Is genetics still metaphysical? Part VI. What might lead to a transformative insight in biology today--if we need one

It's easy to complain about the state of the world, in this case, of the life sciences, and much harder to provide the Big New Insights one argues might be due.  Senioritis makes it even easier: when my career in genetics began, not very much was known.  Genes figuratively had 2 alleles, with measurable rates of recurrence by mutation.  Genetically tractable traits were caused by the proteins in these genes; quantitative traits were too complex to be considered seriously to be due to individual genes, so were tacitly assumed to be the additive result of an essentially infinite number of them.

How many genes there were was essentially unknowable, but using identified proteins as a gauge, widely thought to be around 100,000. The 'modern evolutionary synthesis' solved the problem, conceptually, by treating these largely metaphorical causal items as largely equivalent, if distinct, entities whose identities were essentially unknowable.  That is, at least, we didn't have to think about them as specific entities, only their collective actions.  Mendelian causal genes, evolving by natural selection was, even if metaphorical or even in a serious way metaphysical, a highly viable worldview in which to operate.  A whole science enterprise grew around this worldview.  But things have changed.

Over the course of my career, we've learned a lot about these metaphysical units.  Whether or not they are now more physical than metaphysical is the question I've tried to address in this series of posts, and I think there's not an easy answer--but what we have, or should have, understood is that they are not units!  If we have to have a word for them, perhaps it should be interactants.  But even that is misleading because the referents are not in fact unitary.  For example, many if not  most 'genes' are only active in context-dependent circumstances, are multiply spliced, may be post-trascriptionally edited, are chemically modified, and have function only when combined with other units (e.g., don't code for discretely functioning proteins), etc.

Because interaction is largely a trans phenomenon--between factors here and there, rather than just everything here, the current gene concept, and the panselectionistic view in which every trait has an adaptive purpose, whether tacit or explicit, is a serious or even fundamental impediment to a more synthetic understanding. I feel it's worth piling on at this point, and adding that the current science is also pan-statistical in ways that in my view are just as damaging.  The reason, to me, is that these methods are almost entirely generic, based on internal comparison among samples, using subjective decision-criteria (e.g., p-values) rather than testing data against a serious-level theory.

If this be so, then perhaps if the gene-centered view of life, or even the gene concept itself as life's fundamental 'atomic' unit, needs to be abandoned as a crude if once important approximation to the nature of life. I have no brilliant ideas, but will try here to present the sorts of known facts that might stimulate some original thinker's synthesizing insight--or, alternatively, might lead us to believe that no such thing is even needed, because we already understand the relevant nature of life: that as an evolutionary product it is inherently not 'regular' the way physics and chemistry are.  But if our understanding is already correct, then our public promises of precision medicine are culpably misleading slogans.

In part V of this series I mentioned several examples of deep science insight, that seemed to have shared at least one thing in common:  they were based on a synthesis that unified many seemingly disparate facts.  We have many facts confronting us.  How would or might we try to think differently about them?  One way might be to ask the following questions: What if biological causation is about difference, not replication?  What if 'the gene' is misleading, and we were to view life in terms of interactions rather than genes-as-things?  How would that change our view?

Here are some well-established facts that might be relevant to a new, synthetic rather than particulate view of life:

1. Evolution works by difference, not replication Since Newton or perhaps back to the Greek geometers, what we now call 'science' largely was about understanding the regularities of existence.  What became known as 'laws' of Nature were, initially for theological reasons, assumed to be the basis of existence.  The same conditions led to the same outcomes anywhere.  Two colliding billiard balls here on Earth or in any other galaxy, would react in identical ways (yes, I know, that one can never have exactly the same conditions--or billiard balls--but the idea is that the parts of the cosmos were exchangeable.)  But one aspect of life is that it is an evolved chemical phenomenon whose evolution occurred because elements were different rather than exchangeable.  Evolution and hence life, is about interactions or context-specific relative effects (e.g., genetic drift, natural selection). 

2.  Life is a phenomenon of nested (cladistic) tree-like relationships Life is not about separated, independent entities, but about entities that from the biosphere down (at least) to individual organisms are made of sets of variations of higher-level components.  Observation at one level, at least from cells up to organs to systems to individuals, populations, species and ecosystems, are reflections of the nested level(s) the observational level contains. 

3.  Much genetic variation works before birth or on a population level Change may arise by genetic mutation, but function is about interactions, and success--which in life means reproduction--depends on the nature of the interactions at all levels.  That is, Darwinian competition among individuals of different species is only one, and perhaps one of the weakest, kinds of such interaction.  Embryonic development is a much more direct, and stronger arena for filtering interactions, than competition (natural selection) among adults for limited resources.  In a similar way, some biological and even genetic factors work only in a population way (bees and ants are an obvious instance, as are bacterial microfilm and the life cycles of sponges or slime molds). 

4.  Homeostasis is one of the fundamental and essential ways that organisms interact Homeostasis as an obvious example of a trans phenomenon.  It's complexly trans because not only do gene-expression combinations change, but they are induced to change by extra-cellular and even extra-organismal factors both intra and inter-species.  The idea of a balance or stasis, as with organized and orchestrated combinatorial reaction surely cannot be read of in cis.  We have known about interactions and reactions and so on, so this is not to invoke some vague Gaia notions, but to point out the deep level of interactions, and these depend on many factors that themselves vary, etc. 

5. Environments include non-living factors as well as social/interaction ones No gene is an island, even if we could identify what a 'gene' was, and indeed that no gene stands alone is partly why we can't.  Environments are like the celestial spheres: from each point of view everything else is the 'environment', including the rest of a cell, organ, system, organism, population, ecosystem.  In humans and many other species, we must include behavioral or social kinds of interactions as 'environment'.  There is no absolute reference frame in life any more than in the cosmos.  Things may appear linear from one point of view, but not another.  The 'causal' effects of a protein code (a classical 'gene') depend on its context--and vice versa. 

6. The complexity of factors often implies weak or equivalent causation--and that's evolutionarily fundamental. Factors or 'forces' that are too strong on their own--that is, that appear as individually identifiable 'units'--are often lethal to evolutionary survival.  Most outcomes we (or evolution) care about are causally complex, and they are always simultaneously multiple: a species isn't adapting to just one selective factor at a time, for example.  Polygenic causation (using the term loosely to refer to complex multi-factoral causation) is the rule.  These facts mean that individually identified factors usually have weak effects and/or that there are alternative ways to achieve the same end, within or among individuals.  Selection, even of the classical kind, must be typically weak relative to any given involved factor. 

