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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 II. Is that wrong?

What is the role of theory vs empiricism in science?  How do these distinctions apply to genetics?

Yesterday, we discussed some of the history of contesting views on the subject.  Much of the division occurred before there was systematically theoretical biology.  In particular, when creationism, or divine creative acts rather than strictly material processes, was the main explanation for life and its diversity, the issues were contended in the burgeoning physical sciences, with its dramatic technological advances, and experimental settings, and where mathematics was a well-established part of the science and its measurement aspects.


Around the turn of the 20th century, Darwinian evolution was an hypothesis that not even all the leading biologists could accept.  Inheritance was fundamental to any evolutionary view, and inherited somethings seemed obviously to be responsible for the development of organisms from single cells (fertilized eggs). Mendel had shown examples of discretely inherited traits, but not all traits were like that.  Ideas about what the inherited units were (Darwin called them gemmules, Mendel called them Elements, and hereafter I'll use the modern term 'genes') were simply guesses (or just words).  They were stand-ins for what was assumed to exist, but in the absence of their direct identification they were, essentially, only metaphysical or hypothetical constructs.


The cloak of identity had serious implications.  For example, evolution is about inherited variation, but genes as known in Darwin's time and most of the later 19th century didn't seem to change over generations, except perhaps due to grotesquely nonviable effects called 'mutations'.  How could these 'genes', whatever they were, be related to evolution, which is inherently about change and relative positive effects leading to selection among organisms that carried them?


Many critics thought the gene was just a metaphysical concept, that is, used for something imagined, that could not in a serious way be related to the empirical facts about inherited traits. The data were real, but the alleged causal agent, the 'gene', was an unseen construct, yet there was a lot of dogma about genes.  Many felt that the life sciences should stick to what could be empirically shown, and shy away from metaphysical speculation.  As we saw yesterday, this contention between empiricism and theory was a serious part of the debate about fundamental physics at the time.


That was more than a century ago, however, and today almost everyone, including authors of textbooks and most biologists themselves, asserts that we definitely do know what a gene is, in great detail, and it is of course as real as rain and there's nothing 'metaphysical' about it.  To claim that genes are just imagined entities whose existential reality cannot be shown would today be held to be not just ignorant, but downright moronic.  After all, we spend billions of dollars each year studying genes and what they do!  We churn out a tsunami of papers about genes and their properties, and we are promised genetically based 'precision' medicine, and many other genetic miracles besides, that will be based on identifying 'genes for' traits and diseases, that is enumerable individual genes that cause almost any trait of interest, be it physical, developmental, or behavioral.  That's why we're plowing full budget ahead to collect all sorts of Big Data in genetics and related areas.  If we know what a gene is then the bigger the data the better, no?


Or could it be that much of this is marketing that invokes essentially metaphysical entities to cover what, despite good PR to the contrary, remains just empiricism?  And if it is just empiricism, why the 'just'?  Isn't it good that, whatever genes 'are', if we can measure them in some way we can predict what they do and live to ripe old ages with nary a health problem?  Can't we in fact make do with what is largely pure empiricism, without being distracted by any underlying law of biological causation, or the true nature of these causative entities--and deliver the miraculous promises? The answer might be a definitive no!


The metaphysical aspects of genes, still today

In essence, genes are not things, they are not always discrete DNA sequence entities with discrete functions, and they are not independently separable causative agents.  Instead, even the term 'gene' remains a vague, generically defined one.  We went through decades in the 20th century believing that a gene was a distinct bit of DNA sequence, carrying protein code. But it is not so simple.  Indeed, it is not simple at all. 

It is now recognized by those who want to pay attention to reality, that the concept of the 'gene' is still very problematic, and to the extent that assertions are made about 'genes' they are metaphysical assertions, no matter how clothed in the rhetoric of empiricism they may be.  For example, many DNA regions code for functional RNA rather than protein.  Much DNA function has to do with expression of these coding regions.  Many coding regions are used in different ways (for example, different exon splicing) in different circumstances.  Some DNA regions act only when they are chemically modified by non-DNA molecules (and gene expression works exclusively in that way). Some of 'our' DNA is in microbes that are colonizing us.  And 'traits' as we measure them are the result of many--often hundreds or more--DNA elements, and of interactions among cells.  Each cell's DNA is different at least in some details from that of its neighbors (due to somatic mutation, etc.).  And then there is 'the' environment!  This is central to our biological state but typically not accurately measurable.


Some discussion about these issues can be seen in a report of a conference on the gene concept in 2011 at the Santa Fe Institute.  Even earlier, in 2007 when it seemed we had really learned about genomes, hardly suspecting how much more there was (and is) still to be learned, a review in Genome Research was defined in an almost useless way as follows: 

Finally, we propose a tentative update to the definition of a gene: A gene is a union of genomic sequences encoding a coherent set of potentially overlapping functional products. Our definition sidesteps the complexities of regulation and transcription by removing the former altogether from the definition and arguing that final, functional gene products (rather than intermediate transcripts) should be used to group together entities associated with a single gene. It also manifests how integral the concept of biological function is in defining genes.
Really?!  Is that a definition or an academically couched but empty kicking of the can down the road while seeming to be knowledgeable and authoritative?  Or is it simply so empty as to be risible?

