Mr Darwin's new science

In his recent, marvelous must-read book, Naturalists in Paradise, about the major explorers of the Amazon (Wallace, Bates, and Spruce), John Hemming quotes Alfred Wallace lauding Darwin's Origin of Species in a letter to fellow explorer Henry Bates, saying that "Mr. Darwin has created a new science and a new philosophy."

I am no historian of science by any means, but I think that there is substance in this grand characterization.  Prior to Darwin--taking him as representative and perhaps the most explicit spokesperson for the view--western science had viewed life as the result of one or more divine creation events.  The inanimate, physical universe was also created 'In the beginning', but as a law-like place.  At least, by Galileo and Newton and others, it had come formally to be seen as following universal mathematical principles.  The key, in my view, is the 'universal' aspect of this view of existence.

Later, with various scientists leading up to them, Darwin, Wallace and a few others saw life itself as also having arisen at some 'beginning', but a natural one, and as a process, having diversified thereafter to what is here today.  That process has come to be called evolution.  The idea from Darwin's time to now, with no evidence of serious challenge, as he said, all life today has descended from some beginning in 'a few forms or into one' following universal 'laws acting all around us'.  In asserting his view, in terms of laws, Darwin reflected his essentially explicit Newtonian viewpoint.

These 'laws' were, as specified by Darwin in the elegant last paragraph in his Origin of Species:

1. Growth with Reproduction
2. Inheritance
3. Variability 'from the indirect and direct action of the external conditions of life, and from use and disuse'
4. Resource-limited rates of increase leading to a struggle for life
5. Natural Selection, which led to divergence of Character and Extinction of less improved forms.

I often note my view that Darwin was a product of his times, that is, believing in 'laws' of Nature and a kind of determinism in evolution, and a poor sense of probabilism.  As I note in some recent posts, I think he held this view, expressed clearly in terms of barnacles, but I wonder what he would have said about primates and humans in particular, as recently mused about here.

We're now in the world of probabilism in science, with fundamental probabilistic notions (mutation, drift, quantum mechanics, and so on).  Darwin would certainly have understood the ideas, but I wonder what his view of the probabilistic aspects would be.  That they were just a nuisance on the 'real' selective signal?  That they challenged the idea of precise adaptation?  How would they have affected his analysis of barnacles, as we've discussed recently here?

But is evolution law-like the way physics is?  Physics' 'laws' are universals.  Yet evolution (including selection) happens probabilistically, in the context of specific local circumstances.  This seems at odds with Newtonian universality and its consequent determinism.  Is anything missing in our 'theory' of life and evolution, for example, that vitiates promises of 'precision' genomic medicine?  Or that could be used to derive such predictability?  Or is it just that such promises are Newtonian, and don't fit the evolutionary living world in which we live?

Mr Darwin (and some contemporaries, in particular Alfred Wallace) founded a new science, but we have to go beyond his times to understand where that science will, or should, take us.

The horseshoe crab and the barnacle: induction vs deduction in evolution

Charles Darwin had incredible patience.  After his many-year, global voyage on the HMS Beagle, he nestled in at Down House, where he was somehow able to stay calm and study mere barnacles to an endless extent (and to write 4--four--books on these little creatures).  Who else would have had the obsessive patience (or independent wealth and time on one's hands) to do such a thing?

      From Darwin's books on barnacles (web image capture)

Darwin's meticulous work and its context in his life and thinking are very well described in Rebecca Stott's compelling 2003 book, Darwin and the Barnacle, which I highly recommend, as well as the discussion of these topics in Desmond and Moore's 1991 Darwin biography, The Life of a Tormented Evolutionist.  These are easier, for seeing the points I will describe here, than plowing through Darwin's detailed own tomes (which, I openly confess, I have only browsed).  His years of meticulous barnacle study raised many questions in Darwin's mind, about how species acquire their variation, and his pondering this eventually led to his recognition of 'evolution' as the answer, which he published only years later, in 1859, in his Origin of Species.

Darwin was, if anything, a careful and cautious person, and not much given to self-promotion.  His works are laden with appropriate caveats including, one might surmise, careful defenses lest he be found to have made interpretive or theoretical mistakes.  Yet he dared make generalizations of the broadest kind.  It was his genius to see, in the overwhelming variation in nature, the material for understanding how natural processes, rather than creation events, led to the formation of new species.  This was implicitly true of his struggle to understand the wide variation within and among species of barnacles, variation that enabled evolution, as he later came to see. Yet the same variation provided a subtle trap:  it allowed escape from accusations of undocumented theorizing, but was so generic that in a sense it made his version of a theory of evolution almost unfalsifiable in principle.

But, in a subtle way, Mr Darwin, like all geniuses, was also a product of his time.  I think he took an implicitly Newtonian, deterministic view of natural selection.  As he said, selection could detect the 'smallest grain in the balance' [scale] of differences among organisms, that is, could evaluate and screen the tiniest amount of variation.  He had, I think, only a rudimentary sense of probability; while he often used the word 'chance' in the Origin, it was in a very casual sense, and I think that he did not really think of chance or luck (what we call genetic drift) as important in evolution.  This I would assert is widely persistent, if largely implicit, today.

One important aspect of barnacles to which Darwin paid extensive attention was their sexual diversity.  In particular, many species were hermaphroditic.  Indeed, in some species he found small, rudimentary males literally embedded for life within the body of the female.  Other species were more sexually dichotomous.  These patterns caught Darwin's attention.  In particular, he viewed this transect in evolutionary time (our present day) as more than just a catalog of today, but also as a cross-section of tomorrow.  He clearly thought that what we saw today among barnacle species represented the path that other species had taken towards becoming the fully sexually dichotomous (independent males and females) in some species today: the intermediates were on their way to these subsequent stages.

This is a deterministic view of selection and evolution: "an hermaphrodite species must pass into a bisexual species by insensibly small stages" from single organisms having both male and female sex organs to the dichotomous state of separate males and females (Desmond and Moore: 356-7).

But what does 'must pass' mean here?  Yes, Darwin could array his specimens to show these various types of sexual dimorphism, but what would justify thinking of them as progressive 'stages'?  What latent assumption is being made?  It is to think of the different lifestyles as stages along a path leading to some final inevitable endpoint.

If this doesn't raise all sorts of questions in your mind, why not?  Why, for example, are there any intermediate barnacle species here today?  Over the eons of evolutionary time why haven't all of them long ago reached their final, presumably ideal and stable state?  What justifies the idea that the species with 'intermediate' sexuality in Darwin's collections are not just doing fine, on their way to no other particular end?  Is something wrong with their reproduction?  If so, how did they get here in the first place?  Why are there so many barnacle species today with their various reproductive strategies (states)?

Darwin's view was implicitly of the deterministic nature of selection--heading towards a goal which today's species show in their various progressive stages.  His implicit view can be related to another, current controversy about evolution.

Rewinding the tape
There has for many recent decades been an argument about the degree of directedness or, one might say, predictability in evolution.  If evolution is the selection among randomly generated mutational variants for those whose survival and reproduction are locally, at a given time favored, then wouldn't each such favored path be unique, none really replicable or predictable?

Not so, some biologists have argued!  Their view is essentially that environments are what they are, and will systematically--and thus predictably--favor certain kinds of adaptation.  There is, one might quip, only one way to make a cake in a particular environment.  Different mutations may arise, but only those that lead to cake-making will persist.  Thus, if we could 'rewind the tape' of evolution and go back to way back when, and start again, we would end up with the same sorts of adaptations that we see with the single play of the tape of life that we actually have. There would, so to speak, always be horseshoe crabs, even if we started over.  Yes, yes, some details might differ, but nothing important (depending, of course, on how carefully you look--see my 'Plus ça ne change pas', Evol. Anthropol, 2013, a point others have made, too).


