What Causes Cancer? What is Cancer?

There is some frustration in the literature.

Fifty years into the war on cancer, what have we learned and gained? We do not have a general cure, though we have a few cures and a lot of treatments. We have a lot of understanding, but no comprehensive theory or guide to practice. While some treatments are pin-point specific to certain proteins and even certain mutated forms of those proteins, most treatments remain empirical, even crude, and few provide more than a temporary respite. Cancer remains an enormous challenge, clinically and intellectually.

Recently, a prominent journal ran a provocative commentary about the origins of cancer, trashing the reigning model of "Somatic Mutation Theory", or SMT. Which is the proposition that cancer is caused by mutations that "drive" cell proliferation, and thus tumor growth. I was surprised at the cavalier insinuations being thrown around by these authors, their level of trash talk, and the lack of either compelling evidence or coherent alternative model. Some of their critiques have a fair basis, as discussed below, but to say, as the title does, that this is "The End of the Genetic Paradigm of Cancer" is simply wrong.

"It is said that the wise only believe in what they can see, and the fools only see what they can believe in. The latter attitude cements paradigms, and paradigms are amplified by any new-looking glass that puts one’s way of seeing the world on steroids. In cancer research, such a self-fulfilling prophecy has been fueled by next-generation DNA sequencing."

"However, in the quest for predictive biomarkers and molecular targets, the cancer research community has abandoned deep thinking for deep sequencing, interpreting data through the lens of clinical translation detached from fundamental biology."

Whew!

The main critique, once the gratuitous insults and obligatory references to Kuhn and Feynman are cleared away, is that cancer does not resemble other truly clonal disease / population processes, like viral or bacterial infections. In such processes, (which have become widely familiar after the COVID and HIV pandemics), a founder genotype can be identified, and its descendants clearly derive from that founder, while accumulating additional mutations that may respond to the Darwinian pressures, such as the immune system and other host defenses. While many cancers are clearly driven by some founding mutation, when treatments against that particular "driver" protein are given, resistance emerges, indicating that the cancer is a more diverse population with a very active mutation and adaptation process. 

Additionally, tumors are not just clones fo the driving cell, but have complex structure and genetic variety. Part of this is due to the mutator phenotypes that arise during carcinogenesis, that blow up the genome and cause large numbers of additional mutations- many deleterious, but some carrying advantages. More significantly, tumors arise from and continue to exist in the context of organs and tissues. They can not just grow wildly as though they were on a petri plate, but must generate, for example, vascular structures and a "microenvironment" including other cells that facilitate their life. Similarly, metastasis is highly context-dependent and selective- only very few of the cells released by a tumor land in a place they find conducive to new growth. This indicates, again, that the organ setting of cancer cells is critically important, and accounts in large part for this overall difference between cancers and more straightforward clonal processes. 

Schematic of cancer development, from a much more conventional and thorough review of the field.

Cancer cells need to work with the developmental paradigms of the organism. For instance, the notorious "EMT", or epithelial-mesenchymal transition is a hallmark of de-differentiation of many cancer cells. They frequently regress in developmental terms to recover some of the proliferative and self-repair potential of stem cells. What developmental program is available or allowed in a particular tissue will vary tremendously. Thus cancer is not caused by each and every oncogenic mutation, and each organ has particular and distinct mutations that tend to cause cancers within it. Indeed, some organs hardly foster any cancers at all, while other organs with more active (and perhaps evolutionarily recent) patterns of proliferation (such as breast tissue, or prostate tissue) show high rates of cancer. Given the organ setting, cancer "driver" mutations need not only unleash the cell's own proliferation, but re-engineer its relations with other cells to remove their inhibition of its over-growth, and pursuade them to provide the environment it needs- nutritionally, by direct contact, by growth factors, vascular formation, immune interactions, etc., in a sort of para-organ formation process. It is a complicated job, and one mutation is, empirically, rarely enough.

"Instead, cancer can be broadly understood as “development gone awry”. Within this perspective, the tissue organization field theory is based on two principles that unite phylogenesis and ontogenesis."

"The organicist perspective is based on the interdependency of the organism and its organs. It recognizes a circular causal regimen by closure of constraints that makes parts interdependent, wherein these constraints are not only molecules, but also biophysical force."

As an argument or alternative theory, this leaves quite a bit to be desired, and does not obviate the role of  initiating mutations in the process.

