Proving Evolution the Hard Way

Using genomes and codon ratios to estimate selective pressures was so easy... why is it not working?

The fruits of evolution surround us with abundance, from the tallest tree to the tiniest bacterium, and the viruses of that bacterium. But the process behind it is not immediately evident. It was relatively late in the enlightenment before Darwin came up with the stroke of insight that explained it all. Yet that mechanism of natural selection remains an abstract concept requiring an analytical mind and due respect for very inhuman scales of the time and space in play. Many people remain dumbfounded, and in denial, while evolutionary biology has forged ahead, powered by new discoveries in geology and molecular biology.

A recent paper (with review) offered a fascinating perspective, both critical and productive, on the study of evolutionary biology. It deals with the opsin protein that hosts the visual pigment 11-cis-retinal, by which we see. The retinal molecule is the same across all opsins, but different opsin proteins can "tune" the light wavelength of greatest sensitivity, creating the various retinal-opsin combinations for all visual needs, across the cone cells and rod cells. This paper considered the rhodopsin version of opsin, which we use in rod cells to perceive dim light. They observed that in fish species, the sensitivity of rhodopsin has been repeatedly adjusted to accommodate light at different depths of the water column. At shallow levels, sunlight is similar to what we see, and rhodopsin is tuned to about 500 nm, while deeper down, when the light is more blue-ish, rhodopsin is tuned towards about 480 nm maximum sensitivity. There are also special super-deep fish who see by their own red-tinged bioluminescence, and their rhodopsins are tuned to 526 nm. 

This "spectrum" of sensitivities of rhodopsin has a variety of useful scientific properties. First, the evolutionary logic is clear enough, matching the fish's vision to its environment. Second, the molecular structure of these opsins is well-understood, the genes are sequenced, and the history can be reconstructed. Third, the opsin properties can be objectively measured, unlike many sequence variations which affect more qualitative, difficult-to-observe, or impossible-to-observe biological properties. The authors used all this to carefully reconstruct exactly which amino acids in these rhodopsins were the important ones that changed between major fish lineages, going back about 500 million years.

The authors' phylogenetic tree of fish and other species they analyzed rhodopsin molecules from. Note how mammals occupy the bottom small branch, indicating how deeply the rest of the tree reaches. The numbers in the nodes indicate the wavelength sensitivity of each (current or imputed) rhodopsin. Many branches carry the author's inference, from a reconstructed and measured protein molecule, of what precise changes happened, via positive selection, to get that lineage.

An alternative approach to evolutionary inference is a second target of these authors. That is a codon-based method, that evaluates the rate of change of DNA sites under selection versus sites not under selection. In protein coding genes (such as rhodopsin), every amino acid is encoded by a triplet of DNA nucleotides, per the genetic code. With 64 codons for ~20 amino acids, it is a redundant code where many DNA changes do not change the protein sequence. These changes are called "synonymous". If one studies the rate of change of synonymous sites in the DNA, (which form sort of a control in the experiment), compared with the rate of change of non-synonymous sites, one can get a sense of evolution at work. Changing the protein sequence is something that is "seen" by natural selection, and especially at important positions in the protein, some of which are "conserved" over billions of years. Such sites are subject to "negative" selection, which to say rapid elimination due to the deleterious effect of that DNA and protein change.

Mutations in protein coding sequence can be synonymous, (bottom), with no effect, or non-synonymous (middle two cases), changing the resulting protein sequence and having some effect that may be biologically significant, thus visible to natural selection.

This analysis has been developed into a high art, also being harnessed to reveal "positive" selection. In this scenario, if the rate of change of the non-synonymous DNA sites is higher than that of the synonymous sites, or even just higher than one would expect by random chance, one can conclude that these non-synonymous sites were not just not being selected against, but were being selected for, an instance of evolution establishing change for the sake of improvement, instead of avoiding change, as usual.

Now back to the rhodopsin study. These authors found that a very small number of amino acids in this protein, only 15, were the ones that influenced changes to the spectral sensitivity of these protein complexes over evolutionary time. Typically only two or three changes occurred over a shift in sensitivity in a particular lineage, and would have been the ones subject to natural selection, with all the other changes seen in the sequence being unrelated, either neutral or selected for other purposes. It is a tour de force of structural analysis, biochemical measurement, and historical reconstruction to come up with this fully explanatory model of the history of piscene rhodopsins. 

But then they went on to compare what they found with what the codon-based methods had said about the matter. And they found that there was no overlap whatsover. The amino acids identified by the "positive selection" codon based methods were completely different than the ones they had found by spectral analysis and phylogenetic reconstruction over the history of fish rhodopsins. The accompanying review is particularly harsh about the pseudoscientific nature of this codon analysis, rubbishing the entire field. There have been other, less drastic, critiques as well.

But there is method to all this madness. The codon based methods were originally conceived in the analysis of closely related lineages. Specifically, various Drosophia (fly) species that might have diverged over a few million years. On this time scale, positive selection has two effects. One is that a desirable amino acid (or other) variation is selected for, and thus swept to fixation in the population. The other, and corresponding effect, is that all the other variations surrounding this desirable variation (that is, which are nearby on the same chromosome) are likewise swept to fixation (as part of what is called a haplotype). That dramatically reduces the neutral variation in this region of the genome. Indeed, the effect on neutral alleles (over millions of nearby base pairs) is going to vastly overwhelm the effect from the newly established single variant that was the object of positive selection, and this imbalance will be stronger the stronger the positive selection. In the limit case, the entire genomes of those without the new positive trait/allele will be eliminated, leaving no variation at all.

Yet, on the longer time scale, over hundreds of millions of years, as was the scope of visual variation in fish, all these effects on the neutral variation level wash out, as mutation and variation processes resume, after the positively selected allele is fixed in the population. So my view of this tempest in an evolutionary teapot is that these recent authors (and whatever other authors were deploying codon analysis against this rhodopsin problem) are barking up the wrong tree, mistaking the proper scope of these analyses. Which, after all, focus on the ratio between synonymous and non-synonymous change in the genome, and thus intrinsically on recent change, not deep change in genomes.

• That all-American mix of religion, grift, and greed.
• Christians are now in charge.
• Mechanisms of control by the IMF and the old economic order.
• A new pain med, thanks to people who know what they are doing.

