On the Transition to Godhood

Kicking and screaming, humanity is being dragged into a god-like state.

We thought that harnessing electricity would make us gods. Or perhaps the steam engine, or the first rocket ship, or the atomic bomb. But each of those powerful technological leaps left us wanting- wanting more, and wanting to clean up the messes each one left behind. Next are biotechnology, gene editing, and robotics. What to do?

The fact is that we have powers that traditionally were only given to gods. Vast raw physical powers, the ability to fly, and the ability to communicate with anyone, anywhere, instantly, and to know practically anything at a touch. But the greatest of all is our power to derange the entire biosphere- destroying habitats, exterminating species, filling our geologic layer with plastic and radioactive debris, and changing the composition and physics of the atmosphere. 

We have not come to terms with all this power. Indeed half of our political system can't stand the thought of it, and lives in the fantasy that nothing has changed, humanity is not trashing its home, and we can live as profligately as we wish, if only we don't look out the window. Even more disturbingly, this demographic generally holds to a fantasy god- some bearded male archetype- who will either make magically sure that everything comes out OK, or alternately will bring on the end times in flames of wrath and salvation for the select, making any rational worry for the environment we actually live in absurd.

Judgement day is coming!

This, at a moment when we need to grow into our awesome responsibilities, is naturally disheartening. Growing up out of an infantile mind set, where our parents made everything OK, is hard. Adulthood takes courage. It takes strength to let go of fantasy comforts. But the powers of adulthood are truly god-like, especially in this age. We make and remake our environments, look deep into space, into the past and the future, know and learn prodigiously. We make new people. 

Is is clear, however, that we are not taking these powers seriously enough. Overpopulation is one example. We simply can not go on having all the children we want, taking no responsibility for the load they are putting and will put on our home, the biosphere. As nascent gods, we need to survey our domain holistically and responsibly, looking to its future. And right now, that future is rather bleak, beset by irresponsible actors resistant to their higher calling.

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Tale of an Oncogene

Research on a key oncogene of melanoma, MITF, moves from seeing it as a rheostat to seeing it as a supercomputer.

The war on cancer was declared fifty years ago, yet effective therapies are only now trickling in. And very few of them can be characterized as cures. What has been going on, and why is the fight so slow? Here I discuss one example, of melanoma and one of its drivers and central players, the gene MITF.

Melanocytes are not really skin cells, but neural crest cells, i.e. originating in the the embryonic neural tube and giving rise to various peripheral neural structures in the spine, gut, and head. One sub-population migrates off into the epidermis to become melanocytes, which generate skin pigment in melanosome packets, which they distribute around to local keratinocytes. Evolutionarily, these cells are apparently afterthoughts, after originally having developed as part of photoreceptor systems. This history, of unusual evolution and extensive developmental migration and eventual invasion into foreign tissues, has obvious implications for their capacity to form cancers later in life, if mutations re-activate their youthful propensities.

 

Above is shown a sketch of some genes known to play roles in melanoma, and key pathways in which they act. In red are oncogenes known to suffer activating mutations that promote cancer progression. In grey are shown additional oncogenes, ones whose oncogenic mutations are simpler loss-of function, not gain of function, events. And green marks ancillary proteins in these pathways that have not (yet) been found as oncogenes of any sort. MITF is a transcription regulator that drives many genes needed for  melanocyte development and melanosome formation. It also influences cell cycle control and cytoskeletal and cell surface features relevant to migration and invasion of other tissues. This post is based mostly on reviews of the molecules active in melanoma, and the more focused story of MITF.

MITF binds to DNA near target genes, often in concert with other proteins, and activates transcription of the local gene (in most cases, though it represses some targets as well). The evidence linking MITF with melanoma and melanocytes is mostly genetic. It is an essential gene, so complete deletions are lethal. But a wide variety of "mi" mutations in mice and in humans lead to unusual phenotypes like white hair color, loss of hearing, large head formation, small blue eyes, osteopetrosis, and much else. Originally researchers thought there were several different genes involved, but they all resolved down to one complex locus, now called MITF, for mi transcription factor. Certain hereditary mutations also predispose to melanoma, as do some spontaneous mutations. That the dose of MITF also correlates with how active and aggressive a melanoma is also contributes to the recognition that MITF is central to the melanocyte fate and behavior, and also one of the most central players in the disease of melanoma.

