Illustration Friday: Liquid

My contribution to this week’s IF - the theme is ‘Liquid’. Made in AI in about an hour while watching Grimm with half an eye.

Beyond contempt

Imagine you’re suffering from an illness that gradually destroys your joints. At first, it’s just painful. Then you wake up with the stiffness that takes hours to lift. You feel like some creepy automaton that takes until midday to thaw up. And it’s painful. You start popping NSAIDs, each stronger than the one before, gradually destroying the lining on the stomach, leading to ulcers and pain. You have the fantastic choice between steroids (causing emotional disarray, diabetes, weight gain and brittle bones) or the pleasantly-named DMARDs, disease-modifying antirheumatics, which are basically watered-down chemotherapeutic drugs with all the joy that comes with them.

Now imagine there is a drug that could help you. It’s got a weirdly unpronouncable name (how do you pronounce Xeljanz anyway? SELL-jans? Zel-JENNs? Is it even in English or did they start naming stuff in Klingon?) and it’s fairly expensive (about $2,000 a month), but you’re willing and able to scrounge it together — you might even be able to work full-time if it helps you alleviate your symptoms, in which case it is a trifling expenditure when considering the gains.

Except up comes beyond-contempt Senator Ron Wyden of Oregon, who will make sure you won’t get many of these drugs in the future.

I use the term ‘beyond contempt’ with the utmost discretion. I have worked custody, I have been locked in rooms with the scum of the earth, from rapists to wife-beaters and drug dealers. I’d rather have a hand of poker with any of them than have to breathe the same air as Ron Wyden.

Ron Wyden may be the reason why it’s back to tummy-busting NSAIDs for sick people rather soon. You see, Sen. Wyden, a lawyer whose experience with the pharmaceutical industry spans ingesting the occasional Tylenol, has decided to don the robes of the — notoriously unexpected — Spanish Inquisition, and write to Francis S. Collins, director of the NIH, expecting answers as to what benefit the ‘public’ will have of NIH’s collaboration with Pfizer that yielded Xeljanz, the first kinase inhibitor used in the therapy of RA.

A bit of biochemistry for you nerds: kinase inhibitors have been used in the therapy of cancer for considerable time. Kinases are enzymes that phosphorylate a protein, attaching a phosphate group to an amino acid in the chain forming the protein. This process of phosphorylation is important in certain biological processes, in particular inflammation and cancer. The pathfinder molecules were developed in the early noughties. Trastuzumab (Herceptin), a monoclonal antibody, targeted the Erb2 kinase, which made it a useful drug for HER2+ breast cancer. Imatinib, discovered a couple of years later, reduced the ability of the mutated BCR-Abl region, the classic mutation of chronic myelogenous leukemia, to attach to the interleukin-3 b(c) subunit on other cells and thus speed up cell division by phosphorylating tyrosine in certain enzymes controlling the cell cycle. Inhibiting this process did not get rid of the sick cells, but greatly reduced their proliferation. Today, imatinib (Gleevec), which is also a simpler molecule than monoclonal antibody-based kinase inhibitors like trastuzumab and thus easier to manufacture, is used for CML as well as gastrointestinal stromal tumours (GISTs). A number of protein kinase inhibitors followed, with about a dozen or so approved by the FDA for usually haematological/oncological indications. The key benefit is that as they target mutated phosphorylation, they do not affect healthy cells. Not as badly as other chemotherapeutics, anyway. In short, targeted kinase inhibition rocks.

So, then, it was contemplated to extend the benefits of what was learned about cancer therapeutics and kinase inhibitors to autoimmune illnesses, seeing as they tend to respond to many of the same therapies. Tofacitinib inhibits Janus kinase 3 (JAK3), a kinase within the JAK-STAT pathway, which is the major signalling pathway that cells the nucleus what’s up outside the cell, and is heavily involved in inflammatory processes. The role of the JAK-STAT pathway in inflammation was established by John O’Shea, a scientist working at the federally funded National Institutes of Health, and initially published in 1994.

