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

Piero Anversa -- NYTimes photo by Annie Tritt

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

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

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

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

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

A couple of highlights from the piece.

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

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

 Kolata concluded:

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

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

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

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

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

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

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

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

Tax Breaks and $220 Million for California Stem Cell Agency

The California stem cell agency, which is facing its financial demise, is seeking assurances of "continued tax breaks" for private donors who are being courted for $220 million to support the enterprise, Bloomberg Law reported this week. 

The article by Joyce Cutler referred to the effort to bridge a looming and major stem cell funding gap. The agency says it will run out of cash for new awards at the end of next year. But it does not see additional public funding until November 2020, when the agency hopes that California voters will refinance it with $5 billion from a yet-to-be written ballot initiative. 

Cutler wrote,

"Closing the deal, however, involves getting assurances from elected officials of continued tax breaks to get donors to open their checkbooks and keep CIRM operating until another bond measure can be passed." 

CIRM is the abbreviation for the California Institute for Regenerative Medicine, the formal name of the stem cell agency. It was created in 2004 by voters who provided it with $3 billion in state bonds, but no more. 

Asked for comment by the California Stem Cell Report, Kevin McCormack, senior director for communications at CIRM, said,

"With regard to the tax deductibility issue, that’s really out of our hands but, of course, we’re hopeful that all incentives to potential donors are preserved going forward."

Cutler wrote, 

"Contributions to state agencies currently are deductible from income under state and federal law, H.D. Palmer, state Department of Finance spokesman, told Bloomberg Law in an email.

"'Going forward, that’s going to fall to the next folks who get the keys to the car' in the governor’s office and Legislature, who will decide whether the California deductions remain.

"But the federal Internal Revenue Service is considering regulations to disallow deductibility if the tax credit is for more than 15 percent of the contribution. The Tax Cuts and Jobs Act of 2017 limits the amount of state and local taxes (SALT) an individual can deduct on taxes to $10,000 a year. The proposed regulations crack down on state workarounds to the SALT deduction cap."

Jonathan Thomas, chairman of the CIRM board, is leading the effort to raise funds privately. Bob Klein, who preceded Thomas as chairman, has a role but the agency has declined to go into details. Klein is a real estate investment banker and founder and chairman of Americans for Cures, a nonprofit organization supporting stem cell research. 

Klein has said he has a poll that shows that more than 70 percent of Californians support refinancing the agency. But he has declined to release the poll or identify the firm that provided it when asked by the California Stem Cell Report.  

Klein oversaw the writing of the ballot initiative that created the stem cell agency in 2004 and led the electoral campaign on its behalf. He has said he will try again in 2020 if polls show sufficient support. 

At last week's CIRM board meeting, Thomas gave a short report on the private fundraising effort, which has been underway for many months. He did not announce any contributions or discuss the tax break issue. 

At the meeting, board member Jeff Sheehy expressed concern about progress on a possible 2020 bond measure, noting that there is a relatively short amount of time to mount a major political effort.

Art Torres, vice chairman of the board and a former state legislator, said no real effort can be mounted until after the elections next month. Torres and CIRM general counsel Scott Tocher also noted there are legal limits on what the agency can do in terms of a ballot campaign. 

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

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

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

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

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

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

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

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

Gina Kolata of the New York Times wrote, 

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

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

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

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

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

Autism to Bladder Cancer: California Awards $25.2 Million For Stem Cell Research

The California stem cell agency yesterday approved $25.2 million for research involving a spate of diseases, ranging from HIV and autism to hearing loss and bladder cancer.

The only application involving clinical stage work was submitted by Xiuli Wang of the City of Hope in Duarte, Ca., for her research on a CAR-T treatment to achieve a functional cure for HIV infection without the need for antiretroviral drug therapy.

The application (CLIN1-11223) sought $3.8 million to take her proposed therapy to the point where it can win approval to begin clinical trials. Here is a link to the summary of the review of her application. 

Directors of the California Institute for Regenerative Medicine(CIRM), as the agency is formally known, also approved $13.5 million in awards to translate basic research into clinical work and $7.9 million for more basic research. 

Here is a list of the principal investigators in the translation round. Summaries of the reviews can be found in this document. Translation refers to research that is moving from the basic stage to clinical.

• Steven Schwartz of UCLA, $5.1 million, TRAN1-11265, clinical translation of autologous regenerative cell therapy for blindness
• Karin Gaensler of UCSF, $4.2 million, TRAN1-11259, development of engineered autologous leukemia vaccines to target residual leukemic stem cells
• Ted Leng of Stanford, also $4.2 million, TRAN1-11300, a purified allogeneic cell therapy product for treatment of dry age-related macular degeneration

Here is a list of awards whose approval was stalled in July for financial reasons. The review summaries with scores can be found in this document.

