The First Invasion by the US

History pre-peated itself in our 1775 invasion of Canada.

Rick Atkinson's enormous history of the American Revolutionary war is stuffed with fascinating detail. Some may not be entirely documentary in origin, but his color and flair are undeniable. Having but begun this long read, I was struck by an early episode, the invasion of Canada. The colonies had not quite yet declared independence, nor had they resolved the seige of British-occupied Boston. They were undersupplied, short of manpower, and still on shaky ground politically with a large loyalist population. Yet, they got it into their heads to storm Montreal and then Quebec in the middle of winter, 1775 to 1776, expecting to be greeted by adoring natives as liberators. The fact that our 47th president has once again threatened to invade Canada can be taken as evidence that the expedition did not go as expected.

Within the thirteen colonies, the revolution began in a promising landscape. British governors were hated up and down the Atlantic seaboard, many reduced to bobbing offshore on Navy vessels while they begged for reinforcements that might, in their imaginations, turn the population back in their favor. Rebel congresses were formed, including the Continental Congress, which from Lexongton and Concord onwards realized that it was more than a political body- it was also a military body, responsible for fending off British attempts to cow the colonists with superior naval might, well-trained troops, ability to raise mercenaries all over Europe, and reserves of good will with loyalists and Native Americans. 

But the US is nothing if not a land-greedy society, and the Continental Congress cast its eyes northward, imagining that the recently (fifteen years before) captured colony of New France might want to cast its lot with the American rebels rather than its British overlords. However the way they went about this project spoke volumes. Instead of sending diplomats, rabble-rousers, or writers, they sent an army. In all, about three thousand men tramped north to subjugate the province of Quebec. 

Map of the campaign.

A virtually undefended Montreal was successfully besieged, and surrendered in November, 1775. Quebec, to the north, was another matter, however. It was far more stoutly defended, well supplied, and had competent walls and entrenchments. Conversely, the Americans were farther from their bases, camped in miserable conditions in the middle of winter, beset by disease, and could not make headway against even modest resistance. When the first British relief ship sailed into the harbor after breakup on the St Lawrence, the jig was up, and the Americans fled in disarray.

Transport was awful, with a lot of portaging between rivers.

Meanwhile, the American rule over Montreal hardly won the US any friends either. The governor treated the inhabitants like enemies, even closing Catholic churches. Benjamin Franklin was sent North to awe the natives and save the situation in April 1776, but the time for diplomacy was long past. 

Does all this sound familiar? What starts with high hopes and condescension, looking to win hearts and minds with guns, ends up winning nothing at all. The Philippines, Vietnam, Iraq, Afghanistan.. one wonders whether the invasion of Quebec was ever taught to US military students, or remembered by its politicians.

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When the Battery Goes Dead

How do mitochondria know when to die?

Mitochondria are the energy centers within our cells, but they are so much more. They are primordial bacteria that joined with archaea to collaborate in the creation of eukaryotes. They still have their own genomes, RNA transcription and protein translation. They play central roles in the life and death of cells, they divide and coalesce, they motor around the cell as needed, kiss other organelles to share membranes, and they can get old and die. When mitochondria die, they are sent to the great garbage disposal in the sky, the autophagosome, which is a vesicle that is constructed as needed, and joins with a lysosome to digest large bits of the cell, or of food particles from the outside.

The mitochondrion spends its life (only a few months) doing a lot of dangerous reactions and keeping an electric charge elevated over its inner membrane. It is this charge, built up from metabolic breakdown of sugars and other molecules, that powers the ATP-producing rotary enzyme. And the decline of this charge is a sign that the mitochondrion is getting old and tired. A recent paper described how one key sensor protein, PINK1, detects this condition and sets off the disposal process. It turns out that the membrane charge does not only power ATP synthesis, but it powers protein import to the mitochondrion as well. Over the eons, most of the mitochondrion's genes have been taken over by the nucleus, so all but a few of the mitochondrion's proteins arrive via import- about 1500 different proteins in all. And this is a complicated process, since mitochondria have inner and outer membranes, (just as many bacteria do), and proteins can be destined to any of these four compartments- in either membrane, in the inside (matrix), or in the inter-membrane space. 

Textbook representation of mitochondrial protein import, with a signal sequence (red) at the front (N-terminus) of the incoming protein (green), helping it bind successively to the TOM and TIM translocators. 

