant, merit additional attention, given their implications about the integrity of the agency's grant review process and how the agency does its business.

The California Stem Cell Report recently asked a number of persons connected with the round and other knowledgeable individuals about the process. Their comments included a judgment that the agency staff “took a lot of liberties behind closed doors.” One of the rejected applicants "unequivocally" disputed assertions by CIRM President Alan Trounson that all applicants were informed by him about the need for matching funds, a key criteria for grant reviewers. The request for applications did not contain such a requirement.

The comments came in addition to earlier complaints by rejected applicants that scores had been manipulated in an “appalling” fashion and that scientific merit was not the first order of business in assessing the top four applications.

Also surfacing was a problem generated by Proposition 71, the ballot initiative that created the stem cell agency in 2004. The measure set up a 29-member governing board, including deans of medical schools and others with ties to research organizations. The board was supposed to exercise its expertise on funding decisions. However, only seven members of the board actually voted in the genomics round. Most of the rest had legal conflicts of interest and were not allowed to even participate in the discussion. It is not unusual for that sort of situation to arise during funding decisions by the board.

The CIRM stem cell genomics story began publicly in a scientifically big way with an article in the journal Nature Biotechnology in January 2012  by Trounson and two members of his staff. In it, Trounson said his proposal was needed so that the agency could take a "firm and lasting grip" on stem cell leadership.

Later that month, the governing board of the agency approved the concept for one or two genomics award. In February 2013, grant reviewers for CIRM, whose identities are withheld by the agency, took a crack at the applications. However, they declined to send any applications forward to the board for final action. It was the first time in the agency's nine-year history that has occurred. The reviewers offered no public explanation for the move.

The closed-door review session was marked by a conflict-of-interest violation by Lee Hood of Seattle, Wash., an internationally known genomics specialist, who was recruited by Trounson to be a reviewer in the round. Hood is a close friend of Irv Weissman, who heads Stanford University's stem cell institute. Weissman was named in Stanford's then $24 million application. Hood and Weissman also own a ranch together in Montana.

Trounson has been a guest at the ranch. In 2012, he recused himself during CIRM board discussions of two applications involving Weissman. The applications were from StemCells, Inc., of Newark, Ca., for $20 million each. StemCells, Inc., was founded by Weissman, who still holds a large amount of stock in the firm and serves on its board of directors.

Following the unsuccessful genomics review in February 2013, the applications were sent back to researchers with reviewer comments. The proposals could be retooled for a re-review in the fall, they were told.

After the fall review, the reviewers – minus Hood -- sent the applications to the board with recommendations to fund all four despite the fact that they would cost $146 million, well above the $40 million budgeted for the round. It was the first time that reviewers had made such a decision. Normally they stay within the budget, but they offered no public explanation for their actions in the genomics round.

At that point the CIRM staff, headed by Trounson, became more involved. Under new procedures, the staff may make recommendations concerning applications. In this case, they recommended that only the Stanford application be funded, but only after restoring a provision eliminated by reviewers. Trounson also recommended no funding for the three other top applications in the round. It was the first such major intervention by Trounson and the most aggressive staff move on grant applications.

Trounson offered only a 23-word phrase for recommending the Stanford application and no explanation for rejecting the other three. Stripped from the public review summaries for the three competing applications were the dollar amounts that they had requested. It has been the longstanding practice of the agency to include those figures. The amounts ultimately were made available to the board at its Jan. 29 meeting.

At that meeting, Trounson strongly backed retention of funding in the Stanford application for a project led by Michael Clarke, associate director of Weissman's stem cell institute at Stanford. Following the 2013 conflict violation involving Hood and Weissman, Weissman was removed from Stanford's application. Clarke was included, however. No questions were raised at last month's board meeting about whether Clarke could be regarded as a surrogate for Weissman's interests and whether that would involve a conflict of interest for Trounson.

Late in the meeting, Trounson also said that he had personally told all the applicants, with the exception of Stanford, that matching funds were expected as part of the applications, an assertion disputed following the meeting by Jeanne Loring of the Scripps Research Institute, whose rejected proposal contained no matching funds.

