Easy Does it

The eukaryotic ribosome is significantly slower than, and more accurate than, the bacterial ribosome.

Despite the focus, in molecular biology, on interesting molecules like genes and regulators, the most striking thing facing anyone who breaks open cells is the prevalence of ribosomes. Run the cellular proteins or RNAs out on a gel, and bulk of the material is always ribosomal proteins and ribosomal RNAs, along with tRNAs. That is because ribosomes are critically important, immense in size, and quite slow. They are sort of the beating heart of the cell- not the brains, not the energy source, but the big lumpy, ancient, shape-shifting object that pumps out another essential form of life-blood- all the proteins the cell needs to keep going.

With the revolution in structural biology, we have gotten an increasingly clear view of the ribosome, and a recent paper took it up another notch with a structural analysis of how tRNA handling works and how / why it is that the eukaryotic ribosome is about ten times slower than its bacterial progenitor. One of their figures provides a beautiful (if partial) view of each kind of ribosome, showing how well-conserved this structure is, despite the roughly three billion or more years that have elapsed since their divergence into the bacterial and archaeal lineages, from which the eukaryotic ribosome comes. 

Above, the human ribosome, and below, the ribosome of E. coli, a bacterium, in partial views. The perspective is from the back, relative to conventional views, and only a small amount of the large subunit (LSU) appears at the top of each structure, with more of the small subunit (SSU) shown below. Between them is the cleft where tRNAs bind, in a dynamic sequence of incoming rRNA at the A (acceptor) site, then catalysis of peptide bond addition at the P (peptidyl transfer) site, and ejection of the last tRNA at the E (ejection) site. In concert with the conveyor belt of tRNAs going through, the nascent protein is being synthesized in the large subunit and the mRNA is going by, codon by codon, in the small subunit. Note the overall conservation of structure, despite quite a bit of difference in detail.

The ribosome is an RNA machine at its core, with a lot of accessory proteins that were added later on. And it comes in two parts, the large and small subunits. These subunits do different things, do a lot of rolling about relative to each other, and bind a conveyor belt of tRNAs between them. The tRNAs are pre-loaded with an amino acid on one end (top) and an anticodon on the other end (bottom). They also come with a helper protein (EF-Tu in bacterial, eEF1A in eukaryotes), which plays a role later on. The anticodon is a set of three nucleotides that constitute the genetic code, whereby this tRNA is always going to match one codon to a particular amino acid. 

The ribosome doesn't care what the code is or which tRNA comes in. It only cares that the tRNA matches the mRNA held by the small subunit, as transcribed from the DNA. This process is called decoding, and the researchers show some of the differences that make it slower, but also more accurate, in eukaryotes. In bacteria, ribosomes can work at up to 20 amino acids per second, while human ribosomes top out at about 2 amino acids per second. That is pretty slow, for an enzyme! Its accuracy is about one error per thousand to ten thousand codons.

See text for description of this diagram of the ribosomal process. 50 S is the large ribosomal subunit in bacteria (60S in eukaryotes). 30S is the small subunit in bacteria (40S in eukaryotes). S stands for Svedberg units, a unit of sedimentation in high-speed centrifugation, which was used to study proteins at the dawn of molecular biology.

Above is diagrammed the stepwise logic of protein synthesis. The first step is that a tRNA comes in and lands on the empty A site, and tests whether its anticodon sequence fits the codon on the mRNA being threaded through the bottom. This fitting and testing is the key quality control process, and the slower and more selective it is, the more accurate the resulting translation. The EF-Tu/eEF1A+GTP protein holds on to the tRNA at the acceptor (A) position, and only when the fit is good does that fit communicate back up from the small subunit to the large subunit and cause hydrolysis of GTP to GDP, and release of the top of the tRNA, which allows it to swing into position (accommodation) to the catalytic site of the ribosome. This is where the tRNA contributes its amino acid to the growing protein chain. That chain, previously attached to the tRNA in the P site, now is attached to the tRNA in the A site. Now another GTP-binding protein comes in, EF-G (EEF2 in eukaryotes), which bumps the tRNA from the A site to the P site, and simultaneously the mRNA one codon ahead. This also releases whatever was in the E site of the ribosome and frees up the A site to accept another new tRNA.

See text for description. IC = initiation complex, CR = codon recognition complex, GA = GTPase activation complex, AC = accommodated complex. FRET = fluorescence resonance energy transfer. Head and shoulder refer to structural features of the small ribosomal subunit.

These researchers did both detailed structural studies of ribosomes stuck in various positions, and also mounted fluorescent labels at key sites in the P and A sites. These double labels allowed one to be flashed with light, (at its absorbance peak), and the energy to be transferred between them, resulting in fluorescence of light back out from the second fluorophore. The emitted energy from the second fluorophore provides an exquisitely sensitive measure of the distance between the two fluorophores, since its ability to capture light from the first fluorophore is sensitive to distance (cubed). The graph above (right) provides a trace of the fluorescence seen in one ribosomal cycle, as the distance between the two tRNAs changes slightly as the reaction proceeds and the two tRNAs come closer together. This technical method allows real-time analysis of the reaction as it is going along, especially one as slow as this one.

Structures of the ribosome accentuating the tRNA positions in the A, P, and E sites. Note how the green tRNA in the A site starts bent over towards the eEF1A GTPase (blue), as the decoding and quality control are going on, after which it is released and swings over next to the P site tRNA, ready for peptide bond formation. Note also how the structure of the anticodon-codon pairing (pink, bottom) evolves from loose and disordered to tight after the tRNA straightens up.

Above is shown a gross level view in stop-motion of ribosomal progress, achieved with various inhibitors and altered substrates. The mRNA is in pink (insets), and shows how the codon-anticodon match evolves from loose to tight. Note how at first only two bases of the mRNA are well-paired, while all three are paired later on. This reflects in a dim way the genetic code, which has redundancies in the third position for many amino acids, and is thought to have first had only two letters, before transitioning to three letters.

Higher detail on the structures of the tRNAs in the P site and the A site as they progress through the proof-reading phase of protein synthesis. The fluorescence probes are pictured, (Red and green dots), as is more the mRNA strand (pink).

These researchers have a great deal to say about the details of these structures- what differentiates the human from the E. coli ribosome, why the human one is slower and allows more time and more hindrance during the proof-reading step, thereby helping badly matched tRNAs to escape and increasing overall fidelity. For example, how does the GTPase eEF1A, docked to the large subunit, know when a match down at the codon-anticodon pair has been successful down in the small ribosomal subunit?

"Base pairing between the mRNA codon and the aa-tRNA anticodon stem loop (ASL) is verified through a network of ribosomal RNA (rRNA) and protein interactions within the SSU A site known as the decoding centre. Recognition of cognate aa-tRNA closes the SSU shoulder domain towards the SSU body and head domains. Consequent ternary complex engagement of the LSU GTPase-activating centre (GAC), including the catalytic sarcin-ricin loop12 (SRL), induces rearrangements in the GTPase, including switch-I and switch-II remodeling, that trigger GTP hydrolysis"

They note that there seem to be at least two proofreading steps, both in activating the eEF1A and also afterwards, during the large swing of the tRNA towards the P site. And they note novel rolling motions of the human ribosome compared with the bacterial ribosome, to help explain some of its distinctive proofreading abilities, which may be adjustable in humans by regulatory processes. Thus we are gaining ever more detailed window on the heart of this process, which is foundational to the origin of life, central to all cells, and not without medical implications, since many poisons that bacteria have devised attack the ribosome, and several of our current antibiotics do likewise.

