Senescent, Cancerous Cannibals

Tumor cells not only escape normal cell proliferation controls, but some of them eat nearby cells.

Our cells live in an uneasy truce. Cooperation is prized and specialization into different cell types, tissues, and organs is pervasive. But deep down, each cell wants to grow and survive, prompting many mechanisms of control, such as cell suicide (apoptosis) and immunological surveillance (macrophages, killer T-cells). Cancer is the ultimate betrayal, not only showing disregard for the ruling order, but in its worst forms killing the whole organism in a pointless drive for growth.

A fascinating control mechanism that has come to prominence recently is cellular senescence. In petri dishes, cells can only be goosed along for a few dozen cycles of division until they give out, and become senescent. Which is to say, they cease replicating but remain alive. It was first thought that this was another mechanism to keep cancer under control, restricting replication to "stem" cells and their recent progeny. But a lot of confusing and interesting observations indicate that the deeper meaning of senescence lies in development, where it appears to function as an alternate form of cell suicide, delayed so that tissues are less disrupted. 

Apoptosis is used very widely during development to reshape tissues, and senescence is used extensively as well in these programs. Senescent cells are far from quiescent, however. They have high metabolic activity and are particularly notorious for secreting a witches' brew of inflammatory cytokines and other proteins- the senescence-associated secretory phenotype, or SASP. in the normal course of events, this attracts immune system cells which initiate repair and clearance operations that remove the senescent cells and make sure the tissue remains on track to fulfill its program. These SASP products can turn nearby cells to senescence as well, and form an inflammatory micro-environment that, if resolved rapidly, is harmless, but if persistent, can lead to bad, even cancerous local outcomes. 

The significance of senescent cells has been highlighted in aging, where they are found to be immensely influential. To quote the wiki site:

"Transplantation of only a few (1 per 10,000) senescent cells into lean middle-aged mice was shown to be sufficient to induce frailty, early onset of aging-associated diseases, and premature death."

The logic behind all this seems to be another curse of aging, which is that while we are young, senescent cells are cleared with very high efficiency. But as the immune system ages, a very small proportion of senescent cells are missed, which are, evolutionarily speaking, an afterthought, but gradually accumulate with age, and powerfully push the aging process along. We are, after all, anxious to reduce chronic inflammation, for example. A quest for "senolytic" therapies to clear senescent cells is becoming a big theme in academia and the drug industry and may eventually have very significant benefits. 

Another odd property of senescent cells is that their program, and the effects they have on nearby cells, resemble to some partial degree those of stem cells. That is, the prevention of cell death is a common property, as is the prevention of certain controls preventing differentiation. This brings us to tumor cells, which frequently enter senescence under stress, like that of chemotherapy. This fate is highly ambivalent. It would have been better for such cells to die outright, of course. Most senescent tumor cells stay in senescence, which is bad enough for their SASP effects in the local environment. But a few tumor cells emerge from senescence, (whether due to further mutations or other sporadic properties is as yet unknown), and they do so with more stem-like character that makes them more proliferative and malignant.

A recent paper offered a new wrinkle on this situation, finding that senescent tumor cells have a novel property- that of eating neighboring cells. As mentioned above, senescent cells have high metabolic demands, as do tumor cells, so finding enough food is always an issue. But in the normal body, only very few cells are empowered to eat other cells- i.e. those of the immune system. To find other cells doing this is highly unusual, interesting, and disturbing. It is one more item in the list of bad things that happen when senescence and cancer combine forces.

A senescent tumor cell (green) phagocytoses and digests a normal cell (red).

• Shockingly, some people are decent.
• Tangling with the medical system carries large risks.
• Is stem cell therapy a thing?
• Keep cats indoors.

California Rooftop Revolution

Clawing back benefits for rooftop solar proves politically and programmatically perilous.

California is a leader in fighting climate change. You just have to look at a trace of an average day's electrical power sources to see what is going on:

One day in the life of the California electricity grid. Solar dominates during the day, but fossil fuels are still used heavily. Imports from other states are a mix of solar, nuclear, and fossil fuel sources, even some coal.

Solar power now dominates electricity production during mid-day periods. California has 1.5 million solar roof installations, (supplying 12 GW of capacity), which are, however, dwarfed by utility scale solar of about 24 GW in huge desert arrays. California doesn't have the kind of wind power that Texas and the Midwest have, but we have gone all in for solar, which supplies one fourth of our electricity.

But we are only beginning to reshape the grid. Addressing climate change means getting to zero fossil fuel use. In the graph above, you can see that, even at mid-day, we have natural gas plants humming along, supplying one third of electrical needs. It is the most efficient natural gas power plants (combined cycle) which can not be used as peaker plants, but need to be on full time, more or less, ironically. And then we have a huge fleet of peaker plants (and imported power from those in other states) to provide the mad rush of power required to transition every night from daytime solar to evening. The daily peak of power use comes not at noon, but at 6 PM. On top of this, decarbonizing transportation and heating/HVAC of buildings requires further electrical loads to be added to the grid, not all at convenient times.

California utilities are not state-run, but are heavily regulated. For instance, they make no profit from retail electricity sales, but from grid maintenance and power plant provision, via "decoupling" rules. The California Public Utilities Commission (CPUC) is the regulator, and has the job of planning this enormous transition. One of its biggest headaches is what to do about rooftop solar. Back in 2006, the state set its million solar roofs initiative, with the central component being net metering, or NEM. This said that retail customers get the same rate paid to them for electricity sent into the grid by their solar panels as they pay for electricity they take out of the grid. Back then, with solar barely viable and a tiny proportion of production, this subsidy made a lot of sense. And the program became increasingly attractive as solar costs came down.

But today, NEM is less economical. Solar customers make up 11.5% of total households, an increasingly significant share of the utility customer base. Solar power at mid-day is decreasingly valuable to the grid, failing to relieve the real crunch that happens into the evening. The lost revenue represents not only money for electrical generation, but for grid services and maintenance, which solar households make particularly significant use of, as the grid is essentially their battery and longer-term backup. And who pays the freight? The other rate payers, who on average are less rich than those who can foot the bill for solar. Extrapolating to all residences having solar power, the utilities would no longer have anyone paying for the system, at all. The CPUC made a proposal in 2021, inspired by these imbalances (not to mention the loathing utilities have for NEM), to drastically cut rates paid for exported solar energy, and also charge a grid connection fee of roughly $60 per month for solar households. 