It remains, however, that oncogenic mutations cause cancer, and treatments that address those root causes have time and again shown themselves to be effective cancer treatments, if tragically incomplete. The rise of shockingly effective immunotherapies for cancer have shown, however, that the immune system takes a more holistic approach to attacking disease than such "precision" single-target therapies, and can make up for the vagaries of the tissue environment and the inflammatory, developmental, and mutational derangements that happen later in cancer development. 

In one egregious citation, the authors hail an observation that certain cancers need both a mutation and a chemical treatment to get started, and that the order of these events is not set in stone. Traditionally, the mutation is induced first, and then the chemical treatment, which causes inflammation, comes second. They state: 

"The qualitative dichotomy between a mutagenic initiator that creates ’cancer cells’ and the non-genetic, tissue-perturbing promoter that expands them may not be as clear-cut. Indeed, the reverse experiment (first treatment with the promoter followed by the initiator) equally produces tumors. This result refutes the classical model that requires that the mutagenic (alleged) initiator must act first."

The citation is to a paper entitled "The reverse experiment in two-stage skin carcinogenesis. It cannot be genuinely performed, but when approximated, it is not innocuous". This paper dates from 1993, long before sequencing was capable of evaluating the mutation profiles of cancer cells. Additionally, the authors of this paper themselves point out (in the quote below) a significant assymetry in the treatments. Their results are not "equal":

"The two substances showed a reciprocal enhancing effect, which was sometimes weak, sometimes additive, and sometimes even synergistic, and was statistically most significant when the results were assessed from the time of DMBA application. Although the reverse experiment was not in any way innocuous it always resulted in a lower tumor crop than the classical sequence of DMBA followed by a course of TPA treatment. 

However, the lower tumor crop in the reverse experiment cannot be used to prove a qualitative difference between initiators and promoters."

(DMBA is the mutagen, while TPA is the inflammatory accelerant.)

So chemical treatment can prepare the ground for subsequent mutant generation in forming cancers in this system, while being much less efficient than the traditional order of events. This is not a surprise, given that this chemical (TPA) treatment causes relatively long-term inflammation and cell proliferation on its own.

"An epistemic shift towards a biological theory of cancer may still be an uphill battle in the current climate of thought created by the ease of data collection and a culture of research that discourages ’disruptive science’. Here, we have made an argument for dropping the SMT and its epicycles. We presented new and old but sidelined theoretical alternatives to the SMT that embrace theory and organismal biology and can guide experiments and data interpretation. We expect that the diminishing returns from the ceaselessly growing databases of somatic mutations, the equivalent to Darwin’s gravel pit, may soon reach a pivot point."

One rarely reads such grandiloquent summaries (or mixed metaphors) in scientific papers! But here they are truly beating up on straw men. In the end, it is true that cancer is quite unlike clonal infectious diseases, and for this, as for many other reasons, has had scientists scratching their heads for decades, if not centuries. But rest assured that this chest-thumping condescension is quite unnecessary, since those in the field are quite aware of these difficulties. The various nebulous alternatives these authors offer, whether the "epigenetic landscape", the "tissue organization field theory", or the "biological theory of cancer" all have kernels of logic, but the SMT remains the foundation-stone of cancer study and treatment, while being, for all the reasons enumerated above and by these authors, only part of the edifice, not the whole truth.

• Some more thoughts about crypto.
• Resistance is up to congress, ultimately.
• China takes purges quite a bit more seriously than we do.
• But we are getting there.

Eccentricity, Obliquity, Precession, and Glaciation

The glacial cycles of the last few million years were highly determined by earth's orbital mechanics.

Naturalism as a philosophy came into its own when Newton explained the heavens as a machine, not a pantheon. It was stunning to realize that age-old mysteries were thoroughly explicable and that, if we kept at it with a bit of diligence and intellectual openness, we could attain ever-widening vistas of understanding, which now reach to the farthest reaches of the universe. 

In our current day, the mechanics of Earth's climate have become another example of this expansion of understanding, and, sadly, another example of resistance to naturalism, to scientific understanding, and ultimately to the stewardship of our environment. It has dawned on the scientific community (and anyone else willing to look) over the last few decades that our industrial production of CO2 is heating the climate, and that it needs to stop if the biosphere is to be saved from an ever-more degrading crisis. But countervailing excuses and interests abound, and we are now ruled by an adminstration in the US whose values run toward lies and greed, and which naturally can not abide moral responsibility.

