How do Groups Become Individuals?

Investigating evolutionary transitions in individuality, whereby biological entities team up to form greater entities.

As readers are probably aware, they comprise myriads- legions of cells, each teaming with molecules and genes, plus the galaxies of the microbiome. We feel like individuals, but have been assembled over billions of years of evolution out of alot of smaller components, with dramatic steps taking place in what are called evolutionary transitions in individuality, or ETI. A recent paper introduced me to this literature, but it is so poorly written and conceived that we won't mention it any further. 

Some of the landmark transitions of this type are from an RNA world of individual replicators to that of cells, or at least blobs that collected replicators into genes, now organized on chromosomes. Next was the eukaryotic cell, which arose as the joint project of at least two quite disparate microbial cells, one the bacterium that formed the contemporary mitochondrion, and the other the controlling nucleus. Multicellularity came next, building animals out of these eukaryotic cells, first simple, like sponges, but eventually, something amazing. Last came the animal societies, of which ours has only partially transitioned to a new stage of individuality, but where the insects such as termites and ants have completed virtually complete transitions to being super-organisms.

It is inherent in contemplating these transitions that they are examples of group-level selection. In order to achieve higher levels of organization there must be selective benefits of operating at the group level, often in competition with benefits occuring at the individual level. For groups inherently need to regulate and sometimes kill off their members, whether that is a gene that is sliced apart and recombined to serve the immune system of its host, the leukocytes we sacrifice to ward off infections, or the soldiers we send off to battle. Group selection is very real, whether one wants to recast every selective event as gene-centric, (where the mutation takes place), as Richard Dawkins has, or recognize the actual ecological / operational level of selection.

One important form of regulation is of reproduction, without which a true individual will never emerge at the higher level. The group (say, an organism with lots of cells) needs to suppress to reproduction of most of its members, eliminating individual competition and selection. Instead, it will need to select some representatives to stand for the whole and carry out reproduction, while not themselves having an independent livestyle that would conduce to selection on any relevant traits- i.e. those that might compete with the important traits of the collective. That is where germ cells come from, as much-reduced versions of actual organisms that so briefly carry out the hapoid phase of most organism's lives. 

Humans are obviously nowhere near this kind of reproductive control, outside of science fiction and societies that, if they have ever occurred, are extremely rare in their degree of totalitarian control. So our groups are nowhere near becoming a new level of biological individual. This is unlike the most developed social insects, whose reproduction is totally controlled at the group level. One interesting paper in this field brought up the case of dictyostelium, a soil amoeba whose life cycle, while mostly individual and independent, includes occasional mass aggregation to produce traveling slugs and fruiting bodies, which put out reproductive spores. In their words:

"The single-cell bottleneck and subsequent clonal development is thus a key trait facilitating the evolution of higher-level complexity in fraternal transitions. Two widely studied social organisms, the slime mold Dictylostelium discoideium and bacterium Myxococcus xanthus, appear stuck in the transition to multicellularity, despite ample time to evolve multicellular complexity (>400 Myr ago for the Dictyostelid cellular slime molds and >650 Myr ago for the myxobacteria). While both organisms possess multicellular life histories that include cellular division of labour, neither life cycle includes a single-cell bottleneck, and genetic conflict is rampant."

The general life-cycle of Dictyostelium. Many of the aggregated amoebae get to form spores, but not all.

The dictyostelium aggregate slug forms a base, stalk, case, in addition to the spores, so it is evident that some of the individuals that came together will be left behind, and not have even a chance at reproduction. At the same time, many individuals do get that chance, out of the body they form as a community. So this species, like humans, forms collectives of convenience, while not controlling either its own clonality or the reproduction of its members, and thus is quite far from achieving any higher level of biological individuality.

