Friday, February 3, 2017

Save the Planet? Nonsense! But still.....

One hears a lot of Doomsday pleas that we should cut back on our consumption of carbon fuels, eat less meat, fish less, and so on--or else!  Or else what?  Or else, as it's often expressed, we'll destroy the planet!  Scientists speaking to each other about agricultural sustainability or climate change use less excessively inflammatory rhetoric, though even they can engage in catastrophism when the public media cameras are on.  Concern for the future is understandable, but exaggeration is not sensible if you stop to think about it. Crying "Wolf!" can backfire, because the Earth is not in imminent danger!

Human activity, even if we let our population rise to 10 or more billion and burn every single last chunk of coal and drop of oil, will not destroy the Earth.  No amount of energy conservation and sustainability will save the Earth from destruction, because it's not headed that way anyhow, and people haven't the power to destroy it (though, would we be able to come close with a nuclear WWIII?).

Indeed, it's possible that imminent catastrophe rhetoric reinforces the reactionary view that this is scientific nonsense and we should just close climate-change government-sponsored web sites and de-fund environmental science.

Part of the problem is that this is like the frog in a boiling kettle: the water gets hot so gradually that the frog doesn't notice it until it's too late.  We humans are not very good at long-term thinking or planning, perhaps because longterm thinking wasn't possible or useful as we evolved, when each day's food, safety and mates were what was at stake.  When change is slow, as global warming is, people often feel less inclined to self-denial today in exchange for a viable tomorrow.

In addition, sociologically speaking, climate change messages can be seen as a scientific or 'left-wing' elite telling everyone else that they have to scale-down, while at least some have noticed the fact that the same elite fly all over the world to have meetings, promote their books, and deliver their message (and flying is among the worst CO2 polluters).

In fact, most of what is being said by science, even taking scientists' vanities, frailties, and grant-hungers into account, is basically right.  The climate clearly is changing, the seas rising, agricultural patterns changing, many species endangered.  Of course, there have always been changes in patterns of rainfall, temperature, and vegetation, though the time scale generally has been glacially slow, so to speak, with the possible occasional exception of major meteorite strikes or huge volcanic eruptions etc.  The current speed is one reason human activity seems surely to be at least partially responsible.
Another important point isn't that climate is changing, but that the pace we're seeing today may not be reversible even if our behavior is contributing, because our ability to change the course of geoclimate might be limited.

But that doesn't mean that the science-deniers and their ilk hiding their head in the sand are right. They're as self-willed ignorant as scientists say they are.  They are pretending that the science is wrong, when the real truth is that they don't like the answers the science is giving us.

The real risk
If climate is always changing, and Save the Earth is a misleading slogan, the problem is that even if the Earth is not in danger, we are!  And that is the very, very personal and selfishly short-sighted reason that we should slow down global warming if we can, increase use of renewable energies, keep funding climate sciences, and so on.  Let's take a look at the wolf that really is at our door, and making enough evidentiary noise that we can't miss it.  What is at stake is not the Earth, but the kind of constancy we, like any species, rightfully feel comfortable with.

In fact, climate change does pose very serious, very real, and potentially dire risks. There are at least a few likely, foreseeable consequences of climate change:
1. Threatened lifestyles.  On the more mundane side, having to change where and how we live, what we eat, how we interact with each other, and so on, are major dislocations of lifestyle.  Being animals, we like our 'territory' to be familiar and feel safe.  The levels of ill-will and unhappiness that would ensue major cultural upsets due to climate change and its consequences, would be upsetting to a great many people. There may indeed be changed patterns of wealth, lifestyle, disease in us and/or our animal and plant food sources.  We may exhaust some minerals vital to our technological support systems. Even peacefully, gradually adapting to a lower-consuming lifestyle could avoid this, but would be disruptive; even if we lived very well in lower-consuming times in the past, social and psychological factors will be strained if our life-ways are changed too much or too fast. 
2.  Mass dislocation.  Most cities and urban concentrations are near natural waterways.  That's because they were founded over many centuries when water-borne trade and transport of goods etc., the stuff that makes concentrated populations possible, was the only real means of large-scale transportation.  So, if water levels rise along coasts and major lakes or rivers, or if waterways dry up, there will be dislocations that make todays middle east refugees look like tiddly-winks by comparison.  If tens of millions of Londoners and New Yorkers (not to mention residents of China or India) need to relocate, they'll have to go where there already are people.  This mass internal migration will be seen by the 'recipients' as 'Yugely' more of a threat than refugees today pose. 
3.  Exacerbated inequality and suffering.  Other large-scale dislocations of many sorts will mean economic deprivation for some who were well off, and new privilege for others.  Climate change alters agricultural areas, drying some up and making others flourish. Food being one thing people really do fight over, one can anticipate major economic dislocation and very large-scale competition for the new food producing areas, by those whose breadbaskets dried up.  This means war and potentially on a massive scale.  With 10 billion people, and industrial-scale weaponry (including nukes), the suffering will potentially be massively unprecedented.
In the overall scheme of things, a few island populations imminently needing relocation is an enormous event for the islanders but not a terribly large event globally.  But when cities become inundated, and food hard to come by, when refugees number in the many millions, and they're armed, well, that may be a definition of Arm-aggedon (forgive the pun).

We should be talking turkey to the public. Even if climate change is human-accelerated, it is not the first time there has been major climate change.  The Earth, and even the human species, will survive it.  Scientists should not be pressed by the intentionally uneducated into over-stating the case.  The planet is not in danger.  But in a sense there really is a wolf knocking at the door, and it is worth saving the planet as we know it.