7. The definition of traits is often subjective and affects their 'cause' Who decides what 'obesity', 'intelligence', or 'diabetes' is?  In general, we might say that 'Nature' decides what is a 'trait', but in practice it is often we, via our language and our scientific framework, who try to divide up the living world into discrete categories and hence to search for discrete causal factors.  It is no surprise that what we find is rather arbitrary, and gives the impression of biological causation as packaged into separate items rather than being fundamentally about a 'fabric' of interactions.  But the shoehorn is often a major instrument in our causal explanations. 

8. The 'quantum mechanics' effect: interaction affects the interactors In many aspects of life, obviously but not exclusively applied to humans, when scientists ask a question or publicize a result, it affects the population in question.  This is much like the measurement effect in quantum mechanics.  Studying something affects it in ways relevant to the causal landscape we are studying.  Even in non-human life, the 'studying' of rabbits by foxes, or of forests by sunlight, affects what is being studied.  This is another way of pointing out the pervasive centrality of interaction.  Just like political polls, the science 'news' in our media, affect our behavior and it is almost impossible to measure the breadth and impact of this phenomenon.

All of these phenomena can be shoe-horned into the 'gene' concept or a gene-centered view of life or of biomedical 'precision'.  But it's forced: each case has to be treated differently, by statistical tests rather than a rigorous theory, and with all sorts of exceptions, involving things like those listed here, that have to be given post hoc explanations (if any). In this sense, the gene concept is outmoded and an overly particulate and atomized view of a phenomenon--life--whose basic nature is that it is not so particularized.

Take all of these facts, and many others like them, and try to view them as a whole, and as a whole that, nonetheless can evolve.  Yesterday's post on how I make doggerel was intended to suggest a similar kind of mental exercise.  There can be wholes, and they can evolve, but they do it as wholes. If there is a new synthesis to be found, my own hunch it would be in these sorts of thoughts.  As with the examples I discussed a few days ago (plate techtonics, evolution itself, and relativity), there was a wealth of facts that were not secret or special, and were well-known. But they hadn't been put together until someone thinking hard about them, who was also smart and lucky, managed it. Whether we have this in the offing for biology, or whether we even need it, is what I've tried to write about in this series of posts.

Of course, one shouldn't romanticize scientific 'revolutions'.  As I've also tried to say, these sorts of facts, which are ones I happen to have thought of to list, do not in any way prove that there is a grand new synthesis out there waiting to be discovered. It is perfectly plausible that this kind of ad hoc, chaotic view of life is what life is like.  But if that's the case, we should shed the particulate, gene-centered view we have and openly acknowledge the ad hoc, complex, fundamentally trans nature of life--and, therefore, of what we can promise in terms of health miracles.

Is genetics still metaphysical? Part III. Or could that be right after all?

In the two prior parts of this little series (I and II), we've discussed the way in which unknown, putatively causative entities were invoked to explain their purported consequences, even if the agent itself could not be seen or its essence characterized.  Atoms and an all-pervasive ether are examples. In the last two centuries, many scientists followed some of the principles laid down in the prior Enlightenment period, and were intensely empirical, to avoid untrammeled speculation.  Others followed long tradition and speculated about the underlying essentials of Nature that could account for the empiricists' observations. Of course, in reality I think most scientists, and even strongly religious people, believed that Nature was law-like: there were universally true underlying causative principles.  The idea of empiricism was to escape the unconstrained speculation that was the inheritance even from the classical times (and, of course, from dogmatic religious explanations of Nature).  Repeated observation was the key to finding Nature's patterns, which could only be understood indirectly.  I'm oversimplifying, but this was largely the situation in 19th and early 20th century physics and it became true of historical sciences like geology, and in biology during the same time.

At these stages in the sciences, free-wheeling speculation was denigrated as delving in metaphysics, because only systematic empiricism--actual data!--could reveal how Nature worked. I've used the term 'metaphysics' because in the post-Enlightenment era it has had and been used in a pejorative sense.  On the other hand, if one cannot make generalizations, that is, infer Nature's 'laws', then one cannot really turn retrospective observation into prospective prediction.

By the turn of the century, we had Darwin's attempt at Newtonian law-like invocation of natural selection as a universal force for change in life, and we had Mendel's legacy that said that causative elements, that were dubbed 'genes', underlay the traits of Nature's creatures.  But a 'gene' had never actually been 'seen', or directly identified until well into the 20th century. What, after all, was a 'gene'? Some sort of thing?  A particle?  An action?  How could 'it' account for traits as well as their evolution?  To many, the gene was a convenient concept that was perhaps casually and schematically useful, but not helpful in any direct way.  Much has changed, or at least seems to have changed since then!

Genetics is today considered a mainline science, well beyond the descriptive beetle-collecting style of the 19th century.  We now routinely claim to identify life's causative elements as distinct, discrete segments of DNA sequence, and a gene is routinely treated as causing purportedly 'precisely' understandable effects.  If raw Big Data empiricism is the Justification du Jour for open-ended mega-funding, the implicit justifying idea is that genomics is predictive the way gravity and relativity and electromagnetism are--if only we had enough data!  Only with Big Data can we identify these distinct, discrete causal entities, characterize their individual effects and use that for prediction, based on some implicit theory or law of biological causation.  It's real science, not metaphysics!

But even with today's knowledge, how true is that?

The inherent importance of context-dependency and alternative paths
It seems obvious that biological causation is essentially relative in nature: it fundamentally involves context and relationships.  Treating genes as individual, discrete causal agents really is a form of metaphysical reification, not least because it clearly ignores what we know about genetics itself. As we saw earlier, today there is no such thing as 'the' gene, much less one we can define as the discrete unit of biological function.  Biological function seems inherently about interactions.  The gene remains in that sense, to this day, a metaphysical concept--perhaps even in the pejorative sense, because we know better!

We do know what some 'genes' are: sequences coding for protein or mature RNA structure.  But we also know that much of DNA has function unrelated to the stereotypical gene.  A gene has multiple exons and often differently spliced (among many other things, including antisense RNA post-transcription regulation, and RNA editing), combined with other 'genes' to contribute to some function.  A given DNA coding sequence often is used in different contexts in which 'its' function depends on local context-specific combinations with other 'genes'.  There are regulatory DNA sequences, sequences related to the packaging and processing of DNA, and much more.  And this is just the tip of the current knowledge iceberg; that is, we know there's the rest of the iceberg not yet known to us.

