Primitive Prozac: Religion as Anxiolytic Therapy

Or- I'd rather have a frontal theophany than a bottle in front of me.

"Religious suffering is, at one and the same time, the expression of real suffering and a protest against real suffering. Religion is the sigh of the oppressed creature, the heart of a heartless world, and the soul of soulless conditions. It is the opium of the people. The abolition of religion as the illusory happiness of the people is the demand for their real happiness. To call on them to give up their illusions about their condition is to call on them to give up a condition that requires illusions." -Karl Marx

Marx, unfortunately, lived before modern neuropharmacology. But whether the blunderbuss of opium, (or alcohol), or the scalpel of prozac, we are clearly in need of something to get us through the night, and self-medicate in all cultures and all times. Religion seems to be one such universal method of relieving anxiety, and comes up for a chapter in Jared Diamond's book, The World Until Yesterday, titled "What electric eels tell us about the evolution of Religion". To boil it down brutally, Diamond, wearing his sober sociologist's hat, tabulates seven functions of religion, dialed to various levels among different religions, cultures, and times:

• Supernatural explanation
• Defusing anxiety through ritual
• Providing comfort about pains and death
• Standardized organization
• Preaching political obedience
• Moral codes of behavior towards strangers
• Justification of wars

What I realized in reading this is that most of these points, and probably the most significant ones, can be collected under the head of antianxiety medication, individual and collective. We are a very anxious species. Our great intelligence and ability to model past, future, and social structures, etc. has also granted us an expanded, indeed infinite, ability to worry and fret. Squirrels seem anxious too, so this is not a new phenomenon. Chimpanzees soothe each other mostly via grooming, something we seem to have given up in favor of language and social interaction, of which religion is perhaps the most powerful form. Part of our transition from prey to predator species may have been finding some way to calm down, which in our case became, in part, religious practice, rather than the more biological alterations that allow other top predators, like lions and raptors, to seem so calm and unruffled.

Not knowing something makes us anxious, to the point that we habitually make up stories to fill the gap. There seems to be some kind of law against telling a child "I don't know" in response to all those natural, and pressing, questions. So we make up stories. This can be the fount of the greatest art- a project of self-expression and self-understanding, in the guise of an origin story, story of a constellation, of a deity, etc. But still, it betrays an odd kind of anxiety about gaps in our knowledge- an anxiety that has led us to science as well.

Other people make us anxious, not knowing what is in their minds, especially their intentions toward us. Disease makes us anxious, especially back when next to nothing was know about it. Death makes us extremely anxious, being the end of all we hold dear, and typically involving unspeakable suffering besides. We are existentially anxious, about what it all means, where it all came from, who is in charge, what our life is worth. Similarly, the future makes us anxious. It is a big unknown. Historically, many people didn't even take the sun rising again for granted, but developed elaborate rituals and theologies to help that process along.

All these sources of anxiety can be addressed through religion. It explains the unknown, at least sufficiently to allay naive anxieties about cosmic origins, natural surroundings, biology, and disease. Perhaps it assures us about a destination after death, and furnishes a father figure who provides both ultimate justice and meaning to life. It also relieves an enormous amount of social anxiety, providing us with a "gang" to hang with, with some hierarchical structure and rules of interaction, which relieve the anxiety of social chaos. The meaning that religion provides allays at once our social, existential, and intellectual anxieties. Indeed, Diamond's last point about justifying wars can be framed in a similar way. What keeps us typically from making war is prudence and anxiety about the future, about losing, and about the personal price paid by some, even if the group wins. Religion can wipe away each of those anxities by painting a glorious picture of the cause, the boons to be gained, and glory falling especially to those who die in such a cause.

This is hardly a new observation, but seems insufficiently appreciated by those trapped in the is-religion-true (nor not) debate. Not being remotely true hardly makes it useless or pointless.

For instance, from book on religions of antiquity:

"During the process of acculturation from childhood, this heritage is transmitted to all members of a community who absorb is, and are thus enabled to sidestep the burdensome intellectual challenge of developing a personal or private explanation of the order of the real and its counterpart in the imaginaire. Myths constitute the vehicle of transmission of this collective account, which undergoes adjustment corresponding to changes in the objective conditions of the historico-social formation in which they are elaborated. It this becomes a cultural mediator of great importance, offering a shifting form of explanation that allows members of the community to face, without excessive anxiety, a reality that might otherwise appear chaotic and uncontrollable." - Jaime Alvar Ezquerra, in "Romanizing Oriental Gods: Myth, Salvation, and Ethics in the Cults of Cybele, Isis, and Mithras" 2008.

False as it must necessarily be, the model works just so long as most members don't question it too hard. Like the classic answer about the turtle that holds up the world... "It's turtles all the way down!" Beyond such a superficial level (which, bless them, drives theologians to such contortions), the content hardly matters at all. It is the psychological lifting of weight that is so valuable. Problems only arise when people take their myth too seriously, insisting on a truth that isn't there. A natural corollary is the rise of modern religious toleration (an echo of the polytheistic all-for-on and one-for-all model in Western antiquity). For if deep down, we realize that religions give us a therapeutic service, then the flavor doesn't make much difference, for all their various and impossible claims to truth. It is very similar to the situation of modern psychology, which has realized that talk therapy is highly beneficial, pretty much regardless of the Freudian / Jungian / Dynamic / Cognitive / etc. forms it may take. It works because it throws a lifeline of structured, social, soothing calm.

What is a modern person to do? Our intellectual insecurity has been resolved in vast degree by diligent intellectual practice, i.e. by science and other forms of disciplined inquiry. Our physical insecurities have been resolved in large measure by just government and economic prosperity (and lots of oil!) No one in today's developed world should go hungry, or be crushed under political oppression, let alone be attacked by wild animals. Prosperity has also brought great social freedom, though not solidarity or communalism. Quite the opposite- it has given us atomization and anomie.

Psychotherapy addresses, in some degree, this small facet of the anxieties that religion treats so comprehensively, not touching issues of the collective at all, for example. Prozac is an even less productive solution, relieving the physiological symptom, but not addressing either individual or collective problems, assuming that they are problems, and that social engagement in a religious-style community helps solve them. For our anxieties are not just hindrances, they have a purpose, (at normal levels), driving us to plan for the future, form protective and productive communities, learn all we can about our environment, etc.

So, social isolation, personal meaning, and death remain significant unresolved forms of anxiety for which religion remains a functional prescription, in competition with prozac and other aids. Ritual, for instance, whatever its content, provides a socially calming and organizing activity that has largely been lost to non-religious modern people. We see pieces of ritual in musical concerts, political events, newspaper reading, school attendance, business formalities, even facebook obsessing. But none is as powerful as the religious practice that whips it all together into a compelling Sunday morning multi-ritual production of cultural connection and cosmic import.

And meaning? The modern worldview, for all its anxiety-allaying efforts in other spheres, denies intrinsic meaning in this life, while denying future lives altogether. We have no more meaning than a fly that lives its day in the sun, or a grain of sand. We naturally adopt inborn meanings, through our family and social lives, and our competitive natures. And we create other meanings in profusion, high and low, including that confection of meaning called religion. Religion has been the exercise above all others that assures us of some ultimate reason for it all, and has been exceedingly difficult to replace in that respect. The only answer, in refusing all false meanings and empty faiths, is an astringently stoic / existentialist philosophy that is perhaps the single strongest characteristic of modernity.