The outer membrane carries a protein import complex called TOM, while the inner membrane carries an import complex called TIM. These can dock to each other, easing the whole transport process. The PINK1 protein is a somewhat weird product of evolution, spending its life being synthesized, transported across both mitochondrial membranes, and then partially chopped up in the mitochondrial matrix before its remains are exported again and fully degraded. That is when everything is working correctly! When the mitochondrial charge declines, PINK1 gets stuck, threaded through TOM, but unable to transit the TIM complex. PINK1 is a kinase, which phosphorylates itself as well as ubiquitin, so when it is stuck, two PINK1 kinases meet on the outside of the outer membrane, activate each other, and ultimately activate another protein, PARKIN, whose name derives from its importance in parkinson's disease, which can be caused by an excess of defective mitochondria in sensitive tissues, specifically certain regions and neurons of the brain. PARKIN is a ubiquitin ligase, which attaches the degradation signal ubiquitin to many proteins on the surface of the aged mitochondrion, thus signaling the whole mess to be gobbled up by an autophagosome.

A data-rich figure 1 from the paper shows purification of the tagged complex (top), and then the EM structure at bottom. While the purification (B, C) show the presence of TIM subunits, they did not show up in the EM structures, perhaps becuase they were not stable enough or frequent enough in proportion to the TOM subunits. But the PINK1+TOM_VDAC2 structures are stunning, helping explain how PINK1 dimerized so easily when it translocation is blocked.

The current authors found that PINK1 had convenient cysteine residues that allowed it to be experimentally crosslinked in the paired state, and thus freeze the PARKIN-activating conformation. They isolated large amounts of such arrested complexes from human cells, and used electon microscopy to determine the structure. They were amazed to see, not just PINK1 and the associated TOM complex, but also VDAC2, which is the major transporter that lets smaller molecules easily cross the outer membrane. The TOM complexes were beautifully laid out, showing the front end (N-terminus) of PINK1 threaded through each TOM complex, specifically the TOM40 ring structure.

What was missing, unfortunately, was any of the TIM complex, though some TIM subunits did co-purify with the whole complex. Nor was PARKIN or ubiquitin present, leaving out a good bit of the story. So what is VDAC2 doing there? The authors really don't know, though they note that reactive oxygen byproducts of mitochondrial metabolism would build up during loss of charge, acting as a second signal of mitochondrial age. These byproducts are known to encourage dimerization of VDAC channels, which naturally leads by the complex seen here to dimerization and activation of the PINK1 protein. Additionally, VDACs are very prevalent in the outer membrane and prominent ubiquitination targets for autophagy signaling.

To actually activate PARKIN ubiquitination, PINK1 needs to dissociate again, a process that the authors speculate may be driven by binding of ubiquitin by PINK1, which might be bulky enough to drive the VDACs apart. This part was quite speculative, and the authors promise further structural studies to figure out this process in more detail. In any case, what is known is quite significant- that the VDACs template the joining of two PINK1 kinases in mid-translocation, which, when the inner membrane charge dies away, prompts the stranded PINK1 kinases to activate and start the whole disposal cascade. 

Summary figure from the authors, indicating some speculative steps, such as where the reactive oxygen species excreted by VDAC2 sensitise PINK1, perhaps by dimerizing the VDAC channel itself. And where ubiquitin binding by PINK1 and/or VDAC prompts dissociation, allowing PARKIN to come in and get activated by PINK1 and spread the death signal around the surface of the mitochondrion.

It is worth returning briefly to the PINK1 life cycle. This is a protein whose whole purpose, as far as we know, is to signal that mitochondria are old and need to be given last rites. But it has a curiously inefficient way of doing that, being synthesized, transported, and degraded continuously in a futile and wasteful cycle. Evolution could hardly have come up with a more cumbersome, convoluted way to sense the vitality of mitochondria. Yet there we are, doubtless trapped by some early decision which was surely convenient at the time, but results today in a constant waste of energy, only made possible by the otherwise amazingly efficient and finely tuned metabolic operations of PINK1's target, the mitochondrion.

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The Role of Empathy in Science

Jane Goodall's career was not just a watershed in ethology and primate psychology, but in the way science is done.

I vividly remember reading Jane Goodall's descriptions of the chimpanzees in her Gombe project. Here we had been looking for intelligent alien life with SETI, and wondering about life on Mars. But she revealed that intelligent, curious personalities exist right here, on Earth, in the African forest. Alien, but not so alien. Indeed, they loved their families, suffered heartbreaking losses, and fought vicious battles. They had cultures, and tools, deviousness and generosity. 

What was striking was not just the implications of all this for us as humans and as conservationists, but also what it overturned about scientific attitudes. Science had traditionally had a buttoned-up attitude- "hard science", as it were. This reached a crescendo with behaviorism, where nothing was imputed to the psychology of others, whether animals or children, other than machine-like input/output reflexes. Machines were the reigning model, as though we had learned nothing since Descartes. 

Ask a simple question, get a simple answer.