• Tracy Grikscheit of Children's Hospital Los Angeles, $1.3 million, DISC2-10979, Universal Pluripotent Liver Failure Therapy (UPLiFT)
• Philip Beachy of Stanford, $1.4 million, DISC2-11105, pluripotent stem cell-derived bladder epithelialprogenitors for definitive cell replacement therapy of bladder cancer
• Jonathan Lin of UC San Diego, DISC2-10973, $1.2 million, small molecule proteostasis regulators to treat photoreceptor diseases
• Stuart Lipton of Scripps, DISC2-11070, $1.8 million, drug development for autism spectrum disorder
• Neil Segil of USC, DISC2-11183, $833,971, A screen for drugs to protect against chemotherapy-induced hearing loss, using sensory hair cells derived by direct lineage reprogramming from hiPSCs
• Alan Cheng of Stanford, DISC2-11199, $1.4 million, modulation of the Wnt pathway to restore inner ear function

$144 Million California Stem Cell Research Program Set for 2019

Directors of the California stem cell agency this morning approved a $144 million research budget for next year, which could well be its last for dispensing any major cash in its search for stem cell therapies.

The amount compares to $148 million expected to be awarded this year.  At its peak, the agency was handing out close to $300 million a year in research awards, but the amount varied from year to year.

Most of the funds for the next year will be devoted to clinical stage work. The agency, formally known as the California Institute for Regenerative Medicine (CIRM), is already backing 49 clinical trials, the last stage before a therapy is approved for widespread use. But it has yet to help finance a therapy that can be used by the population at large, despite expectations of voters who approved creation of the $3 billion agency in 2004.

CIRM expects to run out of cash for new awards next year. Possibilities exist for continued funding of research in 2020, but the agency is budgeting conservatively. CIRM Chairman Jonathan Thomas is attempting to raise privately $220 million to maintain the agency's funding. Thomas briefed directors today on that effort but notably did not report that specific additional funding had been secured.

CIRM also expects to recover possibly as much as $30 million in 2019 from projects that do not meet their milestones and possibly use the funds for awards next year or in 2020.

The agency is pinning its hopes for ultimate survival on a yet-to-be-written $5 billion bond measure on the November 2020 ballot.

Where Has The Money Gone? A 10-cent Look at $3 Billion in California Stem Cell Spending

CIRM graphic

California has spent about $2.6 billion on stem cell research over the last 14 years. It has roughly $144 million left for new awards. Here is a quick overview of where cash has gone, based on the agency's records.

Keep in mind that an examination of the state stem cell agency's spending can be like the blind men and the elephant. A lot depends on what you grab.

And tomorrow directors of the California Institute for Regenerative Medicine (CIRM), as the agency is formally known, will  be grabbing a piece of the program to determine what is going to be handed out in 2019.

Since 2004 when the agency was created with $3 billion in funding, CIRM reports that it has spent $898 million on various stages of basic research, which it generally calls "discovery," the largest single category.

It has plowed $632 million into clinically connected research dealing with afflictions ranging from cancer to blindness. The amount involves both more recent clinical research and CIRM's earlier disease team programs. Kevin McCormack, senior director for communications, said the money went for late stage research leading to a clinical trial as well as the trials themselves.

The agency's clinical trial dashboard shows that it has supported 49 clinical trials. The dashboard provides more detail on the status of each trial. (Here is a link to a June CIRM spreadsheet on the trials. Here is a link to a table on the trials released in connection with this week's directors' meeting.) 

CIRM has sunk $482 million into "infrastructure," a term that includes a $271 million building program for new facilities at institutions ranging from Stanford to UC Davis.  (See here and here for more on the infrastructure program.

The agency spent $219 million on education, which probably does not include a more than $40 million program to lure star scientists to the Golden State academic institutions. Those awards were specifically for research projects.

In terms of diseases, CIRM research covers 24 disease areas, ranging from Alzheimer's to strokes. A third of the clinical trial money has gone for cancer. Nineteen percent has targeted blood diseases and 12 percent neuro afflictions.

For a full list of institutions, see here.

Stanford, an already well-endowed institution in 2004, was the top institutional recipient with $360
million. UC Davis was the over-achiever in the top 10 recipient list with $138 million. In 2004, it had what could only be described as a tiny stem cell program.