She said in an email,

"During the ICOC (governing board) meeting, Alan Trounson said that he had told us during his visit to all of the first round grantees that it would be important provide money for 'matching' funds. I state unequivocally that he did not tell me or anyone in my lab about this."   (Loring's boldface)

Stanford said its application contained $7 million in matching funds. The agency withheld the figures when they were requested by the California Stem Cell Report prior to the Jan. 29 board meeting, although it has released the figures in at least one other grant round.

Complaints about manipulation of the scores were raised prior to the board meeting by Pui-Yan Kwok,  leader for an application from UC San Francisco and UC Berkeley. He said that the scores of the top to applications were “based on the reviewers removing from consideration the poorest performing center-initiated projects.” He described the situation as appalling.

The agency defended its practices at the board meeting and in response to questions. It said the scoring procedures were permitted under the RFA. It said that while the procedures may be different than those of the NIH so is the stem cell agency. It said that all persons involved had been screened for conflicts of interest under CIRM rules and state law. 

In response to a query by the California Stem Cell Report concerning the process and the questions that needed to be addressed, Loring replied,

“I am concerned about the interference of the CIRM president in influencing the ICOC decisions. He has de facto power to promote or defeat specific applications, and he often wins by promoting one applicant over another. Stanford and Stanford faculty-founded companies such as Stem Cells. Inc., should not be so blatantly promoted over others. The relationship between the president and the head of the stem cell program at Stanford involves personal favors which make him conflicted and he should at the very least recuse himself from any discussion or recommendation of Stanford faculty's applications.”

Loring continued,

“The 29-member board is difficult enough to deal with, but now that most of the members are considered to be conflicted and are not allowed to even discuss the applications, we are left with a small number of non-scientists making decisions about scientific merit.

“I know that at least 5 members of the ICOC were very upset that they were unable to voice their opinions about what should be their mission- to guide CIRM's policies and choices for funding so that they are in the best interest of the voters.”

(For the full text of Loring's remarks see here.)

Other critical comments came from a longtime observer of the agency, who asked not to be identified, and who said,

“It appears that CIRM staff took a lot of liberties behind closed doors in driving this initiative to its final outcome. For example, what happened to require a resubmission and re-review etc. Did they change anything about this initiative in the process?  Were certain criteria shared with some but not all applicants?

“It also appears that the board was taken by surprise and not prepared to deal with the complexities in this initiative.  Clearly staff has not kept them in the loop and they had little access to the details of the process and how reviewers were managed.  They have always funded the vast majority of what the reviewers scored highly, and still did not break the bank.  This is a brand new situation where the reviewers recommended more grants than they could afford to fund.  This happens a lot in the NIH (especially today with severe budget cuts), so NIH has developed many processes to deal with this.  CIRM has not seen anything like this before.”

During the board meeting, some board members questioned parts of the grant review process. The anonymous observer said, 

“The questions (all legitimate) raised by the certain members of the board were by and large not understood or picked up by the other voting members, so they went nowhere. 

“Too many thoughtful board members were conflicted out, leaving the decision-making to a handful who are not prepared to deal with this complex situation.  I blame the IOM (Institute of Medicine) report in giving too much power, without the appropriate process, to staff.  Staff can recommend, but if the board has no information other than what staff provides, then they are acting in the dark.”

(For the full text of those remarks see here.)

In response to the same query, Michael Snyder of Stanford and Joe Ecker of the Salk Institute in La Jolla, co-leaders of the Stanford-led effort, did not raise any questions about the CIRM review process. They said,

“The net result (of their proposal) is that this center will help bring cutting edge technologies to all stem cell researchers in California and along with the funded projects will help keep California at the leading edge of two important fields: stem cell research and genomics, and thereby help accelerate both the science and therapeutics treatments possible in this field, and spur industry and economic development. questions.”

(For the full text of their remarks see here.)

(Editor's note: An earlier version of this item incorrectly said the first name of Michael Clark was William.)

California's Stem Cell Genomics Award: Text of Remarks by Jeanne Loring of Scripps

Here is the text of comments from Jeanne Loring, director of the Center for Regenerative Medicine at the Scripps Research Institute, in response to questions from the California Stem Cell Report concerning the review process for applications in the $40 million stem cell genomics round.

