The Cycle of Kingship

History shows a repeated cycle between democratic forms and autocratic forms of politics.

Before their history, the Greeks had another long history- the Mycenaean age. As reflected in the Homeric epics, it was an age of kings, palaces, and courts. But by the time of classical Greece, their politics had progressed to a spectrum of aristocracies, oligarchies, and democracies. In Athens, democracy was a sort of aristocracy, as it was far from including all the people of the city. But at any rate, the relatively egalitarian system established in Athens spurred an age of innovation and empire, still culturally influential down to today. Rome likewise progressed in its early days from kings to a republic of the most complex and rigorous kind. Again, it was largely a collective aristocracy of the well-to-do, but represented significant political progress, and again spurred several centuries of growth and empire.

How surprised they would have been to know that kingship would make a comeback as the norm of European political organization for almost the next two thousand years. The decline and fall of the Roman empire is a story of rising autocracy, from the Augustan arrangement that saved the appearance of the Senate and Republic, down to the frank autocracy of Constantine and his successors through the Byzantine Empire. 

In recent times, we have experienced a similar burst of innovation and growth from the egalitarian political systems modeled on Enlightenment ideals. It has been two and a half centuries of social progress and movement towards greater democracy. Indeed, with the end of the Cold War, we had thought a New World Order was on the horizon, and history itself had come to a conclusion. That all countries would inevitably adopt the Western model and live happily ever after, tended to by a European Union-style bureaucracy. 

Well, perhaps not total democracy.

What hubris! Our shock is most keen in the cases of Russia and China, which went through existential crises in their conflicts with the West and with basic economics, and were thought would inevitably open up politically as they freed themselves from the shackles of the various communist -isms of the twentieth century. But deeper political patterns were at work. Neither country had ever experienced functional democracy. Unlike the West with its fleeting (if glorious) experiences of Republican and Democratic systems, neither had ever gotten even to that point. Indeed their traumatic experiences of communism had originated as innovative, supposedly democratic political ideas from the West, which immediately curdled into the most cruel sorts of despotism.

And obviously the US itself, at the very height of its political dominance, is now beset by a would-be king. Autocracy turns out to have numerous points in its favor. First is a fundamental psychological archetype, based on the family and richly embodied by religions like Christianity. One must have a god, a father- someone to bow down to and beseech. In our infant democracy, George Washington took the truly radical step of stepping down from the presidency and retiring to private life. But now, the "base" can not fall over themselves fast enough to worship their leader, to withstand any lie or abuse as long as their side beats the other side, and installs itself in power, however corrupt.

Autocracy has, additionally, a sort of Darwinian logic to it. Our own founders in the Federalist papers and elsewhere explicitly feared the rise of a demagogue who could so twist the people from their better judgement, best interests, and hallowed institutions as to leave the constitutional system in tatters. Well, here we are. And we see it all over- in Julius Caesar and the disintegration of the Roman triumverate, in the rise of Napoleon, in the rise of Vladimir Putin and Xi JinpIng- the truly talented leader with the ability and the desire can shake the foundations of current institutions and remake the political system. Our current would-be king may be a man of fewer talents, yet seems to excite many to insurrection and destruction of democratic political institutions. It may look like a farce, but it is only a farce until they get to write the history books. Then it is glorious.

One must also take a hard look at democracy. There seems to be a dynamic where early democracies are limited to an elite, like the early United States. As the franchise is broadened by the natural / internal logic of democracy, the elites have less of a stake in it, and may indeed be attacked by the state. That leads to the danger of a leader like Julius Caesar taking an anti-elite position, using people against the elites, and installing, not a better democracy, but a dictatorship. Where does the defect lie? The fact is that true democracy is unworkable. We see in California the poor decisions frequently made by the ballot box on referendums. Without controlling the media and education environment in a rigorous fashon for the public interest, good public policy has little chance against moneyed interests, propaganda, and apathy. So the search through history has been for representative or other delegating systems that raise the most talented and public-spirited people to decision-making positions. But there can be no permanent proof against shamelessness, greed, and the other inherent vices of humanity.

• How's the next king doing?
• Ukraine is about the coherence of the whole Russian-dominated eastern sphere, like keeping Belarus from cracking up.

The RNAs Shall Protect Us

The humble skin mole has at least one oncogenic mutation. But it is not cancer- why not?