ViaCyte, Inc., of San Diego, is the only business to make the top ten list, snagging $72 million. With the exception of ViaCyte, all of the institutions in the top ten had or have representatives on the CIRM governing board who are not permitted to vote on awards to their institutions.

As mentioned at the beginning of this item, this was the 10-cent tour of CIRM spending, which may tweak your interest. The high-priced excursion will come another day.

California Stem Cell Agency's Latest Awards: Total of $17 Million for Cancer, Blindness, HIV

The California stem cell agency is set this Thursday to award $3.8 million for research aimed at development of a major improvement in treatment for HIV and another $13.5 million to deal with leukemia and problems that can lead to blindness. 

The proposals have already been approved by the $3 billion agency's reviewers in a closed door session. The governing board of the agency is expected to ratify those decisions at a public meeting on Thursday. 

Xiuli Wang, COH photo

The HIV award is scheduled to go to Xiuli Wang of the City of Hope in the Los Angeles area for work leading to a clinical trial. Wang told the board in a letter, 

"(O)ur approach has the potential to be a single delivery therapy that releases patients from the ART (antiviral drug therapy) regime for the rest of their lives. This strategy could also alleviate the cumulative financial burden that represents life-long medication."

In response to a query from the California Stem Cell Report, Jeff Sheehy, an HIV patient advocate on the CIRM board, said that the proposal (CLIN1-11223) would use a vaccine to "to stimulate one's immune system to proliferate and maintain the engineered anti HIV CAR T cells that are the therapy.

"What makes this especially exciting is that 'the approach of using the CMV vaccine to expand CMV specific T-cells may eliminate the current use of preconditioning chemotherapy that is widely adopted for T cell therapies.'  In short, if successful, this approach would not only give people with HIV the ability to control the virus long term with needing antiretroviral therapy but could also make CAR T therapies in general more efficient and effective as well as safer, plus lead to other uses of CAR T technology."

Theodore Leng, Stanford photo

Karin Gaensler, UCSF photo

Karin Gaensler of UC San Francisco is slated to receive $4.2 million to develop a vaccine that will attack residual leukemia cells.   (Application number TRAN1-11259)

Theodore Leng of Stanford is scheduled to be awarded $4.2 million to develop a "purified allogeneic cell therapy product (called NeuBright) for treatment of dry age-related macular degeneration."  (Application number TRAN1-11300)

The board is also expected to approve $5.1 million for an "autologous regenerative cell  therapy for blindness." The identity of that investigator has not yet been released by the stem cell agency. (Application number TRAN1-11265)

Summaries of the application reviews and scores can be found in this document.

Correction

Based on inaccurate figures on the stem cell agency web site, the NIH/CIRM sickle cell item on Oct. 9,2018, incorrectly reported that the agency had committed more than $200 million to sickle cell research. The correct amount is $38.8 million. CIRM said that the error was created by a computer glitch and that it has corrected the figures on its site. The item has also been corrected. 

Go-ahead Given on $144 Million California Stem Cell Research Budget for Next Year

The California stem cell agency is moving ahead with a proposed $144 million research budget for the coming year, slightly below the $148 million expected to be handed out this year.

However, the award budget for 2019 is well below the $300 million in awards that were made in some past years.

The 2019 plan yesterday cleared the Science Committee of governing board of the California Institute for Regenerative Medicine (CIRM), as the agency is formally known. It is expected to be approved by the full board at a meeting next Thursday.

The committee also juggled some financing and all but assured that six highly rated applications that were stalled will now receive approval, also probably next Thursday.

You can read more about the 2019 research budget here and the stalled awards here. 

Stalled California Stem Cell Projects Now Set for Financing: Bladder Cancer, Autism, Deafness, Blindess Among the Targets

Key directors of the California stem cell agency this afternoon moved to juggle some cash and fund six research proposals ranging from bladder cancer to autism, which had been stalled since July.

The action by the directors' Science Subcommittee came only hours after the affected researchers and patients appealed to another board group to approve the funding. It was stalled because of budgetary issues.

Those financial issues came up again before the Science Committee which approved a workaround on the $7.9 million needed to approve the research. The action may receive final approval by the full board next Thursday.

You can read more here about the session earlier in the day.  

Stem Cell Scientists' Hopes for Research Cash Survive Another Round in California

(Late News Break: It looks like the six applications in the story below are now headed for approval, perhaps as early as next Thursday. See this story.)

Six stem cell research proposals targeting bladder cancer, autism, liver failure and more escaped rejection today as the $3 billion California stem cell agency struggles with its finances.