What is in danger is our way of life.  And that's something humans kill for.

Friday, January 27, 2017

Evolution as a pachinko history: what is 'random'?

We discussed a Japanese pachinko machine in an earlier post, a pinball machine, as an example of the difference between randomness and determinism, in an evolutionary context.   Here we want to use pachinko machine imagery in a different way.

The prevailing, often unstated but just-under-the-surface assumption is that every trait in life is here because of natural selection.  Of course, for a trait to be here at all, bearers of its ancestral states up to the present (or, at least, the recent past) were successful enough to have reproduced.  It would not be here if it were otherwise, unless, for example, it's itself harmful, or without function but connected to a much better, related trait since genes are usually used in many different bodily contexts and may be associated with both beneficial and harmful traits.  Most sensible evolutionary geneticists know that many or even most sites in genomes tolerate variation that has either no effect or effects so small that in realistic population sizes they change in frequency essentially by chance.

However, the widespread default assumption that there must be an adaptive explanation for every trait usually also tacitly assumes that probabilism doesn't make much difference.  Some alert evolutionary biologists will acknowledge that one version among contemporary but equivalent versions of a trait can evolve by chance relative to other versions.  But the insistence, tacit or expressed, is that natural selection, treated essentially as a force, is responsible.  The very typical view is that the trait arose because of selection 'for' it, and that's why it's here.  And speaking of 'here', here's where a pachinko analogy may be informative.

If a bevy of metal balls tumbles through the machine, each bouncing off the many pins, they will end up scattered across the bottom ledge of the machine (the gambling idea is to have them end up in a particular place, but that's not our point here).  So let's take a given ball and ask 'Why did it end up where it did?"

The obvious and clearly true answer is 'Gravity is responsible'.  That is the analogue of 'selection is responsible'.   But it is rather an empty answer.  One can always say that what's here must be here because it was favored (that is, not excluded) by fitness considerations: its ancestral bearers obviously reproduced!  We can define that as 'adaptation' and indeed in a sense that is what is done every day, almost thoughtlessly.

Gravity is, like the typical if tacit assumption about natural selection, a deterministic force for all practical purposes here.  But why did this ball end up in this particular place?  One obvious answer is that each starts out in a slightly different place at the top, and no two balls are absolutely identical. However, each ball makes a different path from the top to the bottom of the obstacle course it faces. Yes, it is gravity that determines that they go down (adapt), but not how they go down.

In fact, each ball takes a different path, zigging and zagging at each point based on what happens, essentially by chance, at that point.   This one might think of as local ecosystems on the evolutionary path of any organism, that are beyond its control.  So, in the end, even if the entire journey is deterministic, in the sense that every collision is, the result is not one that can, in practice, be understood except by following the path of each ball (each trait, in the biological analogy).  And this means that the trajectory cannot be predicted ahead of time. And in turn, this means that our interpretation of what a trait we see today was selected 'for' is often if not usually either basically just a guess or, more often, equates what the trait does today to what it was selected to be, expressed as if it were an express train from then to now.

And this doesn't consider another aspect of the chaotic and chance-affected nature of evolutionary adaptation: the interaction with the other balls bouncing around at the same time in such an obstacle course.  Collisions are in every meaningful sense in the game of life, if not pachinko, chance events that affect selective ones, even were we to assume that selection is simple, straightforward, and deterministic.

The famous argument by Gould and Lewontin that things useful for one purpose, such as 'spandrels' in cathedral roofs, are incidental traits that provide the options for future adaptations--life exploits today with what yesterday produced for whatever reason even if just by chance.  The analogy or metaphor has been questioned, but that is not important here.  What is important is that contingencies of this nature are chance events, relative to what builds on them.  Selectionism as a riposte to creationism is fine but hyper-selectionism becomes just another often thought-free dogma.  Darwin gave us inspiration and insight, but we should think for ourselves, not in 19th century terms.

A far humbler, and far less 'Darwinian' (but not anti-Darwinian!), explanation of life is called for if we really want to understand evolution as a subtle often noisy process, rather than as a faith.  Instead, even serious biologists freely invent--and that's an apt word for it--selective accounts, as if true explanations, for almost any trait one might mention. It's invented because some reason is imagined without any direct evidence other than present-day function, but then treated as if directly observed, which is rarely possible. Here is an interview that I just came across that in a different way makes some of the same points we are trying to make here.

Everything here today is 'adaptive' in the sense that it has worked up to now.  Everything here today is also a 4 billion year successful lineage, that all made its way through the pachinko pins.  But these are almost vacuous tautologies.  Understanding life requires understanding one's biases in trying to force simple solutions on complicated reality.

Thursday, January 19, 2017

Relatedness is relative: How can I be 85% genetically similar to my mom, but only related to her by half?

First of all, no. I am not the lovechild of star-crossed siblings, or even cousins, or even second cousins. 

This is a gee-whiz kind of post. But the issues are not insignificant.

Hear me out with the background, first, before I get to the part where my eyes bug out of my head and I pull out my kid's Crayola box and start drawing.

If you've learned about sociobiology, or evolutionary psychology, or inclusive fitness, or kin selection, or the evolution of cooperation and even "altruism," or if you've read The Selfish Gene, or if you've been able to follow the debate about levels of selection (which you can peek at here)...

