The Death of Boredom and the Future of Politics

Can politics work without a civic sphere?

How can we have a loneliness epidemic when we are connected like never before? It is a problem that perplexed Robert Putnam in "Bowling Alone". He put it mostly down to TV, internet, and the growth of passive and isolated forms of entertainment generally. When you read between the lines of history of any time before about one hundred years ago, you realize that people were, before the modern age, bored out of their minds. Who plays cards? Who puts on operas, or runs numbers, or goes bowling? Who needs an Easter pageant, or a three-to-four-hour baseball game? Only people with nothing better to do. If you wanted music, you had to make it. If you wanted conversation, you had to share it. Human society was built on simple quid pro quos- social rewards and resolution of boredom and isolation for personal participation.

But that deal has broken down dramatically in the modern age. We have a thousand channels, talk radio, recorded music. With AI, we are getting personal chatbots and bespoke romantasy partners. Sports have slid tectonically from participation to spectation. Boredom is a thing of the past, though if you do want to play cards, plenty of computers are willing to take a hand.

An interesting article in the New Republic knit this together very nicely with the problems we are having in politics. In the US, political engagement is increasingly shallow, leaving the field to extremists who can still call up foot soldiers to storm the ramparts. What happened to the Occupy movement? For all its inherent logic and flash organization, it fizzled into nothing because it gave little thought to its own institutionalization (indeed, was allergic to organization) and durable engagement, all the while railing against the overwhelming organization and deep pockets of the entrenched systems of capitalism. The Left is notoriously inable to herd itself into an effective, organized force. While capitalism is naturally organized and institutionalized by virtue of naked self-interest and corporate structures, civic groups grow out of far more disparate, and evanescent, motivations. Unions have been an attempt to organize around a countervailing, while still self-interested logic, which inherently limits their reach and coherence. The true civic sphere, however, is threadbare.

Political parties have similarly shallow roots. In California, the governor's race has 61 candidates, and little control by the party establishment, particularly by the Democratic establishment that supposedly runs the state. Like other non-profits, parties ask little of their adherents, other than possibly a monetary contribution, and wouldn't dream of holding truly social events that could deepen civic engagement. Expectations of civic engagement have hit rock bottom, mostly because people have tuned out across the civic spectrum. The testimonial dinner is a relic. The ice cream social is unheard of. Service organizations like Rotary and Elks are fossils, unions are on life support. Events and organizations that previously kept people entertained and involved in a civic way are scarce. These traditions both trained people for common action, and led to the kind of networking and contact that fed political consciousness and activity. They also helped to vet people directly for office holding (see the recent Swalwell case). 

Bernie Sanders can draw a crowd, but do those crowds go out, organize, and persist?

Republicans have found a partial solution to these problems by ginning up endless outrage through their propaganda outlets, predominantly talk radio and hate TV. While motivating, the results have, naturally, been intellectually disastrous and have us teetering on the edge of fascism. Democrats, as the more level-headed and progressive temperament, have not used the same tools effectively, and shouldn't. What should they do? Well, the field for civic engagement is pretty wide open. For example, one could imagine a tax on political advertisements, say 10%, which is collected by the government / FEC, and sent to counties or municipalities for civic engagement purposes, either election-related or not. This would create a fund for local talks, events, civic education, and the like that would, in theory, complement the advertising that is increasingly vacuous and meretricious. 

Another approach is direct action, where Democrats could use some of their energy and resources to build civic engagement, outside of straight campaigns. Just as the Republicans have harnessed ancillary issues like abortion and tax cuts that energized specific segments of their base, Democrats have to be a bit more canny about asking for more engagement and offering more involvement. Climate change is a great example, where a wide spectrum of individual action (trash pickups, solar panel installation, water quality testing) could be integrated into civic engagement that builds party alignment and ultimately, institutional strength. All great religions know that the more you ask, the more you get, and the deeper the commitment of followers. Additionally, the left already has a bewildering array of non-profits, whose efforts would ideally be more closely integrated with the Democratic umbrella to generate more organizational power- synergy or leverage, in business-speak.

On the other hand, how could civic disengagement be accommodated rather than fought? One approach might be to enhance the vetting and exposure of candidates by having nominating conventions at the local level. Even though California has an open primary, and thus does not grant each party automatic spots on each ticket, the parties should not shy away from selecting, testing, and promoting candidates. This should not be a central commitee operation hidden in the dark, the province of interested apparatchiks, but open forums that promote philosophies as well as people.

We are in a tough position, trying to keep politics alive in a world where its underpinnings- of civic engagement, communal organization and leadership, and simple conviviality- are fading in a deluge of individualized enjoyments. Political parties are at the forefront of this change, and need to think very deeply about how to keep themselves relevant and effective.