The agency expects to run out of cash for new awards by the end of next year. In 2019, it is considering awarding only $144 million compared to $300 million in some years. "We are coming to the end," said CIRM board member Oswald Steward, director of the Reeve, Irvine Research Center at UC Irvine, in July.

The applications had already been held over from July when the agency's directors were presented with a $19 million list of applications approved by its out-of-state reviewers in an earlier closed-door session.

However, the round was budgeted for only $10 million by the governing board of the agency, known formally as the California Institute for Regenerative Medicine (CIRM).

Ten letters of support were filed on behalf of five rejected awards, whose scores ranged from 90 to 87. The agency in July approved three awards with scores of 85.

Some of the researchers and supporters appeared before the board today. Philip Beachy of Stanford, who is seeking $1.4 million for bladder cancer research, said his team was seeking a long term cure for bladder, which has a tendency to recur and is the most expensive cancer to treat per patient.

Other researchers and patients also made a direct appeal to CIRM directors, and on an 11-0 vote, the board kept the applications alive during a telephonic meeting.

Here is a link to the scores and review summaries in this round. Here is the presentation by staff on its recommendations.

Here is a list of letters supporting applications in this round and their authors:

• Daniel Geschwind, director of UCLA Center for Autism Research and Treatment, on behalf of application DISC2-11070, treatment for autism, PI Stuart Lipton of Scripps Research of La Jolla (score 87 out of 100)
• Bridget Vissari, president, Achroma Corp., Butler, Pa., in support of DISC2-10973, PI Jonathan Lin of UC San Diego, dealing with photoreceptor diseases (score 88 out of 100)
• Laura Brady, research manager, Fighting Blindness of Dublin, Ireland, also in support of DISC2-10973
• Avril Daly, CEO, Retina International, also in support of DISC2-10973.
• Philip Beachy, Ernest and Amelia Gallo professor, Stanford, in support of his application, DISC2-11105, dealing with bladder cancer (score 90 out of 100)
• Don Reed, vice president of public policy, Americans for Cures, also in support of DISC2-11105
• David Russell, chief scientific officer, Universal Cells, Inc., of Seattle, a subsidiary of Astellas Pharma, in support of DISC2-10979 PI Tracy Grikscheit of USC, dealing with liver failure therapy (score 90 out of 100)
• Paul Viviano, CEO Childrens Hospital Los Angeles, and two others, also in support of DISC2-10979
• Neil Seigel, co-director USC Hearing and Communication Neuroscience Training Program, in support of his application DISC2-11183, dealing with hearing loss (score 87 out of 100)
• Robert Rainey, research associate of Neil Segil Lab, USC, also in support of application DISC2-11183 (Rainey's letter is in the same file as Segil's)

Dollars Dribbling Away: California Stem Cell Scientists Appeal for More Research Cash

When the cash spigot starts to dry up, the appeals stack up.

Such is the case this week at the now $144 million California stem cell agency, which has been mostly referred to as a $3 billion enterprise. But the cash is dribbling away quickly. And the agency is sticking to its budget in a way that did not happen eight years ago.

The latest evidence comes on the agenda for Thursday's meeting of directors of the agency, known formally as the California Institute for Regenerative Medicine or CIRM. The agenda contains 10 letters appealing to the directors to approve awards for various research projects.

These are projects that have been recommended for funding by the agency's scientific reviewers. However, the reviewers did not have the constraints of meeting the agency's budget for this round of awards.

Only $865,282 is available under the agency's budget. The five applications in question total close to $7 million.

So letters appealing for the cash have been directed to the agency's board.
Here are a couple of samples from the letters.

Phil Beachy, Stanford photo

This one is from Philip Beachy of Stanford University, whose application (DISC2-11105), Beachy wrote, was scored at 90 out of 100 by reviewers. He is seeking $1.4 million for work related to bladder cancer.

"In July we were surprised to learn that our application was not selected for funding, whereas four proposals ranked below ours were funded. We have subsequently learned that an important component of the funding decision made by the ICOC (the CIRM board) is comments from scientists and patient advocates. We wish to have the opportunity to present our comments at the October 11 ICOC meeting, at which our proposal will be considered. Four scientists involved in this proposal will be attending the meeting, including myself (Philip Beachy, Ph.D.), Kyle Loh, Ph.D., Lay Teng Ang, Ph.D., and Joe Liao M.D., Ph.D.)." 

They also enlisted assistance from a patient advocate, Don Reed of Fremont, who is a regular at CIRM board meetings. He wrote,

"Is there a path to defeating the cancer and restoring the bladder’s natural function? Today I had lunch with two people, Drs. Lay Teng Ang and Kyle Loh, who (along with Drs. Philip Beachy and Joe Liao) may have the answer to this particular cancer. Their goal is to use embryonic stem cells to grow a healthy new lining of the bladder....But they need a grant from the California stem cell agency to do it."