This was appalling enough on its own terms, but it really impoverished scientific progress as well. Goodall helped break open this box by showing in a particularly dramatic way the payoff possible from having deep empathy with one's scientific object. Scientists have always engaged with their questions out of interest and imagination. It is a process of feeling one's way through essentially a fantasy world, until one proves that the rules you have divined actually are provable via some concrete demonstration- doing an experiment, or observing the evidence of tool use by chimpanzees. It is intrinsically an empathetic process, even if the object of that empathy is a geological formation, or a sub-atomic particle. 

But discipline is needed too. Mathematics reigns supreme in physics, because, luckily, physics follows extremely regular rules. That is what is so irritating and uncomfortable about quantum mechanics. That is a field where empathy sort of fails- notoriously, no one really "understands" quantum mechanics, even though the math certainly works out. But in most fields, it is understanding we are after, led by empathy and followed by systematization of the rules at work, if any. This use of empathy has methodological implications. We become attached to the objects of our work, and to our ideas about them. So discipline involves doing things like double-blind trials to insulate a truth-finding process from bias. And transparency with open publication followed by open critique.

In the 20th century, science was being overwhelmed by the discipline and the adulation of physics, and losing the spark of inspiration. Jane Goodall helped to right that ship, reminding us that scientific methods and attitudes need to match the objects we are working with. Sure, math might be the right approach to electrons. But our fellow animals are an entirely different kettle of fish. For example, all animals follow their desires. The complexities of mating among animals means that they are all driven just as we are- by emotions, by desire, by pain, by love. The complexity may differ, but the intensity of these emotions can not possibly be anything but universal.

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Cycles of Attention

 A little more research about how attention affects visual computation.

Brain waves are of enormous interest, and their significance has gradually resolved over recent decades. They appear to represent synchronous firing of relatively large populations of neurons, and thus the transfer of information from place to place in the brain. They also induce other neurons to entrain with them. The brain is an unstable apparatus, never entraining fully with any one particular signal (that way lies epilepsy). Rather, the default mode of the brain is humming along with a variety of transient signals and thus brain waves as our thoughts, both conscious and unconscious, wander over space and time.

A recent paper developed this growing insight a bit further, by analyzing forward and backward brainwave relations in visual perception. Perception takes place in a progressive way at the back of the brain in the visual cortex, which develops the raw elements of a visual scene (already extensively pre-processed by the retina) into more abstract, useful representations, until we ... see a car, or recognize a face. At the same time, we perceive very selectively, only attending to very small parts of the visual scene, always on the go to other parts and things of interest. There is a feedback process, once things in a scene are recognized, to either attend to them more, or go on to other things. The "spotlight of attention" can direct visual processing, not just by filtering what comes out of the sausage grinder, but actually reaching into the visual cortex to direct processing to specific things. And this goes for all aspects of our cognition, which are likewise a cycle of search, perceive, evaluate, and search some more.

Visual processing generates gamma waves of information in an EEG, directed to, among other areas, the frontal cortex that does more general evaluation of visual information. Gamma waves are the highest frequency brain oscillations, (about 50-100 Hz), and thus are the most information rich, per unit time. This paper also confirmed that top-down oscillations, in contrast, are in the alpha / beta frequencies, (about 5-20 Hz). What they attempted was to link these to show that the top-down beta oscillations entrain and control the bottom-up gamma oscillations. The idea was to literally close the loop on attentional control over visual processing. This was all done in humans, using EEG to measure oscillations all over the brain, and TMS (transcranial magnetic stimulation) to experimentally induce top-down currents from the frontal cortex as their subjects looked at visual fields.

Correlation of frontal beta frequencies onto gamma frequencies from the visual cortex, while visual stimulus and TMS stimulation are both present. At top left is the overall data, showing how gamma cycles from the hind brain fall into various portions of a single beta wave, (bottom), after TMS induction on the forebrain. There is strong entrainment, a bit like AM radio amplitude modulation, where the higher frequency signal (one example top right) sits within the lower-frequency beta signal (bottom right). 

I can not really speak to the technical details and quality of this data, but it is clear that the field is settling into this model of what brain waves are and how they reflect what is going on under the hood. Since we are doing all sorts of thinking all the time, it takes a great deal of sifting and analysis to come up with the kind of data shown here, out of raw EEG from electrodes merely placed all over the surface of the skull. But it also makes a great deal of sense, first that the far richer information of visual bottom-up data comes in higher frequencies, while the controlling information takes lower frequencies. And second, that brain waves are not just a passive reflection of passing reflections, but are used actively in the brain to entrain some thoughts, accentuating them and bringing them to attention, while de-emphasizing others, shunting them to unconsciousness, or to oblivion.

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