Others argue that evolution is so rooted in local chance and contingency, that there would be no way to predict the details of what would evolve, could we start over at some point.  Yes, there would be creatures in each local niche, and there would be similarities to the extent that what we would see today would have to have been built from what genetic options were there yesterday, but there the similarity would end.

Induction, deduction, and the subtle implications of the notion of 'intermediate' forms
Stott's book,  Darwin and the Barnacle, discusses Darwin's work in terms of the presumed intermediate barnacle stages he found.  But the very use of such terms carries subtle implications. It conflates induction with deduction, it assumes what is past will be repeated.  It makes of evolution what Darwin also made of it: a deterministic, force-like phenomenon.  Indeed, it's not so different from a form of creationism.

This has deeper implications.  Among them are repeatability of environments and genomes, at least to the extent that their combination in local areas--life, after all, operates strictly on local areas--will be repeated elsewhere and else-times.  Only by assuming not only the repeatability of environments but also of genomic variation, can one see in current states of barnacle species today stages in a predictable evolutionary parade.  The inductive argument is the observation of what happened in the past, and the deductive argument is that what we see is intermediate, on its way to becoming what some present-day more 'advanced' stage is like.

This kind of view, which is implicitly and (as with Darwin) sometimes explicitly invoked, is that we can use the past to predict the future.  And yet we routinely teach that evolution is by its essential nature locally ad hoc and contingent, based on random mutations and genetic drift--and not driven by any outside God or other built-in specific creative force.

And 'force' seems to be an apt word here.

The idea that a trait found in fossils, that was intermediate between some more primitive state and something seen today, implies that a similar trait today could be an 'intermediate stage' today for a knowable tomorrow, conflates inductive observation with deductive prediction.  It may indeed do so, but we have no way to prove it and usually scant reason to believe it.  Instead, equating induction with deduction tacitly assumes, usually without any rigorous justification, that life is a deductive phenomenon like gravity or chemical reactions.

The problem is serious: the routine equating of induction with deduction gives a false idea about how life works, even in the short-term.  Does a given genotype, say, predict a particular disease in someone who carries it, because we find that genotype associated with affected patients today?  This may indeed be so, especially if a true causal reason is known; but it cannot be assumed to be.  We know this from well-observed recent history: Secular trends in environmental factors with disease consequences have indeed been documented, meaning that the same genotype is not always associated with the same risk.  There is no guarantee of a future repetition, not even in principle.

Darwin's worldview
Darwin was, in my view, a Newtonian in his view.  That was the prevailing science ethos in his time.  He accepted 'laws' of Nature and their infinitesimally precise action.  That Nature was law-like was a prevailing, and one may say fashionable view at the time. It was also applied to social evolution, for example, as in Marx's and Engels' view of the political inevitability of socialism.  That barnacles can evolve various kinds of sexual identities and arrangements doesn't mean any of what Darwin observed in them was on the way to full hermaphrodism or even later to fully distinct sexes...or, indeed, to any particular state of sexuality.  But if you have a view like his, seeing the intermediate stages even contemporaneously, would reinforce the inevitabilistic aspect of a Newtonian perspective, and seemingly justify using induction to make deductions.

Even giants like Darwin are products of their times, as all we peons are.  We gain comfort from equating deduction with induction, that the past we can observe allows us to predict the future.  That makes it comfortingly safe to make assertions, the feeling that we understand the complex environment in which we must wend our way through life.  But in science, at least, we should know the emptiness of the equation of the past with the future.  Too bad we can't seem to see further.

Darwin the Newtonian. Part IV. What is 'natural selection'?

If, as I suggested yesterday, genetic drift is a rather unprovable or even metaphysical notion, then what is the epistemological standing of its opposite: not-drift?  That concept implies that the reproductive success of the alternative genotypes under consideration is not equal. But since we saw yesterday that showing that two things are exactly equal is something of a non-starter, how different is its negation?  

Before considering this, we might note that to most biologists, those who think and those who just invoke explanations, non-drift means natural selection.  That is what textbooks teach, even in biology departments (and in schools of medicine and public health, where simple-Simon is alive and well). But natural selection implies systematic, consistent favoring of one variant over others, and for the same reason.  That is by far the main rationale for the routine if unstated assumption that today's functions or adaptations are due to past selection for those same functions: we observe today and retroactively extrapolate to the past.  It's understandable that we do that, and it was a major indirect way (along with artificial selection) in which Darwin was able to reconstruct an evolutionary theory that didn't require divine ad hoc creation events.   But there are problems with this sort of thinking--and some of them have long been known, even if essentially stifled by what amounts to a selectionist ideology, that is, a rather unquestioning belief in a kind of single-cause worldview.

What does exactly not-zero mean?

I suggested yesterday that drift, meaning exactly no systematic difference between states (like genotypes) was so illusive as to be essentially philosophical.  But zero-difference is a very specific value and may thus be especially hard to prove.  But non-zero is essentially an open-ended concept and might thus be trivially easy to show.  But it's not!

One alternative to two things being not zero is simply that they have some difference.  But need that difference be specifiable or of a fixed amount?  Need it be constant or similar over instances of time and place?  If not, we are again in rather spooky territory, because not being identical is not much if any help in understanding.  One wants to know by how much, and why--and if it's consistent or a fluke of sample or local circumstance.  But this is not a fixed set of things to check.

Instead of just 'they're different', what is usually implicitly implied is that the genotypes being compared have some particular, specific fitness difference amount, not just that they differ. That is what asserting different functional effects of the variants largely implies, because otherwise one is left asserting that they are different....sort of, sometimes, and this isn't very satisfying or useful.  It would be normal, and sensible, to argue that the difference need not be precisely, deterministically constant, because there's always a luck component, and ecological conditions change.  But if the difference varies widely among circumstances, it is far more difficult to make persuasive 'why' explanations. For example, small differences favoring variant A over variant B in one sample or setting might actually favor B over A in other times or places.  Then selection is a kind of willy-nilly affair--which probably is true!--but much more difficult to infer in a neat way, because it really is not different from being zero on average (though 'on average' is also easier to say than to account for causally).  If a difference is 'not zero', there are an infinity of ways that might be so, especially if it is acknowledged to be variable, as every sensible evolutionary biologist would probably agree is the case.

But then looking for causes becomes very difficult because among all the variants in a population, and all the variation in individual organisms' experience means that there may be an open-ended  number of explanations one would have to test to account for an observed small fitness difference between A and B.  And that leads to serious issues about statistical 'significance' and inference criteria.  That's because most alleged fitness differences are essentially local and comparative.  In turn that means the variant is not inherently selected but is context-dependent: fitness doesn't have a universal value, like, say, G, the universal Newtonian gravitational constant in physics, and to me that means that even an implicitly Newtonian view of natural selection is mistaken as a generality about life. 

If selection were really force-like in that sense, rather than an ephemeral, context-specific statistical estimate, its amount (favoring A over B) should approach the force's parameter, analogous to G, asymptotically: the bigger the sample and greater the number of samples analyzed the closer the estimated value would get to the true value.  Clearly that is not the way life is, even in most well-controlled experimental settings.  Indeed, even Darwin's idea of a constant struggle for existence is incompatible with that idea.

There are clearly many instances in which selective explanations of the classical sort seem specifically or even generally credible.  Infectious disease and the evolution of resistance is an obvious example.  Parallel evolution, such as independent evolution of, say, flight or similar dog-like animals in Australia and Africa, may be taken to prove the general theory of adaptation to environments.  But what about all the not dogs in these places?  We are largely in ad hoc explanatory territory, and the best of evolutionary theory clearly recognizes that.