Robert Rainey, USC photo

Here is an excerpt from another letter. This one was written by Robert Rainey, the primary research associate involved in an application (DISC2-11183) that seeks $833,282 to create a screen to protect against hearing loss caused by chemotherapy.  The proposal by Neil Segil, co-director of the USC Hearing and Communications Neuroscience Training Program, received a score of 87 from reviewers.

Rainey, who is profoundly deaf, wrote,

"In the entire history of CIRM, only three hearing loss-related grants have been awarded. This is not an oversight of CIRM, but rather a reflection of the paucity of experimental approaches for studying problems related to hearing loss in humans. Our approach can now overcome these problems, and the work described in this proposal will allow us to simultaneously improve the efficiency of our direct-reprogramming technique from human iPSCs, while allowing us to immediately begin pilot testing small libraries of FDA-approved drugs for hair cell-protective qualities during cancer treatment."
(Rainey's letter is in the same file as Segil's.)

Segil wrote,

"Talk about adding insult to injury! Imagine that you are the parent of a 4 year old child who has just been diagnosed with a deadly pediatric cancer. You are told that, in spite of this horrible diagnosis, a cure is possible, with a good chance of success. However, the cure has an extremely common side-effect, namely that your child will likely go deaf as a result of the chemotherapy. In fact, more than 60% of kids treated for pediatric cancer end up profoundly deaf."

Neither Segil's or Beachy's applications will be funded if the board sticks with its budget and abides by staff recommendations, which it has usually done in recent years.

You can find on the meeting agenda all the appeal letters, summaries of the application reviews and CIRM's rationale for the last award in this round. The transcript from the July board meeting also carries considerable discussion related to the financial pressures generated in this round along with how the initial decisions were made.

Major Sickle Cell Surge: Feds and California Collaborate on Cell Therapies for the Disease

In August, the stem cell agency staged a live event on Facebook dealing  with 

the current state of sickle cell research. It has since received  more than 2,200

 page views. Here is a link to the event, which featured  Don Kohn of  UCLA  and 

Mark Walters of UCSF Benioff Children’s Hospital. 

California's stem cell agency has embarked on what it calls a "remarkable" collaboration with the federal government aimed at developing cell-based and gene-based therapies for sickle cell disease, which affects 100,000 persons nationwide.

The partnership marks the first time that the state agency has partnered directly with the National Institutes of Health(NIH), which spend $100 million a year on sickle cell research. 

The NIH has committed an additional $7 million to jump start its new effort, dubbed "The Cure Sickle Cell Initiative."   The California stem cell agency has already pumped nearly $39 million into sickle cell research. 

The affliction is caused by a genetic defect that deprives the body of oxygen, "wreaks havoc on the body, damaging organs, causing severe pain, and potentially leading to premature death," says the NIH. 

In the agreement (see below) with California's $3 billion stem cell agency, the NIH said that the agency is "a recognized leader in the development and funding of clinical trials focused on cell-based therapies and is now working to accelerate support for clinical stage candidate treatments that demonstrate scientific excellence."

Millan told directors in in June that the arrangement amounted to a "quite remarkable" recognition of CIRM's capabilities. She said the NIH "made a decision that they needed to partner with us in order to have the best shot at accomplishing what they want to do with this 'cure sickle cell initiative.'"

On Thursday, directors of the California Institute for Regenerative Medicine (CIRM), as the agency is formally known, will receive a more complete briefing about the full range of CIRM's involvement.

CIRM will handle the funding processes for the applications for the late stage research program, making funding decisions in as little as 85 days. The agency's work will include scientific peer review, contracting and post-award management, according to CIRM documents. (The documents are part of the presentation that can be found here.)

Millan said that the NIH has recognized the agency's value in terms of accelerating development therapies, building late development research and translating basic research into clinical use. 

The agency said it will provide funding on approved awards for work done in California, according to CIRM rules. It will have the ability, in consultation with the NIH,  to suspend or terminate research if milestones are missed, including taking back unused funds. Kevin McCormack, a spokesman for the agency, said that it will be compensated by the NIH for additional work that it has to perform but that details are yet to be worked out.. 

Last month, the NIH said in a news release:

"Currently, the only cure for sickle cell disease is a bone marrow transplant, a procedure in which a sick patient receives bone marrow from a healthy, genetically-compatible sibling donor. However, transplants are too risky for many adults, and only about 18 percent of children with sickle cell disease have a healthy, matched sibling donor.