Indeed, regardless of what is said and caveats offered here and there as escape clauses, in practice it is routinely assumed that genes are independent, discrete agents with additive functional effects, even though this additivity is a crude result of applying generic statistical rather than causal models, mostly to whole organisms rather than individual cells or gene products themselves.  Our methods of statistical inference are not causal models as a rule but really only indicate whether, more probably than not, in a given kind of sample and context a gene actually 'does' anything to what we've chosen to measure. Yes, Virginia, the gene concept really is to a great extent still metaphysical.

But isn't genomic empiricism enough?  Why bother with metaphysics (or whatever less pejorative-sounding term you prefer)? Isn't it enough to identify 'genes', however we do it, and estimate their functions empirically, regardless of what genes actually 'are'?  No, not at all.  As we noted yesterday, without an underlying theory, we may sometimes be able to make generic statistical 'fits' to retrospective data, but it is obvious, even in some of the clearest supposedly single-gene cases, that we do not have strong bases for extrapolating such findings in direct causal or predictive terms.  We may speak as if we know what we're talking about, but those who promise otherwise are sailing as close to the wind as possible.

That genetics today is still rather metaphysical, and rests heavily on fancifully phrased but basically plain empiricism, does not gainsay that fact that we are doing much more than just empiricism, in many areas, and we try to do that even in Big Promise biomedicine.  We do know a lot about functions of DNA segments.  We are making clear progress in understanding and combatting diseases and so on.  But we also know, as a general statement, that even in closely studied contexts, most organisms have alternative pathways to similar outcomes and the same mutation introduced into different backgrounds (in humans, because the causal probabilities vary greatly and are generally low, and in different strains of laboratory animals) often has different effects.  We already know from even the strongest kind of genetic effects (e.g., BRCA1 mutations and breast cancer) that extrapolation of future risk from retrospective data-fitting can be grossly inaccurate.  So our progress is typically a lot cruder than our claims about it.

An excuse that is implicit and sometimes explicit is that today's Big Data 'precision, personalized' medicine, and much of evolutionary inference, are for the same age-old argument good simply because they are based on facts, on pure empiricism, not resting on any fancy effete intellectual snobs' theorizing:  We know genes cause disease (and everything else) and we know natural selection causes our traits.  And those in Darwinian medicine know that everything can be explained by the 'force' of natural selection.  So just let us collect Big Data and invoke these 'theories' superficially as justification, and mint our predictions!

But--could it be that the empiricists are right, despite not realizing why?  Could it be that the idea that there is an underlying theory or law-like causal reality, of which Big Data empiricism provides only imperfect reflections, really is, in many ways, only a hope, but not a reality?

Or is life essentially empirical--without a continuous underlying causal fabric?
What if Einstein's dream of a True Nature, that doesn't play dice with causation, was a nightmare.  In biology, in particular, could it be that there isn't a single underlying, much less smooth and deterministic, natural law?  Maybe there isn't any causal element of the sort being invoked by terms like 'gene'.  If an essential aspect of life is its lack of law-like replicability, the living world may be essentially metaphysical in the usual sense of there being no 'true' laws or causative particles as such. Perhaps better stated, the natural laws of life may essentially be that life does not following any particular law, but is determined by universally unique local ad hoc conditions.  Life is, after all, the product of evolution and if our ideas about evolution are correct, it is a process of diversification rather than unity, of local ad hoc conditions rather than universal ones.

To the extent this is the reality, ideas like genes may be largely metaphysical in the common sense of the term.  Empiricism may in fact be the best way to see what's going on.  This isn't much solace, however, because if that's the case then promises of accurate predictability from existing data may be culpably misleading, even false in the sense that a proper understanding of life would be that such predictions won't work to a knowable extent.

I personally think that a major problem is our reliance on statistical analysis and its significance criteria, that we can easily apply but that have at best only very indirect relationship to any underlying causal fabric, and that 'indirect' means largely unknowably indirect. Statistics in this situation is essentially about probabilistic comparisons, and has little or often no basis in causal theory, that is, in the reason for observed differences.  Statistics work very well for inference when properly distributed factors, such as measurement errors, are laid upon some properly framed theoretically expected result.  But when we have no theory and must rely on internal comparisons and data fitting, as between cases and controls, then we often have no way to know what part of our results has to do with sampling etc. and where any underlying natural laws, might be in the empirical mix--if such laws even exist.

Given this situation, the promise of 'precision' can be seen starkly as a marketing ploy rather than knowledgeable science.  It's a distraction to the public but also to the science itself, and that is the worst thing that can happen to legitimate science.  For example, if we can't really predict based on any serious-level theory, we can't tell how erroneous future predictions will be relative to existing retrospective data-fitting so we can't, largely even in principle, know how much this Big Data romance will approximate any real risk truths, because true risks (of some disease or phenotype) may not exist as such or may depend on things, like environmental exposures and behavior, that cannot be known empirically (and perhaps not even in theory), again, even in principle.

Rethinking is necessary, but in our current System of careerism and funding, we're not really even trying to lay out a playing field that will stimulate the required innovation in thought.  Big Data advocates sometimes openly, without any sense of embarrassment, say that serendipity will lead those with Big Data actually to find something important.  But deep insight may not be stimulated as long as we aren't even aware that we're eschewing theory basically in favor of pure extrapolated empiricism--and that we have scant theory even to build on.

There are those of us who feel that a lot more attention and new kinds of thinking need to be paid to the deeper question of how living Nature 'is' rather than very shaky empiricism that is easy, if costly, to implement but whose implications are hard to evaluate. Again, based on current understanding, it is quite plausible that life, based on evolution which is in turn based on difference rather than replicability, simply is not a phenomenon that obeys natural law in the way oxygen atoms, gravity, and even particle entanglement do.

To the extent that is the case, we are still in a metaphysical age, and there may be no way out of it.

Is genetics still metaphysical? Part I. Some general history.

In very broad terms, modern science has had debates about two basic kinds of approaches to understanding the world.  To over-simplify, they are the empirical and the theoretical approaches. Some argue that we can know only what we can detect with our sensory systems (and machines to extend them), but we can never know what general causal principles account for those data, or even if such real, true principles exist. Others view science's essential job as not just accumulating collections of data, which are necessarily imperfect, but to use such observations to build a picture of the true, or perfect underlying regularity--the 'laws' of Nature.

In the former case we just have to make measurements and try to show the ways in which comparable situations lead to comparable outcomes.  In the latter, we want what we call 'theory', that is, perfect generalizations that tell us how a given situation will turn out, and what the causal reasons are.  The standard assumption of the physical sciences is that Nature is, indeed, universally law-like.  Variables like the gravitational constant and the speed of light really are universally, precisely constant.