... then you've heard that you're related to your parents by 1/2, to your siblings by 1/2 as well, to your grandparents and grandchildren by 1/4, to your aunts and uncles and nieces and nephews by 1/4 as well, and to your first cousins by 1/8 and so on and so forth.  (Here's some more information.)

So, for example. For evolution (read: adaptationism) to explain how cooperative social behavior could be adaptive in the genetic sense, we use the following logic provided by Bill Hamilton, which became known as "Hamilton's Rule": 

The cost to your cooperation or your prosocial behavior (C) must be less than its benefit to you (B), reproductively speaking, relative to how genetically related (r) you are to the individual with whom you're cooperating. That could have come out smoother. Oh, here you go:

C < rB, or B > C/r

If you're helping out your identical genetic twin (r=1.0), then as long as the benefit to you is greater than the cost, it's adaptive.

C < B, or B > C

If you're helping out your daughter (r = 0.5) then as long as the benefit to you is greater than twice the cost, it's adaptive.

C < (1/2)B, or B > 2C

So already, the adaptive risk to helping out your daughter or your brother is quite higher. And it's even harder to justify the cooperation between individuals and their sibs' kids, and grandkids, especially ESPECIALLY non-kin. But, of course creatures do it! And so do we.

As relatedness gets more distant and distant, we go from 2 times the cost, to 4 times, 8 times, 16, 32, 64 etc... You can see why people like to say "the math falls away" or "drops off" at first or second cousins when they're explaining where the arbitrary line of genetic "kin" is drawn.  If you offer up a curious, "we're all related, we're all kin," someone out of this school of thought that's focused on explaining the evolution of and genes for social behavior may clue you in by circumscribing "kin" as the members of a group that are r = 1/8 or r = 1/16 but usually not less related than that.

This has long bothered me because we're all genetically related and so much cooperation beyond close kin is happening. And it's been hard for me, as someone who sees everything as connected, to read text after text supporting "kin selection" and "kin recognition" (knowing who to be kind to and who to avoid bleeping), to get past the fact that we're arbitrarily deciding what is "kin" and it seems to be for convenience. I'm not doubting that cooperation is important for evolutionary reasons. Quite the contrary! It's just that why is there so much math, based in so many potentially unnecessary assumptions about genes for behavior, gracing so many pages of scientific literature for explaining it or underscoring its importance? 

(It could just be that as an outsider and a non-expert I just don't understand enough of it and if I only did, I wouldn't be gracing this blog with my questions. But let's get back to my reason for posting anyway because it's potentially useful.)

Right. So. Even for folks who aren't part of evolution's academic endeavor, it's obvious to most that we're one half dad and one half mom. The sperm carries one half of a genome, the egg another, and together they make a whole genome which becomes the kid. Voila!

There's even an adorable "Biologist's Mother's Day" song about how we've got half our moms' genome... 

... but there's biology above and beyond the genes we get from mom (and not from dad). And that song is great for teaching us that the rest of the egg and the gestational experience in utero provide so much more to the development of the soon-to-be new human. So "slightly more than half of everything" is thanks to our mothers. Aw!

But, genetically, the mainstream idea is still that we're 50% our mom. 

I teach very basic genetics because I teach evolution and anthropology.And I'm not (usually) a dummy.* I get it. It's a fact! I'm half, genetically, my mom and I'm also half my dad. 

r = 0.5

Okay! But, given these facts about relatedness and how it's imagined in evolutionary biology, facts that I never ever questioned, I hope you can see why this report from 23andMe (personal genomics enterprise) blew my mind:

Percent similarity to Holly Dunsworth over 536070 SNPs (single nucleotide polymorphisms or, effectively/rather, a subset of known variants in the genome; Click on the image to enlarge).
I am 85% like my mom and I am at least 76% like my students and friends who are sharing with me on 23andMe. Names of comparisons have been redacted. As far as I know, this kind of report is no longer offered by 23andMe. I spat back in 2011/12 and the platform has evolved since.

Okay, first of all, it is a huge relief that, of all the people I'm sharing with on 23andMe, the one who squeezed me out of her body is the most genetically similar to me. Science works.

But that number there, with my mother, it is not 50%. It's quite a bit bigger than that. 

What's more, I am also very similar to every single person I'm sharing with on the site, including example accounts from halfway around the world. Everyone is at least 60-ish% genetically similar to me, according to 23andMe. I know we're all "cousins," but my actual cousins are supposed to be 1/8th according to evolutionary biology. How can my mom be related to me by only one half? How can my actual cousins be only an eighth (which is 12.5%)? 

What is up with evolutionary biology and this whole "r" thing?

Hi. Here is where, if they weren't already, people just got really annoyed with me. Evolutionary biology's "relatedness" or "r" is not the same as genetic similarity like that reported by 23andMe.


But why not? 

Let me help unpack the 85% genetic similarity with my mom. Remember, it's not because I'm inbred (which you have to take my word for, but notice that most everyone on there is over 70% genetically similar to me so...).

It's because my mom and dad, just like any two humans, share a lot in common genetically. Some of the alleles that I inherited from my dad are alleles that my mom inherited from her parents. So, not only is everything I got from her (50%) similar to her, but so are many of the parts that I got from my dad. 

Let me get out my kid's arts supplies.

Here is a pretty common view of relatedness, genetically. In our imagination, parents are not related (r = 0) which can lead our imagination to think that their alleles are distinct. Here there are four distinct alleles/variants that could be passed onto offspring, with each offspring only getting one from mom and one from dad. In this case, the sperm carrying the orange variant and the egg with the blue variant made the baby.