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• Endgame Ukraine.
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• Death by gun.
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• Immigration is the key.

The Way We Were: Origins of Meiosis and Sex

Sex is as foundational for eukaryotes as are mitochondria and internal membranes. Why and how did it happen?

Sexual reproduction is a rather expensive proposition. The anxiety, the dating, the weddings- ugh! But biologically as well, having to find mates is no picnic for any species. Why do we bother, when bacteria get along just fine just dividing in two? This is a deep question in biology, with a lot of issues in play. And it turns out that bacteria do have quite a bit of something-like-sex: they exchange DNA with each other in small pieces, for similar reasons we do. But the eukaryotic form of sex is uniquely powerful and has supported the rapid evolution of eukaryotes to be by far the dominant domain of life on earth.

A major enemy of DNA-encoded life is mutation. Despite the many DNA replication accuracy and repair mechanisms, some rate of mutation still occurs, and is indeed essential for evolution. But for larger genomes, the mutation rate always exceeds the replication rate, (and the purifying natural selection rate), so that damaging mutations build up and the lineage will inevitably die out without some help. This process is called Muller's ratchet, and is why all organisms appear to exchange DNA with others in their environment, either sporadically like bacteria, or systematically, like eukaryotes.

An even worse enemy of the genome is unrepaired damage like complete (double strand) breaks in the DNA. These stop replication entirely, and are fatal. These also need to be repaired, and again, having extra copies of a genome is the way to allow these to be fixed, by processes like homologous recombination and gene conversion. So having access to other genomes has two crucial roles for organisms- allowing immediate repair, and allowing some way to sweep out deleterious mutations over the longer term.

Our ancestors, the archaea, which are distinct from bacteria, typically have circular, single molecule genomes, in multiple copies per cell, with frequent gene conversions among the copies and frequent exchange with other cells. They routinely have five to twenty copies of their genome, and can easily repair any immediate damage using those other copies. They do not hide mutant copies like we do in a recessive allele, but rather by gene conversion (which means, replicating parts of a chromosome into other ones, piecemeal) make each genome identical over time so that it (and the cell) is visible to selection, despite their polyploid condition. Similarly, taking in DNA from other, similar cells uses the target cells' status as live cells (also visible to selection) to insure that the recipients are getting high quality DNA that can repair their own defects or correct minor mutations. All this ensures that their progeny are all set up with viable genomes, instead of genomes riddled with defects. But it comes at various costs as well, such as a constant race between getting lethal mutation and finding the DNA that might repair it. 

Both mitosis and meiosis were eukaryotic innovations. In both, the chromosomes all line up for orderly segregation to descendants. But meiosis engages in two divisions, and features homolog synapsis and recombination before the first division of the parental homologs.

This is evidently a precursor to the process that led, very roughly 2.5 billion years ago, to eukaryotes, but is all done in a piecemeal basis, nothing like what we do now as eukaryotes. To get to that point, the following innovations needed to happen:

• Linearized genomes, with centromeres and telomeres, and >1 number of chromosomes.
• Mitosis to organize normal cellular division, where multiple chromosomes are systematically lined up and distributed 1:1 to daughter cells, using extensive cytoskeletal rearrangements and regulation.
• Mating with cell fusion, where entire genomes are combined, recombined, and then reduced back to a single complement, and packaged into progeny cells.
• Synapsis, as part of meiosis, where all sister homologs are lined up, damaged to initiate DNA repair and crossing-over.
• Meiosis division one, where the now-recombined parental homologs are separated.
• Meiosis division two, which largely follows the same mechanisms as mitosis, separating the reshuffled and recombined sister chromosomes.

This is a lot of novelty on the path to eukaryogenesis, and is just a portion of the many other innovations that happened in this lineage. What drove all this, and what were some plausible steps in the process? The advent of true sex generated several powerful effects:

1. A definitive solution to Muller's ratchet, by exposing every locus in a systematic way to partial selection and sweeping out deleterious mutations, while protecting most members of the population from those same mutations. Continual recombination of the parental genomes allows beneficial mutations to separate from deleterious ones and be differentially preserved.
2. Mutated alleles are partially, yet systematically, hidden as recessive alleles, allowing selection when they come into homozygous status, but also allowing them to exist for limited time to buffer the mutation rate and to generate new variation. This vastly increases accessible genetic variation.
3. Full genome-length alignment and repair by crossing over is part of the process, correcting various kinds of damage and allowing accurate recombination across arbitrarily large genomes.
4. Crossing over during meiotic synapsis mixes up the parental chromosomes, allowing true recombination among the parental genomes, beyond just the shuffling of the full-length chromosomes. This vastly increases the power of mating to sample genetic variation across the population, and generates what we think of as "species", which represent more or less closed interbreeding pools of genetic variants that are not clones but diverse individuals.

The time point of 2.5 billion years ago is significant because this is the general time of the great oxidation event, when cyanobacteria were finally producing enough oxygen by photosynthesis to alter the geology of earth. (However our current level of atmospheric oxygen did not come about until almost two billion years later, with rise of land plants.) While this mainly prompted the logic of acquiring mitochondria, either to detoxify oxygen or use it metabolically, some believe that it is relevant to the development of meiosis as well. 

There was a window of time when oxygen was present, but the ozone layer had not yet formed, possibly generating a particularly mutagenic environment of UV irradiation and reactive oxygen species. Such higher mutagenesis may have pressured the archaea mentioned above to get their act together- to not distribute their chromosomes so sporadically to offspring, to mate fully across their chromosomes, not just pieces of them, and to recombine / repair across those entire mated chromosomes. In this proposal, synapsis, as seen in meiosis I, had its origin in a repair process that solved the problem of large genomes under mutational load by aligning them more securely than previously. 

It is notable that one of the special enzymes of meiosis is Spo11, which induces the double-strand breaks that lead to crossing-over, recombination, and the chiasmata that hold the homologs together during the first division. This DNA damage happens at quite high rates all over the genome, and is programmed, via the structures of the synaptonemal complex, to favor crossing-over between (parental) homologs vs duplicate sister chromosomes. Such intensive repair, while now aimed at ensuring recombination, may have originally had other purposes.

Alternately, others suggest that it is larger genome size that motivated this innovation. This origin event involves many gene duplication events that ramified the capabilities of the symbiotic assemblage. Such gene dupilcations would naturally lead to recombinational errors in traditional gene conversion models of bacterial / archaeal genetic exchange, so there was pressure to generate a more accurate whole-genome alignment system that confined recombination to the precise homologs of genes, rather than to any similar relative that happened to be present. This led to the synapsis that currently is part of meiosis I, but it is also part of "parameiosis" systems on some eukaryotes, which, while clearly derived, might resemble primitive steps to full-blown meiosis.

It has long been apparent that the mechanisms of meiosis division one are largely derived from (or related to) the mechanisms used for mitosis, via gene duplications and regulatory tinkering. So these processes (mitosis and the two divisions of meiosis) are highly related and may have arisen as a package deal (along with linear chromosomes) during the long and murky road from the last archaeal ancestor and the last common eukaryotic ancestor, which possessed a much larger suite of additional innovations, from mitochondria to nuclei, mitosis, meiosis, cytoskeleton, introns / mRNA splicing, peroxisomes, other organelles, etc.  

