Where has all the thinking gone....long time passing?

Where did we get the idea that our entire nature, not just our embryological development, but everything else, was pre-programmed by our genome?  After all, the very essence of Homo sapiens compared to all other species, is that we use culture--language, tools, etc.--to do our business rather than just our physical biology.  In a serious sense, we evolved to be free of our bodies, our genes made us freer from our genes than most if not all other species! And we evolved to live long enough to learn--language, technology, etc.--in order to live our thus-long lives.

Yet isn't an assumption of pre-programming the only assumption by which anyone could legitimately promise 'precision' genomic medicine?  Of course, Mendel's work, adopted by human geneticists over a century ago, allowed great progress in understanding how genes lead at least to the simpler of our traits, with discrete (yes/no) manifestations, traits that do include many diseases that really, perhaps surprisingly, do behave in Mendelian fashion, and for which concepts like dominance and recessiveness been applied and that, sometimes, at least approximately hold up to closer scrutiny.

Even 100 years ago, agricultural and other geneticists who could do experiments, largely confirmed the extension of Mendel to continuously varying traits, like blood pressure or height.  They reasoned that many genes (whatever they were, which was unknown at the time) contributed individually small effects.  If each gene had two states in the usual Aa/AA/aa classroom example sense, but there were countless such genes, their joint action could approximate continuously varying traits whose measure was, say, the number of A alleles in an individual.  This view was also consistent with the observed correlation of trait measure with kinship-degree among relatives.  This history has been thoroughly documented.  But there are some bits, important bits, missing, especially when it comes to the fervor for Big Data 'omics analysis of human diseases and other traits.  In essence, we are still, a century later, conceptual prisoners of Mendel.

'Omics over the top: key questions generally ignored
Let us take GWAS (genomewide association studies) on their face value.  GWAS find countless 'hits', sites of whatever sort across the genome whose variation affects variation in WhateverTrait you choose to map (everything simply must be 'genomic' or some other 'omic, no?).  WhateverTrait varies because every subject in your study has a different combination of contributing alleles.  Somewhat resembling classical Mendelian recessiveness, contributing alleles are found in cases as well as controls (or across the measured range of quantitative traits like stature or blood pressure), where the measured trait reflects how many A's one has: WhateverTrait is essentially the sum of A's in 'cases', which may be interpreted as a risk--some sort of 'probability' rather than certainty--of having been affected or of having the measured trait value.

We usually treat risk as a 'probability,' a single value, p, that applies to everyone with the same genotype.  Here, of course, no two subjects have exactly the same genotype so some sort of aggregate risk score, adding up each person's 'hits', is assigned a p.  This, however, tacitly assumes something like that each site contributes some fixed risk or 'probability' of affection.  But this treats these values as if they were essential to the site, each thus acting as a parameter of risk.  That is, sites are treated as a kind of fixed value or, one might say 'force', relative to the trait measure in question.

One obvious and serious issue is that these are necessarily estimated from past data, that is, by induction from samples.  Not only is there sampling variation that usually is only crudely estimated by some standard statistical variation-related measure, but we know that the picture will be at least somewhat different in any other sample we might have chosen, not to mention other populations; and those who are actually candid about what they are doing know very well that the same people living in a different place or time would have different risks for the same trait.

No study is perfect, so we use some conveniently assumed well-behaved regression/correction adjustments to account for the statistical 'noise' due to factors like age, sex, and unmeasured environmental effects.  Much worse than these issues, there are clearly factors of imprecision, and the obvious major one, taboo even to think about much less to mention, that relevant future factors (mutations, environments, lifestyles) are unknowable, even in principle.  So what we really do, are forced to do, is extend what the past was like to the assumed future.  But besides this, we don't count somatic changes (mutation arising in body tissues during life, that were not inherited), because they'd mess up our assertions of 'precision', and we can't measure them well in any case (so just shut one's eyes and pretend the ghost isn't in the house!).

All of these together mean that we are estimating risks from imperfect existing samples and past life-experience, but treating them as underlying parameters so that we can extend them to future samples.  What that does is equate induction with deduction, assuming the past is rigorously parametric and will be the same in the future;  but this is simply scientifically and epistemologically wrong, no matter how inconvenient it is to acknowledge this.  Mutations, genotypes, and environments of the future are simply unpredictable, even in principle.

None of this is a secret, or new discovery, in any way.  What it is, is inconvenient truth. These things should have been enough, by themselves and without badgering investigators about environmental factors that (we know very well, typically predominate) prevent all the NIH's precision promises from being accurate ('precise'), or even to a knowable degree.   Yet this 'precision' sloganeering is being, sheepishly, aped all over the country by all sorts of groups who don't think for themselves and/or who go along lest they get left off the funding gravy train.  This is the 'omics fad.  If you think I am being too cynical, just look at what's being said, done, published, and claimed.

These are, to me, deep flaws in the way the GWAS and other 'omics industries, very well-heeled, are operating these days, to pick the public's pocket (pharma may, slowly, be awakening-- Lancet editorial, "UK life science research: time to burst the biomedical bubble," Lancet 392:187, 2018).  But scientists need jobs and salaries, and if we put people in a position where they have to sing in this way for their supper, what else can you expect of them?

Unfortunately, there are much more serious problems with the science, and they have to do with the point-cause thinking on which all of this is based.

Even a point-cause must act through some process
By far most of the traits, disease or otherwise, that are being GWAS'ed and 'omicked these days, at substantial public expense, are treated as if the mapped 'causes' are point causes.  If there are n causes, and a person has an unlucky set m out of many possible sets, one adds 'em up and predicts that person will have the target trait.  And there is much that is ignored, assumed, or wishfully hidden in this 'will'.  It is not clear how many authors treat it, tacitly, as a probability vs a certainty, because no two people in a sample have the same genotype and all we know is that they are 'affected' or 'unaffected'.

The genomics industry promises, essentially, that from conception onward, your DNA sequence will predict your diseases, even if only in the form of some 'risk'; the latter is usually a probability and despite the guise of 'precision' it can, of course, be adjusted as we learn more.  For example, it must be adjusted for age, and usually other variables.  Thus, we need ever larger and more and longer-lasting samples.  This alone should steer people away from being profiteered by DNA testing companies.  But that snipe aside, what does this risk or 'probability' actually mean?