We know that mutations cause cancer. But we also know that it takes multiple mutations, not just one, in virtually all cases. This is one reason why age is such a strong risk factor, providing the time to accumulate multiple "hits". One place where this is particularly apparent is the skin. Most people have moles (nevi) and other imperfections, which are no cause for alarm. We are also on the lookout for the unusual signs and forms that indicate melanoma- which truly is a cause for alarm. Moles typically have one of the key oncogenic mutations for melanoma, however: BRAF V600E (which means the 600th amino acid in its protein chain has been changed from valine to glutamic acid). So what is behind the difference? What systems do cells and organs have to keep this train on the tracks, despite a wheel or two coming off?

A recent paper (review) explored this issue, and tells a complicated technical and scientific story. But the bottom line is that certain miRNAs- a novel form a gene regulator discovered just in the last couple of decades- form a firewall against further proliferation. The BRAF mutation is an activating change, which disrupts the normal "off" state of this protein kinase. BRAF is a protein kinase that attaches phosphate groups to serines and threonines on other proteins. And some those other proteins are specifically other (MAP) protein kinases that form cascades promoting cell proliferation and differentiation. In the case of melanocytes in the skin, the BRAF mutation promotes just that: proliferation, mole formation, and, in some cases, progression to full blown melanoma. 

What is a skin mole? Well, it clearly is composed of lots of cells, so whatever is arresting the mutant BRAF-activated proliferation is taking its sweet time. Proliferation goes for a while, but then stops for an unknown reason. It had been thought in the field (and by these researchers as well) that mole cells had gone into senescence- an irreversible division arrest that is frequently activated in cancer cells and is similar to age-dependent cell cycle arrest. But they show now that senescence is not the explanation. If the BRAF mutation state is reversed, the cells resume dividing. And they also have other hallmarks of a different form of (G2/M) cell division arrest. So something more dynamic is going on.

They do a few technical tours de force of modern DNA sequencing and large-scale molecular biology to find what unusual genes are being expressed in these cells, and find two:  MIR211-5p and MIR328-3p. These are miRNAs, which are short RNA pieces that repress the expression of other genes. We have thousands of them, and each can repress hundreds of other genes, forming a somewhat crazy interdigitated regulatory network. They evolved from an immune function of repressing the expression of viruses and other foreign DNA, but have been repurposed to have broad regulatory effects, often in development and disease.

In BRAF-activated skin mole cells, these miRNAs have one effective target, which is AURKB (Aurora B kinase), another protein kinase that is needed for cell division. No AURKB, no cell division. Indeed, skin mole cells have a high rate of cells stuck in the last phase of cell division, with 4 genome equivalents. They found that AURKB has low expression in skin mole cells, but high expression, as expected, in melanoma cells, while the miRNAs had the reverse pattern. And tellingly, artificial inhibition of these miRNAs released mole cells from their proliferation arrest and allowed the BRAF mutation to have its way with them.

Model of this paper's findings about melanocytes. Starting with stem-like melanocytes, mutated BRAF can cause oncogenenic or pre-oncogenic proliferation. Separately, TPA, or some local tissue factor like TPA, can encourage stem melanocytes to grow and differentiate properly into mature melanocytes. But those same activators (TPA and its natural analog) increase miRNA expression of particularly MIR211-5p, which (by inhibiting AURKB) arrests growth as part of the differentiation program, and also shuts down proliferation caused by mutated BRAF, (at late mitosis / G2 arrest), at least most of the time.

But there was still a problem- what activates the miRNA gene expression in the natural setting? It isn't the mutated BRAF protein, since it routinely drives cells through several replication cycles to form moles, and didn't have any regulatory effect on the miRNAs. The researchers focused on the kinds of local secreted hormones, like endothelin, that might locally inhibit overgrowth of cells, and logically lead to a mole-like pattern. What they hit on was TPA, an artificial analog of diacylglycerol, which is an activator of yet another protein kinase, PKC. TPA is paradoxically a tumor promoter, and is routinely used in cell culture systems to goose the proliferation of melanocytes. But for the mutated BRAF- driven cells from moles, TPA arrests their growth, and it does so because PKC activates the expression of MIR211-5p. They showed that taking TPA out of their cell culture mixes dramatically restarted the growth of mole-derived and other BRAF mutation-driven cells. So this closes the circle in some degree, explaining how it is that skin moles form as sort of arrested mini-cancers.