This caused a firestorm, needless to say. In the proud American tradition of the powerful rebelling against any reduction of their ill-gotten gains or structural advantages, the proposal was mercilessly attacked in the press, and the governor forced the CPUC to go back to the drawing board. While the policy was indeed bad and would have destroyed the rooftop solar industry, the reaction was reminiscent of the Prop 13 "revolution", where property owners relieved themselves of taxes, or even the Boston tea party and American Revolution, where taxes meant to maintain the colonies were declared abhorrent impositions, later to be replaced by the far more ruinous costs of war and independence. 

In the newest iteration, just released, the CPUC follows the Prop 13 blueprint and grandfathers in all existing solar installations, selling only future installations down the river of reduced payback rates. It also drops the particularly galling grid connection fee, which was, in a policy sense, entirely appropriate. Someone needs to pay for the grid, after all. For my part, I would support a new grid electricity rate, charged on both import and export of energy. That way, solar users would be charged for the outgoing loads they put on the system, and encouraged to install (and use) batteries to reduce all loads on the grid. Extrapolated to universal participation, this would, instead of killing the grid by underfunding, make it smaller, as a backup resource, with funding aligned with usage.

Anyhow, in a masterful show of bureaucratic obfuscation, the CPUC in its newest proposal sets the future payback rate of solar to be a mysterious function of overall costs and climate impacts over a regional and hourly basis through the year- called the avoided cost calculator, or ACC. From the simplicity of NEM, we now go to a system that is both impenetrable and unpredictable, since the yearly calculations have been wildly varying, and result from a byzantine mechanism that takes 100 pages to explain.

How the ACC was set in three recent years. The variability is evident.

This seems like a case of the road to hell being paved with good intentions. It makes sense (in an ideal economic world) to relate the payback rate of exported solar power to the actual value of that power. The wholesale electricity market deals in such rates on a minute-to-minute basis. But the solar installation industry relies on predictability- the predictability of solar power coming out of solar panels for twenty or more years, and the predictability of its value, which was so neatly supplied by the NEM concept. This variable pricing proposal might be as dangerous for the rooftop solar industry as the grid connection fee was going to be. 

That may have been the plan, I don't know. But the CPUC needs to figure out what it wants at a deeper level. We can grant that on a global basis, residential rooftop solar is a relatively inefficient way to supply electricity and fight climate change. It is roughly 30% more expensive than utility-built mass solar installations. In compensation, the distributed nature of residential solar lowers the typical grid load, evens out production, and supplies important backup capability to customers, when paired with battery storage. Battery storage is something the CPUC aims to make default for solar installations, by using differential rates to offer low rates for electricity export at peak solar times, and paying much higher (if unknown!) rates at peak grid demand and demand growth times. The need to stabilize the grid and get rid of all those natural gas peaker plants is palpable. The CPUC plans for a future of utility scale battery installations that will provide that time-of-day balancing.

The California climate plan- how will we get there?

The key problem is that the state (and CPUC) plan is to grow residential solar, almost doubling penetration over the next decade, and more than tripling over the longer term. The combination of ever-expanding grid scale to electrify the state plus decarbonization means that everything needs to be pursued- utility scale, residential, and storage, all as fast as possible. That is not going to happen with reduced incentives and greater uncertainty for the residential solar sector. After all, the whole regulatory mechanism exists to not to precisely calibrate the lowest cost source of power- markets can do that. It exists to shift costs around, so that the future (and externalized) catastrophic planetary, social, and economic costs of climate change can be brought forward to influence today's choices. 

So there is a solution to this mess, which is to tax fossil fuels at much higher rates. Rather than fighting over marginal solar export rates and which kind of solar installation is better for the grid, we need to assess costs where the real costs lie- at the fossil fuels that are poisoning the biosphere and keeping us from a sustainable future. Since the CPUC is in control of the economics of electricity in the state, it should turn its formidable bureaucratic skills (in collaboration with the other entities that are in charge of fuel taxation, principally the legislature), in a more useful direction, such as raising the costs of the fuels we don't want while lowering those we do. That might mean charging a climate mitigation fee over all fossil fuels (beyond the very modest cap and trade fee California already participates in) that would pay for a moderated NEM bonus for residential solar, plus the batteries, grid strengthening, and everything else needed to put us on a deeper decarbonization path. Raising rates for electricity overall while redistributing prices in this way to favor clean energy would be difficult to sell, but quite justifiable. Especially if it did not penalize electricity use over the direct use of fossil fuels for heating and transportation, by taxing those fuels uniformly.

• But taxing fossil fuels, even a little, is contentious.
• Who among us is not corrupt, after all?
• Crypto really doesn't make much sense.
• Scientist rebellion.
• How work from home is reshaping real estate (prices).
• A universal influenza vaccine is on the way.

Skype for Cells, and Valves for Mitochondria

Connexin is one of those proteins that get more roles the harder people look.

One reason genetics is hard is that genetic products (proteins, generally) can have complicated roles in the organism- i.e. phenotype. For every simple case like sickle cell anemia, there are ten complicated cases where mutations are covered by duplicative functions, or have effects only revealed under unusual circumstances, or have multiple effects that are hard to connect and understand. Today's post focuses on a protein called connexin, which joins up into hexameric (6-member) complexes to form membrane half-channels, or hemichannels. When two such hemichannels on neighboring cells meet up, then join to form a gap junction, which is a small pore, permeable to molecules up to about 1000 Daltons. So ions, water, hormones, and other small molecules get through, but not most proteins or nucleic acids. They also help align the electrical charge or electrical propagation of neighboring cells. These junctions are surprisingly common in our bodies, functioning a bit like Skype, keeping neighboring cells in close touch. They have big roles in development, adhesion, neuron activity, and even cancer. Cancer cells tend to turn their gap junctions off in order to go their own way.

Structures of some connexin complexes, as hemichannels (below), and as full gap junctions (above).  "In" denotes inside each cell, "Ex" denotes the extra-cellular space, and the lipid bilayer would be the plasma membrane in this normal case.

But recent work has shown that hemichannels by themselves have regulated conductance properties and a variety of roles, some of which do not even rely on their channel properties. One recent paper (though with precedent work going back to 2006) raised the prospect of connexin hemichannels functioning in mitochondria, on the inner membrane, as regulated potassium channels. The mitochondrial inner membrane is notoriously impermeable, in order to accumlate the proton-motive force (pmf), which is the product of respiration / catabolism of food, and used for the synthesis of ATP. Protons are pumped out of the innermost mitochondrial matrix and into the inter-membrane space, setting up a pH and charge gradient, usable as energy. The ultimate concentration of hydrogen is not terribly high, however, and the overall ionic (and osmotic) balance remains governed by more conventional gradients of ions like sodium, potassium, and chloride. Thus it is important to regulate those balances using channels that are specific for those ions and don't conduct (i.e. leak) protons. 