These are age-old differences, often 'just' philosophical, but they're quite important.  Comparably important are the still-unanswered question as to whether any phenomena in Nature is irreducibly probabilistic rather than deterministic, or whether probabilistic aspects of Nature really just reflect our imperfect sampling and measurement. This is the important distinction between epistemology--how we know things, and ontology--how things really are.  Can we ever tell the difference?

Empiricism is in some ways the easy part.  We just go out and make measurements and let them accumulate so we can generalize about them.  That's a lot of slogging to get the data, but all you have to do is be systematic and careful.  Don't give me airy generalizations, just the facts, please!

In other ways, theory is the easy part.  All you have to do is sit in your armchair, as the proverbial denigratory model has it, and make up something that sounds exotic (or even mathematically intricate) and claim you know how Nature 'is'.  Data are imperfect, so don't bother me about that! There are long traditions in both kinds of approach, and to a great extent it's only been the past few hundred years in which there has been melding of these two basic approaches.

Often, theory hypothesizes some fundamental objects whose properties and actions can only be seen indirectly, as they are manifest in measurable phenomena. Here there is a delicate boundary between what is essentially 'metaphysical' as opposed to real.  Many object to the use of metaphysical concepts and claims as being essentially untestable, and argue that only empiricism is real and should be taken seriously.  In the 19th and early 20th centuries, as technology revealed more and more about unseen Nature, things that were not yet seen directly but that could be hypothesized and assigned to things we could measure, we taken as true by some but denigrated as metaphysical by pure empiricists.

These distinctions were never that clear, in my view (even if they provided jobs for philosophers to write about).  Empiricism is retrospective but understanding requires some sorts of predictability, which is prospective.  If we cannot reliably generalize, if the same conditions don't always lead to the same result, how can the observing the former lead us to the latter?  Predictive power is largely what we want out of science, even if it's just to confirm our understanding of Nature's laws.

Until fairly recently, these issues have mainly been housed in the physical sciences, but since Linnaeus' time, but especially after Darwin and Wallace, the issues have applied to biology as well.
In this brief series we'll try to explore whether or how we can think of biology as the result of such universal laws or whether all we can do is make observations and rough causal generations about them. What is the place for strong causal theory in biology, or are empiricism and very general notions of process enough?

An example from the early prime era in modern science is the 'atom'.  Matter was conceived as being composed of these unseen particles, that accounted for the weight and properties of chemicals, and whose movement accounted for the weight, temperature, and pressure in gases.  Similar kinds of issues related to electromagnetism: what 'was' it?

An important late 19th-early 20th century example had to do with the existence of 'ether' as the medium through which electromagnetic radiation moved.  Ether could not be seen or felt but wavelike radiation had to be waves in something, didn't it?  Late-century tests failed to find it (e.g., the famous Michelson-Morely experiment).  In well-known interchanges at the time, figures like Ernst Mach, Albert Einstein and Max Planck thought about and debated whether there was a 'real' underlying general 'fabric' of Nature or whether specific empirical data simply showed us enough, and trying to delve deeper was dealing in metaphysics.  Many felt that was simply not justified--measurement or empiricism was what science could hope for.  On the other hand some, like Einstein, were convinced that Nature had a universal, and real underlying reality of which measurements were reflections.  He felt that theory, and in this case mathematics, could reveal or even 'intuit' Nature's underlying fabric.  An interesting article by Amanda Gefter in Nautilus science magazine deals with some of this history, with useful references.

So what about biology?
Biology had been largely a descriptive or even theological field before it became a modern science. But then came Darwin and his idea of evolution.  He viewed natural selection as a kind of Newtonian universal force.  Was it a type of explanation fitted simply around the empirical data that had been collected by Naturalists, or did it constitute some form of universal theory of life as Darwin asserted? Selection as a force had to work through some 'medium' or elements of inheritance.   His causal elements ('gemmules') were (like Lamarck's before him) entirely invented to 'fit' what was being observed about the evolution of diversity.  Indeed, he modeled natural selection itself after intentional agricultural selection because the latter could be demonstrated by human intent, while the former was generally far too slow to observe directly.  But there had to be some 'units' of inheritance for it to work, so he essentially invented them out of thin air.  Even in the early 20th century, 'genes' (as they became known) were largely hypothesized units for whose physical nature--or even reality--there was only indirect empirical evidence.

Assuming these discrete causal particles could enable the force, natural selection, to work on adaptive change was much like assuming that electromagnetic radiation needed ether to do its job.  Since differential reproductive success is observable, one can always define it to be the result of selection and to assume some gene(s) to be responsible. The test for relative success is, after all, only a statistical one with subjective decision-making criteria (like significance level) in empirical data.  In that sense, natural selection is a very  metaphysical notion because after the fact we can always empirically observe what has succeeded over time, or what functions have evolved, and call that the result of selection.  Such an explanation can hardly be falsified.  What is the reality of the underlying force, that Darwin likened to gravity?  Since it is always dependent on changing local conditions, what sort of a 'law' is it anyway?  And if it's basically metaphysical, should we reject it?

Mendelian genetics as metaphysics
If selection is a process, like gravity, it had to work on objects.  Because individual organisms are temporary (they all die), the objects in question had to be transmitted from parent to offspring.  That transmission was also found, by Mendel's experiment, to be a regular kind of process.  Mendel's causative 'elements', that we now call 'genes', appeared in his carefully chosen pea experiments to be transmitted as discrete things.  They fit the discretely causative world of the energized new field of atomic chemistry (see my Evolutionary Anthropology article on Mendel), with its idea that a chemical is made up of a particular kind of atom (thought by some to be multiples of hydrogen at the time), and Mendel's statistical tests showed a reasonably good fit to that discrete-unit worldview (indeed accusations that he or his assistants cheated may reflect his acceptance of discrete underlying but unseen and hence metaphysical, elements). But what were these genes?  In what serious sense did they exist as things rather than just an imaginary but essentially unconstrained variables conjured up to account for actual observations--of some sorts of inheritance, that of discretely varying traits--whose actual nature was entirely inaccessible?

These questions became very important in the debate about how evolution worked, since evolution required inheritance of favored states.  But what Mendelian analysis, the only 'genetic' analysis available at the time, showed was that the causal genes' effects did not change, and they only were shown to fit discretely varying traits, not the quantitative traits of Darwinian evolution.  For these reasons even many mainline evolutionary biologists felt that genes, whatever they were, couldn't account for evolution after all.  Maybe geneticists were indulging in metaphysics.