So, the key requirements of individuality at any level are:

• The entity must have traits subject to darwinian selection
• These traits must be heritable, enabling selection
• The entity must reproduce, to make new entities and enable selection
• The reproduction must not be subject to competition by entity members, (i.e. by their own individual reproduction, with their own selective competition and imperatives)

Clearly, clonal colonies of some sort make it easier to form coherent higher level collectives. But that is not enough- reproduction needs to go through a single germ cell bottleneck, preventing the competition among the vast majority of the collective members, while reflecting the collective's overall genetic complexion.

This paper also presented an experiment of selecting yeast cells for collective behavior / structure by selecting those that precipitated rapidly from their growth medium. This is a selection for multi-cellular aggregates, which is relatively easily done in yeast. Successful isolates tend to have defective cell wall separation machinery, so that cells remain attached after division. These entities reproduce, by breaking off occasional flakes of aggregate. This reproduction is largely clonal, with lineal descendents being attached in local aggregates which break off. And whatever trait the aggregate has is reflected in the descendents genetically. So is this a new level of biological individuality? They claim that yes, it is, though limited to this totally artificial regime of selection.

    "Snowflake yeast display a key emergent property: as clusters grow larger, tension among cells increases until it exceeds the tensile strength of a cell–cell connection, resulting in the release of a multicellular propagule5. Once clusters have evolved, they readily become a unit of selection, as whole clusters either settle rapidly enough to survive, or fail to do so and perish. As a result of this shift to cluster-level selection, we observe extensive cluster-level adaptation, including the evolution of larger size, elevated apoptosis and more spherical, hydrodynamic clusters."

These cells would never succeed in the wild, where entirely different and diverse selective pressures exist. Yet the experiment shows that this transition is not intrinsically as hard as evolution makes it seem. Evolution is terribly conservative, with intense selective pressures to innovate only at the margins, given the network of constraints already satisfied by one's ancestors. Coming together to recognize new cooperative opportunities, while giving up one's individuality, is, frankly, anathema.

        

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Death at the Starting Line- Aneuploidy and Selfish Centromeres

Mammalian reproduction is unusually wasteful, due to some interesting processes and tradeoffs.

Now that we have settled the facts that life begins at conception and abortion is murder, a minor question arises. There is a lot of murder going on in early embryogenesis, and who is responsible? Probably god. Roughly two-thirds of embryos that form are aneuploid (have an extra chromosome or lack a chromosome) and die, usually very soon. Those that continue to later stages of pregnancy cause a high rate of miscarriages-about 15% of pregnancies. A recent paper points out that these rates are unusual compared with most eukaryotes. Mammals are virtually alone in exhibiting such high wastefulness, and the author proposes an interesting explanation for it.

First, some perspective on aneupoidy. Germ cells go through a two-stage process of meiosis where their DNA is divided two ways, first by homolog pairs, (that is, the sets inherited from each parent, with some amount of crossing-over that provides random recombination), and second by individual chromosomes. In more primitive organisms (like yeast) this is an efficient, symmetrical, and not-at-all wasteful process. Any loss of genetic material would be abhorrent, as the cells are putting every molecule of their being into the four resulting spores, each of which are viable.

A standard diagram of meiosis. Note that the microtubules (yellow) engage in a gradual and competitive process of capturing centromeres of each chromosome to arrive at the final state of regular alignment, which can then be followed by even division of the genetic material and the cell.

In animals, on the other hand, meiosis of egg cells is asymmetric, yielding one ovum / egg and three polar bodies, which  have various roles in some species to assist development, but are ultimately discarded. This asymmetric division sets up a competition between chromosomes to get into the egg, rather than into a polar body. One would think that chromosomes don't have much say in the matter, but actually, cell division is a very delicate process that can be gamed by "strong" centromeres.

Centromeres are the central structures on chromosomes that form attachments to the microtubules forming the mitotic spindle. This attachment process is highly dynamic and even competitive, with microtubules testing out centromere attachment sites, and using tension ultimately as the mark of having a properly oriented chromosome with microtubules from each side of the dividing cell (i.e. each microtubule organizing center) attached to each of the centromeres, holding them steady and in tension at the midline of the cell. Well, in oocytes, this does not happen at the midline, but lopsidedly towards one pole, given that one of the product cells is going to be much larger than the others. 