Boldface within Loring's response is hers. Parenthetical identifications of terms or individuals have been inserted in Loring's remarks by the California Stem Cell Report.

California Stem Cell Report: What questions do you think need to be addressed considering the events surrounding the award?

Loring:

 "1. What instructions were given to first round applicants about merging applications?

"Alan (Trounson, CIRM's president) visited all of the first round applicants. On his visit to San Diego, Alan met separately with me and my Illumina partners, Larry Goldstein of UCSD and Craig Venter of the Venter Institute. Alan told me that Larry had taken him to a mens' club and Craig had taken him to a motorcycle dealership. I took him for a tour of Illumina's new facilities, which I thought was appropriate for a scientific site visit. 

"At his visit to all of the first round applicants, Alan Trounson suggested that we merge our applications if we could. My interpretation of that suggestion was that we actually merge our center proposals- UCSF's with ours, for example. I was not told that addition of subcontracts from other institutions could be interpreted as a merger with those institutions. The Stanford group's claim that Scripps and Illumina were consortium members of theirs was disingenuous, since our Scripps/ Illumina consortium was a competing genome center application, and we did not merge any part of our application with Stanford's. 

"To make the claim that they had 'merged' with Scripps and Illumina, Stanford added one project from a junior faculty member at Scripps, and contracted Illumina to do sequencing for them- they have had long-standing contracts with Illumina for services.

"The difference between Stanford's relationship with Illumina and my relationship with Illumina is analogous to Stanford paying a Tesla dealer to repair a car and me teaming up with Tesla to design a new type of car.

"We were not told who the other applicants were, which made it a challenge to determine who we might merge with. We chose to contact Pui Kwok, through my collaborator Susan Fisher at UCSF, Joe Ecker at Salk, Mike Snyder at Stanford, and Josh Stuart at UCSC about potential partnering.

"When I spoke with one of the people we contacted, he said that I could get a place in the consortium put together by Stanford if I were to get my institution to contribute $2 million in matching funds. This was not entirely a surprise; I had heard from colleagues at UCSD that UCSD's vice chancellor, David Brenner, had initiated the collection of matching funds by pledging $2 million to the consortium.

"2. At the Grants Working Group(GWG, the grant review group): what differences were there between the stated requirements in the RFA and what the reviewers were told to do during the meeting?

"Matching funds

"The RFA did NOT require contributions from grantees, and certainly did not suggest that such contributions would be considered to be items for the GWG to judge, since they were tasked with only on the quality of the science, the 'scientific merit.' To quote from the message sent to me from Gil Sambrano(the CIRM staffer who handles most of the review process), announcing my score and the GWG report, 'Applications were reviewed using the criteria detailed in the RFA and scored on scientific merit.'

"That makes me wonder if the reviewers told at the GWG meeting to include monetary contributions from the potential grantees positively in their scoring, in spite of the fact that their scoring is stated by CIRM as being solely on the basis of scientific merit?

"During the ICOC (the agency's governing board) meeting, Alan Trounson said that he had told us during his visit to all of the first round grantees that it would be important provide money for 'matching' funds. I state unequivocally that he did not tell me or anyone in my lab about this. 

"Scoring applications after removal of projects that the GWG scored poorly.

"We learned when the reviews were posted that the GWG scored two of the Stanford center projects very poorly. We do not know the actual scores they gave those projects, nor do we know what scores were given to our own projects. We do know that CIRM instructed the GWG to score the entire Stanford grant after removing the two low scoring projects. All three of our projects scored high enough to be included in the overall review of our application.

"The Stanford project received a range of scores from 70 to 95 after the two projects were removed. Our application received a range of scores from 70 to 88 with all projects left in place. It is not much of a stretch to imagine that if the low-scoring Stanford projects had been kept in, there would not have been scores of 95 by any of the reviewers. It is not too speculative to suggest that their scores would have been lower, perhaps lower than ours, if the low-scoring projects had not been removed.
We were not told of the practice of the GWG altering grants in order to improve the scores of those grants. I am also appalled that this was done, since it is not allowed in NIH review of multi project U and P awards, the closest equivalent to the CIRM genome center award. 'P' awards are Program Project Grants, in which several investigators write sub-proposals to be done in concert with each other. I review these grants, and we are instructed that we cannot remove subprojects in order to change the scores. Similarly, 'U' awards are for consortia that are to be coordinately managed. I also review these applications, and again, it is forbidden for us to alter the applications as written. The goal of the reviewers for these NIH awards is to 'review the grant we are given'.
CIRM staff indicated at the ICOC meeting that the GWG had recommended funding of the Stanford project. 