This was similar to the situation that engaged Einstein, Ernst Mach, and others about physics, but when it came to biology, the difference between empiricism and metaphysics became, literally, quite lethal!  The tragic impact of Profim Lysenko in the Soviet Union was due to a direct rejection by the scientific power structure that he established based on promises of rapid adaptation in plants, for example to the long, frozen Soviet winters, without adaptive 'genes' having to arise by evolution's slow pace.  As I summarized in another Ev. Anth article, it was in part the alleged 'metaphysical' nature of 'genes' in the early 20th century that Lysenko used to reject what most of us would call real science, and put in place an agricultural regime that failed, with mortally disastrous consequences. Along the way, Lysenko with Stalin's help purge many skilled Soviet geneticists, leading many of them to tragic ends. The mass starvation of the era of Lysenkoist agriculture in the USSR may in part have been the result of this view of theoretical science (of course, Lysenko had his own theory, which basically didn't work as it was as much wishful thinking as science).

But how wrong was it to think of genes as metaphysical concepts at the time?  Mendel had showed inheritance patterns that seemed to behave, statistically, as if they were caused by specific particles. But he knew many if not most traits did not follow the same pattern.  Darwin knew of Mendel's work (and he of Darwin's), but neither thought the other's theories were relevant to his own interests.

But in the first part of the 20th century, the great experimental geneticist TH Morgan used Mendelian ideas in careful breeding experiments to locate 'genes' relative to each other on chromosomes.  Even he was an empiricist and avowedly didn't really deal with what genes 'were', just how their causal agency was arranged.

Mendel's work also provided a research experimental approach that led via Morgan and others to the discovery of DNA and its protein coding sequences.  We call those sequences 'genes' and research has documented what they are and how they work in great detail.  In that sense, and despite early vague guesses about their nature, for most of a century one could assert that genes were in fact quite real, not metaphysical, entities at all.  Not only that, but genes were the causal basis of biological traits and their evolution!

But things have turned out not to be so simple or straightforward.  Our concept of 'the gene' is in rather great flux, in some ways each instance needing its own ad hoc treatment.  Is a regulatory element a 'gene', for example, or a modified epigenetic bit of DNA?  Is the 'gene' as still often taught in textbooks still in fact largely a metaphysical concept whose stereotypical properties are convenient but not nearly as informative as is the commonly presented view, even in the scientific literature?

Are we still resting on empiricism, invoking genetic and evolutionary theory as a cover but, often without realizing it, fishing for an adequate underlying theory of biological causation, that would correspond to the seamless reality Einstein (and Darwin, for that matter) felt characterized Nature? Is the gene, like Procrustes, being surgically adapted after the fact, to fit our desired tidy definition?  Is claiming a theory on which genetic-based predictions can be 'precise' a false if self-comforting claim, as a marketing tool by NIH, when in fact we don't have the kind of true underlying theory of life that Einstein dreamed of for physics and the cosmos?

We'll deal with that in our next posts.

Metaphysics in science, Part V: Is 'risk' real or metaphysical?

Metaphysical ideas imposed on the world as if they were derived from the world go against the nature of modern science and bear similarity to a long-standing but rejected idea about how we understand existence.  We've discussed some facets of these issues, from the point of view of modern evolutionary and genomic sciences as we see them, and to provoke thought (but not as professional philosophers or historians of science, to which we make no claim!).

Here we want to conclude by considering these issues related to an aspect of causation that we've dealt with in a previous series of posts, when causation and in applied areas the notion of 'risk', are probabilistic.  Are these metaphysical concepts in any important sense, or are they just plain-vanilla and not-misleading conveniences, like our use of the term 'the human genome' to represent something that really doesn't exist but helps us understand what does exist?

Plato's cave: Wikimedia Commons

Plato's concepts, from his analogy of the cave that we have referred to, were that abstract ideals actually exist, but all we can experience of them are shadowy, imperfect manifestations.  In genetics, we only observe instances of the human genome, but there is no such thing as 'the human genome'.  This doesn't bother us a bit because we understand the usefulness of an arbitrary (that is, agreed-on) reference to organize our discussions of human genetics.

Ideas like 'chair' or 'dog' may not have Platonic reality, but again are very useful without being misleading, relative to real chairs or dogs.  In the case of dogs or genes, we even have very good, wholly material, empirical theories of population, that account for the collection of real-world objects to which we apply terms like 'dog' or 'gene'.  The population concept does not require the existence of some 'ideal'.

Plato also dealt with more elusive examples, like 'good'.  This is much less clear: does 'good' exist out-there in the meta-world with some reality of its own, or do we just observe instances of 'good' in the physical world? It's less clear than 'gene' or 'dog' because we haven't got a way to agree what 'good' is an arbitrary reference for.  'Good' is not a specifiable population of things.

But what about probability, say as expressed in terms of the 'risk' of getting a given disease if you carry a specific instance of some named gene?

Statistical causation: what kind of reality?
As we outlined in our series of posts on probability, the concept isn't always clear. When we speak of the probability of a given variant, say one of the two copies of a gene that a person has, being transmitted to a given offspring, what do we mean?  We mean that in a long series of producing offspring, each copy will be transmitted to an offspring the same fraction of the time.  That's a frequency interpretation.  We have purely materialistic notions of how the molecules (DNA) randomly buzz around the nucleus of the sperm or egg precursor cell, and one of the two just happens to end up in a given sperm or egg cell.  Neither copy has an advantage--that's a functional interpretation of probability.

In these instances, all we actually see are manifestations of the transmission of genes from parent to offspring.  So in a sense, the 'probability' is a purely metaphysical concept: it exists in our heads whether or not anybody ever produces an actual offspring.  In some ways the functional or frequency interpretations don't really matter, but in other ways the metaphysical nature is troubling. That's because we can only test its reality by experience and experience--even if our very  notion of probability is correct--never precisely realizes the expected result!  For example, the probability of your transmitting variant A to your next child may be 50%, and that may be as 'true' as true can be.  But if you only have one child, it either received the A or it didn't.  Further, in some sense (e.g., diploid organisms) we believe that the Mendelian process is universal.  The cave-wall manifestations of shadows of metaphysical truths simply cannot tell you the truth!

So we have other ways to view probability concepts about the world.  One is called 'likelihood', and it's used to say if our metaphysical idea that there is a true probability of transmitting an A to any given child is right, then what do the actual data tell us is the most likely value of that probability?  Again, we're playing around with notions of truth.  But if we believe--and 'believe' is the right word here--that genetic transmission works this way, we can learn from experience about it.  This and other statistical ways of dealing with the probabilistic world reside largely in belief about what might be true in the world, rather than direct proof of what's true. But even in this case we believe that one of the alternatives we are considering is actually true!  But is that not itself a metaphysical statement?

