Saturday, February 28, 2009

de Maistre and Radical chic

Theists daydream about crushing modernity, in favor of "Radical Orthodoxy".

One of Isaiah Berlin's finest works (see the side-links) was his essay about the intellectual outlook of Joseph de Maistre, the staunchly conservative Catholic Savoyard who lived through the French Revolution and wrote whitheringly against it, against modernity, against rationality, and against all points un-Catholic.

His great insight was about the dark side of human nature- how people want to be in chains, want to sin and be forgiven, want to sacrifice their lives on the altar of authority, and thus need and want to be led by their betters, or indeed by anyone with plausible authority. He saw clearly the acidic nature of rationality and atheism, which would wash away the veneration of throne and altar as divine manifestations, imperturbable and unanswerable, which best undergirds such patriarchal, hierarchical systems. He despised the French revolution, yet was fascinated by power, legitimate and illigitimate. One can see clear affinities with Machiavelli, even as de Maistre hewed devotedly to the Roman Catholic church (see fideism). He knew that to see through the contingency of such institutions and theistic rationalizations was to destroy everything- to destabilize the delicate threads of society, with no assurance that anything at all, or at any rate anything worthwhile, was ready to replace them.

Echos of de Maistre's philosophy, which was highly influential in its time, especially in reactionary Russia and restoration France, continue down to our day, through Fascism, opposition to Vatican II, Opus Dei, and most recently, in a curious phenomenon that calls itself "Radical Orthodoxy" (RO). Not coherent enough or palatable enough to be a philosphy, RO calls itself a "sensibility", and seeks the usual conservative dream of universal subservience to clergy and church- of stability promised by verities imbibed unthinkingly and enforced ruthlessly. A medieval world where being outside the church is literally unthinkable, and atheism but a rumor from far away and long ago.

de Maistre's views were a powerful antidote to the enlightenment faith in human rationality, which did indeed have an excessively sangine view of our (or at least revolutionary Frenchmen's) ability to reshape society to the ideals of Liberté, Egalité, Fraternité, instead authoring a rather sanguinary episode that was saved (depending on one's view of him) only by the Machiavellian hand of Napoleon and his even more sanguinary excesses abroad (admittedly, in response to the relentless aggression of the horrified theo/auto-cratic enemies of the French revolution).

Optimism or pessimism about the human condition- that is the question. In the end, even de Maistre knew he was waging at best a holding operation, since the progress of the sciences and rational thought was so demonstrable and invigorating to so many, despite the missteps along the way. It was left to the next century for the full excesses of each extreme to be made explicit in the death-grapple between Germany, with its romantic religion of Volk und Blut, and the Stalinist dictatorship of the proletariat. Each partook in some measure of both extremes, claiming rationalist sanction by way of various pseudosciences (race studies and eugenics on the one hand, and historical determinism on the other, among many others), while also feeding deeply on romantic irrationalist attitudes, including leader-cults and nationalism, to create updated terror-states.

Thankfully, other political systems have cast a less harsh light on the possibilities of reason in the guidance of human affairs, but the modern age remains deeply discomfiting to those who are not at home in the ultimately self-determined and meaningless nihilism of fully realized modernism. This nexus of self-made meaning, rampant liberty, and penetrating skepticism offend those who seek timeless truth and structure in their inner and outer lives, however illusory.

Thus Radical Orthodoxy, a minor theological revolt from the Anglican church that sidles up to Rome, (indeed holding a recent conference right by the Vatican, with the howlingly misleading title "The Grandeur of Reason"), and offers patently irrationalist mystical maunderings to communicate its "sensibility". A sensibility which offers a critique without criticism- a cry of protest against modernism without rational content, as far as I can tell (or Mr. J. Irwin either, who was there). Which seems, at base, to wish its way back into the early middle ages, when life was good for the clergy, everyone knew their place, and none of the doubts introduced by the Renaissance had yet reared their head, let alone the utterly corrosive skepticism of modernity. Indeed, they have something of a bone to pick with the eleventh century pre-scholastic Duns Scotus, [ed. note- a correspondent points out below that Scotus was 13th-14th century, and taught at the height of scholasticism] and his excessive use of reason! No community will be conceivable outside the church, and while the church will be perfectly humble and humanistic, somehow nothing could be done or authorized without its sanction.