Pfizer saw the opportunity to develop what might have been the drug to save people affected by inflammatory disorders from damaging steroid or DMARD treatments by leveraging O’Shea’s discovery. A brief co-operation with NIH followed, which yielded no patentable IP. On their own, they embarked on the process of rational drug design, something most people don’t quite understand. In rational drug design, a target biomolecule is modeled by a computer based on data from NMR or x-ray crystallography, which then will seek a ligand or a structure to, say, competitively inhibit or bind in some other way as desired. The computer eventually pops out a lot of candidate molecules, usually ‘ordered’ by their ‘score’ of fit and affinity. The number of candidates may number into the hundreds or thousands. Some are discarded because they contain known sequences or ligands that are associated with side effects. Others fail in in vitro testing. Yet others fail the multiple rounds of clinical trials. And finally, the entire endeavour may show no benefit at all and has to be abandoned. Fortunately for Pfizer, the final candidate molecule, tofacitinib aka CP-690,550 did show a sufficient benefit in the case of patients who did not respond to DMARDs adequately. By that time, a decade has passed since O’Shea’s discovery, and Pfizer has spent about $1bn on tofacitinib — not counting the dozens and dozens of prospective drugs that have to be abandoned for each drug that ultimately succeeds. To break even before the drug becomes obsolete in about five years, it has to be prescribed to about 9,000 patients for all of five years — make an allowance for those who will not tolerate, or do not respond to, the drug, and we’re at about 30,000 prescriptions — 2.4% of America’s approximately 1.3m RA patients.

Meanwhile, the NIH was hit by sequestration and the consequences of reckless government overspending. The Obama administration sacrificed America’s position as the world leader in science by sharp cuts to the science budget, killing America’s space proficiency and slashing the federal research budget by 8% or $54bn. The NIH is badly hit, having lost about 5% of their budget for the rest of the fiscal year, and unless the sequester is reversed, the budget will go down by further 8% by 2017. While America’s ‘science nerds’ (read: arts people with a very cargo cult understanding of science but a lot of enthusiasm) trembled in fear of what people who question evolution will do to their science budget, their most science-y favourites have just sold American research capabilities downriver.

Jumping on the extremely trendy bandwagon of hating Big Pharma, Sen. Wyden questioned NIH about “what the public can expect as a return on its research investment”. I am not quite sure that Sen. Wyden is entirely aware that one of the very rare arthritis drugs in a pill form was the result. I am not quite sure whether Sen. Wyden regards people with RA, who reap the benefits of this invention, constitute parts of the ‘public’. And I am least of all sure whether it dawns on Sen. Wyden what a bizarre, schizophrenic attitude his party displays — providing healthcare for all on one hand, but also meddling with the fiscal forces that lead to drug development.

Drug development is expensive. Platitudes are cheap. Sen. Wyden is full of them:

In the face of this difficult economic climate and the increasing scarcity of research dollars it is time to revisit the idea of striking a better balance between encouraging profit, innovation, accessibility and affordability.

The way you encourage innovation is by, you know, not starting to demand money by menaces off the people who have done the innovation in this case — and that’s not NIH. The entire enterprise is like the family of Christopher Columbus demanding a percent of all profits made in America, since they have done the ‘innovation. It is accessibility and affordability that Sen. Wyden is most concerned with. Like the impatient kid before Christmas, he’s willing to riffle through the presents, and so be it if the tree falls on his head. As drugs get competition, their price goes down — an obscure tidbit of economics that is apparently not taught at Stanford. And unlike in Wyden’s much beloved Cuba, affordability is not a matter of state mandate.

In his zeal to be remembered as the senator who fought Big Pharma and won, Sen. Wyden is slaughtering the goose that lays golden eggs for a rather poorly prepared roast. The NIH is publicly funded, and a property of the public — which includes corporations as much as it includes RA sufferers. Claiming to act for the benefit of patients, the only person Wyden cares about is himself. For his ambition, generations of people with chronic illnesses will pay with reduced access to new pharmacological developments if the government decides to ‘realise the public benefit’ — that is, forcibly take a percentage — off all profits made from pharmaceuticals that are based, however loosely, on NIH research.

Reminder: these are the people Americans entrusted with their healthcare.