Modeling of different mitotic/meiotic features. All cells modeled have 18 copies of a polypoid genome, with a newly evolved process of mitosis. Green = addition of crossing over / recombination of parental chromosomes, but no chromosome exchange. Red = chromosome exchange, but no crossing over. Blue = both crossing over and chromosome exchange, as occurs now in eukaryotes. The Y axis is fitness / survival and the X axis is time in generations after start of modeling.

A modeling paper points to the quantitative benefits of the mitosis when combined with the meiotic suite of innovations. They suggest that in a polyploid archaean lineage, the establishment of mitosis alone would have had revolutionary effects, ensuring accurate segregation of all the chromosomes, and that this would have enabled differentiation among those polyploid chromosome copies, since they would be each be faithfully transmitted individually to offspring (assuming all, instead of one, were replicated and transmitted). Thus they could develop into different chromosomes, rather than remain copies. This would, as above, encourage meiosis-like synapsis over the whole genome to align all the (highly similar) genes properly.

"Modeling suggests that mitosis (accurate segregation of sister chromosomes) immediately removes all long-term disadvantages of polyploidy."

Additional modeling of the meiotic features of chromosome shuffling, and recombination between parental chromosomes, indicates (shown above) that these are highly beneficial to long-term fitness, which can rise instead of decaying with time, per the various benefits of true sex as described above. 

The field has definitely not settled on one story of how meiosis (and mitosis) evolved, and these ideas and hypotheses are tentative at this point. But the accumulating findings that the archaea that most closely resemble the root of the eukaryotic (nuclear) tree have many of the needed ingredients, such as active cytoskeletons, a variety of molecular antecedents of ramified eukaryotic features, and now extensive polyploidy to go with gene conversion and DNA exchange with other cells, makes the momentous gap from archaea to eukaryotes somewhat narrower.

• SNL says goodbye to George Santos.
• Surveillance vs spying.
• The South China Sea.

Preliminary Pieces of AI

We already live in an AI world, and really, it isn't so bad.

It is odd to hear about all the hyperventilating about artificial intelligence of late. One would think it is a new thing, or some science-fiction-y entity. Then there are fears about the singularity and loss of control by humans. Count me a skeptic on all fronts. Man is, and remains, wolf to man. To take one example, we are contemplating the election of perhaps the dummbest person ever to hold the office of president. For the second time. How an intelligence, artificial or otherwise, is supposed to worm its way into power over us is not easy to understand, looking at nature of humans and of power. 

So let's take a step back and figure out what is going on, and where it is likely to take us. AI has become a catch-all for a diversity of computer methods, mostly characterized by being slightly better at doing things we have long wanted computers to do, like interpreting text, speech, and images. But I would offer that it should include much more- all the things we have computers do to manage information. In that sense, we have been living among shards of artificial intelligence for a very long time. We have become utterly dependent on databases, for instance, for our memory functions. Imagine having to chase down a bank balance or a news story, without access to the searchable memories that modern databases provide. They are breathtakingly superior to our own intelligence when it comes to the amount of things they can remember, the accuracy they can remember them, and the speed with which they can find them. The same goes for calculations of all sorts, and more recently, complex scientific math like solving atomic structures, creating wonderful CGI graphics, or predicting the weather. 

We should view AI as a cabinet filled with many different tools, just as our own bodies and minds are filled with many kinds of intelligence. The integration of our minds into a single consciousness tends to blind us to the diversity of what happens under the hood. While we may want gross measurements like "general intelligence", we also know increasingly that it (whatever "it" is, and whatever it fails to encompass of our many facets and talents) is composed of many functions that several decades of work in AI, computer science, and neuroscience have shown are far more complicated and difficult to replicate than the early AI pioneers imagined, once they got hold of their Turing machine with its infinite potential. 

Originally, we tended to imagine artificial intelligence as a robot- humanoid, slightly odd looking, but just like us in form and abilities. That was a natural consequence of our archetypes and narcissism. But AI is nothing like that, because full-on humanoid consciousness is an impossibly high bar, at least for the foreseeable future, and requires innumerable capabilities and forms of intelligence to be developed first. 

The autonomous car drama is a good example of this. It has taken every ounce of ingenuity and high tech to get to a reasonably passable vehicle, which is able to "understand" key components of the world around it. That a blob in front is a person, instead of a motorcycle, or that a light is a traffic light instead of a reflection of the sun. Just as our brain has a stepwise hierarchy of visual processing, we have recapitulated that evolution here by harnessing cameras in these cars (and lasers, etc.) to not just take in a flat visual scene, which by itself is meaningless, but to parse it into understandable units like ... other cars, crosswalks, buildings, bicylists, etc.. Visual scenes are very rich, and figuring out what is in them is a huge accomplishment. 

But is it intelligence? Yes, it certainly is a fragment of intelligence, but it isn't consciousness. Imagine how effortless this process is for us, and how effortful and constricted it is for an autonomous vehicle. We understand everything in a scene within a much wider model of the world, where everything relates to everything else. We evaluate and understand innumerable levels of our environment, from its chemical makeup to its social and political implications. Traffic cones do not freak us out. The bare obstacle course of getting around, such as in a vehicle, is a minor aspect, really, of this consciousness, and of our intelligence. Autonomous cars are barely up to the level of cockroaches, on balance, in overall intelligence.

The AI of text and language handling is similarly primitive. Despite the vast improvements in text translation and interpretation, the underlying models these mechanisms draw on are limited. Translation can be done without understanding text at all, merely by matching patterns from pre-digested pools of pre-translated text, regurgitated as cued by the input text. Siri-like spoken responses, on the other hand, do require some parsing of meaning out of the input, to decide what the topic and the question are. But the scope of these tools tend to be very limited, and the wider scope they are allowed, the more embarrassing their performance, since they are essentially scraping web sites and text pools for question-response patterns, instead of truly understanding the user's request or any field of knowledge.

Lastly, there are the generative ChatGPT style engines, which also regurgitate text patterns reformatted from public sources in response to topical requests. The ability to re-write a Wikipedia entry through a Shakespeare filter is amazing, but it is really the search / input functions that are most impressive- being able, like the Siri system, to parse through the user's request for all its key points. This betokens some degree of understanding, in the sense that the world of the machine (i.e. its database) is parceled up into topics that can be separately gathered and reshuffled into a response. This requires a pretty broad and structured ontological / classification system, which is one important part of intelligence.

Not only is there a diversity of forms of intelligence to be considered, but there is a vast diversity of expertise and knowledge to be learned. There are millions of jobs and professions, each with their own forms of knowledge. Back the early days of AI, we thought that expert systems could be instructed by experts, formalizing their expertise. But that turned out to be not just impractical, but impossible, since much of that expertise, formed out of years of study and experience, is implicit and unconscious. That is why apprenticeship among humans is so powerful, offering a combination of learning by watching and learning by doing. Can AI do that? Only if it gains several more kinds of intelligence including an ability to learn in very un-computer-ish ways.

This analysis has emphasized the diverse nature of intelligences, and the uneven, evolutionary development they have undergone. How close are we to a social intelligence that could understand people's motivations and empathise with them? Not very close at all. How close are we to a scientific intelligence that could find holes in the scholarly literature and manage a research enterprise to fill them? Not very close at all. So it is very early days in terms of anything that could properly be called artificial intelligence, even while bits and pieces have been with us for a long time. We may be in for fifty to a hundred more years of hearing every advance in computer science being billed as artificial intelligence.