The Cenozoic, our present age after the demise of the dinosaurs, has been characterized by falling levels of CO2 in the atmosphere. This has led to a progression from very warm climates 50 mya (million years ago) to ice ages beginning roughly 3 mya. The reasons for this are not completely clear. There has been a marked lack of vocanism, which is one of main ways CO2 gets back into the atmosphere. This contrasts strongly with ages of extreme volcanism like the Permian-Triassic boundary and extinction events, about 250 mya. It makes one think that the earth may be storing up a mega-volcanic event for the future. Yeet plate tectonics has kept plugging along, and has sent continents to the poles, where they previously hung out in more equatorial locations. That makes ice ages possible, giving glaciers something to glaciate, rather than letting ocean circulation keep the poles temperate. Additionally, the uplift of the Himalayas has dramatically increased rock exposure and weathering, which is the main driver of CO2 burial, by carbonate formation. And on top of all that has been the continued evolution of plant life, particularly the grasses, which have extra mechanisms to extract CO2 out of the atmosphere.

CO2 in the atmosphere has been falling through most of the Cenozoic.

All this has led to the very low levels of CO2 in the atmosphere, which have been stable at about 300 ppm over the last million years, very gradually declining prior to that time. Now we are pushing 420 ppm and beyond, which the biosphere has not seen for ten million years or more, and doing so at speeds that no amount of evolution can accommodate. The problem is clear enough, once the facts are laid out.

But what about those glaciations, which have been such a dramatic and influential feature of Earth's climate over the last few million years? They have followed a curious periodicity, advancing and retreating repeatedly over this time. Does that have anything to do with CO2? It turns out that it does not, and we have to turn our eyes to the heavens again for an explanation. It was Milankovitch, a century ago, who first solidified the theory that the changing orbital parameters of Earth, and particularly the intensity of the sun in the Northern hemisphere, where most of the land surface of Earth lies, that causes this repetitive climatic behavior.  

Cycles of orbital parameters and glaciation, over a million years.

It was in 1976 that a more refined analysis put a mathematical model and better data behind the Milankovitch cycles, showing that one major element of our orbit around the sun- the variation of eccentricity- had the greatest overall effect on the 100,000 year periodicity of recent glacial cycles. Eccentricity is how skewed our orbit is from round-ness, which varies slightly over time, due to interactions with other planets. Secondly, the position of the Earth's tilt at various points of this eliptical orbit, whether closer to the sun in northern summer, or father away, has critical effects on net solar input and on glaciation. The combined measure is called the precessional index, expressing the earth-sun distance in June. The eccentricity itself has a period of about 93,000 years, and the precessional index has a periodicity of 21,000 years. As glacial cycles over the last 800,000 years have had a strong 100,000 year periodicity, it is clearly the eccentricity alone that has the strongest single effect.

Lastly, there is also the tilt of the Earth, called obliquity, which varies slightly with a 40,000 year cycle. A recent paper made a major claim that they had finally solved the whole glaciation cycle in more detail than previously, by integrating all these cycles into a master algorithm for when glaciations start/end. They were curious about exactly what drives the deglaciation phase, within the large eccentricity-driven energetic cycle. The rule they came up with, again using better data and more complicated algorithms, is that it reaches its maximum rate when, after a minimum of eccentricity, the precession parameter (the purple line, below) has reached a peak, and the obliquity parameter (the green line, below) is rising. That is, when the Earth's degree of tilt and closeness to the sun in Norther summer are mutually reinforcing. There are also lags built into this, since it takes one or two thousand years for these orbital effects to build heat up in the climate system, a bit like spring happening annually well after the equinox.

"We find that the set of precession peaks (minima) responsible for terminations since 0.9 million years ago is a subset of those peaks that begin (i.e., the precession parameter starts decreasing) while obliquity is increasing. Specifically, termination occurs with the first of these candidate peaks to occur after each eccentricity minimum."

 

 

Summary diagram from Barker, et al. At the very top is a synopsis of the orbital variables. At bottom are the glacial cycles, marked with yellow dots (maximum slope of deglaciation), red dots (maximum extent of deglaciation) and blue dots (maximum slope of reglaciation, also called inception). Above this graph is an analysis of the time spans between the yellow and red dots, showing the strength of each deglaciation (gray double arrows). They claim that this strength is proportion to an orbita parameter illustrated above with the T-designation of each glacial cycle. This parameter is precession lagged by obliquity. Finally in the upper graph, the orbital cycles are shown directly, especially including eccentricity in gray, and the time points of the yellow nodes are matched here with purple nodes, lagged with the preceeding (by ~2,000 years) rising obliquity as an orange node. The green verticle bars were applied by me to ease the clear correlation of eccentricity maxima vs deglaciation maxima.

