Saturday, April 23, 2016

Locating Abstractions in the Brain

The most human part of the brain is also the murkiest and least understood. Visualization studies of what is going on in the frontal cortex.

While it was in vogue, the lobotomy operation was used to treat in the neighborhood of 100,000 people in the mid twentieth century, rendering them more manageable- something that has since been more easily achieved with drugs. From the Wiki page:
"The purpose of the operation was to reduce the symptoms of mental disorder, and it was recognized that this was accomplished at the expense of a person's personality and intellect. British psychiatrist Maurice Partridge, who conducted a follow-up study of 300 patients, said that the treatment achieved its effects by 'reducing the complexity of psychic life'. Following the operation, spontaneity, responsiveness, self-awareness and self-control were reduced. Activity was replaced by inertia, and people were left emotionally blunted and restricted in their intellectual range."

What is odd is that for such a massive disruption to the brain, the effects were diffuse and hard to understand (though in fairness, the methods used were hardly uniform). "The first bilateral lobectomy of a human subject was performed by the American neurosurgeon Walter Dandy in 1930. The neurologist Richard Brickner reported on this case in 1932, relating that the recipient, known as 'Patient A', while experiencing a flattening of affect, had suffered no apparent decrease in intellectual function and seemed, at least to the casual observer, perfectly normal."

Some effects were that the subject no longer dreamed, they also lost their theory of mind, or the ability to empathize with others. Some entered a stupor or started suffering siezures. There were various intellectual and personality deficits- one became "smiling, lazy and satisfactory patient with the personality of an oyster". Five percent died. One subject mentioned:
"It took a great deal of effort to keep an abstraction in mind. For example, in talking with the speech therapist I would begin to give a definition of an abstract concern, but as I held it in mind it would sort of fade, and chances were that I'd end up giving a simplified version rather than one at the original level of conception. It was as though giving an abstraction required so much of my addled intelligence that halfway through the definition I would run out of the energy available to me and regress to a more concrete answer. Something like this happened again and again."

An irony is that the Soviet Union took the lead in banning the procedure, "Doctors in the Soviet Union concluded that the procedure was 'contrary to the principles of humanity' and 'through lobotomy an insane person is changed into an idiot.'"

Modern brain scanning allows researchers to peer into the frontal lobes and start figuring out what is going on there. A recent paper described some early work in that direction, devising simple tasks to differentiate levels of abstract thought and mapping where they happen, using fMRI. They manage to map separate zones in the frontal cortex that handle temporal / time shifting abstractions, category switching abstractions, and feature attention control.

The subjects were presented with points that through several frames that added up to a diagram, (C), a star with letters on the outside, with a color applied. There were several rules imposed, such as if the color setting was purple, the letters were supposed to be added up to form a word across the star (TABLET, in this case). If the color was orange, the subject was supposed to just trace the points of the star with her eyes. Then delay rules were added, asking whether the trail was the same type or a different type than the one before. Or the subject was given a new diagram but asked to maintain their place in the old diagram, to be recalled later. Then distraction periods were added in between to test for memory retention. It all begins to look like an intelligence test, for the subject's ability to keep ideas and rules in mind successfully.

Test design, in part. C shows the basic image presented to the subject, which would have included color as well, and varied the shape and text presented. The points of the star were not presented at once, but fed out one point at a time. B shows the combined tests that were devised. For instance. The restart test asked the subject not to delay their analysis, but just presented with a new diagram and asked to resolve the color and text diagram by the agreed rules.

The tests were designed to separate three topics of thought, and were added together in various combinations to allow the researchers to run combinatorial tests. The upshot was that they were able to map the three tasks to different parts of the frontal cortex:

Distinct mappings of each task to its region. Handling time delay and abstraction occupies the very front of the brain, (rostral), while simpler abstractions keeping track of the local context of a task, or attending to selected features of an image/task occupy precincts farther back (caudal). This is in addition to separate zones in the mid-brain
"Regressing these measures onto activation revealed a clear gradient such that caudal LPFC [lateral prefrontal cortex] was related to current, but not future processing, while rostral LPFC was related to future, but not current processing, with mid LPFC showing activity related to both current and future processing "


They end up with a beautiful depiction of the regions of the brain where their various tasks took place. Unfortunately, fMRI imaging technology remains very crude, in time and space, so their task breakdown was similarly crude to suit. It will probably take new technology to go to deeper detail on what is going on in the human frontal cortex- the part of the brain most responsible for making us human, but also, since it handles abstractions farthest from detailed concrete processing, the most nebulous and hard to define.