Unfortunately, TPA is not a natural chemical, and diacylglycerol is not hormone, though many hormones, such as thyroid hormone and oxytocin, do affect PKC activity. So the natural PKC and miRNA activator, and inhibitor of excess proliferation in these BRAF mutation-driven melanocytes remains unknown. I am sure that this research group will be hunting diligently for it, since it is an extremely interesting issue not just in oncology, but in skin and tissue development generally.

• The walls may be closing in.
• Jung on Trump.
• Yeah, there was voter fraud.
• Electrification.
• Those precarious human-soil relations.
• Plastic rain.
• Efficient housing.

Cooking With Solar

Who knew cooking with energy from the sun would be so difficult?

Cooking with rays from the sun- what could be more delightful, or more efficient? The same rays that warm the skin can heat food as well- one merely needs to concentrate the heat a few fold. Well, doing so is remarkably difficult to do in practical terms. Not only do you need to concentrate the sun's heat, but then you have to preserve the heat you collect, without blocking out the light with all that insulation. This can be quite a trick. Thermostatic control? You must be joking- none of the currently sold or proffered DIY projects incorporate such an extravangance. The current state of play is a slightly demented world of youtube videos, fly-by-night companies, and charitable efforts pointed at developing regions. But rest assured, it can be done.

Naturally, the most significant drawback is that the sun doesn't shine all the time, confining solar cooking to mid-day times, and sunny conditions. Several kinds of cookers have been developed, each with individual drawbacks and features. 

• Parabolic stove
• Vacuum tube oven
• Closed box oven
• Open panel oven

First off, the parabolic solution puts the premium on power. While the other cookers are akin to ovens, this one is more like a range / stove. It gets extremely hot and cooks in a hurry. The concentrated light from the sun needs, however, to be constantly tracked and aimed at the pan on the burner. Yet it is an invisible flame, presenting some difficulty. It can burn a finger or blind you in an instant. One company developed a reasonably practical design, complete with glowing video. But then it promptly shut down and disappeared, I assume due to the daunting legal liability implied in selling such an appliance. These cookers remain very much a DIY, and at your own risk, proposition.

A parabolic cooker- adjust often, and use with care!

Second are vacuum tube ovens, which are basically thermos bottles with sun-facing inputs. These have outstanding insulation, so they capture the radiation coming in very effectively, storing it as heat. They can be used in cloudy conditions and maybe in non-mid-day conditions. The downside is that the thermos structure limits capacity for food, and also hides it from view. These also come in water-heating versions, filling a core camping and emergency need.

A vacuum tube style of oven. This one has quite high capacity. The central thermos provides extremely effective insulation, collecting every bit of the insolation.

Third are closed-box ovens, which are perhaps the most widely used form of solar cooking. Given enough insulation and a well-sealed glass top, you can make a reasonably practical oven out of cardboard boxes, wood, or metal, which get up to 350 degrees °F. This is a slow kind of cooker, perhaps more like a crockpot than an oven, taking quite a bit of time to heat up. They are not so sensitive to light direction, so can be left out for lazy afternoon and will still work. This is an amazingly active area of DIY activity, with endless variations. One of the most impressive I have seen is a sleek, low oven build of glass and wood, meant to stay outside full time.

 A commercially made box oven, with glass top and room for one or two pots.

A DIY version of a box oven, with clean lines and very high capacity.

Lastly, a more portable version of a solar oven is an open panel oven, where a set of foldable or collapsable reflective panels surround the pot, without much other structure. These are maximally simple, and aimed at camping and other portable needs. But they need something extra to hold in the heat around the pot, which may be a plastic oven bag, or a pair of glass bowls that go around the black pot inside. When properly protected, set up, and with large enough collectors, these can get to 300 degrees and work well cooking stews, rice, etc. These enjoy a wide variety of DIY efforts and styles as well, and one of the best is offered by a maker in Southern California.

A panel cooker being used on the go. Note the glass bowl holding the central pot.