The MITF gene spreads over 229,000 base pairs, though it codes for a protein of only 419 amino acids. The gene contains nine alternate transcription start sites, 18 exons (coding regions), and five alternate translation start sites, as sketched above. This structure allows dozens of different forms of the protein to be produced in different tissues and settings, via alternative splicing. The 1M form (above, bottom) is the main one made in melanocytes. Since the gene is essential, mutations that have the phenotypes mentioned above tend to be very small, affecting one amino acid or one splice site, or perhaps truncating translation near the end of the protein. Upstream of the MITF gene and in some of its introns, there are dozens of DNA sites that bind other regulators, which either activate or repress MITF transcription in response to developmental or environmental cues. For example, a LEF1/TCF site binds the protein LEF1, which receives signals from WNT1, which is a central developmental regulator, driving proliferation and differentiation of melanocytes from the stem neural crest cells.

That is just the beginning of MITF's complexity, however. The protein contains in its sequence codes for a wide array of modifications, by regulatory protein kinases (that attach phosphate groups), and other modifiers like SUMO-ylation and ubiquitination. Key cellular regulators like GSK3, AKT, RSK, ERK2, and TAK kinases each attach phosphates that affect MITF's activity. Additionally, MITF interacts with at least a dozen proteins, some of which also bind DNA and alter its target gene specificity, and others that cooperate to activate or repress transcription. One of the better-known signaling inputs is indirectly from the kinase BRAF1, which is a target of the first precision melanoma-fighting drugs. BRAF1 is mutated in half of melanoma cases, to a hyper-active form. It is a kinase responsive to growth factors, generally, and activates a core growth-inducing (MAP) kinase cascade (as shown above), among other pathways. BRAF1 has several effects on MITF by these pathways, but the dominant one seems to be its phosphorylation and activation of PAX3, which is a DNA-binding regulator that activates the MITF gene (and is, notably, absent from the summary figure above, showing how dynamic this field remains). Thus inhibition of BRAF1, which these precision drugs do, effectively reduces MITF expression, most of the time.

Then there are the gene targets of MITF, of which there are thousands, including dozens known to have significant developmental, cell cycle, pigment synthesis, cytoskeletal, and metabolic effects. All this is to say that this one gene participates in a bewilderingly complex network of activities only some of which are recognized to date, and none of which are understood at the kind of quantitative level that would allow for critical modeling and computation of the system. What has been found to date has led to a "switch", or rheostat hypothesis. One of the maddening aspects of melanoma is its resistance to therapy. This is thought in part to be due to this dynamic rheostat, which allows levels of MITF to vary widely and send individual cancer cells reversibly into several different states. At high levels of MITF, cancer cells are pigmented and proliferative (and sensitive to BRAF1 inhibition). But at medium levels of MITF, they revert more to their early migratory behavior, and become metastatic and invasive. So melanoma benefits from a diversity of cell types and states, dynamically switching between states that are both variable in their susceptibility to therapies like anti-BRAF1, and also maximally damaging in their proliferation and ranging activities (diagrammed below).

The theme that comes out of all this is enormous complexity, a complexity that only deepens the more one studies this field. It is a typical example in biology, however, and can be explained by the fact that we are a product of 4 billion years of evolution. The resulting design is far from intelligent- rather, it is a compendium of messy contraptions, historical compromises, and accreted mechanisms. We are very far from having the data to construct proper models that would critically analyze these systems and provide accurate predictions of their behavior. It is not really a computational issue, but a data issue, given the vast complexity we are faced with. Scientists in these fields are still thinking in cartoons, not in equations. 

But there are shortcuts of various kinds. One promising method is to analyze those patients who respond unusually well to one of the new precision treatments. They typically carry some hereditary alteration in some other pathway that in most people generates resistance or backup activity to the one that was drug-treated. If their genomes are fully sequenced and analyzed in depth, they can provide insight into what other pathway(s) may need to be targeted to achieve effective combination treatment. This is a lesson from the HIV and tuberculosis treatment experiences- that the redundancy and responsiveness of biological systems calls for multiple targets and multiple treatments to meet complex disease challenges.

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Hunting for Lost Height

Progress in sequencing technologies and genetic analysis nails down the genetic sources of variability in the trait of human height.

PBS has an excellent program about eugenics- the push by some scientists and social reformers in the early 1900's to fix social problems by fixing problematic people. Both the science and the social ethics fell into disrepute, however, and were completely done in by the Nazi's version. While the stigma and ethical futility of eugenics remains, human genetics has advanced immeasurably, putting the science on much firmer footing. One example is a recent announcement that one research group has found all the sources of genetic variation that relate to human height.