The Climate is Changing

Fires in LA, and a puff of smoke in DC.

An ill wind has blown into Washington, a government of whim and spite, eager to send out the winged monkeys to spread fear and kidnap the unfortunate. The order of the day is anything that dismays the little people. The wicked witch will probably have melted away by the time his most grievous actions come to their inevitable fruition, of besmirching and belittling our country, and impoverishing the world. Much may pass without too much harm, but the climate catastrophe is already here, burning many out of their homes, as though they were made of straw. Immoral and spiteful contrariness on this front will reap the judgement and hatred of future generations.

But hasn't the biosphere and the climate always been in flux? Such is the awful refrain from the right, in a heartless conservatism that parrots greedy, mindless propaganda. In truth, Earth has been blessed with slowness. The tectonic plates make glaciers look like race cars, and the slow dance of Earth's geology has ruled the evolution of life over the eons, allowing precious time for incredible biological diversification that covers the globe with its lush results.

A stretch of relatively unbroken rain forest, in the Amazon.

Past crises on earth have been instructive. Two of the worst were the end-Permian extinction event, about 252 million years ago (mya), and the end-Cretaceous extinction event, about 66 mya. The latter was caused by a meteor, so was a very sudden event- a shock to the whole biosphere. Following the initial impact and global fire, it is thought to have raised sun-shielding dust and sulfur, with possible acidification, lasting for years. However, it did not have very large effects on CO2, the main climate-influencing gas.

On the other hand, the end-Permian extinction event, which was significantly more severe than the end-Cretaceous event, was a more gradual affair, caused by intense volcanic eruptions in what is now Siberia. Recent findings show that this was a huge CO2 event, turning the climate of Earth upside down. CO2 went from about 400 ppm, roughly what we are at currently, to 2500 ppm. The only habitable regions were the poles, while the tropics were all desert. But the kicker is that this happened over the surprisingly short (geologically speaking) time of about 80,000 years. CO2 then stayed high for the next roughly 400,00 years, before returning slowly to its former equilibrium. This rate of rise was roughly 2.7 ppm per 100 years, yet that change killed off 90% of all life on Earth. 

The momentous analysis of the end-Permian extinction event, in terms of CO2, species, and other geological markers, including sea surface temperature (SST). This paper was when the geological brevity of the event was first revealed.

Compare this to our current trajectory, where atmospheric CO2 has risen from about 280 ppm at the dawn of the industrial age to 420 ppm now. That is rate of maybe 100 ppm per 100 years, and rising steeply. It is a rate far too high for many species, and certainly the process of evolution itself, to keep up with, tuned as it is to geologic time. As yet, this Anthropocene extinction event is not quite at the level of either the end-Permian or end-Cretaceous events. But we are getting there, going way faster than the former, and creating a more CO2-based long-term climate mess than the latter. While we may hope to forestall nuclear war and thus a closer approximation to the end-Cretaceous event, it is not looking good for the biosphere, purely from a CO2 and warming perspective, putting aside the many other plagues we have unleashed including invasive species, pervasive pollution by fertilizers, plastics and other forever chemicals, and the commandeering of all the best land for farming, urbanization, and other unnatural uses. 

CO2 concentrations, along with emissions, over recent time.

We are truly out of Eden now, and the only question is whether we have the social, spiritual, and political capacity to face up to it. For the moment, obviously not. Something disturbed about our media landscape, and perhaps our culture generally, has sent us for succor, not to the Wizard who makes things better, but to the Wicked Witch of the East, who delights in lies, cruelty and destruction.

• The oligarchy is upon us. Oh, and they will help the working class!
• The attention economy.
• Which distorts our public understandings.
• Good coverage will never win in the attention economy.
• Keep Greenland white!

Eeking Out a Living on Ammonia

Some archaeal microorganisms have developed sophisticated nano-structures to capture their food: ammonia.

The earth's nitrogen cycle is a bit unheralded, but critical to life nonetheless. Gaseous nitrogen (N2) is all around us, but inert, given its extraordinary chemical stability. It can be broken down by lightning, but little else. It must have been very early in the history of life that the nascent chemical-biological life forms tapped out the geologically available forms of nitrogen, despite being dependent on nitrogen for countless critical aspects of organic chemistry, particularly of nucleic acids, proteins, and nucleotide cofactors. The race was then on to establish a way to capture it from the abundant, if tenaciously bound, dinitrogen of the air. It was thus very early bacteria that developed a way (heavily dependent, unsurprisingly, on catalytic metals like molybdenum and iron) to fix nitrogen, meaning breaking up the triple N≡N bond, and making ammonia, NH3 (or ammonium, NH4+). From there, the geochemical cycle of nitrogen is all down-hill, with organic nitrogen being oxidized to nitric oxide (NO), nitrite (NO2-), nitrate (NO3), and finally denitrification back to N2. Microorganisms obtain energy from all of these steps, some living exclusively on either nitrite or nitrate, oxidizing them as we oxidize carbon with oxygen to make CO2. 

Nitrosopumilus, as imaged by the authors, showing its corrugated exterior, a layer entirely composed of ammonia collecting elements (can be hexameric or pentameric). Insets show an individual hexagonal complex, in face-on and transverse views. Note also the amazing resolution of other molecules, such as the ribosomes floating about.

A recent paper looked at one of these denizens beneath our feet, an archaeal species that lives on ammonia, converting it to nitrite, NO2. It is a dominant microbe in its field, in the oceans, in soils, and in sewage treatment plants. The irony is that after we spend prodigious amounts of fossil fuels fixing huge amounts of nitrogen for fertilizer, most of which is wasted, and which today exceeds the entire global budget of naturally fixed nitrogen, we are faced with excess and damaging amounts of nitrogen in our effluent, which is then processed in complex treatment plants by our friends the microbes down the chain of oxidized states, back to gaseous N2.

Calculated structure of the ammonia-attracting pore. At right are various close-up views including the negatively charged amino acids (D, E) concentrated at the grooves of the structure, and the pores where ammonium can transit to the cell surface. 