  • Inequality isn't just a bleeding heart issue, but an investment and prosperity issue.
  • Solow on labor power and inequality.
  • Tax complexity isn't entirely the government's fault, but another dividend of corruption.
  • Retirement is another big front in the inequality debate.
  • Utopia now and then.
  • Globalization is a problem.
  • Some problems with supply side theory. Perhaps taxes make people work harder.
  • Pay is a complicated construct.
  • We need more debt.
  • But perhaps less bail.

Saturday, April 16, 2016

Euhemerization

People making gods, as usual- and the mythical nature of Jesus.

All aspects of the existence and nature of Jesus are a matter of theory, not fact. So much of the early literature about him is forged, made-up, laced by myth and parable, and templated by religious traditions, philosophical preconceptions and political exigencies, that the nature of (or existence of) the actual, historical Jesus is a matter of speculation and inference at best.

Bart Ehrman wrote an exasperated book about the evidence for the historical Jesus, affirming, despite his own lack of conventional faith, and through his dedicated scholarship in the field, that the consensus position of Christians and scholars is correct. The problem of the thin-ness of the evidence remains, however, since all the evidence comes from internal (Christian) and late (not contemporaneous) sources. This is not unusual or unexpected for any Roman of this time, other than the very highest levels of emperors and writers, but hardly allows a solid case either pro or con. A great deal turns, for instance, on one's interpretation of the word "brother", since Paul, in letters that are widely agreed to be reasonably authentic, refers to James as a brother of Jesus. If this means a biological brother, it means that Jesus, by this chain of evidence, really existed biologically. Whether his mother was a perpetual virgin is another matter, of course! Or was James a spiritual brother, as is the common usage has been for many religious communities? Ehrman, as an expert, comes down clearly on the biological side.

Myth, or just mythic?


Both cases, for and against the historicity of Jesus, are thus circumstantial, based on the credibility of scraps of evidence, or the credibility of a counter-story elaborated by the mythicists, where Jesus begins as a deity who is brought down to earth (euhemerized) for a variety of motives that are quite understandable, and precedented by similar gods and god-men before and since. Casting one's god as a real person makes the provenance and stability of his teachings more secure than that of a deity that communicates through revelation, and could do so again at any time. And stories are easy to make up and write down. A recent talk by Richard Carrier makes this case with gusto.

I am not going rehash the arguments here. But only say that the pro-historical case, while certainly traditional, popular, and even likely, is, even by Bart Ehrman's telling, hung on very thin threads of internal evidence, on texts whose transmission to us is an endless story of copying, re-copying, correction, obfuscation, politics, and forgery. The early Christian times are a fascinating period of political and archetypal turmoil. No path is straight, least of all the texts that purport to tell the story. Take for instance, the case of Marcion, who supposedly collected letters of Paul and devised the first Christian cannon. Marcion is thought to have written a good bit of it himself, and founded a theology that was very popular in its day, only to ripen into heresy later on at the hands of what comes down to us as orthodoxy.

The project of making Christianity's hodge-podge of scriptures fit the orthodox story as it evolved through the centuries is mind-bogglingly complicated and obviously ongoing, given the many versions of the Bible and of Christianity that are still running around. The process is reminiscent of the paradox of Islam, where those who take its origins and scripture most seriously are the most righteous and violent, whereas those who merge into more mature traditions, as they ripened through time into human, and typically humane, institutions, are much more resistant to the fundamentalist call.

Getting back to the foundations, what is the precedent for euhemerization such as what happened to the person or entity we call Jesus? And for its complement, apotheosis? These days, the traffic between heaven and earth has hit some kind of traffic jam. But in antiquity, it was far more common for people such as kings and emperors to become gods, and also for gods to come down to earth, in tales such as the Homeric epics. Divinity was assumed to exist, and divine beings were pretty much formed in the image of ourselves, at our most powerful. Both the Jewish god(s) and the Greek gods were distinguished by their power much more than their knowledge, let alone their emotional wisdom or kindness.