"The Cure Sickle Cell Initiative seeks to develop cures for a far broader group of individuals with the disease, and it is initially focusing on gene therapies that modify the patient’s own hematopoietic stem cells (HSCs), which make red and other blood cells. These modified HSCs can then be given back to the patient via a bone marrow transplant, making a cure available to more patients who lack a matched donor."

Below is a CIRM video on sickle cell disease and a copy of the agreement between the stem cell agency and the NIH. 

(Editor's note: An earlier version of this item incorrectly reported that the agency had committed more than $200 million to sickle cell research, based on inaccurate figures on the CIRM web site. The correct amount is $38,8 million. CIRM said the error was created by a computer glitch and that it has corrected the figures on its site.)

Sickle Cell Cirm-nhlbi Mou ... by on Scribd

The Final $144 Million and the California Stem Cell Agency's Future

The Golden State's stem cell research program is down to its last $144 million after nearly 14 years of financing searches for therapies for everything ranging from diabetes to bubble baby syndrome. 

Funded with $3 billion in November 2004, California's stem cell agency has yet to back a therapy that is widely available to the public. Its directors are scheduled to meet on Wednesday to approve plans for what could be the last year for new awards. 

Known formally as the California Institute for Regenerative Medicine (CIRM), the agency was created by voters through a ballot initiative. The measure provided $3 billion in bond support but no additional cash beyond that. 

The agency is pinning its hopes for survival on a yet-to-be-written $5 billion bond measure for the November 2020. It is attempting privately to raise $200 million to bridge the gap between the end of 2019 and the election. 

On Thursday, CIRM's 2019 research award budget is slated to come before the Science Committee of its board of directors. The public can participate in the meeting via the Internet and at a number of locations throughout the state. More information about access can be found on the agenda. 

The agency's staff has proposed $123 million in awards for clinical trials during 2019 with another $20 million going for translational research, which is an effort to take basic research and translate it into a clinical application. An additional $600,000 is slated for "educational" awards. 

CIRM documents said there were "insufficient" funds to finance additional basic research. The agency also aims to limit its clinical/translational awards to research that has been previously backed by the agency.

By the end of this year, CIRM expects to have made $2.6 billion in awards. The remainder of the $3 billion has gone or will have gone for administrative expenses, which will continue for a few years as multi-year awards wind down. 

The agency may recover an estimated $30 million in 2019 from research that does not pan out, making those possible funds available for awards in 2020. 

Currently, CIRM is backing 49 clinical trials, the last stage before a therapy is certified for widespread use. But there is no guarantee that any of those trials will generate a treatment prior to the November 2020 election. 

State of Stem Cells: Three-day Conference Opens Today, Includes Japanese Research, Affordability and More

A three-day session to kick around business and scientific developments involving genes and stem cells begins today in La Jolla with live Internet video casts of many of the presentations and panels.

The state of Japanese research, therapies for stroke, commercialization pathways, affordability and much, much more are available. Some samples and times for today for the Cell and Gene Meeting on The Mesa:

7:15am – 8:45am -- Learning Theater, Readiness strategies for cell therapy commercial manufacturing workshop

7:20am – 8:00am -- Ballroom 2, Panel, Session 1: U.S.-based Clinical Programs

7:50am – 8:05am -- Magnolia Room, Development of an “off the shelf” cell therapy for ischemic stroke and other indications under the regenerative medicine regulatory framework in Japan
Speaker: Gil Van Bokkelen, Ph.D., Chairman and CEO, Athersys

1:15pm – 2:15pm -- Ballroom 1, Panel, Navigating acceptance, uptake and affordability across the life cycle 

The full agenda can be found here. The webcasts are available here.  Webcasts can be found by room location. 

Possible Federal Restrictions on Stem Cell Research and the Multi-Billion Dollar California Angle

The recent federal crackdown on the use of fetal tissue in scientific research could well be a harbinger of an effort to revive restrictions on the use of human embryonic stem cells, placing a roadblock in the way of creation of therapies to treat often deadly afflictions that affect millions of Americans.

And it could have an impact on the fate of California's $3 billion stem cell program, which expects to run out of money for new awards by the end of next year.

A leader of the pro-life movement signalled today that anti-abortion groups' next target is likely to be the National Institutes of Health(NIH), which provide billions of dollars in research funding, including use of embryonic stem cells (hESC).

Writing on The Hill web site, Tom McClusky, president of March for Life Action, denounced current federal research practices. His opinion piece was headlined.

