At the Climate's Mercy

Volcanic eruptions have interrupted our fragile existence.

A recent research article made the news, telling of the worst year to be alive: 536 AD. This was surely the darkest moment of a dark age, and scientists have tracked its source to volcano(s) in Iceland. It darkened skies around the world, led to a ~4ºF drop in temperature, and crop failures throughout Europe and the near east, and crop delays in China. There seem to have been repeated eruptions over the ensuing years, though perhaps volcanos elsewhere contributed. The result was the coldest decade in at least 2,000 years, and a plague in 541-3 that wiped out at least 1/3 of the Byzantine population, among others. It took decades for Europe to recover, notably shown by ice cores with high lead pollution about 640 AD, showing that silver mining in France had recovered, presumably being pursued for minting coins.

Turner's "Chichester Canal", of 1828, thought to reflect some of the atmospheric effects of the  1816 global volcanic pall.

There have been several similar, though less extreme, events, like the "year without a summer" in 1816, due to the eruption of Tambora in Indonesia. This vocano is estimated to have ejected 40 cubic miles of material, but only lowered temperatures in Europe by about 3ºF, yet caused substantial famine, snowfalls in June, frost in August. A much smaller eruption, of Krakatoa in 1883 also caused dramatic sunsets and world-wide cooling, but had far less devastating effects, being smaller, and because it happened in August, and did not affect the following summer as severely.

Are our agricultural systems robust enough to withstand such an event today? I doubt it. We have optimized and stretched in every direction, supporting vast urban populations, without a thought given to adverse events of global scope. The only significant failsafe is that most agricultural production goes to supporting livestock, which under duress could be used directly for human consumption.

Conversely, we are engineering a permanent climate disruption of equal proportion but in a warming direction, by our emissions of CO2. Will temperatures go up by 3ºF? 4ºF? 5ºF? We are already at 2ºF, (vs temperatures at 1900), with much more baked in from our past emissions, and from their relentless continuance and growth. Will we survive if agriculture has to move to Canada and Siberia? If Florida and New York are under water? Sure, but at what cost to ourselves and more importantly, to the natural world?

• Doonsbury's Duke, in real life.
• On the way to modern capitalism: guilds.
• We are not as prepared as we think we are.
• Medical pricing in the US is insane. Weren't insurance companies supposed to solve this problem?
• Asset? Yes. And where is the outrage?

Chromosomes Blown to Smithereens

Where do cancers and cancer relapses come from?

DNA is a treasure trove that keeps on giving. The human genome sequence was a milestone that may not have been self-interpreting, but has provided grist for leaps of technical advancement and knowledge. Ancestry studies are one example, but disease studies are of more immediate interest. Cancer is now understood to be a molecular disease where the DNA suffers mutations that release various brakes on cell proliferation. One of the most influential types of mutations are gene fusions, where one gene that has roles in proliferation is broken from its normal regulatory controls, either within its coding sequence (such as a repressing protein domain) or its upstream expression controls, and hooked up with some other gene that drives its expression in new places and high levels. A recent paper studied several cancers in detail, sequencing samples from various time points and locations, coming up with very interesting findings about the origins of these mutations and the nature of metastasis.

One example of a genome blow-up, called "chromoplexy". A few regions of the genome got caught in some kind of spindle, and came out with several breaks which then were repaired to form re-joined fusions. In this diagram (right) of one resulting fusion, of genes BCLAF1 and GRM1, the chromosome 6 parts on the outside have rejoined, while the broken parts between the rejoined ends have fused to each other and then to chromosome 16, with one small bit unassigned and perhaps ending up somewhere else. The diagram seems to indicate that GRM1 ends up upstream of BCLAF1, (these are divergently transcribed in the native chromosome), which I think is an error.

Chromoplexy is one form of a genome blowup, one that is restricted in scope (at least compared with the even more destructive chromothripsis). The best theory about its origin posits that the affected portion of the genome (typically an early-replicating and transcriptionally active region) gets caught outside the normal nucleus, forming a temporary mini-nucleus which is cut off from normal controls, causing the trapped DNA to break up. The cell has strong controls against free DNA ends, and uses end-joining DNA repair to patch things up, pasting ends together essentially at random. This is obviously quite dangerous, and leads to unexpected gene fusions, of which hundreds of different examples are now known that drive various cancers. One such fusion, diagrammed above, is between genes BCLAF1 (upstream) and GRM1 (downstream).  GRM1 is a receptor for glutamate, the most prevalent excitatory neurotransmitter. While most highly expressed in the brain, glutamate receptors act throughout the body, and malfunctions are connected with a variety of diseases. Increased expression and activation can drive cell proliferation. The other fusion partner, BCLAF1, is a promoter of cell suicide, or apoptosis. That function will be lost in the fusion, which might have some importance to the disease (though a second copy presumably remains intact elsewhere). The important part is that it is very widely expressed, especially in bone marrow. An earlier paper describing this fusion states:

"The GRM1 coding region remains intact, and 18 of 20 CMFs (90%) showed a more than 100-fold and up to 1,400-fold increase in GRM1 expression levels compared to control tissues. Our findings unequivocally demonstrate that direct targeting of GRM1 is a necessary and highly specific driver event for CMF [bone tumor chondromyxoid fibroma] development."

This pattern of mutation, and the specific fusions that resulted, became apparent due to the deep sequencing the researchers did, taking samples from the patient's tumors and from normal tissues. An important concept here is of mutational signatures. Each mechanism of mutation has its characteristic pattern of mutations left in the genome. Exposure to UV light, which causes C->T mutations, will leave a much different pattern in the genome than the localized chromoplexy blowup mentioned above. So a forensic analysis of the patient's DNA can tell what happened, in some mechanistic detail. For example, the various fusions seen in these samples were not part of extensive copy number variations- reduplications that are common in cancerous cells, which indicated that this blowup took place once as a discrete event, not repeatedly or slowly over a long period of time.

It can also tell when it happened, and here we get to a particularly interesting message from this paper. When they sequenced primary and relapsed tumors, (with comparisons to normal tissue), such tumors shared some key mutations, those which drove the overall cancer. But they failed to share many others. Indeed, the metastatic tumors carried none of several mutations that were uniformly present in the primary tumor. This says that metastases or relapse cancers, (this part of the study was specific only to Ewing's sarcoma, a bone cancer typically arising around ages 1-20), typically do not develop from the primary tumor, but from cells that carry the same driver mutation, but diverged before primary tumor formation. They are independent events, and metastatic prognosis has little to do with the fate of the primary tumor.

The author's proposed time course of Ewing's sarcoma evolution, placing the origin of metastatic and relapsing tumors well before and outside of the primary tumor at the time of diagnosis.

Whether this observation about metastisis applies to other tumors is naturally important to follow up. It would alter significantly how we deal with primary tumors, and informs the kind of conservative treatments (lump-ectomies, for instance) that are becoming more common. As sequencing becomes cheaper and more common for all kinds of tumors, the particular drivers, from whatever mutational source, can be identified and used to direct specific, (buzzword: "precision") treatments. GRM1 can be targeted by direct or indirect means. But if one has Ewing's sarcoma, typically associated with a fusion of EWSR1-FLI1, where FLI1 is a transcription factor that drives growth factor production and hence cell proliferation, a different set of therapies would be indicated.

• The Green dream is on.
• Our cold war with China.
• AIPAC is the NRA of foreign policy.
• Bill Mitchell on economics education, especially macro.
• Election crisis.. no problem.
• Give to the rich, take from the poor.
• Notes on experts.

Truth, Justice, and the American Way

Stephen Walt's critique of our overextended, idealist, militarized, and not very bright foreign policy: The Hell of Good Intentions.

Americans have gotten rather used to running the world. Whenever news arrives about some horror or injustice, action is expected. No matter how distant the crisis, we now have interests, and assets, close-by. It is a mindset we inherited from the Greatest Generation, who build a post-war order out of constant vigilence and activity- first to reform the perpetrators of the war, and then to forestall the spread of communism. After the Soviet Union imploded, we were left free, with a vast whirring mechanism of diplomatic and military machinery. For those raised on Lone Ranger episodes and Superman comics, which may describe a good portion of the foreign policy community over the last few decades, the answer was obvious- do good.

Stephen Walt takes direct aim at this mindset, which in his telling is borne as much from laziness and stupidity as from good intentions and US interests. We have committed terrible blunders in our rush to save people from predatory states- the prime examples being Vietnam and Iraq, which cost roughly 1.3 million and 0.5 million lives respectively, though the latter remains open-ended, due to our responsibility for creating ISIS. The people responsible for these comprehensive, mind-boggling disasters should have been tried as war criminals. But instead, our system barely batted an eye, and most of the architects of both horrors went on to continued participation in the US foreign policy commmunity, often at high levels.