Height is obviously genetic, and twin studies show that it is 80% heritable. There has been an interesting literature on the environmental effects on height, to the extent that whole populations of malnourished immigrants find that, after they move to the US, their children grow substantially taller. So genetic influences are only apparent (as indicated by the 80% figure) in the absence of over-riding environmental constraints. 

The first attempts to find the genetic loci associated with height took off after the human genome was sequenced, in the form of GWAS studies (genome-wide association study). It was easier in this era to probe short oligonucleotide sequences against the sampled genomic DNA, rather than sequence whole genomes of many people. So GWAS typically took a large sample of about 500,000 locations through human genomes that were variant, and used them to test which of those variants a set of human populations had. A massive correlation analysis was done versus the traits of those people, say their height, or weight or health, to see which markers (i.e. variants) correlated with the trait of interest. 

Such studies only found about 5% to 25% of the heritability of height, perplexing researchers. They were sampling the entire genome, if sparsely. The 500,000 markers corresponded to about one every 6,000 base pairs, so should be near enough to most genes, if they have significant effects on the trait of interest. And since most human genome regions are inherited as relatively large blocks, (haplotypes), due to our near-clonal genetic history, the idea was that sampling a sparse set of markers was sufficient to get at any significant effect from any gene. Later work could then focus in on particular regions to find the actual genes and variations that were responsible for the trait in question.

But there was a big problem, which was that the variants selected to go into the marker pool were from a very small population of a few hundred people. Recall that sequencing whole genomes was very expensive at this time, so researchers were trying to wring as much analysis out of as little data as possible. By 2018, GWAS type studies were still only finding genetic causes for about 25% of the variability of height, clearly short of what was known from simple genetic analysis of the trait. Not only that, but the number of genes implicated was rising into the thousands, each with infinitesimal effect. The first 40 genes found in these studies only accounted for about 5% of the variation in height. 

The large effect of rare alleles. MAF (minor allele frequency) in the human population, plotted against the trait variance it accounts for. The color code (LD, or linkage disequilibrium) indicates selection against the locus (if high) and other predicted characteristics of the variation, in the color scheme. It is very rare protein-altering variants (blue) that have the strongest individual effects.

The current work (review, review) takes a new approach, by virtue of new technologies. They sequence the full genomes of over 20,000 people, finding a plethora of rare alleles that had not been included in the original marker studies- alleles that have significant effects on height. They find variations that account for 79% of height heritability, which is to say, all of it. It turns out that the whole premise of the GWAS study, that common markers are sufficient to analyze diverse populations, is incorrect. The common markers are not as widely distributed, or as well-linked to rare variants, as was originally assumed. The new technologies allow vastly more depth of analysis (full genome sequencing) and broader sampling (20,000 vs a few hundred) to find rare and influential variants. We had previously learned that using common variants confines the GWAS analysis to uninteresting variants- those that are not being selected against. This may not be an enormous issue in height trait, (though these researchers find that many of their new, rare loci are being selected against), but it was a big issue in the analysis of disease-linked genetic loci, like for diabetes or alcoholism. While these traits may be common, the most influential genetic variants that cause them are not, for good reason.

One can imagine that over time, everyone will have their genome sequenced, and that this data will lead to a fuller, if not complete, understanding of trait genetics. But what are the genes responsible for the traits? All this is still an abstract mapping of locations of variability (what used to be called mutation) correlated with variations of a trait. This newest data identifies thousands of influential variants covering one third of the genome. This means that, like most interesting traits, the genetics of human height are dispersed- a genetic fog. All sorts of defects or changes can influence this trait to infinitesimal degrees, making it a fool's errand to look for a gene for height.

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Viruses Have Always Been With Us

Some researchers argue that viruses form their own kingdom of life, and originated prior to the last common cellular ancestor.

Viruses are all about, even more of them than bacteria. The pandemic has focused our attention on one of them, but they are truly astronomical in diversity and numbers. Where did they come from? This has historically been thought a pointless question, since, even if one concedes that they are life forms of a sort, they mutate and evolve quite a bit faster than cells and organisms do, erasing most of their history. Additionally, they have been thought to exchange genes at a high rate with their hosts, also tending to erase whatever history they retain. But an article published back in 2015 fought back against all this pessimism, and made the case that virus histories can be reconstructed on a global scale and have some very interesting things to tell us.