"Trump's move on unethical fetal tissue experimentation isn't enough"

McClusky wrote,

"The head of NIH, Frances Collins, has been a long-time supporter of unethical research and has a reputation of disinterest for the countless lives lost as long as it produces results.
"His track record not only includes support for fetal tissue research but also human-embryonic stem cell experimentation, human-animal chimeras and even human cloning. Of the many great nominations made by President Trump, Frances Collins sticks out as a counter to his stated pro-life agenda."

This is a bit of deja vu for the California stem cell agency, whose $3 billion program was approved by voters in 2004. The impetus for creation of the agency, known formally as the California Institute for Regenerative Medicine (CIRM), was generated by then President Bush's restrictions on federal funding for hESC research. State cash, however, was not similarly restricted.

Trump has not yet revived Bush's restrictions, but the issue seems to be increasing in importance for Trump's evangelical political base and at least 102 congressmen. The opposition is based on the belief that using human embryonic stem cells for research is tantamount to murder.

The stem cell agency is hoping that California voters will extend its life in November 2020 by approving $5 billion more for the research. However, the agency has not delivered on 2004 expectations that stem therapies were right around the corner. The agency has yet to finance a therapy that is widely available.

Overcoming voter disenchantment could be difficult. But a Trump crackdown could energize stem cell supporters much as Bush's did in 2004. Scientists, patient advocate groups, venture capitalists and others banded together to win approval of the ballot initiative that created the state stem cell program, using Bush as a handy villain in the argument for more stem cell research.

Ironically, the article by the pro-life group came almost exactly one year after the then president of the International Society for Stem Cell Research,  Hans Clever, wrote on the Stat website that fetal tissue is absolutely necessary to produce cures and therapies. He said,

"The development of vaccines against polio, rubella, measles, chickenpox, adenovirus, rabies, and treatments for debilitating diseases such as rheumatoid arthritis, cystic fibrosis, and hemophilia all involved fetal tissue."

"Fetal tissue has been essential in research used to develop therapies that have saved millions of lives, and it continues to be necessary for the future of medicine."

The Reality of Stem Cell Research vs. Results: A Scientist/Blogger Speaks Out on California's Efforts

A researcher writing on the web site of Science Translational Medicine weighed in last week on California's $3 billion stem cell agency, raising questions about its progress, hype and the fate of the nearly 14-year-old effort. 

In an item Sept. 28 on the blog "In The Pipeline," Derek Lowe said, 

"It’s not like the CIRM money has all been wasted, of course. There’s been a lot of basic research done, and there certainly has been a lot that needed to be done. The amount of brush to be cleared in human developmental cell biology is just monumental. A quick thought the way that all of your body, all the bodies of every human being, comes each from their own single cell will make that clear. If you want stem cell therapies to regenerate organs – as who doesn’t – then you’re asking for a thorough understanding of that process. You may well be asking to do even more than it can tell us how to do."

CIRM is the California Institute for Regenerative Medicine, as the agency is formally known. Lowe's brief bio on the the site says he has worked for "several major pharmaceutical companies since 1989 on drug discovery projects."

The occasion for his remarks was the recent lengthy look at the agency by the San Francisco Chronicle at CIRM and its performance. Lowe wrote, 

"What’s happened? What you’d have expected, if you knew the field at all (or were familiar with basic research in general). None of the bigger promises made during the campaign to fund the CIRM have come true. No approved therapies have come out of the work yet – and that’s one of the class of promises that were most egregious, in California and elsewhere. Just imagine the time it takes from discovery to approval for something like this, and then factor in that the needed discovery hadn’t even been made yet. But if you don’t know anything much about stem cells, or regulatory approvals, or medicine in general, the idea of get-out-of-that-wheelchair cures being just around the corner becomes more plausible."

Lowe also noted that voters may be asked in 2020 to provide more billions for the agency. He said, 

"If you measure it (the agency's work) against what was known and what had been accomplished then versus what’s been done since, you can make a case, for sure. If you measure it against the promises made at the time, though, things look bad. And that informs how you’re going to campaign for renewal: do you point at what’s been done and make the argument that it’s been a success, or do you promise them miracle cures again, because now they just have to be around the corner after all this work, eh?"

Lowe's article received comments from nine readers, who appear also to be researchers. One, who was identified as Miguel Sanchez, wrote, 

"Just at my small CA research institute, the amount of poor science that has been funded by CIRM is staggering. I would say that roughly half the CIRM money we have received has gone to research programs that are prima facie bad science but the PIs are well connected so hey shut up. I don’t think any outright fraud has been published, but the taxpayers of CA are for damn sure not getting their moneys worth on these investments here."