There is a danger in this and it seems to relate to the reason metaphysics was strongly rejected in the age of modern science, beginning around 400 years ago.  The danger is that we can assume that ideas in our heads are real, yet nothing other than actual experience can tell us if we're right.  So, instead, the new scientific method said, why not rely entirely on experience?  Let experience show us what the truth is.  After all, we want our ideas to enable us to predict future experiences, things not yet observed.  That's what scientific theory is all about.  As long as our theory is actually about reality, rooted in experience, this seems to work rather well, at least in practical terms.

Let's look at another example that we referred to earlier in this series.  What is the 'probability' that a human with curly hair and agile thumbs will evolve from monkey stock?  This is not about frequency of events in any useful sense; it's about something-or-other regarding things that might have happened.  (We did, in fact, evolve, but we could ask the similar question, like "what is the probability that a  4-fingered, 6-toed language-speaking fully aquatic primate will evolve?")

These really are basically metaphysical questions.  What is the chance that human-like life exists on other planets (something we've discussed earlier, as well, in posts about 'infinity')?  Such questions seem to be about reality, but hardly are because the answer requires a numerical value ('chance', between 0 and 1) and there is no serious way of finding out the value, much less whether it's true, much less whether the idea that some such value there actually exists is itself correct.

As we've said in this series, metaphysics is vulnerable to beliefs not clearly shown by reality.  Religious assertions are often accused of this fundamental fallacy.  But scientific assertions clearly are also vulnerable in this way, because unlike religion, science is purported to be strictly about the real, material world.  Yet, we believed Isaac Newton--clearly a modern scientist--until Einstein came along.  So, when probabilistic causation is important, or seems to be the case, we are very vulnerable.  What should we 'believe'?

To bring things back to earth, so to speak, these issues arise in full dress when it comes to interpreting genomics and in inferring genetic causation today and in evolution.   The promises made of individual life-experience prediction from genomes sequenced at birth, or that GWAS or biobank whole genome sequence will do that, or enable all known human ills to disappear, are examples.  They are based not just on what are largely metaphysical notions about causation, and when this is admitted to be probabilistic, about predicted outcomes.  This is treated as if in the functional or frequency sense of probability, but the evidence is really clear that this is only mildly accurate.  The point is that while advocates freely admit that we're not there yet, they believe that accurate--indeed perfect?--prediction is possible in principle. 

When traits like the objects of GWAS and other 'omics are due not just to practicably countless contributing factors, some genetic and perhaps identifiable but others not known, but each of them somehow working only probabilistically, then we are more squarely in the metaphysical world.  The probabilities now are really not of the frequency or even functional sort, except very abstractly.  They are more of the belief sort.  The same statements apply to many aspects of inferences made about how evolution has worked, and in particular, stories offering adaptive genetic explanations for traits seen today.  Those, too, are probabilistic in the belief sense ("it seems likely that upright-walking hominids were able to compete to secure food from .....").

It is not just a belief that no immaterial forces intervene in genetic causation, say, of a disease.  It is that if we knew everything, everything could be predicted.  But there is no way to replicate unique events, like individual genomewide genotypes and all environmental experiences, we can never actually know how true this is.

Yet, and here is where we think people are dabbling in metaphysics when doing this kind of genetics: the belief system is so strong that it goes beyond an assertion that we just don't yet have adequate evidence, but actually goes against the evidence, which in the face of probabilistic complexity is already generally quite weak.  It becomes, as we have said, imposing metaphysics on the real world, rather than the other way around.  And this then can be very misleading to science and the distribution of limited resources we have to understand the world.  It again becomes an obeisance of belief, or the exact opposite of science--a form of denial: again, it is the zen of genomics, when No means Yes.

What is metaphysical?  What can we hope actually to know?
Metaphysics as we use the term in this series is the Platonic ideal that truth does exist somehow, and all we see is approximate manifestations of it.  Science claims to have rejected that notion.  We've seen examples where metaphysical abstractions still used in science are not particularly damaging. 
But in genomics we are seeing something that was predictable (and predicted) for the right reasons decades ago--complexity is the rule, but people still want traits to parse simply.  It is the investigator as an ostrich, hiding from the very truth he claims dedicated to find.  It is the assumption of higher-level truth, in some ways thumbing one's nose at the evidence.

Coming full circle: when is a finding a 'finding'?
We return to where we began in this series, the assertion that unless you find some hoped-for, dramatic, simple tractable result, you haven't made a 'finding'.  This attitude is such a shallow shadow of any semblance of an understanding of the nature of reality and our understanding of it, that we think it's not too much of a stretch to say that it poses a threat to society.  That's because overly Platonic views of the world are misleading, divert resources, can lead to awful conflicts, and so on, as history very clearly shows.

Again, Plato provided a metaphysical view of existence.  Ideas about things were real, and things themselves were, in some sense, not as real.  Philosophers have sliced and diced these ideas over the centuries, in many sophisticated ways.  Metaphysics grew from being rather central to humans (in western cultures, at least) trying to make sense of the world, to an airy-fairy world that scientists love to sneer at.  But do we not much more, and much more culpably, indulge in implicit Platonic metaphysics than we care to admit?

Many philosophers have dealt with the difference between the real, empirical world we can touch and smell, and the world our neurons construct within our heads.  From Aristotle and solipsists in classic times, to Kant and many others, the issue of how or whether our limited sensory apparatus and brain can actually and truly know anything other than itself has been an open one for philosophizing.  And of course there are the works of countless religious thinkers about the nature or even existence of  'things' and non-things.

Here, we're not dabbling in such ultimates, nor are we qualified even to summarize the centuries of sophisticated thought about those issues--nor, for that matter, the thoughts of poets and artists whose work deals directly with them.  We are simply assuming there is a reality 'out there', and that the interest of science is in how to understand it, both pragmatically and ultimately.  Our context is genetics and evolution, not whether neutrons outrace light or electrons exist in fixed locations and all that.

But life goes beyond ordinary physics in which, anywhere at all, every oxygen molecule is alike and all photons speed equally through vacuums.  Physics and chemistry are comfortable with concepts about collections of such identical things, as abstractions representing tractable realities whose collective behavior follows nice principles, or laws. Even when they are probabilistic, as in describing the pressure of a gas in a container, when this is due to random buzzing of huge numbers of identical objects.  Pressure is empirical as a pragmatic stand-in for practically assessable instances.  But it's metaphysical to the extent of the assertion that 'it', whatever it is, exists uniformly, eternally, and ubiquitously.