Uneven development is going to continue to be the pattern, as we seize upon topics that seem interesting or economically rewarding, and do whatever the current technological frontier allows. Memory and calculation were the first to fall, being easily formalizable. Communication network management is similarly positioned. Game learning was next, followed by the Siri / Watson systems for question answering. Then came a frontal assault on language understanding, using the neural network systems, which discard the former expert system's obsession with grammar and rules, for much simpler statistical learning from large pools of text. This is where we are, far from fully understanding language, but highly capable in restricted areas. And the need for better AI is acute. There are great frontiers to realize in medical diagnosis and in the modeling of biological systems, to only name two fields close at hand that could benefit from a thoroughly systematic and capable artificial intelligence.

The problem is that world modeling, which is what languages implicitly stand for, is very complicated. We do not even know how to do this properly in principle, let alone having the mechanisms and scale to implement it. What we have in terms of expert systems and databases do not have the kind of richness or accessibility needed for a fluid and wide-ranging consciousness. Will neural nets get us there? Or ontological systems / databases? Or some combination? However it is done, full world modeling with the ability to learn continuously into those models are key capabilities needed for significant artificial intelligence.

After world modeling come other forms of intelligence like social / emotional intelligence and agency / management intelligence with motivation. I have no doubt that we will get to full machine consciousness at some point. The mechanisms of biological brains are just not sufficiently mysterious to think that they can not be replicated or improved upon. But we are nowhere near that yet, despite bandying about the word artificial intelligence. When we get there, we will have to pay special attention to the forms of motivation we implant, to mitigate the dangers of making beings who are even more malevolent than those that already exist... us.

Would that constitute some kind of "singularity"? I doubt it. Among humans there are already plenty of smart people and diversity, which result in niches for everyone having something useful to do. Technology has been replacing human labor forever, and will continue moving up the chain of capability. And when machines exceed the level of human intelligence, in some general sense, they will get all the difficult jobs. But the job of president? That will still go to a dolt, I have no doubt. Selection for some jobs is by criteria that artificial intelligence, no matter how astute, is not going to fulfill.

Risks? In the current environment, there are a plenty of risks, which are typically cases where technology has outrun our will to regulate its social harm. Fake information, thanks to the chatbots and image makers, can now flood the zone. But this is hardly a new phenomenon, and perhaps we need to get back to a position where we do not believe everything we read, in the National Enquirer or on the internet. The quality of our sources may become once again an important consideration, as they always should have been.

Another current risk is that the automation risks chaos. For example in the financial markets, the new technologies seem to calm the markets most of the time, arbitraging with relentless precision. But when things go out of bounds, flash breakdowns can happen, very destructively. The SEC has sifted through some past events of this kind and set up regulatory guard rails. But they will probably be perpetually behind the curve. Militaries are itching to use robots instead of pilots and soldiers, and to automate killing from afar. But ultimately, control of the military comes down to social power, which comes down to people of not necessarily great intelligence. 

The biggest risk from these machines is that of security. If we have our financial markets run by machine, or our medical system run by super-knowledgeable artificial intelligences, or our military by some panopticon neural net, or even just our electrical grid run by super-computers, the problem is not that they will turn against us of their own volition, but that some hacker somewhere will turn them against us. Countless hospitals have already faced ransomware attacks. This is a real problem, growing as machines become more capable and indispensable. If and when we make artificial people, we will need the same kind of surveillance and social control mechanisms over them that we do over everyone else, but with the added option of changing their programming. Again, powerful intelligences made for military purposes to kill our enemies are, by the reflexive property of all technology, prime targets for being turned against us. So just as we have locked up our nuclear weapons and managed to not have them fall into enemy hands (so far), similar safeguards would need to be put on similar powers arising from these newer technologies.

We may have been misled by the many AI and super-beings of science fiction, Nietzsche's Übermensch, and similar archetypes. The point of Nietzsche's construction is moral, not intellectual or physical- a person who has thrown off all the moral boundaries of civilization, expecially Christian civilization. But that is a phantasm. The point of most societies is to allow the weak to band together to control the strong and malevolent. A society where the strong band together to enslave the weak.. well, that is surely a nightmare, and more unrealistic the more concentrated the power. We must simply hope that, given the ample time we have before truly comprehensive and superior artificial intelligent beings exist, we have exercised sufficient care in their construction, and in the health of our political institutions, to control them as we have many other potentially malevolent agents.

• AI in chemistry.
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• The racism runs very deep.
• An appreciation of Stephen J. Gould.
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Are Archaea Archaic?

It remains controversial whether the archaeal domain of life is 1 or 4.5 billion years old. That is a big difference!

Back in the 1970's, the nascent technologies of molecular analysis and DNA sequencing produced a big surprise- that hidden in the bogs and hot springs of the world are micro-organisms so extremely different from known bacteria and protists that they were given their own domain on the tree of life. These are now called the archaea, and in addition to being deeply different from bacteria, they were eventually found to be the progenitors of eukaryotic cell- the third (and greatest!) domain of life that arose later in the history of the biosphere. The archaeal cell contributed most of the nuclear, informational, membrane management, and cytoskeletal functions, while one or more assimilated bacteria (most prominently the future mitochondrion and chloroplast) contributed most of the metabolic functions, as well as membrane lipid synthesis and peroxisomal functions.

Carl Woese, who discovered and named archaea, put his thumb heavily on the scale with that name, (originally archaebacteria), suggesting that these new cells were not just an independent domain of life, totally distinct from bacteria, but were perhaps the original cell- that is, the LUCA, or last universal common ancestor. All this was based on the sequences of rRNA genes, which form the structural and catalytic core of the ribosome, and are conserved in all known life. But it has since become apparent that sequences of this kind, which were originally touted as "molecular clocks", or even "chronometers" are nothing of the kind. They bear the traces of mutations that happen along the way, and, being highly important and conserved, do not track the raw mutation rate, (which itself is not so uniform either), but rather the rate at which change is tolerated by natural selection. And this rate can be wildly different at different times, as lineages go through crises, bottlenecks, adaptive radiations, and whatever else happened in the far, far distant past.

Carl Woese, looking over filmed spots of 32P labeled ribosomal RNA from different species, after size separation by electrophoresis. This is how RNAs were analyzed, back in 1976, and such rough analysis already suggested that archaea were something very different from bacteria.

There since has been a tremendous amount of speculation, re-analysis, gathering of more data, and vitriol in the overall debate about the deep divergences in evolution, such as where eukaryotes come from, and where the archaea fit into the overall scheme. Compared with the rest of molecular biology, where experiments routinely address questions productively and efficiently due to a rich tool chest and immediate access to the subject at hand, deep phylogeny is far more speculative and prone to subjective interpretation, sketchy data, personal hobbyhorses, and abusive writing. A recent symposium in honor of one of its more argumentative practitioners made that clear, as his ideas were being discarded virtually at the graveside.

Over the last decade, estimates of the branching date of archaea from the rest of the tree of life have varied from 0.8 to 4.5 Gya (billion years ago). That is a tremendous range, and is a sign of the difficulty of this field. The frustrations of doing molecular phylogeny are legion, just as the temptations are alluring. Firstly, there are very few landmarks in the fossil record to pin all this down. There are stromatolites from roughly 3.5 Gya, which pin down the first documented life of any kind. Second are eukaryotic fossils, which start, at the earliest, about 1.5 Gya. Other microbial fossils pin down occasional sub-groups of bacteria, but archaea are not represented in the fossil record at all, being hardly distinguishable from bacteria in their remains. Then we get the Cambrian explosion of multicellular life, roughly 0.5 Gya. That is pretty much it for the fossil record, aside from the age of the moon, which is about 4.5 Gya and gives us the baseline of when the earth became geologically capable of supporting life of any kind.