In oocytes, cell division is highly asymmetric with a winner-take-all result. This opens the door to a mortal competition among chromosomes to detect which side is which and to get on the winning side. 

One of the mysteries of biology is why the centromere is a highly degenerate, and also a speedily evolving, structure. They are made up of huge regions of monotonously repeated DNA, which have been especially difficult to sequence accurately. Well, this competition to get into the next generation can go some way to explain this structure, and also why it changes rapidly, (on evolutionary time scales), as centromeric repeats expand to capture more microtubules and get into the egg, and other portions of the machinery evolve to dampen this unsociable behavior and keep everyone in line. It is a veritable arms race. 

But the funny thing is that it is only mammals that show a particularly wasteful form of this behavior, in the form of frequent aneuploidy. The competition is so brazen that some centromeres force their way into the egg when there is already another copy there, generating at best a syndrome like Down, but for all other chromosomes than #21, certain death. This seems rather self-defeating. Or does it?

The latest paper observes that mammals devote a great deal of care to their offspring, making them different from fish, amphibians, and even birds, which put most of their effort into producing the very large egg, and relatively less (though still significant amounts) into care of infants. This huge investment of resources means that causing a miscarriage or earlier termination is not a total loss at all, for the rudely trisomic extra chromosome. No, it allows resource recovery in the form of another attempt at pregnancy, typically quite soon thereafter, at which point the pushy chromosome gets another chance to form a proper egg. It is a classic case of extortion at the molecular scale. 

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Sex in the Brain

The cognitive effects of gonadotropin-releasing hormone.

If you watch the lesser broadcast TV channels, there are many ads for testosterone- elixir of youth, drive, manliness, blaring sales pitches, etc. Is it any good? Curiously, taking testosterone can cause alot of sexual dysfunctions, due to feedback loops that carefully tune its concentration. So generally no, it isn't much good. But that is not to say that it isn't a powerful hormone. A cascade of other events and hormones lead to the production of testosterone, and a recent paper (review) discussed the cognitive effects of one of its upstream inducers, gonadotropin-releasing hormone, or GnRH. 

The story starts on the male Y chromosome, which carries the gene SRY. This is a transcription activator that (working with and through a blizzard of other regulators and developmental processes) is ultimately responsible for switching the primitive gonad to the testicular fate, from its default which is female / ovarian. This newly hatched testis contains Sertoli cells, which secrete anti-Mullerian hormone (AMH, a gene that is activated by SRY directly), which in the embryo drives the regression of female characteristics. At the same time testosterone from testicular Leydig cells drives development of male physiology. The initial Y-driven setup of testosterone is quickly superceded by hormones of the gonadotropin family, one form of which is provided by the placenta. Gonadotropins continue to be essential through development and life to maintain sexual differentiation. This source declines by the third trimester, by which time the pituitary has formed and takes over gonadotropin secretion. It secretes two gondotropin family members, follicular stimulating hormone (FSH) and leutinizing hormone (LH), which each, despite their names, actually have key roles in male as well as female reproductive development and function. After birth, testosterone levels decline and everything is quiescent until puberty, when the hormonal axis driven by the pituitary reactivates.

Some of the molecular/genetic circuitry leading to very early sex differentiation. Note the leading role of SRY in driving male development. Later, ongoing maintenance of this differentiation depends on the gonadotropin hormones.

This pituitary secretion is in turn stimulated by gonadotropin releasing hormone (GnRH), which is the subject of the current story. GnRH is produced by neurons that, in embryogenesis, originate in the nasal / olfactory epithelium and migrate to the hypothalamus, close enough to the pituitary to secrete directly into its blood supply. This circuit is what revs up in puberty and continues in fine-tuned fashion throughout life to maintain normal (or declining) sex functions, getting feedback from the final sex hormones like estrogen and testosterone in general circulation. The interesting point that the current paper brings up is that GnRH is not just generated by neurons pointing at the pituitary. There is a whole other set of neurons in the hypothalamus that also secrete GnRH, but which project (and secrete GnRH) into the cortex and hippocampus- higher regions of the brain. What are these neurons, and this hormone, doing there?