This is simply untrue. As the message from Gil Sambrano states: 'The GWG understood that this initiative will support only one or two centers and only a single data coordination and management component within a total budget of $40M.  However, as the GWG's scores and recommendations were based solely on scientific merit, the group did not select which center(s) should ultimately be funded as this is a programmatic assessment.'

The GWG was tasked with scoring based on 'scientific merit' (which CIRM instructed them would include monetary contributions). Programmatic assessment is required to choose an application, and CIRM is not part of the Programmatic committee, according to the following quote from the message from Sambrano:
'ICOC/Application Review Subcommittee MeetingFunding decisions will be made by the Application Review Subcommittee of CIRM’s governing board, the Independent Citizens Oversight Committee (ICOC), at a public meeting that will be held in Berkeley, CA on January 29, 2014.  The Subcommittee, which meets concurrently with the Board, is composed of 16 voting members (the Patient Advocate and Industry members of the Board, along with the Chair and statutory Vice Chair of the Board) and 13 non-voting members (the 13 members of the Board who are appointed from institutions that are eligible to receive CIRM funding).
'The Applications Review Subcommittee will conduct a programmatic assessment of applications reviewed by the GWG. The Subcommittee may consider any factors (such as availability of funds, overall grant portfolio, RFA priorities, strategic considerations) that might impact on their decision to fund or not fund applications. The Subcommittee aims to fund applications that are both scientifically meritorious and that bring programmatic value to the CIRM portfolio.'

In the meeting, CIRM did not present information about any application except Stanford's, giving the strong impression that this application was the only one of merit. The ICOC members of the Application Review Subcommittee were not provided with the applications in order to assess the factors they were charged to assess.

California Stem Cell Report: Are there structural issues created by Proposition 71, the measure that created the agency, that made things more or less difficult?

Loring: 

"The 29-member board (ICOC) is difficult enough to deal with, but now that most of the members are considered to be conflicted and are not allowed to even discuss the applications, we are left with a small number of non-scientists making decisions about scientific merit.

"I know that many members of the ICOC were very upset that they were unable to voice their opinions about what should be their mission- to guide CIRM's policies and choices for funding so that they are in the best interest of the voters."

California Stem Cell Report: Are there processes at CIRM that show weaknesses or need to be re-examined? Do you have any specific recommendations for changes?

Loring: 

"The ICOC members should be provided with all of the grant applications as well as the reviews. They can choose to ignore them, but if they find that certain grant apps or disease-specific areas require more high level consideration, they should have the tools to provide that guidance.

"I am concerned about the interference of the CIRM president in influencing the ICOC decisions. He has de facto power to promote or defeat specific applications, and he often wins by promoting one applicant over another. Stanford and Stanford faculty-founded companies such as Stem Cells Inc, are blatantly promoted over others. The relationship between the president and the head of the stem cell program at Stanford involves personal favors which make him conflicted and he should at the very least recuse himself from any discussion or recommendation of Stanford faculty's applications."

Loring also included the following:

Text of message from Gil Sambrano on Friday, January 10, 11:06 am
"Dear Dr. Loring:

Thank you for submitting your application under the California Institute for Regenerative Medicine’s (CIRM) Stem Cell Genomics Centers of Excellence Awards RFA 12-06. We are providing you this report as the Program Director (PD) and designated point of contact on the application, but it is your responsibility to share this information as appropriate with members of your team.

The applications underwent peer review at a meeting held on November 7-8, 2013 by the members of CIRM’s Grants Working Group (GWG). Applications were reviewed using the criteria detailed in the RFA and scored on scientific merit.

Review ReportBelow, please find the Review Report of your application.  This report includes the average scientific score and the funding recommendation of the GWG. Applications are scored on a scale that ranges from 1 – 100, with 100 being the highest achievable score.