What is the Grandeur of reason, in their eyes? Well to quote Irwin, "What brings this reductionism to pass, it is claimed by both [pope] Benedict and Radical Orthodoxy, is the ‘self-imposed limitation of reason to the empirically falsifiable’." The grandeur of reason turns out to be its extension and broadening into faith- thus giving blind faith the name "reason" just because, well, reason has a nice ring to it in this modern age, doesn't it? Apparently the outright proclamation of faith, pure and simple, is unappetizing for theologians who call themselves "thinkers", so their answer is to slap the sticker of reason on whatever they happen to hold as faith, and hope no one notices.

The self-applied moniker of "Radical" is not RO's only claim to chic, for they are self-avowedly postmodernist as well. Whatever claims to deconstruct modernism and reach beyond the horrors of penetrating rational thought is their friend, and postmodernism is certainly that, since in most understandings it attacks the very capability of humans to understand anything, as per Lyotard, Derrida, and Foucault, to the point that their own writings demonstrate what they set out to prove. It is a fellow obscurantism with which the RO theists feel very much at home. All the same, they appear blind to how postmodernism is even more thoroughly critical of the "logocentrism" and other universal narratives that RO wishes to shelter from thought than it is of the residual certainties of modernism.

For that is the point of RO, isn't it? To proclaim, propagate, and enforce an orthodoxy (kerygmatically, as they would say) without skepticism, quarter or second thought. That is why they yearningly look up to the Catholic church, which stands as such a monolith of unappealable, unapologetic, infallible orthodoxy in a sea of doubt and skepticism, even as it quietly steers its ship with the times, claiming to be best friends with the Muslims and Jews after all, casting off limbo with a press release, settling pederasty case after case as quietly as it can, and otherwise reluctantly trimming its course to the critiques of enlightened reason and morality. And the ruby slippers, dresses, and hats- out of this world!

de Maistre would be deeply pleased by the continued appeal of ultra-conservative thought. His battle goes on an on, one golden age replaced by another in the rear-view mirror, and those who have authority based on nothing other than superstition and tradition deathly afraid that the winds of reason will lift up their skirts and blow them away.

Incidental links:
  • Mullahs and the postmodernists.
  • Fascinating and revolting tale of a postmodernist taking it to the limit.
  • The Sokal hoax, uncovering postmodern pretensions and obscurantism.
  • A theist puzzles over RO.
  • A correspondent provides an excellent primer on RO.

Saturday, February 21, 2009

The meaning of charisma

It is curious how religion propagates through charismatic personalities. What does that say about its truth?

The charismatic personality is something mysterious and powerful. People such as Bernie Madoff, Robert Schuller, Joan of Arc, Steve Jobs, Jesus of Nazareth, and Barak Obama project an aura of complete conviction and meaning that leads to great social power. When everyone yearns for meaning, those who seem to have it figured out and wrapped up with a bow, yours for only $99.99, are the purveyors of the ultimate product.

This came to mind while reading that the televangalism empire of Robert Schuller is falling apart amid his attempt to grant, and then revoke, succession to his son, also named Robert Schuller. Do scientists and engineers spread their "truths" by such fragile and nepotistic means, dependent on the salesmanship of motivational speaking and the intimacies of televised rhetoric? Apparently not.

Personal meaning is the currency of charisma, and speech its medium. Obama electrified the nation with his "journey" which said implicitly that we collectively might not be bad people, but good people. We might not be torturers, bigots, and killers, but a generation that heals and transcends the divides of race, terror, and culture. What that meant for each of us was powerful, and resonated increasingly the more we learned of his capacity to be the change through his own moral composure and competence.

Very well- the political system has granted us the means to re-imagine and redefine our social meanings. It is religion, however, that traffics in even more ultimate meanings, purporting to situate us in narratives of cosmic importance, artfully contrived out of the many myths and imaginings of our ancestors, refined into a supremely addictive product that, once ingested and believed, appears to be virtually impossible to kick.