So, in what sense does natural selection actually exist?  Or neutrality?  If they are purely comparative, local, ad hoc phenomena largely demonstrable only by subjective statistical criteria, we have trouble asserting causation beyond constructing Just-So stories.  Even with a plausible mechanism, this will often be the case, because plausibility is not the same as necessity.  Just-So stories can, of course, be true....but usually hard to prove in any serious sense.

Additionally, in regard to adaptive traits within or between populations or species, if genetic causation is due to contributions of many genes, as typically seems to be the case, there is phenogenetic drift, so that even with natural selection working force-like on a trait, there may be little if any selection on specific variants in that mix: even if the trait is under selection, a given allelic variant may not be.

Some other slippery issues

Natural selection is somewhat strange.  It is conceptually a passive screen of variation, but often treated as if an inherent property of a genotype (or an allele), whose value is determined on what else is in the same locus in the population.  Yet it's also treated as if this is inherent and unchanging property of the genotype...until any competing genotypes disappear.  As the favored allele becomes more common, its amount of advantage will increasingly vary because, due to recombination and mutation, the many individuals carrying the variant will also vary in the rest of their genomes, which will introduce differences in fitness among them (likewise, early on most carriers of the favored 'A' variant will be heterozygotes, but later on more and more will be homozygotes).  When the A variant becomes very common in the population, its advantage will hardly be detectable since almost all its peers fellws will have the same genotype at that site.  Continued adaptation will have to shift to other genes, where there still is a difference.  Some AA carriers will have detrimental variants at another gene, say B, and hence reduced fitness. Relatively speaking, some A's, or eventually maybe all A's, will have become harmful, because even in classical Darwinian terms selection is only relative and local.  So, selection even in the force-like sense, is very non-Newtonian, because it is so thoroughly context-dependent.  

Another issue is somatic mutation.  The genotypes that survive to be transmitted to the next generation are in the germ line.  But every cell division induces some mutations, and depending on when and where during development or later life a mutation occurs, it could affect the traits of the individual.  Even if selection were a deterministic force, it screens on individuals and hence that includes any effects of somatic mutation in those individuals.  But somatic mutations aren't inherited, so even if the mechanism is genetic their effects will appear as drift in evolutionary terms.  

Most models of adaptive selection are trait-specific.  But species do not evolve one trait at a time, except perhaps occasionally when a really major stressor sweeps through (like an epidemic).  Generally, a population is always subject to a huge diversity of threats and opportunities, contexts and changes.  Every one of our biological systems is always being tested, of in many ways at once. Traits are also often correlated with one another, so pushing on one may be pulling on another.  That means that even if each trait were being screened for separate reasons, the net effect on any one of the must typically be very very small, even if it is Newtonian in its force-like nature.  

The result is something like a Japanese pachinko machine.  Pachinko is popular type of gambling in Japan. A flurry of small metal balls bounces down from the top more or less randomly through a jungle of pins and little wheels, before finally arriving at the bottom.  The balls bounce off each other on the way in basically random collisions. The payoff (we could say it's analogous to fitness) is based on the balls that, after all this apparent chaos, end up in a particular pocket at the bottom.  In biological analogy, each ball can represent a different trait or perhaps individuals in a population. They bounce around rather randomly, constrained only by the walls and objects there--nothing steers them specifically. What's in the pocket is the evolutionary result. 

Pachinko machine (from Google images)

 (you can easily find YouTube videos showing pachinkos in action)

All similes limp, and these collisions are probably in truth deterministic, even if far too too complex to predict the outcome.  Nonetheless, this sort of dynamics among individuals with their differing genes of varying and context-specific effects, in diverse and complex environments, suggests why in this dynamic complex, change related to a given trait will be a lot like drift; there are so many that if each were too strongly force-like extinction would be more likely the result.  Further, since most traits are affected by many parts of the genome, the intensity of selection on any one of them must be reduced to be close to the expectations of drift. Adaptive complexity is another reason to think that adaptive change must be glacially slow, as Darwin stressed many times, but also that selection is much less force-like, as a rule.  After the fact, seeing what managed to survive, it looks compatible with force-like, straight-line selection.

Here, the process seems to rest heavily on chance.  But as we discussed in a post in 2014 in a series on the modes and nature of natural selection, we likened the course that species take through time to the geodesic paths that objects take through spacetime, that is determined (and there it really does seem to be 'determined') by the splattered matter and energy in any point it passes through.

An overall view

This leaves us in something of a quandary.  We can easily construct criteria for making some inferences, in the stronger cases, and testing them in some experimental settings.  We can proffer imaginative scenarios to account for the presence of organized traits and adaptations.  But evolutionary explanations are often largely or wholly speculative.  This applies comparably to natural selection and to genetic drift as well, and these are not new discoveries although they seem to be in few peoples' interest to acknowledge them fully.

Darwin wanted to show by plausibility argument that life on earth was the result of natural processes, not ad hoc divine creation events.  He had scant concepts of chance or genetic drift, because his ideas of the mechanism of inheritance were totally wrong.  Concepts of probabilism and statistical testing and the like were still rather new and only in restricted use.  Darwin would have no trouble acknowledging a role for drift.  How he would respond to the elusiveness of these factors, and that they really are not 'forces', is hard to say--but he probably would vigorously try to defend systematic selection by arguing that what is must have gotten here by selection as a force. 

The causal explanation of life's diversity still falls far short of the kind of mathematical or deterministic rigor of the core physical sciences, and even of more historical physical sciences like geology, oceanography, and meteorology.  Until someone finds better ways (if they indeed are there to be found), much of evolutionary biology verges on metaphysical philosophy for reasons we've tried to argue in this series.  We should be honest about that fact, and clearly acknowledge it.

One can say that small values are at least real values, or that you can ignore small values, as in genetic drift.  Likewise one can say that small selective effects will vary from sample to sample because of chance and so on.  But such acknowledgments undermine the kinds of smooth inferences we naturally hunger for.  The assumption that what we see today is what was the case in the past is usually little more than an assumption. This is a main issue we should confront in trying to understand evolution--and it applies as well to the promises being made of 'precision' prediction of genomic causation in health and medicine.  The moving tide of innumerable genotypic ways to get similar traits, at any time, within or between populations, and over evolutionary time, needs to be taken seriously. 

It may be sufficient and correct to say, almost tautologically, that today's function evolved somehow, and we can certainly infer that it got here by some mix of evolutionary factors.  Our ancestors and their traits clearly were evolutionarily viable or we wouldn't be here.  So even if we can't really trace the history in specifics, we can usually be happy to say that, clearly, whales evolved to be able to live in the ocean.  Nobody can question that.  But the points I've tried to make in this series are serious ones worth thinking seriously about, if we really want to understand evolution, and the genetic causal mechanisms that it has produced.

Genetics in an age of fundamentalism

I heard a program the other day on the BBC Radio 4's In Our Time about the origins, rise, and persistence of Chinese Legalism. Introduced in the 4th century BC, and the hallmark of the rule of the first emperor, the philosophy of Legalism was based on laws and their strict implementation.  It was the basis of a brutal, authoritarian state, elements of which have lasted 2500 years.

Here's one description (found here):

...Legalism is a Classical Chinese philosophy that emphasizes the need for order above all other human concerns. The political doctrine developed during the brutal years of the Fourth Century BCE. The Legalists believed that government could only become a science if rulers were not deceived by pious, impossible ideals such as "tradition" and "humanity." In the view of the Legalists, attempts to improve the human situation by noble example, education, and ethical precepts were useless. Instead, the people needed a strong government and a carefully devised code of law, along with a policing force that would stringently and impartially enforce these rules and punish harshly even the most minor infractions. 

                                                                                              L. Kip Wheeler 

To overly simplify, but I'm just trying to make a point, in Legalism, allegiance must be paid to the role of the ruler, rather than to a particular leader.  And, the system of rulership is absolute.  Further, Legalism views people as much easier to control if they are uneducated, and there's no sense in which they are expected to improve themselves.