Applications are separated into three funding tiers.  An application’s average score determines the funding tier as follows:

75-100 = Tier 1 - recommended for funding
65-74 = Tier 2 - moderate scientific quality or consensus on scientific merit cannot be reached, and may be suitable for programmatic consideration by the ICOC
1-64 = Tier 3 - not recommended for funding

The Review Report provides only a brief summary of the evaluation of your application by the GWG. The report is not an exhaustive critique and does not cover all of the factors that may have contributed to the final score or the final recommendation. The report highlights key points relevant to the review criteria that were captured from reviewers’ written comments and from the discussion of your proposal by the GWG during the review meeting.

ICOC/Application Review Subcommittee MeetingFunding decisions will be made by the Application Review Subcommittee of CIRM’s governing board, the Independent Citizens Oversight Committee (ICOC), at a public meeting that will be held in Berkeley, CA on January 29, 2014.  The Subcommittee, which meets concurrently with the Board, is composed of 16 voting members (the Patient Advocate and Industry members of the Board, along with the Chair and statutory Vice Chair of the Board) and 13 non-voting members (the 13 members of the Board who are appointed from institutions that are eligible to receive CIRM funding).

The Applications Review Subcommittee will conduct a programmatic assessment of applications reviewed by the GWG. The Subcommittee may consider any factors (such as availability of funds, overall grant portfolio, RFA priorities, strategic considerations) that might impact on their decision to fund or not fund applications. The Subcommittee aims to fund applications that are both scientifically meritorious and that bring programmatic value to the CIRM portfolio.

Under California’s open meeting laws, members of the public, including applicants for CIRM funding, may provide written and oral comments to the ICOC regarding items on the Board’s agenda. Applicants may attend and observe the ICOC meeting. Applicants may contribute oral comments for not more than three (3) minutes during the public comment periods. The ICOC Chairman will announce the public comment period, which typically occurs prior to the Board’s voting on any motion. Applicants may also provide written comments to the ICOC. All correspondence to the ICOC must be submitted to the Executive Director of the ICOC, Maria Bonneville, at mbonneville@cirm.ca.gov. Please do not send correspondence to the ICOC that relates to an appeal of a funding recommendation by the GWG as it will be redirected to the CIRM Review Office (see “Response to Review” below).

In preparation for the ICOC meeting, the Review Report (with PI and institution identities removed) will be posted no later than Friday, January 17, 2014 on our website at http://www.cirm.ca.gov/ReviewReports. Additional information for CIRM’s public meetings can also be found on our website.

Award NotificationCIRM will notify you by email of the ICOC’s funding decisions following the ICOC meeting.

Response to ReviewThe GWG conducts the scientific evaluation of proposals submitted to CIRM. If the applicant (PI/PD) wishes to appeal the scientific review by the GWG (or seek reconsideration of the recommendation), the PI/PD must first consult with the CIRM Review Office. All appeal requests must be made through the CIRM Review Office within 10 days of CIRM making this report available (i.e., deadline is January 21, 2014). Grounds for an appeal are limited to the circumstances described in “Guidance for Appeal of Scientific Review and Reconsideration Policy” available via this link: http://www.cirm.ca.gov/board-and-meetings/guidance-appeals-and-requests-reconsideration-grants-working-group-funding
--
Gilberto R. Sambrano, Ph.D.
Associate Director, Review
California Institute for Regenerative Medicine
210 King Street
San Francisco, CA 94107
(415) 396-9103
To:  jloring@scripps.edu; wynne@scripps.edu
REVIEW REPORT FOR CIRM RFA 12-06R GENOMICS CENTERS OF EXCELLENCE AWARDS (R)
Application: Center for Advanced Stem Cell Genomics