The Nitrosopumilus genus is so successful because it has a remarkable way to capture ammonia from the environment, a way that is roughly two hundred times more efficient than that of its bacterial competitors. Its surface is covered by a curious array of hexagons, which turn out to be ammonia capture sites. In effect, its skin is an (relatively) enormous chemical antenna for ammonia, which is naturally at low concentration in sea water. These authors do a structural study, using the new methods of particle electron microscopy, to show that these hexagons have intensely negatively charged grooves and pores, to which positively charged ammonium ions are attracted. Within this outer shell, but still outside the cell membrane, enzymes at the cell surface transform the captured ammonium to other species such as hydroxylamine, which enforces the ammonium concentration gradient towards the cell surface, and which are then pumped inside.

Cartoon model of the ammonium attraction and transit mechanisms of this cell wall. 

It is a clever nano-material and micro-energetic system for concentrating a specific chemical- a method that might inspire human applications for other chemicals that we might need- chemicals whose isolation demands excessive energy, or whose geologic abundance may not last forever.

• Is reality getting through?
• Insurrection or not insurrection?
• The fluoride is OK.
• Cigarettes and ... wow!
• Bad judgement, ill discipline, and low morals. How did we get here?

A Housing Guarantee

A proposal for an updated poor house.

I agree with MMT economists who propose a job guarantee. That would put a floor on the labor market with an offer to anyone who wants to work for a low, but living wage, probably set below the minimum wage mandated for the private sector. State and local governments would run cleanups, environmental restoration, and care operations as needed, requiring basic discipline and effort, but no further skills. But they could use higher skilled workers as they come along for more beneficial, complex tasks.

Similarly, I think we could offer a housing guarantee, putting a floor on homelessness and misery. In the state of California, homelessness is out of control, and we have not found solutions, despite a great deal of money spent. Housing in the private market is extremely expensive, far out of reach of those with even median incomes. The next level down is housing vouchers and public housing, of which there are not enough to go around, and which is extremely expensive. And below that are shelters, which are heavily adverse settings. They are not private, chaotic, unpleasant, meant to be temporary, can be closed much of the time. And they also do not have enough space. 

A local encampment, temporarily approved during the pandemic under the freeway.

As uncompassionate as it sounds, it is unacceptable, and should be illegal, for public spaces to be commandeered by the homeless for their private needs. Public spaces have many purposes, specifically not including squatting and vagrancy. It is a problem in urban areas, because that is where people are, and where many services exist at the intersection of public and private spaces- food, bathrooms, opportunities to beg, get drugs, etc. Just because we have been, as governments and citizens, neglectful of our public spaces, does not mean we should give them over to anyone who wants to camp on them. I was recently at San Francisco city hall and the beautiful park surrounding it. But at lunch time, I realized that there was nowhere to sit. The plague of homelessness had rendered park benches untenable. We deserve to keep these public spaces functional, and that means outlawing the use of public spaces by the homeless. At the same time, provision must be made for the homeless, who by this policy would have nowhere to go in fully zoned areas. Putting them on busses to the next town, as some jurisdictions do, is also not a solution. As a rich country, we can do more for the homeless even while we preserve public spaces.

I think we need to rethink the whole lower end of housing / shelter to make it a more regular, accessible, and acceptable way to catch those who need housing at a very basic level. The model would be a sort of cross between a hostel, an SRO (single room occupancy hotels) and army barracks. It would be publicly funded, and provide a private room as well as food, all for free. It would not throw people out, or lock them in.

This poor house would not demand work, though it would offer centralized services for finding jobs and other places to live. It would be open to anyone, including runaway teens, battered women, tourists, etc. It would be a refuge for anyone for any reason, on an unlimited basis. The space and the food would be very basic, motivating clients to seek better accommodation. It would be well-policed and its clients would have to behave themselves. The next step down in the ladder of indigent care would not be homelessness, which would be outlawed in areas offering this kind of poorhouse, but would be institutionalization, in increasingly stringent settings for either criminal or mental issues. 

Such a poor house might become a community center, at least for the indigent. It would be quite expensive, but given the level of inequality and lack of care for people in various desperate straits, we need to furnish a humane level of existence between the market housing system and institutionalization. Why not give everyone a house? That is neither financially practical, nor would that co-exist well with the market housing system. Certainly, more housing needs to be built and everything done to bring prices down. But to address the current issues, stronger housing policy is needed.

Why not go back to a public housing model? It turned out that public housing was somewhat unrealistic, promising far more than it could deliver. It promised fully functional neighborhoods and housing, pretty much the equivalent of market housing, but without the ongoing discipline from the market via private financial responsibility by the residents or from the programs via their bureaucratic structures and funding, to follow through on the long term. The public authorities generally took a hands-off approach to residents and their environment, in line with the (respectful) illusion that this was the equivalent of market housing. And the long-term is what counts in housing, since it is ever in need of repair and renovation, not to mention careful use and protection by its residents. Building is one thing, but maintaining is something quite different, and requires carefully though-out incentives. 

With a public poorhouse model, the premises and residents are extensively policed. Individual rooms may descend to squalor, but the whole is built, run and maintained by the public authorities with intensive surveillance and intervention, keeping the institution as a whole functioning and growing as needed for its mission. There is going to be a sliding scale of freedom vs public involvement via financing and policing. The less functional a person is, the more control they will have to accept. We can not wash our hands of the homeless by granting them "freedom" to thrash about in squalor and make dumps of public spaces.

• Or you could join the squid game.
• Economic policy should not be about efficiency alone, let alone rewarding capital and management, but about long-term cultural and environmental sustainability.
• Could AI do biology?
• Carter was an evangelical. But that was a different time.

Drilling Into the Transcriptional Core

Machine learning helps to tease out the patterns of DNA at promoters that initiate transcription.

One of the holy grails of molecular biology is the study of transcriptional initiation. While there are many levels of regulation in cells, the initiation of transcription is perhaps, of all of them, the most powerful. An organism's ability to keep the transcription of most genes off, and turn on genes that are needed to build particular tissues, and regulate others in response to other urgent needs, is the very soul of how multicellular organisms operate. The decision to transcribe a gene into its RNA message (mRNA) represents a large investment, as that transcript can last hours or more and during that time be translated into a great many protein copies. Additionally, this process identifies where, in the otherwise featureless landscape of genomic DNA, genes are located, which is another significant process, one that it took molecular biologists a long time to figure out.