The molecules of living organisms, however, form a digital record of history. Following evolutionary theory, each organism descends from others, and carries, in mutated and altered form, traces of that history. We have parts of our genomes that vary with each generation, (useful for forensics and personal identification), we have other parts that show how we changed and evolved from other apes, and we have yet other areas that vary hardly at all- that carry recognizable sequences shared with all other forms of life, and presumably with LUCA. This is a real treasure trove, if only we can make sense of it.

But therein lies the rub. As mentioned above, these deeply conserved sequences are hardly chronometers. So for all the data collection and computer wizardry, the data itself tells a mangled story. Rapid evolution in one lineage can make it look much older than it really is, confounding the whole tree. Over the years, practitioners have learned to be as judicious as possible in selecting target sequences, while getting as many as possible into the mix. For example, adding up the sequences of 50-odd ribosomal proteins can give more and better data than assembling the 2 long-ish ribosomal RNAs. They provide more and more diverse data. But they have their problems as well, since some are much less conserved than others, and some were lost or gained along the way. 

A partisan of the later birth of archaea provides a phylogenetic tree with countless microbial species, and one bold claim: "inflated" distances to the archaeal and eukaryotic stems. This is given as the reason that archaea (lower part of the diagram, including eukaryotes, termed "archaebacteria"), looks very ancient, but really just sped away from its originating bacterial parent, (the red bacteria), estimated at about 1 Gya. This tree is based on an aligned concatentation of 26 universally conserved ribosomal protein sequences, (51 from eukaryotes), with custom adjustments.

So there has been a camp that claims that the huge apparent / molecular distance between the archaea and other cells is just such a chimera of fast evolution. Just as the revolution that led to the eukaryotic cell involved alot of molecular change including the co-habitation of countless proteins that had never seen each other before, duplications / specializations, and many novel inventions, whatever process led to the archaeal cell (from a pre-existing bacterial cell) might also have caused the key molecules we use to look into this deep time to mutate much more rapidly than is true elsewhere in the vast tree of life. What are the reasons? There is the general disbelief / unwillingness to accept someone else's work, and evidence like possible horizontal transfers of genes from chloroplasts to basal archaea, some large sequence deletion features that can be tracked through these lineages and interpreted to support late origination, some papering over of substantial differences in membrane and metabolic systems, and there are plausible (via some tortured logic) candidates for an originating, and late-evolving, bacterial parent. 

This thread of argument puts the origin of eukaryotes roughly at 0.8 Gya, which is, frankly, uncomfortably close to the origination of multicellular life, and gives precious little time for the bulk of eukaryotic diversity to develop, which exists largely, as shown above, at the microbial level. (Note that "Animalia" in the tree above is a tiny red blip among the eukaryotes.) All this is quite implausible, even to a casual reader, and makes this project hard to take seriously, despite its insistent and voluminous documentation.

Parenthetically, there was a fascinating paper that used the evolution of the genetic code itself to make a related point, though without absolute time attributions. The code bears hallmarks of some amino acids being added relatively late (tryptophan, histidine), while others were foundational from the start (glycine, alanine), when it may have consisted of two RNA bases (or even one) rather than three. All of this took place long before LUCA, naturally. This broad analysis of genetic code usage argued that bacteria tend to use a more ancient subset of the code, which may reflect their significantly more ancient position on the tree of life. While the full code was certainly in place by the time of LUCA, there may still at this time have been, in the inherited genome / pool of proteins, a bias against the relatively novel amino acids. This finding implies that the time of archaeal origination was later than the origination of bacteria, by some unspecified but significant amount.

So, attractive as it would be to demote the archaea from their perch as super-ancient organisms, given their small sizes, small genomes, specialization in extreme environments, and peripheral ecological position relative to bacteria, that turns out to be difficult to do. I will turn, then, to a very recent paper that gives what I think is much more reasoned and plausible picture of the deeper levels of the tree of life, and the best general picture to date. This paper is based on the protein sequences of the rotary ATPases that are universal, and were present in LUCA, despite their significant complexity. Indeed, the more we learn about LUCA, the more complete and complex this ancestor turns out to be. Our mitochondrion uses a (bacterial) F-type ATPase to synthesize ATP from the food-derived proton gradient. Our lysosomes use a (archaeal) V-type ATPase to drive protons into / acidify the lysosome in exchange for ATP. These are related, derived from one distant ancestor, and apparently each was likely to have been present in LUCA. Additionally, each ATPase is composed of two types of subunits, one catalytic, and one non-catalytic, which originated from an ancient protein duplication, also prior to LUCA. The availability of these molecular cousins / duplications provides helpful points of comparison throughout, particularly for locating the root of the evolutionary tree.

Phylogenetic trees based on ATP synthase enzymes that are present in all forms of life. On left is shown the general tree, with branch points of key events / lineages. On right are shown sub-trees for the major types of the ATP synthase, whether catalytic subunit (c), non-catalytic (n), F-type, common in bacteria, or V type, common in archaea. Note how congruent these trees are. At bottom right in the tiny print is a guide to absolute time, and the various last common ancestors.

This paper also works quite hard to pin the molecular data to the fossil and absolute time record, which is not always provided The bottom line is that archaea by this tree arise quite early, (see above), co-incident with or within about 0.5 Gy of LUCA, which was bacterial, at roughly 4.4 Gya. The bacterial and archaeal last common ancestors are dated to 4.3 and 3.7 Gya, respectively. The (fused) eukaryotic last common ancestor dates to about 1.9 Gya, with the proto-mitochondrion's individual last common ancestor among the bacteria some time before that, at roughly 2.4 Gya. 

This time line makes sense on many fronts. First, it provides a realistic time frame for the formation and diversification of eukaryotes. It puts their origin right around the great oxidation event, which is when oxygen became dominant in earth's atmosphere, (about 2 to 2.4 Gya), which was a precondition for the usefulness of mitochondria to what are otherwise anaerobic archaeal cells. It places the origin of archaea (LACA) a substantial stretch after the origin of bacteria, which agrees with the critic's points above that bacteria are the truly basal lineage of all life, and archaea, while highly different and pretty archaic, also share a lot of characteristics with bacteria, and perhaps more so with certain early lineages than with others that came later. The distinction between LUCA and the last common bacterial ancestor (LBCA) is a technical one given the trees they were working from, and are not, given the ranges of age presented, (see figure above), significantly different.

I believe this field is settling down, and though this paper, working from only a subset of the most ancient sequences plus fossil set-points, is hardly the last word, it appears to represent a consensus view and is the best picture to date of the deepest and most significant waypoints in the deep history of life. This is what comes from looking through microscopes, and finding entire invisible worlds that we had no idea existed. Genetic sequencing is another level over that of microscopy, looking right at life's code, and at its history, if darkly. What we see in the macroscopic world around us is only the latest act in a drama of tremendous scale and antiquity.

• Platitude.
• There are a lot of single-celled eukaryotes.
• Hitting bottom.

Truth and the Silo

Living in a silo, and wondering what is outside.

