The Problem of Desire, Part 2

What is the future of capitalism?

Last week, I discussed how capitalism is a natural way for many of our desires to organize economic activities, though leaving important other desires out in the cold. The philosophical work to come up with alternatives to capitalism appeared, in the end, to be a practical dead end, however appealing to idealists. But what comes next? Once we have settled on the mixed political / economic system that is the rule over most of the modern world, how can we envision it serving humanity into the future? Is it sustainable?

The answer to that is: obviously not. We have far higher population, and use far more resources than the earth can supply sustainably. We might blame capitalism, but that is just the ugly packaging covering our own desires. There was a nice article in the NYRB recently about "degrowth communism", promoting the ideas of Kohei Saito, another provocative self-labeled Marxist. It makes of Marx some kind of prophet of green, which frankly could hardly be farther from the truth. Marx wanted workers to own the means of production so that they could all share in the fruits of modern technology, not to make them return to the idiocy of rural life. So, while degrowth is an important idea, its connection with Marxism is specious, other than the catastrophic degrowth unintentionally induced by the various implementations of Marxism through the last century.

If we excercised our wisdom, we would desire, first and foremost, a sustainable form of life. Unfortunately, our technologies and forms of pillaging the earth have ranged so widely by this point that we hardly have any idea of the harms we are causing and the shortages that are building up. Who would have predicted that plastics and forever chemicals would turn into a growing plague? Who has the answer to climate change? The key thing to realize, however, is that we have the power. We do not need a revolution overturning capitalism, because we have the state. The state can regulate, it can nationalize, it can utility-ize, it can crush companies or create them. It can make the rules and change the rules. It is through the state that we can express our larger desires for sustainable and decent living. 

For example, states can (and have) set up a carbon tax to move the transition away from fossil fuels. California has done so, as have many other countries. Just because we in the US are at a corrupt and mean political moment where short-term (at best) thinking rules the roost does not mean that people's deeper and longer-term interests will forever remain submerged. Indeed, this moment has provided an instructive (if appalling) window into how powerful the state can be. 

The article cited above also maintains that growth is inherently tied to capitalism, and that degrowth requires a revolution of some kind. Again, I beg to differ. Capitalism simply is a way to satisfy our desires. If we want to live simply, it will still serve us. Whether growing or contracting, capitalism marches on doing its best to satisfy our desires. Companies compete for business and growth, but there are plenty who have stable business models, such as, to take one example, the toothpaste business. 

More interesting is the popular revolt against growth that is expressed in declining birth rates. All over the modern economies, people are having fewer children, and causing a great deal of head-scratching and alarm. Is this due to the death of patriarchy? A fear of the future? The death of boredom? I think it has a lot to do with the fundamental contraction of our frontiers and a sense of limits. After a couple of centuries of breakneck growth, when large families were common and there were always new territories to occupy, we in the US hit the ceiling in the 1970s. Cities stopped growing, housing construction slowed, zoning enforced stasis. The expense and complexity of raising children in this environment grew as well, becoming subtly more competitive than cooperative. 

So, growth is slowing already, but not enough to save us from extreme ecological harms. We do need a more conscious degrowth strategy, encompassing accommodation of lower population, slowing down of lifestyles in some regards, strong movement through the sustainable energy transition, expanding natural habitats instead of degrading them. In all these issues, capitalism is not the problem. The problem is figuring out what we really want. In Europe over the centuries, there was a gradual transition from building with wood to building with stone. Which is to say, the value of sustainability gradually won out over wasteful short-term solutions. We need to start building in stone, metaphorically, thinking of the next hundred and thousand years, not just our own brief lifetimes.

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• Continuously unconstitutional.
• Is nothing sacred?

The Problem of Desire

We got what we want... are we happy now?

I have been enjoying a podcast on philosophy, which as is typical for the field, dances around big questions and then pats itself on the back for thinking clearly. What really got to me was a discussion of why Zizek, who calls himself a communist, couldn't be bothered to frame a positive system for how the world should be run. No, he is merely the philosopher and critic of the screwed up system we are in. Plenty of hard work there! Asking for a way forward, well, that would be like making the visionary have to build the rockets and recruit the astronauts to build the new world. That is someone else's work ... grubby details!