This is because foreign policy is a strongly political field, at least as practiced in the US. Who would have hired Jared Kushner to run US Middle East policy? No one in their right minds, that's who. But the rot runs much deeper. Foreign policy is not science, and is difficult to evaluate, especially considering our problems with prophecy. So standards are virtually absent, replaced with a go-along-get-along ethic within a tight zone of conventional ideas. A big change since the Reagan era has been the intrusion of neoconservatives into this community, via right-wing administrations and their partisan think tanks like the Cato institute, American Enterprise Insitute, and Heritage Foundation. These were the minions who pushed the Iraq war, and they keep pushing the zone of mainstream thought rightward. Their current project is to demonize Iran. Which is odd, because Iran is a more functional democracy than Saudi Arabia, and intellectually far richer and more dynamic as well. The motivation for all this comes mostly from Israel, which has tacitly allied itself with Saudi Arabia and Egypt in a new cynical status quo ... just so long as no one says anything about the Palestinians.

The checkered career of Elliott Abrams is if anything more disturbing for those who believe that officials should be accountalbe and advancement should be based on merit. Abrams pleaded guilty to withholding information from Congress in the 1980's, after giving flase testimony about the infamous Iran-Contra affair. He received a pardon from President George H. W. Bush in December 1992, and his earlier misconduct did not stop George W. Bush from appointing him to a senior position on the National Security Council, focusing on the Middle East. 

Then, after failing to anticipate Hamas's victory in the Palestinian legislative elections in 2006, Abrams helped foment an abortive armed coup in Gaza by Mohammed Dahlan, a member of the rival Palestinian faction Fatah. This harebrained ploy backfired completely: Hamas soon learned of the scheme and struck first, easily routing Dahlan's forces and expelling Fatah from Gaza. INsted of crippling Hamas, Abrams's machinations left it in full control of the area. 

Despite this dubious resume, Abrams subsequently landed a plum job as a senior fellow at the Council on Foreign Relations, where his questional conduct continues. In 2013, he tried to derail the appointment of the decorated Vienam veteran and former senator Chuch Hagel as secretary of defense by declaring that Hagel had "some kind of problem with Jews". This baseless smear led the CFR president Richard Haass to distance the council from Abrams's action, but Haass took no other steps to reprimand him. Yet, apparently, the only thing that stopped the neophyter secretary of state Rex Tillerson from appointing Abrams as deputy secretary of state in 2017 was President Donald Trump's irritation at some critica comments Abrams had voiced during the 2016 campaign.

Naturally, Abrams has recently been appointed as the Trump Administration's envoy for the crisis in Venezuela, which should inspire confidence. The most that the mainstream press can manage as a description is that he is "controversial".

What is worse, not only are egregious blunderers and arguable criminals never held to account, (Bush, Cheney, Kissinger), but truth-tellers and whistle-blowers are routinely side-lined. Remember Eric Shinseki? He was quickly sidelined from the military in the Bush administration, after giving an accurate estimate of the number of troops needed to stabilize Iraq. He was later rescued from exile by Barack Obama, but did he re-enter the military? No, he was put in charge of the VA, safely out of the way, and in an impossible job to boot.

In September 2002, for example, thirty-three international security scholars paid for a quarter-page advertisement in the New York Times' op-ed page, declaring 'War with Iraq Is Not in the U.S. National Interest.' Published at a moment when most of the inside-the-Beltway establishment strongly favored warm the ad warned that invading Iraq would divert resources from defeating Al Qaeda and pointed out that the Unites States had no plausible exit strategy and might be stuck in Iraq for years. In the sixteen-pus years since the ad was printed, none of its signatories have been asked to serve in government or advise a presidential campaign. None are members of elite foreign policy groups such as the Aspen Strategy Group, and none have spoken at the annual meetings of the Council on Foreign Relations or the Aspen Security Forum. Many of these individuals hold prominent academic positions and continue to participate in public discourse on international affairs, but their prescience in 2002 went largely unnoticed.

One interesting point that Walt makes along the way is that one capability that has atrophed due to all this dysfunction is true diplomacy. The Iran nuclear deal was one of the few recent episodes where we actually sat down with friends and enemies and hammered out a peaceful deal, agreed to by all sides. It is far more frequent these days to make big pronoucements, whether bland or insulting, then threaten punitive action like sanctions or drone strikes. Granted, the Al Qaedas and ISISs of the world are not likely to come to any Geneva tea parties, but there is a lot of good we could be doing by diplomacy, such as in Latin America and Africa, which is being left on the table. Instead, we have very secretive military activities in about 20 African countries. Militarization has colored our foreign policy to an excessive degree. And how has our "Peace Process" been going in the Middle East? This one was not a casualty of militarization, but of Israelization. Because of our failure to bring sufficient pressure to get to a Palestinian state solution, Israel continues to be an Apartheid state, and our reputation in the region is a shambles, shown to be the lapdog of Israeli interests.