Control over transcription is generally divided into two conceptual and physical regions- enhancers and promoters. Enhancers are typically far from the start site of transcription, and are modules of DNA sequences that bind innumerable regulatory proteins which collectively tune, in fine and rough ways, initiation. Promoters, in contrast, are at the core and straddle the start site of transcription (TSS, for short). They feature a much more limited set of motifs in the DNA sequence. The promoter is the site where the proteins bound to the various enhancers converge and encourage the formation of a "preinitiation complex", which includes the RNA polymerase that actually carries out transcription, plus a lot of ancillary proteins. The RNA polymerase can not initiate on its own or find a promoter on its own. It requires direction by the regulatory proteins and their promoter targets before finding its proper landing place. So the study of promoter initiation and regulation has a very long history, as a critical part of the central flow of information in molecular biology, from DNA to protein.

A schematic of a promoter, where initiation of transcription of Gene A, happens, with the start site (+1) right at the boundary of the orange and green colors. At this location, the RNA polymerase will melt the DNA strands, and start synthesizing an RNA strand using the (bottom) template strand of the DNA. Regulatory proteins bound to enhancers far away in the genomic DNA bend through space to activate proteins bound at the core promoter to load the polymerase and initiate this process.

A recent paper provided a novel analysis of promoter sequences, using machine learning to derive a relatively comprehensive account of the relevant sequences. Heretofore, many promoters had been dissected in detail and several key features found. But many human promoters had none of them, showing that our knowledge was incomplete. This new approach started strictly from empirical data- the genome sequence, plus large experimental compilations of nascent RNAs, as they are expressed in various cells, and mapped to the precise base where they initiated from- that is, their respective TSS. These were all loaded into a machine learning model that was supplemented with explanatory capabilities. That is, it was not just a black box, but gave interpretable results useful to science, in the form of small sequence signatures that it found are needed to make particular promoters work. These signatures presumably bind particular proteins that are the operational engines of regulatory integration and promoter function.

The TATA motif, found about 30 base pairs upstream of the transcription start site in many promoters. This is a motif view, where the statistical prevalence of the base is reflected in the height of the letter (top, in color) and its converse is reflected below in gray. Regular patterns like this found in DNA usually mean that some protein typically binds to this site, in this case TFIID.

For example, the grand-daddy of them all is the TATA box, which dates back to bacteria / archaea and was easily dug up by this machine learning system. The composition of the TATA box is shown above in a graphical form, where the probability of occurrence (of a base in the DNA) is reflected in height of the base over the axis line. A few G/C bases surround a central motif of T/A, and the TSS is typically 30 base pairs downstream. What happens here is that one of the central proteins of the RNA polymerase positioning complex, TFIID, binds strongly to this sequence, and bends the DNA here by ninety degrees, forming a launchpad of sorts for the polymerase, which later finds and opens DNA at the transcription start site. TFIID and the TATA box are well known, so it certainly is reassuring that this algorithmic method recovered it. TATA boxes are common at regulated promoters, being highly receptive to regulation by enhancer protein complexes. This is in contrast to more uniformly expressed (housekeeping) genes which typically use other promoter DNA motifs, and incidentally tend to have much less precise TSS positions. They might have start sites that range over a hundred base pairs, more or less stochastically.

The main advance of this paper was to find more DNA sites, and new types of sites, which collectively account for the positioning and activation of all promoters in humans. Instead of the previously known three or four factors, they found nine major DNA sequences, and a smattering of weaker patterns, which they combine into a predictive model that matches empirical data. Most of these DNA sequences were previously known, but not as part of core promoters. For example, one is called YY1, because it binds the YY1 protein, which has long been appreciated to be a transcriptional repressor, from enhancer positions. But now it turns out to also be core promoter participant, identifying and turning on a class of promoters that, as for most of the new-found sequence elements, tend to operate genes that are not heavily regulated, but rather universally expressed and with delocalized start sites. 

Motifs and initiator elements found by the current work. Each motif, presumably matched by a protein that binds it, gets its own graph of relation of the motif location (at 0 on the X axis) vs the start site of transcription that it directs, which for TATA is about 30 base pairs downstream. Most of the newly discovered motifs are bi-directional, directing start sites and transcription both upstream and downstream. This wastes a lot of effort, as the upstream transcripts are typically quickly discarded. The NFY motif has an interesting pattern of 10.5 bp periodicity of its directed start sites, which suggests that the protein complex that binds this site hugs one side of the DNA quite closely, setting up start sites on that side of the helix.

Secondly, these authors find that most of the new sequences they identify have bidirectional effects. That is, they set up promoters to fire in both directions, both typically about forty base pairs downstream and also upstream from their binding site. This explains a great deal of transcription data derived from new sequencing technologies, which shows that many promoters fire in both directions, even though the "upstream" or non-gene side transcript tends to be short-lived.

Overview of the new results, summarized by type of DNA sequence pattern. The total machine learning prediction was composed of predictions for larger motifs, which were the dominant pattern, plus a small contribution from "initiators", which comprise a few patterns right at the start site, plus a large but diffuse contribution from tiny trinucleotide patterns, such as the CG pattern known to mark active genes and carry activating DNA methylation marks.

A third finding was the set of trinucleotide motifs that serve as the sort of fudge factor for their machine learning model, filling in details to make the match to empirical data come out better. The length was set more or less arbitrarily, but they play a big part in the model fit. They note that one common example is the CG pattern, which is one of the stronger trinucleotide motifs. This pattern is known as CpG, and is the target of chemical methylation of DNA by regulatory enzymes, which helps to mark and regulate genes. The current work suggests that there may be more systems of this kind yet to be discovered, which play a modulating role in gene/promoter selection and activation.

The accuracy of this new learning and modeling system exemplifies some of the strengths of AI, of which machine learning is a sub-discipline. When there is a lot of data available, and a problem that is well defined and on the verge of solution (like the protein folding problem), then AI, or these machine learning methods, can push the field over the edge to a solution. AI / ML are powerful ways to explore a defined solution space for optimal results. They are not "intelligent" in the normal sense of the word, (at least not yet), which would imply having generalized world models that would allow them to range over large areas of knowledge, solve undefined problems, and exercise common sense.