Whether it is the story that we are loved unconditionally and utterly by an invisible god, (though if we do not believe we will burn in hell forever), or the story that we are on the side of good with our god Ahura Mazda in an eternal fight against evil, as proclaimed by Zarathustra, each religious construct exists to situate us as meaningful, valuable beings in what is otherwise an intrinsically meaningless universe.

What is different about these narratives, each full of meaning, yet so different in their premises and plausibility? Must personal meaning come from narratives involving supernatural beings, or can it also derive from reality-based narratives? That is the existential question, and the answer is that reality-based meanings are always relational and relative. They are situated in our historical, social and intellectual worlds, which are fluid and changing as new issues, new goals, and new forms of consciousness arise. They can never be absolute.

Religion offers absolute meaning staked on completely exterior references. That is why the supernatural is such a fixture of the religious experience. It offers a separate geography for the safe-keeping of ideals, dreams, and wishes, completely unsullied and unaccountable to the here and now. That is also why religious leaders claim their truths and guidance to be unchanging (even infallible!), even as they work tirelessly to keep up with social trends, or else give up the ghost to others that do.

The artists of religion are its charismatic preachers and especially prophets, who offer themselves as mediums of divine inspiration and fulfillment, conduits to a more perfect world. But of course that ideal world is not separate or absolute, but is entirely a matter of imagination, and some of its imagineers are more in tune with the times and persuasive than others. The competition between such imaginative visions is called theology, except when it degenerates into actual warfare, in which case it is called Jihad, or Crusade, or the thirty-years war, etc.

A similar phenomenon takes place these days on the "motivational" speaking circuit, where luminaries of rhetorical skill and celebrity draw audiences searching for meaning and fulfillment, though this time it is, as a rule, meaning in their work, and fulfillment in the form of money. The economic system relies on many jobs that are extremely hard to construe in any deeply meaningful way, yet people need to find meaning to keep their sanity. Thus the need for motivational speaking, which reframes the work of capitalism as life fulfillment, as Olympic-caliber competition, or as military valor. Inspiration comes in a kaleidoscope of heroic forms.
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These threads all come together in the work of the Reverend Dr. Creflo A. Dollar, whose Christian ministry (and "Change Experience" revivals) promise earthly prosperity and eternal happiness, all for a low contribution, since, as his scriptural motto goes: "Give, and it shall be given unto you".

Most divines naturally look down their noses at this crass mixture of the sacred and the prosperous, as if real human meaning could never be found in this world, but only in the next. In this position they may be less personally fraudulent than the Reverend Dollar, but they are still selling what has to be termed a big lie. Indeed, Christians often will argue that they recognize that their Christ story is, on the face of it, so preposterous and absurd that they would be the last to believe it, were it not that it really did happen and really is true. (Unlike all those other religions!)

Anyhow, the common denominator in these insprirational interactions is the imaginative construction and infusion of meaning into human existence- an existence that has little meaning on its own, and thus cries out for assistance, whether high or low. Assistence comes from those who have the gift to convey their own certitude and faith so well that they can sweep others up into what has been called in Steve Jobs's case, a "Reality distortion field". That was the job of the shaman, as it is of the priest and pastor today. Humans are very suggestible- a property that is essential to our sense of meaning and continuing social existence, but which is also prone to misuse by advertisers, con men, politicians, et al., when not studiously counterbalanced with skepticism.

In government, this essential skepticism has been installed by means of constitutions, separations of power, checks and balances, and party competition, so that suggestibility and mania can be slowed down by some degree of automatic critique and review.

It was the wisdom of the enlightenment to agitate for a similar check on religious zeal: the policy of dissociating it from the state. Given that religions come in all intensities and sizes, and do not necessarily have internal checks and balances, their effect on the society in general needs to be limited lest, as is so common historically, they unite with the state and its instruments of coercion to carry their zeal to all, whether voluntarily receptive or not (see Constantine, et al.).

This separation protects the society at large from religious extremes, but does little to protect those caught in the clutches of religious movements from their own suggestibility. Whether the cult is small (Scientology, CUT) or large (Christianity), human suggestibility and its allied capacities of total belief and commitment can lead to tremendous grief (as well as to tremendous happiness).