I have to say that the communication of this paper is not crystal clear, and the data a bit iffy. The T5 deglaciation, for instance, which is relatively huge, comes after a tiny minimum of eccentricity and at a tiny peak of precession, making the scale of the effect hard to understand from the scale of the inputs. T3 shows the opposite, with large inputs yielding a modest, if extended, deglacial cycle. And the obliquity values that are supposed to drive the deglaciation events are quite scattered over their respective cycle. But I take their point that ultimately, it is slight variations in the solar inputs that drive these cycles, and we just need to tease out / model the details to figure out how it works.

There is another question in the field, which is that, prior to 800,000 years ago, glacial cycles were much less dramatic, and had a faster cadence of about 40,000 years. This is clearly more lined up with the obliquity parameter as a driver. So while obliquity is part of the equation in the recent period, involved in triggering deglaciation, it was the primary driver a million years ago, when CO2 levels were perhaps slightly higher and the system didn't need the extra push from eccentricity to cycle milder glaciations. Lastly, why are the recent glacial cycles so pronounced, when the orbital forcing effects are so small and take thousands of years to build up? Glaciation is self-reinforcing, in that higher reflectivity from snow / ice drives down warming. Conversely, retreat of glaciers can release large amounts of built-up methane and other forms of carbon from permafrost, continental shelves, the deep ocean, etc. So there may be some additional cycle, such as a smaller CO2 or methane cycle, that halts glaciation at its farthest extent- that aspect remains a bit unclear.

Overall, the earlier paper of Hays et al. found that summer insolation varies by at most 10% over Earth's various orbital cycles. That is not much, yet it drives glaciation of ice sheets thousands of feet thick, and reversals back to deglaciation that uncovers bare rock all over the far north. It shows that Earth's climate is extremely sensitive to small effects. The last time CO2 was as high as it is now, (~16 mya), Greenland was free of ice. We are heading in that direction very rapidly now, in geological terms. Earth has experienced plenty of catastrophes in the past, even some caused biologically, such as the oxygenation of the atmosphere. But this, what we are doing to the biosphere now, is something quite new.

• That new world order we were working on...
• Degradation and corruption at FAA.. what could go wrong?
• Better air.
• Congress has the power, should it choose to use it.
• Ongoing destruction, degradation.
• Oh, Canada!

Realism in Foreign Policy

Idealism or realism? This is not just a left-right issue, but a deeper issue of values in foreign policy.

Think tanks on both the right and the left tout foreign policy realism, impatient with the demands that the post-war era have placed on the US as the unique, exceptional (and rich) leader of the free and democratic world. Whether from a cost perspective or a peace perspective, backing off from our world-wide commitments and ideals is attractive to many. The current administration has dramatically taken up their banner, reversing US policy, dropping Ukraine, allying with Russia, and ending idealism, generosity and empathy as a elements of foreign policy. What was firmly planted after World War 2 and flowered under John F. Kennedy has now been buried. So, are we great yet?

Where idealism in foreign policy takes up moral crusades, like human rights, women's rights, and global equity, even climate change, realism sticks to power and assumes anarchy, not order, as the natural state of international affairs. Realists sell themselves as hard-headed, unsentimental, and into the bargain, less likely to get us mixed up in wars. The most recent US wars, after all, from Vietnam to Iraq, were all crusades to foster democracy, in one form or other. Better to wash our hands of it all, care less about saving the people of the world, and more about bullying our neighbors to get what we want.

These are not really exclusive approaches, but rather shades of emphasis. The raw power of military and economic kinds is central to both, even if soft power is more of a focus for the idealists. But if you think about it more deeply, even these distinctions fade away, and both approaches end up being idealistic, just differing in the ideals they vaunt. The current administration clearly has its ideals- of Putin, Victor Orban, and authoritarianism ascendant world-wide. Its lack of empathy is not realism, it is a crabbed idealism- that of the rich and powerful lording it over the masses, both domestically and internationally.  

International power is composed of many things. But mostly, it is made up of relationships multiplied by technological capabilities. Two people can always overpower one person, and the same is true internationally. Bigger countries can field bigger armies. Bigger countries can field more researchers and manufacturers to arm those people with better weapons. Alliances between countries can make even more menacing combinations. 