• A lecture on promoter complex assembly, in bacteria and other organisms.
• A dose of honesty.
• Starfish are all head, no body.
• The meaning of financialization.

Money For Nothing: Two Views of Crypto

Is crypto more like gold or a simple scam?

I have to confess some perplexity over crypto. Billed as currencies, they are not currencies. Billed as securities, they are not securities, either. They excite a weird kind of enthusiasm in libertarian circles, in dreams of asocial (if not anti-social) finance. From a matter of fringe speculation, they are migrating into the culture at large, influencing our politics, and becoming significant economic actors, with a combined market cap now over three trillion dollars. For me, there are two basic frames for thinking about crypto. One is that they are like gold, an intrinsically worthless, but attractive object of fascination, wealth storage, and speculation. The other is that they are straight Ponzi schemes, rising by a greater-fool process that will end in tears.

Currencies are forms of money with particular characteristics. They are widely used among a region or population, stable in value, and easy to store and exchange. They are typically sponsored by a government to ensure that stability and acceptance. This is done in part by specifying that currency for incoming taxes and outgoing vendor and salary payments. They are also, in modern systems, managed elastically, (and intelligently!), with ongoing currency creation to match economic growth and keep the nominal value stable over time. Crypto entities would like to be currencies. However, they have far from stable value, are not easy to work with, and are not widely used. Securities, on the other hand, have a basis in some kind of collateral (i.e. the "security" part) like business ownership, a contract of bond interest payments, etc. Crypto does not have this either. Crypto has only its own scarcity to offer, a bit like cowrie shells, or gold. Crypto entities are not investments in productive activity. Indeed, they foster the opposite, as their only solid use case has been, at least to date, facilitating crime, as demonstrated by the ransomware industry, which asks to be paid in Bitcoin.

So how about gold? Keynes railed against gold as the most useless, barbaric form of wealth, inducing people to dig holes in the earth and cause environmental degradation. And for what? A shiny substance that looks good, and is useful in a few industrial applications, but mostly was, at the time, held by governments in huge vaults, notionally underpinning their currency values. Thankfully we are past that, but gold still holds fascination, and persists as a store of value. Gold can be held in electronic forms, making it just as easy to hold and transfer as crypto entities, if one is so-inclined. Critically, however, gold is also physical, and humanity's fascination with it is innate and enduring. Thus, after the apocalypse, when the electricity is off and the computers are not connected anymore, gold will still be there, ready to serve as money when crypto has evaporated away. 

Bitcoin barely recovered from an early crisis. 

How durable is the fascination with crypto, as a store of wealth, or for any other purpose, under modern, non-apocalyptic conditions? Bitcoin is the grand-daddy of the field, and seems to have achieved dominance, certainly the field of criminal money laundering and transfer, as well as libertarian speculation. It appears to have a special mystique, whether from the blockchain, its "mining" system, or its mysterious pseudonymous founder. The other forms of crypto range from respectible to passing memes. There is a fascinating competition in the attention space that constitutes the crypto markets. Since they do not have intrinsic value, nor governmental buy-in, they float entirely on buyer sentiment, in a greater-fool cycle of rises and falls. Crashes in the stock market are halted by fundamental value of the underlying asset. As the speculative fervor wanes, vultures step in to, at worst, liquidate the assets. But for crypto, there are no assets. No fundamental value. So crashes can and do go to zero.

There are also external factors, like the fact that many crypto entities have been outright scams, or the environmental costs of Bitcoin, or their facilitation of criminality, which may eventually draw popular and regulatory scrutiny. Boosters have been trying to get the Federal Reserve and other validating entities to buy into the crypto craze, and political contributions from newly crypto-riche holders and exchanges have transformed the landscape to one that seems increasingly sympathetic, especially on the Republican side. Thankfully, the smaller memecoins have market caps in the low millions, so do not present a threat as yet to the financial system, in the almost certain event of their evaporation once each meme passes. This blasé acceptance of "securities" that are pure schemes of speculation is a sad commentary on our current age. The sophisticated investor of today would not study corporate efficiency, market prospects, or finances. He or she would be conversant in current memes on social media, ready to jump on the newest one, and sensitive to the withering of older memes, in an endless conveyor belt of booms and busts. 

It is weird how people fail to learn the lessons of the past, from the tulip craze and other speculative booms. Where there is no value, there is likely to be a very deep crash. The libertarians among us, who may have been gold bugs in the past and now have flocked to the new world of crypto, may represent a psychological type that is ineradicable, so motivated to ditch the humdrum official currency for anything that offers a whiff of notional independence, (though being tethered to the new crypto infrastructure of exchanges and wallets is not for the faint of heart or independent-minded), that they can float these crypto entities indefinitely. But in the absence of deeper value, might their psychologies change to those of hawkers who get in at the ground floor and make out, while the schlubs who buy at the top are left holding the bag? It comes down to human psychology in the end- what is personally and socially valuable, who you think your counterparts are on the other ends of all these trades, and who (and what sort of motivation) is making up the institutions and communities of crypto.

• Star Trek was fighting the cold war.

Inside the Process of Speciation

Adaptive radiations are messy, so no wonder we have a hard time reconstructing them.

Darwin drew a legendary diagram in his great book, of lineage trees tracing speciation from ancestors to descendants. It was just a sketch, and naturally had clear fork points where one species turns into two. But in real life, speciation is messier, with range overlaps, inter-breeding, and difficulties telling species apart. Ornithologists are still lumping and splitting species to this day, as more data come in about ranges, genetics, sub-populations, breeding behavior, etc. And if defining existing species is difficult, defining exactly where they split in the distant past is even harder.

Darwin's notebook sketch of speciation, from ancestors ... to descendants.

The advent of molecular data from genomes gave a tremendous boost to the amount of information on which to base phylogenetic inferences. It gave us a whole new domain of life, for one thing. And it has helped sharpen countless phylogenies that not been fully specified by fossil and morphological data. But still, difficulties remain. The deepest and most momentous divergences, like the origin of life itself, and the origin of eukaryotes, remain shrouded in hazy and inconclusive trees, as do many other lineages, such as the origin of birds. It seems to be a rule that when a group of organisms undergoes rapid evolution / speciation, the tree they are on (as reconstructed by us from contemporary data) becomes correspondingly unclear and unresolved, difficult to trace through that tumultuous time. In part this is simply a matter of timing. If dramatic events happened within a few million years a billion years ago, our ability to resolve the sequence of those events is going to be weak in any case, compared to the same events spread out over a hundred million years.