In contrast, another ancient Chinese philosophy, Confucianism, was much more benevolent, with an optimistic view of human potential; people are basically good, and if taught new things they can be cultivated into better people.  Confucians see authority and leadership as something everyone has the potential to achieve, whereas in Legalism, the ruler dictates and people are expected to follow.

This contrast between people as good and improvable vs inherently evil, the absolute vs the relative, is of course a familiar dialectic, not at all restricted to philosophy of nation states.  Theism vs agnosticism,  laissez faire or free market vs regulation, the US Constitution as fixed or as flexible, cultural relativism vs universal human rights, free will vs predetermination, and of course tabula rasa or blank slate vs inherency, or nature vs nurture.

Confucius

The consistency with which people view the world in either absolute or relative terms is curious to me, and indicates that we aren't necessarily learning from observation, evaluating and interpreting the facts as we see them as we go about choosing our favorite economic system, or whether cultural practices that are alien to our own have any merit.  It seems instead that we've got an a priori view of the world that informs those decisions, an ideology that guides us in what turns out to be a fairly predictable direction.  In a loopy sort of way, those with an absolutist ideology would say that that ideology is genetic (and, indeed, that things like how we vote are genetic), while those with a relativist ideology would disagree, saying it's learned.

But at least our mythology about science is that it's supposed to be fact-driven, not ideological.  Often it is, though how do most people decide whether or not they accept that humans are driving climate change, or that all life evolved from a common ancestor?  Unless we're climate scientists or evolutionary biologists, we generally don't have the knowledge to evaluate the data in any meaningful way.  So these decisions become ideological.  In that sense, facts do not rule, not even in relation to science.

And what about the role of genes in making us who we are?  Ken and I have been sneeringly called "blank slaters" more than once, because we don't embrace the idea that who we are is determined by our genes.  The assumption is that if one doesn't accept that genes are always destiny, one must accept that they never are.

But, there's another way, and it's more subtle, and more nuanced, and that is to recognize that there's a continuum of gene action, from predictable to unpredictable.  Some alleles pretty reliably are associated with a given trait (alleles associated with Tay Sachs or cystic fibrosis), while others are not (APOE4 and dementia, HFE and  hemochromatosis).  With a few exceptions, specific genetic variants can't be predicted from most complex traits, and vice versa.  So, sometimes Legalism might be a good analogy for the relationship between genes and traits -- dictator, strong-arm genes -- and sometimes Confucianism; genes interacting with environment.  But there's also Daoism, another ancient Chinese philosophy, which taught that people were to live in harmony with nature, that government is unnatural, and that the best government is a weak government -- no dictator genes, mostly environment.

It used to be said that one's politics could be predicted from one's stand on genetic determinism, but determinism has become so pervasive that this is no longer true.  Atheist free-market constitutional modernist cultural relativist Bernie Sanders supporters are as likely to be genetic determinists these days as are, well, the opposite.  Determinism has become a pervasive ideology, and this despite a lot of evidence to the contrary.  Philosophers of science have long tried to define and describe how science is done, but I think fundamentally, while science is different from a lot of other human endeavors in that we do have ways of verifying that we're learning things, the role of ideology in what we think we've learned should not be underestimated.  And in many ways, it is heavily affected by emotions and by scientists' personal situations (careers, biases, and so on), even when they try to be 'objective'.  In recent decades, some 'science studies' work has clearly shown this (even if the practitioners have their own sociocultural axes to grind); given human nature, it should be no surprise. 

When did Lyndon Johnson propose the Great Society in the US?  It was in the mid 1960's, when we saw communism as a huge threat.  We reacted by becoming more like our 'enemy'.  Is it too simplistic to suggest that the same could be happening now, when our 'enemy' is religious fundamentalism?  

The visible colors: and the falseness of human races as natural categories

There is a constant tension between the tendencies to view the world in continuous vs discrete terms.  Even in science, this can be a problem, because a continuous view can lead to different interpretations than a discrete view.  Disputes about reality can arise, perhaps, over the distinction.  Is something a particle, or is it a wave?  Are the categories of a discrete view natural realities, or are they being imposed on Nature for some human reason?

The argument currently afoot has to do with how culpable it is to use genomic variation data to claim that there are a small number (usually stated as 5) major or primary human races, that blur at the intersections between them.  And, as commonly used software has it, those 'blurred' individuals are considered to be admixed between parents from the 'pure' races.

This is very misleading scientifically and, worse, unnecessarily so.  No analogy is perfect, but we can see the major issues using the example of color, which is often cited as comparable and showing the validity of the 'race' assertion (here, e.g.).  Color is the word we use for our sensory perceptions, the qualia, or psychological experience, by which we perceive light.  In physical terms, a given color is produced by light photons with a given energy level, with particular wavelengths or frequency (since light has a fixed speed, higher frequency means more waves pass by per second, and hence are shorter so they add up to the distance traveled in a second). From that point of view, here is the range of the colors to which the 'standard' human eye (that is, genotype) can respond, that is, a graphic portrayal of the wavelengths we detect:

The spectrum of visible light (wavelength in nanometers).  Wikimedia commons

The word 'color' refers to the qualia of perception, but we assign names to particular wavelengths, a cultural phenomenon based on our particular detection system. In those terms, visible light is a continuum of detectable wavelengths.  But traditionally, given that we are trichromat beings (with three distinct opsin genes, that is, whose three coded proteins each responds most efficiently to a different wavelength--see diagram below) we name three what we term 'primary' colors.  Each retinal 'cone' cell normally produces one of these opsin pigment proteins.  Each color of light that enters the eye triggers an appropriately weighted mix of red, green, and blue signals.  So for example pure
blue' frequency light basically only triggers a response from retinal cone cells that express the blue opsin gene product.

Basically, our ability to perceive any wavelength across the visible range is due to our brain's ability to mix the signal strength received from the retinal cells reporting its respective color activations. We often think of colors as being a mix of these primary colors, but there is nothing physically primary about them. They are artificial mark-points chosen by us because of our particular opsin repertoire.  One could choose other mark-points, and there need not be three (some species have fewer or more), and still perceive light in the entire visible (or even broader) wavelength range.  Various activities such as printing and the like have used different 'primary' colors (e.g., Google primary colors).   When we receive a mix of frequencies, our brain can sort out that mix and identify it.

What 'typical' human cone cells respond to.  Source: http://www.unm.edu/~toolson/human_cone_response.htm

In a sense, so long as you realize what is being done, there is no problem.  But if you think of the light-world as being inherently made of truly primary color categories, and of other colors as blurs in the edge of these categorical realities, then you are seriously misunderstanding the physical reality. First, the color spectrum reflects the color, as we perceive it, of single-wavelength radiation.  No individual wavelength is 'primary'.  Second, other colors are a mix of wavelengths that a trigger response by red, green, and blue opsins, and are synthesized (such as to be interpreted as 'pink') by the brain.

This is also a stereotype for two other reasons.  First, there is considerable variation among humans in the response characteristics of our opsins--the figure shows a typical response pattern for a reference blue, green, and red rhodopsin protein.  And of course a substantial fraction of people can't see some colors because they are missing one or more normally functioning opsin gene.  Secondly, the qualia, or what makes a given wavelength be experienced as 'blue,' is beyond current understanding, nor do we know that what you see as blue is the same as what I see as blue--even if we both have learned to call it 'blue'.  At present this is in the realm of philosophers, and causes a discussion--but no harm is done.

But that is not always the case.  Sometimes when falsely dividing a phenomenon into categories assumed to be true units rather than arbitrary reference points, with some rather unimportant blurs at the boundaries between the categories, the results of the error can be, literally, lethal.  This has been one consequence of the mis-use of theoretical misrepresentation of quantities as categories in human affairs.