• But others wonder whether it isn't just peer pressure and indoctrination.
• Calculus was once heretical.
• Atheists have mystical experiences too. But they interpret them skeptically.
• American atomization, anxiety, and anomie.
• Brain injury can give, as well as take away.
• Sado-monetarism, Swedish edition.
• The mortgage system is still rife with fraud and lawlessness.
• Korean ferry disaster is another story of corruption and revolving doors.
• Some successful government programs. 
• But we have not been keeping up with the highway fund / gas tax.
• Why does "freedom" not extend to all users of the internet?
• Colbert does Cliven. Plus, more on guns.
• Wolf on money: nationalize it!
• Solow on Piketty. "This is Piketty’s main point, and his new and powerful contribution to an old topic: as long as the rate of return exceeds the rate of growth, the income and wealth of the rich will grow faster than the typical income from work."
• Doutat on Piketty.
• And for remarkable disclosure (and self-disclosure)... WSJ on Piketty. After explaining how CEOs certainly don't deserve what they are paid, (what a foolish theory that would be!), but are the fortunate cronies of crony capitalism, they conclude:

"A more useful prescription, long before anyone heard of Mr. Piketty and his gloomy novelties, is the prescription promoted by boring-old Social Security reformers. They've long argued for turning Social Security into a system of real savings, via private accounts, so every American can become a capital owner and benefit from [CEO] Mr. Mulally's incentives too."

The Big Brain Domain

The mystery of protein domain DUF1220 and brain evolution.

Someday, the human genome will be an open book to us, telling us how we develop from an egg, and what is likely to go wrong along the way. But for now, we know only glimmers about it. We know all the letters of the DNA code, but frustratingly little about what they mean. An example is the fascinating story of DUF1220.

DUF stands for "domain of unknown function". DUF1220 is family of brief protein sequences, one example of which is "EKVQELYAPREVQKAEEKEVPEDSLEECAITCSNSHHPCESNQPYGNTRITFEEDQVDSTLID". This uses a code where each amino acid constituent of a protein is one letter. A slightly more sensible way to look at it is put several family members in a linup, as it were:

Alignment of 10 family members of DUF1220, with most conserved amino acids in red, and hydrophobic amino acids marked with green bars.

Each member of the domain family is in its own row, lined up with the others as best a computer can do. The well-aligned positions, with mostly the same amino acid, are in red, and less so are blue. I have added a few green markers above to show which positions are hydrophobic, carrying amino acids like F, V, I, L, A, W, Y, and the like, which tend to lie inside folded proteins like oil drops form in water. So, by my own speculation, it looks a bit like an alpha helix, with regular hydrophobic residues lying at roughly seven or so amino acid intervals, appropriate to one face of the helix lying against the interior of a protein while the rest is exposed to the outside, to water and other molecules.

One human gene is 3768 amino acids long and contains 43 iterations of the DUF1220 domain, marked in pink.

But this is very conventional. Many, many proteins take on this kind of structure. Going up a level to the genes, we see that in one gene carrying this domain, it occurs tandemly 43 times. Wow! What could be going on? Such a long protein, singing the same song, over and over again. This is common in structural types of proteins, less so in enzymatic or regulatory proteins, but who knows? An ancestor of this family seems to be involved in regulation of protein phosphorylation and activity, but very little else is known about what it might be doing in any physical way.

Up one more level, to the genome, we see that there is a family of ~23 of such genes in humans, mostly on chromosome 1, which carry various numbers of this small domain, adding up to about 277 copies in all of this domain in the genome. Why so many genes, why so many approximate copies of this domain? This kind of amplification tends to be a quick and dirty solution on the part of evolutionary processes, to get more of some beneficial gene product. Later on, once the regulation of some of these genes is optimally tuned up, extra copies can be left to die as pseudogenes and deletions.

Going up to the evolutionary level, we find that there has been a dramatic expansion of these genes and this domain over the mammalian and especially primate lineage, from none in birds, to a few in rodents, to a hundred in monkeys, to 290 copies of DUF1220 in humans:

Evolutionary history of DUF1220-containing genomes. Years before present are listed up the middle line.  Numbers of DF1220 domains are listed at right. The miscellaneous notes in the tree refer to named sub-families of DUF1220-containing genes, and a few other related issues.

There seems to be a strong correlation of duplications of this gene or segments of it with closeness to humans in the primate lineage, which would make sense if this gene, say, had something to do with generating bigger and better brains.

And that is something we do know something about, since mutations in these genes come up in a variety of disease conditions, which is to say, human phenotypes. A recent paper found that deletions in this chromosome 1 family lead to microcephaly (small head), while duplications lead to macrocephaly (big head) birth defects. Other mutations among these genes lead to autism and other mental disorders.

"... we have shown that of all the 1q21 genes examined (n 1 ⁄ 453 [subjects]), only DUF1220 sequences exhibit a significant direct correlation with brain-size phenotypes in both pathological and normal human populations. Although we provide data implicating the loss of DUF1220 copy number in 1q21-associated microcephaly, the data are also fully consistent with the view that increases in DUF1220 copy number underlie 1q21-associated macrocephaly." 

"Twelve genomic diseases have been linked to CNVs [copy number variations] in the 1q21.1- 1q21.1 region. They ... include autism, congenital heart disease, congenital anomaly of the kidney and urinary tract, epilepsy, intellectual disability, intermittent explosive disorder, macrocephaly, Mayer-Rokitansky-Küster-Hauser syndrome, microcephaly, neuroblastoma, schizophrenia, and thrombocytopenia-absent-radius syndrome." 

"However, multivariate linear regression detected a linear increase in CON1 [a sub-famliy of the genes carrying DUF1220] dosage that was progressively associated with increasing severity of each of the three primary symptoms associated with ASD [autism spectrum disorder] as measured by the ADI-R. With each additional copy of CON1, Social Diagnostic Score increased on average 0.25 points (SE 0.11 p = 0.021), Communicative Diagnostic Score increased 0.18 points (SE 0.08 p = 0.030) and Repetitive Behavior Diagnostic Score increased 0.10 points (SE = 0.05 p = 0.047)." 

"Given our recent data linking DUF1220 with neural stem cell proliferation (J. Keeney, submitted), this effect could be related to the timing and rate of neurogenesis, such that too many neurons produced too quickly may result in an overabundance of poorly connected neurons. This initial overabundance would in turn inhibit the formation of long distance projection neurons. This process, resulting from (or exacerbated by) CON1 dosage increase, could in turn lead to the excess of localized versus long-distance connectivity seen in individuals with ASD [autism spectrum disorders]."

These clues drive a great deal of interest in finding out what these genes and their encoded proteins do. They have apparently been under intense positive selection (for accumulating duplications and variants) over recent evolutionary time. And this is despite setting up a fraught situation in the genome, since repetitive sequences are more prone to rearragements and other errors, as seen in the various genetic defects located at the 1q-21 chromosomal position. They are clearly part of what makes us human, and diverse as humans.

• Doubt is still faith, if you are unwilling to change your mind.
• Australia's environmental policy... going downhill.
• But the climate can be saved, for a low, low price.
• Hits to Wikipedia can track influenza in real time.
• We are still on FIRE.
• Artificial intelligence is back, baby!
• Low taxes are not enough: Romney and friends pay no taxes at all, off-shore.
• Adam Smith was pro-Occupy.
• Wolf on Piketty: Do we really want to go back to Victorian / Dickensian capitalism?
• Polanyi: "free" markets brought and will bring disaster.
• Krugman psychoanalyzes the right. Is it too easy?
• Economics quote of the week, Brad DeLong on conservative arguments, based on maximizing overall GDP, against the minimum wage and other social controls on income, if one even grants that premise:

"The problem with this, of course, is that maximizing real income per capita does take a stand, and a very fictional stand, on interpersonal value comparisons. To maximize real income per capita is to assert that each dollar at the margin--no matter how rich is the person that goes to--has the same effect on marginal utility, has the same effect on the greatest good of the greatest number."

The Dogs of War

Review of "Savage Continent", about post-war violence in Europe.