The researchers note that people with Down Syndrome characteristically have both cognitive and sexual defects resembling incomplete development, (among many other issues), the latter of which resemble or reflect a lack of GnRH, suggesting a possible connection. Puberty is a time of heightened cognitive development, and they guessed that this is perhaps what is missing in Down Syndrome. Down Syndrome typically winds up in early-onset Alzheimer disease, which is also characterized by lack of GnRH, as is menopause, and perhaps other conditions. After going through a bunch of mouse studies, the researchers supplemented seven men affected by Down Syndrome with extra GnRH via miniature pumps to their brains, aimed at target areas of this hormone in the cortex. It is noteworthy that GnRH secretion is highly pulsitile, with a roughly 2 hour period, which they found to be essential for a positive effect. 

Results from the small-scale intervention with GnRH injection. Subjects with Down Syndrome had higher cortical connectivity (left) and could draw from a 3-D model marginally more accurately.

The result (also seen in mouse models of Down Syndrome and of Alzheimer's Disease) was that the infusion significantly raised cognitive function over the ensuing months. It is an amazing and intriguing result, indicating that GnRH drives significant development and supports ongoing higher function in the brain, which is quite surprising for a hormone thought to be confined to sexual functions. Whether it can improve cognitive functions in fully developed adults lacking impeding developmental syndromes remains to be seen. Such a finding would be quite unlikely, though, since the GnRH circuit is presumably part of the normal program that establishes the full adult potential of each person, which evolution has strained to refine to the highest possible level. It is not likely to be a magic controller that can be dialed beyond "max" to create super-cognition.

Why does this occur in Down Syndrome? The authors devote a good bit the paper to an interesting further series of experiments, focusing on regulatory micro-RNAs, several of which are encoded in genomic regions duplicated in Down Syndrome. microRNAs are typically regulators that repress transcription, explaining how this whole circuitry of normal development, now including key brain functions, is under-activated in those with Down Syndrome.

The authors offer a subset of regulatory circuitry focusing on micro-RNA repressors of which several are encoded on the trisomic chromosome regions.

"HPG [hypothalamus / pituitary / gonadal hormone] axis activation through GnRH expression at minipuberty (P12; [the phase of testoserone expression in late mouse gestation critical for sexual development]) is regulated by a complex switch consisting of several microRNAs, in particular miR-155 and the miR-200 family, as well as their target transcriptional repressor-activator genes, in particular Zeb1 and Cebpb. Human chromosome 21 and murine chromosome 16 code for at least five of these microRNAs (miR-99a, let-7c, miR-125b-2, miR-802, and miR-155), of which all except miR-802 are selectively enriched in GnRH neurons in WT mice around minipuberty" - main paper

So, testosterone (or estrogen, for that matter) isn't likely to unlock better cognition, but a hormone a couple of steps upstream just might- GnRH. And it does so not through the bloodstream, but through direct injection into key areas of the brain both during development, and also on an ongoing basis through adulthood. Biology as a product of evolution comprises systems that are highly integrated, not to say jury-rigged, which makes biology as a science difficult, being the quest to separate all the variables and delineate what each component and process is doing.

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One China or Two?

It is time we recognize reality.

Nancy Pelosi's trip to Taiwan (ROC) certainly stirred up a hornet's nest. The PRC (mainland China) threw a fit of hate, saber rattling, and jingoism. The US has been playing into this situation for decades, after the Nixon administration acceded to the PRC's demand to recognize the "one China" policy. Originally, this was not such a big lift, since this was also the policy of the ROC- with the only difference that in its view, China would eventually be unified under the auspices of the ROC, not the PRC. Today, things are different, with the PRC having westernized its economy and grown into a behemoth that vies with the US for world leadership and threatens all its neighbors.

