The Lucky Country

The story of California, the story of the US, and optimism about free frontiers.

I am reading "California, the great exception". This classic from 1949 by Cary McWilliams is stoutly jingoistic and pro-California. But it also provides a deeper analysis of the many things that made California such an optimistic and happy place. Mainly, it boils down to free land and rapid settlement by ambitious working people. The Native Californians were so weak, and so ruthlessly extirpated, that they did not present the irritating conflict that happened elsewhere in the US. California's gold was so widely and thinly distributed (as placer in streams) that mining was a matter of small partnerships, not huge businesses, as it became elsewhere in the West, in the deep hard rock silver and later copper mines of Nevada (Carson city and the Comstock lode) and Montana (Butte). The immigrants were of working age and enthusiastic to work, dismissing slavery and corporatism in favor of a rapacious entrepreneurialism. 

California never had a paternal territorial government, but transitioned directly from self-rule to statehood, its riches speaking volumes to the national government in Washington. And the national government was anxious lest secessionist sentiment spread to the still far-distant west, so it funded the building of a transcontinental railway, during the civil war when money must have been extremely tight. That feared secession was not to join the South, but rather to found a new and prosperous nation on the West Coast. San Francisco went on to serve as the financial capital of the West, particularly of western mining, creating almost overnight a collusus to rival the centers of the East. In due time, gushers of oil also appeared on the California landscape. It is no wonder that Californians became fundamentally optimistic, ready to take on huge challenges such as water management, building a great education system, and the entertainment of the world.

California was also blessed by weak neighbors on all sides. There were no foreign policy predicaments or military threats. It could nurse its riches in peace. It was, in concentrated form, the story of America- of a new continent limited more by its ability to attract and grow its population than by its land and the riches that land held. An isolated continent that wrote its society almost on a blank slate- a new government and a melting pot of people from many places. 

Bound for California, around 1850.

How stark is the contrast to a country like Ukraine, neighbor of imperialist Russia and before that host to the Scythians, Goths, and Huns. A flat land exposed on all sides, that has been overrun countless times. A fertile land, but always contested. The idea that history would stop, that Ukraine could join the West, and enjoy its riches in peace and security- that turns out to have been a dream that bullies in the neighborhood have a different view on. Better to beat up on the little "brother" than to build up both nations and economies through beneficial exchange and prosperity. Better for both to go down in flames than that the little "brother" escapes the bully's clutches into a more humane world.

But the happy place of the US and Calfornia has hit some rough patches too. It turns out that our resource riches are not endless after all. The foundation of material wealth- the agricultural land, the mines, the lumber- underwrote social and technological innovation. No wonder the US was first in flight, and led the way in electricity, automobiles, the internet, the cell phone. Now we have an innovation economy, and get much of our materials and lower-grade goods from far-off places. The people we have attracted and continue to attract are the new wealth, but therein lies a conflict. Places like California have huge homeless populations because we have ceased to grow, ceased to embody the hope and optimism of our lucky past. Conflict has raised its head. There is no more free land, or gold in the streams. Now, with the land all parcelled up and the forests mowed down, everyone wants to hold on to what they have, and damn those who come after. Prop 13 was the perfect expression of this sour and conservative mood- let the newcomers pay for public services, not us.

California is transitioning from a visionary frontier into a cramped, normal, and not especially lucky place. The fabulous climate is suffering under fire and drought. The population is growing significantly older, while next generation is educated less well then their parents. The app innovation economy has fostered a nightmare of surveillance and social dysfunction. The pull of a new frontier is so strong, however, that some of our richest people now imagine it on other planets. The irony of sending rockets, fueled by vast amounts of fossil carbon and compressed oxygen, to other worlds where there isn't even air to breathe, let alone plants to cut down, begs belief. It is the final gasp of a dream that somewhere, out there, is another lucky country.

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Neutrophils Ask: How Did I Get Here?

With apologies to the Talking Heads... how the amoeboid cells of our immune system travel around in response to outside cues like cytokines.