Chris elsewhere: On eulogising a tyrant

I’m featured over at Anna Raccoon’s, rather disgusted at the Chavez eulogies:

The Chavez fans are right. The corporate media has indeed misled us. In its mad scramble to save ground lost to political blogs that cater for the hard left, it has painted Chavez as a jovial South American archetype, a ‘friend of the people’ and a social reformer (and never mind the torture and police brutality). There is, indeed, a ‘conspiracy’ — one to paint our generation’s most noxious fascist dictator as a populist hero, and in a sickening act of political necrophilia, use the fact that he just died to white-wash his blood-stained legacy.

If there is one thing to eulogise about Hugo Chavez, it is his keen awareness of the Western establishment of ‘useful idiots’. Chavez knows that there is nothing he cannot get away with if he dons certain fashionable ideas. No police brutality will not find its fierce defenders amidst ‘human rights advocates’ in the West, as long as whoever committed it was sufficiently anti-imperialistic. No theft of a nation’s oil reserves and squandering it on useless social programmes with no impact won’t go uncriticised, as long as Chavez ‘sticks it to the Man’. No complicity in, and support for, global terror is unforgivable if the motives were sufficiently anti-American.

Go read the rest.

Boxing Day

It’s been a strange year. It’s been a year of learning three-letter acronyms like HLH, PCA and TPN, acronyms not even I, a devoted fan of TLAs, could wish to acquire. It’s been a year of agonising pain at times, and while my pain relief has improved by leaps and bounds, sometimes it still is. I don’t like to talk about pain. I don’t even like the word. It’s not easy to explain without sounding wimpy. I’ve been stabbed, cut, punched, kicked, and generally didn’t make much of it. The chronic pain you get from a lot of stuff being broken in the gut region is different. It radiates into everything until basically all between your knees and your neck is a bundle of agony. Then there is the anaemia, which feels like a million tiny needles in your muscles as walking upstairs to your first-floor apartment feels like tackling Everest or the Eiger’s North Wall. There’s the Duchess-of-Cambridgesque nausea (that won’t go away after nine months, nor will I have a baby to show for it), and there are all the other vicissitudes of life. I still don’t have my own space station, for instance. But I hear it’s fashionable to shrug those off as ‘first world problems’.

“So,” the cabbie asks me, as we sped towards Heathrow Airport, “what do you want for Christmas?”

“I don’t know,” I replied. “I’ve pretty much got everything. World peace, maybe?”

A cure. A promise that I’ll be in that lucky percent that live an ‘average’ lifespan. More time. More waking hours. And that damn space station. With the ion cannon.

I live life at the cutting edge of survivability. My luggage was delayed by 48 hours. It took a full frontal tweetssault of all my dear friends, whom I love so much, to force Lufthansa into getting it to me expeditiously. I’m not pushy - by the end it got to me, I was sick, shivering from the hypoglycaemia, cranky from the hunger pangs and too dizzy to stand up from the fluid loss. If life is fragile, mine is a butterfly’s wing.

And yet I throw anchors into that fragile life.

I do so because I can afford to. I can afford to because there are people who make it possible. People who raise my head and hold my hands.

In the Spring, when my gruelling course of treatment ended, my doc suggested I ‘do something crazy’. I’ve had the best ever excuse. I was alive.

So I asked out a girl. She said no. I told the story to a lady on Twitter. In September, I would kneel before her in the Fellows’ Garden of University College, stammering like Demosthenes and shaking like a leaf in a hurricane. She said yes, and I fumbled for what felt like eternities to get the necklace clasp to fit together. She gives me strength. When I hold her hand, I’m invincible. I like being invincible for a change.

I have a big sister. She’s all a big sister can be, and then some - fiercely defensive, smart, funny and loving. This year has been a tough one for her, and I’ve spent a lot of it in prayer for her. At the same time, she’s pulled off feats of courage that made me look with eyes rounder than a penny piece. I’m proud of her, and blessed to have her, and her family - an awesome husband and a wonderful little girl -, in my life.

There’s the man with a kind, gentle heart and the courage to survive a lifetime’s suffering, grief and disappointment, hidden behind a space-faring rodent, whom I exchanged e-mails with. There’s the artist with the creepy trailing voice and morbid sense of humour who taught me wax sculpture. There’s a kind and understanding GI doc who worked with me to find a solution to keep me going. And a lot of other people.

They, and a lot of others, are gifts that give every day of the life.

They are what matter. Against all of us, not even a life-limiting illness has power.