Races are not like primary colors
We are writing this because there has been a recent resurrection of science that knowingly misrepresents the global distribution of human biological variation.  People are not photons, and we do not exist in 'primary' groups with blurred boundaries between them--any more than blue, red, and green are sacred and special points in the color spectrum.

We hear a lot of innocent-sounding talk about how one can argue for the existence of human 'races' as genetic, not just sociocultural, entities--but not be a 'racist'.  Yes, the argument goes, there is blurring at the edges, but the categories are real and they exist.

Human populations have long lived on different continents and some of our recent evolution as a species has taken place across great spans of distance, with geographic effects on the rates of gene flow over distance. Time and local geography, climate, culture, food sources, prey and predators and the like vary over space as well, and have in various ways led to adaptive differences among people, differently in different places.  Both cultural and genomic variation has accumulated around the globe.  But with few exceptions, such as truly isolated islands, genomic differences are correlated with geographic distance. 

Europe and Africa are not wholly discrete parts of the world.  The Americas may have been close to that, but only for about 10,000 or so years.  To assert that Europeans are genomically different from Africans, you must define what you mean by these categories.  Do you mean Italians are different from Egyptians?  Or do you mean Bantu speakers from South Africa are not the same as Norwegians?  This is important because with the same statistical methods of analysis, the same sorts of variation, if proportionately less in quantity, occur within these areas.  And had the analysis been done 1000 years ago, the major population of the world might be considered to be the Middle East, not Europe, because the decision of what are the major races, and what the admixed blurs would have been made by Islamic scholars, perhaps with some complaints by the high culture in India.   Choosing other populations as reference points ('parental' populations, or actual 'races')--Tahitians, Mongolians and South Indians, say, rather than the usual Africans, Europeans and Native Americans--would yield very different admixture statistics, because admixture programs are based on assumptions about history, not some inherent 'truth'.

So even those who want to stress differences, for whatever reasons, and who want to make assertions based on the several 'continents', themselves somewhat arbitrarily defined, have to be clear about what they are asserting--what they define as 'race', in particular.  This, of course, is made far more complicated by the 'admixture' that has occurred throughout known history of mass migration. Indeed, even the concept of 'admixture' itself requires specifying who is mixing with who--which in turn determines the outcome of admixture studies.

This sort of analysis has another aspect that is not properly understood.  The user chooses which and/or how many populations are considered parentals, of which other sampled individuals are admixed product.  These are statistical rather than history-based assumptions, using various sorts of significance criteria (which are subjective choices).  And, importantly, this type of analysis is based on alleles that were chosen for study because they are global--that is, the same variants are shared by the different  'races', just in different frequencies. Truly local variation is just that, local, so groups can't be compared in the same way.  Any sample you might choose to take will have lots of rare variants, found nowhere else.  So races in much if not most of the modern discussion, are groups defined in part because their frequencies of the same variants differ.  The genotypes in one 'race' can appear in others as well, but with lower probability.  If you want group-specific variants, you will usually find that they depend essentially on how you define the groups, and very rarely will everyone in a group that is more than very local have the purportedly characteristic variant.  A given genotype may be more likely in one pre-defined sample or group, but these are quantitative rather than qualitative differences largely based on local proximity.  Locally restricted variants can be important in adaptive traits, depending on the dynamics of history, and they can be exceedingly important, but they are generally far from characterizing everyone in a group or in defining groups.  People come into this world as discrete entities, but this is not how populations are generally constructed or evolve.

If we were talking about turtles or ostriches or oaks, nobody would care about these distinctions, even if there is absolutely no need to use such categories.  There are ways to represent human biological variation over space in more continuous terms, avoiding the obviously manifest problems with false, vague, or leaky categories of people, or making excuses for the 'blurring' at the edges, as if those blurred individuals were just no-accounts staggering around polluting the purity of our species!  Asserting the supposed reality of 'race', that is, of true categories on the ground rather than just in the mind, leads to all sorts of scientific problems and, of course, historically to the worst of human problems.

Does it make sense to ask whether members of 'the' European' race are taller than those in the African 'race'?  What part of Europe, and what part of Africa do you mean?  Ethiopia?  Nigeria?  Botswana?  Norway?  Greece? And does the person have to be living there now, or just have had all his/her ancestry from there?  And what about that 'his/her'?  Do we have to consider only living 'Africans' and 'Europeans', or can we use, say, skeletons from these 'races' from any time in the past (should be OK, if the trait is really 'genetic' since gene pools change slowly).  Or can we use Kazakhs or Saamis or Mbutis in our 'race' comparison?  Clearly we have to start refining our statements, and when that is the case even for societally rather neutral traits like stature, how much more careful need we be when we raise topics--as those who like to assert the reality of 'race' can't resist focusing on--with sociocultural or policy relevance (criminality, intelligence, addictability, reckless behavior, genes for ping-pong skill or running speed or being a violinist)?  Why do we need the categories, unless it really is a subterranean desire to focus on such traits to make a political point....or to affect policy?

At the same time, when scientists who think carefully and avoid this sort of categorical thinking, or even deny the reality of categories, or denigrate the idea that the categories are 'just' social constructs, they (the scientists) are denying what is an even greater reality.  That is that, for many people, 'race' is an entirely real category, one they experience on a daily basis.  If in the US you are 'black' or 'white' or 'Hispanic' or 'Asian' you are treated in a group-based way culturally.  If you have any phenotypically discernible African ancestry, for example, you may very well be treated as, and feel as if you were  'black', regardless of your ancestry fraction.  You may have some legal rights if you have at least 1/8 Native American ancestry, and for that and other reasons, you may know very well that 'race' does exist as a reality in your life.  This is inherently a sociocultural construct, and hence a reality.  In that very correct sense, the existence of 'race' is a scientific fact.

Scientists who acknowledge this but then continue to assert the genomic reality of race, essentially  because it is a convenient shorthand and because the bulk of data come from widely dispersed people, play into the hands of the ugliest aspects of human history, and given that history, which they know very well, they do so willingly.  Some even do it with great glee, knowing how it angers 'liberals'. One can speak of genetic (and cultural) variation having a geographic-historic origin that is (except for recent long-distance admixture) proportional to distance, and can think about local adaptations,  without using categorical race concepts.  Some may argue with what is genomic, what is the result of natural selection, and what is basically cultural. But there is no need to wallow in categories, and then  no need to try to define the 'fuzzy boundaries' between them.

Evolutionary genetic models as they are conventionally constructed contribute to the problem, because they are based on the frequency of genetic variants, and frequency is inherently a sample statistic. That is, frequencies are based on a population of inference, specified by the user.  A population is defined as if it had specific boundaries.  Natural selection is also modeled as if 'environments' were packaged in population-delimited ways.  For many reasons, it would be better if we developed less boxed-in evolutionary concepts and analysis, but that's not convenient if it takes time or means your book or grant can't just be dashed off without considering serious underlying issues like these, or if the hurried press likes to take whatever you say and make hay with it.

The use of 'primary' color category concepts is arbitrary relative to the actual color spectrum, but at least is based on our retinal genes, which in a natural way provide a convenient set of what are otherwise arbitrary physical reference points.  Nobody is disadvantaged by the use of those categories in human affairs.  But human populations are not in natural categories, categories are not needed, and they are not neutral relative to human affairs.

Like the light spectrum, there are not, and never have been 'primary' colors of humans.  What is true, however, is that when it comes to that topic, a lot of people cannot see the light.

Science and faith and Mussolini

By Anne Buchanan and Ken Weiss

We were in Italy for the last few weeks.  One of the things we did while there was to spend a few days at a lovely agriturismo in Tuscan.  On one of our walks, to the small village of Lucignano d'Asso, we came across this old barn still sporting a legend from the days of Mussolini.  