It is, at base, social relationships that create power, and this is where realism really falls down. If one's ideal is transactional and bullying, worshipping power and taking a small-minded and greedy approach to international affairs, (that is to say, a zero-sum approach), then one will find that the few friends one has are fair-weather friends of convenience. Alliances between such partners frequently fall apart and re-arrange, creating the extremely dangerous environment conducive to major wars. Relationships are fungible and disposable. Europe had a long balance-of-power phase in the 1800's after the Napoleonic wars, until it collapsed in the 1900's in cataclysmic world wars, thanks in both cases to unstable alliance structures, not to mention authoritarian manias. The post-World War 2 era, the one we are witnessing the collapse of right now, was founded on something much more stable- true friendship and shared ideals of democracy. 

One can reply that helping the weak defend themselves against the strong is a sure recipe for entanglement in a lot of wars. Our involvement (up to now) in Ukraine is a case in point. We encouraged Ukraine to pursue a democratic path, thwarting Russia's clear and stated interests. And then we got dragged into this cataclysmic war. Why not side with the strong against the weak, instead? Wouldn't that make for a more stable world? Well, at some point we may be the weak one, not the strong one. What then? In the ever-shifting constellation of international alliances in a transactional, "realistic" world, there is no telling what tomorrow may bring, since values are not anchored in natural friendship or sympathy, but in naked interests, which are subject to rapid adjustment and negotiation. The disastrous Ribbentrop-Molotov pact comes to mind, as an example of such "realistic" foreign policy.

That is not a good world to live in, even if it has represented most of history. Realists may be right that their view is the mafia-like baseline of international relations, devoid of any human values and run on a power basis. Well, we can do better, both morally and objectively. That is what the last eighty years of international relations were all about. They were about setting up an international system where big countries at least tried to cloak their leadership in common interests, progress, and values. Where there was order, of some basic sort, which led to prosperity and security. And the Soviets bought into it as well, trying desperately to sell their adventures as standing for some kind of progressive, pro-worker ideology. Which lasted all the way to the end of the cold war, till its contradictions had grown too glaring. The US-led system has had its contradictions and hypocrisies as well, but the latest leap into the authoritarian camp is hardly fore-ordained or natural to our traditions.

Now, it looks like Winter is Coming. If the US forcibly devolves the international system into a value-less scramble for power, no one can rely on, or be satisfied with, stable friendships, so the system will be in greater flux, as powers test each other. When friendships are devalued, what is left but competition, such as trade wars, causing general destruction, and eventually desperate measures to regain relative power. 

• The policy is plain.
• Social insecurity.
• Nothing strategic about it.
• Wells on the pandemic. For me, the remarkable memory is how little we collectively knew about the simplest things- masks, aerosols, surfaces. That was inexcusable.

The Train Tracks of Synapsis

Structures that align and tether the chromosomes in meiosis are now understood in some molecular detail.

It has been one of the wonders of biology- the synaptonemal complex that aligns homologous chromosomes during meiosis. While chromosomes regularly line up in the middle of the cell during mitosis, so that they can be evenly divided between the daughter cells, in this process they only have to join at their centromeres, which get dragged to the midline of the cell, and then pulled back apart at cell division. In meiosis, on the other hand, not only do the sister chromosomes that have just replicated stick together at their centromeres, but the homologous chromosomes, which have never bothered about each other since sperm fused with egg, suddenly seek each other out and pair up in an elaborate dance of DNA breakage, alignment, cross-over, and repair. Then in the first division, these cross-over-joined homologs line up at the midline and get pulled apart as their crossovers are repaired. The second division follows, much more like mitosis, where the duplicated sister chromosomes line up at the midline based on their centromere attachments, and then separate into haploid gametes.

Comparison of mitosis vs meiosis, which goes through an extra division and alternate chrosomosome pairing and separation processes in the firsts division.

The two divisions are fundamentally different, with the first involving novel chromosome pairings and attachments. The opening act of all this, which I won't go into further, is a sprinkling of ~400 DNA strand breaks induced specifically all over the genome, which sets up a repair process at each site, where the chromosomes (using Rad51) seek out good copies of the damaged DNA- that is, another, matching, DNA molecule. There are specific processes that appear to prevent use of the recently replicated "sister", which would be the most closely identical copy that could be used. Instead, there is a bias to use the "homologous" copy from the other parent. But these homologous chromosomes have just been replicated as well. How to line all this up so that the chromosomes all line up neatly and separate neatly during the first meiotic division? The answer is the synaptonemal complex.