And that in the end is the meaning of charisma. Like scientific knowledge, it is a tool that can be used for good or ill. But it is in some ways far more powerful than knowledge alone, since it puts that knowledge to active use. It can unite and carry people into common projects that uplift, give meaning and improve the world, but its generated meanings can just as well be profoundly destructive, as the extreme movements of the twentieth century (Nazi-ism, Boshevism, Mao-ism) make so clear. The charismatic leader can only express and channel what his listeners are prone to hear- what is current or nascent in the zeitgeist. Thus we as individuals have a reciprocal duty to cultivate the better angels of our natures, both in our routine debates and in our responses to extraordinary leadership.

Each of us individually has a duty to recognize our susceptibility to charismatic suggestion and to bring skepticism to bear. But more deeply, we have to recognize that our own skepticism and reason is insufficient in the face of our biases, so we need to seek humility and continually listen to and face honestly what critics have to say. And we should lead our lives, defining our own meaning, rather than following the dictates of others, living or dead.

Related links:
  • Old but good book on human herd instincts, by Wilfred Trotter.
  • Topical cartoon.
  • Suicide-martydom correlates more with service attendance than with religious belief.

Saturday, February 14, 2009

PTSD politics

Thoughts on Palestine as a case of PTSD politics.

Trauma and victimization are profoundly and permanently damaging. Recent stories about Iraq veterans show the permanent changes that can be wrought by PTSD, analogous to the permanent brain alterations that follow tobacco, alcohol, or cocaine addiction. Our brains are plastic and impressionable, degraded by degrading conditions. People who are ground down by traumatic conditions are prone to act irrationally and harbor bottomless resentments. Conversely, those brought up in security and prosperity tend to be optimistic and open-minded. That is the underlying rationale for America's "special role" in world affairs, borne as much of our long-term prosperity and security as of our ideals and political example.

To illustrate, the post-9/11 mood on the east coast, especially in Washington, was completely out of proportion to the threat posed, either by the World Trade towers attack or the antrax attacks. The terrorists terrorized (some of) us out of our collective wits without doing very much damage in absolute terms, mostly because Americans had been coddled for decades in a placid, secure country whose major questions revolved around the levels of interest rates and consumer confidence. Our much-vaunted ideals collapsed in a heartbeat, replaced by the vengeful drum-beating of an opportunistic president.

Imagine how we would have reacted had such devastation rained down on us on a daily basis, as in the recent Gaza war, where proportionate damage would have been 83,000 dead per week in the US. Or the recent civil carnage in Iraq, where proportionate damage in the US would have been roughly 20,000 to 30,000 dead per week, every week, for six years. The mind reels at what would have happened to our society. (Compare also the current US-wide death toll of ~825 per week from car accidents and 8,300 premature deaths per week from tobacco).

With this perspective, we can appreciate the intransigence and horror of the Israeli-Palestinian relationship. Locked in enmity and mutual trauma, they hate and are hated. They seek revenge and self-respect in the face of dehumanization. The open each other's scabs, and rub salt in the wounds.

Who is at fault? Well, the problem started with the displaced trauma of European antisemitism, reaching its climax in the holocaust.* While Palestinians where largely pro-Hitler and antisemitic by long Islamic tradition, they were peripheral to the convulsive drama of Europe's Jews .. until those Jews showed up on their doorstep, looking for a home. The Zionist project long pre-dated World War two, but that was when a trickle turned into a flood, and integration of the rising tide of Jews became impossible. They wanted their own space- Lebensraum, one might say- in Palestine.

They pursued all sorts of means, fair and foul, to get it, ranging from purchases of land to terrorism of the local Arabs. Already from the start, the Palestinians had dysfunctional politics, self-defeating reponses, and some bewilderment as to why, exactly, they were supposed to give up their land because some Europeans had been evil to other Europeans. The claims of Jews to their promised land fell on deaf Palestinian ears, as did the pleadings of the British, who were nominally in charge of the territory. The whole deal just did not make any sense.

Yet with force majeure on their side, and the sympathy of the former colonial powers as well as the US and the UN, the Israeli state was born in the teeth of Arab enmity- teeth which were shortly chipped and broken on the highly westernized military know-how of the young Jewish state in the 1948, 1967, and 1973 wars, culminating in Israel's control of the entire territory of Palestine. Incidentally, as a Europeanized, Westernized outpost, Israel also fulfilled in an ironic way the dreams of the European Crusades for conversion and repossession of the so-called "holy" land.

