What do you expect for $3B?

Five years ago California chartered CIRM - a state body to facilitate spending $3B on stem cell research over a 10 year period. The money for CIRM came from a CA bond issuance (i.e. a self-tax on Californians) and was intended to fund stem cell research to 1) keep California's bioscience competitive with or ahead of the rest of the world, and 2) fund embryonic stem cell research that the US federal government would not fund due to ethical restrictions.

(As context, at the time of the ballot initiative to fund CIRM, California was worried that South Korea, Singapore, and other locations would be more attractive for stem cell research. Also, my impression was that Cali voters were eager to flip Pres. Bush the bird on anything, particularly when his social policies impacted science.)

I commented a year ago on the return on stem cells investment , and now Nature has a good article summarizing CIRM at the five year (half way) mark (with better figures than my estimates.) Since Nature is tied to the science community (including CIRM researchers) they don't go out and say it directly, but there are few tangible results so far from ~$1.5B in spending. (Presumably some great papers (published in Nature) and some shiny new on-campus labs, but other than that, nothing.)

Ordinarily, I would not fault anyone for not dramatically improving human health in just 5 years (even with $1.5B to spend), but as I pointed out on my personal blog in 2005, the stem cell community has a terrible track record of overselling the benefits of its' efforts.

But the lessons here are less about how regenerative medicine is following the same growth curve of revolutionary new technologies before it, where hype runs ahead of reality, until a crash and subsequent rebirth with success (think gene therapy in the 90's).

The lessons here are instead related to business and economic strategy:

1) even in the case of outstanding science, local funding only produces marginal local benefits. Presumably CIRM proceeds have enabled research that has global benefits (through great papers, worker training, and new research tools and methods.) However, knowledge doesn't stay local. Good papers are read around the world, workers are recruited to other labs in other places, and tools are copied. Everyone should probably thank Californians for funding the research, but unless CIRM can claim a few million more tourists to California because of stem cell research, we probably aren't returning value to the state because of CIRM.

2) anyone touting near-term economic or other gains from long-term basic research is either dumb or dishonest. As the Nature article highlights, CIRM has funded only 1 clinical trial (which aborted), meaning that the impact on human health is still a long term proposition, and that aside from some advances in research tools, little tangible economic value has been created. I think much of the excitement of alternative energy ("Green jobs!") is similarly oversold regarding near-term impact.

3) It is an esoteric concept, but no analysis of CIRM or similar efforts is complete without asking "is/was there a better use of $3B instead of stem cells/CIRM, including just leaving the $$$ in voters' pockets?"

The status quo has strong gravity, so California should be praised for considering a bold move like CIRM (whereas with the exception of a few states that invested their tobacco settlement $$$ in life science research, most states never got beyond talking about making a difference), but the truth is, governments and the general populace are ill-equipped to consider alternatives beyond yes/no.

California is massively in debt ($361B as of Feb 1, 2012), so NOT starting CIRM could have been $3B less debt (which is still a lot of money to me), or a minuscule <1% of the problem, depending on your point of view.

In addition to the idea of just pocketing the $3B (which I would advocate, in retrospect), I'm sure that other interest groups could have contributed other higher-returning ideas for state investment - be it green energy, synthetic biology, infrastructure improvements, or whatever.

4) (personal biases showing here:) bioscience needs to admit that no matter which topic or which spin, if you have to rely on convincing the general public to fund your initiative, you should just stop.

I don't think that the California public has conducted a cost/benefit analysis on CIRM, but they (or the newspapers, or whatever) will do so eventually, and it won't be pretty.

Selling the public isn't the hard part. (I'm thinking of the Simpsons' Marge vs. the Monorail episode as a great illustration of this concept). Instead, delivering on the grand promises is what is difficult, and until research becomes predictable (oxymoron - predictable research is then a technology), science will continually over promise and under deliver, likely proving to be a longer term hindrance than a source of short term funding.

(Perhaps this is observable in today's funding climate for therapeutic development. The bioscience investing base is probably smaller today and in the long term than if reality had kept pace with hype, and not instead burnt a great many investors.)

Big speed bump on the way to the stem cell revolution

A report this week indicates that induced pluripotent stem cells (IPS), the technology whereby adult stem cells (ASCs) are used to create novel stem cell lines may be inherently flawed, as the resulting cells and cell lines have been found to have important mutations.

Adult stem cells in this case are more appealing than embryonic stem cells (ESCs), which come with ethical/moral challenges. So - assuming the research is confirmed - we're back to the core conflict with stem cells - do we use morally complicated ESC technology, or potentially flawed ASCs.

The news this week will be used to aggressively promote the still controversial ESC research over ASC, but I suspect that with research we will become very comfortable with the known mutations in certain applications, but not without time and additional research.

I mention all of this because - like most emergent life science technologies - stem cells have been substantially hyped and oversold.

I just took a look at the timeline of some of the hype involved. Christopher Reeve led a big PR campaign in 2001, and California passed Proposition 71 in 2004, which raised $3B to be spent by CIRM over 10 years on stem cell research in California.

We're in year 7 of CIRM, and presumably 70% of the bond proceeds ($2.1B) have been allocated and spent. Along with annual Federal (NIH) spending - estimated at $1.1B in 2010, state funding (estimated at $400M/year) other academic basic research, and billions by pharma (hard to track) we may be spending $2B/year on stem cell research, and likely >$15B since 2001. Funding doesn't seem to be the problem.

What does this tell us:

-we should be EXTREMELY cynical in evaluating expectations for new life science technologies. It is not unreasonable to double estimated costs and timelines.

-technologies should be measured and advanced on the basis of their disease impact. The stem cell crusade in the 2000's was an effort to advance basic research as a whole. The better basis would be on a more accountable disease-basis, which would emphasize that stem cells would be one therapeutic tool among many.

-we should do whatever we can to keep technology development from being a political issue. I still believe that the kerfuffel over embryonic stem cells in the early 2000's was as much about a tug of war for $$$ (and pushback against the notion that politicians should have a voice in research agendas) as it was a morality debate. Ultimately, I do not know conclusively if the debate helped or hurt stem cell research (my guess is helped with funding, net), but it certainly drew a great deal of intellectually dishonest speculation.

-just plain don't invest in public companies at the front of a technology wave. Stem cells will ultimately have a commercial impact, but as anyone who bought Geron shares in 2000 at a price >$60 per share, investing too early represents dumb money. (10 years later, Geron is now trading for one 12th of the price ten years earlier.)

Of course, one might have been able to say the same thing about genomics (take a look at the HGSI valuation over time (peak of ~$25B in value, now worth $5B, after the approval Benylista), so let's hope that the billions spent on stem cell research have brought research to the tipping point.