Taiwan has a native population, the Formosans, who are not, unfortunately, part of this discussion at all, but are an oppressed minority on their own island. The island became a province of China roughly from 1700 to 1900 (after being colonized by the Dutch). Then it was ruled by the Japanese empire, after which it was over-run by the nationalists fleeing the Chinese Civil War. Supporting the ROC was reflexive for Western anticommunists, despite it being a dictatorship up to 1987. But now, after it has evolved into a healthy democracy, the US position should be even more simple and direct- we should recognize reality, which is that Taiwan is an independent country on its own historical path that is one of self-determination and independence from the mainland.

All this is subject to the decisions of the Taiwanese themselves, naturally. They have not yet declared independence from China, for instance, and may yet come to some accommodation with their neighbor. But we shouldn't be selling them out to be another Hong Kong. Instead, we should support their right to self-determination and independence, to preserve their highly successful economic and political culture, and their membership in international organizations.

So, what of the PRC? Won't they be irritated, even enraged, if we formally renounce the one-China policy? Absolutely. Would they break diplomatic relations? They might, but we have so many important areas of cooperation and negotiation that such a step would not likely last long. I don't think the PRC can hold out on a diplomatic boycott of this kind for very long, especially if the US is joined by other countries recognizing the reality of an independent, self-determining Taiwan. Back in the Nixon era, we had a very specific goal, which was to use relations with China to scare the Russians. That was quite successful, and led to a long and productive relationship, especially for China.

In general, it is better to irritate bullies than to appease them. The Taiwan situation has reached a critical point for a variety of reasons. On Taiwan's side, they are now the foremost world center of advanced semiconductor manufacture. The PRC would naturally view it as a critical asset in their drive to control the global economy. Mainland China has bided its time for many decades, while it slowly and painfully rebuilt its own power, and one can sense an almost convulsive urge to consummate the re-unification by force, which would be conveniently accompanied by the final destruction of its founding enemies. It is carefully laying groundwork all over the South China sea, in its navy, armed forces, alliances, soft power, and internal propaganda. It is the only actor on the scene threatening war.

It is a situation very similar to that of Ukraine. Russia has had a "one-Russia" policy, in that it regards Ukraine as "little Russia" even though it butchered Ukrainians during its own civil war and then more thoroughly during the great famine under Stalin. They have a fraternal, and fratricidal, relationship. The West nevertheless encouraged Ukraine to become a Westernized country, with possible membership in the EU and NATO. And how we have a war, which has ripped Ukraine apart, with no end in sight. Are we asking for the same outcome in Taiwan? As I write, Russia and China are planning joint military exercises.

Well, we might be, but ultimately it is up to Taiwan to figure it out, as it was for Ukraine to decide which way they wanted to go. We should stand for self-determination and against bullying. At this point in history, seventy years on, there is very little justification for us or the PRC to maintain that the ROC is merely a province and should be subject to hostile re-absorption. It is an ambiguity that may have been diplomatic in the past, but now is misleading and dangerous. No, the ROC has made its independent place in the world, and the sooner we recognize that reality, the more realistic and productive relations throughout the region can be. That includes a recalibration of the PRC's views of the matter, and the recognition internationally that while Taiwan might concievably want to re-unify with the PRC for its own cultural and economic reasons, we fully oppose, on every level, any coerced or military takeover. Our military relationship doesn't have to change. We do not need to enter into a full alliance with Taiwan, only to recalibrate relations to recognize their right to an independent existence, however they choose to carry that out.

There is also a more positive view. The PRC in its current condition would not be an attractive partner for re-unification- it has not been for Hong Kong, or for Tibet, and much less so for the ROC. But mainland China might also change. There is no telling what the future may hold. The recent passing of Mikhail Gorbachev reminded us that history can move pretty quickly, and while the "communist" government of the PRC seems very stable, there are many tensions and problems under the surface. The more they fulminate against the ROC, the more their people would be exposed to the question of what exactly is so terrible about the extremely prosperous, peaceful, and democratic system lying across the Taiwan strait.

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