PI: Jeanne Loring
Institution: Scripps Research Institute

Recommendation Overview: The GWG provided two final scores for each application as follows: 1) an overall center score (covering the center-initiated projects, collaborative research activities, and center organization and operations plan) and 2) a data coordination and management component score.
The overall scientific merit and quality of the proposals submitted under this RFA were viewed by the GWG to be deserving of high scores. Overall center scores placed four proposals in Tier 1, one proposal in Tier 2 and none in Tier3. The separate data management and coordination component scores placed two proposals in Tier 1, two in Tier 2 and one in Tier 3.
The GWG understood that this initiative will support only one or two centers and only a single data coordination and management component within a total budget of $40M.  However, as the GWG's scores and recommendations were based solely on scientific merit, the group did not select which center(s) should ultimately be funded as this is a programmatic assessment. CIRM staff is recommending that the ICOC fund only the highest scoring genomics center and the corresponding highest data coordination and management center which together will fulfill the goals of this initiative.
The scores, GWG Tier recommendation and CIRM staff recommendation are as follows:

GWG Overall Center Recommendation: Tier 1GWG Overall Final Score: 76

GWG Data Center Recommendation: Tier 2GWG Data Center Final Score: 72
CIRM Staff Recommendation: Do not fund
EXECUTIVE SUMMARYThis Genomics Center will be led by a program director (PD) from an academic institution and a co-PD from an industry organization. Three Center-Initiated Projects (CIPs) are proposed, and, as required by the RFA, a plan for inclusion of Collaborative Research Projects and a Data Coordination and Management Center are described.


Center Organization and Operational Plan - The organization of the proposed Genomics Center is well conceived as a collaboration between highly qualified investigators from an academic institution and an industry partner, representing a diversity of competencies. The balance between expertise in stem cell biology and genomics technologies is a particular strength.

- The PD has extensive research experience at the interface of stem cell biology and genomics and is committed to serving the stem cell community; he/she is well suited to lead this program.

- The industry partner institution, and especially the co-PD, is well positioned to develop novel cutting edge genomics technologies and make them accessible to customers.
- The teams from the two applicant institutions have a well-established, strong working relationship; reviewers considered this an important attribute of this proposal.

- All elements necessary for the establishment and operation of a successful Genomics Center are in place; the structure and composition of the proposed administrative and oversight committees are appropriate and should ensure both delivery of projects and high standards of work.

- The three CIPs are designed to support the service aspects of this Genomics Center by focusing on the development of tools that can be generally used to explore genomics data. Reviewers considered it a strength that, if successful, these projects will both create novel tools and technologies and validate them. There was some concern that some of the tools may not be made easily and widely available.

- Although a letter from leadership indicates enthusiastic institutional support from the academic institution, no additional funds or specific dedicated space have been designated. Reviewers expressed serious concern about this lack of material commitment.

- Some reviewers expressed concern that both the PD and co-PD are already heavily committed individuals and questioned whether they would have the capacity to fully provide a strong commitment to this project.


Center Organization and Operational Plan - The proposed Genomics Center appears well designed to support collaborative research projects and to make relevant state-of-the-art genomics technologies readily accessible to investigators with primary expertise in stem cell biology or translational research.

- The proposed application process is appropriate, review procedures and criteria are well thought out.

- The offer to culture cells for external collaborators in the Genomics Center's core lab is especially appealing, as that would remove a variable from the experiments and thus help with standardization of conditions for genomics assays.

- Concern was expressed about whether potential collaborators who have limited experience in genomics would receive adequate assistance in designing their proposed studies.


CIP-1The applicants propose to develop an updated and expanded version of an existing genomics tool. They plan to make available global gene expression and epigenomic data, obtained through a series of systematic analyses of human pluripotent stem cells and their derivatives, to serve as reference for future experiments. They also propose to analyze the heterogeneity of stem cell populations and to develop genomic tools for the assessment of stem cell quality. Finally, they intend to use disease-specific induced pluripotent stem cells (iPSC) to study the molecular basis of two neurodevelopmental diseases and identify disease-modifying compounds.

- This project adopts a broad approach toward developing pragmatic, accessible tools for basic research on stem cells in vitro, and to lay the groundwork for more effective clinical translation. This would represent a valuable resource to the stem cell community.

- Enthusiasm was diminished by the notion that most of the activities are applications of existing tools or extensions of existing work. While important goals, the activities were not viewed as particularly innovative.

- The goals of this project are overly ambitious, raising doubt that all aims can be achieved. Given the tremendous track record of the principal investigator (PI), though, it is expected that substantial progress will be made.