We have, typically, a very positive view of Europe, as home (though not exclusively) to philosophy, literature, classical music, enlightened politics, science, socialist government (more or less), capitalism, human rights, the UN, and the whole package of first world development. But then there are World Wars 1 and 2. What happened? Were they some kind of aberration, or a deeper expression of our humanity? Are we finally "civilized" now, able to keep the genie in the bottle forever more?

And are Europeans, and developed countries in general, different from other peoples of the world? Obviously not. That is one of the most important messages of this book, for better or for worse. We are all human, and the systems that keep inhumanity at bay are delicate social structures, unspoken virtues of civic morality, and prodigies of carbon-fueled prosperity that are probably much less robust than we take for granted.

What happens when those structures are blown away, and armies rape and pillage their way over the land? Everyone is traumatized, and long-cultivated morals fall away. Tribal affinities, long subsumed under nationalist, or even internationalist ideologies, resurface, because the basic question is.. who is left that can I trust? Injustice begets further injustice, as those who have been violated, or live in fear and desperate straights, rationalize retaliation and pre-emption without great care as to the targets. Rumor and hatred run rampant. Those who can get away with murder and robbery, do so. We are in a dog-eat-dog setting, as social circles and controls contract dramatically, down to practically nothing.

Author Keith Lowe describes this process in the wake of World War 2, when countless scores were settled, more people were dispossessed and killed, and new wars started, all after VE day. He brings tremendous detail and narrative flair to an enormous story, spanning the continent. A recent blog post mentioned how perilous it was for Jews miraculously spared from the holocaust to return to Poland, where their homes and property had long been taken by others, and where, more significantly, German-radicalized antisemitism was alive and well.

Another example is the widespread ritual shaming of women who had slept with the enemy. A few were killed, but most were stipped and shorn for their participation in the emasculation of their own country's men and honor. Their children often had a far more difficult time, shunned both in the home country as well as in Germany, if they turned in that direction. There were vast movements of refugees, as the slave labor force of Germany was freed to return home, concentration camps emtied, and new ones were set up. Germans were kicked out of the newly West-shifted Poland, and out of Hungary and Czechoslovakia, almost 12 million in all. And even those who were not driven to move crawled out from under the rubble of war, in Germany and especially in Eastern Europe, which had been brutally overrun two or more times.

Of eleven million prisoners of war, one million died in the Soviet gulag, while 100,000 died in camps of the other occupying powers, according to Lowe. On the other hand, formal efforts to hold the perpetrators of the war accountable were virtually toothless, due partly to the continuity of fascist power structures, incensing populations across the continent, who often, particularly in Italy, took justice into their own hands.

Lowe gives particularly welcome attention to the new wars that broke out in Greece and Yugoslavia, as the new reality of an east-west cold war began to set in. In Greece, the Western allies shockingly tended to side with what had been the fascist right over the communist left, who had constituted the resistance during the war. In Yugoslavia, Tito and his communist partisans had long prioritized winning the civil war over winning against Germany, and made no bones about shooting whoever needed to be shot when it was all over. They had no time for prisoners at all.

So this is an important book, however cursorily I treat it. Right now, we are tiptoe-ing backwards into European history with Russia's "protection" of its ethnic comrades in Ukraine. Ukraine was one of the "burned-over" regions of World War 2, as if its own prior holocaust from Stalin's starvation campaign wasn't bad enough. Now Putin wants to dismember it, if he can't corrupt the whole of it into servility. Shades of German policy at Hitler's height, which brought on the previous horrors, one has to say.

But what to do? How do we respect and learn from the tragedies and mistakes of yesteryear? By starting wars more expeditiously when lines of international civility are crossed (modelled by World War 1, perhaps)? Or by foreswearing all war, until we are at the wall and must, perforce, start World War 3? Or by threading some kind of diplomatic middle way between the would-be dictators and the apathetic democracies? Putin is no Hitler, but follows the same fragile logic of bullying to power, internally and externally, with a side of external revanchism. Lowe's book does illustrate that avoiding war, even at some moral and other cost, does have enormous virtues. It also re-animates the virtues of having a decent, and powerful world government that would reign in the lawlessness of international relations.

• The nuts and bolts of the mortgage fraud machine. How Goldman got away with buying insurance against losses it itself engineered, and then got the government to pay out the policies via bankrupt AIG.
• "Eight Rich Americans Made More Than 3.6 Million Minimum Wage Workers". Why, exactly?
• Fundamentalist Biblicalism: putting head in sand.
• Wall Street- even worse landlords than regular old landlords.
• Krugman on Piketty and inequality: it's the wealth, stupid, not just the income.
• Who is running things, anyhow? "... the collective preferences of ordinary citizens had only a negligible estimated effect on policy outcomes, while the collective preferences of “economic elites” (roughly proxied by citizens at the 90th percentile of the income distribution) were 15 times as important."
• Police pay. Self-dealing doesn't just happen in board rooms.
• Economic quote of the week- Felix Salmon, reviewing Flash Boys:

"After all, the fact of the matter is that of all the various actors screwing your mom and pop out of the money in their retirement account, high-frequency traders are at the very bottom of the list. If, that is, they’re on the list at all."

• Economic graph of the week, on age-ism of the recession. Another chance for the free market to defeat the public good.

Weeks unemployed, different age groups, over recent years.

Other ways of knowing

What are "other ways of knowing", and are they any good? 

"There are more things in heaven and earth, Horatio,
Than are dreamt of in your philosophy." -Hamlet

This is a favorite Shakespeare quote for religionists of all stripes annoyed by skepticism from the new atheists, or others who do not understand how anything called knowledge could come from non-empirical sources.

It is a basic question in philosophical epistemology, but also in practical life. Do we trust new age clairvoyants and clairsentients? Why not? Do we trust anecdotal miracle cures in medicine? Do we trust the traditional patriarchial "discernment" at the heart of main-line religions, which insists that however mysterious and unknowable, somehow, somewhere, god exists, and "his" pastors & priests know what is best?

When I discuss religion, at even the most tenuous level, with believers, they frequently resort to this kind of statement, that science doesn't know everthing. The corollary is that their form of "knowledge" is therefore valid, or at least reasonable, and one should respect "other ways of knowing".

An interesting podcast recently spoke about a class of self-certified midwives- the Midwives Alliance of North America and allied groups internationally. This is a new-age-y group who favor home births, natural childbirth and no medical intervention. The results are obviously not very good on a statistical basis, though complications are rare enough that most births come out fine, and everyone can be lulled into complacency. They have a very antagonistic relationship with the medical establisment, being mutually shunned and distrustful. And their rationale for all this is not only that they have sufficient training for what is *usually an uncomplicated and of course natural process. Rather, it is that they have "other ways of knowing" that are not only appropriate to their task, but superior to the cold and sterile knowledge of the medical profession.

It is a sad and alarming story, but very common all over the alternative medicine and new age fields. But it is central to normal religions as well, since at their core, they posit that their prophets, if not many or even all of their practitioners, have some mystical connection with reality and perhaps a deity, which grants them special knowledge of a "true reality" transcending the mundane day-to-day, whatever that might be.

The skeptic assigns this to obviously psychological sources, and would prefer to ignore it entirely. But unfortunately, this way of thinking is so common that it has enormous effects on our world in practical ways, both doing harm and preventing rational planning and other good works from being done. James Frasier's The Golden Bough is a classic catalog of such superstitious and magical thinking, from all corners of anthropology.

So what do we know, what don't we know, and why are we so strongly tempted to claim knowledge we don't actually have? I think it does come down to psychology- the strength of intuition and other psychological propensities (narcissim, confirmation bias, optimism) that induce us to make up stories and then stick to them out of pride. This has been well covered in recent popular books.

It must be said that the scientific corpus is hardly perfect in this regard. Even this most respected class of knowledge is rife with out-of-date theories, bad papers, and biased research. Scientific history is always changing and throwing out the old in favor of the new. While there are bedrocks of knowledge, from the Newtonian system to DNA, there are always frontiers of hypothesis if not ignorance, and whole areas like medical research rife with sloppy and self-interested practices.