Whoa! The thinker who is just a critic is leaving the job almost wholly undone. Everyone is a critic, after all. The paying work should be in thinking up better worlds and solutions, and standing behind them in the face of the inevitable, yes, criticism. A major obsession of the show and these philosophers (around the 200 episode mark) is capitalism- why it is so terrible, the many critiques and complaints about it, and throwing some love at the anarchists, communists, and other outré comrades ... on the highest philosophical plane, of course. 

But what it all boils down to for me is the problem of desire. The capitalist system is one natural and highly refined way to get what we want. We pay into the system with our toil, and get back the products of everyone else's toil. Fair and square, right? The system is wholly shaped by desire. What the consumer wants out of the system, what the worker knows they need to do in order to be that consumer, and what the capitalist and managerial classes need to do to put the two together, and make a killing for themselves in the bargain. This system is a wonder of labor allocation, providing the most varied and productive forms of work, and of products, ever known.

A still from Chaplin's Modern Times.

And yet... and yet, this system doesn't really give us everything we want, because, well, there are other desires that aren't met in the capitalist market. Desires for love, for community, for a virtuous and just political system, for a wholesome environment. There are a lot of other desires, and letting capitalism gobble everything up and sell itself as the end-all of social organizing principles is obviously not a healthy way to go. Though we have surely tried! Not to mention the warped psychology of pitting everyone against each other in the many competitive planes of capitalism- the labor market, the exploitation by capitalists, assaults of marketing and advertising, and the resulting inequality of income and wealth. There is plenty to complain about here.

The problem is that we have many desires, of which many conflict with the desires of others, and many conflict with each other. Even for the individual person, prioritizing one's own many desires is an excruciating exercise of tradeoffs and negotiation. Imagine what that is like for a whole society. That is why figuring out what is "good" is such a chestnut in philosophy. We all know what is good at some very abstract level, but the variety and relationship of goods is what does us in. 

So it is easy enough to say that the capitalist system is evil, and we would like a new and better system, please. Much more difficult to frame a replacement. Following our desires makes it clear that capitalism is an element of the good life, but far from the only element. Even something as simple as providing toothpaste can not be left entirely to the capitalist system. Our desire for effective toothpaste can easily conjure up fraudulent business "models", where the fluoride is left out, or lead contamination gets in. The government has a role in this most humdrum of capitalist goods, to provide a legal framework for liability, perhaps direct regulation of medical / food products, not to mention guarding against monopolies other forms of business regulation. 

We end up, as we have in practice, with a mixed system where natural capitalist motivations are fostered to provide as much organization as they can, but our many other, often much more lofty and significant, desires lead us to regulate that system extensively. To put a larger frame around this, consider what the good life is in general terms. It is a life where each person is educated to the extent they wish, and contributes in turn to society in some useful way, building a life of mutual respect with others in their community. It aligns very strongly with the American dream of work, striving, and self-reliance, at least once the genocidal clearance of the original inhabitants was taken care of. The Civil war was premised on the abhorrence of slavery, not only on behalf of the abused Blacks, but also as a philosophical system of life where people thought it their right to live parasitically by the sweat of other people's brows. 

This has strong implications for our current moment, where inequality is higher than ever. A well-organized society would reward work with the kind of pay that supports a respectable life. It would not tolerate immiseration and abuse in the labor market. At the same time, it would not allow the incredible concentration of wealth we see today. And especially, it would not allow the intergenerational transfer of that wealth, nor the complexity and laxity of a tax system that provides the majority of work that the rich appear to engage in- that of avoiding taxes. In order for everyone to live a good life, children should neither be born to so much money that they fritter their lives away, nor to so little that their whole futures are immediately wiped away. All this requires a strong and moral state, working in collaboration with a strongly regulated capitalist system.