Among other things, those candid enough to admit it know that environmental and lifestyle factors have a role, interacting with the genotype if not, usually, overwhelming it, meaning, for example, that the genotype only confers some, often modest, risk probability, the actual risk much more affected by lifestyle factors, most of which are not measured or not measured with accuracy, or not even yet identified.  And usually there is some aspect that relates to age, or some assumption about what 'lifetime' risk means.  Whose lifetime?

Aspects of such a 'probability'
There are interesting issues, longstanding issues, about these probabilities, even if we assume they have some kind of meaning.  Why do so many important diseases, like cancers, only arise at some advanced age?  How can a genomic 'risk' be so delayed and so different among people?  Why are mice, with very similar genotypes to humans (which is why we do experiments on them to learn about human disease) only live to 3 while we live to our 70s and beyond?

Richard Peto, raised some of these questions many decades ago.  But they were never really addressed, even in an era when NIH et al were spending much money on 'aging' research including studies of lifespan.  There were generic theories that suggested from an evolutionary theory why some diseases were deferred to later ages (it is called 'negative pleiotropy'), but nobody tried seriously to explain why that was from a molecular/genetic point of view.  Why do mice only live only 3 years, anyway?  And so on.

These are old questions and very deep ones but they have not been answered and, generally, are conveniently forgotten--because, one might argue, they are inconvenient.

If a GWAS score increases the risk of a disease, that has a long delayed onset pattern, often striking late in life, and highly variable among individuals or over time, what sort of 'cause' is that genotype?  What is it that takes decades for the genes to affect the person?  There are a number of plausible answers, but they get very little attention at least in part because that stands in the way of the vested interests of entrenched too-big-to-kill Big Data faddish 'research' that demands instant promises to the public it is trephining for support.  If the major reason is lifestyle factors, then the very delayed onset should be taken as persuasive evidence that the genotype is, in fact, by itself not a very powerful predictor.

Why would the additive effects of some combination of GWAS hits lead to disease risk?  That is, in our complex nature why would each gene's effects be independent of each other contributor?  In fact, mapping studies usually show evidence that other things, such as interactions are important--but they are at present almost impossibly complex to be understood.

Does each combination of genome-wide variants have a separate age-onset pattern, and if not, why not?  And if so, how does the age effect work (especially if not due to person-years of exposure to the truly determining factors of lifestyle)?  If such factors are at play, how can we really know, since we never see the same genotype twice? How can we assume that the time-relationship with each suspect genetic variant will be similar among samples or in the future?  Is the disease due to post-natal somatic mutation, in which case why make predictions based on the purported constitutive genotypes of GWAS samples?

Obviously, if long delayed onset patterns are due not to genetic but to lifestyle exposures interacting with genotypes, then perhaps lifestyle exposures should be the health-related target, not exotic genomic interventions.  Of course, the value of genome-based prediction clearly depends on environmental/lifestyle exposures, and the future of these exposure is obviously unknowable (as we clearly do know from seeing how unpredictable past exposures have affected today's disease patterns).

The point here is that our reliance on genotypes is a very convenient way of keeping busy, bringing in the salaries, but not facing up to the much more challenging issues that the easy one (run lots of data through DNA sequencers) can't address.  I did not invent these points, and it is hard to believe that at least the more capable and less me-too scientists don't clearly know them, if quietly.  Indeed, I know this from direct experience.  Yes, scientists are fallible, vain, and we're only human.  But of all human endeavors, science should be based on honesty because we have to rely on trust of each other's work.

The scientific problems are profound and not easily solved, and not soluble in a hurry.  But much of the problem comes from the funding and careerist system that shackles us.  This is the deeper explanation in many ways.  The  paint on the House of Science is the science itself, but it is the House that supports that paint that is the real problem.

A civically responsible science community, and its governmental supporters, should be freed from the iron chains of relentless Big Data for their survival, and start thinking, seriously, about the questions that their very efforts over the past 20 years, on trait after trait, in population after population, and yes, with Big Data, have clearly revealed.

Genes: convenient tokens of our time

My post today, perhaps typically cranky, was triggered by an essay at Aeon about the influence that the film Still Alice has had on thinking about Alzheimer's Disease (AD). As the piece puts it, AD is presented in the film as a genetic disease with a simply predictable doom-like known genetic cause.  The authors argue that the movie is more than entertainment.  It's a portrayal that raises an important ethical issue, because it is very misleading to leave the impression that AD is a predictable genetic disease.  That's because a clear genetic causation, and thus the simple 'we can test for it' representation, applies only to a small fraction of AD.  The film badly misrepresents the overall reality of this awful form of the disease (a good treatment of Alzheimer's disease and its history is Margaret Lock's thoughtful The Alzheimer Conundrum, 2013, Princeton Press).

While focusing on AD, the Aeon piece makes strong statements about our obsession with genes, in ways that we think can be readily generalized.  In a nutshell, genes have become the convenient tokens of our time.

Symboling is a key to making us 'human'
If there is any one thing that most distinguishes our human species from others, it may be the use of language as a symbolic way to perceive the world and communicate to others.  Symboling has long been said by anthropologists to be an important key to our evolution and the development of culture, itself based on language.

Symbol and metaphor are used not just to represent the world and to communicate about it, but also to sort out our social structure and our relationships with each other and the world.  Language is largely the manipulation or invocation of symbols.  In a species that understands future events and generalities, like death and sex, in abstract terms, the symbols of language can be reassuring or starkly threatening.  We can use them to soothe ourselves or to manipulate others, and they can also be used in the societal dance around who has power, influence, and resources.

Symbols represent a perception of reality, but a symbol is not in itself reality.  It is our filter, on or around which we base our interactions and even our material lives.  And, science is as thoroughly influenced by symbols as any other human endeavor.

Science is, like religion, a part of our culture that purports to lead us to understand and generalize about the world, but because science is itself a cultural endeavor, it is also part and parcel of the hierarchy and empire building we do in general, part of a cultural machinery that includes self-promotion, and mutually reinforcing service industries including news media, and even scientific journals themselves.

The current or even growing pressures to maintain factory-like 'productivity' in terms of grants coming in and papers going out is largely at odds with the fundamental purpose of science (as opposed to 'technology').  Unlike designing a better product, in the important, leading-edge areas of science, we don't know where we're going.  That is indeed the reason that it is science.  Exploring the unknown is what really good science is about.  That's not naturally an assembly-line process, because the latter depends on using known facts.  However, our society is increasingly forcing science to be like a factory, with a rather short-term kind of fiscal accountability.