"La scienza, la volontà, la fede, possono attenuare gli effetti delle forze non benefiche della nature." (Science, will, faith, can attenuate the effects of the non-beneficial forces of nature.)

This is a statement of faith; with science, faith, and the will to do so, we will conquer nature.  This was part of the modernist time in history (we may still be in it), in which the idea of determined rationalism can improve our lot, as a replacement for blind religious-type faith.

Also part of that, and in line with Hitler, Mussolini was a believer in racial supremacy, of Italians and the Aryan 'race'.  This was more stridently evil at that time and place, but indeed in post-Darwinian science more generally, the belief was (is) that our essence (and our value) was built into our genes.  Society, being modern and hence rationale, could use science to alter nature at will, to make life better (at least, for the alterers in power).  This belief was held even though specific genes were not even identifiable at the time.  

A document reported to have been written by the Ministry of Popular Culture under precise instructions from Mussolini, and signed by 180 prominent scientists, called 'The Manifesto of Racist Scientists' ('Manifesto degli Scienziati Razzisti'), was published in the Giornale d'Italia on 14 July 1938.  Briefly, its 10 points were these (the full document, in Italian and English, is here):

1. Human races exist. This is obvious simply by observation. Racial characteristics are inherited, but the existence of races doesn't necessarily imply the superiority of any.

2. There exist large races (white or black) and small races ( i.e. Nordic or Mediterranean). Biologically, the smaller groups constitute the real races; this is just obvious. 

3. The concept of race is a purely biological concept. The Italians are different from the French, the Germans, the Turks, the Greeks, etc., not only because each has a different language and a different history, but because of different racial constitutions of these people. 

4. The majority of the population of contemporary Italy is Aryan in origin and its civilization is Aryan. 

5. The influx of huge masses of men in historical times is a legend. For the most part, the racial composition of today is what it has been for thousands of years.

6. There exists by now a pure "Italian race”, based on the ancient purity of Italian blood. 

7. It is time that the Italians proclaim themselves frankly racist.  The question of racism in Italy ought to be treated from a purely biological point of view, without philosophic or religious intentions.  This implies a great responsibility on the part of Italians.

8. It is necessary to make a clear distinction between the European (Western) Mediterranean races on one side and the Eastern [Mediterranean] and Africans, and Semitic and North African on the other. That is, Italians aren't African.

9. Jews do not belong to the Italian race and represent the only race that has never assimilated.

10. The purely European character of the Italians ought not to be altered in any way.

This was the foundation for the race laws that were enacted over the next five years in Italy, including stripping Jews of Italian citizenship and from positions in the government and many other professions, prohibiting Jews from employing Aryans, and so forth.  Italy had never been particularly anti-Semitic before this, but during World War II 10,000 Italy sent Jews to Auschwitz, 8,000 of whom were killed.  Mussolini was said to have boasted to his mistress in 1938, with respect to the notion that he learned his racism from Hitler, that he was a racist even before Hitler was born (odd that though, since he was only 6 years older than Hitler).

"I have been a racist since 1921. I don't know how they can think I'm imitating Hitler," Mussolini is quoted as boasting in August 1938. "We must give Italians a sense of race."

The idea was, of course, that some people are better than others.  The 'others' included those with inherent diseases that made them a burden on the better parts of society, or whose genes made them undesirable, such as by making them criminals, prostitutes, druggies, and so on -- as opposed to noble officials in our societies.  But it was not just the odd psychotic or gypsy here and there who were the burden, it was the societal load of the inferior groups, that is, less desirable races.

The classificatory approach:  truth, approximation, or illusion?
The expression of such beliefs was strident at the time, but the tenor is eerily current.  The idea (belief, fact -- even the choice of word here belies ideological underpinnings) that we can delimit races with genetics, that races are biologically definable categories, is very much with us again: it is again tolerable, if not in some quarters downright fashionable, to make such assertions.  It's even entrenched in the way that many apply the statistical methods that human geneticists often use to classify populations.  When a computer program (e.g., STRUCTURE) tells us there are 5 human races, why shouldn't we believe it?

Ken and Jeff Long wrote about this in a paper in Genome Research in 2009 ("Non-Darwinian estimation: My ancestors, my genes' ancestors").  The idea -- and it goes back very clearly to the eugenics era -- is that there are specific categories of humans (call them 'races' or, if you want to be politically correct, call them 'geographic populations') that exist, such that everyone is either a member of such a category or has admixed ancestry among them.  Ken has written several other papers on this subject (e.g., 'Racing around, getting nowhere', Evol. Anthropol., 14: 165, 2005).

The point in essence is that these admixture-based approaches assume 'pure' populations to actually exist now, or in the recent enough past.  The methods themselves can find such categories, and essentially define them in a statistical way.  That is, the methods can 'find' such groups even if they don't exist historically; this is an important point.

The authors of STRUCTURE and similar programs do not use them for racist purposes and include all the requisite disclaimers; but the use by many prominent investigators, and their interpretation by those for whom it is convenient, is as we discuss in this post.

It is obvious even to the most racist racist that not everybody in a given race is identical (despite the common unstated implication that they all may have some group-specific value, such as being more intelligent, athletic, musical, etc. than some other group).  But if a group is sealed off from other groups, and its members mate at random within the group, even if the very same variants are found, but at different frequencies, in other groups, the genetic profile (the frequency of variants at a set of measured genes, or in the whole genomes) of the group can be characterized statistically.  Then, if members of different groups move somewhere and mate, their offspring will be statistically seen to be a genetic mix, an admixture, of the two parental groups.

Leaving aside the technical details, if you take some samples from different places in the world and assume this admixture scenario, then your statistical program can find the parental and admixed groups, and estimate each person's admixture percentages.  But this will happen even if there are not and never were distinct sealed-off groups; that is, the analysis takes your assumptions and gives you a best answer to the nature of the groups.

Genomes are connected by history, so of course you are like your parents, and someone from another continent will resemble his/her parents (here we assume no long-range migration).  Extending this over history and space, you expect to find genomic differences across the continents.  But human history is such that populations have not generally been isolated so that they reflect the assumptions of admixture analysis, except in the very approximate way that your analysis simply reflects the differences that gradually accumulate with geographic distance.  People differ everywhere, and the differences are everywhere in the genome.  But our species is not evolved as packages sealed from other packages.

This is easy to see by computer simulation.  If you assume no packaging into discrete categories in the actual historical generation of human variation, but analyze samples of populations assuming that they do represent discrete populations and their admixed progeny, the analysis will give you an answer that is strictly the product of your assumptions and contrary to the actual history.  Ken and Brian Lambert showed this in a recent article ('What type of person are you? Old-fashioned thinking even in modern science', Cold Spring Harbor Perspectives in Biology).  

This reflects the problem with racial thinking that looks for differences (and, so often, differences in traits with societal value, like intelligence or criminality or political leanings).  Of course, because we evolved across wide time and space ranges, it is comparably wrong to assume or assert that there are no important geographically distributed differences.  Unfortunately, people looking at this subject take polarized stances about it.

Perhaps we will opine on the subject of race itself in some future posts, in a way that lays out the issues rather than taking a political stance (or using selective citation to take a non-PC racist view to get attention or sell books).  Part of the problem with the discussion of 'race' and many similar kinds of subjects that science can address in principle is that we become polarized, taking emotionally held belief systems that may (as in the case of 'race') take on and reflect inherently social or political positions.  The truth of climate change, or of evolution are other such areas. This is different from arguments among scientists about such detached subjects as the existence of life-bearing planets, or the evolution of 5-toed animals from earlier precursors. There can be strongly held debates about these things, but societal politics are not at issue.