This has caused a lot of well-deserved criticism. But what else have we got? That is the big question. The scientific process, of competition, of public description and discussion of results and theories, and of ultimate empiricism, is one designed to defeat the principle ills of bad epistemology, which are claims to private knowledge and failure to judge one's knowlege by the yardstick of reality.

Another fascinating interview, with anthropologist Tanya Luhrman, takes a more positive view of religion and magic, especially of guided imagery- the common religious practice of praying, engaging imaginatively with theological concepts, talking with god, and related practices. This happens in all kinds of religion, from witchcraft to new age to hippie-influenced evangelicals, buddhists, and beyond. If you try hard enough, you can talk to god ... and even get a reply. It can be a powerful experience, and leads people to very deep belief, as well as to significant psychological health.

We all have voices in our heads. Many different "selves" who compete to guide our lives and nag and pester without end. Some of our better voices are perhaps a little shy and need a bit of encouragement. Sitting down and sorting through this in a calm way, perhaps with a institutional template and communal support, doubtless can be a great practice.

But is it knowledge? That is the question. Other ways of knowing (or OWOK) can generally be brought under the umbrella of intuition and experience. Shamanic experience with herbs, practical psychology, sweat therapy.. the list of significant knowledge is truly extensive. But all that can be validated empirically, and much of it has been. The central issue that OWOK raises is whether intuition is itself a significant source of knowledge that can be claimed against the now-traditional and dominant model of normal science.

I will try to answer "no", though there are caveats. Firstly, there are infinitely more questions than anyone has time to answer on a scientific basis, and indeed questions that can not be answered. Yet people have a real (psychological) problem with saying something as simple as "I don't know", and of course we typically have to act with incomplete knowledge. That leads us to make up stories when we are faced with a hole in our world view / model. Religion is full of such fanciful stories- the older, the more mythical. These stories of course tell us a great deal more about our psychological contents than any "knowledge" .. which I will take as meaning some aspect of a mental model of reality that is correct.

Secondly, intuition is indeed a powerful way of knowing. Much of our intelligence seems to have evolved to meet the social demands of dealing with each other- an arms race of intelligence and counter-intelligence. Our social intuition is thus a finely honed instrument, far more sensitive than any questionaire or brain scan. The home-brewed midwives above believe that they have intuitive approaches to their clients that beat the antiseptic hospital battlefield, and in some ways they are doubtless correct.

But firstly, this knowledge is not explicit and transferrable. One can't institutionalize intuition. We can nurture it, but in the end, either you have the bedside manner and personal touch, or you don't. And secondly, a real danger is in thinking that the your intution is always correct. We know that is not right, even though we are psychologically inclined to put a great deal of faith in our personal convictions. So how can you tell when your hunch about some situation is correct or not? By experience, of course ... which is the same as the emprical test.

Thirdly, intuition is not at all effective for precisely the non-human-scale questions that are such grist for the magical and theological mill- where did the world come from? How does biology work? Do we have souls? Do voodoo dolls work? Is there a god? Or many gods? Insofar as these are not questions of inner psychology, they are scientific questions which religion has done abysmally poorly in answering. I mean.. they have gotten nothing right on this score, ever. As a way of knowing, the track record is simply not there.

The reason is clear enough- that this kind of traditional magical thinking patterns the outside world on our social intelligence, assuming that everything of significance to us, from trees and rocks to the weather and the cosmos, is part of a kind of social world, and has spirits of some intentional essence, singular or collective, which have attitudes, occult forms of communication, and above all, respond to our thoughts. The ESP and psi fields of research are relict representatives of this form of thinking in the fringes of the scientific community, but without any discernable success.

So one can conclude that OWOK is a thoroughly humanist, psychological, and interpersonal concept. It does apply to a high degree in settings of caring and therapeutic support not to mention art and literature, and to business, politics and warfare, as more adversarial settings. Formal science has but scratched the surface of this kind of social knowledge that humans naturally gather and use daily. That is probably what people are instinctively thinking about when they give credence to the OWOK mantra.

But conversely, OWOK is AWOL when it comes to its stabs at scientific explanation and practice. The midwives above evidently do not know or care about the painstakingly empirical, critical and statistically supported wonders that have been instituted by modern medicine to deal with rare but catastrophic cases, learned systematically over long, bitter experience, sometimes quite contrary to what intuition (and pleasant bedside manner) might instruct. And more generally, the kinds of stories and rationalizations that myth-makers, mystics, and theologians traffic in are entirely valueless as ways of explaining the non-human world. While humans are born with some basic (Kantian a priori) implicit knowledge about the world, (vision, gravity, language, smells, etc.), this is a very far cry from "knowing" about reality in any rigorous way. There is simply no way of getting this knowledge without looking outward and doing the work of empirical science.

• Nor is Bible Science the way to go.
• Why do we have athletic scholarships?
• We need that Tobin tax. 
• The catastrophic jobs situation is still catastrophic- individually, and collectively.
• GOP declares class warfare, in case we were wondering. Ending in ... Westeros.
• Arrakis, ergs, and climate heating...  Dune is our future.
• Money is corruption, not speech.
• How's the Fed gonna get those horses back in the stable? A country rendition.
• Quote of the week, from Lawrence Lessig, on McCutcheon:

"We’re on our way from Lesterland to Sheldon City — from a democracy where about 150,000 Americans are the relevant funders of campaigns (the same as are named “Lester”) to a world where about 40,000 Americans are the relevant funders of campaigns (the same as are named “Sheldon”)."

• Another quote of the week, from Charles Koch:

"The more government tries to control, the greater the disaster, as shown by the current health-care debacle. Collectivists (those who stand for government control of the means of production and how people live their lives) promise heaven but deliver hell. For them, the promised end justifies the means. ... ... despots ... ... Those in power fail to see that more government means less liberty, and liberty is the essence of what it means to be American. Love of liberty is the American ideal." This, while he crows about all the awards he has gotten from the EPA for meeting or exceeding regulatory standards!

Jesus & reality, part three

Jesus seems to have been real, but the diagnosis would be .. more than a little bonkers. More from Bart Ehrman's "Did Jesus exist?"

In part 1, I considered the theory that Jesus as a historical figure did not exist at all and was made up out of whole cloth, drawing on the rich archetypes, mistold tales, and inflated belief that characterize religion generally. Then in part 2, the opposing view, based on Bart Ehrman's book "Did Jesus exist" was presented, concluding that Jesus really did exist historically, though that is far from implying that all that was later written about him was true. The truth is somewhere in the middle, between complete fabrication and a kernel of truth surrounded by many-colored and textured swaths of fabrication.

The later parts of Ehrman's book touch on the next logical question- if we can use critical historical methods to conclude that Jesus really existed, what else do they allow us to conclude with confidence about him?

The central point of this analysis is that Jesus was a apocalyptic preacher, in the template of John the Baptist. This is a very significant conclusion, since this was a relatively small group in the community of his time. The Jewish community of Palestine had about five noticeable social-theological groupings, as Ehrman and others present it.

First were the Saducees. This was the establishment, ran the temple, and was the economic elite. They collaborated with Rome, and were thus thought traitors by more orthodox Jews, not to mention theologically impure, permissive, corrupt, etc.

Second were the Pharisees. These get plenty of airtime in the gospels, as they were more orthodox than the Saducees, sticklers for Jewish law, kosher, etc.. One might think of them as the hat-and-locks wearing set of the time. Jesus makes lots of points off them, but who killed him? The Saducees, as discussed further below.