Aside from the connexin channel discussed here, there are numerous other potassium conducting channels in the mitochondrial inner membrane, with individual regulation.

For potassium, there are at least seven channels now known, each regulated differently. That is amazing, really, for a membrane that should be so impermeable, though most are present at low levels. There is a K+/H+ antiporter that extrudes K+ to maintain osmotic balance, and then the other channels are all leakage channels that allow K+ back in, under various regulated conditions. The logic seems to be that the electron transport chains of respiration can easily run too "hot", giving off poisonous reactive oxygen species like peroxide, instead of the coordinated O2 reduction to water and proton export, as intended. So the major transport chain stations appear to have associated potassium channels that are inducible by reactive oxygen species, among other things, in order to fine-tune the local membrane potential and respiration rate. It seems like a curious way to run things, reducing the efficiency of a system that would be better inhibited earlier in the respiration process. 

Another model is that the fine-tuning by these channels forestalls the more catastrophic activation of PTP channels (mitochondrial permeability transition pore). These are more like gap junctions, totally non-discriminating in their channel characteristics, and are induced by high levels of stress from reactive oxygen species. When induced, these can totally leak away the protonmotive force, and if sustained, can kill the mitochondrion and even the whole cell. This would lead to what the current researchers found, which was that genetic reduction of the levels of the connexin Cx43 caused all kinds of bad outcomes in cells treated with peroxide, such as lower proton motive force, lower electron transport chain coupling, and lower ATP production.

ATP production is raised by leaking K+ into the mitochondrial matrix, and lowered conversely by reduction of connexin levels. "CxKD" denotes a genetic knock-down, or reduced expression, of the Cx43 connexin protein. They note, however, that expression of one ATP synthase component is reduced as well in this setting, so there may be yet other (gene regulation) effects going on here.

 

At any rate, the finding that one connexin that participates in cell surface gap junctions, called Cx43, is also specifically transported to the inner membrane of mitochondria during reactive oxygen species stress, (a stress that has very wide-ranging occurrence and effects, at the cellular and organismal levels, not just in mitochondria), and then acts there as a regulated K+ leakage channel, is quite unexpected. While the gap junction is a promiscious, wide channel, this activity must be far more discriminating. Add to that that it associates specifically with the H+ consuming ATP synthase, at the matrix side of the inner mitochondrial membrane, and we have a protein with a double life.

• We're not a cult!
• Why not put parking lots to some use?

The Politics of Resentment

Ann Applebaum has seen where all this Trumpism is going ... in Eastern Europe.

Liberals in America are baffled. How could anyone vote for Republican candidates at this point? How could anyone, let alone half the electorate, vote for Trump? We are befuddled and anxious for the future of America, which, far from becoming great again, is turning into a banana republic before our eyes, if, hopefully, not worse. We in California are particularly dissociated, as Democrats run the whole state, and Republican voter registration continues to decline year after year and is now under one quarter of the electorate. What does the rest of the country see that we do not? Or vice versa?

Ann Applebaum has written a trenchant book on the matter, "Twilight of Democracy". She lives in Poland, so has had a front-row seat to the illiberalization of a political system, both in Poland and in nearby Hungary, which seems farther advanced. Eastern Europe has more reason than most, perhaps to be disillusioned with the capitalist orthodoxy, after their rather rough transition from Communism. But this is a world-wide phenomenon, sweeping fringe rightists into power from Brazil to Sweden. What is going on? Applebaum posits that the whole structure of meritocratic representative democracy, with its open competition for (good) public policy, and use of educated expertise over vast areas of state interests from foreign affairs to monetary regulation and education policy, have come under fundamental critique. And this critique comes partly from those who have been shut out of that system: the not-well-educated, not-bicoastal, not-rich, not-acronymed-minority, not-hopeful about the American future. It is, in short, a politics of resentment.

How have the elites done over the post-world war 2 period? They won the cold war, but lost virtually every battle in it, from Vietnam to Afghanistan. They let the lower classes of the US sink into relative poverty and powerlessness vs business and the well-educated classes, in a rather brutal system of collegiate competition, de-unionization, off-shoring and worker suppression. They have let the economy fester through several crushing recessions, particularly the malaise of the 70's and the real estate meltdown of 2008. While the US has done pretty well overall, the lower middle and poor classes have not done well, and live increasingly precarious lives that stare homelessness in the face daily. In the heartland, parents at best saw their children fly off to coastal schools and cultures, becoming different people who would not dream of coming home again to live.

America is heavily red, geographically.

And the elite-run state has become increasingly sclerotic, continually self-criticizing and regulating its way to inaction. A thousand well-meaning regulations have paved the way to a bloated government that can not build a high-speed rail line in California, or solve the homelessness crisis. Everyone is a critic, including yours truly- it is always easier to raise objections, cover one's ass, and not get anything done. So one can sympathize with evident, if inchoate, desires for strength- for someone to break the barriers, bring the system to heel, and build that wall. Or get Brexit done. Or whatever the baying right wing media want at the moment.

The elite party in this sense is the Democratic party - capturing the coastal and well-educated, plus public employee unions. The Republican party, the party of money and the rich, (not the elite at all!), has conversely become the party of the downtrodden, feeding them anti-immigrant, anti-elite, anti-state red meat. It was a remarkably easy transformation, that required only shamelessness and lying to make hay out of the vast reserves of resentment seething in middle America. 

But Applebaum's point is not that the elites have messed things up and it may be time to do things differently. No, she suggests that the new protofascists have reframed the situation fundamentally. The elites in power have, through the hard work of meritocratic institutions, set up pipelines and cultures that reproduce their position in power almost as hermetically as the ancien régime of France and its nobility. That anyone can (theoretically) enter this elite and that it is at least somewhat vetted for competence and rationality is disregarded, or actively spat upon as "old" thinking- definitely not team thinking. The path to power now is to stoke resentment, overturn the old patterns of respect for competence and empathy, discard this meritocratic system in favor of one based on loyalty and fealty, and so bring about a new authoritarianism that brooks no "softness", exercises no self-criticism, has no respect for the enemy or for compromise, and has no room for intellectuals. 

But Hungary is way ahead of us, in the one-party rule department.

