Wednesday, March 11, 2015

Stimulate the phagocytes! (a distant mirror)

There is widespread acknowledgment that we have generally not achieved the biomedical (or evolutionary) predictive power that our research institutions' leaders have repeatedly been promising.  This applies to genomic as well as environmental causation.  It’s very natural, and easy to see why the public buys into these promises to the extent that it does, because as with religion we’re dealing with the quality of life, and with death, and doctors and preachers play on these (with no implication that they may not believe what they are saying or promising).

One can, and we think should, criticize superficial or misleading promises, even if they are made with good intention and especially to the extent they are made by politicians or bureaucrats to manipulate a funding or research establishment.  Spin is part of our society, but should be resisted especially in science, which should always be about truth, as objectively as we can see and explain it.

It’s no surprise that these sorts of promises are not new.  As a relatively recent and cogent example within the age of science, in George Bernard Shaw's (typically) lengthy 1911 Preface to his 1906 play The Doctor's Dilemma, and the play itself, reflected the similar situation at that time.  The essay and play are delightful, and if you have time or interest you’ll enjoy reading it (or viewing the great 1958 movie with Leslie Caron, Dirk Bogarde--and the inimitable Robert Morely). 

Robert Morely

Here are some quotes from Shaw's Preface, about the state of medicine and medical science at the turn of the 20th century.  We think you can translate them into 21st century equivalents:

In those days the causes were bacteria (the ‘genomics’ of the age), and the magical approach was to "stimulate the phagocytes" which would enable the body to cure everything.

In their desperation most people, “to save themselves from unbearable mistrust and misery…fall back on the old rule that if you cannot have what you believe in you must believe in what you have….what you want is comfort, reassurance, something to clutch at, were it but a straw.  This the doctor brings you.  You have a wildly urgent feeling that something must be done; and the doctor does something.”

“There is a fashion in operations as there is in sleeves and skirts.”

“There is no harder scientific fact in the world than the fact that belief can be produced in practically unlimited quantity and intensity, without observation or reasoning, and even in defiance of both, by the simple desire to believe founded on a strong interest in believing.”

“…it is useless to tell him that what he or his sick child needs is not medicine, but more leisure, better clothes, better food, and a better drained and ventilated house.”

“…no doctor seems able to advise you what to eat any better than his grandmother or the nearest quack….”

“Each of them believes that he is on the verge of a great discovery, in which Virginia Snake Root will be an ingredient, heaven knows why.”

“…we are left in the hands of the generations which, having heard of microbes much as St Thomas Aquinas heard of angels, suddenly concluded that the whole area of healing could be summed up in the formula:  Find the microbe and kill it. . . .The popular theory of disease is the common medical theory: namely, that every disease had its microbe duly created in the garden of Eden, and has been steadily propagating itself and producing widening circles of malignant disease ever since.”

“When the bacillus was found, as it frequently was, in persons who were not suffering from the disease, the theory was saved by simply calling the bacillus an impostor, or pseudo-bacillus.”

Shaw goes on to critique the rationales given to justify vivisection (research on animals), ideas like hormesis (or homeopathy) which are still around, noting that  “….the list of diseases which vivisection claims to have cured is long; but the returns of the  Registrar-General shew that people persist in dying of them as if vivisection had never been heard of.”

But it isn’t just scientists who are guilty:  “What the public wants, therefore, is a cheap magic charm to prevent, and a cheap pill or potion to cure, all disease.  It forces all such charms on the doctors.”

Even Shaw, a non-scientist, recognized that “Even trained statisticians often fail to appreciate the extent to which statistics are vitiated by the unrecorded assumptions of their interpreters…Thus it is easy to prove that the wearing of tall hats and the carrying of umbrellas enlarges the chest, prolongs life, and confers comparative immunity from disease; for the statistics shew that the classes which use these articles are bigger, healthier, and live longer than the class which never dreams of possessing such things….It does not take much perspicacity to see that what really makes this difference is not the tall hat and the umbrella, but the wealth and nourishment of which they are evidence.”

We could go on (and on and on, as Shaw did).  He tried to suggest some sorts of cures for the social ills he critiques, and of course much of what he says is out of date.  But the sorts of issues he lampoons have not gone away and it is important not to lose sight of that.  It's a distant mirror of our own times, and presumably you can translate his snipes into modern terms, such as where ‘gene’ replaces ‘microbe’ (or, where microbiomics replaces genomics?).