1. (Please, if you're horrified by the "r" business in these figures, read the post for explanation.)
But few genes have four known alleles, at least not four that exist at an appreciable frequency. Some could have three. What does that look like? 

The green allele doesn't exist in the next example. As a result of there being only three variants for this gene or locus, mom and dad must share at least one allele, minimum. That means, they look related and that means that, depending on which egg and sperm make the kid, the kid could be more related to mom than to dad. 

2. (Please, if you're horrified by the "r" business in these figures, read the post for explanation.)
Now here's where people who know more than I do about these things say that the kid is not more related to mom than dad because she got only one allele from mom and that keeps her at r = 0.5. 

Well, that's just insane. What does it matter whether she got the allele from mom or dad? I thought genes were selfish? (Sorry, for the outburst.)

Again, I realize I'm annoying people and probably much worse--like stomping all over theory and knowledge and science--by mixing up the different concepts of genetic similarity (e.g. 50%) with "r" (e.g. 0.5) and horribly misunderstanding all the nuance (and debate) about "r," but I'm doing it because I'm desperately trying to know why these two related ideas are, in fact, distinct. 

One last pathetic cartoon. 

In this third example, as is common in the genome, there are only two alleles/variants in existence (at an appreciable frequency, so not accounting for constant accumulation of de novo variation). An example of such a gene with only two known alleles is the "earwax gene" ABCC11 (there's a wet/waxy allele and dry/crumbly one). Here, the two alleles are orange and blue. Most humans in the species will have at least one allele in common with their mate for a gene with two alleles, and it's not because most humans are inbred, unless we want to redefine inbreeding to include very distant relatives (aside: which may be how the term is used by experts). 

3. (Please, if you're horrified by the "r" business in these figures, read the post for explanation.)
But as a result of the chance segregation of either the blue or orange allele into each of the gametes, two people with the same genotype can make a kid with the same genotype. 

And of course, making a kid with your same genotype is the only possible outcome if you and your mate are both homozygous (i.e. where both copies are of the same variant so that leaves no chance for variation in offspring unless there is a new mutation). 

So, I wandered a little bit away from my point with these drawings, but I had to because I wanted to get down from where my imagination has me (us?) with "r" versus how things really are with reproduction. We are baby-making with vastly similar genomes to ours, so we are making babies with vastly similar genomes ours. 

So, I do see why biology says I'm related to my mom by one half. But, on the other hand, what does it matter if I got the thing I have in common with my mom from my mom or whether I got it from my dad? Because I got it. Period. It lives. Period. 

[Inserted graf 1/20/17] Saying it matters where I got the similarity to my mom keeps us at r = 0.5. Saying it matters only that I inherited DNA like hers keeps us always, all of us, at r > 0.5 with our parents and our kids because any two babymakers share much of their genome.

And the fact that this (see 2 and 3) happens so often is why I'm a lot more than 50% genetically like my mom, and the same can be said about my genetic similarity to my dad without him even spitting for 23andMe. 

So, here we are. I don't understand why our relatedness to one another, based on genetic similarity, is not "r."

I hope it's for really beautifully logical reasons and not something political. 


If "r" was defined by genetic similarity, then would cooperating with my 76% genetically similar students and friends be more adaptive than the credit I currently get from evolutionary biology for cooperating with my own flesh and blood son? 

If "r" was defined by genetic similarity, then could we use the power of math and theoretical biology to encourage broader cooperation among humans beyond their close kin? 

So many questions.

Maybe I should re-learn the math and learn all the other math.

Nah. Not myself. At least, it wouldn't come fast enough for my appetite. Maybe someone who already knows the math could leave a comment and we could go from there... 

And it would be worth it, you know, because despite my relatively weaker math skills, I bet we're more than 50% genetically similar.

*from 23andMe: "You have 321 Neanderthal variants. You have more Neanderthal variants than 96% of 23andMe customers."

Wednesday, December 28, 2016

Post-truth science?

This year was one that shook normal politics to its core.  Our belief in free and fair elections, in the idea that politicians strive to tell the truth and are ashamed to be caught lying, in real news vs fake, in the importance of tradition and precedent, indeed in the importance of science in shaping our world, have all been challenged.  This has served to remind us that we can't take progress, world view, or even truth and the importance of truth themselves for granted.  The world is changing, like it or not.  And, as scientists who assume that truth actually exists and whose lives are devoted to searching for it, the changes are not in familiar directions.  We can disagree with our neighbors about many things, but when we can't even agree on what's true, this is not the 'normal' world we know.

To great fanfare, Oxford Dictionaries chose "post-truth" as its international word of the year.
The use of “post-truth” — defined as “relating to or denoting circumstances in which objective facts are less influential in shaping public opinion than appeals to emotion and personal belief” — increased by 2,000 percent over last year, according to analysis of the Oxford English Corpus, which collects roughly 150 million words of spoken and written English from various sources each month.  New York Times
I introduce this into a science blog because, well, I see some parallels with science.  As most of us know, Thomas Kuhn, in his iconic book, The Structure of Scientific Revolutions, wrote about "normal science", how scientists go about their work on a daily basis, theorizing, experimenting, and synthesizing based on a paradigm, a world view that is agreed upon by the majority of scientists.  (Although not well recognized, Kuhn was preceded in this by Ludwik Fleck, Polish and Israeli physician and biologist who, way back in the 1930s, used the term 'thought collective' for the same basic idea.)