Amoeboid cells seem so alive and even conscious. They seek out prey, engulf, and kill it. How is that done, and what are they thinking? Molecular biologists naturally come at this from a molecular perspective, asking what the signals are, how are they received, what pathways relay them to the cytoskeleton, and so forth. No soul is assumed, and none has been found, despite the great complexity of these cells and their activities.

The story starts with receptors at the surface, which can sense many of the cytokines of the immune system, of which there are roughly a hundred. These have many roles, including pro-inflammatory and anti-inflammatory effects. Neutrophils, which are the subject of today's paper, also have receptors that directly sense pathogens, like bacterial cell coats, viral double stranded RNA, and also broken cells, like DNA out in the environment where it shouldn't be. One question is how these cells sense shallow gradients- they can orient properly with as little as two percent difference in concentration between back and front. This is thought to involve pretty strong feedback systems that accentuate the stronger signal and then keep strengthening it in concert with the cytoskeleton that the receptors ultimately organize and orient. But that then leads to the next question of what turns this feedback process off, preventing locking on one target, so that neutrophils can turn on a dime and pursue a new target, if needed?

The molecular basics of cell orientation in eukaryotes have taken a long time to establish. The cell surface receptors typically activate G proteins, specifically the beta/gamma subunit, which can activate an enzyme called PI3 kinase (PI3K). This enzyme puts a phosphate group on the membrane lipid inositol, generating inositol triphosphate, or IP3. This lipid is a sort of beacon, which attracts a variety of other proteins to come to the membrane, among which is DOCK2, and other members of its family of guanine exchange proteins, which in turn activate RAC, by encouraging it to release GDP and bind GTP. RAC is a key node here that is active with GTP. RAC then activates other proteins like WAVE and PAK1, which go on to activate ARP2 and its family members, which are, finally, the proteins which nucleate extension and branching of actin in filaments, which provide the actual power behind cell protrusions and movement.

A sketch of the signaling cascade from outside the cell to cytoskeletal re-orientation. R stands for receptor. One form of feedback is shown, which is positive reinforcement from locally active Rac and actin, back to PI3K. This helps the local front stay coherent in pursuit of prey or gradients of signals.

It has also been found that both RAC and actin have some kind of local positive feedback effect on neutrophils, allowing migrating cells to establish stable fronts that respond to gradients of stimulating molecules. At the same time, there is a global negative regulation system, mostly due to the tension from actin and on the cell membrane, which encourages retraction of cellular fronts that are not experiencing stimulating signals. All this obviously contributes to the ability of cells to go one way, and have their back ends follow. 

The current paper asked in a little more fine grained detail how the front mechanism works- how does it avoid locking up from positive feedback, and how does it allow other areas of the cell to take over if they see stimulation on their sides? They set up a remarkable system of light-activated PI3 kinase, where they could shine blue light on one side of the engineered cells and see them move in that direction, from the excess PI3K activity. This system derives from an obscure bacterial protein that rearranges a flavin cofactor under blue light, in a way that can allow binding surfaces to be hidden or revealed. 

In the key experiement, they shined light on one side of their cells, then turned it off for a bit, and the shined light on the entire cell. This tests whether there is a residual effect from the prior stimulation. Would the cells be entrained to keep going where they were going before? Or would they not care, or would they try something new? The answer clearly (and reproducibly) was that they struck off in a new direction. This shows that there is a habituation or inhibition mechanism at work, over some slow time period, which acts in activated regions. 

 The source for this video is the main paper behind this post. The dashed circle indicates where the researchers shined their blue light which induces local PI3K activity. Note how at first, they are leading the cell by just the front. When this cell gets to the midline, they switch to illuminating the whole cell, to ask whether there is residual activation or inhibition from the earlier illumination. The observation that the cell then veers off opposite to the original stimulation indicates that inhibition is the residual effect from the former activation.

 

Such habituation is a critical piece of behavior that follows gradients. It gets used to what it just saw, and if the next unit is the same intensity, it doesn't care that much (though probably will keep going). If the next unit of stimulation is increased, then it will keep going. But if it is decreased, then the inhibition kicks in and the front slows down, allowing other areas of the cell to expand if they are seeing increased gradients. Thus temporal and spatial gradients can both be negotiated, using a finely tuned mix of positive and negative feedbacks.

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