Science as a way of knowing, but only one way of thinking
There is a very fine book by John Moore called Science as a Way of Knowing (Harvard Press, 1993), written by biologists who wanted to teach teachers how to teach what science is, by taking the evolution of biology from its classical origins to the present (of the 1990s).  The books is now a bit dated, but still it uses biology to lay out the way of thinking that is science, not as a way to the one and only truth, but as a method of approach to thinking about Nature.

The belief that if science says it, it must be true didn't disappear with the end of fascism, of course. For many, science has taken over from philosophy and religion as the source of truth in a material world.  Beliefs such as that with science we can avoid the disastrous effects of climate change or over-population or food insecurity or the end of fossil fuels, or that science will soon keep us alive for hundreds of years if not forever, are widespread.  They are based on assumptions about the nature of truth, about causation, and so on, but just as much about who is accepted as the authority figure when dealing with human problems.

As our son-in-law -- an Italian musician, philosopher, and historian -- said one day, as we were discussing these issues, "The biggest taboo is the absurd, because science has made it so."  Those of us who don't find our truths in religion tend to believe that science can and will make sense of the universe, from the subatomic to the cosmological.  And we assume that objectivity is possible and that there are singular objective truths to be discovered, that the cosmos is unitary in its material causation.

The cosmos could be unitary but even if it is, we forget that what we as humans take from science is based to a great extent on what we put in -- our assumptions, beliefs, chosen methods and ways of approach, and the questions we ask and how we frame them.  These are often very largely subjective rather than objective aspects of science.  Historians of science have clearly shown this to be true, regardless of the degree to which the underlying assumptions about the cosmos are correct.  We come to science with assumptions about how the world is -- the sun revolves around the earth, we can understand diseases by understanding single genes, or ideas about how humans should be classified -- and our assumptions define and color our results.

Red wine, resveratrol, and the credibility factor

On Tuesday we blogged about the latest Hot News that resveratrol, the long-established purportedly disease-protection ingredient in red wine and other foods, isn't protective after all.  The study was a modest-sized one in the Chianti region of Italy where the wine is good and the sunshine warm and welcoming.

Though not large or in any sense exhaustive, this study made the news outside of Vatican City only, we might suggest, because it seemed to contradict the literature that has for many years praised resveratrol, and red wine, for its benefits for supposed physiological or biochemical reasons.  Naturally, the news media were hot to seize on the new study.  It stirred controversy, a favorite of the media.

But how do we know which to believe?  Should this study cast doubt on the prior studies' results?  If it is a good and reliable result, one can see why it could be reported as News.  But hold on.

On what possible grounds would this study be viewed as definitive, or at least definitive enough, to cast doubts on the extensive prior work?  If a responsible reporter were contacted by the author or a journal about this, why should the reporter believe or even report these results?

Given the numerous studies supporting a protective effect for resveratrol, on what grounds would this be viewed as credible, or should the media assume there may be problems with the study and that possibility be the headline and basis of the the story?  One can think of many issues to do with the epistemology of this kind of study, such as confounding, including confounding socioeconomic factors, as we mentioned in our original post on this story.  Why isn't the first reaction of the media that there must be something wrong with the latest results, and the study's bottom line be incorrect?

Indeed,  why shouldn't the media treat this as a junk study, not worth reporting, since it did not seem to have any clear or definitive reason for countering prior results?  Or at least ask what other factors may have been correlated with exposure to resveratrol, to negate its normally reported effect?

One possibilities is that the result is just a statistical fluke, and the actual resveratrol effect in the Chianti population is protective but that the roll of the sampling dice by chance turned up an opposite result.  How would we know?

We can put this another way: doesn't the study show that the media, and perhaps some scientists, treat this as a more definitive study than the prior work, and that that is what they seem to assume makes it newsworthy?  One can ask whether we can't expect this one study to be used as a rationale for proposals for funding for yet more, larger studies to resolve this 'controversy'.  Or, should we not expect that next week or next year another study will appear, and be given credibility by the media and authors, that will reverse the current wisdom?

The idea that one factor has an important net effect that will be realized is the kind of reductionistic thinking we often criticize, including in our prior resveratrol post.  No author would admit to thinking in a one-factor way, because we all know that would make us vulnerable to criticism, but this story shows that underlying the work is just that sort of approach.  At some point, if this is the kind of result we get, and we don't assume the current study is flawed, we should say we know enough to conclude that resveratrol has a protective effect, and go forth with other studies rather than repetitions of this one.

Or, if for some reason we actually give credence to this story, we need to ask why so many prior studies were junk studies, and then the question arises as to who to believe, and when we actually have an answer--rather than just another rationale for not going on to something more important, or at least to questions that have actual answers.

Or, it's possible that both results are correct; resveratrol is protective in some populations and some contexts, and not in others.  As always, it's hard to know how to interpret contradictory results, and too often it's the latest results that are given most credence for no reason other than that they are the latest results.

Meanwhile, drink red wine if you like red wine,  but then don't drive, because that is a risk factor we should actually believe!

The beetle age

If the way of ushering in modern science in the 1600s was largely based on instruments such as lenses and clocks, the 1700s became an age of exploration, as recently characterized by a BBC radio 4 series on the history of science (7 Ages of Science, episode 2).  Extensive commercial, imperial, and military shipping (thanks to some better ship-making and navigational instruments) including gathering of plant, animal, and rock specimens from around the world. Darwin and many others were examples. In biology that time is now often dismissively referred to as the age of beetle collecting, to denote the unconstrained and often unsystematic assembly of specimens.

As part of this, in the mid-1700s the development of better telescopes led to huge advances in understanding the stars and their motion.  Among the pioneers of this work were William Herschel and his wife Caroline.  They discovered Uranus as the then most-distant planet known, and galaxies, and began to reveal to us for the first time how immense the universe is. 

However, other questions also arose, or so one would think.  But when Herschel said to the Astronomer Royal "I want to know what the stars made of," the latter replied, somewhat annoyed, "What we're interested in, is mapping."

Replica of the telescope the Herschels used to discover Uranus; Wikipedia

Modern mapping
Once, about 15 years ago, I was on a site visit to evaluate and make a funding decision on whether to award the requested grant.  The investigator was describing how the trait, call it Disease X, would be investigated with the latest GWAS tools.  This was that one required greater sample sizes than had been available before to be able to identify spots in the genome that might be potential causes of X, as the investigator proposed to do.

There had already been smaller studies that had rather convincingly identified about 5 or so genes that seemed to lead to high risk of the disease.  The mechanism and reason that these genes might be causal were, however, not at all clear nor could anything be done about the problem for persons carrying the seemingly causal variation in these genes.  By analogy to Herschel's question to the Astronomer Royal (What were these genes made of?), when I asked why the investigator was proposing to search for even weaker signals than the ones already known, rather than working on understanding how the latter worked, the investigator replied: "Because mapping is what I do."

In the 15 years since then, lots of mapping has been done in this spirit, and a modest number of additional genes or possible-genes have been found, but no real progress has been made in the treatment or prevention of X, nor has there been much increased understanding of the mechanisms of the previously known genes, nor any gene-based therapy.  

This reveals the attitude of so many in science today.  "What I do is collect [specify some form of] Big Data!"  'Big Data' has become a fashionable term that, when dropped, may suggest gravitas or insight.  But we aren't doing astronomy and while we certainly are highly ignorant about much of the nature of genomes, when it comes to funding the study of disease, for purposes of public health, this is a lame excuse for business as usual. What we need are more instances of what is (also fashionably) called proof of principle: proof that knowing about risk-conferring genetic variants leads to doing something about it.  That's very tough, and we have precious few instances of such principle in genetics, but we do have enough to suggest, to us, that we should not be funding further gene-gazing expeditions, into the astronomical realm of genomic complexity and the astronomical costs of the studies.  We should be focusing and intensifying the efforts to know how to do something to alleviate the problems caused by the genes, and there are many, that we know about, or the problems that seem to be truly 'genetic'. 