A second angle on all this is that conservatives feel resentful for another good reason- that they have lost the culture war. Despite all their formal power, winning the presidency easily half the time, and regularly running legislative branches and judicial branches in the US, their larger cultural project to keep progress at bay, fight moral "decadence" and all the other hobby horses, have gone nowhere. The US is increasingly woke, diverse, and cosmopolitan, and the "blood and soil" types (including especially conservative Catholics and Evangelicals), are despondent about it. Or apoplectic, or rabid, etc., depending on temperament. Their triumph in overturning Roe may allow some backwater states to turn back the clock, but on the whole, it looks like a rearguard action.

This is what feeds disgust with the system, and with democracy itself. Republicans who used to sing the praises of the US government, the flag, and democracy now seem to feel the opposite, that the US is a degenerate wasteland, no better than other countries, not exceptional, not dedicated to serious ideals that others should also aspire to. Democracy has failed, for them. And Applebaum points out how this feeling licenses the loss of civility, the lying, the anything-goes demagoguery which characterizes our new right-wing politics. Naturally the internet and its extremism-feeding algorithms have a lot to do with it as well. Applebaum is conservative herself. She spent a career working in the Tory media in Britain, but is outraged at what Tory-ism, and conservatism internationally, has become. She sees a dramatic split in conservatism, between those that still buy into the democratic, liberal system, and those who have become its opponents, in their revolutionary, Trumpy fervor. In the US, the fever may possibly have broken, after a very close brush with losing our institutions during the last administration, as election after election has made losers of the far right.

Over the long haul, Applebaum sees this as a cyclical process, with ample precedent from ancient Egyptian times through today, with a particularly interesting stop in the viciously polarized Drefussard period in France. But I see one extra element, which is our planetary and population crisis. We had very good times over the last few centuries building the human population and its comforts on the back of colonization, fossil fuels, and new technologies. The US of the mid to late-20th century exemplified the good times of such growth. Now the ecological bells are ringing, and the party is coming to an end. Denial has obviously been the first resort of the change-averse, and conservatives have distinguished themselves in their capabilities in that department. But as reality gradually sets in, something more sinister and competitive may be in the offing, as exemplified by the slogan "America First". Not first as in a leader of international institutions, liberal democracies and enlightenment values, but first as in looking out for number one, and devil take the rest. 

Combined with a rejuvinated blood and soil nationalism, which we see flourishing in so many places, these attitudes threaten to send us back into a world resembling that before world war 1 or 2, (and, frankly, all the rest of history), when nationalism was the coin of international relations, and national competition knew no boundaries- mercantile or military. We are getting a small foretaste of this in Russia's war on Ukraine, which is a product of precisely this Russia-first, make Russia great again mind-set. Thankfully, it is accompanied by large helpings of stupidity and mismanagement, which may save us yet. 

• It can be done.
• Another view of the fascism process.
• Corporate values and power are at all time highs.
• The penguins are in peril.
• "Intelligent" design is still about.
• Go Fetterman, and others with disabilities.

LPS: Bacterial Shield and Weapon

Some special properties of the super-antigen lipopolysaccharide.

Bacteria don't have it easy in their tiny Brownian world. While we have evolved large size and cleverness, they have evolved miracles of chemistry and miniaturization. One of the key classifications of bacteria is between Gram positive and negative, which refers to the Gram stain. This chemical stains the peptidoglycan layer of all bacteria, which is their "cell wall", wrapped around the cell membrane and providing structural support against osmotic pressure. For many bacteria, a heavy layer of peptidoglycan is all they have on the outside, and they stain strongly with the Gram stain. But other bacteria, like the paradigmatic E. coli, stain weakly, because they have a thin layer of peptidoglycan, outside of which is another membrane, the outer membrane (OM, whereas the inner membrane is abbreviated IM).

Structure of the core of LPS, not showing the further "poly" saccharide tails that would go upwards, hitched to the red sugars. At bottom are the lipid tails that form a strong membrane barrier. These, plus the blue sugar core, form the lipid-A structure that is highly antigenic.

This outer membrane doesn't do much osmotic regulation or active nutrient trafficking, but it does face the outside world, and for that, Gram-negative bacteria have developed a peculiar membrane component called lipopolysaccharide, or LPS for short. The outer membrane is assymetric, with normal phospholipids used for the inner leaflet, and LPS used for the outside leaflet. Maintaining such assymetry is not easy, requiring special "flippases" that know which side is which and continually send the right lipid type to its correct side. LPS is totally different from other membrane lipids, using a two-sugar core to hang six lipid tails (a structure called lipid-A), which is then decorated with chains of additional sugars (the polysaccharide part) going off in the other direction, towards the outside world.

The long, strange trip that LPS takes to its destination. Synthesis starts on the inner leaflet of the inner membrane, at the cytoplasm of the bacterial cell. The lipid-A core is then flipped over to the outer leaflet, where extra sugar units are added, sometimes in great profusion. Then a train of proteins (Lpt-A,B,C,D,E,D) extract the enormous LPS molecule out of the inner membrane, ferry it through the periplasm, through the peptidoglycan layer, and through to the outer leaflet of the outer membrane.

A recent paper provided the structural explanation behind one transporter, LptDE, from Neisseria gonerrhoeae. This is the protein that receives LPS from a its synthesis inside the cell, after prior transport through the inner membrane and inter-membrane space (including the peptidoglycan layer), and places LPS on the outer leaflet of the outer membrane. It is an enormous barrel, with a dynamic crack in its side where LPS can squeeze out, to the right location. It is a structure that explains neatly how directionality can be imposed on this transport, which is driven by ATP hydrolysis (by LtpB) at the inner membrane, that loads a sequence of transporters sending LPS outward.

Some structures of LptD (teal or red), and LPS (teal, lower) with LptE (yellow), an accessory protein that loads LPS into LptD. This structure is on the outer leaflet of the outer membrane, and releases LPS (bottom center) through its "lateral gate" into the right position to join other LPS molecules on the outer leaflet.