But evolution is not about the collective and eternal behavior of identical items, but instead is inherently about variable, ephemeral ones--from genes on up to ecosystems.  We cannot assert identity in the way a chemist does, because the entirety of the life sciences is in a meaningful sense about variation.

This means that elusive issues like emergence or statistical causation, by individually unique collections of elements, isn't really like physics (even if all the elements, like you and us and globin genes and genomes, ultimately follow physical and chemical principles).  It is the organization of life that's different in the sense we're considering.

One can argue that making assumptions about that organization, when it does not have specific, replicable instances, verges on Platonic metaphysics, and goes beyond convenient pragmatism.  It is like asking whether 'good' exists.  The danger is not that we have things we profoundly don't understand, even deep concepts like probability when we cannot confirm it in any actual way.  The danger is that we really do indulge in metaphysics in the guise of science, by being immune to the messages that the real world, when it is not just instances like shadows on a cave-wall, sends us.

In a way, that has always been the deepest problem with metaphysics: it is not sufficiently constrained by reality. Yet of all fields of human endeavor, science should try very hard to understand the real world, not the ideal world or the wished-for world.  Instead, of the current kind of metaphysics, we should be out in the sun where the truth, as well as is shadows can be seen.  But things can be more comfortingly simple in the cave--the cave of denial of evidence.  Like the original cavemen, perhaps we prefer the comfort of the dark.   At least, to a great extent, for convenience and self-interest, even some scientists are staying in the cave on purpose.

We may respect Plato, but we should not become neo-Cavemen!

A request for comments by those who know!
We have said many times in this series, that we are not professional historians or philosophers of science, and that we are using terms--especially, 'metaphysics'--in a particular restricted sense.  We also know of the existence of a vast literature over 2500 years on aspects of the subject.  But we've only read, or dabbled, really, in a tiny fraction of that literature.  So if there are any MT readers who are expert in these areas, we'd be happy to have commentary that constructively addressed the issues, as we have raised them, or to add to or modify what we've attempted to say.

Metaphysics in science, Part IV. When causation is complex, what is it? Real or metaphysical?

This series has dealt with what it means to be scientific but not metaphysical, whether in a sense science has not really abandoned its ages-long flirtation with ideas imposed on the world rather than the world determining our ideas.

In previous posts we dealt with metaphysical notions like 'the human genome' or 'the globin gene', which do not really imply the actual existence of Platonic ideals, and serve mainly as pragmatic guides for our understanding of the world and the practice of science.

We then addressed why, whether, and how failure of data to replicate a theory should lead us to abandon it.  If it doesn't, then the theory is in a way shown to be a Platonic ideal assumed to be true rather than the kind of empirical truth we supposedly are seeking in science.  We mentioned a couple of examples in which Darwin held to his theory, correctly believing the overall evidence overriding mistaken notions of genes, but also imposed his theory on data as in making what amounted to 'progressive' theories of evolution when he studied barnacles.

Then we asked why GWAS and related omics, that did not find the expected, and promised, high accounting for important diseases, has not led to an abandonment of the underlying theory about major-gene causation, and whether that showed that for whatever set of reasons, metaphysics was driving our material assessment of the world of genetics and evolution.  These are all real and, we think, important issues that are rarely addressed by scientists. 

However, there are other issues that are important and we'd like to comment on two of them.  They are complexity, and statistical causation.  Here, we discuss the first of these two issues. 

Complexity and emergence: what are they?
So far in this series, we've considered rather simple theories:  A gene exists.  It codes for protein or its regulation in cells.  Antibiotic resistance results from genetic variants rising in frequency if they help the organism surmount the lethal challenge.

We've seen that these don't really seem to pose any serious systematic or fundamental threat to the notion that we can express our understanding of  the world in such abstract terms.

But what about when the theory gets more complex, when, say, many different factors interact to contribute to a single net result?  The net result, like a building, is sometimes called an 'emergent' phenomenon relative to the contributing components (bricks and steel beams).  That is, enumerating the components, or even studying them even down to the level of the atom, won't tell you much at all about the building itself.  What shape will it take?  How many stories will it be?  (We could estimate that by counting the bricks and beams, yes, but that won't be very precise.)  What's it going to be used for?  Who will use it?  Will the roof leak? 

Let's apply this to disease genetics.  Let's say that diabetes is the building, and many different genes and environmental factors the bricks and mortar.  We can't easily go forward or backward from here -- we can't reliably predict diabetes from the genes, and we certainly can't predict future environments, nor can we retrodict genes or environment knowing someone has diabetes.  In this instance, what kind of truth is an emergent phenomenon, relative to a material theory of the world?  Is it metaphysical in any way that should concern us?

If the result can't be predicted from the components, then more is going on than a list of those components.  The net result may be given a name, but this becomes more metaphysical than physical in some causal senses.  It's causally not so strictly utilitarian in the way 'the globin gene' guides us to study the instances of globin genes in actual people.

If every case of diabetes is due to a different set of causal factors, working and interacting in different ways in each instance, then diabetes is a different kind of reality, a somewhat metaphysical notion that exists independent of its assumed ordinary causality.  These are not just abstract philosophical questions, but in fact underlie our decisions about how to approach causation.  When our assumptions are unstated, and we don't think about why we're asking the scientific questions we ask, and designing the studies we design, our understanding of complex traits can easily become ensnared by their complexity, and this all becomes even more problematic if we assume we're looking at a simple trait. Even iron-clad ideas about causation, or the most appropriate uses of metaphysical convenience, can lapse into metaphysical vapor.

These are things you have to think about to grasp them, perhaps.  At least,  we do! If every instance is causally different so that we cannot enumerate the causes (because, for example, we need large samples or replications to show that they are really causes), then the emergent thing verges on a metaphysical ideal:  the trait may seem real enough, in our heads, but causally elusive in the world.  It is an assumption that it is a causally unitary....what?  It is too easy to assume its reality and force that onto assuming that if we but have big enough studies, or whatnot, we will be able to treat it by the usual reductionist methods (enumerating its causal bricks), when that may not be its reality as far as the current scientific method is concerned.  That is the 'emergence' problem, and we're not very good at solving it.  Instead, we wish it away through metaphysical ideals.

One strongly problematic aspect of all of this is related to, but goes far beyond, complexity and arbitrary agreed-on working definitions.  It is how we view probabilistic 'causation', to which we turn next.