The traditional and Biblical method of dealing with the Palestinians at this point would have been to kill the males of age and sell the rest into slavery. Unfortunately, the requisite markets for slaves no longer existed, and the Jews had raised their ethical norms in the intervening millennia. Forced exile was another option that was explored, (called, in our hygenic age, "ethnic cleansing"), but naturally, no neighbor wanted to take in the now-traumatized and bitter Palestinians, or indirectly thereby help Israel out of its enormous problem.

So Israel was faced with an existential and moral conundrum: how to deal with an embittered enemy on their doorstep, in territory under their own control, within their own ethical precepts, so recently sharpened by their own travails? The answer was to semi-officially apply a water torture of gradual land purchase and expropriation driven by the most rabidly religious settlers, (who, because they are viewed as "more Jewish" than other Israelis, are given a pass on their unethical behavior and fanaticism, not to mention the irony of being excused from military service), along with big helpings of degrading treatment and collective punishment of the Palestinians via the ensuing occupation. In return, the Palestinians mounted what resistance they could, generally small-scale terrorism and guerrilla warfare.

It is clear that Israel has fundamentally violated its own morals and those of the modern enlightened age in its treatment of the Palestinians. The Palestinians for their part have violated the same norms, though they never subscribed to them, and would never have presented any problem had their territory not been disturbed in the first place. At any rate, the problem is one for the Israelis to resolve, since it is they who have the power: the airforce, the billions in weaponry supplied by the US, the nuclear bombs. For them to claim that the Palestinians are not "partners for peace" is totally disingenuous, since the historical process they have sponsored has rendered the Palestinians justifiably aggrieved, embittered, and traumatized, not to mention powerless in all respects other than to say the one word they can manage ... "No".

It might be useful to note here that there are only two ways to win a war- one is to kill the enemy, and the other is for the enemy to give up. An enemy who refuses to give up is one you can not defeat, (see Vietnam), thus the importance of winning "hearts and minds" in the current parlance, which is far more important than realized, even now.

I had thought that the border wall against the West Bank was the beginning of a good solution, hewing the old adage that good fences make good neighbors. But unfortunately, the Israelis placed the fence not on the 1967 border which would have been the logical (and legal) place to put it, but snaking through Palestinian territory, breaking up numerous communities, all in an effort to include as many settler zones as possible, and to impair as many Palestinian communities in their vicinty as possible.

And on top of that, they still couldn't stay out of the West Bank or Gaza, continuing to build settlements on the other side of the fence, building roads restricted to Israelis, blocking Palestinian roads, patrolling, subjecting Palestinians to checkpoints, blockading trade from time to time, bombing and destroying buildings, etc., etc., etc. So the fence has been highly successful from the Israeli perspective, keeping the other side at bay and pacified in a state comparable to apartheid, as Jimmy Carter put it. But it has not been an equitable boundary upon which to build a peaceful or neighborly relationship.

That is where we are now, and the way forward is for Israel to do what is right- not to give up its own territory in the form of a "right of return" for Palestinian re-assimilation of Israel, but to fairly divide the territory using the 1967 border as a starting point, and make that division stick by getting out of the Palestinian side completely, with a relocated fence. The Palestinians will need a road corridor to communicate between the West Bank and Gaza, so negotiations could exchange land, inch-for-inch, for such a corridor in exchange for selected settlements on the Israeli border.

We can grant that the Palestinian political system is thoroughly dysfunctional, corrupt, and self-defeating. That is no reason for Israel to not do what is right- to disengage its expropriation and occupation activities and let the Palestinians take care of themselves (with reasonable means to do so, like ports of their own in Gaza, open trade, etc). Only by disengaging will either side be able to heal its particular traumas and wounds.

Additionally, the Palestinians have been egged on and used by their false friends in Iran and Syria, doing themselves precious little good, and keeping them from tending to their own interests. The only way to break these relationships is to cut the ground from under the extremists by unilaterally offering and carrying out a fair deal for the Palestinian people.