LPS shields Gram-negative bacteria from outside attack, particularly from antibiotics and antimicrobial peptides. These are molecules made by all sorts of organisms, from other bacteria to ourselves. The peptides typically insert themselves into bacterial membranes, assemble into pores, and kill the cell. LPS is resistant to this kind of attack, due to its different structure from normal phospholipids that have only two lipid tails each. Additionally, the large, charged sugar decorations outside fend off large hydrophobic compounds. LPS can be (and is) altered in many additional ways by chemical modifications, changes to the sugar decorations, extra lipid attachments, etc. to fend off newly evolved attacks. Thus LPS is the result of a slow motion arms race, and differs in its detailed composition between different species of bacteria. One way that LPS can be further modified is with extra hydrophobic groups such as lipids, to allow the bacteria to clump together into biofilms. These are increasingly understood as a key mode of pathogenesis that allow bacteria to both physically stick around in very dangerous places (such as catheters), and also form a further protective shield against attack, such as by antibiotics or whatever else their host throws at them.

In any case, the lipid-A core has been staunchly retained through evolution and forms a super-antigen that organisms such as ourselves have evolved to sense at incredibly low levels. We encode a small protein, called LY96 (or MD-2), that binds the lipid-A portion of LPS very specifically at infinitesimal concentrations, complexes with cell surface receptor TLR4, and sets off alarm bells through the immune system. Indeed, this chemical was originally called "endotoxin", because cholera bacteria, even after being killed, caused an enormous and toxic immune response- a response that was later, through painstaking purification and testing, isolated to the lipid-A molecule.

LPS (in red) as it is bound and recognized by human protein MD-2 (LY96) and its complex partner TLR4. TLR4 is one of our key immune system alarm bells, detecting LPS at picomolar levels. 

LPS is the kind of antigen that is usually great to detect with high sensitivity- we don't even notice that our immune system has found, moved in, and resoved all sorts of minor infections. But if bacteria gain a foothold in the body and pump out a lot of this antigen, the result can be overwhelmingly different- cytokine storm, septic shock, and death. Rats and mice, for instance, have a fraction of our sensitivity to LPS, sparing them from systemic breakdown from common exposures brought on by their rather more gritty lifestyles.

• Econometrics gets some critique.
• Clickbait is always bad information, but that is the business model.
• Monster bug wars.
• Customer-blaming troll due to lose a great deal of money.

Magellan, the Movie

The story of Magellan's voyage is positively cinematic.

It has now been five hundred years since the first circumnavigation of the world, by Ferdinand Magellan. This feat doesn't generally get as much fame as Columbus's discovery of the Caribbean, even though Columbus didn't know what he was doing, and kept not understanding what he had done long after he returned. By the time, thirty years later, that some more of the new world had been explored, and the Portuguese had also entered the Indian ocean around the bottom of Africa, the overall geography of the earth had not advanced a great deal, still being based on Ptolemy's significantly (about 30%) too-small estimate. But the lure remained- how to get to the all-important spice islands in a more convenient way. 

And it was a very commercial lure. Magellan had little scientific interest in all this, per se. He was a mariner through and through, and had done extensive research with his colleagues, mapmakers, and astronomers. But most of all he was desperate to make some money after a wide-ranging, but not very well-paid, career with the official Portuguese fleet. He had visited India and what is now Malaysia, and had heard from a friend who had finally found the spice islands, and had decided to stay there. So when Magellan went to the King of Portugal to propose his westward voyage around the tip of South America, it was a strictly commercial venture, hopefully easier and shorter than the trip around Africa and through the Indian ocean. But the king was uninterested, as the Portuguese already were using the eastern route, and didn't seem much point in trying another, unknown one. Columbus had already tried that gambit and had not gotten much for it. Not much in the way of spices, at any rate.

So Magellan stormed off in a huff, renounced his allegiance to the Portuguese crown, and made his proposal to the Spanish king instead. Now that logic made more sense. The Spanish and Portuguese had come up with a colonial demacation line, the treaty of Tordesillas, that split the Atlantic, which is what gave Brazil to the Portuguese. But this line in imaginary fashion extended around the globe to the other side, and depending how big that globe was, might award the spice islands (the southern islands of the Indonesian archapelago) to Spain, not Portugal. Devising a route from the other side might get Spain there faster, and also avoid unpleasant conflict with sea lanes that were now busy with Portuguese shipping. So the expedition was approved and launched in 1519.

It is a fascinating story, and gets more and more interesting as it goes on, with exotic locations, spectacular discoveries, first contact with far-flung natives, mutiny, hangings, and maroonings. It is very well-told by Tim Joyner, in his definitive and meticulous 1992 book. One aspect that did not come up, however, was that Magellan and colleagues could have come up with a much more accurate estimate of the circumference of the globe by their thorough knowledge of latitude. Longitude- that was difficult to calculate, though his voyage made amazing advances in this respect as well. But if they were imaginative enough to consider that the globe was round in all directions, then the circumference around the poles, which was well within their ability to calculate with precision, would have told them that Ptolemy was way off, and that scurvy was going to be their lot in traversing the Pacific ocean (which Magellan named, incidentally).

A top-secret 1502 map of the known world, from Portugal. The coast of Africa is well-detailed, while farther areas are quite a bit murkier. Crucially, nothing is known of the southern extent of South America.

The last ship, of the five that embarked on the expedition, limped back into San Lucar, near Seville, Spain, three years later, bedraggled and desperately bailing out their bilge. But it brought back a treasure of cloves, as well as a treasure of information. The expedition had poisoned relations with numerious natives, not to mention the Portuguese, who quickly overtook and imprisoned the small contingent left at Ternate, one of the spice islands. In fact, Magellan himself died in a reckless attack on a thousand natives in what is now the Philippines. 

So the mini-series version would have to be told by someone else. And that should be Antonio Pigafetta, the self-appointed anthropologist of the expedition. A worldly fellow from Lombardy who had been employed at the Vatican, he was part of its ambassadorial delegation to Spain when he heard about Magellan's plans. He appears to have jumped at the chance for adventure, and kept detailed dairies of the events of the voyage, to which all subsequent authors are hugely indebted. He even kept a day log which he was surprised to see finally came up a day short- precisely the day that one loses when following the setting sun around the world. He seems to have been quite a character, who had high respect for Magellan, and whose adventurousness also saved him from scurvy, which tended to afflict the more squeamish eaters, who were put off by eating rats and whatever else came to hand. 

So there you have it, perhaps a twelve part miniseries spanning the globe, rich with drama, suffering, scenery, deceit, greed, blind ambition, valor, and victory, telling of one of the great adventures of mankind.

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Xi Jinping Thought on Socialism with Chinese Characteristics for a New Era

China girds for defense against infiltration by Western ideas. And Wang Huning leads the way.