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Pumping Calcium

An ornate ion pump manages rapid outflow of calcium.

In the beginning, the egg cell experienced a wave of calcium release, triggered by union with a sperm cell. This blocked other sperm from entering, and prepared the egg to become a zygote and embark on embryogenesis. It is but one example of the pervasive role of calcium signaling among animals. Another is the muscle activation cycle, which relies on calcium release from the specialized sarcoplasmic reticulum (in response to a nerve activation) to get the cell as a whole contracting. Generally, calcium is kept very low in the cytoplasm, and high in the endoplasmic reticulum and outside the cell. Thus, channels gated by electrical activation or other signals can cause rapid cytoplasmic calcium spikes and signal widely within a cell. 

On the flip side, there have to be pumps that keep the cytoplasmic concentration low, and a recent paper elucidates the structure of one such pump that is remarkably fast, while also closely regulated. It is an impressive machine. PMCA2 is an ATP-using calcium pump that sits in the plasma membrane and carries out what is called the Post-Albers cycle. This is a flip-switch mechanism for pumping ions, where ATP drives conformational switches alternately exposing ion binding sites to each side of the membrane. When the pore is open to the cytoplasm, there is no competition from higher concentrations outside, so the active site can bind one internal calcium, given a high-affinity site. Then, after the conformational switch, the pore is exposed to the outside, and at the same time the site is reconfigured to be lower-affinity, releasing the calcium ion into a high concentration environment. Neurons especially use calcium signaling extensively to operate synapses and regulate growth and development. Their rapid and frequent signaling requires a pump that has especially high capacity. PMCA2 operates at a maximal rate of several thousands of Ca2+ ions pumped per second.

Cartoon of the Post-Albers cycle, which is shared by a large family of active ATP-using pumps that transfer ions against their chemical concentration gradient. M is the main transmembrane domain of the pump, where the ions traverse the membrane. The N, P, and A domains are regulatory, especially binding and cleaving ATP  at an interface between the N, P, and A domain. The cycle links power steps (1,2) with conformational changes that carefully gate the pumping process.

And that is not all. Since calcium has a charge of 2+ and this pump does not intend to alter charge across the membrane, the pump simultaneously has binding sites for counter-ions (generally two OH-) that are transferred in the opposite direction from the calcium. Not only that, but every pump of this kind requires regulation of various kinds. PMAC2 is activated by phosphatidyl inositol 4,5 bisphosphate (PIP2), which is another important signaling molecule generated by specific PI kinases in response to activation of G-protein coupled receptors or protein kinase C, which may respond to external signals. In very general terms, these tend to be pro-growth or stress-induced pathways. These regulatory processes can tune the overall rate of recovery from rapid Ca2+ signaling events, by adjusting the level and activity of pumps like PMAC2. 

ATP binds at the N/P/A domain interface, and its hydrolysis (and loss of ADP) generates extensive shape changes, including into the transmembrane M domain. At the very bottom, the calcium ion is shown in green, bound inside the M domain pumping channel. The motions here are subtle, but enough to dramatically reshape the calcium channel.

The authors, using various substrate variants and other tricks, were able to develop structures of PMAC2 in several steps of the pumping cycle, using cryo-electron microscopy. The ATPase site in the N domain (red) is far from the channel that conducts the calcium ion (brown, far bottom). They show extensive shape changes from binding or losing the ATP molecule, though they mostly concern the intracellular domains (red, blue, yellow). The effects on the transmembrane pore domain are rather subtle, shown on right. The authors claim that, compared to other pumps of this large family, the structural changes are significantly less, suggesting that evolution for speed has caused the mechanism to become more efficient, with less wasted motion per conduction event, at least in the channel region itself.

Relation of the PIP2 binding domain (orange/red stick figures) to the calcium core binding site. PIP2 appears to be essential for rapid pump operation. At bottom is shown some schematics of the gating provided by PIP2 in bound and unbound states, especially via the D873 side chain (negatively charged aspartic acid).

They also find that the activating molecule PIP2 is neatly parked right next to the main calcium binding and conduction region, and is more or less essential for enzyme activity. In the graph above (e), they show that several single mutations made in the calcium binding high affinity site, for example switching the negatively charged D873 for the positively charged K (lysine), kills ion pumping activity. Mutation of the PIP2 binding pocket (KKQ->TLL, around position 347) likewise kills enzyme activity.

Relation of the counter-ion channel (red dots) with the calcium channel. Both are essential parts of the mechanism. Closeups with the coordinating protein side chains shown on the right.