Those are the current types, each with its pluses and minuses. Once one considers solar cooking, it is natural to want to deploy it to those who really need it- the rural and poor around the world, who have lots of sun, and not many other resources. The scourge of traditional cooking fuels in these areas is particularly alarming, usually being wood, coal, or dung, which lead to deforestation, climate change, land depletion, and copious pollution, both indoor and outdoor. Thus solar cooking becomes another sort of colonial dream foisted on the less fortunate, who have not set up proper infrastructure to pillage the earth and pollute the atmosphere. But the various impracticalities of solar cooking, including inconvenient timing, outdoor location, low capacity, slow speed, unusual, non-local, and fragile materials, have doomed such efforts to marginal effectiveness. Maybe some further leap in the technology, like incorporating a heat storage mechanism (rocks?) might solve some of these problems. It is amazing, really, how convenient the stored /reduced forms of carbon (in biomass and fossil fuels) are for our needs, and how hard they are to replace.

• Shades of WW2: All Russia wants is a little elbow room.
• The gravitational wave observatories are running, and recording the death spirals of black holes.
• The next presidential election could start a civil war.
• Carbon tax, now.
• Good sleep, good life.

Supergroups in Search of Their Roots

The early stages of eukaryotic evolution are proving hard to reconstruct.

There is normal evolution, and then there are great evolutionary transitions. Not to say that the latter don't obey the principles of normal evolution, but they go by so fast, and render so many transitional forms obsolete along the way, that there is little record left of what happened. Among those great transitions are the origin of life itself, the origin of humans, and the origin of eukaryotes. We are slowly piecing together human evolution, from the exceedingly rare fossils of intermediate forms and branch off-shoots. But looking at the current world, we are the lone hominin, having displaced or killed off all competitors and predecessors to stand alone atop the lineage of primates, and over the biosphere generally. Human evolution didn't violate any natural laws, but it seems to have operated under uniquely directional selection, especially for intelligence and social sophistication, which led to a sort of arms race of rapid evolution that laid the groundwork for an exponential rate in the invention of technologies and collective social forms over the last million years.

Similarly, it is clear that however the origin of life started out, it was a very humble affair, with each innovation quickly displacing its progenitors, just as the early cell phones came out in quick succession, until a technological plateau was reached from which further development was / is less obvious. While the origin and success of eukaryotes did not erase the prokaryotic kingdoms from which they sprang, it does seem to have erased the early stages of its own development, to the point that those stages are very hard to reconstruct, especially given the revolutionary and multifarious nature of their innovations.

Eukaryotes differ from prokaryotes in possessing: nuclei and a nuclear membrane with specialized pores; mitochondria descended from a separate bacterial ancestor (and photosynthetic plastids descended from yet other bacterial ancestors in some cases); sex and meiosis; greater size by several orders of magnitude; phagocytosis by amoeboid cells; internal membrane organelles like golgi, peroxisomes, lysosomes, endocytic and exocytic vesicles; cyclins that run the cell cycle; microtubules that participate in the cell cycle, cytoskeleton, and cilia; cilia, as distinct from flagella; an active actin-based cytoskeleton, with novel motor proteins; a greatly elaborated transcriptional apparatus with modular enhancers and novel classes of transcription regulators; histones; mRNA splicing and introns; nucleolus and small nucleolar RNAs; telomeres on linear chromosomes; a significant increment in the size of both ribosomal subunits. Indeed, the closer one looks at the molecular landscape, the more differences accumulate. This was quite simply a quantum leap in cellular organization, which happened sometime between 1.8 and 3 billion years ago. Indeed, eukaryotes are not just the McMansions of the microbial world, but the Downton Abbeys- with dutiful servants and complex and luxurious internal economies that prokaryotic cells couldn't conceive of.

Major lineages of eukaryotes are traced back to their origins in a molecular-based phylogeny. Animals (and fungi!) are in the Opisthokonta, plants in the Chloroplastida. So many groups connect right to the "root" of this tree that there is little way to figure out which came first. Also, the dashed lines indicate uncertainty about those orderings/rootings as well, which leaves a great deal of early eukaryotic evolution obscure. Some abbreviations / links are- CRuMs: collodictyonids (syn. diphylleids) + rigifilida + mantamonas; excavates, hemimastigophora, haptista, TSAR:  telonemids, stramenopiles, alveolates, and rhizaria.

A recent paper recounts the current phylogenetic state of affairs, and a variety of other papers over the last decade delve into the many questions surrounding eukaryotic origins. While molecular phylogenies have improved tremendously with the advent of faster, whole-genome sequencing and the continued collection of obscure single-celled eukaryotes, (aka protists), the latest phylogeny, as shown above, remains inconclusive. The deepest root is both uncertain with regard to its bacterial progenitor, and to which current eukaryotes bear the closest relation. There are occasional fossil kelps, algae, and other biochemical traces back to 2.0 to 2.7 billion years, (though some do not put the origin earlier than 1.8 billion years) but these have not been able to shed any light on the order of events either.