A recent paper documented some of this about phylogeny in general, by correlating times of morphological change with times of phylogenetic haziness, which they term "gene-tree conflict". That is to say, if one samples genes across genomes to draw phylogenetic trees, different genes will give different trees. And this phenomenon increases right when there are other signs of rapid evolutionary change, i.e. changing morphology.

"One insight gleaned from phylogenomics is that gene-tree conflict, frequently caused by population-level processes, is often rampant during the origin of major lineages."

They identify three mechanisms behind this observation: incomplete lineage sorting (ILS), hybridization, and rapid evolution. Obviously, these need to be unpacked a bit. ILS is a natural consequence of the fact that species arise not from single organisms, but from populations. Gene mutations that differentiate the originating and future species happen all over the respective genomes, and enter the future lineage at different times. Some may happen well after the putative speciation event, and become fixed (that is, prevalent) later in that species. Others may have happened well before the speciation event, and die off in most of the descending lineages. The fact is that not every gene is going to march in lock step with the speciation event, in terms of its variants. So phylogenetic inference is best done using lots of genes plus statistical methods to arrive at the most likely explanation of the diverse individual gene trees.

Graphs drawn from different sources relating gene conflicts in lineage estimation, (top), versus rate of morphological change from the fossil record, (bottom), in birds, and over time on the X axis. There are dramatic upticks in all metrics going back towards the end-Cretaceous extinction event.

Similarly, hybridization means that proto-species are still occasionally interbreeding with their ancestors or other relatives, (think of Neanderthals), thereby mixing up the gene trees relative to the overall speciation tree. This can even happen by gene transfer mediated by viruses. "Rapid evolution" is not defined by these authors, and comes dangerously close to using the conclusion (of high morphological change during periods of "gene-tree conflict") to describe their premise. But generally, this would mean that some genes are evolving rapidly, due to novel selective pressures, thus deviating from the general march of neutral evolution that affects most loci more evenly. This rate change can mess up phylogenetic inferences, lengthening some (gene) tree branches versus others, and making a unitary tree (that is, for the species or lineage as a whole) hard to draw.

But these are all rather abstract ideas. How does this process look on the ground? A wonderful paper on the tomato gives us some insight. This group traced the evolutionary history of a genus of tomato (Solanum sect. Lycopersicon) in the South American Andes (plus Galapagos islands just off-shore, interestingly enough). These form a tight group of about thirteen species that evolved from a single ancestor over the last two million years, before jumping onto our lunch plates via intensive breeding by native South Americans. This has been a rapid process of evolution, and phylogenies have been difficult to draw, for all the reasons given above. The tomatoes are mostly reproductively isolated, but not fully, and have various specializations for their microhabitats. So are they real species? And how can they evolve and specialize if they do not fully isolate from each other?

Gene-based phylogenetic tree of Andean tomato species. The consensus tree is in black at the right, while alternate trees (cloud) are drawn from 2,745 windows of 100 kb across the tomato genomes, clearly giving diverse views of the lineage tree. Lycopersicon are the species under study, while Lycopericoides is an "outgroup" genus used as a control / comparison. 

In the graph above, there is, as they say, rampant discord among genomic segments, versus the overall consensus tree that they arrived at:

"However, these summary support measures conceal rampant phylogenetic complexity that is evident when examining the evolutionary history of more defined genomic partitions."

For one thing, much of the sequence diversity in the ancestor survives in the descendent lineages. The founders were not single plants, by any means. Second, there has been a lot of "introgression", which is to say, breeding / hybridization between lineages after their putative separation. 

Lastly, they find a high rate of novel mutations, often subject to clear positive selection. Ten enyzmes in the carotenoid biosynthesis pathway, which affects fruit color in a group that has evolved red fruits, carry novel mutations. A UV light damage repair gene shows strong signs of positive selection, in high-altitude species. Others show novel mutations in a temperature stress response gene, and selection on genes defending plants against heavy metals in the soil. 

Their conclusion (as that of the previous paper) is that adaptive radiations are characterized by several components that scramble normal phylogenetic analysis, including variably preserved diversity from the originating species, post-divergence gene flow (i.e. mating), and rapid adaptation to new conditions along with strong environmental selection over the pre-existing diversity. All of these mechanisms are happening at the same time, and each position in the genome is being affected at the same time, so this is a massively parallel process that, while slow in human time, can be very rapid in geologic time. They note how tomato speciation compares with some other well-known cases:

"Nonetheless, based on our crude estimates within each analysis, we infer that relatively small yet substantial fractions of the euchromatic genome are implicated in each source of genetic variation. We find little evidence that one of these processes predominates in its contribution, although our estimates suggest that de novo mutation might be relatively more influential and cross-species introgression relatively less so. This latter observation is in interesting contrast with several recent studies of animal adaptive radiations, including in Darwin’s Finches [18], Equids [14], and fish [13], where evidence suggests that hybridization and introgression might be much more pervasive and influential than previously suspected, and more abundant than we detect in Solanum."

Naturally, neither of these studies go back in time to nail down exactly what happened during these evolutionary radiations, nor what caused them. They only give hints about causation. Why the stasis of some species, and the rapid niche-finding and filling by others? Was the motive force natural selection, or god? The latter paper gives some clear hints about possible selective pressures and rationales that were at work in the Andes and Galapagos on the genus of Solanum. But it is always frustratingly a matter of abstract reasoning, in the manner of Darwin, that paints the forces at work, however detailed the genetic and biogeographic analyses and however convincing the analogous laboratory experiments on model, usually microbial, organisms. We have to think carefully, and within the discipline of known forces and mechanisms, to arrive at intellectually honest answers to these questions, insofar as they can be answered at all.

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Capitalism on the Spectrum

Prospects for the new administration.