At this point, one might ask about the Gaza situation. Didn't Israel disengage there, and didn't Hamas keep sending rockets into Israel? I would offer that compared to the problems of outright occupation, the problems of occasional rockets were minor. Additionally, the disengagement was far from complete, since Israel turned around and blockaded the elected Hamas government and otherwise made life very difficult for Gaza. And the proper solution to the rocket attacks was (and remains) to reply with immediate return fire to the point of rocket origin- easily possible with basic spotting capability- rather than to wait in silence, and then indulge in a frenzy of collective punishment, intended to "send a message" or "teach a lesson" in the form of 100-to-1 killing rates ... lessons that are never learned at the point of a gun. (See a revolting piece of embedded reporting in TNR.)

The remaining problem will be their continuing economic relationship, which is extensive. Palestinian workers endure dehumanizing daily crossings to work in Israel, and many other critical if fraught relationships exist. No doubt Israel will be tempted to exert pressure on its neighbor in perpetuity by these means, its economy being far more vibrant and influential. It is, of course, a temptation to be resisted, since nothing good comes of such pressure, as amply documented in the relationship to date. Israel's interest on every count- demographically, economically, and strategically, is to promote the economic development of Palestine, and Israel should offer treaties to that effect.

In the same vein, it is not Israel's job or right to control the tunnels or other trade routes into Gaza. If Gazans want to import their own bombs, tanks, etc., they should be able to do so. Using such weapons is another matter, but it is ultimately deceptive as well as futile to claim disengagement from the Palestinians while controlling their most basic contacts with the outside world. Without having responsibility for themselves, Palestinians will never take responsibility vis-a-vis Israel.

At any rate, the solution lies in fairness, separation, and disengagement. The only power the Palestinians have is to say no to the Israeli offers of peace, to offer token resistance with small arms and suicide terror, or rioting and rocks when pressed to extremis. Even this power/resentment would largely dissolve if Israel unilaterally provided a fair and sustainable territorial solution as outlined above, rather than continuing to treat the Palestinians as subhuman objects of slow-motion expropriation. And how do we get Israel to do what is right? Simply by withdrawing our various forms of support if they don't. Whether Israel got to this intransigent and immoral position consciously or not, the US has the leverage to dislodge them from it. (See a Cohn piece on tough love..)

It is sad and ironic that, to realize their Zionist dream, Jews turned around and created the very ghettos, dehumanization, and hatred that they fled in Europe. It is time to recover the humanity of both sides, by giving the Palestinians what is right (with or without negotiations) and allowing both sides to begin a healing process that will take generations.

Related links:
  • Podcasted discussion along the lines above, with Antony Loewenstein, heard after I wrote this.
  • Bush secretly supplies arms to Fatah, in hopes of a coup against Hamas.
  • Friedman makes similar points, indirectly.
  • Cohen, on how similar rational engagement with Iran would be extremely helpful.
  • Lengthy podcast on Israel and the fence, putatively "balanced".
  • Lengthy historical treatment.
  • Frontline segment about settlers.
  • Later article on Obama's reluctance in this area.
  • Later, Hitchens with an excellent piece on Israeli clerical extremism
Incidentally, an excellent review of Darwin, on this anniversary



* Let me note as an aside that one of the anti-semites in chief was none other than the founder of Protestantism- Martin Luther:
Martin Luther, "On the Jews and their lies", 1543
My advice, as I said earlier, is: First, that their synagogues be burned down, and that all who are able toss in sulphur and pitch; it would be good if someone could also throw in some hellfire. That would demonstrate to God our serious resolve and be evidence to all the world that it was in ignorance that we tolerated such houses, in which the Jews have reviled God, our dear Creator and Father, and his Son most shamefully up till now, but that we have now given them their due reward.
... Third, that they be forbidden on pain of death to praise God, to give thanks, to pray, and to teach publicly among us and in our country.
... Fourth, that they be forbidden to utter the name of God within our hearing.
... So let us beware. In my opinion the problem must be resolved thus: If we wish to wash our hands of the Jews' blasphemy and not share in their guilt, we have to part company with them. They must be driven from our country.
... But since they lack the power to do this publicly, they remain our daily murderers and bloodthirsty foes in their hearts. Their prayers and curses furnish evidence of that, as do the many stories which relate their torturing of children and all sorts of crimes for which they have often been burned at the stake or banished.