The first season of Apple's Silo series was beautifully produced and thought-provoking. Working from a book series of the same name which I have not read, it is set in a devastated world where about 10,000 people live in a huge underground silo. As the show progresses, it is clear that the society got a little totalitarian along the way. We are introduced to a "pact", which is the rules set up ~150 years ago, when a revolution of some undescribed sort happened. Now there is a "judicial" department that sends out goons to keep everyone in line, and there are the rules of the pact, which seem to outlaw fun and inquiry into anything from the past or the outside. It also outlaws elevators.

On the other hand, the population has a window to the outside, which shows an extremely drab world. A hellscape, really. But due to the murky nature of political power and information control within the silo, it is hard to know how real that view is. I won't give away any spoilers because I am interested in exploring the metaphors and themes the show brings up. For we are all working in, living in, and raised in, silos of some sort. Every family is a world more or less closed, with its own mood and rules, generally (hopefully) unwritten. The Silo portrays this involution in an incredibly vivid way.

(Third) Sheriff Nichols meets with the (second) mayor in a lovingly retro-decorated set.

It is fundamentally a drama about truth. One could say that most drama is about seeking truths, whether in a literal form like detective and legal dramas, or in more personal forms like romance, coming of age, and quest-for-power dramas. The point is to find out something, like how attractive the characters are, who will betray whom, who has lined up the better alliances, what a person's character is really like. Why read a story unless you learn something new? Here, the truths being sought are in bold face and out front. What is outside? Who really runs this place? What built this place? Why are we here? Why is everyone wearing hand-knit woolens? And the lead character, Juliet Nichols, is the inveterate truth-seeker. A mechanic by inclination and training, she really, really, wants to know how things work, is proud of mastering some of that knowledge, and is dedicated to dealing with reality and making it work. This quest leads her into rebellion against a system that is typical for our time ... at least in China, North Korea, and Russia. A surveillance and control state that watches everyone, pumps out propaganda, outlaws contrary thought, symbols, and objects, imprisons those who disagree, and ultimately sends inveterate truth seekers outside ... to die.

The nature of truth is of course a deep philosophical question. A major problem is that we can never get there. But even worse, we don't necessarily want to get there either. We automatically form a narrative world around ourselves that generally suffices for day-to-day use. This world is borne largely of habit, authority, instinct, and archetypes. All sorts of sources other than a systematic search for truth. For example, the easiest truth in the world is that we and our group are good, and the other group is bad. This is totally instinctive, and quite obvious to everyone. Religions are full of such truths, narratives, and feelings, developed in the least rigorous way imaginable, ending up with systems fired in the crucible of personal intution, and the imperatives of group dynamics and power. But truth? 

Lighting tends to be a little dark in the Silo, as are the politics.

The Orwellian society is curious, in a way. How can people's natural thirst for truth be so dangerous, so anti-social, and so brutally suppressed? Due to the processes mentioned above, each person's truth is somewhat distinct and personal, each person's quest goes in a different direction. But a society needs some coherence in its narrative, and some people (say, our immediate former president) have an intense yearning for power and need to dominate others, thus to bend them to their own version of truth. Reality distortion fields do not occur only in the tech industry, but are intrinsic to social interaction. The Silo, with its literally closed society, is a natural hothouse for a social fight for dominance and control of reality. Oh, and it has a eugenic program going on as well, though that is not a big focus in the first season.

One can almost sympathise with the fascists of the world, who see truth as functional, not philosophical. Whatever glorifies the state and its leader, whatever keeps the society unchanging and sheltered from uncomfortable truths and surprises. Who needs those pesky and divergent people, who just want to make trouble? And the more baroque and unhinged the official narrative has become, the more dangerous and easy the work of the social sabateur becomes. If the emperor has no clothes, it only takes a child to ask one question. In the Silo, there are various underground actors and uneasy officials who are losing faith in the official line, but where can they go? Is their doubt and desire for the facts more important than the continuation of this very tenuous and smothered society? Could a free-er society work? But why risk it?

In our contemporary world, the right wing is busy making up a parallel universe of obvious and button-pushing untruths. The left, on the other hand, is pursuing a rather righteous investigation into all the mainstream truths we grew up with, and finding them lies. Is the US founded on genocide, slavery, and imperialism? Or on democracy and opportunity? Is capitalism salveagable in light of its dreadful record of environmental, animal, and human abuses? It is not a comfortable time, as the truths of our society are shifting underfoot. But is the left unearthing the true truth, or just making up a new and self-serving narrative that will in time be succeeded by others with other emphasis and other interests? 

History is a funny kind of discipline, which can not simply find something true and enshrine it forever, like the laws of gravity. There is some of that in its facts, but history needs to be continually re-written, since it is more about us than about them- more about how our society thinks about itself and what stories it selects from the past, than it is about "what happened". There are an infinite number of things that happened, as well as opinions about them. What makes it into books and documentaries is a matter of selection, and it is always the present that selects. It is a massive front in the formation / evolution of culture- i.e. the culture war. Are we a culture that allows free inquiry and diverse viewpoints on our history, and welcomes observations that undercut comfortable narratives? Or are we a more Orwellian culture that enforces one narrative and erases whatever of its history conflicts with it?

The top level dining room has a viewport to the outside.

The Silo is definitely a culture of the latter type, and its history is brutally truncated. Yet interestingly, character after character nurtures some object that violates the pact, representing a bond with the forbidden, hazy past - the forebears and former world that must necessarily have existed, even as nothing is officially known about them. The urge to know more, especially about our origins, is deeply human, as is the urge to keep one's society on an even keel with a unified and self-satisfied narrative. This tension is built up unceasingly in the Silo, which is as far as we know a unique and precious remnant of humanity. It asks the question whether its stability is worth so much oppression and ignorance.

Parenthetically, one might ask how all this connects to the dystopia outside. The Silo is only painting in extreme colors trends that are happening right now in our world. As the climate gets weirder, we spend more time inside, increasingly isolated from others, entertaining ourselves with streaming offerings like the Silo. Its apocalypse appears more nuclear than climatological, but for us, right now, a dystopia is unfolding. After decades of denial and greed, the truth of climate heating is no longer at issue. So what if the truth is known- has gotten out of the bag- but no one wants to act on it? Another form of courage is needed, not any more to uncover the truth, but to meet that truth with action- action that may require significant sacrifice and a fundamental re-design of our Silo-like system of capitalism.

• Leave your silo, please.
• How many lies can one person believe?
• How one Confederate resolved to move on in Reconstruction.
• Want to turn off your brain for a little while? How about some stutter house?

Missing Links in Eukaryotic Evolution

The things you find in Slovenian mud! Like an archaeal cell that is the closest thing to the eukaryotic root organism.

Creationists and "intelligent" design advocates tirelessly point to the fossil record. Not how orderly it is and revealing of the astonishingly sequenced, slow, and relentless elaboration of life. No, they decry its gaps- places where fossils do not account for major evolutionary (er, designed) transitions to more modern forms. It is a sad kind of argument, lacking in imagination and dishonest in its unfairness and hypocrisy. Does the life of Jesus have gaps in the historical record? Sure enough! And are those historical records anywhere near as concrete and informative as fossils? No way. What we have as a record of Christianity's history is riven with fantasy, forgery, and uncertainty.

But enough trash talk. One thing that science has going for it is a relentlessly accumulating process by which new fossils appear, and new data from other sources, like newly found organisms and newly sequenced genomes, arise to clarify what were only imaginative (if reasonable) hypotheses previously. Darwin's theory of evolution, convincing and elegantly argued as it was originally, has gained such evidence without fail over the subsequent century and a half, from discoveries of the age of the earth (and thus the solar system) to the mechanics of genetic inheritance.

