I’ve previously raised the possibility that, in its quest for economic revitalization, state governments are not suited to pick and choose among emergent industries to invest in, much less make the risky decision to invest in unproven technologies. Now I wonder whether some taxpayer-funded initiatives to attract high-tech jobs to Connecticut amount to anything more than glossy-sounding buzz-words thrown out by policymakers who have very little idea how to get the lagging Nutmeg State back on track.

Exhibit A for exciting-to-talk-about but dubiously significant state job-growth efforts is the Connecticut Stem Cell Research Program. The state initiative came up on Tuesday, in a discussion of the state job situation on Where We Live, WNPR’s daily Connecticut news program (disclaimer: my wife, Libby, is a producer for the show). Stem-cell jobs were one of the few items that the state politicians and economist on the show were particularly upbeat about.   Is the stem-cell program really something worthy of so much hope and attention?

First of all, no one is jumping out of their seats to say anything bad about an emergent scientific field that has enormous potential to cure many diseases. (Though I must interject that biomedicine has a history of “magic bullets” that didn’t really pan out; real advance comes from broad efforts combining many independent–and often iconoclastic–researchers and disciplines.)

In the midst of a depressing discussion of Connecticut’s daunting problems (regulatory instability, high energy costs, poor infrastructure, a 20-year slide in employment), one of the show’s guests, UConn economist Fred Carstensen, brought up the stem-cell initiative, in part because its continued funding is in question in the new, downsized state budget.  He described it as “phenomenally successful…we’ve had some extraordinarily important breakthroughs.”  He cites the fact that “we literally have had world-class researchers moving to Connecticut and looking to move to Connecticut because of our stem-cell initiative”.

Stem-cells funding may have brought a few researchers and their labs to Connecticut, and encouraged good ones that are already here to apply for more funding and, perhaps, hire a few new postdocs or technicians to perform research.  But Yale already has over 270 different labs working on biomedical science.  In 2008, it received $300 million from the NIH alone, not counting that from other major funders like the Howard Hughes Medical Institute.  UConn took in over $70 million from the NIH last year.  The total outlay of the Connecticut Stem Cell Initiative?  Ten million dollars per year.  Denise Merrill, the majority leader of the state house of representatives said that with stem cells, the state brings benefits “for a relatively small amount of money”.  The characterization of price is true, but what benefits do $10 million bring when spent on stem-cells instead of, say, transportation or inner-city education?

Proponents argue that stem-cells will become a centerpiece of some future, high-tech Connecticut economy.  However, a brief history of turbulent stem-cell politics brings this aspiration into doubt.  Connecticut began the stem-cell initiative in 2005, hoping to get a corner on the research after the Bush Administration had announced tight restrictions.  However, the Nutmeg State was not alone.  Our neighbors in Massachusetts, which considerably outranks Connecticut in the biotech sector, got in on the act, pledging $100 million over 10 years.  California voters approved a $6 billion state stem-cell initiative; unsurprisingly, perhaps, this program has been criticized for its enormous cost and lax oversight.

The problem with these programs is that they represent frenzied competitive maneuvering between states, but with dubious outcomes, especially for those that, like Connecticut, didn’t put that much on the table in the first place.  In fact, our tax dollars are already hard at work on biomedical research in a very serious way, through the NIH and other, federal, entities.  Compared with our centralized national programs, state science initiatives, on the other hand, are heavy with ambition but starved for good organization and sufficient money to fund more than a few research goals.

In hindsight, the stem-cell money appears to have been thrown at a good, celebrity-supported cause, but with uncertain prospects for Connecticut.  We absolutely need research investment to create future jobs.  I say “future”, because the short-term expense of research is not only in personnel, but in equipment, expendables, and energy, which might provide jobs where they are manufactured or generated, but that is unlikely to be Connecticut.  Why should we bet that Connecticut research dollars will stay, as future employment, in Connecticut if the research might be spun-off more efficiently in one of the big biotech regions already humming with infrastructure?

At its best we can hope that a bit of good science was supported by the CT stem-cell initiative.    At worst, the state stem-cell program is a rather pathetic talking point for politicians without the nerve to tell their constituents how poorly their state competes for jobs compared to other regions.  If policymakers want to use the state budget resources to engineer our way into the future, they should focus on the tasks that state government does best.  Oh, hold on, perhaps the Connecticut should figure out how to do the things it should be doing best first, instead of waiting for a small investment in stem cells to grow into a fresh, economic heart-transplant for the state.

• Update: John Dankosky and the folks over at Where We Live put up this post on their blog that summarizes the main discussion points in Tuesday’s “jobs” show.   The show included an interview with an official from Virginia, which leads the 37 states doing a better job than Connecticut in growing their economies, according to one survey.

Academic research institutions and drug companies alike have been criticized for the high prices of their patent-protected drugs–particularly when these high prices are maintained in poor countries, where patients can least afford them.  Yale was the site of a conference last week where it and five other universities signed on to a statement of principles governing technology licensing in developing countries.  While this document is primarily a statement of shared philosophy, does it provide a good model for improving access to medicine in the poor nations–and perhaps even here at home?