It has been abundantly proven that neither anarchism, nor communism, nor libertarianism provide the basis for practical societies. No amount of reframing, or consciousness raising, or struggle sessions, will bring such systems to pass. Only theocracies and autocracies have shown a comparably durable basis, though of a distinctly unpleasant kind. Therefore, philosophies that dabble in such utopianism should recognize that they are dealing in abstractions that can be instructive as extreme ends of a spectrum, as well as object lessons in failure. It is simply malpractice to tease people with glimmering alternatives to our communal realities, rather than doing the gritty work of reform within them.

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• Science, schmientz
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What Happens When You Go on Calorie Restriction?

New research pinpoints some very odd metabolites that communicate between the gut and other tissues.

The only surefire way to extend lifespan, at least so far, is to go on a calorie restricted diet. Not just a little restricted- really restricted. The standard protocol is seventy percent of a normal, at-will diet. In most organisms tested, this maintains health and extends lifespan by significant amounts, ten to forty percent. There has naturally been a great deal of interest in the mechanism. Is it due to clearance of senescent cells? Increased autophagy and disposal of sub-optimal cell components? Prevention of cancer? Enhancement or moderation of the immune system? The awesome austerities of the ancient yogis and other religious hermits no longer look so far out.

A recent pair of papers took a meticulous approach to finding one of the secret ingredients that conveys calorie restriction to the body. They find, to begin with, that blood serum from calorie-restricted mice can confer longevity properties to cultured cells. Blood from calorie-restricted mice can also confer relevant properties to other mice. This serum could be heated to 133 degrees without detriment, indicating that the factor involved is not a large protein. On the other hand, dialysis to remove small molecules renders it inactive. Lastly, they put the serum though a lipid-binding purification system, which diminished its activity only slightly. Thus they were looking for a mostly water-soluble metabolite in the blood.

Traditionally, the next step would have been to conduct further fractionation and purification of the various serum components. But times have changed, and their next step was to conduct a vast chemical (mass-spectrometry) analysis of blood from calorie restricted vs control mice. Out of that came over a thousand differential metabolites. Taking the most differential and water-soluble metabolites, they assayed them over their cultured cells for a major hallmark of calorie restriction, activation of the AMPK kinase, a master metabolic regulator. And out of this came only one metabolite that had this effect at concentrations that are found in the calorie restricted serum: lithocholic acid.

Now this is a very odd finding. Lithocholic acid is what is known as a secondary bile acid. It is not natively made by us at all, but is a byproduct of bacterial metabolism in our guts, from a primary bile salt secreted by the liver, chenodeoxycholic acid. These bile salts are detergent-like molecules made from cholesterol that have charged groups stuck on them, and can thus emulsify fats in our digestive tract. Bile salts are extensively recycled through the liver, so that we make a little each day, but use a lot of them in digestion. How such a chemical became the internal signal of starvation is truly curious.

The researchers then demonstrate that lithocholic acid can be administered directly to mice to extend lifespan and have all the expected intermediary effects, including decreased blood glucose levels. Indeed, it did so in flies and worms as well, even though these species do not even see lithocholic acid naturally- their digestion is different from ours. They evidently still have key shared receptors that can recognize this metabolite, perhaps because they use a very similar metabolite internally. 

And what are those receptors and the molecular pathway of this effect? The second paper in this pair shows that lithocholic acid binds to TULP3, a member of the tubby protein family of transcription regulators, which binds to lipids in the plasma membrane and shuttles back and forth to the nucleus to provide feedback on the membrane condition or other events at the cell surface. TULP3 also binds to sirtuins, which are notoriously involved in metabolic regulation, aging, and cell suicide. These latter were all the rage when red wine was thought to extend life span, as sirtuins are activated by resveratrol. At any rate, sirtuins inhibit (by de-acetylation) the lysosomal acidification pump that has been known (curiously enough) to go on to inhibit AMPK, and play basic roles on cell energy balance regulation.