The current Chinese Communist Party congress prompts us to take stock of where we are in our relations with China and where China is going. The major theme is of course conservativism. Xi Jinping remains at the helm, and may stay there for several cycles to come. The party remains uniquely in control, using all elements of new and old technologies to "guide" Chinese culture and maintain power. And increasingly is trying to shape the international environment to abet its internal controls and maybe spread its system abroad.

It is worth recounting the fourteen points of Xi Jinping thought in detail, as stated on the Wiki page:

• Ensuring Communist Party of China leadership over all forms of work in China.
• The Communist Party of China should take a people-centric approach for the public interest.
• The continuation of "comprehensive deepening of reforms".
• Adopting new science-based ideas for "innovative, coordinated, green, open and shared development".
• Following "socialism with Chinese characteristics" with "people as the masters of the country".
• Governing China with the Rule of Law.
• "Practice socialist core values", including Marxism-Leninism and socialism with Chinese characteristics.
• "Improving people's livelihood and well-being is the primary goal of development".
• Coexist well with nature with "energy conservation and environmental protection" policies and "contribute to global ecological safety".
• Strengthen the national security of China.
• The Communist Party of China should have "absolute leadership over" China's People's Liberation Army.
• Promoting the one country, two systems system for Hong Kong and Macau with a future of "complete national reunification" and to follow the One-China principle and 1992 Consensus for Taiwan.
• Establish a common destiny between the Chinese people and other peoples around the world with a "peaceful international environment".
• Improve party discipline in the Communist Party of China.

The casual reader will note that Communist party dominance and retention of control is the subject of roughly four or five of these points, depending on interpretation. One can sense that control is absolutely the central obsession and fear of party. And no wonder- there are plenty of structural and historical reasons.

China has had a tumultuous history from earliest recorded times, cycling between centralization and dissolution and civil war. The golden periods were always ones of stability, while the worst were times of anarchy, banditry, decline. Then there were the colonial humiliations, from the opium wars to Japanese occupation. Whether one adds in the disastrous legacy of Marxism- which also came from the West- into the mix, is a matter of taste. As noted above, the current CCP still gives lip service to Marxism-Leninism (though pointedly not to Maoism!).

In the more current era, the West promotes free trade, human rights, and democracy as a way to contest the power and ideology of the CCP. Each have their ulterior aspects, certainly in relation to China. Human rights and democracy are obviously direct attacks on the very core values of the CCP. Free trade might seem like a no-brainer and objectively desirable. But in reality, it cements the advantages of highly developed countries, since less developed countries can never gain an advantage in high technology if their only advantage is low labor cost and poor education & other infrastructure. Therefore, China has had to protect itself from the onslaught of the West, economically, politically, and socially.

This is the basic theme of the CCP ideology, driven particularly by Wang Huning, a social scientist. academic, and now politbureau member and close advisor of Xi Jinping. Huning has been a close advisor to the last three leaders of China, and evidently a major architect of their signature mottos, "The Three Represents", "The Chinese Dream", and now "Xi Jinping thought ...". He is a close student of the US, and appears generally to be the "vision guy" for the Chinese leadership. (Maybe even the brains behind the operation, if one wants to be hyperbolic.) While Huning in his earliest writings advocated for the democratic development of China, in line with general development of a modern, mature state, and with models such as Japan, that has all been deferred and subsumed under the more immediate needs of the party. His public writing ceased after he joined the central government. 

The biggest and most traumatic historical shock guiding the CCP today was undoubtedly the collapse of the Soviet Union. (As it guides Putin as well.) Before everyone's eyes, the siren song of the West, of capitalism, and of "freedom" (particularly the freedom to be nationalist) captured the populace, and destroyed the Soviet state from within, resulting in a gangster Russia that has only painfully re-established its strength and order, turning back into an authoritarian (and nationalist) state and a colleague of China on the anti-Western world stage. 

The Chinese Communist Party avoided all that through its merciless grip on power. It never let its eye stray from the ball, or softened it heart towards its dissidents and malcontents. It patiently experimented with a mixed capitalist / one party rule system, which has turned out (so far) to be highly successful. It availed itself of all available technology and capitalist methods from the West to develop its economy at a pell-mell rate, learning especially from its fellow-tigers, Singapore, Taiwan, Japan, Hong Kong, and South Korea. However, it continues to (rightly) fear the siren songs of freedom, democracy, etc. as core threats. It conveniently uses psychological projection to blame the West for all these attractive ideas, which in truth are not exclusively Western at all, but are dreams that Chinese people have as well. (See Hong Kong, see Singapore, see Taiwan) So the ideology and the propaganda follows the age-old script of justifying a bloated, intrusive, and often very cruel state by casting the blame for dissent on outsiders.

That's a big TV screen.

The CCP has also been highly effective in many areas. It obviously keeps tabs on everyone with not just surveillance, but with social surveys and party members at the grass roots, and even allows limited local protests, so that it has a feeling for what the people want, despite a lack of formal democracy. It has engineered a miracle of infrastructure, trains, and housing. Indeed, there is an overhang of construction that it is slowly winding down, in the current real estate crunch. It has protected its population comprehensively from Covid, surely saving millions of lives, even as it imposes stark, and likely not sustainable, costs. It has recognized the dangers of bitcoin and shut down the cryptocurrencies in comprehensive fashion- something we might learn from. And it is leading the way in solar manufacturing and installation, even while its use of coal remains catastrophic. It continually identifies and fights corruption in its own ranks, recognizing that a one-party state is an invitation to rot and sclerosis.

But the fundamental conundrum remains- how to justify and strengthen a one-party state in the midst of the rising well-being, education and sophistication of its own population. The other tigers, including even Singapore, all began with strongly authoritarian systems that each evolved, in parallel with their economic development, into more or less free democracies today. While one can sympathize with the CCP's desire to avoid the chaos of the Soviet Union's demise, the now more cogent and relevant models of political evolution in the local region are far more positive stories, which the CCP seems to pointedly, and lamentably, ignore. 

Indeed, China appears to be heading in a different direction, a bit more like that of North Korea. Their wolf warrior diplomacy is given to vitriolic statements and bullying, now showcased over Taiwan. Their internal propaganda is increasingly nationalistic and strident, following the Xi Jinping thought's guidelines of shaping the cultural values of China to be more cohesive and disciplined. (Covid hasn't helped, either.) It is increasingly intolerant of diversity, as shown against minority ethnic groups, which are being wiped out in systematic terms. For example, the government offers generous subsidies to minority members who marry Han ethnic partners, and drives the same policy by locking up large numbers of Uyghur men for re-education. China's ideological leaders are groping for CCP-friendly "values" that can effectively block what they view as foreign viruses, but which are, in point of fact, endogenous and natural to the human condition.

