NIH Budget cuts

http://www.forbes.com/sites/matthewherper/2013/03/06/drug-industry-greats-say-the-u-s-must-reverse-the-cuts-to-our-investment-in-science/

The usual diatribe around NIH budget cuts and the end of research.   Aside from the particularly interesting notion that unless NIH funds medical research, we won't have treatments for the looming large aging population and the diseases they will have, when NIH funding hasn't produced any effective treatments for chronic disease.  Might be the opposite, in fact.  But that off the specific point, on how the budget cut of 8% will devastate research.  Hmmm.  Sounds fishy, considering even conservative estimates suggest at least 33% of the budget goes to overhead.  What's that?  That is the charge that research organizations and universities levy on top of the actual cost of the research project funded.  There are places that command even over 100% overhead, but most of that gouging is directed at the DoD where they are less adverse to it.  So if NIH is sending $1.50 to an organization for every research dollar requested, it seems that there is a nice spot for the cutting, overhead.  If overhead rates are reduced to a more reasonable rate, maybe the 15% maximum that many foundations allow, we'd get more research done for every tax dollar, as well as absorb the budget contraction.  Of course, that would mean the massive artifices that have evolved by living on the overhead would go.  Of course, less bureaucracy is generally untenable in these kinds of institutions.  Perfect!  We can just turn to more adaptive institutions.  Not all that hard.

Megamicrons

I know you never read Voltaire.  And if you did, it wasn't the entitled piece.  It is a short satire about the senses.  Beings that have many compared to our few.  They pitied us. The senses allowed them to know the world across many scales simultaneously.  Unlike we humans.

As the metaphor that biology and more importantly our bodies are machines fades into history, our understanding about the organization and function of our bodies as nonlinear systems grow.  But practices related to health, from medicine to exercise still largely ignore this fact and people engage in those practices without recognizing that the so-called 'facts' that formed the foundation of those practices are no longer true.  While the persistence of memory constrains most people and their practices, some innovators are developing new practices, from medicine, exercise and diet to interpersonal relationships and group functioning.  Broadly, these 'system' based practices entail aligning those practices with the complex functioning of bodies.  There are new metaphors that better describe the complex, nonlinear, systems functioning of our bodies.   By complex, we mean many simultaneous, interdependent processes are always happening and they are iterative, meaning the output of one process is a partial input to itself and other processes.  This collective is a non-linear system, where the 'size' of the inputs are not directly correlated with the degree or size of the output.  Small inputs can have large effects and large inputs can have negligible effects.  One common feature of these kinds of nonlinear systems, biological or otherwise, is something called 'scalar invariance.'  This means that relationships and/or structures are highly similar no matter the scale at which they are viewed.  Like a tree to a branch to a twig, they have the same structures across all those scales, constituting a 'fractal.'

For us, this is a fundamental property of humans and especially human health.  In the old metaphor, human health was about machine maintenance.  Isolated, compartmentalized, virtually independent sub-systems interacting in very specific ways.   But the body is not a set of separate systems, but an active community of self which can only function as a complete unit.  Like other fractals, we can see that what people take for health, meaning the ability to function readily and easily in everyday life, is only at one level of resolution, the 'eyeball' level.  But investigate across scale, to systems, organs, tissues, the very cells themselves and you will find a similar level of 'health,'  the whole body functions as robustly or as poorly as the organs function, so too tissues and finally cells.  Health is the same at all scales. 

Interventions have been designed at the level of the body, say exercise, which does translate to improved cellular function, i.e. exercise engages the body across scale, or much more narrow interventions, like drugs, that are designed to effect, in general, some specific cellular activity.  That kind of intervention can and does have effects at other scales, but is not aimed specifically at health, but at disease.

Directly addressing the cellular function, liken that to cellular health and the inter-cellular milieu, think of that as the culture and influence cells have on each other, begins to get at the generation of health from the cell up, through the other levels of health and finally even to interpersonal healthy functioning. 

Another core feature of biological systems, unlike machines, is timing.  Our bodies are not the same over time.  Not in birth, adulthood and  old age, and not in summer and winter and not in day and night.  Different systems are in use, different genes are being transcribed, different behavior, from cells to our whole body are taking place.  Most interventions, whether cellular or behavioral, simply ignore this biological fact.  Fitting intervention to the best time is as critical as fitting it to the best scale.

In the same way that our bodies function across scales and time, so do interventions that are most empathic to the challenge.  Design the proper intervention, from exercise to supplements to mediation aimed at the right scale, from cells to selves and deliver them at the right time, day or night, summer or winter.  Then we can begin to rebuild health and wellness in its own organic image and leave the ancient machinery behind.

Is it the drug companies? Really?

Interesting article from Scientific American (which I viewed as a sacred text when I was you): how-drug-company-money-undermining-science.  Sort of an investigative journalism take on the ideas of conflict and research.  Easy to get excited about, but hardly news nor possibly the most pressing problem.  Lots of the activity of academic research in medicine is problematic.  Sure, for-profit interests funding 'independent' researchers on one hand and directly paying them on the other has literally changed the face of medical practice.  But the institutions themselves are bound up tightly, as well.  For every dollar that gets paid for research anywhere from $0.25 to $1.50 go to 'overhead,' meaning the institution itself. And as companies often pay higher overhead rates, there is plenty of graft to go around.  As this article suggests (but avoids investigating) the way in which money is dolled out by the government, the 'public' funding of research is hardly different.  The folks who control the 'advisory' boards are able to continue to feed funding to favored colleagues and projects.  Really innovation from unknown investigators is highly unlikely to be funded.  So the vast majority of research amounts to simply reproducing the existing paradigm.  This is despite hundreds of billions of dollars spend in cancer, for instance, that have produces few real, substantial changes at the clinical level. 

The culture of medical research isn't bad or good, it merely is unreasonable when evaluated against its stated aims.  And no one is in charge of it, there is no single 'source' nor accountable person, group, nor entity.  Change will come from the margins, as it always does.  That's why I like it out there.  Lonely, but almost unfettered. 

Paradigmatic mice

 In a fine article, researchers describe the optimal temperature for mice in nature and the way lower ambient temperatures common in research buildings alter their behavior (the mice have to eat about 30% more in order to generate the necessary body heat. Of course, the convenience of not working in a steam bath (mice apparently prefer 30 C - 86 F but become feisty when warm) for the lab staff probably effects the results of the experiments, unless the experiments are supposed to be done on cold mice.  Seems like a simple thing and the intervention is simple as well, just provide some material for the mice to build a nest.  So maybe folks will start, so they can have a better idea of how their interventions actually affect mice.  Maybe some failed drugs, for example, become viable again.  Oh, and a few viable ones end up 86'd.

Of course, that leaves us with the inverted time structure, meaning mice are noctural, but we wake them up during the day to do our work.  Even this article describes their lighting conditions to be 14/10 (light and dark).  Hmmm.  Single major regulator of every biological function is light.  What kind, how much and when.  So think of all the drugs that worked so well in mice (who were given those drugs mostly during the daylight hours, which is sleep time for mice) and not so well in humans (who were given them during the waking hours for humans).  The more central a practice is to reproducing the basic assumptions of the practitioners, the less likely it is to be changed, obviously.  And research science must first reproduce the assumptions and then it can proceed.  But only then.  Which is why we have had 50 years or more of incrementalism is science.  People even expect it "adding to the knowledge base."  Maybe it is time for a little creative destruction.  At least we'd have happier mice....


http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0032799

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.