Our culture, like any culture, creates symbols to use as tokens as we go about our lives.  Tokens are reassuring or explanatory symbols, and we naturally use them in the manipulations for various resources that culture is often about.  Nowadays, a central token is the gene.

DNA; Wikipedia

Genes as symbols
Genes are proffered as the irrefutable ubiquitous cause of things, the salvation, the explanation, in ways rather similar to the way God and miracles are proffered by religion.  Genes conveniently lead to manipulation by technology, and technology sells in our industrial culture. Genes are specific rather than vague, are enumerable, can be seen as real core 'data' to explain the world.  Genes are widely used as ultimate blameworthy causes, responsible for disease which comes to be defined as what happens when genes go 'wrong'.  Being literally unseen, like angels, genes can take on an aura of pervasive power and mystery.  The incantation by scientists is that if we can only be enabled to find them we can even cure them (with CRISPR or some other promised panacea), exorcising their evil. All of this invocation of fundamental causal tokens is particulate enough to be marketable for grants and research proposals, great for publishing in journals and for news media to gawk at in wonder. Genes provide impressively mysterious tokens for scientists to promise almost to create miracles by manipulating.  Genes stand for life's Book of Truth, much as sacred texts have traditionally done and, for many, still do.

Genes provide fundamental symbolic tokens in theories of life--its essence, its evolution, of human behavior, of good and evil traits, of atoms of causation from which everything follows. They lurk in the background, responsible for all good and evil.  So in our age in human history, it is not surprising that reports of finding genes 'for' this or that have unbelievable explanatory panache.  It's not a trivial aspect of this symbolic role that people (including scientists) have to take others' word for what they claim as insights.

This token does, of course, have underlying reality
We're in the age of science, so that it is only to be expected that we'll have tokens relevant to this endeavor.  That we have our symbols around which to build other aspects of our culture doesn't mean that the biology of genes is being made up out of whole cloth.  Unlike religion, where things can be 'verified' only by claims of communication with God, genes can of course, at least in principle, be checked and claims tested.  Genes obviously do have major and fundamental roles in life.  If that isn't true, we are really misperceiving fundamentals of our existence.  So, even when complexities of causation are daunting, we can claim and blame what we want on genes and in a sense be correct at least at some level.  That enhances and endorses the token value of genes.

Genes do have great sticking power.  The Aeon piece about AD is just one of countless daily examples.  A fraction of cases of AD are so closely associated with the presence of some known variants in a couple of genes, that true causation--whatever the mechanism--seems an entirely plausible explanation.  Likewise, there are hundreds or thousands of disorders that seem clearly to be inherited and as the result of malfunction of one or two specific genes.  The cultural extension of this in our society that we are stressing here is the extension of these clearly causative findings to the idea that causation can be enumerated in convenient ways mainly by peoples' inherited genomes and that other aspects of biological causation are often treated as being rather superficial or incidental.  That in a sense is typical of deeply held cultural icons or tokens.

The problem with genes as tokens is that they are invoked generally or generically in the competition for cultural resources, material and symbolic.  Personally, we think there are issues, genetic issues in fact, that deserve greater investment, rather than just the easier to invoke bigger-is-better approach. They include a much more intense attack on those many traits that we already know without any serious doubt are tractably genetic--due to one or only a couple of genes, and therefore which real genetic therapy might treat or prevent effectively.  By contrast, most traits even if they are affected by genetic variation as all traits must be, are predominantly due to environmental or chance causative factors.  We have ways to avoid many diseases that don't require genetic approaches, but as vague entities they're perfect subjects for invoking the gene token, and policy in the industrial world clearly shows this.

Some progress does of course occur because of genetically-based research, but the promise far outpaces the reality of genetic cures.  But genes are the material tokens that keep the motor running far beyond the actual level of progress.  They effectively reflect our time--our molecular, computer, technological culture imagery, our love of scale, size and the material grandeur they generate.

Every culture, every generation has its tokens and belief systems.  Genes are among ours.  They're never perfect.  People seek hope, and what velvet robes and gilded cathedrals and mosques provide for many, whereas the humming laboratories do for a growing number of others.

Tokens, symbols and metaphors: they drive much of what people do, even in science.

Running and neurogenesis; the plastic brain

A new paper online in the Journal of Physiology ("Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained," Nokia et al.), and described here by the NYT, reports that running is good for the brain.  At least the rat brain.

From the paper (emphasis mine):

Adult hippocampal neurogenesis (AHN) is a continuous process through which cells proliferate in the subgranular zone of the dentate gyrus, mature into granule cells, and ultimately become incorporated into hippocampal neuronal networks. In rodents, adult-born hippocampal neurons seem crucial for a variety of adaptive behaviors such as learning, pattern separation, and responses to stress. Aerobic exercise, e.g. running, increases AHN and improves cognitive performance in both male and female adult rodents. The increase in AHN in response to running is reported to be in part due to an increase in the number of surviving neuronal precursor cells (type 2) rather than to the shortening of the cell cycle. There are also studies indicating that running increases the survival and incorporation of newly divided hippocampal cells, born days before commencing training, to increase net neurogenesis. [See the paper for citations for reported findings, which I've removed here for length.]

It has already been well-established that aerobic exercise is associated with an increase in adult hipocampal neurogenesis, the number of neurons in the hippocampus, the region of the brain associated with producing long-term memory among other functions.  But, Nokia et al. wondered if it was only aerobic exercise, or whether other kinds of exercise have the same effect.

So they compared the number of neuronal cells of mice subjected to high-intensity interval training, resistance training and distance running.  They found no increase in the rats who did resistance training compared to sedentary rats, and a smaller than expected increase in rats that did the interval training.  It was only in the brains of the rats who did aerobic exercise that neurogenesis was significantly increased.  The authors hypothesize that this is because running stimulates the production of  brain-derived neurotrophic factor and insulin-like growth factor, which are associated with neurogenesis. The more aerobic exercise the animal does, the more of these the animal produces, and thus the more neurons.