So we are finally at AMPK, a protein kinase that responds to AMP, which is the low-energy converse of ATP, the energy currency of the cell. High levels of AMP indicate the cell is low on energy, and the kinase thus phosphorylates and thus regulates a huge variety of targets, which generally increase energy uptake from the blood, (glucose and fats), reduce internal energy storage, and increase internal recycling of materials and energy, among much else. At any rate, the researchers above show that AMPK activation is absolutely required for the effects of lithocholic acid, and also for life extension more generally from calorie restriction. On the other hand, lithocholic acid does not touch the AMP level in the cell, but, as mentioned above, activates through a much more circuitous route- one that goes through lysosomes, which are sort of the stomach of the cell, and are increasingly recognized as a central player in its energy regulation.

Some beautiful antibody staining to different types of myosin- the key motor protein in muscles- in muscle cells from various places in the mouse body (left to right). The antibodies are to slow-twitch myosin (red), which marks the more efficient slow muscle fibers, and blue and green, which mark fast twitch myosins- generally less efficient and markers of aging. The bottom two rows are from a AMPK knockout mouse, where there is little difference between the two rows. The pairs of rows are from normal (top) and (bottom) a specific mutant of the lysosomal proton pump that has its acetylation sites all mutated to inactivity, thus mimicking in strongest form the action of the sirtuin/lithocholic acid pathway. Here, (second row, especially last frame), there is a higher level of red vs blue, and of blue vs green staining/fibers, suggesting that these muscles have had a durable uptick in efficiency and, implicitly, reduced atrophy and higher longevity.

These are some long and winding roads to get to positive effects from calorie restriction. What is going on? Firstly, biology does not owe it to us to be concise or easy to understand. Lithocholic acid is going to always be around, given that we eat food, but has mostly, heretofore, been regarded as toxic and even carcinogenic. It, along with the other bile acids, bind to dedicated transcription regulators that provide feedback control over their synthesis in the liver. So they are no strangers to our physiology. The authors do not delve into why calorie restriction durably raises the level of lithocholic acid in the gut or the blood, but that is an important place to start. It might well be that our digestive system squeezes every last drop of nutrition out of meagre meals by ramping up bile acid production. It is a recyclable resource, after all. This could have then become a general starvation signal to tissues, in advance of actual energy deficits, which one would rather not face if at all possible. So it is basically a matter of forewarned is forearmed. One is yet again amazed by the depth of biological systems, which have complexity and robustness far beyond our current knowledge, let alone our ability to replicate or model in artificial terms.

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• Department of injustice, lying, and corruption.
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Water Sensing by WNKs

WNK kinases sense osmotic condition as well as chloride concentration to keep us hydrated.

"Water, water, everywhere, nor any drop to drink." This line from Coleridge evokes the horror of thirst on the ghost ship, as its crew can not drink salt water. Other species can, but ocean water is too strong for us, roughly four times as salty as our blood. Nevertheless, our bodies have exquisite mechanisms to manage salt concentrations, with each cell managing its own traffic, and the kidneys managing most electrolytes in the blood. It is a very difficult task that has led to clever evolutionary solutions like counter-current exchange across the nephron loops, and stark differences in those nephron cell membranes, over water or salt permeability, to maximize use of passive ion gradients. But at the heart of the system, one has to know what is going on- one has to monitor all of the electrolyte levels and overall osmotic stress.

One such monitoring thermostat for chemical balances turns out to be the WNK kinases- a family of four proteins in humans that control (by phosphorylating them) a secondary set of regulators, which in turn control many salt transporters, such as SLC12A2 and SLC12A4. These latter are passive, though regulated, co-transporters that allow chloride across the membrane when combined with a matching cation like sodium or potassium. The cations drive the process, because they are normally kept (pumped) to strong gradients across cell membranes, with high sodium outside, and high potassium inside. Thus when these co-transporters are turned on (or off), they use the cation gradients to control the chloride level in the cell, in either direction, depending on the particular transporter involved. Since the sodium and potassium levels are held at relatively static, pumped levels, it is the chloride level that helps control the overall osmotic pressure in a finely tuned way. 

A few of the ionic transactions done in the kidney.