Next was the Essenes, the ascetics whose Dead Sea scrolls have provided such trove of knowledge about their time. They were an even more extreme off-shoot of the Pharisees, and might be thought the mystics of the society, segregating themselves in the desert, (for the most dedicated), seeking purity, celibacy, poverty, silence, and community (men only!). They thought the temple, as run by the Saducees, hopelessly corrupt and impure. They certainly didn't have any role in running things, and seem to have strongly messianic hopes.

The last substantial set mentioned by Ehrman are the revolutionaries, (the Zealots), sort of the heirs to the Maccabee tradition. This was a more political outlook, that chafed strongly under the boot of Rome, and thought that the Jewish land was defiled not so much from lack of fidelity to the Levitical and Mosaic laws, as from lack of their own laws, and own government. This class would eventually lead the revolt of the later first century, which prompted the final destruction of the second temple by Rome.

Last is the apocalypticists. Ehrman paints them (as exampled by John the Baptist and Jesus) as quite different from the Essenes, let alone the other groups. But I have to say that the more I read about the Essenes, the closer these two groups appear. While the Essenes were very secretive about their teachings and mostly kept to themselves, the teachings were largely the same- a messianic assumption that someday, each would get what was coming, and that some kind of resurrection would occur. Each were strongly moral and focused on service to others. Each was anti-family, almost pathologically so, preferring to live in like-minded community. So it looks to me as though John the Baptist and Jesus could be thought of as Essenes who took the teaching outwards, to the people at large, and even challenged the Temple and its sponsors directly.

A side-note of interest was their attitude towards morality. The Essenes and apocalypticists were intense moralists and demanders of repentence. But the point was not to make a more pleasant or successful society for us all to live in. No, it was to get right with god before the judgement day, lest you be sent off to everlasting torment in hell. Family values it was not.. the exact opposite, actually. But somehow, subsequent generations have so bowlderized and cherry-picked it that, naturally, it now means that open carry is a Christian commandment, plus whatever else one favors.

This all was kooky enough. But Jesus took it up a notch by predicting that the Kingdom would come soon. In his lifetime, or in that of this hearers. And that his apostles would be the 12 kings, sitting on 12 thrones of the 12 tribes of Israel. This implied that he himself would be the top King.. the new David.

Ehrman makes a highly significant surmise that this plays right into the Judas story. What was his notorious "betrayal"? Jesus couldn't have been hard to find, with an entourage and all, staying in a city he didn't know very well, speaking in the public square to crowds. No, the betrayal had nothing to do with location, but everything to do with theology and politics, since if Jesus gave his disciples a secret teaching that they would inherit the kingdoms and he was to be the messiah and future super-king, then this was something both the Saducees and the Romans might want to hear about.

"Jesus, of course, did not understand his kingship [cause of his conviction and execution] in this way. He was an apocalypticist who believed that God would soon interfere in the course of human affairs and destroy the Romans, and everyone else who opposed him, before setting up his kingdom on earth. And the Jesus would be awarded the throne."

Needless to say, the kingdom never came, Jesus never returned, and never became king (except in our hearts!). Jesus himself was evidently somewhat surprised by the turn of events which left him hanging, so to speak, without god's intervention. His followers never expected him to resurrect, as shown by their complete lack of vigilence over his body, but came up with that story later on to rationalize a commitment and ministry whose rationale had otherwise been buried.

Which gets us to the theme of this post, which is that the historical record, as far as we can make it out with any reliability, indicates that Jesus was real, and was clinically insane. He believed not only in all the normal crack-pot things that were prevalent in his time, and were concentrated within the Essene sect. But on top of that he believed he was the ONE, the future king, and judge of all, etc.. etc.. When we see people in our day calling themselves Jesus Christ, or the postapocalyptic king, who will separate the sheep from the goats after the resurrection, etc.. etc.. we typically call them insane.

• Ehrman on Jesus. Excerpt from Erhman's next book, same topic.
• On the ideology and propaganda of individualism.
• The institutions we have are not working.
• AA is a religious crock.
• Yes, there really is a conflict between science and religio-science.
• Liberal religion isn't going to carry the load for liberal government. We need to make the case on a secular basis.
• Capitalism naturally devolves into feudalism and oligarchy if we do nothing.
• The frustrating contradictions of Afghanistan. Where will it all end?
• And Ukraine.. will the IMF help or hurt? Maybe default is a better answer.
• Parts of Russia that the rest of us want back.
• Labor markets do not clear. And are not efficient or ideal. Among other asymmetries, capital is patient while labor can not be.
• Economic headline of the week:"Inflation Below Fed Target for 22nd Month in a Row".
• Jerry Brown lays an egg.
• Economic quote of the week, about the interaction inequality with overall economic prosperity:

"But perhaps even more interesting are the implications for the secular stagnation hypothesis, which holds that we are in a long-run stagnating economy because of inadequate demand. Is it a coincidence that the secular stagnation hypothesis is being revived exactly when income inequality is accelerating? If a higher share of income goes to the wealthiest households who spend very little of it, then perhaps these two trends are closely related."

Memory on the knife's edge

Amyloid-type proteins may be essential for long-term memory, even as they risk destroying it.

As we learn about the genetic aspects of many diseases, one is prompted to ask.. how could susceptibility to such a conditions ever have evolved? Susceptibility to Alzheimers and other degenerative dementias is a case in point. If they are caused by amyloid, or prion-like proteins that aggregate excessively, thereby destroying their cells and tissues, then the obvious question is: what do they normally do, and why hasn't this tendency towards aggregation been more stringently policed by evolution?

A recent paper on memory in flies (reviewed) offers the theory that in the case of memory, proteins that aggregate are central to the ability to form long-term memories. Aggregation is a feature, not a bug, and the only problem would then arise when this system works too well, or with abnormal partners.

Following the general trend in brain science, memory is being studied as, and found to be, a physical phenomenon. As far as we know, it consists of the persistence of physical and functioning synaptic connections among neurons that are re-inforced by use. The vast mesh of synapses connecting neurons in the brain form engrams that can be read back out upon partial stimulation of the encoded pattern. And memories are quite resistant to brain degradation- when symptoms of Alzheimer's appear, vast amounts of brain tissue are already gone. On the other hand, a specific injury to a key area can instantly destroy a lifetime of memory, the ability to form new ones, or other functions.

How do synapses work? Neurons have to grow if we are to learn, and they have to selectively connect with their downstream partners, the dendrites, cell bodies, and axons of other neurons, via synapses. All these are molecular processes, and one can imagine that if we are to have durable memories of anything, that molecular process has to have the contradictory features of durability as well as reversibility. We forget most of what we have ever experienced, and our sleep seems to be some kind of clearance and consolidation process, keeping some, and throwing out the rest. However that works, the synapse is well-known to be the focal point of memory, and protein synthesis has long been known to be required for new synapses to be made.

The fruit fly, despite its lowly intellect, has been an excellent organism to study neuronal activities, and even cognition and learning. In this case, prior work has identified one protein, CEPB, as one that is essential to memory durability. Without it, synapses still form, but then die off within a day of a training regimen, corresponding to the fly's inability to remember what it was trained for.

"Interestingly, ApCPEB [name of this gene/ protein in the sea snail] and Orb2 [the gene name in the fly] form self-sustaining amyloidogenic oligomers (prion-like) in response to the neurotransmitters serotonin in Aplysia and octopamine or tyramine in Drosophila. More importantly, the oligomeric CPEB is required for the persistence of synaptic facilitation in Aplysia and for the stabilization of memory in Drosophila. These observations led us to propose that the persistent form of memory recruits an amyloidogenic oligomeric form of neuronal CPEB to the activated synapse, which in turn maintains memory through the sustained, regulated synthesis of a specific set of synaptic proteins."