Currently the best advice for preventing dementia in old age is to maintain a social life, quit smoking, and exercise.  And, if this rat study can be applied to humans, this should at least qualify that as aerobic exercise; running or biking, say.  As with all such lifestyle advice, this surely won't work for everyone, but the evidence is increasingly in its favor, at least on a population basis.

But there are deeper implications of this work, I think.  If exercise changes the architecture of the brain in ways that can affect learning, even in adults, and, as has been repeatedly demonstrated, stimulating children by reading to them, using lots of words, playing music to them, and so on, or the reverse, growing up in poverty,  or with disease, or amid famine all can affect brain architecture and thus cognitive ability for better or for worse, why do so many continue to privilege genes and genes alone -- or even more, a single gene -- for the creation of intelligence?

Source: "Effects on brain development leading to cognitive impairment:  A worldwide epidemic," Olness,
Journal of Developmental & Behavioral Pediatrics:
April 2003 - Volume 24 - Issue 2 - pp 120-130

It seems that the brain responds to experience at all ages, but it's possible that there's a 'sensitive period' for cognition.  As just one example, the cognitive abilities of children reared in institutions in Bucharest were compared to that of children never placed in an institution to those whose lives began there but who moved to foster care before age two.  Those who were reared entirely in institutions had much lower cognitive ability than the other two groups; the cognitive abilities of those who were moved to foster care before age two significantly improved.  The authors of this study suggest that there may be a sensitive period for developing cognitive ability, just as there is one for learning language, and many other aspects of brain function.

Of course, as with any trait, genes play a crucial role in the development of the brain.  But they don't do it alone.  E.g., a 2010 paper in Child Development describes the genetic underpinnings of the developing brain, but its plasticity as well.

The foundations of brain architecture are established early in life through a continuous series of dynamic interactions between genetic influences and environmental conditions and experiences (Friederici, 2006; Grossman, 2003; Hensch, 2005; Horn, 2004; Katz & Shatz, 1996; Majdan & Shatz, 2006; Singer, 1995). There is increasing evidence that environmental factors play a crucial role in coordinating the timing and pattern of gene expression, which in turn determines initial brain architecture. Because specific experiences potentiate or inhibit neural connectivity at key developmental stages, these time points are referred to as sensitive periods (Hess, 1973; Knudsen, 2004). Each one of our perceptual, cognitive, and emotional capabilities is built upon the scaffolding provided by early life experiences. Examples can be found in both the visual and auditory systems, where the foundation for later cognitive architecture is laid down during sensitive periods for basic neural circuitry.  

Genetic determinists might acknowledge the plasticity of the brain but then say that how the brain responds to experience is what's genetically determined, and thus that there are children who just aren't genetically equipped to be the next Einstein, or even to learn calculus.  We know this is true at least at one extreme of the distribution of intelligence, because there are many alleles known to be associated with low cognitive ability.  These usually cause syndromic conditions, however, so aren't related only to how quickly synapses are crossed, or memories made, or whatever it is that underlies -- or defines -- intelligence.  As with many other trait distributions, what happens at the extremes doesn't necessarily represent what's going on in the middle, so I think the jury is still out as to the overriding importance of single or even a small number of alleles in the development of normal or above normal intelligence (again, whatever that is -- for the moment, let's call it the ability to score well on IQ tests).  And indeed no genes with large effects on intelligence have yet been identified, despite decades of looking.  That has so far included comparison of the tails of the distribution among individuals without a clear-cut pathology.

So, of course there are genes involved in how quickly people think, or make connections between ideas, or memorize, or invent things, or remember -- how people learn.  But it's not either mainly genes or environment.  It's both, interacting, and molding the reactive brain.  There is enough evidence now to show that the brain is a hungry organ, soaking up and responding to experience at all times, throughout life.  Whether or not we believe that society should be investing in optimizing the environment of every child to maximize their potential is a social and political decision, not a scientific one.

So...it's not genetic after all! (but who's listening?)

Is it time to predict the gradual out-cycling of a focus on genetic causation and a return of environmental causation, in our mainstream scientific dialog (and funding-pot)?  Such a recycling is bound to happen--even if, say, genetics' claims were correct.  Why?  Because the new generation has to have something to show they're smarter than their elders, and because the abuse of genetic determinism by society is a nearly inevitable consequence of the fervid love-affair we're now having with genomics and its glittering technology.  But maybe there's another reason:  maybe genetics really has been oversold!  Is it possible?

Bees and societal (in)determination
Honey bee harvesting is a social phenomenon and experiments by various authors have found that only a fraction (in some studies, 20%) of the workers actually do most of the work.  But a recent controlled study reported in the journal Animal Behavior by Tenczar et al (vol. 95, pp41-48, 2014, but paywalled) found that if those 'busy-bees' are removed, others step in to fill the work gap.  The gist of the evidence seems to be that among the gatherer work force (and presumably other castes as well, though that's not reported), there is a spectrum of contribution and it's condition or context-dependent.  As the paper says:

These bees resembled ‘elite workers’ reported in a number of other species. However, our results also show that honeybee foraging activity level is flexibly adjusted during a bee's lifetime, suggesting that in honeybees, elitism does not involve a distinct subcaste of foragers but rather stems from an extreme of a range of individual activity levels that are continuously adjusted and may be influenced by environmental cues.  . . . these results support the view that individual workers continuously adjust their activity level to ensure that the colony's nutritional needs are being adequately and efficiently met, and that the net activity of the whole foraging population is likely to be one of the factors that influences this decision. 

The authors discuss the fact that these patterns have not been studied, with varying levels of rigor, in many species of social insects.  While it is not clear that genetic differences are never partly responsible, the evidence is that social roles are not rigidly pre-programmed.  This study was presented by the NYTimes with a captivating video from the authors, but while that was nice and led us to the research story itself, the Times characterized this as a system allowing upward social mobility.  That's a bit pandering to middle-class readership, and didn't really critique this work in the context of today's prevailing genetic-deterministic viewpoint. However, the idea of context-dependent roles, based on the needs and opportunities in society at large, is noteworthy and of course is something that also happens in humans.

Honeybee; Wikimedia Commons

This of course raises the question of how the bees perceive the needs or different roles, or if the role pattern is a spectrum of activity of each bee, then how does it know when and what to do.  This would relate to the bees' brains' ability to digest quite complex information and make decisions, something very interesting to try to understand, and something we wrote about here not long ago.

Intelligence
A new paper in PNAS reports the results of a large study of the genetics of IQ.  Essentially, they found three genes with very small effect and unknown functional association with cognition.  Indeed, one of the genes may not even be a gene. To sort this all out, of course, they say they would need a sample of a million people.  One of the authors faced with this mountain of chaff is quoted this way in the story:

Benjamin says that he and his colleagues knew from the outset that their efforts might come up empty handed. But the discovery that traits such as intelligence are influenced by many genes, each having a very small effect, should help to guide future studies and also temper expectations of what they will deliver. “We haven’t found nothing,” he says.

Nice try!  But the truth is that that is just what they have found: nothing.  Or, at least, nothing new, that is, no thing.  We knew very well that this was the most likely sort of finding.  We have countless precedents, including the results of countless earlier searches for genes for intelligence (and, for that matter, similar findings for most psychological/behavioral traits).  Like other traits from normal ones like stature and IQ, to body weight and major diseases of all sorts, we find polygenic control--countless contributing genetic factors with individually minimal effect. This even though usually the heritability of the trait is substantial, meaning that variation in genes together accounts for a non-trivial fraction of the overall variation in the trait (the environment and other factors contribute the rest, usually around 60-70%).  

But heritability is a persistently subtle and misunderstood (or ignored) measure. Even with nontrivial overall heritability, the aggregate nature of the measure means we cannot say in any given individual whether his/her IQ is based on this or that particular genes, or is some specifiable percent due to genes (that is itself difficult to make sense of when referring to an individual).  And heritability is often measured after taking out, or controlling for the major real causal factors, such as age and sex.  Arguing for a sample for a million, if allowed and funded, is a huge fool's errand and a corrupt way to spend money (because it's mainly to keep professors off the street of unemployment).

Yet the issues in these cases are subtle, because we also know of many different individual genes that, when seriously mutated, cause direct, major, usually congenital damage to traits like intelligence.  Yet few if any of these genes show up in these mega-mapping studies.  It is this sort of landscape of elusive complexity that we need to address, rather than just building expensive Big Data resources that will largely be obsolete before the DNA sequence is even analyzed, based on the daydream that we are not, knowingly, chasing rainbows.

The primary question one thinks to ask is whether 'intelligence' is a biologically meaningful trait.  If not, even if it can be measured and be affected by genes, it isn't really an 'it' and one can't be surprised that no strong genetic influences are found even if the measure is stable and heritable.  Asking about the genetic basis of intelligence under such circumstances is not asking a well-posed question.

Baby stories
The other day we posted about the recent Science issue on non-genetic influences on parenting,  environmental effects on traits and how long-term and subtle they can be, and how they are not Genetic in the sense of the G-rush we are currently experiencing.  The stories are many and diverse and tell the same tale.  

Here the fascinating question is how the various environmental factors could influence a fetus in factor-specific manners that even relate to the factor itself (e.g., maternal diet affecting the future baby's obesity level, or the effect of the mother eating garlic or being exposed to odors on taste preference or specific odor-related behavior in the child).  To answer such questions we have to know more than just about a gene or two.

So, why aren't these findings grabbing headlines?
The bee story made the front-page of the NYTimes, but mainly because of the video and not because it is a counter to the strong genomic hard-wiring ethos so often promoted by scientists these days.  Likewise, the baby influences made the cover of Science, but we didn't see a Hot-News blare announcing that genetics isn't, after all, everything.  And of course the IQ story didn't make that clear either, given that the author said he wanted studies of a million to find the real genetic causes of IQ.  And, determinists say this isn't going to change their mind about the genetics of intelligence, because it's definitely genetic.  

Will we, or when will we, see people begin to back off their claims of strong genetic determinism, and begin addressing the really hard questions concerning how complex genomes interact with complex environments to produce what we are clearly observing?  In my opinion, these questions cannot be addressed from a genetic, or from an environmental, or from a simple Gene + Environment point of view.

The Turner Oak effect: unexpected explanations

We are just catching up on a backlog of reading after three weeks away, which means that while the immediate subject of this post may be a bit dated, the topic certainly is not. The August 15 special issue of Science, which we're just now reading, is so fascinating that we can't let it go unremarked.  The issue, called "Parenting: A legacy that transcends genes," provides example after example of the effects of environmental factors on development, taste preferences, the way the brain works, disease risk, and many other aspects of life.  We can't of course evaluate the reliability of all of these results, but the evidence does seem to be pointing strongly in the direction of a mix of genes and environment in explaining the effects of parenting on growth and development.

We don't know that mounting such a strong challenge to the idea that genes are predominantly what make us who we are was the editors' intention, but the subtitle suggests that, and in our view, that's certainly what they have done.  Indeed, we can't help noting that this is an unintended but eloquent counterpoint to Nicholas Wade's view of life, in which everything including the kitchen sink is genetic (or at least we assume he'd say this, since sinks are designed by Eurasians who are because of natural selection genetically of superior inventiveness).

Cover of Science, Aug 15, 2014

Given the papers in this special issue, it's clear that more and more is being learned about how extra-genetic factors affect growth and development. What the mother eats in the days around conception, uterine conditions before conception, conditions during development, components of breast milk, ways of parenting and so forth all apparently affect the growth, development and health of a child.  In vitro fertilization may have life-long effects including risk of disease, starvation during pregnancy may affect risk of disease in offspring, what a mother eats while she's pregnant can influence her child's taste for specific foods, lack of parental care during infancy and early childhood can have lifelong effects, maternal mental illness may affect the development of the fetal brain, and so on.

Lane et al. write about "Parenting from before conception".  Infant health, they write, seems to be particularly influenced by conditions during 'fertilization and the first zygotic divisions, [when] the embryo is sensitive to signals from the mother's reproductive tract.'

The oviductal fluid surrounding the embryo varies according to maternal nutritional, metabolic, and inflammatory parameters, providing a microcosm that reflects the outside world. In responding to these environmental cues, the embryo exerts a high degree of developmental plasticity and can, within a discrete range, modulate its metabolism, gene expression, and rate of cell division. In this way, the maternal tract and the embryo collaborate to generate a developmental trajectory adapted to suit the anticipated external environment, to maximize survival and fitness of the organism. But if the resulting phenotype is a poor match for conditions after birth, or if adaptation constrains capacity to withstand later challenges, offspring are at risk.

Further,

Maternal diet at conception has a major impact on the developmental program. Reduced protein content for just the first 3 days of embryogenesis retards cell proliferation and skews the balance of cell lineage differentiation in the blastocyst.  The effect of nutritional disturbance at conception persists through implantation and influences placental development and nutrient transfer capacity, then after birth, the neonate gains weight more rapidly, developing higher systolic blood pressure and elevated anxiety.

Some of the effect is epigenetic, that is, modifications to the DNA structure that affect gene expression.  And some of the effect is, Lane et al. write, on oocyte mitochondria.  These organelles, "powerhouses of the cell", support blastocyst formation.  Their location and activity levels are known to respond to the mother's nutritional status, and ultimately affect the health of the child, as well as affecting gene expression in the brain, among other things.  Epigenetic effects on sperm, influenced by environmental conditions, also can affect the developing embryo.  But it's the "epi" in epigenetic that tells the tale: it's not the genetic (DNA sequence) variants that cause the trait difference, but variation in the use of the same sequence.

Many of the essays in this issue use the word 'plasticity', meaning that developing embryos are able to respond to various and varying environmental conditions.  If conditions are too extreme, of course, the embryo can't survive, but in general, how an embryo responds to immediate conditions may have lifelong effects.  From the review by Rilling and Young ("The biology of mammalian parenting and its effect on offspring social development"):

Parenting... shapes the neural development of the infant social brain. Recent work suggests that many of the principles governing parental behavior and its effect on infant development are conserved from rodent to humans.

That parenting has a strong effect on the infant's physiology, and that the effects of parent/child interactions have evolved to be strong is not a surprise, of course, given that parenting in mammals is essential for the survival of the offspring.  And plasticity, or adaptability, is a fundamental principle of life.  We have referred to this as 'facultativeness' in the past.  Organisms that are able to adapt to changing environments -- within survivable limits -- are much better equipped to survive and evolve.  Indeed, the final piece in this special section on parenting is titled "The evolution of flexible parenting."  Parenting behaviors among many species are well-documented to respond to environmental changes.  Put another way, it is not being genomically hard-wired that is most adaptable in these ways.

So, with all these examples of the interdigitation of nature and nurture, can we declare the death of genetic determinism?  Well, no.  Genetic determinism is alive and well, thanks in large part to Mendel and the resulting expectation that there are genes for traits that are out there to be found.  But in many ways, we've become prisoners of Mendel -- while many genes have been found to be associated with disease, we know very well that most traits are polygenic, and/or due to gene-environment interaction and we've know this for a century.  So the idea that the effect of parenting might transcend genes shouldn't be surprising.  And the idea that there might be factors that we haven't predicted that affect traits such as diseases or how brains work shouldn't be surprising, either.

The BBC recently aired an excellent 25-part program called "Plants: From Roots to Riches" about the history of Kew Gardens, and because the gardens have been so central to botany for so long, about the history of botany in general.  The series is still accessible online, and well worth a listen.  I bring this up because a story told on one of the episodes struck me as a very apropos lesson about causation.  A "Great Storm" hit the UK in 1987.  This was a hurricane that did tremendous damage, including killing millions of trees, 700 at Kew alone.

Before the storm, arborists had been concerned about a 200 year old tree at the Gardens, the Turner Oak.  It was clearly not well; leaves were stunted, growth was slow, but it wasn't clear what was wrong with it.  During the storm, the tree was uprooted completely and tossed into the air, but as luck would have it, it came back to earth right in the hole its exodus had created.  The arborists decided it didn't need as much attention as many other trees in the gardens after the storm, though, so they left it until they were finished tending to others.  This was three years later, at which time they discovered that the tree was thriving, growing again, and looking healthier than it had in decades.

Quercus x turneri at Kew Gardens; Royal Botanic Gardens

Why?  The arborists eventually realized that all the foot traffic at the Gardens had compacted the soil to the extent that the roots, and thus the tree, were suffering.  It turns out that the soil around a tree must be aerated if the tree is to thrive.

I love this serendipitous discovery.  A tree was ailing, no one knew why, until an unexpected event uncovered the explanation, and it turned out to be something that no one had thought to consider.  Many of the discoveries reported in the August 15 issue of Science strike me as of the same ilk.  Scientists have been looking for genes 'for' diabetes, taste, mental illness, obesity, and so on for decades now, and the explanation for these conditions may be instead events that happen even before conception, where it never occurred to anyone to look before.

There are numerous other examples; a few years ago it was reported that age at death (for late-life, not infant mortality) is affected by the month in which someone is born.  The authors, for some reason, did not follow up this potentially very important finding.  Maybe the effect is due to seasonal foods consumed by the mother during what turn out to be the riskier months of conception--if so, should there be lifelong evidence, if we but looked for it, of accelerated disease prodromes like obesity, hypertension and the like.

Perhaps the Turner Oak effect should be a thing -- it might encourage investigators to explicitly look for the unexpected.  What causes asthma? Could it be disposable diapers?  Who knows?  Broccoli has never been blamed for anything -- maybe it's time for broccoli to be implicated in some disease.  The problem is that we don't think to look because we all 'know' that broccoli is good for us.

Some ideas are kooky, but when it turns out that some kooky ideas really do seem to explain cause and effect, it means we shouldn't always be looking in the same place for our answers (the drunk under the lamppost phenomenon).  The cause and effect relationships described in the parenting issue of Science involve some unexpected environmental effects on gene expression -- epigenetic effects of various kinds -- and plasticity, meaning that cross-talk between genes and environment creates a give-and-take that can't be called genes or environment alone.  We don't know that these are final answers, but we know that we should expand our range of expected possibilities.

Perhaps the Turner Oak effect should guide more of our thinking in science.

The genetics of olfaction -- is a rose a rose by any other nose?

Laura Spinney writes about the genetics of olfaction in The Independent this week, and about population variation in what we can smell.  The genetics of olfaction have been pretty well worked out; in fact, the 2004 Nobel Prize in Physiology or Medicine went to Linda Buck and Richard Axel for this work.  But there is much still left to understand. 

Genes for olfactory receptors (ORs) comprise the largest gene family in the mammalian genome -- at about 900 genes and pseudogenes in humans, they make up approximately 3% of our total genome. On average, we've each got about 400 working olfactory receptor genes, and the rest have accumulated enough mutations to no longer be functional, and are now pseudogenes.  This is not quite accurate, because we are diploid so that we actually have about 800 OR genes, 2 copies of the 400.  Of the hundreds of these genes, many are polymorphically pseudogenes, meaning their sequence works in some copies in the population, but has been mutated out of function in others.

In addition, the copies we each have of each of our functional OR are themselves highly variable in their odorant binding pockets (the part of the receptor that binds to odorant molecules that float by in the nose).

"When I give talks, I always say that everybody in this room smells the world with a different set of receptors, and therefore it smells different to everybody," says Andreas Keller, a geneticist working at the Rockefeller University in New York City. He also suspects that every individual has at least one odorant he or she cannot detect at all – one specific anosmia, or olfactory "blind spot", which is inherited along with his or her olfactory apparatus.

Each olfactory receptor responds to several odorants.  But with so many genes, how on earth could we actually distinguish what we're smelling?  The answer is remarkable and one of the most interesting unsolved problems in genetics.  Our hundreds of OR genes are located in many different clusters of a few to hundreds of adjacent duplicate OR genes.  And we have two copies of each.  But in each individual olfactory neuron, only one of these hundreds of genes is expressed!  The other 799 genes, all over the genome, are inactive.

From Genetics and the
Logic of Evolution,
Weiss and Buchanan, 2004

Further, neurons expressing a given OR are in some way guided by that choice to collect in OR-specific locations in the olfactory bulb of the brain.  That's what makes it possible for the brain to tally what specific receptors have been triggered.  That is, the binding of an odorant to its receptor triggers its perception in the brain.  The wiring pattern is to some extent, at least, conserved among individuals, so in that sense we may share not only the ability to identify, say, 'lemon', but to experience it in somewhat similar ways.

Most odor perception involves a combination of signals from a number of different receptors.  And, some of those receptors may be non-functioning pseudogenes in some people, and if the subset of pseudogenes differs, the odor perceived will be different.

That genetic variability is reflected in behavioural variability, as Keller, with colleague Leslie Vosshall and others, recently demonstrated when they asked 500 people to rate 66 odours for intensity and pleasantness. The responses covered the full range from intense to weak, and from pleasant to unpleasant, with most falling in the moderate range – a classic bell curve in each case.

There is also variation in how intensely people can smell.  Some people are born with no ability to smell, while others are acutely aware of odors.  This may have nothing to do with odorant receptors, but instead how efficiently the odorant signal is transmitted to the brain.

One of us (Ken) spent a sabbatical in England working with Manolis Dermitzakis at the Sanger genome institute outside of Cambridge, trying to find genomic DNA sequence 'signals' that might help explain the extensive monoallelic and monogenic expression of only one OR per olfactory neuron.  Unfortunately, the search was frustratingly unfruitful. In fact, earlier we had done a study in the Pennsylvania Amish, collaborating with one of the experts cited in the Spinney story to see if, in this classic founder-effect population, we could work out the genetics of the ability to identify specific odorants, for which the ability to smell seemed, in other studies, to be polymorphic.  We couldn't find any pattern, because essentially everyone could smell all the test odorants.

The unusual expression pattern of this huge gene family, and the bookkeeping by which its detection of complex odorants allows us to identify our surroundings with a great deal of reliability (and, much more so in other species like dogs, who use the same system) is one of the remarkable, and incompletely understood, facts of genetic life.

The (lawless) laws of (human) nature

This week on The Forum, a BBC radio program, Bridget Kendall presented a show on translation -- specifically, the translation of Chinese poetry into English, the translation of science for the public, and the translation of the fall of the Berlin Wall -- what is gained and what is lost in translation. One of her guests was British Astronomer Royal, Lord Martin Rees, who has written a number of popular books about cosmology and astronomy.

Kendall asked Rees how scientists benefit from interpreting their science for popular consumption. He said that scientists often have a difficult time thinking beyond the details and remembering the larger picture, so that having to explain the big ideas is good for them. Kendall said that it must be particularly difficult for a cosmologist because people tend to feel that everyday phenomena should be easy to understand, but grander things like the cosmos are much harder. Rees says that's not true, that everyday things that people really care about, like diet or child rearing, are in fact much harder to understand than the stars; even experts don't understand them. If they did, ideas about what's healthy to eat or how to bring up a child wouldn't be changing all the time.

Now, we can't say whether or not cosmologists really have deciphered the stars. But, in some senses it doesn't really matter how much they've got wrong, because what we do with what we know about stars isn't nearly as relevant to everyday life as what we make of advice about what to eat and the like. Rees's point is reminiscent of things we write about all the time.

Why don't we know these things? We aren't stupid (well, 'we' here refers to science generally!). What is it about complex phenomena that's so hard to deconstruct? How on earth can a measly human be more problematic than zillions of stars, galaxies, and even voracious Black Holes!?

Why can't science even tell us what to eat? Here's our explanation -- we think it's because organisms have evolved to survive in a wide range of environments, and environmental changes can have from no to little to crippling to fatal effects, and their effects can vary along that continuum, even within a given species. This makes prediction nearly impossible, and the effects of change nearly undecipherable, due to the confounding effects of other, unnoticed, unmeasured changes, or to the fact that most changes don't happen in isolation.

Just as genes don't function in isolation, but in networks of genes, all of which are taking the measure of their environment all the time, via signaling, and responding by emitting signals of their own, to which other genes respond. And even when the information is false, in our current society, as soon as the latest Now-Eat-This story appears in the media, we modify what we eat, what kind of exercise we do, and so on, which then can change gene function and interaction, and down the road, disease risk. Stars, so far as we know, don't change their orbits just because some astronomer announces a different equation!

Which all, in a convoluted way, brings us back to Freud. Freud's explanation for behaviors was that they were the result of early childhood. One's upbringing. As opposed to the genetic determinism that's so prevalent today (though, in either case, mothers still get the blame). Well, we wouldn't go all the way with Uncle Sigmund, but there is clear evidence that even things happening in utero affect later life -- behavior, language, and even the late-onset disease risks. And add to this the way we meander according to our cultural fads and self-help advice, much less our exposures to chemicals, diets, lifestyles, and so on.