When thoughtful observers recognize that an unwieldy number of facts no longer fit the prevailing paradigm, and develop a new synthesis of current knowledge, a 'scientific revolution' occurs and matures into a new normal science.  In the 5th post in Ken's recent thought-provoking series on genetics as metaphysics, he reminded us of some major 'paradigm shifts' in the history of science -- plate tectonics, relativity and the theory of evolution itself.

We have learned a lot in the last century, but there are 'facts' that don't fit into the prevailing gene-centered, enumerative, reductive approach to understanding prediction and causation, our current paradigm.  If you've read the MT for a while, you know that this is an idea we've often kicked around.  In 2013 Ken made a list of 'strange facts' in a post he called "Are we there yet or do strange things about life require new thinking?" I repost that list below because I think it's worth considering again the kinds of facts that should challenge our current paradigm.

As scientists, our world view is supposed to be based on truth.  We know that climate change is happening, that it's automation not immigration that's threatening jobs in the US, that fossil fuels are in many places now more costly than wind or solar.  But by and large, we know these things not because we personally do research into them all -- we can't -- but because we believe the scientists who do carry out the research and who tell us what they find.  In that sense, our world views are faith-based.  Scientists are human, and have vested interests and personal world views, and seek credit, and so on, but generally they are trustworthy about reporting facts and the nature of actual evidence, even if they advocate their preferred interpretation of the facts, and even if scientists, like anyone else, do their best to support their views and even their biases.

Closer to home, as geneticists, our world view is also faith-based in that we interpret our observations based on a theory or paradigm that we can't possibly test every time we invoke it, but that we simply accept.  The current 'normal' biology is couched in the evolutionary paradigm often based on ideas of strongly specific natural selection, and genetics in the primacy of the gene.

The US Congress just passed a massive bill in support of normal science, the "21st Century Cures Act", with funding for the blatant marketing ploys of the brain connectome project, the push for "Precision Medicine" (first "Personalized Medicine, this endeavor has been, rebranded -- cynically? --yet again to "All of Us") and the new war on cancer.  These projects are nothing if not born of our current paradigm in the life sciences; reductive enumeration of causation and the ability to predict disease.  But the many well-known challenges to this paradigm lead us to predict that, like the Human Genome Project which among other things was supposed to lead to the cure of all disease by 2020, these endeavors can't fulfill their promise.

To a great if not even fundamental extent, this branding is about securing societal resources, for projects too big and costly to kill, in a way similar to any advertising or even to the way churches promise heaven when they pass the plate. But it relies on wide-spread acceptance of contemporary 'normal science', despite the unwieldy number of well-known, misfitting facts.  Even science is now perilously close to 'post-truth' science. This sort of dissembling is deeply built into our culture at present.

We've got brilliant scientists doing excellent work, turning out interesting results every day, and brilliant science journalists who describe and publicize their new findings. But it's almost all done within, and accepting, the working paradigm. Too few scientists, and even fewer writers who communicate their science, are challenging that paradigm and pushing our understanding forward. Scientists, insecure and scrambling not just for insight but for their very jobs, are pressed explicitly or implicitly to toe the current party line. In a very real sense, we're becoming more dedicated to faith-based science than we are to truth.

Neither Ken nor I are certain that a new paradigm is necessary, or that it's right around the corner. How could we know? But, there are enough 'strange facts', that don't fit the current paradigm centered around genes as discrete, independent causal units, that we think it's worth thinking about whether a new synthesis, that can incorporate these facts, might be necessary. It's possible, as we've often said, that we already know everything we need to know: that biology is complex, genetics is interactive not iterative, every genome is unique and interacts with unique individual histories of exposures to environmental risk factors, evolution generates difference rather than replicability, and we will never be able to predict complex disease 'precisely'.

But it's also possible that there are new ways to think about what we know, beyond statistics and population-based observations, to better understand causation.  There are many facts that don't fit the current paradigm, and more smart scientists should be thinking about this as they carry on with their normal science.

Do strange things about life require new concepts?
1.  The linear view of genetic causation (cis effects of gene function, for the cognoscenti) is clearly inaccurate.  Gene regulation and usage are largely, if not mainly, not just local to a given chromosome region (they are trans);
2.  Chromosomal usage is 4-dimensional within the nucleus, not even 3-dimensional, because arrangements are changing with circumstances, that is, with time;
3.  There is a large amount of inter-genic and inter-chromosomal communication leading to selective expression and non-expression at individual locations and across the genome (e.g., monoallelic expression).  Thousands of local areas of chromosomes wrap and unwrap dynamically depending on species, cell type,  environmental conditions, and the state of other parts of the genome at a given time; 
4.  There is all sorts of post-transcription modification (e.g., RNA editing, chaperoning) that is a further part of 4-D causation;
5.  There is environmental feedback in terms of gene usage, some of which is inherited (epigenetic marking) that can be inherited and borders on being 'lamarckian';
6.  There are dynamic symbioses as a fundamental and pervasive rather than just incidental and occasional part of life (e.g., microbes in humans);
7.  There is no such thing as 'the' human genome from which deviations are measured.  Likewise, there is no evolution of 'the' human and chimpanzee genome from 'the' genome of a common ancestor.  Instead, perhaps conceptually like event cones in physics, where the speed of light constrains what has happened or can happen, there are descent cones of genomic variation descending from individual sequences--time-dependent spreading of variation, with time-dependent limitations.  They intertwine among individuals though each individual's is unique.  There is a past cone leading of ancestry to each current instance of a genome sequence, from an ever-widening set of ancestors (as one goes back in time) and a future cone of descendants and their variation that's affected by mutations.  There are descent cones in the genomes among organisms, and among organisms in a species, and between species. This is of course just a heuristic, not an attempt at a literal simile or to steal ideas from physics! 
Light cone: Wikipedia