Schematic of the synaptonemal complex joining two homologous chromosomes. The lateral elements are on each side, and the central element lines up the center. Crossing the gap is the transverse elements, now known to be composed of the SYCP1 protein. At bottom is a diagram from its atomic structure of how SYCP1 coils together, and how its ends join to zip up the synaptonemal gap. 

This is a train track of connecting proteins between the homologous chromosomes. It is evident that the DNA breaks come first, followed by the search for matching homologs, followed by the radiating and progressive assembly of the synaptonemal complex out from the break repair sites. The components of its major structures have been mostly characterized- the lateral element where the DNA loops line up; the transverse element that spans the gap between the homologous chromosomes, and the central element, proteins at the midline that help the transverse elements assemble. A paper from 2023 characterized the transverse element protein, SYCP1, which is a long coil of a protein that dimerizes to make a strong coil, and then dimerizes again head-to-head to create the symmetric bridge over the whole width of the synaptonemal complex. Which is about 100 nanometers in width. 

These authors then focus on a series of experiments using key mutations at the dimer-dimer head-to-head interaction area, to demonstrate how this head-to-head zippering works in detail. Mutating just two amino acids in this contact region eliminates the head-to-head interaction, making synapsis impossible. In these cases, the homologous chromosomes (from mice) remain in proximity, especially at crossover sites, but are no longer zippered up and closely aligned.

Spreads of mouse meiotic chromosomes, labeled as shown with antibodies against two synaptonemal proteins. From the top, wild-type SYCP1, then single individual mutations in the end-joining region, and at bottom SYCP1 with two point mutations that eliminate its function entirely. The chromosomes at the bottom are aligned only by virtue of their crossover points, but not by a zippered up synaptonemal complex. Needless to say, mice like this are not fertile.

Thus what was once a hazy mystery in the highest power microscopes has been defined in molecular terms, highlighting once again the power of curiosity, and the essentially moral aim of truth-seeking- to reveal what is true, rather than dictate it. But who cares about all that? Truth, knowledge, science... these values are now not only in question, but under active attack. Who is making America great, and who is diminishing it? Those in our institutions of power who have a voice will hopefully see the consequences and act on them, before our history and values are entirely corrupted.

• Sociopaths at work.
• Evidently the model is that we become a version of China/Russia, and make a tripolar world. Not a little Orwellian. And who knows, perhaps we will offer Russia a deal to partition Canada. That is, after we get done partitioning Ukraine.
• A black day.
• Oh, wait, the next day was even worse.
• Shades of Stalin, with a sad sartorial hat-tip to Steve Jobs.
• Unlawful and vindictive destruction at the NIH, and of biological research in general.
• And all for love.

Impeachment is Inevitable

Whether congress wants to or not, it will be forced to defend its role in government.

Looking out over the incredible destruction the new president has already wrought at home and abroad, it is hard to see this continuing for a full four-year term. There is a honeymoon now, and a shock campaign. There is delirium in hard-right circles that their fondest dreams of rampant chaos in the bureaucracy, with racism and fascism ascendant, are coming true. But there will come a time when the costs begin to appear, the appetite for dysfunction will wane, and the tide turns. Congress has small Republican margins, and it won't take many members to face up to our rapidly expanding constitutional crisis.

Maybe I am spinning a fantasy here, but one thing seems certain. The current president is constitutionally (pardon the expression) unable to follow directions. His oath of office was barely out of his mouth before he started violating the constitution and running roughshod over the explicit authorizations and appropriations of Congress. Not to mention direct assertions that the constitution doesn't mean what it plainly says, about birthright citizenship. This is not going to stop, and the only way our system of government is going to survive is that the other branches, specifically congress, use their powerful tools to reset the balance.

Article 2

Harder to judge are the attitudes of the congresspeople who are on the spot. The Republicans have largely rolled over in approving the first, abysmal slate of cabinet nominees. Again, there is a honeymoon of sorts. Party discipline is particularly strong on the conservative side, and the president has eagerly used his tools of intimidation and hatred to obtain obedience. So it is hard to say when they will crack. But as the functions of government degrade, the country is laughed at and reviled around the world, the economic damage accumulates, and constituents line up to complain, the equation will change. And anyhow, they would merely be elevating the vice president, who is hardly an opponent of their ideological aims, and is part of the Senate community (however disliked on both sides). So impeachment becomes a much less imposing action than it might otherwise be. 

As they say, the third time's the charm!