What's built in is our ability to assess our environment and act as we think is best, and that starts right at the beginning. What we're wired 'for' is not to be too wired, but to be responsive. That's a claim Betelgeuse can't match, and why the stars are condemned to circle obediently while our fault is in ourselves, not in our stars.

Einstein meets Newton, or Diabetes and the Theory of Relativity

Isaac Newton was one of the founders of modern science. He helped promulgate the idea of formal Laws of Nature, that Nature was law-like in that everywhere and every time the same fixed principles were at work, like the totally deterministic Law of Universal Gravitation. Because the Law worked everywhere and was deterministic, it worked at the smallest possible level, such as in time or space. That's why Newton could formulate natural law in terms of the calculus or, rather, that's why Newton developed what we call calculus. And this worked in part because space and time were absolutes. In that sense, causation was absolute as well.

Charles Darwin was clearly a product of the Newtonian age. He repeatedly wrote about natural selection as if it were at Law of Nature -- one Nature, indivisible, with Liberty and Justice for all. Justice here, would be the realization of your inherent fitness.

But life is not necessarily like that. Einstein spoiled Newton's party by showing, so to speak, that things were not absolute but only had meaning in terms relative to each other.

In evolution, we usually frame natural selection in relative terms -- this variant at a gene does better than that one does in this particular population and time. We could also view evolution in more absolute terms: this species or population, as a whole, does better today than it did yesterday. Usually this would refer to population expansion which would come at the expense of some other species, so would be relative in that sense.

In genetics, we tend to want to be Newtonian/Darwinians. We want genes to cause things in a rigorously predictable, law-like way. Thus we think of genetic variants as having inherent fitness value. And the important area of biomedical genetics is GWASh in such deterministic thinking.

But life's not like that! There is, for starters, a substantial number of 'known' disastrous disease-associated variants in humans that are normal in other vertebrates (one estimate is that 10% of our 'disease' mutations are like that). In fact, it's true even within our own species: in every individual whose whole genome sequence has been published to date, there are many 'disease' alleles, though the person is unaffected as of his current age.

And then there's the environment, which geneticists pray to Newton will go away! Genes have their effect in context, a point so obvious that it's easy to ignore if it's bad for business.

An area of Finland had the world's highest recorded risk of heart disease. But over a 20 year period, change of diet was the major factor in reducing heart disease mortality in Finland by something like 65% (that's no typo!).

And a new paper in The Lancet on diabetes, comparing outcomes in progression to diabetes in at-risk adults reports that "intensive lifestyle intervention" was significantly more effective in preventing diabetes than medication or placebo.

We've talked of Newton and Einstein, and how causation is relative. But even Einstein hungered for Newtonian lawlike deterministic Nature. And along came quantum mechanics.....

Who doesn't 'believe' in genes? Who does believe in miracles?

Disputes in science, as in any other field, can become polarizing and accusatory. Skepticism is almost by definition the term applied, usually in a denigrating way, to a minority view. Minority views are often if not usually wrong, but history shows that majority views can be similarly flawed (as we mentioned in our post of April 6). Indeed, major scientific progress occurs specifically when the majority view is shown to be incorrect in important ways.

It is sometimes said, or implied, about those who doubt some of the statements made about mapping complex traits by GWAS (see previous posts) and other methods, that the skeptics 'don't even believe in genes!' The word 'believe' naturally comes to the tongue when characterization of heretics is afoot, and reflects an important aspect of majority views (including the current basic theory in any science): they are belief systems.

In genetics, we know of nobody who doesn't 'believe' in genes. The question is not one of devil-worship by witches like those Macbeth met on a Scottish heath. The question is about what, where, and how genes work and how that is manifest in traits we in the life sciences try to understand. Not to believe in genes would be something akin to not believing in molecules, or heat.

In the case of human genetics, genes associated with and/or responsible for hundreds of traits including countless diseases, have been identified (you can easily read about them in OMIM and elsewhere). Many of these are clearly understandable as the effects, sometimes direct effects, of variation in specific genes.

In some examples, like cystic fibrosis, almost every case of a trait or disease is due to variation in the same gene. In others, such as hereditary deafness, different affected people or families are affected because of the effects of different genes, but it appears that the causal variants are so rare in the population that in each family deafness is only one of them. This is called multiple unilocus causation, and many different genes have been found for such traits (as in the deafness case shown).

Even for more complex traits like, say, diabetes or various forms of cancer, variation at some genes has strong enough effect that standard methods of gene-hunting were able to find them (and, yes, GWAS can find them, too!). BRCA1 and its association with risk of breast cancer is a classic instance of that. But often the results can't be replicated in other studies or populations, or even different families, a problem that has been much discussed in the human genetics literature, including papers written by us.

So, what is at issue these days is not whether genes exist, are important, or are worthy of study (and the same applies to human disease, or studies of yeast, bacteria, insects, flowering plants, or whatever you're interested in). Instead, what is at issue is how genes work in the context of complex traits that involve many interacting genetic and environmental factors.

And in addition to the basic understanding of how genes work in this context (and, incidentally, the rapidly expanding senses of DNA functions besides the usual concept of what a 'gene' is), is the question of how to find the genes and their effects, and what kinds of information that may provide in regard to applications in agriculture or human health.

In the latter case especially, the promise has been that we can predict your health from your DNA. Widely publicized companies are selling this idea in various ways from customer-submitted DNA samples, and some medical geneticists are promising personalized medicine in glowing terms, too.

Indeed, there has long been an effective profession dedicated to this general problem. It's called genetic counseling. Genetic counselors work in a monitored setting, with standardized approaches and ethical procedures in dealing with clients. They systematically collect appropriate clinical and other information. And for known genetic variation associated with disease they, or knowledgeable physicians, can make useful, personalized predictions, explaining options for treatment, family planning, and so on.

It is not a lack of 'belief' in genes, but the opposite--an understanding of genetics--that leads some scientists to question the likely efficacy of this or that proposed direction in health-related research, or in other areas such as criteria for developing evolutionary explanations (i.e., scenarios for past natural selection) for various traits including complex traits like diabetes and even social behavior.

Dispute in science should not be viewed or characterized as if it were the same as dispute in religion....even though both are similar cultural phenomena that often center around accepted theory or dogma. Questions about priorities and dramatic promises for scientific approaches are legitimate and all dogma should be questioned.

Every biologist we know 'believes' in genes. But not all biologists believe in miracles!