Paradigm, Paradigm, uber alles!

JAMA published a study looking at the effects of bone marrow derived stem cells on patients with heart failure.  Predictably, the study did not demonstrate significant benefits for the patients who actually received the stem cells as compared to the placebo group, which is not an uncommon outcome in these kinds of stem cell therapy trials.

From a scientific perspective, what is important is that the underlying (and unstated) paradigm is preserved.  In this case, as in virtually any other in this area, the putative stem cells are used precisely like a drug would be used, as a stand alone intervention.  Which is precisely the inverse of what in vivo tissue regeneration is.  And rather than the methodology, which is biologically unsound (well, it is really absurd, but if that is written folks get offended), is unshakeable, so the discussion degenerates to a mostly morally driven discussion about the 'value' of the autologous pluripotent bone marrow cells use here and the vaunted 'embryonic stem cell."   The value of virginal stem cells has significant appeal independent of efficacy and a constituency that has significant economic interest in their use, but 'parts is parts' as the story goes.  The elusive feature is the dangerous one as well.  The gruelingly childish, no, make that magical, idea that investigations in biology require careful manipulation of a single variable at a time is not supportable, not true and virtually impossible.  But aside from that, even if it were possible to operationalize, it is contrary to the basic of biological activity.  All biologic emerges within a recursively non-linear milieu and is wholly dependent upon that milieu for initial trajectory and outcomes.  Without concurrent nurturing (whatever that may mean) of the context, the milieu for stem cells, there is no plausible reason to expect any enduring efficacy.  But it's "Paradigm, paradigm, uber alles!" in the stem cell field for the foreseeable future, at least in the mainstream of medical research, however backwater it really is.

In 2011 a new cancer drug was approved, Provenge, from Dendreon Corp.  And I blogged about it then.  First of its kind, blah, blah, blah.  Short answer, about 4 months longer survival, which I do not oppose.  And it is $93,000.  But I already covered that.  This is about the business side of that equation.  The company just tok a header on an announcement of slower that anticipated growth:

"Chris Raymond, an analyst with Robert W. Baird & Co, who rates the company “Neutral” with a price target of $14, said he was unimpressed with the latest disclosure, and that it’s a sign Dendreon needs to do a better job of persuading its current base of physician customers to start prescribing the drug more avidly. “For us to get more constructive on the stock, we would need to see tangible evidence of an inflection point in Provenge account penetration,” he wrote"(Xconomy)

My interest is in the way in which the analyst identifies the 'problem' and the solution.  Dendreon has to do a better job of talking MDs into prescribing their drug.  Hmmmm.  Why would that be?  If the drug is so effective at improving outcomes, then what is the hesitation?  Could it be the model, where oncologist think about drug sales to patients as a principle profit center?  Or that the side-effects + benefits/costs is not as attractive to anyone as purported?  The state of oncology today is the incremental extension of a life at the very terminal end.  Pharmaceutical involution continues. 

I do work for a variety of companies outside of my usual work, all involved in some way in therapeutics or nutrition, or the like.  In general, much of what these non-medical companies are doing is developing regimen's of 'discipline,' whether it be ingest something, wear something and/or do something, that have an underlying commonality that is unspoken.  All of these kinds of 'clothes' are cut from fabric laid out thousands of years ago.  At least the Greeks had fairly elaborate criteria and mechanisms for self-discipline that rest (and still do) on a tautology of sorts.  The Romans continued these 'arts' and elevated them, and the practitioners.  The basic presumption is that men should resist that which is natural, but animal like, in order to achieve a higher human existence.  And the 'governing" of the self was the same degree to which a man could be fit to govern a wife, a family, a business, and ultimately empires.  Those who were fit to govern would be recognized by their ability to govern their own natural urges.  I understand the impulse to discipline here, the notion of creating order from chaos (and I do also understand the order in chaos...), but there aren't any data that support this.  Lots of crappy leaders were  likely regimented and loads of dynamic, effective leaders are personal train wrecks.  For those who don't get to (or won't, you undisciplined lot) read Foucault's 3 volume History of Sexuality, the wonderful observations he conveys are subtitles for the political theater of our day (and sad as it is).  The game is played out around these ancient ideas of discipline, at least until the unfit are weeded out.  Of course, they are only unfit on the grounds of self-discipline, and specifically self-discipline in sexual affairs, with damaging, but not fatal, chinks for ethnic, financial and social affairs.  But the dismissal of potentially outstanding leaders due to thousand year old imperatives is probably not a very intelligent algorithm.  But it is one that has infiltrated much of our sense of excellence.  Maybe we can just start to look for excellence itself?  Maybe that would be a better indicator of potential?  Just an idea...

Don't let the facts stand in the way of a good story...

The graphic (thanks Nature) is a linear representation of a way to think about how tumors develop blood supplies.  It is, of course, not actually what happens, but a way of thinking.  And that way of thinking has produced lots of attempts at intervention.  Of course, the interventions are not just applied to thinking, but to bodies.  And therein lies the trouble.  Recent work (http://www.sciencedirect.com/science/article/pii/S1535610811004478) has demonstrated what was likely a fairly obvious outcome.  Very popular (meaning blockbuster) anti-angiogenic drugs have been demonstrated to slow tumor progressions.  But hypoxia (lack of oxygen) is a primary driver in cancers becoming metastatic.  So primary tumors may not grow as swiftly, but metastatic tumors appear more frequently.  Of course, that was not part of the thinking.  But again, this is a real system, a complex biological web, not a thought experiment.

I remember the almost fever pitch of effort promoting Judah Folkman (pioneer of anti-angiogenic therapy) in a poorly disguised effort to deliver a Nobel Prize to him before he died.  It generated a simple, fatally-flawed logic of how to treat cancers by denying blood supply.  So we have another of the common, killer beliefs about medicine and science.  Killer, sadly.

It is a great company, trying to great things.  And has done some, from the standard model.  But when Geron announced that they were closing their embryonic stem cell efforts, it was like a lead weight falling on all the hopes of the embryonic promoters.  Geron had persevered where others had failed and got the FDA to approve an embryonic stem cell clinical trial.  As many know, they stopped that trial and closed down the whole division.  Startling to many (especially shareholders).  But the inevitable outcome for efforts that are born of a defiance to the facts of basic biology.  The facts are that the human body, given the right conditions, will rebuild itself.  

For the bulk of modern medical thinking, the adult body was "terminally differentiated," meaning it was a finished product and unrenewable, except for some few exceptions, the liver and bone marrow.  That's one reason bone marrow transplants have been done for 40+ years.  But what was a bone marrow transplant, but a kind of stem cell transplant, with blood stem cells.  And yet, our collective unconscious in medicine remained derived from what we can only think of as a long-standing view of the 'body' as a complete entity, a finished product that then slowly wore out.  As folks have found, bodies do regenerate, although inefficiently.  Think of how an injured brain 'rewires' itself, essentially 'regrowing' the kinds of connections that lead to function.  A transplanted female heart, in a male body, will become partly "male" with male heart cells (cardiomyoctes).  Where did they come from?  And a woman who gives birth to a boy, expecially if she has a sick heart, will find that some of her heart muscle is colonized with her son's stem cells.  The latter has greater relevance about what it is to be an "individual," not just about stem cells.

So, as the real stem cell business, using your own stem cells to cure disease, begins to gain momentum, we may find many of the unspoken presumptions of an old way of understanding bodies will fall away in the face of facts.  But do not look for it to go gladly.  We still hold ourselves above and outside of biology and the natural world.  But underneath it all, we are dynamic, renewable organisms, despite our unwillingness to do that.  Someday, maybe, we will stop fighting nature, supporting the myth of domination.  And then, maybe, we can learn the beauty of living within that nature, and within ourselves.