Sanchez did not further identify his employer. The agency's list of grantees did not contain Sanchez's name. 

$10 Million More for Viacyte for a Virtual Stem Cell Cure for Type 1 Diabetes

The San Diego stem cell company that has snagged $72 million from the state of California  announced this week another $10 million infusion from the firm that created the rain gear fabric known as Gore-Tex.

The San Diego firm is Viacyte, Inc., a privately held company that has received more than any other company from the $3 billion California stem cell agency. In 2017, Viacyte became involved with W.L. Gore & Associates, Inc., a materials science company that deals with drug delivery technologies.

Gore is also the enterprise whose Gore-Tex product has shaped the current outerwear industry.

On Tuesday, Viacyte announced the $10 million investment by Gore. The funds are coming in the form of a convertible promissory note.

Paul Laikind, president of Viacyte, said this week that the collaboration with Gore "has been exceptionally productive." He said the use of Gore membranes "has proven invaluable for improving the performance of the PEC-Encap product candidate in non-clinical studies that have been shown to be reflective of the human experience."

He said the additional support "should allow us to resume clinical testing of PEC-Encap as early as the first half of 2019."

California's $72 Million Diabetes/Stem Cell Bet: A New Partner from Massachusetts

CRISPR Therapeutics is the latest firm to become involved in a California-
backed stem cell research effort. It uses gene-editing techniques to devise cures.

The California stem cell agency has invested $72 million in a San Diego firm that is pursuing a a functional cure for diabetes and which announced this week it was moving to dodge a major obstacle facing its potential therapy. 

The firm is Viacyte, Inc., a privately held enterprise that has received more funding by far than any other state-backed stem cell firm. It announced on Monday that it had hooked up with publicly traded CRISPR Therapeutics, Inc., of Cambridge, Mass., to collaborate on a gene-editing treatment that would evade the body's immune response to earlier Viacyte therapies.

In a Q&A with UC Davis researcher Paul Knoepfler, Paul Laikind, CEO of Viacyte, said,

"The advantage of an islet cell replacement therapy that has been gene-edited for immune evasion is simply that patients would not need to take immunosuppressive drugs, which can have side effects. Our main mission is to improve the lives of patients with insulin-requiring diabetes by delivering transformative new therapeutic options. The work we are doing on PEC-Direct, PEC-Encap, and now an immune-evasive approach, known as PEC-QT, are all a part of that mission."

The treatment is principally aimed at type 1 diabetes, which afflicts 1.25 million persons in this country, the stem cell agency said in a piece on its blog about the new collaboration.

Viacyte was one of the earliest firms to receive cash from the agency, officially known as the California Institute for Regenerative Medicine (CIRM). The awards began with only $48,950 in 2008 when Viacyte was known as Novocell.

The arrangement with CRISPR will provide more funding for Viacyte, $15 million from its new partner and possibly another $10 million in the form of a convertible promissory note.

CRISPR's stock closed at $48.99 yesterday, down from $55.36 last Friday. Its 52-week high was $73.90 and its 52-week low $16.16.  The firm announced on Wednesday that it was planning to sell $200 million in common stock.  (Here is a detailed presentation on the firm's strategy and research. Here is a link to one analysis of the firm as an investment.)

In the piece on Knoepfler's blog, Laikind also provided an update on Viacyte's other related research. He said,

"(T)he PEC-Encap (also known as VC-01) product candidate has a bright future! We remain enthusiastic regarding the prospects of PEC-Encap, and are actively working on it. In June, two-year data from ViaCyte’s STEP ONE clinical trial were presented at ADA 2018. Although consistent and robust engraftment has been limited in this study to date, results showed that when engraftment does occur, viable mature insulin-expressing endocrine islet cells can be formed. In some cases, insulin-expressing cells have persisted for up to two years after implantation, the longest time point investigated in the study.

"Building on insights gained during the STEP ONE study, ViaCyte is working with W.L. Gore & Associates, one of the world’s top materials science companies with expertise in medical device development and drug delivery technologies, to modify the Encaptra Cell Delivery System and improve the potential for long-term engraftment. This work has yielded positive results in non-clinical models that, based on clinical experience, have been selected to reflect the response in patients. If the progress continues as expected, we plan to resume STEP ONE trial enrollment in 2019.

"As for PEC-Direct (also known as VC-02), the Phase 1/2 clinical evaluation of that product candidate is also continuing. We are now evaluating patients in the second cohort of the trial. As you know, PEC-Direct has the potential to help the patients with type 1 diabetes with the greatest need."