Saturday, February 7, 2009

How to read DNA

A review of DNA sequencing technologies, from the paleolithic to the bleeding edge.

While one of the greatest discoveries of the last century, indeed of all time, was the role and structure of DNA, it did not amount to much in practical terms until methods were devised to read its code- its sequence. There has been a fascinating evolution in technologies to read DNA, and I have experienced a good share of it. Most methods are dependent on harnessing nature's own enzymes that replicate DNA in increasingly clever ways. The resulting flood of information will serve the age-old project of "know thyself".

DNA exists in almost endless lengths (bacterial genomes are typically circular, and the average human chromosome is 1.3E8 base pairs in length). So the first step in sequencing, in typical reductive fashion, is to break this linear structure into small pieces, place them into bacterial mini-genomic circles with independent replicative ability (plasmids or their relatives), and replicate/amplify them to large amounts that can be handled, sampled, sequenced, filed, bar-coded and stored.

The paleolithic method of sequencing (I've used it a few times) is based on chemistry instead of on enzymes, and is called the Maxam-Gilbert method, after its developers. First, one cuts a large batch of DNA at a specific sequence site with what is called a "restriction" enzyme- a pair of molecular scissors. Then its ends are labeled with radioactive phosphorous (P32), and one of the two ends removed with yet another restriction cut, and the remaining DNA split up into several pools, treating each pool lightly with quite hazardous chemicals that modify the DNA at certain bases (hydrazine at T and C, dimethyl sulfate at G, and formic acid at G and A). The individual units of DNA are called nucleotides, and their key parts are called bases- the A, G, C, and T of the genetic code, after their basic pH.

These chemical reactions are only roughly base-specific, and hit other bases as well, so the whole thing is woefully inefficient. The DNA is then further chemically processed to break the backbones at the modified bases, and the mixtures are eletrophoretically separated on a gel that allows fragments differing in length by a single nucleotide base to be distinguished. The radioactive label on one end ensures that only those fragments spanning from the radioactive label to the randomly cut point appear on the X-ray film that is exposed to the gel.

All the other methods to sequence DNA use the magic of DNA replication enzymes (polymerases) to read sequence, using methods devised by Fred Sanger (who is one of only three people to have received two nobel prizes in science). They do this by getting the enzyme to incorporate occasional bases with some special property- the nucleotides either stop chain elongation at random positions, allowing fragments like the ones described above to be produced directly by the polymerase, or they have other complex modifications to be described below. The enzyme does the work of reading along the DNA, and the experimenter coaxes it to tell which nucleotide base it is seeing as it goes along.

The original Sanger method used radioactive tracers such as P32 or S35 to detect the resulting DNA fragments, but advances in fluorescence technology have revolutionized this aspect of biology, as so many others (one of the latest nobel prizes went to fluorescence labeling technologies for proteins)

How do these enzymes know where to start? The DNA is continuous, but just like in a book or a chapter or a page, you have to start somewhere. And since the text in this case is A, T, G, and C with no further punctuation, the problem of knowing where you are is quite a bit more difficult than in a book. Usually a "primer" is used to start off the DNA polymerase- a short DNA fragment that can be made by pure chemistry, perhaps 20 nucleotides long, which hybridizes to its complementary sequence in the target DNA (after it has been heated up to melting temperature). If the cloning was done in clever fashion (abutting the DNA fragment to be sequenced right up to a known part of the cloning plasmid), then the same primer can be used for an entire sequenceing project.


The original human genome project used a variation of this method, where primed DNA polymerases on templates are fed a low ratio of nucleotides that have both chain terminating capacity, (di-deoxy, as opposed to DNA's single deoxy), and also have fluorescent labels (different for each of the four bases). Then the full four-label reactions with their resulting synthesized fragments are run through an extremely tiny (capillary) electrophoretic gel, at the end of which a fluorescence detector reads off the labels from the size-sorted fragments as they travel past. This is done with expensive machines, using miniaturized reactions that attain large scales of operation, taking all this work out of the hands of regular bench scientists.