There are many now who advocate a 'Third Way' that in a rather generic sense of advocating less dogma and more integrative and indeed innovative or integrative approaches.  But even this doesn't say what the Third Way actually is, though one thing for sure is that it's every Third Way member's favorite way of coopting the concept of biological causation as his or her own.  I'm being cynical, and I'm associated with the Third Way myself and believe that serious rethinking about biological causation and evolution is in order, but that doesn't seem to be too unfair a way to characterize the Third Way's characterization of mainline genome-centered or perhaps genome-obsessed thinking. At least, it acknowledges that we don't just have 'genes' and 'environment', but that biological causality is based fundamentally on interactions of many different kinds. 

DNA is basically an inert molecule on its own
In genetic terminology, DNA is basically an inert molecule.  That is, whatever you want to call genes act in a context-specific way, and this goes beyond what is known as cis interactions among local DNA elements (like regulatory sequences flanking coding sequences) along a given strand. Instead, genetic function is largely a trans phenomenon, requiring interaction among many or even countless other parts of DNA on the different chromosomes in the cell.  And often if not typically, nothing happens until the coded product--RNA or protein--itself is modified by or interacts with other compounds in the cell (and responds to external things the cell detects).

Beyond even that complexity provides comparable evolutionary or physiological complexity.  There are many, perhaps often also countless alternative biological pathways to essentially the same empirical result (say, height or blood pressure or intelligence).  These causally equivalent combinations, if we can even use the term 'causal', are many and un-enumerated, and perhaps un-enumerable.  The alternatives may be biochemically different, but if it they confer essentially no difference in terms of natural selection, they are evolutionarily as well as physiologically equivalent. Indeed, the fact is that every cell, and hence every organism is different in regard to the 'causal' bases of traits.  We may be able to define and hence measure some result, such as blood pressure or reproductive fitness; but to speak of causes as if they are individually distinct or discrete entities is still essentially being metaphysical. Yet, for various sociocultural and economic reasons, we seem unwilling to acknowledge this.

You might object by saying that in fact most geneticists, from Francis Collins down to the peons who plead for his funding support, are being essentially empirical and not indulging in theory.  Yes, they drop words like 'gene' and 'epigenome' and 'microbiome' or 'network' or 'system', but this are on or over the edge of metaphysics (speculative guessing).  Many who feed at the NIH (and NSF) trough might proudly proclaim that they are in fact not dealing with airy-fairy theory, but simply delivering empirical and hence practical, useful results.  They do genomewide mapping because, or even proudly declaring, they have no causative theory for this disease or that behavioral trait.  Usually, however, they confound statistical significance with formal theory, even if they don't so declare explicitly.

For example, most studies of genotypes and genetic variation relative to traits like disease, are based on internal comparisons (cases vs control, tall vs short, smart vs not-smart, criminal vs non-criminal, addictive vs sober, etc.).  They don't rest on any sort of theory except that they do implicitly identify entities like 'genes'.  Often this is so metaphysical as to be rather useless, but it is only right to acknowledge that these results are occasionally supported by finding an indicated 'gene' (DNA sequence element), whose manipulation or variation can be shown to have molecular function relevant to the trait, at least under some experimental conditions.  But this causative involvement is usually quite statistical, providing only weak causative effects, rather than in any clear sense deterministic.  We are enabled by this largely pure empiricism to argue that the association we saw in our retrospective study is what we'll see prospectively as causation in the future.  And we now know enough to know that when it seems to work it is (as, indeed, in Mendel's own time) it's only the simplest tip of the causative iceberg.

We are tempted to believe, and to suggest, that this 'gene' (or genetic variant, an even cruder attempt at identifying a causative element) will be predictive of, say, a future disease at least in some above-average sense. That is, even if we don't know the exact amount of associated risk.  But even that is not always the case: the associated risks are usually small and data-specific and often vary hugely from study to study, over time, or among populations.  That means, for example, that people--typically by far most people--carrying the risk variant will not get the associated disease! It may often do nothing when put into, say, a transgenic mouse.  The reason has to be context, but we usually have scant idea about those contexts (even when they are environmental, where the story is very similar). That is a profound but far under-appreciated (or under-acknowledged) fact with very widespread empirical support!


Indeed, the defense of pure empiricism is one of convenience, funding-wise among other reasons; but perhaps with today's knowledge all we can do if we are wedded to Big Data science and public promises of 'precision' genomic prediction.  When or if we have a proper theory, a generalization about Nature, we can not only test our empirical data agains the theory's predictions, but also use the theory to predict new, future outcomes with a convincing level of, yes, precision. Prediction is our goal and the promises (and, notably, research funding) rest on prediction, not just description. So, as Einstein (and Darwin) felt, an underlying theory of Nature makes data make sense. Without it we are just making hopeful guesses.  Anyone who thinks we have such a theory based on all the public rhetoric by scientists is, like most of the scientists themselves, confusing empiricism with theory, and description with understanding. Those who are thoughtful know very well that they are doing this, but can't confess it publicly.  Retired people (like me) are often less inhibited!

Or could there perhaps be another way to think about this, in which genetics as currently understood remains largely metaphysical, that genetics is real but we simply don't yet have an adequate way of thinking that will unite empiricism to some underlying global reality, some theory in the proper scientific sense?


Tomorrow we'll address the possibility that genetics is inherently metaphysical in that there isn't any tractably useful universal natural law out there to be discovered.

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.

Rare Disease Day and the promises of personalized medicine

O ur daughter Ellen wrote the post that I republish below 3 years ago, and we've reposted it in commemoration of Rare Disease Day, Febru...