- Reviewers' opinions about the utility of an already existing analytical tool, to be further developed under this award, were divided. Some judged it positively as an important tool that has been made freely available in its current form and were enthusiastic about the plan for dissemination of the updated version. Conceptually, they considered the proposed approach to be very valuable, as it has the potential to provide objective standards for assessing cell fate and for quality control of cell populations. Other reviewers expressed concern that the current tool has not been widely adopted in the stem cell community, calling into question its usefulness.
- The proposed work on neurodevelopmental diseases is disconnected from the central focus of this project and might have been better developed as a separate project.
- Reviewers criticized the general lack of experimental detail, particularly in aims 4 and 5, which impeded assessment of feasibility.
- The project plays to the strengths of the PI as a well-established leader in the stem cell field with a strong record of productivity and innovation.

- The broad scope of the project is matched by the experience and expertise of the team involved.

CIP-2This project addresses the integrity of stem cells for clinical transplantations and their utility in translational and clinical research. The goals are to establish informatics tools for determining the functional significance of genome wide molecular variations in therapeutic stem cell populations and to develop and validate methods for assessing the prevalence of deleterious alterations in stem cell populations. The applicants also plan to develop and validate a workflow for integrating genomics information with identification of potential therapeutic compounds and their effects on patient-derived induced pluripotent stem cells and on patient treatment outcomes. Finally, the plan is to disseminate all developed tools and protocols to the stem cell community.

- The utility of the proposed tools and protocols for translational genomics-based research would be high.
- The first goal is straightforward and feasible. Reviewers emphasized that input data must be high quality, as noted by the applicants, and suggested that applicants consider that the cellular differentiation state may affect functional significance of specific genomics variation.

- Other goals are more risky, but if successfully developed, they should be widely applicable and help stimulate the use of stem cell-based systems to explore both disease mechanisms and potential therapies.
- Toward assessing prevalence of deleterious alterations in stem cell populations, reviewers recommended that a variety of additional stem cell datasets, especially some originating outside the team, be included in the project.

- The feasibility of a key component of the study, linking genomic information from patients to potential therapeutics and individualized treatments, was difficult to assess, since the applicants did not specify the types of diseases to be studied.
- Reviewers observed that parts of this proposal are vague and hard to follow, and it was unclear what some of the deliverables would be.

- There is a clear plan for dissemination of the acquired expertise and knowledge.

- The PI is well qualified for this work and has assembled a powerful leadership team that possesses the necessary expertise.


CIP-3This project is led by the industry partner organization and is focused on the development of several single cell genomic technologies and tools for large-scale epigenetic analyses.

- Reviewers noted that only one of the technologies under development is truly stem cell-specific, but the proposed work would nevertheless deliver technologies extremely valuable to the stem cell community.

- The tools to be improved or developed are at the forefront of technical advances.

- Reviewers geatly appreciated the novelty of one of the proposed technologies.
- Some reviewers were concerned that the project essentially constitutes commercial development of genomic products and questioned whether it was appropriate for CIRM to support this activity.  Others felt that the developed technologies would provide valuable research tools and could have great potential impact on stem cell science.
- Concern was expressed about whether the new technologies would be specifically disseminated to California investigators and whether their cost might be prohibitive to many researchers.

- The basic technologies underlying this proposal have already been developed and it should therefore be feasible to complete the proposed developments in the proposed time scale.

- The PI and team are exceptionally well qualified to deliver on this project.


Data Coordination and Management - The DCM team is led by two individuals. One has a track record of developing a highly successful, adaptable, user-friendly platform. The other is an expert in medical informatics, although reviewers expressed concern that a biosketch for this individual was not included in the proposal.

-The proposed DCM structure and leadership would likely ensure solid database structure, data access and visualization capabilities.
- Reviewers considered the details provided on the data management plan to be inadequate; there was little description of how the DCM Center will participate in data integration and analysis or interact with various projects.

- Reviewers acknowledged the importance of patient privacy protection but felt the focus on this issue in the application was overemphasized and distracting.

- The descriptions of data visualization tools are reasonable but not particularly innovative or tailored to the specific needs of the stem cell community."