Their first point is that gene exchange between viruses and hosts is less confusing than thought. Cells certainly have adopted viral genes at a high rate. Our own genomes are chock full of retroviral remnants, for instance. But functional genes are a different story. Relatively few seem to have gone either way (though see Koonin et al., arguing that many viral capsid and coat proteins were adopted from cellular genomes). The core viral replication proteins, such as the SARS-CoV2 RNA polymerase, for instance, is not related to cellular enzymes, and seems to be very ancient. The authors suggest that such key components originated even before the last common cellular ancestor- the point of divergence between archaea, bacteria, and eukaryotes.

To overcome the main technical hurdle of rapid evolution, the authors use protein fold analysis. Instead of studying DNA sequences, (which evolve quite rapidly), or protein sequences, (which evolve more slowly), this uses the shape of the protein, which tends to persist even after sequence similarity is completely lost. This is one way to get at very deep phylogenies, and they claim that it points to a substantial set of protein folds that are specific to viruses and wide-spread within viral families. They point out additionally that these proteins tend also to be confined to families of viruses, one more indication that virus evolution has not been promiscuous, but rather remarkably traceable through time. Viruses are classified into major families by their mode of replication. Thus RNA viruses and DNA viruses appear to have, for instance, distinct and ancient lineages.

One way to make sense of these observations and claims is that viruses were actually cells at very early times. It is common for parasites to progressively lose functions that are needed in the free-living state but become unnecessary when living off one's parents, er some other fully competent cell. The closer the symbiotic or parasitic association, the fewer functions the parasite needs. If the parasite is intracellular, then a huge amount of cellular overhead can be dispensed with. Mitochondria evolved this way, from free-living bacteria to organelles now with only about 33 genes. 

Viruses come in all sorts of sizes, from nearly cell size, encoding a thousand genes, down to specks of RNA only 250 nucleotides long. This diversity suggests the plausibility of their origination as cells, and subsequent down-scaling through a parasitic lifestyle.

But what were those cells, and whom did they parasitize? The distinct and peculiar gene complements and mechanisms of viruses, particularly the RNA viruses, suggests that they originated prior to the major split of existing cellular kingdoms. It stands to reason that cellular life has been saddled with parasites and viruses almost since the advent of cells, so some of these virus families may predate the advent of DNA, thus the prevalence of RNA viruses. The authors do an analysis of ages of the protein folds they find and their distribution, and suggest that those folds shared in all domains of life (viruses, archaea, bacteria, and eukaryotes) show that those from this set found in RNA viruses are significantly older than those found in DNA viruses. Such protein folds that are universal would be the most ancient, so finding differention among which viruses have them suggests that the major virus lineages come from different epochs of this most ancient era of cellular evolution. Interestingly, the pattern they do not find is one reflecting the cellular domains of life, which would be the case if viruses arise continuously or in relatively modern times from their cellular milieu.

Phylogenetic tree of protein folds from all domains of life, including viruses. Note the close clustering of RNA viruses near the root, and the early distribution of other viruses, compared to the later divergence of cellular domains. This kind of stretched phylogenetic tree is unfortunately symptomatic of an unsually high evolutionary rate, which is also a viral property. So it is not clear whether these authors have fully resolved this issue with their protein fold-based methods.

 

The upshot is that these authors promote the idea that viruses should constitute their own superkingdom of life, in parallel with the major cellular superkingdoms- archaea, bacteria, and eukaryotes. The rooting/ordering of the cellular tree remains quite controversial, but viruses are clearly something else again. They exchange a fair amount of genetic material with cells, but retain noticeable traces of early protein and RNA evolution. The idea that they arose from primitive or proto-cells also makes sense as a general proposition, for otherwise it is difficult to imagine their origin, such as from naked nucleic acids. This whole view remains quite controversial in the field, however, given the difficulties of the molecular analysis and the general prejudice against viruses as proper forms of life. But I think time will bear out this view and add a significant feature to early, as well as current, evolution.

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The Parables of Octavia Butler

Review of Parable of the Sower, and Parable of the Talents, about earily familiar dystopias and the religions they call forth.