Under Xi and Wang Hunting, the party is still searching for those elusive "socialist core values" that are uniquely Chinese, not Western, not from the backward (and somewhat feudal) countryside, and supportive of the Communist party. But all they have come up with are greed/capitalism, nationalism, an obsession with stability, and a new personality cult. 

While I can not foretell the future, this does not seem like a good way to go. In foreign policy, one can measure success by how friendly the neighboring countries are- in this case to China, and to the US. There are areas of the world where very peaceful relations exist, such as across the EU, and between the US and its neighbors. That does not seem to be the case in the South China Sea. The constant drumbeat of threats and bullying by China, against Taiwan in particular, but others as well, various territorial disputes, and a enormous military building spree have put everyone very much on edge, and not on friendly terms. This is a fundamental problem for China, and for the rest of us if they bull their way into a world war.

Domestically, it is quite possible for the repressive system to continue indefinitely, given its continuing determination and often very intelligent management, always on guard against the heresies of freedom and goodwill. But that would be giving up an important future path. The Chinese culture would have greater growth prospects, and greater beneficial consequences at home and abroad, if it opened up and tolerated greater pluralism. Its economic dynamism is up till now built on foreign technology, and its ability to innovate and operate truly in the vanguard of world development depends on some significant degree of political and social dynamism as well, not on Big-Brotherism. 

So I see a future where inevitably, the CCP will have to experiment with grass-roots democracy in order to resolve its fundamental value and motivation conflicts as growth slows and China becomes a wealthier country. These will be frought and dangerous experiments. But in time, there is a chance that they will lead to the same kinds of opening that other Asian countries have experienced so successfully, with the gradual development of another party, and a more humane and less paranoid culture. Conversely, insistence on repression tends to spiral into a need for additional repression, with corresponding chances for a dramatic crackup that might produce another one of the grand cycles of Chinese history.

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From Geo-Logic to Bio-Logic

Why did ATP become the central energy currency and all-around utility molecule, at the origin of life?

The exploration of the solar system and astronomical objects beyond has been one of the greatest achievements of humanity, and of the US in particular. We should be proud of expanding humanity's knowledge using robotic spacecraft and space-based telescopes that have visited every planet and seen incredibly far out in space, and back in time. But one thing we have not found is life. The Earth is unique, and it is unlikely that we will ever find life elsewhere within traveling distance. While life may concievably have landed on Earth from elsewhere, it is more probable that it originated here. Early Earth had as conducive conditions as anywhere we know of, to create the life that we see all around us: carbon-based, water-based, precious, organic life.

Figuring out how that happened has been a side-show in the course of molecular biology, whose funding is mostly premised on medical rationales, and of chemistry, whose funding is mostly industrial. But our research enterprise thankfully has a little room for basic research and fundamental questions, of which this is one of the most frustrating and esoteric, if philosphically meaningful. The field has coalesced in recent decades around the idea that oceanic hydrothermal vents provided some of the likeliest conditions for the origin of life, due to the various freebies they offer.

Early earth, as today, had very active geology that generated a stream of reduced hydrogen and other compounds coming out of hydrothermal vents, among other places. There was no free oxygen, and conditions were generally reducing. Oxygen was bound up in rocks, water, and CO2. The geology is so reducing that water itself was and still is routinely reduced on its trip through the mantle by processes such as serpentinization.

The essential problem is how to jump the enormous gap from the logic of geology and chemistry, over to the logic of biology. It is not a question of raw energy- the earth has plenty of energetic processes, from vocanoes and tectonics to incoming solar energy. The question is how a natural process that has resolutely chemical logic, running down the usual chemical and physical gradients from lower to higher entropy, could have generated the kind of replicating and coding molecular system where biological logic starts. A paper from 2007 gives a broad and scrupulous overview of the field, featuring detailed arguments supporting the RNA world as the probable destination (from chemical origins) where biological logic really began. 

To rehearse very briefly, RNA has, and still retains in life today, both coding capacity and catalytic capacity, unifying in one molecule the most essential elements of life. So RNA is thought to have been the first molecule with truly biological ... logic, being replaced later with DNA for some of its more sedentary roles. But there is no way to get to even very short RNA molecules without some kind of metabolic support. There has to be an organic soup of energy and small organic molecules- some kind of pre-biological metabolism- to give this RNA something to do and chemical substituents to replicate itself out of. And that is the role of the hydrothermal vent system, which seems like a supportive environment. For the trick in biology is that not everything is coded explicitly. Brains are not planned out in the DNA down to their crenelations, and membranes are not given size and weight blueprints. Biology relies heavily on natural chemistry and other unbiological physical processes to channel its development and ongoing activity. The coding for all this, which seems so vast with our 3 Gb genome, is actually rather sparse, specifying some processes in exquisite detail, (large proteins, after billions of years of jury-rigging, agglomeration, and optimization), while leaving a tremendous amount still implicit in the natural physical course of events.

A rough sketch of the chemical forces and gradients at a vent. CO2 is reduced into various simple organic compounds at the rock interfaces, through the power of the incoming hydrogen rich (electron-rich) chemicals. Vents like this can persist for thousands of years.

So the origin of life does not have to build the plane from raw aluminum, as it were. It just has to explain how a piece of paper got crumpled in a peculiar way that allowed it to fly, after which evolution could take care of the rest of the optimization and elaboration. Less metaphorically, if a supportive chemical environment could spontaneously (in geo-chemical terms) produce an ongoing stream of reduced organic molecules like ATP and acyl groups and TCA cycle intermediates out of the ambient CO2, water, and other key elements common in rocks, then the leap to life is a lot less daunting. And hydrothermal vents do just that- they conduct a warm and consistent stream of chemically reduced (i.e. extra electrons) and chemical-rich fluid out of the sea floor, while gathering up the ambient CO2 (which was highly concentrated on the early Earth) and making it into a zoo of organic chemicals. They also host the iron and other minerals useful in catalytic conversions, which remain at the heart of key metabolic enzymes to this day. And they also contain bubble-like stuctures that could have confined and segregated all this activity in pre-cellular forms. In this way, they are thought to be the most probable locations where many of the ingredients of life were being generated for free, making the step over to biological logic much less daunting than was once thought.

The rTCA cycle, portrayed in the reverse from our oxidative version, as a cycle of compounds that spontaneously generate out of simple ingredients, due to their step-wise reduction and energy content values. The fact that the output (top) can be easily cleaved into the inputs provides a "metabolic" cycle that could exist in a reducing geological setting, without life or complicated enzymes.