We are not supposed to be just star gazing with public health funds; society expects and is promised benefits (whereas only NASA expects benefits, in the form of more funding, for star-gazing; for the rest of us, it's basically no different from watching science fiction on television).

Science requires data, and we never have enough.  There are areas where modern style beetle collecting is still very much worth doing, because our knowledge is sufficiently rudimentary.  But there are areas in which we've done enough of that, and the challenge is to concentrate resources on mechanism and intervention.  In many instances, that really has nothing to do with technology, but has everything to do with lifestyle, because we have clear enough understanding to know that the diseases are largely the result of environmental exposure (too many calories, smoking, and so on).  Funding for public health should go there, in those important instances.

From a genome point of view there are certainly areas where primary data-collection is still crucial.  To take one example, it has been clear for decades that we don't yet have nearly a clear enough idea of how mutations arise in cells during development and subsequent life, nor how those mutations lead to disease and its distribution by age and sex, including interacting with environmental components and each other.  But identifying mutations and their patterns in our billions of cells, as they arise by age, and how they affect cells is a major technological challenge, far harder than collecting larger case-control studies for traits we've already studied that way before.

Adam's sin and Next Generation Sequencing

Before the Enlightenment, in western scholarship at least, our understanding of the world was based on data we could detect with our senses, without much of a systematic sampling framework (except, perhaps, in astronomy).  Thinkers generalized from this with inborn reasoning power.  Aristotle, Plato, and many others worked basically in this way.  The idea was, in essence, that there were truths to be found, and our brains and reason were structured in ways that would lead us to them.  There were general principles of natural organization as well, such as were represented by mathematics.

Adam's sin
What else could we expect?  While not part of Aristotelian or classical Greek scholarship, the Judeo-Christian understanding of the cosmos was that when Eve fell to temptation and ate from the forbidden fruit of the tree of knowledge of good and evil, and in turn tempted Adam, mankind's vision was blurred: in our sin, we lost the ability to see Nature clearly.  Forever benighted, then, we had to turn to the religious authorities, and they (that is, mainly the Catholic authorities) had accepted Aristotelian worldviews as basically correct--and hence unchallengeable.

Rubens' Adam and Eve

However by about the 17th century, as discussed in the first in a seven-part radio series on the BBC, "Seven Ages of Science", a variety of activities in Europe led to an increase in instrument-making, for various purposes.  But the most relevant examples, so far as we know at least, were the making of lenses and of mechanisms for measuring time.  Machines to generate vacuums were another.  These led rapidly over the next century or two to all sorts of things, including steam engines, accurate navigation instruments, and so on.

Telescopes, microscopes, and clocks opened huge new frontiers, and their major impact was on what became modern science as we know it.  The iconic instances are Galileo's use of telescopes on the moon and planets, and Newton's use of mathematics and more accurate astronomical data, together showing us that the accepted Aristotelian wisdom about the nature of the universe was inaccurate (or, sometimes, just plain wrong). Meanwhile, as astronomers gazed and measured things big, the likes of Robert Hooke looked at things small.  Various devices like the vacuum pump (Hooke helped make one for Robert Boyle) contributed to a new sense of chemistry and physiology.

Hooke microscope; 1665

The Enlightenment period that these activities helped usher in, was one in which empirical observation of Nature rather than mere thought and dogma, became watchwords.  We could understand--and control--the world through what we now would call technology.  The ideas were extended to the belief that by acting rationally, by being reasonable, we would understand.  This became the belief in what science should be about, and of course we still share that view today.

At the time, there was no substitute for technology, when so much became quickly discernible to us that our biological senses could not detect.  Chemistry, physics, astronomy, and biology all became formalized disciplines through various uses of technology.  Geology and evolution owed their modern origins in part to better navigation and global economies, and so on.

In those times, technology drove science because, in a sense, we were seeing things for the very first time, and there was so much to see.  But in the process, technology became part of the scientific method: if you did not document something with appropriate detection and measurement technology, your 'theory' about Nature would be viewed as mere speculation.  Even Darwin used microscopes, global travel technology, and his era's version of 'Big Data', along with globally expanded measures of geological formation and change, to develop his theory of evolution.

Instrumentation became more elaborate and expensive, and science gradually morphed from private rich-men's basement labs to university and other institutionalized research centers.  In a cultural sense instrumentation became what was needed for cachet, as well as the vital tool for understanding the problems of the day from physics to medicine.  Generally, this was a correct understanding of the state of things, though one could argue that investigators thought up the ideas they did because they had instrumentation.

The clockwork universe
The Enlightenment idea was to find through such instrumentation that God's creation was a clockwork universe that, like the instruments being developed, worked in universally, according to specific--and discoverable!--principles that gave certainty to cause-and-effect patters if but we knew the laws of Nature that drove them.

But the laws of the creation had been kept from our vision by the serpent who had tricked Eve into her forbidden taste test.  All it showed to Adam and Eve was that they were naked and needed to find the nearest fig leaf.  But now, thousands of years later, us flawed humans had developed ways to take the scales off our eyes and see what we would otherwise have been able to see.

The astounding realization, one might say, was that the universe was a clockwork place, a place of laws that applied always and everywhere and thus were ordained by God when the universe was created.  What else could it mean?  The success of the many great and lesser luminaries who avidly pursued instrument-based observations, and the exciting new ethos of empiricism before theory, livened up a basically new area of human endeavor: organized science and technology.

Next-Generation sequencing as an icon of current thinking
This has evolved rapidly and it integrated well with commercially based economies, so that multiple inter-dependencies grew.  We not only depended on technology for finding things not findable before, but we used technology to drive what we would study, even as a rationale.  That is currently the system today.  We drop various terms, knowingly, to justify or give gravitas to our work.  Thus 'next generation' DNA sequencing becomes what you have to propose if you expect to get grant funding, even if the old technology could have answered your question.  Indeed, that's how you get more DNA than the next fellow, so you can study what s/he cannot 'see', and then getting more becomes part of the point.

Older generation, Sanger sequencing; Wikipedia

The problem, for those of us who see it as a problem, is not the value of the technology where appropriate, but that it first of all determines the very questions we ask (or that being in the science tribe will let you get resources for), and secondly leads to repetitive me-too, ever-larger but often not better thought-out work.  The costly imitative nature will reach, if it hasn't already reached, a point where the incremental new knowledge is as trivial as collecting yet another tropical flower or beetle would have been to Victorians.

When the point of diminishing returns is reached, so is a kind of conceptual stagnation.  When and whether we're at such a point, or where we are, is certainly widely debated.  Is another, bigger GWAS, with sequence rather than marker data, going to deliver a body blow to, say cancer or heart disease?  Or will it just add some pin-striping to what we already know?  Will identifying every neural connection in a brain be worth billions?  Or will it be mainly another form of very costly beetle collection?

Where and how can we focus the incredibly powerful tools that we now have to things that we truly have never been able to see before.  Are we pressing Enlightenment science to its useful limits, in need of better kinds of insights than we can get from ever more Big Data?  Or is the priority given to sexy instrumentation still worth the central or even driving role it plays in today's science?

It is a cultural fact that we are so assured of, believe in, depend on, or hide behind (?) technology in our industrial-scale science system, that technology has pride of place these days.  That cultural fact gives a lot of us jobs and a feeling of importance.  In many areas it's also a feeling of profound discovery.  Some of that really is profound.  But just as profoundly, much of it is a waste of creative energy. Finding a right balance is something that will have to happen on its own, probably involve the chaos of the modern form of disputation sphere (such as blogs), since it can't be ordered up by some sort of administrative decision.