I’m blessed. Truly, I am.

Merry Christmas. I hope you feel the same way this Christmastide. If not, let me know. Let me see if I could do something for you.

Pardoned in heaven, the first by the throne

Just for a handful of silver he left us,

Just for a ribbon to stick in his coat—

Found the one gift of which fortune bereft us,

Lost all the others she lets us devote.

By now, I expect, the Petraeus story has been chewed over from all its various angles: the realist (unlike, say, Bill Clinton, Gen Petraeus is a man of stout morals and astonishing personal ethics — and certainly not the man to even contest the call to resign), the conspiratist (it is indeed odd why he resigned a weekend before he was due to appear before the Benghazi inquiry) and the sordid (I leave that to the reader’s imagination). One angle not quite explored is how the downfall of Petraeus, albeit for completely unrelated reasons, marks the end of the Year That Killed 4GW.

We that had loved him so, followed him, honoured him,

Lived in his mild and magnificent eye,

Learned his great language, caught his clear accents,

Made him our pattern to live and to die!

The year is 2006. I am working as a visitor in Leiden, writing my dissertation in humanitarian law in the context of Counter-Insurgency (COIN)/4th Generation Warfare. It’s a hot topic - FM 3-24, the Counterinsurgency field manual put together by General Petraeus, has just been published. Meanwhile, a lot of rather smart ideas are thrown into the ring by a lieutenant-colonel who just took command of 1/34th Armor Regiment and was tasked specifically with the development of MiTTs — military transition teams —, 10-20 strong teams that would liaise with the local forces in Afghanistan and Iraq, train them and otherwise do as Mao said a guerrilla would — swim among the local population as a fish swims in the sea. A few months later, the 2007 troop surge into Iraq would revitalise a war that was breaking the bodies, nerves and minds of its fighters. For once, it seemed that casting the old Napoleonic principle of never sending reinforcements to a failed effort would yield favourable results as the surge gave momentum to a war that was haemorrhaging momentum to the drag of fighting an invisible enemy. The surge was to be more than merely pouring more personnel into a war that was on the verge of being lost — it was also to transition to a different kind of war, the kind of war the United States has never really had the chance to fight — the first Fourth Generation war, in which the dividing lines between the political and the kinetic would dissolve. War wasn’t merely the continuation of politics by the admixture of different means, as the old Clausewitzian wisdom claimed, but rather a form of politics, a strand in the woven thread of insurgency politics. Such a war would, as the COIN pundits loved to state with perhaps more self-aggrandisement than was strictly necessary, require more brainpower than kinetic effort. The mantra that counter-insurgency was not merely the thinking man’s war but the ‘graduate level of war’, attributed to a special forces operator in Iraq, appealed to the new class of military philosophers — educated, politically liberal-leaning, from comfortable middle class backgrounds and with impeccable academic credentials (and a shocking preponderance, I must add, of old St Anthony’s men), not only did they fancy fighting this more intellectual form of war more than they wished to fight good, old-fashioned, straightforward messy warfare: there was increasingly a reluctance to fight any other kind of war in evidence.

And that’s where, to quote a friend who graciously permitted me to share his comments made in a private conversation, “it all went to shits. We went into this game with the best of intentions, and you know that, you were there — but then it became a massive effort of putting the cart before the horse, of achieving an intellectualised war at all costs rather than discovering the ways in which the war, being as it was, demanded applied intellect”. He is, as he was throughout our acquaintance and cautious moth’s dance around the flame of counter-insurgency doctrine, spot on.

None of us saw that at the time, though. What began as a dissertation burgeoned into notebooks full of ideas and comments, contributions to various discussions (most of which would not have, and will not, see the light — thankfully!), written mostly in a small shrimp and fries outfit on the seaside in Katwijk and later under the dim lights of the Codrington Library at All Souls’. By late 2009, though, I have become quite disillusioned. In 2008, President Obama took power. As a Democrat, a fair portion of his constituents were the same anti-war protesters and so-called progressives who ran the full-page ad criticising Petraeus in the NYT only a short while earlier. Much of old Democratic rhetoric rested on ‘smart power’, on speaking softly well ahead of any thoughts of a big stick and on a fundamental disregard for the principles of warfare. The last two Democratic Presidents have not served in uniform, and both had their blunders reflecting on that fact, such as when Obama recounted a Captain stating his platoon [sic] had to use AK-47s because they were short on rifle supplies — mind-blowing nonsense that would not be tolerated from a freshly minted Marine LCpl, never mind the future Commander-in-Chief. The Democratic establishment had to find its way to somehow deal with the fact that it will have to continue fighting the war in Afghanistan and Iraq (lest it be seen as cowardly and lose to the Republicans, who would have seized upon that with a vulture’s grasp), but also had to make the war palatable to its liberal audience.