The TCA cycle, for instance, is absolutely at the core of metabolism, a flow of small molecules that disassemble (or assemble, if run in reverse) small carbon compounds in stepwise fashion, eventually arriving back at the starting constituents, with only outputs (inputs) of hydrogen reduction power, CO2, and ATP. In our cells, we use it to oxidize (metabolize) organic compounds to extract energy. Its various stations also supply the inputs to innumerable other biosynthetic processes. But other organisms, admittedly rare in today's world, use it in the forward direction to create organic compounds from CO2, where it is called reductive or reverse (rTCA). An article from 2004 discusses how this latter cycle and set of compounds very likely predates any biological coding capacity, and represents an intrisically natural flow of carbon reduction that would have been seen in a pre-biotic hydrothermal vent setting. 

What sparked my immediate interest in all this was a recent paper that described experiments focused on showing why ATP, of all the other bases and related chemicals, became such a central part of life's metabolism, including as a modern accessory to the TCA cycle. ATP is the major energy currency in cells, giving the extra push to thousands of enzymes, and forming the cores of additional central metabolic cofactors like NAD (nicotine adenine dinucleotide), and acetyl-CoA (the A is for adenine), and participating as one of the bases of DNA and RNA in our genetic core processes. 

Of all nucleoside diphosphates, ADP is most easily converted to ATP in the very simple conditions of added acyl phosphate and Fe3+ in water, at ambient temperatures or warmer. Note that the trace for ITP shows the same absorbance before and after the reaction. The others show no reaction either. Panel F shows a time course of the ADP reaction, in hours. The X axis refers to time of chromatography of the sample, not of the reaction.

Why ATP, and not the other bases, or other chemicals? Well, bases appear as early products out of pre-biotic reaction mixtures, so while somewhat complicated, they are a natural part of the milieu. The current work compares how phosphorylation of all the possible di-phosphate bases works, (that is, adenosine, cytidine, guanosine, inosine, and uridine diphosphates), using the plausible prebiotic ingredients ferric ion (Fe3+) and acetyl phosphate. They found surprisingly that only ADP can be productively converted to ATP in this setting, and it was pretty insensitive to pH, other ions, etc. This was apparently due to the special Fe3+ coordinating capability that ADP has due to its pentose N and neighboring amino group that allows an easy electron transfers to the incoming phosphate group. Iron remains common as an enzymatic cofactor today, and it is obviously highly plausible in this free form as a critical catalyst in a pre-biotic setting. Likewise, acetyl phosphate could hardly be simpler, occurs naturally under prebiotic conditions, and remains an important element of bacterial metabolism (and transiently one of eukaryotic metabolism) today. 

Ferric iron and ATP make a unique mechanistic pairing that enables easy phosphorylation at the third position, making ATP out of ADP and acyl phosphate. At step b, the incoming acyl phosphate is coordinated by the amino group while the iron is coordinated by the pentose nitrogen and two existing phosphates.

The point of this paper was simply to reveal why ATP, of all the possible bases and related chemicals, gained its dominant position of core chemical and currency. It is rare in origin-of-life research to gain a definitive insight like this, amid the masses of speculation and modeling, however plausible. So this is a significant step ahead for the field, while it continues to refine its ideas of how this amazing transition took place. Whether it can demonstrate the spontaneous rTCA cycle in a reasonable experimental setting is perhaps the next significant question.

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Science Fiction as Theology

Let's look higher than the clouds. Let's look to the stars.

I have always been rather dismissive of theology- the study of something that doesn't exist. But if one takes it in a larger sense of a culture of scripture, story telling, morals, and social construction, then sure, it makes more sense. But then so do alot of other stories. I have been enjoying the Foundation series via streaming, which is at best "inspired" by the original books, yet takes its premises reasonably seriously and grows a complex and interesting set of story lines to what by the end of the first season is a positive and promising conclusion. I would ding it for excessive adherence to Star Wars-style action and simplistic morality, compared with the more cerebral original, but that is only to be expected these days.

Science fiction is having a golden age, as a way to tell important, probing stories and consider alternative futures. The Star Trek franchise generally sticks with hopeful futures, which I certainly favor. Their world is post-money, post internal conflict, post-disease. But philosophically alive through contact with other civilizations. The theological implications are momentous, as we envision a culture very different from our own, and blessed with various magical means of deliverance, like transporters, replicators, and warp drives. Where the "science fiction" books of the Bible were mostly dystopian (Job, Revelation, Genesis), Science fiction in our era straddles the line, with plenty of dystopian offerings, but also hopeful ones. Whether Star Wars is hopeful might be a matter of debate, since bad guys and bad empires never seem to go away, and the position of the resistance is always impossibly dire.

White male mathematician Hari Seldon takes on the role of god, in the Foundation series. He calculates out the future of the galaxy, clairvoyantly predicting events, and then comes back from beyond the grave to keep guiding his flock through crisis after crisis.

Are Star Trek futures any more realistic than those of Revelation? Are they theologically more sound? I think yes on both counts. Revelation is a rather unhinged response to the late Jewish era in its apocalyptic relations with Rome, as it headed into exile and the diaspora. There is a welter of reworked Old Testament material and obscure references, turning into florid visions that have misled Christians for centuries. Star Trek and the other science fiction franchises, on the other hand, are a bit more restrained in their visionary quests and escatologies, and more hopeful, for abundant futures where some problems have been solved while other forms of politics and history continue to call for strong moral values. This is quite different than the bizarre and ecstatic culmination of Revelation at the end of history, in the last days.

We also get to live out the visions, on a small scale, as technology advances in the real world. Smart phones have transformed our lives, for instance, one promise kept from the early science fiction days. And our only real hope for dealing with climate change is to harness better technologies, rather than going down dystopian roads of degrowth, famine, and war. So there are real futures at stake here, not just visions of futures.

While our current physics totally bars the adventures that are portrayed in contemporary science fiction epics, their theological significance lies in their various visions of what humanity can and should do. They, as Revelation, are always keyed to their historical moment, with America ascendent and technologically advanced over other cultures. But they do not use their magical elements and story arcs to promote quiescence and slack-jawed wonder at the return of the son of god, who will make everything right and mete out judgement to all the bad people. (Or do the opposite, in the case of Job.) No, they uniformly encourage resistance against injustice, and hopeful action towards a better world, or galaxy, or universe, as the case may be.

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