Metaphysics in science, Part III. It's there because I say it's there....and I must be right!

This series is about the nature of reality and what is loosely referred to as metaphysics, the idea of reality above, apart from, or somehow different from material, real reality.  When abstractions about things of this sort, like 'the human genome,' are understood as no more than practical working baselines, there may be no problem.  But when what we have in mind, so to speak, are processes or theories rather than things, the situation is far less clear.

What is the reality of a theory?  When is a theory an assertion....or a belief?
A theory in our context is a general principle or 'law' of nature of some sort.  The theory of gravity states that objects have specific quantitative relationships with each other, that are universal no matter what the objects are or where they are--in the entire universe!  We may have a difficult time falsifying a theory like that, because if there is even one single minor exception that would show the theory is not literally true, we may never come across that exception.

On the other hand, there are so many direct tests, experimental and otherwise, of such a theory, that we have very good reason to believe it. At that point the theory is accepted as an abstraction of reality, essentially in some Platonic sense.  All we can directly see are specific manifestations of the theory, but we assume in essence that every single possible instance would obey the theory--even instances that have not yet arisen.

If a theory is just an approximation, what's it an approximation of?
In some instances we agree that the theory is an approximation of reality, at least insofar as we can measure it.  Thus, we may not know the exact speed of light, but we assume there is such a speed, whether or not we can measure it perfectly, and that this speed--this ultimate limit--somehow exists above and beyond any instances we might observe.  So even our imperfect measures are, in a sense, given metaphysical meaning.  They tell us about the real speed limit.

The human genome sequence may be an easily recognized abstraction rather than any sort of metaphysical (in the sense of unreal or mystical) view of existence.  But the speed of light is rather different.  So, what about the theory of evolution and, in particular for our purposes, the theory that it is due to divergence from common ancestry as a result of natural selection?

Darwin used barnacles, among other groups, to argue for these points. He found shared traits among different types of barnacles, and shared traits between barnacles and crustaceans.  He compared the organization of their bodies, their segments and so on.  He reconstructed an hypothetical ancestor based on the idea of common ancestry.  There is no problem about his reasoning from instance back up to principle.

Among the traits he studied were the various aspects of sexual reproduction among barnacle species.  In particular, the differences between separate sexes, females with separate but dependent degenerate males (well, most males are degenerate, you might say!), and those who were complete hermaphrodites (both sexes in one animal).  He inferred this as being due to selection clearly showing that he meant this to reflect instances of the concept (and we can ask if it is metaphysical) that applies more broadly.

But he also inferred, at least implicitly in what we're familiar with, that barnacles with partial hermaphrodism were on the way to complete hermaphrodism.  His reasoning was that he's seen some modern hermaprhodites, and these intermediates could be seen as....intermediates!  That builds into an instance, his metaphysical or Platonic ideal. Rather than the instance showing the idea, in the way your genome is an instance of 'the human genome', Darwin imposed the theory onto the data.  That, in many ways, makes it fundamentally metaphysical, something science doesn't like to acknowledge.

Darwin knew that his idea of inheritance (called pangenesis) did not fit the data, and he wriggled about that, but it made problematic his theory of ubiquitous natural selection.  His estimate of the age of geological formations, such as the valley near his home in Kent, was far too old for what  astronomers were estimating.  But he stuck to his guns!  He believed he was right.  That in many ways is a commitment to metaphysical truth in the absence of the required evidence.

Then he extended this to human evolution, human racial variation, and our relationship to other modern primates.  We agree with Darwin in general, but not with the kind of racial hierarchy he invoked as being due to natural selection.  So we would say Darwin was extending his theory too broadly (some argue still today that in many ways there is a racial hierarchy--again raising the same kinds of issues about whether natural selection is a real 'law' or just something that can happen and that has to be shown separately in each case).

One might say he knew he was right about the process (the Platonic ideal of evolution?), and just that his measurements were wrong. But was he right about barnacles being 'on the way' to hermaphrodism?  Or about racial hierarchies?

If the truth is that all we have are instances rather than universal law, how can we know that?  How can we know whether our knowledge is incomplete or our ideas (our theory) is wrong?  Or, if we accept that theory may only be approximate, how can we know that, as opposed to the theory being simply wrong?

When and why should a theory be abandoned?
This raises the metaphysical question in a somewhat new way.  If a theory, like gravity or evolution, is truly universal, then that is somehow a metaphysical concept of which we can only see instances.  It seems a bit less clear than the idea of 'chair' accepted to stand for the various actual chairs that we see.

And in science other questions arise here.  We can look at an object and see if it is an instance of chair or not, because chair is a human-defined symbol.  But universal principles or laws of nature are human-discovered and their universality is effectively assumed as an ideal.  If we assume a theory, and don't find the evidence for it, when do we abandon it and admit we were wrong, and when do we just say that the evidence simply is still flawed?

We see the problem in areas we write a lot about here on MT: evolution and genetic causation.   GWAS attempt to identify 'the' genes responsible for a particular trait, with the clear if sometimes unstated expectation that it's tractable in the number of genes and rather stable, replicable, and quasi-deterministic (high predictability).  What that's not what's found--as is routinely the experience--then why don't we abandon the idea of simple causation, or that we can use enumerative approaches to find 'the' causes?  Why do we cling to the theory, the Platonic abstraction of causation, and demand larger, longer, more expensive studies to find the elusive truth?

One can quibble about the terminology we're using relative to professional philosophy, but this to us shows that even modern science, that sneers so readily at metaphysics, is very metaphysical at its core.  Vested interests, beliefs, hunger for simple or tractable theories, unstated appeal to satisfying theories in other sciences, and so on, as well as occasionally supportive evidence, all lead us to generalize from instances to theory by forcing the theory on the instances.

In this sense, as we often say, rather than siding with those who complain about its lack of dramatic results, that GWAS have not been a failure.  They've been over-done for many unjustified reasons, and will be over-done even more in the future, but these studies have shown that some of our deeply wished-for ideas about nature, our abstractions, our Platonic ideas, simply aren't that way.  But we don't want to hear that message, and certainly not to be accused of delving in metaphysics. So we cling to the theory even in the face of clear evidence that it's inaccurate at best--or we reinvent the theory so that we water down our criterion for calling effects 'major'.

Is this the Zen of genomics:  when No means Yes?
There are some relevant issues here that make the story less clear than we've stated.  They have to do with the real, or metaphysical, nature of 'emergence' or 'interactions', and we'll comment on that next time.