Octavia Butler is having a moment. The late science fiction author published the parable books in 1993 and 1998, not even knowing of the coming G. W. Bush administration, let alone that of Donald Trump. But her evangelical-supported right wing presidential candidate issues a call to "Make America great again". Her insight and prescience is head-spinning, in books that portray an America much farther gone into division, inequality, corporate power, and chaos (all owing to climate change(!)) than we in actual reality are- yet only by degrees. That is only the window dressing and frame, however. Her real subjects are religion and human purpose. I will try to not give away too much, since these make dramatic and interesting reading.

The books introduce heroine Lauren Olamina, who is totally together and possessed of a mission in life. She grows up in a neighborhood compound walled off from the chaos outside, but quite aware of the desperate conditions there. Her father is a pastor, and both she and her brother become, through the books, preachers as well. The brother in a conventional Christian mode, but Lauren founds a new religion, one maybe tailored for the generally skeptical science fiction audience. God is change. That is it. Lauren emphasizes empathy, usefulness, education, and the shaping of change, but there is no god as traditionally conceived. It is a sort of buddhistic philosophy and educational / communal program rather than a supernaturalist conjuring, and love (or fear), of imaginary beings.

One question is whether such a philosophy would actually gain adherents, form communities and function as a religion. I get the sense that Butler would have dearly loved for her ideas to gain a following, to actually ripen, as did those of fellow science fiction writer L. Ron Hubbard, into an actual religion (however horrible his escapade actually turned out to be!). But their difference is instructive. Hubbard's Dianetics/Scientology is a floridly imagined narrative of super-beings, secret spiritual powers, and crazy salvation. Absolute catnip to imaginative seekers wanting to feel special and purposeful. On the other hand, Olamina's system is quite arid, with most of the motive force supplied, as the book relates, by her own determination and charisma. Her philosophy is true, and therein lies a big, big problem. Truth does not supply purpose- we already knew that scientifically. Natural selection is all about change, and makes us want to live, flourish, and propagate. Change is everpresent, and while it might be healthy to embrace it and work with it, that is hardly an inspiring and purpose-filling prospect, psychologically. As the books relate in their narrative of Lauren's life, change is also often quite terrible, and to be feared.

But the more important question is what role people such as Lauren play, and why people like her followers exist. People need purpose. Life is intrisically purposeless, and while we have immediate needs and wants, our intelligence and high consciousness demands more- some reason for it all, some reason for existence, collectively and individually. An extra motive force beyond our basic needs. We naturally shape our lives into a narrative, and find it far easier and more compelling if that narrative is dramatic, with significance beyond just the humdrum day-to-day. But such narratives are not always easy to make or find. Classic epics typically revolve around war and heroic deeds, which continue to make up the grist of Hollywood blockbusters. Religion offers something different- a multi-level drama, wrapped up in collective archetypes and usually offering salvation in some form, frequently a hero, if not a militaristic one. Last week's post mentioned the life of Che Guevara, who found purpose in Marxism, and was so fully seized by it that he bent many others, possibly the whole nation of Cuba, to his will / ideology. Lauren Olamina is a similar, special person who has, through her own development and talents, discovered a strong purpose to her life and the world at large that she feels compelled to share, pulling others along on her visionary journey. Are such people "strong"? Are their followers "weak"? 

Human social life is very competitive, with the currency being ability to make others think what you want them to think, and do what you want them to do. Our ideology of freedom was built by a founding class of dominant, slave-holding rich white men who wanted only to come to a reasonable accommodation for political power within their class, not extend freedom to women, blacks, or the poor. This ideology was highly successful as a sort of civic religion, coming down to us in two traditions- the "winning" tradition of native American extermination, ruthless capitalism, and growing international empire- all set within a reasonably stable elitist political system. And the second "freedom" tradition, which gave us abolitionism, the civil rights movement, and the modern Democratic party, which takes Jefferson's ideals at their word, however little he actually meant them.

Religion is a particularly powerful engine of political and social ideology, making people go through ridiculous rituals and abasements to keep on the safe side of whatever the powerful tell them. So yes, domineering social personalities like Lauren and Che, (and Trump), are very powerful, deservedly treated as larger-than-life, charismatic figures. Their powers are archetypal and dangerous, so it falls to skeptics and free-thinkers to offer antidotes, if their charisma goes off the rails. Butler offers a hero who is relentlessly good and positive, as well as charismatic and strong, so the only competition comes from ignorance, conventional wisdom, and from the competing religious powers like traditional Christianity. But the power of artificial purposes, and of the charismatic figures who propound them, is almost uniformly corrupting, so Lauren's opposition is, in the end, far more realistic as a portrayal of what we are facing, now and in the future.

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