A second protein/gene was also found in this process, called Erb2. Mutations in either Orb2 or Erb2 do not affect initial learning, but destroy the fly's ability to remember a day afterwards what it would otherwise have remembered, as shown by unmutated control flies. The two proteins bind to each other, and Erb2 promotes the oligomerization of Orb2, which it to say, it helps it form long strings or globs, as one sees in magnified, extreme form in amyloid plaques, tau tangles, and the other hallmarks of the Alzheimers and related diseases.

The present researchers add a little to our knowledge by finding that Erb2 performs this feat of altering the behavior of Orb2 by getting a third protein, Lim kinase, to phosphorylate Orb2. Phosphorylation is a very common way to modify and regulate the activity of proteins, so this is not shocking. It is also quite reversible, in this case by yet another protein, protein phosphatase 2A. Erb2 apprears to be regulated itself by the state of the synapse, so it is a leading candidate to transmit the establishment / maintenance signals from neighboring cells or firing rates to the activities of Orb2.

But what is the point of this interaction, phosphorylation, and oligomerization? Orb2 interacts with a variety of other proteins active in protein translation, and seems to promote the various translation events needed for building a synapse. "The Cytoplasmic Polyadenylation Element Binding (CPEB) proteins are a family of RNA binding proteins that regulate the translation and subcellular distribution of a specific set of cellular mRNAs in various cell types including neurons." This is the hypothesized mechanism by which the signals transmitted by Erb2 to alter the behavior of Orb2 end up growing and stabilizing the synapse.

What is their data? First, they do a general assay for proteins that stick to Orb2. This nets over 50 proteins, many of which are involved in translation, like eIF4E, EIF3-S4, etc. Others are specific to the synaptic location, like Snap25 an Vap33. And one was Erb2, which they also saw stablized one form of Orb2, a tip-off to an important function. Then they show that Erb2 promotes oligomerization of Orb2 in vitro as well as promoting its collection in tiny physical globs in fly neurons.

This is typical data, and not very user-friendly. But it shows that Erb2 (here called Tob) and Orb2 interact, and that this interaction is promoted by neuronal activity, and that the resulting Orb2 protein complexes are amyloid-like. They used an antibody to Erb2 to collect anything sticking to it in a soup made from ground-up fly heads. They had used the chemical tyramine (top) to put the flies into neuronal overdrive before killing them. The matrix is full of controls: with tyramine, without, and with the anti-Erb2(Tob) antibody, or without (using "pre"-immune serum lacking the antibody). Then they ran all the proteins out on an electrophoretic gel that separated them by size (biggest at top), and stained the result with a separate antibody that binds to the Orb2 protein (in fact two of them: versions against only one of its forms (Orb2b) or against both (Orb2a, b)). This way, they can see only the Orb2 that was "brought down" by the Erb2 protein.

You can see that the Orb2 protein comes in two forms- a small monomer, and the larger dimer and higher oligomers, as indicated at the 107 kDa (aka molecular weight) and higher levels. Part B shows the whole experiment redone while treating the collected proteins with 2M urea, which is denaturant that blows up any conventional protein complexes. But it does not dissociate these Orb2 oligomers; evidence that they are very strongly associated as is typical for amyloid-type proteins.

Similar work explores the phosphorylation of Orb2 by Erb2, and its regulation by the protein phosphatase 2A and Lim kinase. This phosphorylation dramatically alters the lifespan of Orb2, from 1 hour to 24 hours or more, which is again a sign that its amyloid-like character can be specifically regulated.

"PP2A, an autocatalytic phosphatase, is known to act as a bidirectional switch in activity-dependent changes in synaptic activity. PP2A activity is down-regulated upon induction of long-term potentiation of hippocampal CA1 synapses (LTP) and up-regulated during long-term depression (LTD). Similarly, Lim Kinase, which is synthesized locally at the synapse in response to synaptic activation, is also critical for long-term changes in synaptic activity and synaptic growth."

Finally, they show data for the theory that Erb2 (Tob) is specifically needed in vivo to support long-term memory, not short-term memory. The test is a little sad. They place male flies with unreceptive females. Normal males get the hint in a hurry, and quit courtship attempts within 5 minutes. And normal males remember that female and her brushoff for several days, as shown in the controls in the two graphs at left. Red is the trained males, with suppressed (learned lack of) courtship. The "UAS-TobRNAi" and "201:Gal4" are partial versions of the transgenic construct, which is fully present in the far-right graph, and which expresses a sort of anti-Erb2, (by way of RNAi), when engineered into these flies. When the genetic alteration is fully present (right), the males have totally forgotten their training at 24 and 48 hours.

So, while the steps are small, these researchers have dug up some evidence for the idea that a central molecular component of memory in fly neurons, which has relatives in all animals including humans, has a regulated interaction with signalling molecules upstream that induce it to form aggregates that resemble those formed far more extravagantly by the culprits in degenerative brain diseases like Alzheimers. These aggregates have the virtue of longevity, though how they act on their downstream targets remains rather vague. Which may explain why those proteins susceptible to aggregation have been kept around in evolution, despite their dire risk when aggregation gets out of hand.

One might well ask a follow up question whether this Orb2 protein resembles in its sequence any of those known to go pathogenic in brain disease. I think the answer is no, but it is known to interact with an actual amyloid protein APLP1 in the mouse system, which provides a logical connection to a role in creating the kind of goop / plaque that can run amok in our heads. What those amyloid proteins are originally there for remains unsolved, but probably relates pretty closely to this synaptic establishment and maintenance system.

• Yes, we can end poverty, by giving the poor money, and other services.
• The bad drive out the good, in government as business. In high tech too.
• On certainty.
• Sales commission systems attract least attractive people, and makes them do stupid things.
• If corporations are people, we need to know who they are.
• Unemployment is forever.
• Wait- didn't Hitler use the excuse of ethnic Germans to annex Austria and Czechoslovakia?
• So, now containment is back.
• Morality depends on fairy tales, right?
• Gun nuts: we're not crazy at all, dammit!
• Reading the tea leaves at the Fed.
• Economic chart of the decade, or two or three:

Jesus & reality, part two

The opposite view, supporting the historical reality of Jesus, from Bart Ehrman.

In a recent blog post on the Jesus as myth theory, I reviewed a book by Robert Price who tentatively holds the myth position (i.e. that there was no historical person with the name or characteristics of Jesus), and puts the best case he can for it. But it is far from the mainstream, and Bart Ehrman, an equally if not better-versed(!) scholar recently wrote the opposite position in "Did Jesus exist?", kindly linked by a commenter on that previous post. Ehrman's is the better organized and better argued book, and makes the more pursuasive case. Indeed he brings up some very interesting topics, like the traces of other languages in the Greek of the gospels, and the Jewish understanding of a messiah. But there are some interesting themes that come up from the synthesis of both positions.

Ehrman offers numerous strands of evidence that Jesus was a real, historical person. They include the fact that the mythicists mis-represent the evidence of Paul. Paul did indeed quote Jesus's sayings, about three times. It is not much, but more than the "none" claimed by the mythicist position. And more importantly, Paul clearly says and knows of Jesus as having been a true person, killed by crucifixion. Paul says he met with two of the apostles, even though he only met Jesus in a vision. So at least Paul is clearly convinced of Jesus's reality, which was incidentally as true prior to his conversion as it was after, since his earlier opposition to the Christians was (Ehrman speculates) due to the traditional Jewish position that the messiah would be a powerful king, not someone nailed to a cross by the Romans. In either case, a real person was the object of scorn or adoration.

Secondly, everyone else who reports anything about the Jesus movement likewise regards Jesus as a real person, whatever they think about it. Ehrman cites Pappias, Ignatius, Josephus, as well as the gospel writers, Paul, the non-Pauline letters / acts, and all the later church leaders. Even the gnostics, however way-out their theology, didn't say he didn't exist, only at worst that he seemed like a real person, while actually being a god. So that is broad agreement, among those we know anything about, that the core of the Jesus tradition was of one mind on this matter.