What better than the graduate level of war, then? Suddenly, John Nagl was being welcomed — welcomed! — by Rachel Maddow (another product of St Anthony’s), even when he spoke approvingly of then-President Obama’s further allocation of troops to the conflict in Afghanistan. Nagl, soft-spoken and witty and with the intellectual pedigree, if not necessarily the actual acumen, of a Rhodes Scholar, expounded upon this new doctrine of war. The Army went so far as to send anthropologists and social scientists to combat zones, and dressed it up as a sort of OSINT/HUMINT effort called the Human Terrain System. How far HTS was about the Army using social scientists to reach out to the ‘uncommitted’ population and not about using it as a pretext to reach out to some social scientists and give the war the liberal arts bona fides that many have felt it was lacking remains as questionable as whether the HTS has ever achieved anything other than burning through $150m a year (!). The ‘cultural’ factor became not only the crucial idea in understanding what was happening and what was to be done with the war, but also the all-around go-to for explanations and a universal obsession. Greg Mortenson’s fauxmoir went on the USMC Commandant’s reading list and was discussed with mind-blowing earnestness. Learning to Eat Soup with a Knife, Nagl’s book, was everywhere (I have personally seen a two-page briefing sheet that tries to condenses its content into a format intelligible for your average journalist, prepared by a major news organisation — if I can get permission, I will post it here someday, just for the giggles). The war became the continuation of anthropology by the admixture of things that go bang and boom. Ideologically, the war went for the social scientists. Those with a more analytical background, who have arrived to the counter-insurgency arena via the work of e.g. Col. John Boyd — including myself — were marginalised in favour of creating a war that was palatable in the cultural anthropology department of an Ivy League university.

Which is where, to quote my friend, it all went to shits. The products of U of Chicago anthro and St Anthony’s were more than delighted to be part of this new smart war. Obama’s approval rating surged as the precision of our concept of victory waned. We were fighting a war without a clear concept of victory. Indeed, one might argue that victory itself, as a notion, is inimical to COIN theory. Consider, for instance, Martin van Creveld’s metaphor for counter-insurgency warfare — shooting a child. There is no way to conceptualise ‘victory’ while still retaining integrity of the values we profess, and abandoning those values is exactly what orthodox Boydian theory states is driving the uncommitted away.

The problem there is this: if there’s no concept of victory, or at least an end and an outcome, the whole effort dissolves into an endless exercise in doing things that are seen as somehow useful, but all in all going nowhere. And with a budget that was experiencing severe cuts, the Long War was losing appeal rapidly. And this year, it all came down.

A year later, Petraeus is resigning in infamy, never really making the mark on the war that we all waited for. Col. John Nagl, whom many have seen as a general in waiting, gets a headmaster’s robes instead of a general’s stars. In their effort to fight an intellectual’s war, bloodless and sophisticated, a war of targeted precision strikes and cultural anthropology, they have cast aside the wisdom of General MacArthur: in war, there is no substitute for victory. And when there is no definition of victory, when war is about process and not outcomes, eventually the best theories will fall to the power of reality.

We shall march prospering, —not thro’ his presence;

Songs may inspirit us, —not from his lyre;

Deeds will be done, —while he boasts his quiescence,

Still bidding crouch whom the rest bade aspire:

Blot out his name, then, record one lost soul more,

One task more declined, one more footpath untrod,

One more devils’-triumph and sorrow for angels,

One wrong more to man, one more insult to God!