The WNK kinases were discovered genetically, in families that showed hypertension and raised levels of chloride and potassium in the blood. These syndromes mirrored complementary syndromes caused by mutations in SLC12A2, the Na/Cl co-transporter, indicating the WNK kinases inhibit SLC12A2. It turns out that WNK, which are named for an unusual catalytic site (with no lysine [K]) are sensors for both chloride, which inhibit them, and for osmotic pressure, which activates them. They are expressed in different locations and have slightly different activities, (and control many more transporters and processes than discussed here), but I will treat them interchangeably here. The logic of all this is that, if osmotic pressure is low, that means that internal salt levels are low, and chloride needs to be let into the cell, by activating the cation/chloride co-transporters. Likewise, if chloride levels inside the cell are high, the WNK kinase needs to be inhibited, reducing chloride influx. 

A recent paper (and prior work from the same lab) discussed structures of the WNK regulators that explain some of this behavior. WNK kinases are dimers at rest, and in that state mutually inhibit their auto-phosphorylation. It is separation and auto-phosphorylation that turns them on, after which they can then phosphorylate their target proteins, such as the secondary kinases STK39 and OSR1. The authors had previously found a chloride binding site right at the active site of the enzyme that promotes dimerization. In the current paper, they reveal a couple of clusters of water molecules which similarly affect the dimerization, and thus activity, of the enzyme.

Location of the inhibitory chloride (green) binding site in WNK1. This is right in the heart of the protein, near the active kinase site and dimerization interface with the other WNK1 partner.

While X-ray crystal structures rarely show or care much about water molecules, (they are extremely small and hard to track), here, those waters were hypothesized to be important, since WNK kinases are responsive to osmotic pressure. One way to test this is to add PEG400 to the reaction. This is a polymer (400 molecular weight) that is water-like and inert, but large in a way that crowds out water molecules from the solution. At 15% or 25% of the volume, PEG400 displaces a lot of water, lowers the water activity of a solution, and thus increases the osmotic pressure- that is its tendency to draw water in from outside. Plants use osmotic pressure as turgor pressure, and our cells, not having cells walls, need to always be at an osmotic pressure similar to the outside, lest they swell up, or conversely shrink away. Anyhow, WKN kinases can be switched from an inactive to active state just by adding PEG400- a sure sign that they are sensors for osmotic pressure.

Water network (blue dots) within the WNK1 kinase protein. Most of the protein is colored teal, while the active site kinase area is red, and a tiny amount of the dimer partner is colored green. When this crystal is osmotically challenged, the water network collapses from 14 waters to 5, changing the structure and promoting dissociation of the dimer. In B is show a sequence alignment over a wide evolutionary range where the amino acids that coordinate the water network (yellow) are clearly very well conserved, thus quite important.

Above is shown a closeup of the WNK1 protein, showing in teal the main backbone, including the catalytic loop. In red is the activation loop of the kinase, and in green is a little bit from the other WNK1 protein in the dimer pair. The chloride, if bound, would be located right at top center, at K375. Shown in blue are a series of fourteen water molecules that make up one so-called water network. Another smaller one was found at the interface between the two WNK1 proteins. The key finding was that, if crystalized with PEG400, this water network collapsed to only five water molecules, thereby changing the structure of the protein significantly and accounting for the dissolution of the dimer. 

Superposition of WNK1 with PEG400 (purple) and activated vs WNK1 without, in an inactive state (teal). Most of the blue waters would be gone in the purple state as well. This shows the significant structural transition, particularly in the helixes above the active site, which induce (in the purple state) dissociation of the dimer, auto-phosphorylation, and activation.

Thus there is a delicate network of water molecules tentatively held together within this protein that is highly sensitive to the ambient water activity (aka osmotic pressure). This dynamic network provides the mechanism by which the WNK proteins sense and transmit the signal that the cell requires a change in ionic flows. Generally the point is to restore homeostatic balance, but in the kidney these kinases are also used to control flows for the benefit of the organism as a whole, by regulating different transporters in different parts of the same cell- either on the blood side, or the urine side.

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