• Presidents day.
• Oh the irony. Science comes up with a vaccine that saves millions, who turn into idiots.

Cloudy, With a Chance of RNA

Long RNAs play structural and functional roles in regulation of chromosome replication and expression.

One of the wonderful properties of the fruit fly as a model system of genetics and molecular biology has been its polytene chromosomes. These are hugely expanded bundles of chromosomes, replicated thousands of times, which have been observed microscopically since the late 1800's. They exist in the larval salivary gland, where huge amounts of gene expression are needed, thus the curious evolutionary solution of expanding the number of templates, not only of the gene needed, but of the entire genome. 

These chromosomes where closely mapped and investigated, almost like runic keys to the biology of the fly, especially in the day before molecular biology. Genetic translocations, loops, and other structural variations could be directly observed. The banding patterns of light, dark, expanded, and compressed regions were mapped in excruciating detail, and mapped to genetic correlates and later to gene expression patterns. These chromosomes provided some of the first suggestions of heterochromatin- areas of the genome whose expression is shut down (repressed). They may have genes that are shut off, but they may also be structural components, such as centromeres and telomeres. These latter areas tend to have very repetitive DNA sequences, inherited from old transposons and other junk. 

A diagram of polytene chromosomes, bunched up by binding at the centromeres. The banding pattern is reproducible and represents differences in proteins bound to various areas of the genome, and gene activity.

It has become apparent that RNA plays a big role in managing these areas of our chromosomes. The classic case is the XIST RNA, which is a long (17,000 bases) non-coding RNA that forms a scaffold by binding to lots of "heterogeneous" RNA-binding proteins, and most importantly, stays bound near the site of its creation, on the X chromosome. Through a regulatory cascade that is only partly understood, the XIST RNA is turned off on one of the X chromosomes, and turned on the other one (in females), leading the XIST molecule to glue itself to its chromosome of origin, and then progressively coat the rest of that chromosome and turn it off. That is, one entire X is turned into heterochromatin by a process that requires XIST scaffolding all along its length. That results in "dosage compensation" in females, where one X is turned off in all their cells, allowing dosage (that is, the gene expression) of its expressed genes to approximate those of males, despite the presence of the extra X chromosome. Dosage is very important, as shown by Down Syndrome, which originates from a duplication of one of the smallest human chromosomes, creating imbalanced gene dosage.

A recent paper described work on "ASAR" RNAs, which similarly arise from highly repetitive areas of human chromosomes, are extremely long (180,000 bases), and control expression and chromosome replication in an allele-specific way on (at least) several non-X chromosomes. These RNAs, again, like XIST, specifically bind a bunch of heternuclear binding proteins, which is presumably central to their function. Indeed, these researchers dissected out the 7,000 base segment of ASAR6 that is densest in protein binding sites, and find that, when transplanted into a new location, this segment has dramatic effects on chromosome condensation and replication, as shown below.

The intact 7,000 base core of ASAR6 was transplanted into chromosome 5, and mitotic chromosomes were spread and stained. The blue is a general DNA stain. The green is a stain for newly synthesized DNA, and the red is a specific probe for the ASAR6 sequence. One can see on the left that this chromosome 5 is replicating more than any other chromosome, and shows delayed condensation. In contrast, the right frame shows a control experiment where an anti-sense version of the ASAR6 7,000 base core was transplanted to chromosome 5. The antisense sequence not only does not have the wild-type function, but also inhibits any molecule that does by tightly binding to it. Here, the chromosome it resides on (arrows) is splendidly condensed, and hardly replicating at all (no green color).

Why RNA? It has become clear over the last two decades that our cells, and particularly our nuclei, are swimming with RNAs. Most of the genome is transcribed in some way or other, despite a tiny proportion of it coding for anything. 95% of the RNAs that are transcribed never get out of the nucleus. There has been a growing zoo of different kinds of non-coding RNAs functioning in translational control, ribosomal maturation, enhancer function, and here, in chromosome management. While proteins tend to be compact bundles, RNAs can be (as these ASARs are) huge, especially in one dimension, and thus capable of physically scaffolding the kinds of structures that can control large regions of chromosomes.

Chromosomes are sort of cloudy regions in our cells, long a focus of observation and clearly also a focus of countless proteins and now RNAs that bind, wind, disentangle, transcribe, replicate, and congregate around them. What all these RNAs and especially the various heteronuclear proteins actually do remains pretty unclear. But they form a sort of organelle that, while it protects and manages our DNA, remarkably also allows access to it for sequence-specific binding proteins and the many processes that plow through it.