Political economics can be seen as a spectrum from anarchic gangsterism (Haiti) to total top down control such as in communism (Cuba, North Korea). Neither works well. Each end of this spectrum ends up in a state of terror, because each is unworkable on its own terms. Capitalism, in its modern form, is a compromise between these extremes, where free initiative, competition, and hierarchical relations (such within corporations) are allowed, while regulation (via the state and unions) makes humane what would otherwise a cutthroat system of gangsterism and corruption. The organization and stability allowed by state-sponsored legal systems raises system productivity far above that of the primeval free-for-all, while the regulatory rules also make it bearable to its participants- principally the workers. The magic comes from a dynamic balance between competition and guardrails to keep that competition focused on productive ends (that is, economic/business competition), rather than unproductive ones (war, assassination, corruption, capture of the state, etc.)

The new Trump administration promises to tear up this compromise, slash regulations, and cut government. That means that the workers that voted for this administration, and who are the primary beneficiaries of the regulatory state, will be hurt in countless ways. The grifting nature of so many in this incoming administration is a blazing alarm to anyone who pays attention. Whether it is stiffing workers, bloviating on FOX, hawking gold sneakers, making a buck off of anti-vax gullibility, defrauding the government of taxes, promoting crypto, or frankly asking for money in return for political favors like petroleum deregulation, the stench of corruption and bad faith is overwhelming. Many of them, starting from the top, see capitalism as a string of scams and frauds, not exactly Milton Friedman's vision of capitalism. An administration of grifty billionaires is unlikely to rebuild US manufacturing, help workers afford housing, or fulfill any of the other dreams of their voters. Indeed, a massive economic collapse, on the heels of bad policy such as crypto deregulation, or a world-spanning trade war, is more likely, and degraded conditions for workers all but certain.

Freedom for capitalists means permission for companies to abuse workers, customers, the environment, the law, and whatever else stands in the way of profit. We have been through this many times, especially in the gilded age. It can spiral into anarchy and violence when business owners are sufficiently "free" from the fetters of norms and laws. When the most powerful entities in the economy have only one purpose- to make money- all other values are trampled. That is, unless a stronger entity makes some rules. That entity can only be the government. It has been the role of governments from time immemorial to look to the long term interests of the collective, and organize the inherent competition within society into benign and productive pursuits.

OK, more than a little ironic, but you get the idea.

On the other hand, there is a problem even at the golden mean of governmental rule-making over the capitalistic free-for-all, which is that the quality of the rule makers and their rules, their attention to real conditions, and their prompt decision making, all can decline into bureaucratic inertia. While this may not be a Stalinist system of top-down planning and terror, it still can sap the productive energies of the system. And that is what we have been facing over the last few decades. For instance, there is the housing crisis, where home construction has not kept up with demand, mostly due to zoning stasis in most desirable places in the US, in addition to lagging construction after the 2008 financial and real estate crisis. Another example is public infrastructure, which has become increasingly difficult to build due to ever-mounting bureaucratic complexity and numbers of stakeholders. The California high speed rail system faces mountainous costs and a bogged-down legal environment, and is on the edge of complete inviability.

Putting rich, corrupt, and occasionally criminal capitalists at the head of this system is not, one must say, the most obvious way to fix it. Ideally, the Democrats would have put forward more innovative candidates in better touch with the problems voters were evidently concerned with. Then we could have forged ahead with policies oriented to the public good, (such as planetary sustainability and worker rights), as has been the practice through the Biden administration. But the election came up with a different solution, one that we will be paying for for decades. And possibly far worse, since there are worse fates than being at a well-meaning, if sclerotic, golden mean of governmental regulation over a largely free capitalist system. Hungary and Russia show the way to "managed democracy" and eventual autocracy. Our own history, and that of Dickensian Britain, show the way of uncontrolled capitalism, which took decades of progressivism, and a great depression, to finally tame. It would be nice to not have to repeat that history.

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Cranking Up DNA, One Gyration at a Time

The mechanism of DNA gyrase, which supercoils bacterial DNA.

Imagine that you have a garden hose that is thirty miles long. How would you keep it from getting tangled? That is unlikely to be easy. Now add randomly placed heavy machinery that actively twists that hose as it travels / pulls along, causing it to wind up ahead, and unwind behind. And that machinery can be placed in either direction, often getting into head-on conflicts, not to mention going at quite different speeds. That is the problem our cells have, managing their DNA. 

They use a set of topoisomerases to manage the topology of DNA- that is, its twist-i-ness. One easy method is to nick the DNA on one of its two strands, allowing it to relax by spinning around the remaining phosphate bond, before resealing it back to a double strand and sending it on its way. But what if you encounter coils or knots that can't be resolved that way? The next level is to cut one entire DNA molecule, not just one side/strand of it, and pass the conflicting one though it. All organisms contain topoisomerases of both kinds, and they are essential.

How DNA gets twisted. While most topoisomerases relax DNA (top) to resolve the many twisty problems posed by transcription and replication, gyrase increases twist by grabbing and holding a quasi-positive twist, then cutting and resolving it, as shown at bottom.

Bacteria have an additional enzyme that we do not have, called gyrase, to crank up the supercoiling of their DNA, to make it easier to open for transcription. Gyrase works just like a type II topoisomerase that cuts a double-stranded DNA and lets another DNA through, but it does so in a special way that puts a twist on the DNA first, so instead of relaxing the DNA, it increases the stress. How exactly that works has been a bit mysterious, though gyrases and the general principles they operate under have been clear for decades. Gyrase uses ATP, and grabs onto two parts of a DNA molecule, one of which is pre-twisted into coil, after which one is cut and the other passed through to create a change (-2) in the twisting number of that DNA.

A general model of gyrase action. The G segment of DNA is firmly held by the gyrase dimer in the center.  The same DNA is forcibly twisted about, around the pinwheel structures, and bent back around to enter through the N-gate (as the T segment). Then, the N gate closes, paving the way for the G-segment to be cut and separated (step 3). ATP is the energy source behind all this structural drama. The T-segment then passes through the cut, enters the C-gate, and the cycle is complete.

A recent paper determined the structure of active gyrase complexes, and was able to trace the pre-twisted conformation. This, combined with a lot of past work on the ATPase and cleavage functions of gyrase, allows a reasonably full picture of how this enzyme works. It is a symetric dimer of a two-subunit protein, so there are four protein chains in all. There are three major regions of the full structure. The N-gate at top where one segment (the T-segment) of DNA binds, then the central DNA gate, where the other (G-segment) DNA binds and is later cut to let the T-segment through, and the C-gate, where the T segment ends up and is released at the end of the cycle. 