A recent paper describes the occurence of cytoskeletal proteins and structures in an organism that is neither a bacterium nor a eukaryote, but appears to be within the family of Archaea that is the closest thing we have to the eukaryotic progenitor. These are the Asgard Archaea, a family that was discovered only in the last decade, as massive environmental sequencing projects have sampled the vast genetic diversity hidden in the muds, sediments, soils, rocks, and waters of the world. 

Sampling stray DNA is one thing, but studying these organisms in depth requires growing them in the lab. After trolling through the same muds in Slovenia where promising DNA sequences were fond, this group fished out, and then carefully cultured, a novel archaeal cell. But growing these cells is notoriously difficult. They are anaerobic, never having made the transition to the oxygenated atmosphere of the later earth. They have finicky nutritional requirements. They grow very slowly. And they generally have to live with other organisms (bacteria) with which they have reciprocal metabolic relationships. In the ur-eukaryote, this was a relationship with the proto-mitochondrion, which was later internalized. For the species cultured by this research group, it is a pair of other free-living bacteria. One is related to sulfur-reducing Desulfovibrio, and the other one is related to a simpler archaeal Methanogenium that uses hydrogen and CO2 or related simple carbon compounds to make methane. Anaerobic Asgard archaea generally have relatively simple metabolisms and make hydrogen from small organic compounds, through a kind of fermentation.

A phylogenetic tree showing relations between the newly found organisms (bottom) and eukaryotes (orange), other archaea, and the entirely separate domain of bacteria (red). This is based on a set of sequences of universally used / conserved ribosomal proteins. While the eukaryotes have strayed far from the root, that root is extremely close to some archaeal groups.

Micrographs of cultured lokiarchaeal cells, with a scale bar of 500 nanometers. These are rather amoeboid cells with extensive cytoskeletal and membrane regulation.

Another micrograph of part of a lokiarchaeal cell, showing not just its whacky shape, but a good bit of internal structure as well. The main scale bar is 100 nanometers. There are internal actin filaments (yellow arrowheads), lined up ribosomes (gray arrowhead) and cell surface proteins of some kind (blue arrowheads).

What they found after all this was pretty astonishing. They found cells that are quite unlike typical bacterial or even archaeal cells, which are compact round or rod shapes. These (termed lokiarchaeal) cells have luxurious processes extending all over the place, and a profusion of internal structural elements reminiscent of eukaryotic cells, though without membrane-bound internal organelles. But they have membrane-bound protrusions and what look like vesicles budding off. At only six million base pairs (compared to our three billion) and under five thousand genes, these cells have a small and streamlined genome. Yet there are a large number (i.e. 258) of eukaryotic-related (signature) proteins (outlined below), particularly concerning cytoskeletal and membrane trafficking. The researchers delved into the subcellular structures, labeling actin and obtaining structural data for both actin and ribosomes, confirming their archaeal affinity with added features. 

A schematic of eukaryotic-like proteins in the newly cultured lokiarchaeal Asgard genome. Comparison (blue) is to a closely related organism isolated recently in Japan.

This work is the first time that the cytoskeleton of Asgard cells has been visualized, along with its role in their amoeboid capabilities. What is it used for? That remains unknown. The lush protrusions may collaborate with this organism's metabolic partners, or be used for sensing and locomoting to find new food within its sediment habitat, or for interacting with fellow lokiarchaeal cells, as shown above. Or all of these roles. Evolutionarily, this organism, while modern, appears to be a descendent of the closest thing we have to the missing link at the origin of eukaryotes, (that is, the archaeal dominant partner of the founding symbiosis), and in that sense seems both ancient in its characteristics, and possibly little changed from that time. Who would have expected such a thing? Well, molecular biologists and evolutionary biologists have been expecting it for a long time.

• Fossil fuel consumption is still going up, not down.

Credit where Faith is Due

The enormous, and sometimes underrated, value of faith and credit in the US financial instruments and institutions.

To hear the chaos caucus in congress put it, the country can go to hell, because their pet peeves- abortion, culture war, gay rights, gun rights ... have already gone to hell, so how much worse can it really get? Well, it could get a lot worse. We are a rich country for many reasons, but an important one is good management at the federal level of our financial and monetary affairs. It is this stability that undergirds not only the currency, but also economic expectations of the future, as expressed in inflation, and markets such as the commodities, bond, and stock markets, not to mention political stability, such as it is.

Every dollar is a credit instrument, staked on the faith and credit of the United States. Without that faith, it is worthless. Even with that faith, it is a debt of the government, counted under the vast rubric of "the federal debt". The more money we have (or that is out in the wild somewhere), the more that debt is. And that money has proliferated remarkably. Quite a few small countries have formally dollarized their economies, such as Ecuador, Zimbabwe, Palau, and Panama. Many more countries use dollars as a defacto currency or black market currency, including much of the criminal world. Most countries hold large reserves of dollars to anchor their international trade and financial stability. So we should not be surprised that our federal debt is very large. Does anyone (maybe our children!?) have to "pay it back"? Not really, since all those dollars can keep floating around forever. That is, until some other country's currency becomes the reserve currency of the world, and those dollars become either worth less, or we buy them back with that new currency. Forestalling that day should be one of our major foreign policy and economic goals.

Another dimension of the credit of the US is the formal debt, in bonds that the Treasury department issues to account for spending that was not matched by incoming taxes. The Federal Reserve accumulates Treasury bonds as it issues new dollars, but these bonds come with the obligation to keep paying interest. While this makes it convenient and profitable for other countries and rich people to hold bonds instead of dollar bills, (and earns the Fed itself plenty of notional money), it puts us on the hook for endless payments (of newly minted dollars) to support those interest payments. This is a rather dangerous situation, since the level of interest is not always under tight control. Depending on your view of financial affairs, the interest rate is dictated by the market, or by the Fed, or by the general level of inflation, which in turn influences the actions of both the market and the Fed. In any case, the interest on thirty trillion dollars is a heck of a lot more at higher rates than at low ones. This strongly motivates the Fed to use all its tools to curtail inflation and keep long term interest rates under control.

A graph of the price/earnings ratio of the SP500 collection of stocks, over the long term. This ratio indicates the length of time holders of stock are willing to wait for their returns to come in, in years. Notice how in the last few decades, the P/E ratio has persisted at significantly higher-than-historical levels, indicating, despite ups and downs, increased faith in the long-term stability of the economic and financial system. There may be other reasons- better regulation, technological innovation, 401K rules, lowered taxes, etc. But financial markets like the stock market are sensitive indicators of the credit given to our institutions.

All this comes back to the sound management of our financial affairs. We have a lot of room to maneuver due to economic expansion, both at home and abroad, which makes ongoing federal debts a built-in necessity. But we do not have endless room, and taxation plays an important role in making up the difference between money we can freely spend/issue to satisfy growth without inflation, and the rest of the money needed for government operations. What that gap is, is difficult to say, in the same way that the causes and time course of inflation are hard to pin down, but there is a gap, which taxes cover. Incidentally, in the MMT view of things, taxes reduce the level of private spending and consumption to make room for government spending, vs actually "funding" the government, which issues the money in the first place. But either way, taxes are an essential part of the financial cycle, and haphazardly forgiving tax obligations (or hobbling enforcement) is just as bad management as profligate spending or lax control of interest rates and inflation.