Thirdly, Ehrman puts quite a bit of credence in the gospels as historical sources, at least to the extent of, firstly, agreeing on the historicity of Jesus, and secondly, of integrating and drawing on what appear to be numerous oral and written sources in the movement (Q, sayings, M, L, and Luke's claimed numerous other sources, etc.) that were by that time, of about 40 to 60 years after the putative death of Jesus, rather separate, even conflicting, traditions, each, however, agreeing on this central point. Some even carry traces of their source in the Aramaic language, which is significant in dating their origin well before the transition to the Greek of the gospels, back to the Palestinian Jesus movement.

There is a great deal more, of course, but that is a brief capsule that indicates that, in any normal historical sense, one has to accept that the bulk of evidence, despite its scanty & distant nature, supports the historicity of Jesus.

Where I would bring back Price's work is in his critique of the gospels as anything like historical documents. While Price's contention is that the midrash-ic and mythic nature of the gospels point to the entirely mythic nature of their protaganist, one can easily take a less extreme position. Which is that the failure of Paul to mention much of this material, (which Ehrman subjects to extensive defense, not entirely successfully in my view), its so-often unbelievable nature, and its heavily templated nature, based on passage after passage of the old testament, indicate that most of it was made up by the later Greek authors (and their various oral sources) who followed the time-honored practice of classic historians of putting words in people's mouths, presenting likely scenarios, and generally creating what they thought was the case, rather than documenting what was actually the case. In this case also heavily larded with their own theological agendas, which are so clearly different among Mark, Luke, and John. After all, no one had tape recorders. The problems of accurate history are truly enormous in this kind of setting.

Stories about Jesus multiply and expand in fabulousness over time. When traced back, do they hit the Y-intercept at zero, or at some point of positive factuality?

Price also makes a point that Ehrman expounds on at some length, which is the rapidly inflating nature of Jesus over time. At first, he had a brother, taught in the Jewish tradition, was thought a wise person, maybe a healer and philosophical deviant, and was finally killed by the Romans. Then he became the Jewish messiah, then rose from the dead, then the redeemer of sins, then the redeemer for all people, then the son of god, then literally born of a virgin by the direct seed of god, and eventually co-substantial with god, etc. Paul didn't give a fig for any birth stories. That mythology, among so much else, was clearly added later on. There is no question that the vast majority of the later understandings, creeds, and traditions- as is usual in any social movement, let alone a religion- had nothing to do with the originating facts of the matter, in any historical sense, versus in an archetypal sense.

So we are left with a more narrow debate, if one is interested, on the nature of the original Jesus movement, and, if one wants to engage in science fiction arguments, whether the various miracles attributed to Jesus happened. The Jesus Seminar is, to me, looking a bit better on that front, throwing out the mythical bathwater, while retaining something of the oral traditions that may or may not have flowed from the person or at least immediate time period of Jesus. Yet it should still be said that they are groping in the historical dark. Making the case for the bare historicity of Jesus is a far different matter than judging every jot of the gospels and other traditions. Ehrman writes extensively of the novelistic (historical novel, in this case) nature of the gospels, partaking both of invention and oral transmission, little of which itself originated in fact. But what was the proportion?

"Once we move from the fact of Jesus's existence to the question of who he really was, we move from the remarkably firm ground of virtual historical certainty to greater depths of uncertainty." -Ehrman

What is the significance of all this? The mythicist position is a bracing and useful one, in the spirit of offering a counter-hypothesis to the conventional wisdom. But it does not withstand sustained scrutiny. I might add that Robert Price has another skeleton in his closet, which is flagrant denial of climate heating. It makes one wonder about his critical judgment in general, despite his great knowledge and humor.

• Fraud and criminality = business as usual among our "leading" corporations.
• Finance is parasitic, non-productive. And still above the law.
• The ultimate costs of corruption- paid by Ukraine.
• Good news from Afghanistan, and interview with one of the trailing prez candidates.
• What on earth went wrong with Barack Obama?
• Robert Reich on what we have lost as a middle class. And on the myth of labor value.
• Inequality will get worse if we do nothing.
• Banks are lending less, not more ... we need to be more worried about growth than inflation.
• Solar is working.
• Jehovah is disgusted!

What is the oldest cell?

Some comparisons of the most ancient lineages of life- Archaea, Bacteria, and Eukaryotes.

Take your mind back.. way back.. four billion years back. Now fast-forward over chemical evolution, or whatever happened to cause the origin of life, a few hundred million years, on to the first cellular life. Now stop- what was that? A recent paper argues from a novel analysis of protein domain lineages that, of the major domains of life, the Archaea (also called archaebacteria) are in some respects closest to that original form, and that the other domains- Bacteria (also called eubacteria) and Eukaryotes- are more distant. (Apologies that biologists use the term "domain" in these two very different senses.) This is an interesting hypothesis, since up till now, it has been indeterminate which of the two bacterial lineages came first, or at least, most resembles the ur-life form, also called the progenote.

Tree of life, deep edition. Note that while eukaryotes arose from Archaea, (with plenty of later additions from Bacteria by engulfment / symbiosis, but that is another story), the root between Archaea and Bacteria as shown here is indeterminate. Which was really first, or is that even a reasonable question to ask? The current paper also disputes that Eukaryotes derived from Archaea as diagrammed, and puts Archaea at the root of the tree.

Non-biologists may not get excited about the distinction between Archaea and Bacteria, but molecular biologists regard it as the most fundamental division of life, far more consequential than vertebrates / invertebrates, plants / animals, etc. All of the latter you can see in the little brown stubs far to the right of the diagram above. In molecular and deep phylogenetic terms, they don't contribute much to the diversity of life.

The Archaea / Bacteria division was only recognized relatively recently, however, since the nature of Archaea was not appreciated until the 1970's when ribosomal RNA began to be sequenced. It provided the first primitive molecular sequence that was common to every single form of life and thus provided a metric of diversity and geneology. The great American microbiologist Carl Woese labored to gather these sequences from obscure organisms and bacteria of all sorts. He made the shocking discovery that there were "bacteria" out there that were very, very different from the usual run of laboratory bacteria- the E. coli and various other disease-causing and easily-cultured bacteria that were the staff of biology since Pasteur. When he plotted out the sequences, these "bacteria" had ribosomal RNA that was a little more like animal sequences than bacterial, but not terribly similar to either. They weren't from another planet, but they were different enough that he took the very bold step of claiming an entirely new domain of life, co-equal with the heretofore only domains of life, Bacteria and Eukaryotes.

He named them Archaebacteria, on a hunch that they had something important to say about the origin of life. This name has subsequently been shorted to Archaea, so that the traditional bacteria can just be called Bacteria. These Archaea look like Bacteria, however- they are the same tiny cells whose wonders are not apparent from their looks. They are super-diverse, living in all sorts of environments from the coldest to the hottest known. They have phenomenal metabolic diversity, creating the methane in our guts and living off rocks, sulfur, and other obscure chemicals. Some have a primitive form of photosynthesis. They are typically sensitive to oxygen, a sign of their preference for a world predating the oxygenation of the atmosphere about 2 billion years ago (and making them very difficult to culture).

They also share most of their informational machinery (transcription, translation) with Eukaryotes, indicating strongly that Eukaryotes derived from Archaea that later engulfed bacteria (which eventually turned into mitochondria and chloroplasts) that provided some of the remarkable resources, both genetic and metabolic, for the eukaryotic triumph over the macroscopic world.

But ribosomal RNA, as convenient and informative as it is, has some problems. It is only a single, if large, molecule, among the thousands of other genes an organism has, and its sequence is somewhat inaccurate as a "clock" for molecular evolution. Few other sequences, such as those encoding proteins, are as completely universal among all life forms, however. The authors of a recent paper take a broader approach to the question of sharpening the universal geneology (or, tree of life) by treating whole complements of proteins and their domain, or "fold" sub-sections as geneological markers, testing which protein domains arose when, and which were lost in various lineages.