Many would agree that universities should automatically subscribe to the principle of removing barriers to medication in developing countries; few but the most cynical would expect academic institutions to desire profits over the advancement of global health.  Unfortunately, it is unclear whether universities have the legal or practical potential to ensure that fruits of their researchers are equitably available–mostly because universities are not in the business of actually making the drugs.

The new licensing principles are crafted to address that disconnect between academic (and mostly publicly funded) research and the patient end-user.  In the context of academic biomedical patents, licenses are the contracts that the university (which reserves the right to patent anything invented within its facilities) signs with companies that agree to develop and market the innovation.  These licenses can contain anything mutually agreeable to both parties, but the main thing at stake is money: the university wants to get as large a percentage as possible in royalties, while still providing sufficient incentive to the company taking the risk of developing the drug.  The right of universities to profit, financially, from publicly funded research was codified by Congress almost thirty years ago, and major research universities have offices dedicated to working out license agreements.  What several universities, including Yale, have now agreed to in principle, is to exercise their rights as patent holders, to ensure licenses are written in such a way that, at the very least, they won’t be barriers to distributing discounted drugs in poor countries.

From an extremely idealistic vantage, it is appealing to compare these activist, principled licenses to the copyright licenses that have enabled the open-source software revolution, where creators invoke their intellectual property rights to ensure their creations are openly available.  Such a philosophy lies behind Creative Commons licenses, covering the words you’re reading right now, as well as the GPL, which has enabled a software revolution.

Of course, the comparison is completely metaphorical.  The major problem is that a license can be as activist and idealistic as anyone wants it to be, reserving rights to free distribution across Africa, Asia, Detroit and the Mississippi Delta, but it will have no impact unless the terms are acceptable to a drug company.

Furthermore, like many high-tech products, drugs are often born of quite complicated intellectual-property parenthood.  A company might license a research patent from a university, but then make several more patentable innovations, perhaps related to the process of actually manufacturing the drug, before the medication enters the marketplace.   Those who negotiate licenses on behalf of universities will have to be exquisitely shrewd to anticipate such complexities, and ensure that they can retract licenses if drug companies don’t follow through with equitable drug distribution.

The proposal enshrining the new guiding principles recognizes the pitfalls in ensuring access to medicines.  Time will tell whether universities can, within the current patent regime, exert a measurable influence over drug distribution, or whether their new principles are merely P.R. posturing.

Finally, by stating the principle of equitable access should be embodied in license agreements, how long can universities ignore patients here at home, in the U.S., that can’t afford medicine?  Drug companies are afraid that cheap drugs distributed even across the ocean in Africa will make it back to rich countries, diluting their market share and profits.  However, poverty is as globalized as ever, global warming threatens to bring tropical diseases to the temperate homeland, and meaningful health-care reform remains elusive.  Is it possible for Yale and other institutions to remain true to their goal of “implementing technology transfer strategies that promote the availability of health-related technologies”, without doing the same at home as in poor countries?

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More reading:

• Universities Allied for Essential Medicines: detailed proposals for Equitable Access Licenses.
• Yale press release.

Patent 7,553,674 : Methods of identifying compounds useful for modulating intraflagellar transport . Granted June 30, 2009. full text from USPTO.

Inventors:  George B. Witman, Gregory J. Pazour, Joel L. Rosenbaum (Yale faculty), Douglas G.Cole.

Background

It’s the goal of any cell biologist to discover and describe a totally new molecular mechanism or cellular process.  Just such a discovery was made during the mid-90s, in the laboratory of Joel Rosenbaum at Yale.

Cross-section of two Chlamydamonas cilia. Click for Wikipedia entry.

Rosenbaum and colleagues were looking at the green algae Chlamydamonas–specifically at the long, slender cilia that project outward from its cell body.  Cilia, called flagella in cells that have only one of these structures, are present in many eukaryotic cells and can function both as a type of cellular paddle (as in the case of a swimming sperm cell) or as an antenna, positioned to sense the surrounding environment.

What the Yale researchers saw when they looked carefully inside the cilia, at high magnifications, were tiny granules that were moving along the cilia.  What became clear in subsequent experiments is that these particles move back and forth along the cilium, like miniature cargo elevators, to transport proteins and lipids.  These cargo include sensory molecules, as well as the building blocks needed to extend the growing structure.

Rosenbaum and colleagues termed this mechanism intraflagellar transport (IFT). Most importantly, though it was discovered in the model green algae cells, IFT is a mechanism that has been exquisitely conserved during evolution.  Microscopic parasites and human beings, confronted alike with the necessity of building and maintaining cilia and flagella in many different types of cells, all use the same basic transport molecules, with only minor variations.

As with any molecules so central to diverse cellular functions, when something goes wrong, like an inherited mutation in the gene coding for an IFT protein, severe diseases can develop.  In humans, difficulty building and maintaining cilia and flagella contribute to diseases of organs that depend on these structures, like the kidneys, the eyes and the heart during early development

Patent implications

The new patent claims the use, for “diagnostic, screening, and therapeutic” purposes, of 14 key proteins that are present in humans and other organisms with flagella.  These proteins are assembled together within the cell to make a multi-molecular machine for transporting cargo in the flagellum.  The exact workings of these protein complexes are still poorly understood.