"In addition, recent studies have proposed that abundant nuclear proteins such as HNRNPU nonspecifically interact with ‘RNA debris’ that creates a dynamic nuclear mesh that regulates interphase chromatin structure."

• What it takes to be a real Christian.
• Courts, schmorts.
• Assholes.
• I wonder what Christians think about the destruction of US AID? Or of consumer protections?
• A disconnect down at Silicon Valley.
• Retaliation is real.

Sugar is the Enemy

Diabetes, cardiovascular health, and blood glucose monitoring.

Christmas brought a book titled "Outlive: The Science and Art of Longevity". Great, I thought- something light and quick, in the mode Gweneth Paltrow or Deepak Chopra. I have never been into self-help or health fad and diet books. Much to my surprise, however, it turned out to be a rather rigorous program of preventative medicine, with a side of critical commentary on our current medical system. A system that puts various thresholds, such as blood sugar and blood pressure, at levels that represent serious disease, and cares little about what led up to them. Among the many recommendations and areas of focus, blood glucose levels stand out, both for their pervasive impact on health and aging, and also because there are new technologies and science that can bring its dangers out of the shadows.

Reading: 

• Outlive
• The many facets and forms of damage by high blood sugar, at the level of molecular biology.
• Recent analyses of blood sugar variability, from researchers at Stanford
• ... with tool for anyone with a CGM to upload their own data

Where do cardiovascular problems, the biggest source of mortality, come from? Largely from metabolic problems in the control of blood sugar. Diabetics know that uncontrolled blood sugar is lethal, on both the acute and long-terms. But the rest of us need to realize that the damage done by swings in blood sugar are more insidious and pervasive than commonly appreciated. Both microvascular (what is commonly associated with diabetes, in the form of problems with the small vessels of the kidney, legs, and eyes) and macrovascular (atherosclerosis) are due to high and variable blood sugar. The molecular biology of this was impressively unified in 2005 in the paper above, which argues that excess glucose clogs the mitochondrial respiration mechanisms. Their membrane voltage maxes out, reactive forms of oxygen accumulate, and glucose intermediates pile up in the cell. This leads to at least four different and very damaging consequences for the cell, including glucose modification (glycation) of miscellaneous proteins, a reduction of redox damage repair capacity, inflammation, and increased fatty acid export from adipocytes to endothelial (blood vessel) cells. Not good!

Continuous glucose monitored concentrations from three representative subjects, over one day. These exemplify the low, moderate, and severe variability classes, as defined by the Stanford group. Line segments are individually classed as to whether they fall into those same categories. There were 57 subject in the study, of all ages, none with an existing diagnosis of diabetes. Yet five of them had diabetes by traditional criteria, and fourteen had pre-diabetes by those criteria. By this scheme, 25 had severe variability as their "glucotype", 25 had moderate variability, and only 7 had low variability. As these were otherwise random subjects selected to not have diabetes, this is not great news about our general public health, or the health system.

Additionally, a revolution has occurred in blood glucose monitoring, where anyone can now buy a relatively simple device (called a CGM) that gives continuous blood glucose monitoring to a cell phone, and associated analytical software. This means that the fasting blood glucose level that is the traditional test is obsolete. The recent paper from Stanford (and the literature it cites) suggests, indeed, that it is variability in blood glucose that is damaging to our tissues, more so than sustained high levels.

One might ask why, if blood glucose is such a damaging and important mechanism of aging, hasn't evolution developed tighter control over it. Other ions and metabolites are kept under much tighter ranges. Sodium ranges between 135 to 145 mM, and calcium from 8.8 to 10.7 mM. Well, glucose is our food, and our need for glucose internally is highly variable. Our livers are tiny brains that try very hard to predict what we need, based on our circadian rhythms, our stress levels, our activity both current and expected. It is a difficult job, especially now that stress rarely means physical activity, and nor does travel, in our automobiles. But mainly, this is a problem of old age, so evolution cares little about it. Getting a bigger spurt of energy for a stressful event when we, in our youth, are in crisis may, in the larger scheme of things, outweigh the slow decay of the cardiovascular system in old age. Not to mention that traditional diets were not very generous at all, certainly not in sugar and refined carbohydrates.

• First, Twitter was turned into a dumpster fire, next the US.
• US government to be rebranded as X.
• Truth must die.
• "Not strictly constitutional"
• Let's go there.

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.