All these factors are part of the credit of the United States, and have been under fire from the right wing for several decades. When they are not cutting taxes of the rich or spending mindlessly on the military, they are shutting the government down or muttering about the deep state, the evils of the civil service, and how we should get back on the gold standard. Meanwhile the whole stability of our position as a rich economy and leader among nations hangs in the balance when thoughtless policy and extreme politics encroach from the fringes. Can the US run things better? Absolutely. Are there tradeoffs between humane and cultural virtues and financial / economic success? Absolutely. But from our founding era, when the Treasury Department under Alexander Hamilton established the US debt as a powerful instrument of union and stability, the credit of the US has been an underappreciated pillar of our position both domestically and internationally. Toying with it, via artificial crises and bad policy, is correspondingly an under-appreciated danger to our way of life.

• Business needs more regulation.
• Misogyny has a new hero.
• Hospitals are becoming scarcer and poorer. In part due to medicare "advantage".
• My congressperson is on the job.
• The state of solar.

Melting Proteins Through a Wall

Peroxisomes use a trendy way to import their proteins.

As has been discussed many times in this space, membranes are formidable barriers ... at the molecular level. Having a plasma membrane, and organelles enclosed within membranes, means needing to get all sorts of things across them, from the tiniest proton to truly enormous mega-complexes like ribosomes. Almost eight percent of the proteins encoded by the human genome are transporters, that concern themselves with getting molecules from one place to another, typically across membranes. A critical type of molecule to get into organelles is the proteins that belong there, to do their day-in, day-out jobs. 

But proteins are large molecules. There are two ways to go about transporting them across membranes. One is to thread them across linearly, unfolding them in process, and letting them refold once they are across. This is how proteins get into the endoplasmic reticulum, where the long road to secretion generally starts. Ribosomes dock right up to the endoplasmic reticulum membrane and pump their nascent proteins across as they are being synthesized. Easy peasy.

However other organelles don't get this direct (i.e. cotranslational) method of protein import. They have to get already-made full-length proteins lugged across their membranes somehow. Mitochondria, for instance, are replete with hard-working proteins, virtually all of which are encoded in the nucleus and have to be brought in whole, usually through two separate membranes to get into the mitochondrial matrix. There are dedicated transporters, nicknamed the TOM/TIM complexes, that thread incoming proteins (which are detected by short "signal" sequences these proteins carry) through each membrane in turn, and sometimes use additional helpers to get the proteins plugged into the matrix membrane or other final destination. Still, this remains a protein threading process, (of the first transport type), and due to its need to unfold and the later refold every incoming protein, it involves chaperones which specialize in helping those proteins fold correctly afterwards.

Schematic of the nuclear pore. The wavy bits are protein tails that are F-G rich (phenylalanine-glycine) that are unstructured and form a gel throughout the pore, allowing like-minded F-G proteins through, which are the nuclear transport receptors. These receptors carry various cargo proteins in an out of the nucleus, without having to unfold them. "Nup" is short for nuclear pore protein; GLFG is short for glycine, leucine (another hydrophobic amino acid), phenylalanine, glycine.

But there is another way to do it, which was discovered much more recently and is used principally by the nucleus. The nuclear pore had fascinated biologists for decades, but it was only in the early 2000's that this mechanism was revealed. And a recent paper found that peroxisomes also use this second method, which side-steps the need to thread incoming proteins through a pore, and risk all the problems of refolding. This method is to use a curiously constructed gel phase of (protein) matter that shares some properties with membranes, but has the additional property that specifically compatible proteins can melt right through it. 

The secret lies in repetitive regions of protein sequence that carry, in the case of the nuclear pore, lots of F-G sequences. That is, phenylalanine-glycine repeated regions of proteins that form these transit gel structures, or pores. The phenylalanine is hydrophobic, the glycine is flexible, and the protein backbone is polar, though not charged. This adds up to a region that is a totally disordered mess and forms a gel that can keep out most larger molecules, like a membrane. But if encountered by another F-G-rich protein, this gel lets it right through, like a pat of butter through oil. It also tends to let small molecules through quite easily. The nuclear pore is quite permeable to the many chemicals needed for DNA replication, RNA production, etc.

Summary from current paper, making the case that peroxisomes use PEX13 to make something similiar to the nuclear pore, where targeted proteins can traverse easily piggybacked on carrier proteins, in this case PEX5. The yellow spaghetti is the F-G or Y-G protein tails that congregate in the pore to make up a novel (gel) phase of matter. This gel is uniquely permeable to proteins carrying the same F-G or Y-G on their outsides, as does PEX5. "NTR" is short for nuclear targeting receptor, to which nuclear-bound cargoes bind.

Peroxisomes are sites for specialty chemistry, handling some relatively dangerous oxidation reactions including production of some lipids. They combines this with protective enzymes like catalase that quickly degrade the resulting reactive oxidative products. This suggests that the peroxisomal membrane would need to be pretty tight, but the authors state that the gel-style mechanism used here allows anything under 2,000 Daltons through, which certainly includes most chemicals. Probably the solution is that enough protective enzymes, at a high local concentration, are present that the leakage rate of bad chemicals is relatively low. 

Experimenters purify large amounts of the Y-G protein segments from PEX13 and form macroscopic gels out of them. In the center is a control, where the Y residues have been mutated to serine (S). N+YG refers to the N-terminus of the PES13 protein plus the Y-G portion of the proteins, while Y-G alone has only the Y-G segment of the PEX13 protein.

For its gel-containing pore, the peroxisome uses (on a protein called PEX13) tyrosine (Y) in place of phenylalanine, resulting in a disordered gel of Y-G repeats for its structure. Tyrosine is aromatic, (thus hydrophobic) like phenylalanine and tryptophan, and apparently provides enough distinctiveness that nucleus-bound proteins are not mistaken in their destination. The authors state that it provides a slightly denser packing, and by its composition should help prevent nuclear carriers from binding effectively. But it isn't just the Y-G composition that directs proteins, but a suite of other proteins around the peroxisomal and nuclear pores that, I would speculate, help attract their respective carrier proteins (called PEX5 in the case of peroxisomes) so that they know where to go. 

Evolutionary conservation of the Y-G regions of PEX13, over a wide range of species. The semi-regular periodicity of the Y placements suggests that this protein forms alpha helixes with the Y chains exposed on one side, more or less, despite general lack of structure. 

The authors show some very nice experiments, such as making visible gels from purified / large amounts of these proteins, and then showing that these gels indeed block generic proteins, and allow the same protein if fused to PEX5 to come right through. The result shown below is strikingly absolute- without its peroxisome-specific helper, the protein GFP makes no headway into this gel material at all. But with that helper, it can diffuse 100 microns in half an hour. It is like making jello that you can magically pass your hand through, without breaking it up ... but only if you are wearing the magic glove.

Experimental demonstration of transport. Using macroscopic gel plugs like those shown above, the diffusion of green fluorescent protein (GFP) was assayed from a liquid (buffer) into the gel. By itself (center, bottom), GFP makes no headway at all. But when fused to the PEX5 protein, either in part or in whole, it diffuses quite rapidly into the Y-G gel.

• Some history on immigration, leading to our curious current positions.
• What is China's GDP, anyhow?
• Whence the Francophone world?
• Humanism.
• Humanism.
• Wind energy faces some headwinds.