The Lone Ranger brings in the bad guy to close a successful episode.

Walt's solution to these dysfunctions is to reel back our ambitions, from what he describes currently as a policy of "liberal hegemony" to one of "off-shore balancing". Liberal hegemony is the idea, which is sort of a hat-tip to Karl Marx, really, that liberal prosperous democracy is the desirable endpoint for all peoples everywhere, so we should not mind giving history a shove every now and then to get everyone there faster. The benefit for the US is clear as well- the more democracies there are, especially as encouraged by us, the more friends we have and the more stable the world in general.

Off-shore balancing, in contrast, is more hands-off, and regards US interests involved only where some region of the world is being taken over by a large hegemon, (like China), which could create such a global imbalance that we in the Western Hemisphere may be threatened. The Middle East should be left to its devices, especially as long as the Iran and Saudi axes are reasonably closely matched. Likewise, Europe is not a problem, even with Russia glowering from the east, since power is heavily diffused, and Europe even without US help is well able to take care of itself. While seemingly cynical and isolationist, this is really a very traditional approach to foreign policy, steeped in centuries of experience with Metternich-ian balance-of-power practices in Europe.

While Walt offers some very accurate and telling critiques of the state of the US foreign policy establishment, I think the prescription does not quite fit the problem and he tends to soft-pedal its implications. While the Middle East would obviously be better off with a little less US meddling, would it be better off with more Russian meddling? I have previously advocated for prompt, decisive involvement in Syria, which might have led to a better outcome than what is happening now, for both the people of Syria, and our own strategic position. But it may have been just another costly fiasco- that is what makes this field so treacherous. (Incidentally, Walt mentions the US Holocaust Museum's extensive research on Syria, especially on the prospects of US involvement. It casts a rather dubious light overall, but does suggest that early intervention can be far more effective than late intervention.) Turning to China, Walt does not mention the fate of Taiwan, of the South China sea, of the Philippines, or Japan. Would keeping Australia out of Chinese domination be a vital interest of the US? How many interests would he be willing to give up before things get truly serious?

But the deeper issue is one of stupidity. Doing less will not make us smarter. Walt gives some very positive reviews to the various anti-establishment views of Donald Trump and the demographic that he connected with in winning the presidency. Trump was all about throwing the bums out, and retrenching US foreign policy with fewer entanglements and a more modest approach. How has that turned out? Walt decries what is quite evident- our policy, which seemingly couldn't get any worse, now has gotten much worse, with a dotard and his various short-lived protectors and yes-men running things. US interests and influence throughout the world are shriveling by the hour.

A second observation is that the Iraq was not brought to us by idealism. It originated in the psychology of unfinished business on the part of Bush, Cheney, and their extended right-wing establishment. Their idealism was, as anyone could see, paper-thin pablum, matched by their total disinterest in the actual country, its people, and what was to become of them in the aftermath. Stupidity reigned supreme, and hundreds of thousands were killed, and countless more lives destroyed and ravaged for that stupidity.

The case of Vietnam was different. We had recently half-won the Korean war, and saved its Southern half from bondage- a fate that becomes more shocking every year as we view what goes on in Chinese-backed North Korea. Due to our loss of the Vietnam war, all of Vietnam remains a totalitarian state- the South would have been much better off had we/they won the war. Our involvement there was heavily idealistic. But it was stupid. The smart people knew the lay of the land, knew the experience of the French, and knew that it was a civil war that the North had a huge head start on, in comparison with the corrupt, illigitimate Southern government. It was a triumph of hope over experience.

So what we need is more experience and smarts. The US needs a better foreign policy system, not different ideals. We need to rigorously insulate our intelligence and analysis system, of which the State Department is a prominent part, from politics. That means stopping the revolving doors of personnel coming from think tanks, lobbying organizations, corporations, and political appointments. Country and region experts need to have long-term relations with their areas, not short posts. Analyses need to be given something like five-year reviews, with promotion dependent on success. Those let go should never be let back in. Accountability needs to replace hackery, corruption, and amateurism. This community needs to be de-militarized as well, which has been a rising problem for decades. These analyses should have public and secret components, with as much as possible made public so that the country can see the work that is being done, and learn what the basis of our foreign policy is. Like militarization, excessive secrecy has also degraded discourse and accountability.