Focus on the pinwheel structure that dramatically pre-twists the DNA around between the G and T segments, pre-positioning the complex for strand passage and increased supercoiling.

The magic is that the T-segment and the G-segment of DNA are parts of the same DNA molecule, by being wrapped around the ears of the protein, which are also called pinwheels. That is what the newest structure solves in greatest detail. These pinwheels essentially allow the enzyme to yank an otherwise normal DNA strand into a pre-knotted (positive supercoil) form that, when cut and resolved as shown, results in a negative increment of supercoiling or twist. If they mutated the pinwheels away, the enzyme could still hold, cut, and relax DNA, but it could not increase its supercoiling. It is the ability of the pinwheel structures to set up a pre-twisted structure onto the DNA that makes this enzyme a machine to increase negative supercoiling, and thus ease other DNA transactions. 

Topoisomerase enzymes through evolution, from gyrase (left) to human topoII on the right. Note how the details of the protein structure are virtually unrecognizable, while the overall shape and DNA-binding stays the same.

Bacteria also have more normal type II topoisomerases that cut DNA merely to relax it, so one might wonder how these two enzymes get along. Well, gyrase is responsible for the overall negative supercoiling of the bacterial genome, while the other topoisomerases have more localized roles to relieve transient knots and over-twisting. Indeed, if you negatively twist DNA enough, you can separate its strands entirely, which is not usually desirable. Further research shows that too much of either topoisomerase is lethal, and that they are kept in balance by transcriptional controls over the amount of each topoisomerase. This suggests a futile cycle of DNA winding and unwinding, as the optimal condition in bacterial cells when both are present in just the right amounts. 

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To the Stars!

Reviews of "Making it So", by Patrick Stewart, and "The Silent Star" from DEFA films.

When I think about religion, I usually think about how wrong it all is. But at the same time, it has provided a narrative structure for much of humanity and much of human history, for better or worse. It could be regarded as the original science fiction, with its miracles, and reports of supernatural beings and powers. Both testaments of the Bible read like wonder tales of strange happenings and hopeful portents. While theology might take the heavenly beings and weird powers seriously, it is obvious these were mere philosophical gropings after the true gears of the world, while the core of the stories are the human narratives of conflict, adversity, and morality.

In our epoch features a welter of storytelling, typically more commercially desperate than culturally binding. But one story has risen above the rest- the world of Star Trek. From its cold war beginnings, it has blossomed into a rich world of morality tales combined with hopeful adventure and mild drama. The delightful recent autobiography by Patrick Stewart brought this all back in a new way. Looking at the franchise from the inside out, from the perspective of a professional actor who was certainly dedicated to his craft, but hardly a fan of the franchise- someone for whom this was just another role, if one that made him an international, nay galactic, star- was deeply interesting. Even engaging(!)

As a Shakespearean actor, Stewart was used to dealing with beloved, culturally pivotal stories. And this one has become a touchstone in Western culture, supplying some of the models and glue that have gone missing with the increasing irrelevance of religion. It is fascinating how heavily people depend on stories for a sense of what it should, can, and does mean to be human, for models of leadership and community. Star Trek, at least for a certain segment of the population, has provided a hopeful, interesting vision of the future, with well-reasoned moral dramas and judgments. Stewart embodied the kind of leadership style that was influential far beyond the confines of Starfleet. And his deeply engaged acting helped carry the show, as that of Leonard Nimoy had taken the original series beyond its action/adventure roots.

Where the narrative of Christianity is obscurantist, blusteringly uncertain how seriously to take its own story, and focused on the occasional miracles of long-ago, Star Trek values the future, problem solving and science, while it makes little pretense of realism. On the other hand, it is fundamentally a workplace drama, eliding many important facets of humanity, like family and scarcity. Though in the Star Trek world money is worthless and abundance is the rule, posts on starships remain in short supply. There always will be shortages of something, given human greed and narcissism, so there is always going to be something subject to competition, economics, possibly warfare. Christianity hinges on preaching and conversion, based on rather mysterious, if supposedly self-serving, personal convictions. Its vision of the future is, frankly, quite frightening. Star Trek, on the other hand, shows openness to other cultures, diplomacy, and sharing in its eschatological version of the American empire, the Federation. (Even if they get into an inordinate number of fights with un-enlightened cultures.)

The Star Trek story is so strong that it keeps motivating people to make spaceships. Just look at Elon Musk, who, despite the glaringly defective logic of sending humans to Mars, persists in that dream, as does NASA itself. It is a classic case of archetypal yearnings overwhelming common sense, not to mention clear science. But that is a small price to pay for the many other benefits of the Star Trek-style world view- one where different cultures and races get along, where solving problems and seeking knowledge are the highest pursuits, where leadership is judicious and respectful, and humans know what they stand for.

In a similar vein, the Soviets, who led humanity into space, had their own fixations and narratives of space and the future. I recently watched the fascinating movie from the East German DEFA studios, The Silent Star, (1960), which portrays a voyage to Venus. It strikingly prefigures the entire Star Trek oeuvre. There are the scientists on board, the handsome captain, the black communications officer, the international crew from all corners of the earth, the shuttle craft, the talking computer, the communications that keep breaking up, and the space ship that rattles through asteroid fields, jostling the crew. While there are several pointed comments on the American bombing of Hiroshima to set the geopolitical contrast, there is, overall, the absolute optimism that all problems can be solved, and that adventuring to seek the truth is unquestionably the most exciting way to live. One gets the distinct sense that Star Trek was not so original after all.

It was time when technology had pried open the heavens for direct investigation, and what humanity found there was stunningly unlike what had been foretold in the scriptures. It was a vast and empty wasteland, dotted with dead planets and lacking any hint of deities. We had to create an alternative narrative, with warp drive and M-class planets, where humans could recover a sense of agency and engagement with a future that remains tantalizing, even if sober heads know it is as wishful as it is fictional. It is the story, however, that is significant, in its power to give us the fortitude to go forth, not out among the stars, but into a better, more decent community here on earth.

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