Turning 10 years old may not quite mark adolescence for a human child, but for a major government research effort such as California's stem cell program, it's well past middle age.
So it's a little strange to hear C. Randal Mills, the new president and chief executive of the program known formally as the California Institute for Regenerative Medicine, say it's time to instill in CIRM "a clear sense of mission."
But that's what Mills is planning for the coming year, as he launches CIRM 2.0, a comprehensive reboot of the program.
Mills, a former biotech company chief executive, took over as CIRM's president last May. His first task, he told me, was to "take a step back and look broadly at how we do our business." He reached the conclusion that "there was a lot of room for improvement."
That's a striking admission for a program that already has allocated roughly two-thirds of its original $3-billion endowment.
Biomedical researchers are sure to find a lot to like about CIRM 2.0, especially Mills' commitment to streamline the program's grant and loan approval process for projects aimed at clinical trials of potential therapies. Reviews of applications take about 22 months on average; Mills hopes to cut that to about three months. The process can be made more efficient without sacrificing science: "We need to do it quickly and also focus on quality," he says in a videotaped presentation on the CIRM website. The CIRM board last month approved a six-month, $50-million round of funding under the new system, all to be aimed at testing new therapies.
Yet the focus on drug development shows that CIRM remains a prisoner of the politics that brought it into existence. The Proposition 71 campaign in 2004 employed inflated promises of cures for Parkinson's disease, Alzheimer's, diabetes and other therapy-resistant conditions to goad California voters into approving the $3-billion bond issue ($6 billion with interest) for stem cell research.
CIRM says it has funded clinical trials of 10 therapies and has backed an additional 87 projects "in the later stages of moving toward clinical trials." In scientific terms that's progress, but it may fall short of the public expectations of "cures" stoked by the initiative's promoters 10 years ago.
And that poses a political problem. At its current rate of grant and loan approvals of about $190 million a year, CIRM has enough funding to last until 2020. What happens after that is an open question, but any campaign to seek new public funding may depend on CIRM's having a successful therapy to show off to voters.
Mills says winning approval for more public funding isn't the goal of CIRM 2.0. "It's not our job at CIRM to extend the life of CIRM," he told me. Instead, he couches the need for urgency in terms of serving patients. As chief executive of Maryland-based Osiris Therapeutics, where he worked before joining CIRM, he says, he had "a firsthand view into the significance of stem cell treatment, and of how important urgency is in this game." Osiris received approval from the Food and Drug Administration and Canadian regulators for a stem cell drug to treat children with severe complications from bone marrow and other blood transplants.
As head of CIRM, however, Mills can't escape the tyranny of public expectations. CIRM's mandate, as he describes it, is "to accelerate stem cell treatments to patients with unmet needs." That presupposes that stem cell treatments exist or will be found for the major medical conditions at which Proposition 71 was aimed. What if science and nature don't cooperate?
Nor may it be so easy to mix speed and scientific quality, or to balance the rush to clinical testing with the need to maintain funding for basic research. Basic science provides the raw materials for the clinical pipeline, but often after a span of many years. Up to now, about 91% of CIRM's funding has gone to academia, almost entirely for basic science, with the rest going to private industry to fund drug development.
Mills says he's "agnostic" about what that ratio should be, but CIRM funding began to shift toward industry even before his arrival. In late 2013, CIRM's intention to stop funding a program for academic facilities created an uproar among researchers. Nine of them appeared before the board to plead for continuation of the $72-million program, which they said supported not only the upkeep of crucial academic labs but the training of young researchers. "If we don't have this facility," said David Warburton, a professor of pediatrics at Children's Hospital Los Angeles, where a dozen stem cell projects were underway, "we're going to see a lot of our pipeline go down the tubes." The board terminated the facilities program anyway.
Mills says his goal is to keep funds flowing to all stages of stem cell research — from basic science in the academic lab to drug development in California biotech firms — without showing deference to any stage. "For someone to say 'our piece is the most important' is just false," he says.
Academic researchers may have a legitimate concern about too much money shifting toward late-stage research prematurely. "The field is so young," says Arnold Kriegstein, director of the stem cell lab at UC San Francisco, "that it's unreasonable to expect that fully transformational therapies are just a few years away. This is the time to continue basic research programs, not cut them off."
There may be less risk of wasting scarce resources in basic research programs than in late-stage projects — if one line of inquiry hits a dead end, others may still be served by the same grant. By contrast, if the clinical trial of a specific therapy fails, the whole project may have to be abandoned.
Just last month, CIRM cut off funding for what may have been its highest-profile drug development project ever: a $19-million 2012 loan to StemCells Inc. for an Alzheimer's treatment. The highly controversial loan had been rejected twice by CIRM scientific advisors but was approved by the board after an appeal by Robert Klein II, CIRM's founder and first chairman. CIRM and the company disclosed late last year that the project hadn't passed a key milestone for progress. The $9.6 million CIRM already disbursed to StemCells Inc. won't have to be repaid.
CIRM shouldn't be faulted for putting money into a failed trial — as Kriegstein observes, most clinical trials fail. Its problem lies much deeper. Proposition 71 was so poorly drafted and sold to the public so deceptively that CIRM has struggled from its inception to function as a pure research program. It's always looking for a blockbuster success that may never come.
Despite the program's unquestionably positive impact on stem cell science, especially in California, it still lacks a coherent sense of its proper role. CIRM 2.0 is the latest effort to find that role, but it may not be the last.