The patent claims any pharmaceutical agent to diagnose or treat a problem with these complexes, or at least those drugs designed to interact with the 14 patented proteins, for uses including to “modulate flagellar function”.  Although much of the biomedical research into IFT has been directed at curing human genetic disorders, this patent would also appear to cover the design of any antibiotics targeting the IFT proteins in human parasites, such as Leishmania or Trypanosoma brucei,  which rely on their flagella for survival.

The diagnostic claim appears to broaden the scope of the patent in a significant way.  Severe diseases resulting from cilia defects, such as Bardet-Biedl syndrome, may not be cured by drugs that target IFT proteins, because there are many other molecules involved.  However, a diagnostic test, using IFT proteins to evaluate the “size”, “beating” or “cell motility” of a sample, as is imagined by the authors of the patent, may not be as far-fetched.

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Read this recent New York Times article on ciliary diseases, flagellum research and IFT.

In the midst of the healthcare debate, the skyrocketing cost of care–including the tens of thousands now spent on some medicines–is a constant target for complaints and solutions.  Responding to criticism of the particularly high cost of “biologic”, or biotech-based, drugs, a recent op-ed in the Hartford Courant insists that encouraging the manufacture of cheaper, generic versions of drugs is a dead end, short-sighted attempt to cut costs. According to this view, the cost of biologics justifies lengthy “data exclusivity” periods, during which time the  clinical test data generated by the original drug maker cannot be reused by generic companies:

For investors to risk the $1.4 billion it takes to bring a new medicine from concept to approved product, inventor companies must have at least 12 years of data exclusivity. Anything short of this will shortchange investors, who won’t be able to recoup their biotech investments, and will mean an end to investment in biotech.

The author of this opinion piece, Paul Pescatello, is president and CEO of Connecticut United for Research Excellence, an industry group and cheerleader for biotech in the Nutmeg State.  It’s certainly not surprising to hear an industry representative lobby against unfavorable regulations.  However, a visit to the CURE website will reveal that among its more high-profile members are the major research universities in Connecticut, both private (Yale, Trinity) and public (UConn, University of New Haven).  A number of towns (Branford, West Haven, Trumbull) and the state Department of Public Health are also on the rolls.

I understand the hopes, shared alike by local universities and municipalities, that biotech will reenergize Connecticut’s sagging industry and employment landscape.  The actual realization of a wealthy, well-educated workforce and lucrative industry may someday redeem the subsidies and other favors made to incentivize the growth of local biotech shops and drug manufacturers in CT.

However, is the dividing line between profit and public interest crossed when a lobby group that is sponsored in part by government and academia dives into a debate over healthcare and technology policy in the public forum?

Reasonable people disagree about the benefits society will reap from lengthy monopolies on biological drugs–for periods of a decade or more.  For instance, is it true that a certain, dozen-year period of drug exclusivity is required for firms to recoup their research?  After all, manufacturers of generic biological drugs will, in all likelihood, confront the same bevy of expensive safety and efficacy testing as the original producer.  In some cases, the sheer cost of reproducing the process for making a biologic treatment may make these inventions immune to the kind of generic versions that can be made of simpler, small-molecule based drugs (mainstream antibiotics and antidepressants, for instance).

In addition, the monopoly provided by government-guaranteed data exclusivity has nothing to do with the already decades-long patent protections that cover the inventions packaged into drugs.

Considering the enormous price that our society will likely pay for high-tech drugs in the coming decades, we should at least understand what kind of deal we’re getting with drug manufacturers as we negotiate the monopolies they’ll receive on the next generation of life-saving treatments.  It is in the interest of the university community, not to mention the Connecticut taxpayer, to keep industry lobbyists like CURE at arms length, at the very least, so that meaningful, two-sided debate can occur on the enormous issues of drug cost and healthcare reform.

N.B. To say that local industry groups like CURE are against the public interest is, of course, an unearned generalization.  CURE shows a promising ability to direct local industry dollars to education (and PR).  For example, check out the cool-looking BioBus, which would have satisfied both of my biggest childhood interests: (1) science and (2) large, diesel vehicles.

The Yale alumni magazine has an article in the current issue called “Company Town”,

Photo: Joe Franklin

part of a set of articles on the revitalization of the Elm City in recent years.  The article highlights Yale’s work toward establishing technology-spinoff businesses in New Haven to bring the university’s patents to market.

The “local” element of academic research patents, to be explored in yalepatents.org, clearly extends to the local economy and community.  Universities, looking for a concrete means of local economic stewardship, obviously see spinoff businesses as a source of local jobs and goodwill.  As recognized in the alumni magazine article, Yale/New Haven is a bit behind in this endeavor–clear enough to anyone with experience in Boston, RTP or the California research hubs.  The optimism is present, however, that New Haven would take the lead in recruiting modern industry to southern Connecticut.