8.  Descent cones exist among the cells and tissues within each organism, because of somatic mutation, but the metaphor breaks down because they have strange singular rather than complex ancestry because in individuals the go back to a point, a single fertilized egg, and of individuals to life's Big Bang;
9.  For the previous reasons, all genomes represent 'point' variations (instances) around a non-existent core  that we conceptually refer to as 'species' or 'organs', etc.('the' human genome, 'the' giraffe, etc.);
10.  Enumerating causation by statistical sampling methods is often impossible (literally) because rare variants don't have enough copies to generate 'significance', significance criteria are subjective, and/or because many variants have effects too small to generate significance;
11.  Natural selection, that generates current variation along with chance (drift) is usually so weak that it cannot be demonstrated, often in principle, for similar statistical reasons:  if cause of a trait is too weak to show, cause of fitness is too weak to show; there is not just one way to be 'adapted'.
12.  Alleles and genotypes have effects that are inherently relativistic.  They depend upon context, and each organism's context is different;
13.  Perhaps analogously with the ideal gas law and its like, phenotypes seem to have coherence.  We each have a height or blood pressure, despite all the variation noted above.  In populations of people, or organs, we find ordinary (e.g., 'bell-shaped') distributions, that may be the result of a 'law' of large numbers: just as human genomes are variation around a 'platonic' core, so blood pressure is the net result of individual action of many cells.  And biological traits are typically always changing;
14. 'Environment' (itself a vague catch-all term) has very unclear effects on traits.  Genomic-based risks are retrospectively assessed but future environments cannot, in principle, be known, so that genomic-based prediction is an illusion of unclear precision; 
15.  The typical picture is of many-to-many genomic (and other) causation for which many causes can lead to the same result (polygenic equivalence), and many results can be due to the same cause (pleiotropy);
16. Our reductionist models, even those that deal with networks, badly under-include interactions and complementarity.  We are prisoners of single-cause thinking, which is only reinforced by strongly adaptationist Darwinism that, to this day, makes us think deterministically and in terms of competition, even though life is manifestly a phenomenon of molecular cooperation (interaction).  We have no theory for the form of these interactions (simple multiplicative? geometric?).
17.  In a sense all molecular reactions are about entropy, energy, and interaction among different molecules or whatever.  But while ordinary nonliving molecular reactions converge on some result, life is generally about increasing difference, because life is an evolutionary phenomenon.
18. DNA is itself a quasi-random, inert sequence. Its properties come entirely from spatial, temporal, combinatorial ('Boolean'-like) relationships. This context works only because of what else is in (and on the immediate outside) of the cell at the given time, a regress back to the origin of life.

Tuesday, December 27, 2016

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

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

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

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

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

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

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

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

1. Evolution works by difference, not replication Since Newton or perhaps back to the Greek geometers, what we now call 'science' largely was about understanding the regularities of existence.  What became known as 'laws' of Nature were, initially for theological reasons, assumed to be the basis of existence.  The same conditions led to the same outcomes anywhere.  Two colliding billiard balls here on Earth or in any other galaxy, would react in identical ways (yes, I know, that one can never have exactly the same conditions--or billiard balls--but the idea is that the parts of the cosmos were exchangeable.)  But one aspect of life is that it is an evolved chemical phenomenon whose evolution occurred because elements were different rather than exchangeable.  Evolution and hence life, is about interactions or context-specific relative effects (e.g., genetic drift, natural selection). 
2.  Life is a phenomenon of nested (cladistic) tree-like relationships Life is not about separated, independent entities, but about entities that from the biosphere down (at least) to individual organisms are made of sets of variations of higher-level components.  Observation at one level, at least from cells up to organs to systems to individuals, populations, species and ecosystems, are reflections of the nested level(s) the observational level contains. 
3.  Much genetic variation works before birth or on a population level Change may arise by genetic mutation, but function is about interactions, and success--which in life means reproduction--depends on the nature of the interactions at all levels.  That is, Darwinian competition among individuals of different species is only one, and perhaps one of the weakest, kinds of such interaction.  Embryonic development is a much more direct, and stronger arena for filtering interactions, than competition (natural selection) among adults for limited resources.  In a similar way, some biological and even genetic factors work only in a population way (bees and ants are an obvious instance, as are bacterial microfilm and the life cycles of sponges or slime molds). 
4.  Homeostasis is one of the fundamental and essential ways that organisms interact Homeostasis as an obvious example of a trans phenomenon.  It's complexly trans because not only do gene-expression combinations change, but they are induced to change by extra-cellular and even extra-organismal factors both intra and inter-species.  The idea of a balance or stasis, as with organized and orchestrated combinatorial reaction surely cannot be read of in cis.  We have known about interactions and reactions and so on, so this is not to invoke some vague Gaia notions, but to point out the deep level of interactions, and these depend on many factors that themselves vary, etc. 
5. Environments include non-living factors as well as social/interaction ones No gene is an island, even if we could identify what a 'gene' was, and indeed that no gene stands alone is partly why we can't.  Environments are like the celestial spheres: from each point of view everything else is the 'environment', including the rest of a cell, organ, system, organism, population, ecosystem.  In humans and many other species, we must include behavioral or social kinds of interactions as 'environment'.  There is no absolute reference frame in life any more than in the cosmos.  Things may appear linear from one point of view, but not another.  The 'causal' effects of a protein code (a classical 'gene') depend on its context--and vice versa
6. The complexity of factors often implies weak or equivalent causation--and that's evolutionarily fundamental. Factors or 'forces' that are too strong on their own--that is, that appear as individually identifiable 'units'--are often lethal to evolutionary survival.  Most outcomes we (or evolution) care about are causally complex, and they are always simultaneously multiple: a species isn't adapting to just one selective factor at a time, for example.  Polygenic causation (using the term loosely to refer to complex multi-factoral causation) is the rule.  These facts mean that individually identified factors usually have weak effects and/or that there are alternative ways to achieve the same end, within or among individuals.  Selection, even of the classical kind, must be typically weak relative to any given involved factor. 
7. The definition of traits is often subjective and affects their 'cause' Who decides what 'obesity', 'intelligence', or 'diabetes' is?  In general, we might say that 'Nature' decides what is a 'trait', but in practice it is often we, via our language and our scientific framework, who try to divide up the living world into discrete categories and hence to search for discrete causal factors.  It is no surprise that what we find is rather arbitrary, and gives the impression of biological causation as packaged into separate items rather than being fundamentally about a 'fabric' of interactions.  But the shoehorn is often a major instrument in our causal explanations. 
8. The 'quantum mechanics' effect: interaction affects the interactors In many aspects of life, obviously but not exclusively applied to humans, when scientists ask a question or publicize a result, it affects the population in question.  This is much like the measurement effect in quantum mechanics.  Studying something affects it in ways relevant to the causal landscape we are studying.  Even in non-human life, the 'studying' of rabbits by foxes, or of forests by sunlight, affects what is being studied.  This is another way of pointing out the pervasive centrality of interaction.  Just like political polls, the science 'news' in our media, affect our behavior and it is almost impossible to measure the breadth and impact of this phenomenon.

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

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

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

Monday, December 26, 2016

Is genetics still metaphysical? Part V1/2. A relevant holiday exercise?

It's the holiday season, and what with family and friends, and over-eating (and drinking), one can't operate at full speed.  So I thought that by writing a quick half-post in this series (post V 1/2), I could stall for a day or two before wrapping it up.

Yesterday, as in the past on Christmastime, I took some familiar verse and turned it into some science-relevant doggerel.  In prior years I've mainly reworked well known carols or Christmas songs.  This year I chose some verses that most readers of MT will have been familiar with or even have read in school.  I do it for the fun and challenge, but what exactly does the process involve?  On thinking about that, in the context of the current series of posts about genetic and evolutionary theory, and advances in scientific theory generally, it struck me that the process of writing this kind of doggerel has some inadvertent lessons to teach.

I don't know how you or anyone else cobbles a bit of doggerel together (here, I guess I can't resonate with those of you who take a common view, and think doggerel is so inane that it should be against the law).

I take a well-known poem or stanza, that has long been in my head and that I think most readers will recognize.  This is a form, or we could even think of it as a 'species', with a kind of unity.  My objective is to try to modify that unity to give some other sort of message, but without changing the recognizability of the original.

I try my best to keep as many of the original words as possible, as well as the meter and even the punctuation.  But I substitute words to achieve a very different meaning.  In my obviously amateurish way, I at least try with these new words to keep the phrasing, stress, consonants and vowels as similar as I can.  In that sense, it should 'feel' like the same verse, but have a totally different, unrelated or even reversed message.  Here is how I modified the first 4 lines of Trees:

Original :                                                       My doggerelic changes:                    
I think that I shall never see                          I think that I shall never see
A poem lovely as a tree.                               A gene as lovely as a tree
A tree whose hungry mouth is prest             A gene whose  histones' mouth is pres'd
Against the earth's sweet flowing breast;      'Gainst coiled enhancer's flowing twist;

Reading the new version should feel, in a metric sense and beyond, like the original.  The changes can be humorous, satirical, or poignant, but the new poem should be a kind of new species in the same genus as the original.  It is in that sense an evolutionary product: it did not start from scratch, and it retained the 'fitness' characteristics--the basic framework and substance--of the original.

You can see that no single word-change, not even a groan-worthy pun, can achieve this.  Each new word or modification, alters the meaning of a phrase, or its impact or 'feeling', but in itself would make no sense.  This is obvious, when you look at the famous two lines:

Poems are made by fools like me,                   Genes are named by fools like me,
But only God can make a tree.                         But lonely genes can't make a tree.

Here, my hopefully obvious contrast was of individual causal elements (individual genes) and the composite action of many genes working together.

In a second example from yesterday's post, here is what I did with Browning's very famous sonnet:

How do I love thee?  Let me count the ways.
I love thee to the depth and breadth and height
My soul can reach, when feeling out of sight

My doggerelic changes:
How do I leaf thee?  Let me count the ways.
I leaf thee to the depth and breadth and height
My bows can reach, when flow'ring out of sight

For survival as a unit, multiple changes must be made, and there may be many ways to do it (or to try it, at least, as I can tell you from the effort  to make yesterday's doggerel versions worth posting!).   The revision should read, or sound, or feel like the original, even if the overall meaning is profoundly changed.  One can build a new sense to a slight extent, with a single change, but the thing really wouldn't fly until many changes are made and a key point is that the changes must work in trans: they must relate to each other!  As in the original, the various parts interact to generate the end result. Even to be viable as a working intermediate, I find that I must make at least a few changes, but I can vary these, adding or removing some, always going back to the original, as I work towards what (when it's done) I find acceptable.  In fact, if I look back, I can see better ways I might have done it.

This is an evolution, but it is of course not like biological evolution in one very important--and relevant--sense:  I have some goal in mind.  My goal is usually generic, and it may change, so it's not entirely teleological (it leads to 'spandrels', if you're familiar with that famous view of the evolution of novelty), but when I make even my first change test, I have a thought about the general direction.

However, this process does involve a kind of overall, integrative synthesis--the topic of our 'metaphysical gene' series here.  At some point, for an amateur like me at least, it just feels right as a unit.  Each individual change may then be examined and re-modified, but only in the context of the new whole.  For me, it feels as if I have seen the many parts of both the original and the bits I've changed, or other bits I might change, or alternatives in the context of the overall product, just as the original poet had an original, whole in mind.  That is, there is a kind of gestalt change of the whole, not its separated parts, each of which have their own strong and weak points, otherwise unrelated to that overall gestalt.

In my next post, I'll try to  provide some genetically specific examples of the sorts of facts we have in our science, that we know are true, but that we may not be integrating into the kind of gestalt that I've been discussing here.  Perhaps, in a way similar to other changes in science, concentrating on these separate, not obviously similar, facts may help stimulate a whole new picture.

But as I've said already in this 'Metaphysical' series, perhaps the fragmented nature of what we see is, as they say, what there is: perhaps thinking we'll have, or even that we need, a new Darwinian insight, is romantic thinking.  Perhaps life is just a causally messy phenomenon, not one we can unite with a grand synthesis.  Perhaps causal prediction won't turn out to be precise in our field as it is (or at least seems to an outsider to be) in physics.  Maybe life is already the doggerel we've been dealt!

Meanwhile, try it yourself!
If you look again at my tinkered verses in yesterday's post, or even try do do the same yourself with some favorite verse (or take one of my choices and change it in a very different way), perhaps you can get a sense of what I'm trying to convey about the nature of synthesis, how changes are brought about when it must be done in the whole, and with many equivalents, and so on.

Just pick some verse and in a word processor copy it so you can see both versions at the same time. Then with some objective, start modifying, one word or phrase at the time.  Try to keep the meter, basic sounds and stresses, and even the flow of the logic similar, but give it a whole different meaning. In my experience, it's a good kind of enjoyable brain exercise, if nothing else.  It forces you to try to see a whole 'above' its parts, a synthesis one might say, and then make it a different but still functioning kind of 'whole'.

In any case, in my next post I'll try to be clearer about the sorts of facts (the current version of the verse, so to speak) that we face in genetics today.

Saturday, December 24, 2016

A Season's diversion

Odes to the Season (sort of) 

Wikimedia commons images:Chrismas Magic 2008 - panoramio.jpg

The CRISPR's frustration
Pace Joyce Kilmer: Trees
I think that I shall never see
A gene as lovely as a tree.
A gene whose histones’ mouth is pres’d
‘Gainst coiled enhancer’s flowing twist;
A tree that links its genes all day,
For lofting leafy arms to splay;
No gene alone in Summer bears
A nested interaction’s fare;  
Upon whose basis shape is lain;
Who intimately breathes the rain.
Genes are named by fools like me,
But lonely genes can’t make a tree.

How do I leaf thee?
After Elizabeth Barrett Browning: Sonnet 43
How to I leaf thee?  Let me count the ways.
I leaf thee to the depth and breadth and height
My bows can reach, when flow’ring out of sight
For the ends of branching in ideal place.
I leaf thee to the level of every day’s
Most quiet need, by shade in clearing’s light.
I leaf thee fully, as my stomates’ right
I leaf thee petally, as I've ta’en from phloem.
I leaf thee with the pollen put to use
In my old grafts, and with my saplings’ fronds.
I leaf thee with a leaf I’m doomed to lose
With my lost seas’ns.  I leaf thee with the branch,
Stems, tips, of all my life; and, if Ground choose,
I shall but mulch thee better after death.

Instructor's lament
After Emily Dickinson: I am Nobody
I'm nobody!  Who are you?
Have you no funding, too?
Then there's a pair of us--don't tell!
They'd banish us--to teach!

How dreary to be somebody!
How pander, like a fraud
To boast your name the livelong day
To the reviewing bawd!

....And finally, here's another adulteration, that we might read, even in a season for joy, a thought for our ecologically destructive age:
Forest, Osaka, Japan.  Source: Wikimedia images

After HW Longfellow: Evangeline (opening lines)
This is the foresters’ evil,
The sawing of pines and the hemlocks,
Once bearded with moss, and in garments green, that indistinct in the twilight,
Stood like Druids of old; but now with voices sad and prophetic,
Sounding like harpers' howl, weep tears that rest on their bosoms.
Loud from its raucous cuttings, the deep-voiced neighboring ocean
Hears, and in accents disconsolate answers the wail of the forest.
This was the forest primeval; but where are the hearts that beneath it
Leaped like the roe, when he heard in the woodland the oncoming humans?
Where is the thatched-wild vista, then home of a Halcyon fauna?

Source: Holly Wreath: Wiki images