Shaw was a wit and cynic and of course we all naturally seek health and well-being.  In many ways science has become the new religion to which we turn for salvation.  It certainly has ideological aspects that lead to its making of global promises.  To what extent is it fair to use such quotes from a century ago, to characterize aspects of biomedicine and society today?

The living world is made of molecules and must obey the laws of physics and chemistry. Genes are molecules and ‘environmental’ factors affecting organisms must work through molecular or physical means.  So it cannot be wrong to think that understanding must come, if from anywhere, from science.  But that doesn’t mean that reducing everything to molecular terms is the right or best way to deal with problems, like disease and death, that operate at the individual or societal level.

Except for irresponsible promises made by some who are transparently lobbying for research budgets and the like, death is inevitable.  Promises to cure some of the major common diseases of today could lead to longer life, but also likely to worse quality of life, because everything you avoid today enables something else to bring you down later on, and most later-ons are worse to bear.  Our hunger for life in the short-term, leads us conveniently not to think of the consequences of getting our wish. 

In The Doctor’s Dilemma, a physician has to decide whether to use a limited curative method to save a starving artist, who was young but arrogantly obnoxious (but has a sexy young wife) and a struggling but conscientious physician, both of whom will die without the treatment.  We, too, should accept that we inevitably must make a trade-off between values.  In this sense, one of these should be a focus on early onset severe diseases, where causation is understood, at least gives the beneficiaries decades of good quality life. 

Science is an attempt to understand Nature, and there is no indication that we’re anywhere close to a perfect understanding.  We are always at some ‘frontier’ of knowledge, and if the public or even self-image of science is of the Einsteins and Darwins, the truth is that most of us are drones, as is the case in any other occupation.  What becomes culpable is when we let our claims and promises get ahead of the reality, especially if we do it for self-promoting reasons that delude the public, our funders.  Of course we’re members of our society, and self-promotion is a part of that these days.  But if one thing is vital to science, it’s honesty, and as we allow ourselves to be shills for various professional or venal reasons, then where does dissembling end and truth begin?

Science cannot be blamed for a failure to address all human ills or for using methods or approaches that aren’t perfect, nor is it surprising when for expedience we do objectionable things (e.g., much animal research, studies done in the developing world or on prisoners, that can’t be done on our own citizens, or doing the same thing over and over knowing it won't lead to much).  Of course we always have a rationale, always offered as a justification.  Faced with difficult problems, it’s only natural to want to do what we know how to do.  And, of course, to do good!

But where society can and should blame us is for accepting inertia, protecting costly business as usual in areas where we’ve done enough of that business to know its basic outcome.  This applies to much of the current genomewide association and other 'omics and Big Data science, which is now very widely understood to be a form of wheel-spinning in the absence of better ideas, even by many who acquiesce in the practice.  

Better ways of operating might be possible: don’t force investigators to defend their current approaches by making them dependent for their labs and even their salaries on proposing to do what they already know how to do but has reached diminished returns.  Incentives for being adaptive and relief from score-counting on publications, students, or grants or grant-writing might help.  Could the legendary Bell Labs approach work better?

There will always be problems, because humans are fallible, but for the same reason there must also always be critics.  No one can ever know whence the next break will come.  But just as we should let obsolete industries rust out to be replaced by something better, the same should apply to science, where inertia is also an obstacle to progress.

We write these points here regularly, because that’s what we feel we can do in this stage of our lives (Anne and I have retired from running our own lab, except for some computer simulations and collaborations), and hopefully to stimulate discussion of what should come next.  Repetition is important if a message is to get through.  If Shaw can be writing things a century ago that ring true in similar ways today, then there is a problem, and it’s not a trivial one.  It has to do with science, but also with science in society.

So what we as a community should be asking is what have the recent series of approaches shown us and where the problems lie, so we might at least think about new directions to attack them, beyond just an increase of scale, except where an increase is likely to reveal substantially different things that current resolution can’t see.  Sometimes that's surely to be the case, though often it's an excuse for not changing gears.  But when we see patterns and attitudes today that are hardly different from those a century ago, we should think about the implications.  Just proclaiming "stimulate the phagocytes!" isn't going to get us there.

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