The whole mechanism is alluded to in the last figure, where the central calcium binding site is shown, with the general direction of calcium pumping. The counter-ion transport area is shown nearby as a flurry of red dots (standing for water molecules, which at this scale are interchangeable with OH ions). Specific single mutations in either area, either changing negatively charged E412 to positively charged lysine at the calcium binding pocket, or changing polar S877 in the water/hydroxy binding area to the bulky and hydrophobic F (phenylalanine), each kill pumping activity (graph). 

While it would be ideal to have a more dynamic representation of what is going on, the new structures give tremendous detail, including the associated ATP, PIP2, calcium, and water molecules. The mutations also nail down several functional points. Obviously a rather intricate and well-oiled machine that keeps its bit of cellular calcium homeostasis on an even keel. It is hard to believe that the sum of thousands of machines like this one is life, but the deeper we look the more true that appears to be.

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Not Every Transcript is Golden

 Reflections on junk DNA, and junk transcripts.

Some time ago, a large project in molecular biology determined that most regions of the genome are transcribed. The authors and most observers took this to mean that most regions are functional, quite in contrast to the reigning theory up to that point, that our genomes host a smattering of genes floating in a sea of "junk" DNA. That theory was based on the now-ancient observations of reannealing curves for bulk DNA from humans and other species which found that most of our DNA re-anneals very quickly, due to the fact that it is repetitive. Most of our genomes (60%) are taken up with LINE repeats, SINE repeats, old retro-transposons, stray duplications, and other repetitive material that, at a first glance, seems like junk. There has been a battle ever since, between proponents of junk DNA and those who see function around every corner. As we learn more about the genome, many more functions have indeed come to light, like distant enhancers and regulatory RNAs of many flavors. But overall, there still seems to be a lot of junk. 

A recent paper took an oblique shot at this field, looking at the profusion of alternative gene transcripts, which can number into the hundreds for a single gene. (This was also reviewed.) These are generally called isoforms, and arise due to variable ways one gene's RNA products can be initiated, terminated, and spliced. So not only are most regions of the genome transcribed in some form, actively transcribed regions can be transcribed and processed in myriad ways to lead to different RNA products. Here again, there has been an analogous argument, about whether every such isoform has a function, or whether isoforms might arise from more or less sporadic processes, often as unintended and non-functional sparks coming out of the machinery. The importance of isoforms is very well documented in many cases, so the possibility of function, sometimes highly conserved, is not in question. Only the importance of every last variation in combinatorial collections of isoforms that can number into the hundreds.

Here is an image from the first page (of about six pages) of RNA transcripts coming off the notorious BRCA1 gene, which is intensely studied for its role in breast cancer. Each line is a distinct mRNA transcript. Each darker bar is an exon, which are separated by introns. The darker colored exons are in the protein coding region, while the lighter exons signify the untranslated upstream and downstream ends. I count about 315 transcripts described for this genetic locus. The idea that each of these has some evolutionarily constrained and important function is, on the face of it, absurd.

The authors took an interesting evolutionary approach, reasoning that species with larger population sizes experience more stringent purifying selection, and thus should (in theory) show tighter control over stray genomic products such as isoforms, if most transcript isoforms are neutral (or even deleterious) accidents, rather than intentional and functional forms. Thankfully, animals come in a wide range of population sizes, from insects to crocodiles and primates; very large to very small. While population size is hard to calculate, several convenient proxies are known, like lifespan, body size, etc. When they totted everything up, they saw clear correlations between these proxies and the number of alternative RNA products per gene- also termed transcript diversity. They sliced up the data by organ where the RNA was expressed, and by the source of the RNA variation- either different initiation, different termination, different splicing. In all cases the trend was the same. In species with larger population sizes, the diversity of transcripts was lower, agreeing with their hypothesis that when greater selecive force is available, the slop from the transcription and transcript processing machinery declines.

The authors draw correlations between alternative splicing (AI) diversity in an organism's cells and its population size. 

The authors additionally note that there is a similar relationship between alternative splice site usage and expression level of a gene. That is, the higher the gene expression, the less likely that minor splice sites are used, indicating that here again, higher selective pressure helps to clear out non-functional off-products of the transcription apparatus.

The correlations found here are only that- correlations. While significant, they are not terribly strong, let alone stark. So it is evident that our gene expression machinery has a lot of play in it, and this falls on a spectrum from deleterious to critically functional. It is, after all, machinery, not divine. It is also grist for evolution itself- it is useful to have some slop so that there is always some diversity in the gearing to accommodate new selective pressures. But the idea that just because a distinct transcript exists, it is biologically functional, or that, similarly, because a genomic region is transcribed, it is a "gene" rather than junk DNA.. that does not hold water. Every nucleotide in the genome has its own unique selective constraints, and for many of them, that constraint is zero.

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