Lastly, we need a more mature media discourse about foreign policy, less reactive to the news of the day, (let lone the twitter-minute), and more analytic and historically aware. Off-shore balancing is a very credible view in this discussion, but so are more idealistic approaches. Helping abused populations in foreign lands is a good thing, if it succeeds. The point is to succeeed rather than fail in our foreign policy projects, which requires deep experience, accountability, good information, and mature discussion. Perhaps we will find out that we should be doing less, once we filter out the bad ideas. Or perhaps we will find out that to do the things we might want to do (think of the second Iraq war) would be, if done properly, unrealistically expensive and unfeasible for that reason.

• Faux-ocracies are a rising challenge.
• The Taliban is weary of gaining ground in Afghanistan.
• New Taliban, same as the old Taliban.
• Yes, we are dealing with a fascist.
• Medical insurance should be left to the private sector?
• We need a wealth tax.
• And a bigger inheritance tax.

The Power of Prophecy

What makes prophecy such a compelling narrative device in fantasy and myth, and a psychological fixation?

Humans have been obsessed, from the beginning, with the future. As the only animal conscious of the future, its inscrutibility quickly became a frustrating obsession. One wikipedia page lists 372 forms of divination. Some of the earliest far Eastern writing we have is from divination using bones with wishes or questions written on them. How natural is it, then, to imagine that there is someone on the other end to tell us the answers, or some people gifted intrinsically or through some divine possession or shamanic training to foretell the future? My newspaper still publishes the daily horoscope, a sadly watered-down echo of these most fervent longings to peer into the unknowable.

It has been a fixation in drama, from Oedipus to Harry Potter. The Greeks went to Delphi and received dramatically cryptic answers, which could be famously misinterpreted. Oedipus fell into this trap, fulfilling precisely what he had strained every nerve to prevent. When used in fiction, prophecies are relentlessly fulfilled, since otherwise, why bring them up? Like for the more generic foreshadowing technique, the magic only works when the portents are true, and the characters, while twisting every which way to evade or fulfill them, find in the end that fate has spoken with one voice out of the timeless dimension.

The Harry Potter series makes generous use of prophecy, both in its main plot lines, where Harry is marked in advance in various ways for his extraordinary fate, including the special symbol tattooed on his face, and in one particular episode, where the characters fight it out in a hall of phophetic orbs, climax of the fifth book. The bible, of course would hardly be the book it is without a flood of prophecies. The new testament was in large part composed around the supposed fulfillment of various prophecies made in the old, with some squeezing and patching required. The king of the Jews who came to save the world  bears hardly any resemblence to what the old prophets were expecting! Yet, mysteriously and gloriously, the fulfillment came about in the least expected way, etc... Then the New Testament closes with another round of even more feverish prophecies, in the form of revelations where the mundane world will finally receive its just deserts and be swept away in favor of a new and perfect dispensation.

Stonehenge, in part an astronomical prediction machine.

Obviously, it is empowering to feel even a little in control of fate, a little gifted with insight into the future. Why else are countless people betting on sporting events? Why else make such a fetish of astronomy and the prediction of what can minimally be predicted- the steady progress of the days and seasons? It is endlessly maddening to know that the future is coming, but know so little about it. But the tide has turned a bit over the last few centuries as a new mode of thought came to the fore- science. The successful analysis and prediction of Halley's comet showed on a poplular level the power of Newton's system and its ability to predict the future. Now we can predict the weather with startling accuracy, at least a week or so in advance, and can likewise predict the climate decades into the future, somewhat to our horror. Yet there is so much that still eludes prediction. Even in the physical world, earthquakes remain a frustrating challenge, apparently fundamentally unpredictable. And despite the "end of history", human affairs remain not just unpredictable, but irrational, as our current political regime so amply demonstrates.

In its humbler incarnations, prophecy is merely evidence of intelligence- a keen imagination or intuition that is able to discern where things are going sooner than the next person. This is where sports betting and stock picking get their acolytes. But beyond that it is clearly a fictional device- one that we love in its fateful foreshadowings and tragic struggles, but one that has never risen above that level to divine inspiration, reading the mind of god. Naturally, that is because such a thing does not exist. We are trapped within the plodding arrow of time, as we are under the spatial light-speed limit, as we are under our own mastery of fate, such as it is, having no other to turn to.

• Like we need more billionaires running things, and preaching about the national debt.
• Wealth is the problem, far more than income.
• And we have the candidates to solve it.
• George Will does something good.
• Protect your and your country's health- leave facebook.
• Treason and corruption, continued.
• Income tax rates have no effect on economic growth.
• But what do economists know, anyway?