War is hell. Whether as theorists or under the force of arms, we should endeavour to make it less so — this is our duty to ourselves and the men we are privileged to lead and command, and to the humanity of our adversary (there is a reason why the laws of war are called ‘humanitarian law’). To do so, however, requires more than denial. This is the lesson of the failure of the COINdinistas (a term coined by Kelley Beaucar Vlahos in her incisive article). As many, including Vlahos, have suggested, sometimes it is not a bad idea to try to eat soup with a spoon first. There is truth in that. Eating soup with a knife should not be an option but a contingency. It should be something one learns after, and ideally in complementation of, eating soup with a spoon. It’s not a circumstance to be courted, and definitely not one to be pretended to work in order to score political points.

Petraeus’s downfall is a personal drama. It is unlikely that he will ever command or have a major role of responsibility, and it was a thoughtless affair for which he is now paying a serious price. Yet, it seems like the conclusion of a Sophoclean play, the collapse of the hero in tragedy, the leader’s mask of command crumbling in disgrace, as the house of cards built around him breaks down. It is only fitting in this drama that the other character to the affair was Petraeus’s hagiographer herself. It is hard not to feel like the entire story is straight out of Segal’s Tragedy and Civilization. Yet it punctuates the end of an era, and a major challenge to the military establishment, TRADOC and the Beltway Bandits who flocked around Petraeus, Nagl and other COIN theorists. The COINdinista establishment, with their obsession with population-centric warfare, have lost their leader. History will remember Petraeus kindly — for he is an honourable man, and his personal misstep will wane next to his achievements as commander. Whether his theoretical missteps, his increasing obsession with the ‘graduate level of war’ and his role as military philosopher and warrior poet will also remain a footnote remains to be seen. There is clearly little risk of any more hagiographers like Major Broadwell cropping up.

Life’s night begins: let him never come back to us!

There would be doubt, hesitation, and pain,

Forced praise on our part—the glimmer of twilight,

Never glad confident morning again!

Counter-insurgency under Nagl, Petraeus and their groupies has turned into a politicised movement, often filled with arrogance subtle and unsubtle (the spite for ‘knuckle-draggers’ like Odierno is sometimes vitriolic enough to burn holes into steel plating). How it recovers from the decapitation it experienced over the last year will show whether there is more substance to the theory than St Anthony’s men who can go on Maddow and be still treated with civility when they approve of increasing troop numbers in a war without a concept of victory. True counter-insurgency theory may have to roll back to more rigorous intellectual foundations, and those aren’t found in mirages like HTS but often in traditional doctrine. We must re-evaluate whether the often reiterated notion of David Galula that counter-insurgency is about gaining the population’s support rather than territorial control is a sustainable strategy. We must re-evaluate whether a war without a clear victory is worth fighting, and what our instruments are to define an achievable victory. And most of all, we must stop the astonishing self-deception that the COIN theorising of the last decade consisted of, with its attractive self-delusions of a war fought by social scientists sitting in at a jirga, sipping tea and learning about pashtunwali. Petraeus’s fall, as tragic as it is, may punctuate the end of an era of military theory that was uncommonly self-deceptive and misguided even where well-intentioned. ‘War-by-think tank’ is not a feasible option. The war in Afghanistan is not grad school. Qabili palao ain’t grad school ramen soup and Helmand ain’t Jon Stewart’s studio. With Petraeus, the community has lost a capable leader and an extremely intelligent senior officer — but his downfall hopefully also punctuates the end of the annus horribilis for the COINdinistas, and a chance that come spring, reality will return to war.

Like Petraeus, I am a lover of poetry. The son of a librarian, he spent his youth among books, much as I would, decades later, in my father’s library. Browning’s piercing words at Wordsworth, who left the radical fold for “a ribbon to stick in his coat”, came to my mind immediately. But like Browning saw Wordsworth, I see Petraeus remembered kindly. For counter-insurgency warfare, as we all understood, was an experiment, whichever way the strategy would turn. A costly experiment, expending the most precious resource we have — human lives. Yet Petraeus, an honourable man, I have no doubt wished to save us from the waste of even more lives. And so, perhaps the final lines of Browning’s poem should be recalled by those who, like Vlahos, wish to mete out judgment perhaps all too harshly.

Menace our heart ere we master his own;

Then let him receive the new knowledge and wait us,

Pardoned in heaven, the first by the throne!

— Robert Browning, The Lost Leader