A more recent technology is the 454/Illumina system (named for the companies they are offered by), which has finally dispensed altogether with the electrophoretic separation step, which has been such a painful bottleneck.

These systems lay single molecules of template on tiny islands on a glass slide (or a bead), and do an in-place PCR amplification step to park at lot of copies at that location. Then the sequencing step is performed, with A, G, C and T successively washed over all the template islands, and a luminous flash registered wherever a single step of incorporation takes place, before the next washes and next step of polymerization is performed, etc.

The virtue of this system is its extreme miniaturization and large parallelism- many different molecules can be laid down, amplified, and sequenced in one experiment. However, the read length is paltry- only about 35 (Illumina) or 300 (454) nucleotides, compared to the 800 nucleotides regularly attainable with the gel-sorting methods above.

Read length is critically important, since the next step for all these technologies is the reverse of reductionism: the re-assembly of the sequence from all the individual sequence reads, like doing a jigsaw puzzle. The reads (for a whole genome, say) are all poured into a computer program which lines up sequences that overlap, building back up to the sequence of the entire source DNA as best it can. As with jigsaw puzzles, the bigger the pieces you start with, the easier the puzzle is to solve, to an almost exponential degree.

Last, and most amazing, a recent report in Science introduces what is sure to be the next iteration- monitoring the production of a single strand of DNA on a single polymerase from a single template strand with an extremely miniaturized apparatus. Originating in the labs of Watt Webb (of which I am an exceedingly minor alumnus), and Harold Craighead at Cornell, this technique uses an odd optical property to peek into extremely tiny volumes of solution (one zeptoliter ~1E-21 liter).

It turns out that if you shine light through holes made in a conductor whose diameter are less than half the light's wavelength, the light does not get very far. If a solution is put into those holes, you can look at the fluorescent properties of the super-tiny volume right at the floor of the hole (containing in this case a DNA polymerase with template) without being distracted by the rest of the solution which may contain a high concentration of other fluorescent compounds (nucleotides). The fluorescence system looking into the bottom of the hole essentially just "sees" the occasional one or two fluorescent molecules bouncing along the bottom, or binding to the polymerase located there.

The sequencing method is then to add a solution of four different fluorescent nucleotides which contain color labels at their outer-most phosphates, which get clipped off as they are added to the growing chain. The polymerase attached to the bottom of the view-hole can use and incorporate these nucleotides with no problem, and fluorescence from the incoming nucleotide appears transiently, as it is positioned in the enzyme's active site, but before the reaction takes place that clips off the label and incorporates the rest of the nucleotide into the growing chain.

Thus the detector sees a parade of distinct fluorescence signals, one by one, as the lone polymerase does its work synthesizing a new DNA strand along the template. The tricky part is that this process happens stochastically. One incorporation event may go fast, the next slow, as diffusion of the nucleotides and even quantum effects come into play. Several incorporations of the same nucleotide may occur in succession on the template, requiring the observers to make sure they are tracking the pauses in fluorescence that occur between each step of the elongation reaction. Much of this uncertainty can be resolved technically, and also by doing a few replicates.

One advantage of this method is that read lengths are substantially increased. The researchers (who have now duly set up shop in Silicon Valley) show an experiment using a circular template with alternating G (red, below) and C (blue) halves to run off a potentially infinitely long sequencing read. They report a rate of ~3 bases incorporated per second under their conditions, with clear alternation of C and G signals, up to 4,000 nucleotides in an hour's time. This is very promising for problems in genomic sequencing like the occurrence of repetitive regions that are very difficult to piece together from short sequencing reads, and one may hope that these lengths can be extended and the polymerization times speeded up as the technique is further optimized.


All these advances mean that it will not be long before individuals can get their entire genomes sequenced at a reasonable price. The information will allow divination of the future, in the form of improved personal medical prognoses as we slowly learn more about how the genome works. And also divination of the past, since complete genomes will allow geneological analysis of unprecedented detail and depth. Our long evolutionary inheritances reside in these ~3 billion base pairs, and bringing them into the light will generate great benefits, individually and collectively.

Incidental links:
Steven Pinker on his own genome.
Very basic TED talk on genomes by Barry Schuler.
Dire warnings about privacy issues.