This gets around the issue of aligning individual sequences, to some extent, taking a wider lens view of the evolutionary process. A view that is well-suited to this question of the ultimate priority of the most ancient life forms. Protein domains / folds have been generated and lost quite frequently on this time scale, though there are core domains that are universal over all life forms. Eukaryotes are particularly prolific in generating new protein domains. About 3% of protein domains are unique to primates, for instance, though this may have as much to do with sampling & investigation bias as with reality.

"In fact, recruitment of ancient domains to perform new functions is a recurrent phenomenon in metabolism."

A protein with two domains. This one binds to DNA. The domains fold independently, have structure that is distinct from other domains, and can be easily linked, making them easy to re-shuffle in evolution, hooking functions together, leggo-like.

The authors assembled a compendium of about 2400 protein domain, or fold "families" from 420 sequenced organisms of all kinds, and used well-known methods to arrange them into trees based on their occurrence in the individual organisms (though sometimes a fold might be missed even if present, if its sequence diverged from its family consensus pattern too far). The gain and loss of such folds is a particularly powerful method of lineage analysis, giving more information than the comparison of sequences can, if those sequences are distant, with all the problems of alignment, assumed modes of mutational change, etc. Thirteen of their folds were present in every single organism, and 62 more were recognizably present in 95% or more.

A Venn diagram showing the distribution of fold families among the three domains of life, whether shared or not. Note than a large core is shared by all life forms, while Eukaryotes take the prize for the development of new protein domains, despite originating after the divergence of Bacteria and Archaea.

"To determine the relative age of FF [fold family] domains in our dataset, we reconstructed trees of domains (ToDs) from the abundance and occurrence matrices used in the reconstruction of ToLs [trees of life]. The matrices were transposed, treating FFs as taxa and proteomes as characters. The reconstructed ToDs described the evolution of domains grouped into FFs and identified the most ancient and derived FFs. ... Specifically, it considers that abundance and diversity of individual FFs increases progressively in nature by gene duplication (and associated processes of subfunctionalization and neofunctionalization) and de novo gene creation, even in the presence of loss, lateral transfer or evolutionary constraints in individual lineages. Consequently, ancient domains have more time to accumulate and increase their abundance in proteomes. In comparison, domains originating recently are less popular and are specific to fewer lineages."

The next diagram shows the phylogenetic tree they deduce from all this data, with time along the horizontal axis, and species ordered up the side. The two trees were created from the same data by slightly different methods. Note how in both of these trees, the Eukaryotes (green) split from the Bacteria (blue) only a short time after the Bacteria split from the Archaea (red). The lavender arrows are mine. Both trees also show (the numbers, which are percentage of time their simulations came out the same way) that this split is relatively less clearly supported than some of the other major divergences.

Author's phylogenetic trees.

Returning to the Venn diagram, the Archaea-only group of folds is tiny, and does not seem particularly ancient, even though their trees put Archaea first. The hypothesis is that the other groups (The BE and AB (or AE) groups) generated far more protein diversity later on, whereas the Archaea did not, indeed losing quite a bit of the original complement of protein domains. In this way, Archaea end up resembling the progenote somewhat more than the Bacteria that diverged from the progenote simultaneously, but were more active in later evolution, in molecular terms.

Both the Bacteria and Archaea took the streamlining route in evolution, casting off quite a bit of machinery, focusing on small-ness of size and specialization of metabolism. The Eukaryotes, in contrast, branched off from the Archaea after the Bacteria did, and retained a good deal of the transcriptional, replicational, and translational machinery that the bacteria particularly lost or reduced (at least, by the conventional theory). And Eukaryotes in general took the opposite route with respect to streamlining, retaining molecular diversity & sloppiness, metabolic generalization, great physical size, gaining sex as a means to more effective evolution, and gaining the final upper hand with the endosymbiosis of two different Bacteria- the proto-mitochondrion, and the proto-chloroplast. These properties led eventually to multicellularity and the invasion of land. It was (depending on what one values!) a triumph of complexity and cooperation over brutal, cost-cutting competition.

The authors plot their organisms in an "economic" space. This is based on two scores- the number of protein folds occurring that are unique (economy), and the redundancy of protein folds occurring in each organism (flexibility), with the ratio between them serving as the last measure (robustness), which is, frankly, sort of an amplification of the flexibility score. Obviously, Eukaryotes will do very well in these measures.

Since in the author's scheme the AE goup of domains appeared very late, and the BE group was the first to branch off from the universal ancestors, they hypothesize that Eukaryotes branched off from Bacteria, and their informational-class resemblance to Archaea is due either to later lateral transfer, or to comprehensive loss in many Bacterial lineages (though the latter is very unlikely). To me this seems hard to swallow, as this class of functions is particularly unlikely to be transferred wholesale between organisms.

"Informational FFs were significantly over-represented in the AE taxonomic group and appeared during the late evolutionary epoch. This suggested that both Archaea and Eukarya work with a very similar apparatus for decoding their genetic information, which is different from Bacteria. However, as we explained above, all these innovations occurred in the late epoch (nd>0.55), highlighting ongoing secondary adaptations in the superkingdoms. In comparison, the BE taxonomic group was enriched in metabolic FFs (Figure 2A). This toolkit was probably acquired via HGT [horizontal gene transfer] during endosymbiosis of primordial microbes rich in diverse metabolic functions."

This idea would significantly alter / extend the well-known endosymbiotic hypothesis, in that the Eukaryotic precursor would presumably have to acquire not only the proto-mitochondrial cell, but also the proto-nuclear cell that provided these informational functions, from Archaea. It is hard to know what would characterize this original precursor at all ... why not just take the crucial Archaeal additions as the benchmark of the whole lineage? Wouldn't the large protein repertoire commonality between Bacteria and Eukaryotes be better accounted by the known endosymbiosis than by this proposed lineage derivation? The authors have very little to say about what this early Eukaryotic stem organism might be, other than that it was quite advanced and had escaped the brutal streamlining that characterizes both the Archaeal and Bacterial lineages. Thus it, whatever it was, might represent the closest thing to the progenote, in some respects, before the vast elaborations that have been added in that line since, and the massive losses that took place in the other two domains.

"Thus, the primordial stem line, which was already structurally and functionally quite complex, generated organismal biodiversity first by streamlining the structural make up in Archaea (at nd = 0.15), then by generating novelty in Bacteria (nd = 0.26), and finally by generating novelty and co-opting bacterial lineages as organelles in Eukarya (nd less than 0.55)". [nd is their measure of time, from beginning (0) to now (1).]

In the end, the progenote is heavily veiled from our view. The common repertoire of sequences common to all cells is small, (484 fold families in this analysis), and not enough to model what it may have been like, other than to say it had a membrane, functioning metabolism, and informational / genetic system likely similar to what archaebacteria have today. It may have been a good deal more complex, depending on how one interprets the intervening events- as ones primarily of loss, or ones of gain.

• From Russia, with love.
• What happens when you tune your own brain.
• Secularism invades the last preserve of religious freedom, with moral injunctions. Sorry about that!
• Annals of imaginary religious victimhood.
• Legal representation for the non-rich leads to prejudicial witch hunt.
• Computer language that knows a lot. Though less than advertised.
• Martin Wolf: Democracy is for grownups.
• What are the prospects in Afghanistan?
• The 1% can't understand why their rule is not uncontested. Noblesse oblige, right?
• Krugman: Feudal drudgery does not equal "opportunity".
• Does the casino of Wall Street help or hinder economic growth?
• Economic quote of the week: "More unequal societies have slower and more fragile economic growth."
• Economic graph of the week. Demand components in the US: