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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.

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...