Nevertheless, the field can agree on a few ideas. One is that the assimilation of mitochondria (whether willing or unwilling) is perhaps the dominant event in the sequence. That doesn't mean it was necessarily the first event, but means that it created a variety of conditions that led to a cascade of other consequences and features. The energy mitochondria provided enabled large cell sizes and the accumulation of a whole new household full of junk, like lipids in several new membrane compartments. The genome that they contributed brought in thousands of new genes, including introns. 

Secondly, the loss of cell walls and the adoption of amoeboid carnivory is likely one of the first events in the evolutionary sequence. Shedding the obligatory cell wall that all bacteria have necessitates a cytoskeleton of some kind, and it is also conducive to the engulfment of the proto-mitochondrion. For while complicated co-symbiotic metabolic arguments have been devised to explain why these two cells may have engaged in a long-term mutual relationship long before their ultimate consumation, the most convenient hypothesis for assimilation remains the simplest- that one engulfed the other, in a meal that lasted well over a billion years.

Thirdly, the question of what the progenitor cell was has been refined somewhat. One of the most intriguing findings of the last half-century of biology was the discovery of archaebacteria (also called archaea)- a whole new kingdom of bacteria characterized by their tendency to occupy extreme habitats, their clear separation from bacteria by chemical and genetic criteria, and also their close relationship to eukaryotes, especially what is presumed to be the original host genome. Many proposals have been made, (including that archaea are the original cell, preceding other bacteria), but the best one currently is that archaea split from the rest of bacteria rather late, after which eukaryotes split off from archaea, thus making the latter two sister groups. This explains the many common traits they share, while allowing significant divergence, plus the incorporation of many bacterial features into eukaryotes, either through the original lineage, or by later transfer from the proto-mitochondrion. So here at last is one lineage that survived out of the gradual development of eukaryotes- the archaea, though one wouldn't guess it from looking at them. It took analysis at the molecular level to even know that archaea existed, let alone that they are the last extant eukaryotic sister group.

A comically overstuffed figure from an argument for the late development of archaebacteria out of pre-existing bacteria (prokaryotes), with subsequent split and diversification of eukaryotes out of a proto-archaeal lineage. Many key molecular and physiological characters are mentioned.

Lastly, surveying the various outlying protist lineages for clues about which might hearken back to primitive eukaryotic forms, one research group suggests that the collodictyonids might fit the bill. Being an ancient lineage means that it is lonesome, without a large family of evolutionary development to show diversification and change. It also means that in molecular terms, it is highly distinct, branching deeply from all other groups. Whether that all means that it resembles an ancient / early form of the eukaryotic cell, or went its own way on a unique evolutionary trajectory, is difficult to say. For each trait, (including sequence traits), a phylogenetic analysis is done to figure out whether it is differential- shared with some other lineages but not all- whether those without the trait lost it at some later point, or whether it was gained by a sub-group. After analyzing enough such traits, one can make a statement about the overall picture, and thus the "ancient-ness", of an organism.

Is anything special about collodictyon? Not really. It is predatory, and has four flagella and a feeding groove, which functions as a sort of mouth. It can make pseudopods, has normal microtubule organizing centers for its flagella, and generally all the accoutrements of a eukaryotic cell. It lacks nothing, and thus may be an early branching eukaryote, but is not in any way a transitional form.

An unassuming protist (collodictyon) as possible representative of early eukaryotes. Its cilia are numbered.

At this point, we are left still peering darkly into the past, though obscure living protists and their molecular fossils, trying to figure out what happened when they split from the bacteria and archaea. A tremendous amount happened, but little record survives of the path along the way. That tends to be characteristic of the most momentous evolutionary events, which cause internal and external cataclysms, (including the opening of whole new lifestyles to exploit), that necessitate a rapid dynamic of further adaptation before their descendents achieve a stable and successful state sufficient to ride out the ensuing billion or more years ... before we come on the scene with the ability and interest to contemplate what went before.

• Red regions have three times the death rates from Covid as blue regions. Will that change electoral math?
• Annals of secession, cont.
• Sad spectacle at the court.
• Analysis of how the energy transition might go. Again, a carbon tax would help.