Even farther back, the template is of course the family, and the trauma of death. The death of any person, let alone a powerful, archetypal person like a parent, is unimaginable. How can life stop cold, how can existence simply end? Impossible. We have thus come up with a rich set of rationalizations and theologies of additional existence. They typically involve the movement of people (souls) from this world to some other invisible world, where they look back with fondness to what is still the important place, our world.

But then comes the important question of whether and how this spritual world, if it is to have any ongoing function for us, interacts with ours. Our souls clearly have some modus operandi by which they co-function with our living bodies, mortal though they are. Likewise, spirits and gods must have some way back into the world if we wish to involve them in our dramas. Thus we end up with a rich literature of heroic journeys to heaven (or the underworld) and back, gods taking up disguises as women or men (or animals), throwing thunderbolts, causing natural cataclysms, etc.

It is only the higher psychological and philosophical sophistication of our age that has slowed down this traffic, though it peeks out of our unconscious in the endless array of super-hero movies, not to mention a majority of the country that still holds fast to some version of the traditional theological stories.

Let us close with a couple of quotes from Thomas Paine speaking of the Christian believer, vs a true deist, from his deist book, "The Age of Reason":
"Yet, with all this strange appearance of humility, and this contempt for human reason, he ventures into the boldest presumptions. He finds fault with everything. His selfishness is never satisfied; his ingratitude is never at an end. He takes on himself to direct the Almighty what to do, even in the govemment of the universe. He prays dictatorially. When it is sunshine, he prays for rain, and when it is rain, he prays for sunshine. He follows the same idea in everything that he prays for; for what is the amount of all his prayers, but an attempt to make the Almighty change his mind, and act otherwise than he does? It is as if he were to say -- thou knowest not so well as I."
"The Bible of the creation is inexhaustible in texts. Every part of science, whether connected with the geometry of the universe, with the systems of animal and vegetable life, or with the properties of inanimate matter, is a text as well for devotion as for philosophy -- for gratitude, as for human improvement. It will perhaps be said, that if such a revolution in the system of religion takes place, every preacher ought to be a philosopher. Most certainly, and every house of devotion a school of science."

  • Shadows from the past: Hillary and Honduras, one reason for a new influx of refugees to the US.
  • Freedom for me, but not for thee.
  • Who pays for corporate taxes? Is corporate power and capital mobility so great that they can off-load all costs onto workers and taxpayers? "We need also to account for the financial, administrative, and strategic costs of tax avoidance." Maybe we need stronger international governance.
  • Should central banks be unaccountable?
  • Lobbying and corruption is by far the best investment.
  • Stiglitz on negative rates... too little too late.
  • Mice who stutter!
  • The national debt is not a problem, at all.

Sunday, April 10, 2016

Who am I? Mechanics of Cell Identity




How do neurons in the fly know which segment they are in?

Organismal development is a biological mystery that is being gradually unravelled in labs all over the world in that heroic endeavor called "normal science". Which is the pedestrian counterpart to the Kuhnian revolutions termed paradigm shifts. That the endogenous materials and genetic code of the egg/embryo generate the later adult forms has been known ever since scientists gave up vitalistic and other religious ideas about our biology. But how that happens ... approaching that question has taken lots of modern technology and persistence.

Fruit flies are the leading model system for embryonic and organismal development, due to their marriage of complex body plans, simple experimental handling, and extraordinarily deep genetics. After almost a century of productive study, a revolution happened in the 1980s in fruit fly genetics, following new mutant screens that uncovered some of the most basic mechanisms in body plan development. The genes found and analyzed during this period established a basic paradigm that has extended to all metazoans that have segmented body plans. Do we have segments? Yes, our backbone is a testament to our segmented ancestors.

The fly is built out of segments, whose cells know where/what they are by virtue of special genes expressed in them- the homeotic genes. The major genes of the fly homeotic complexes are, in order, Labial, Proboscipedia, Deformed, Sex combs reduced, Antennapedia, Ultrabithorax, Abdominal-A, and Abdominal-B.
The theme of these studies was that a series of genes, typically regulators of the expression of other genes, are turned on in sequence during development to identify progressively finer regions of the developing body. So at first, the two ends of the egg cell or synctium are set as different, then some gross regions are defined, and later on, each segment (and each side of each segment) expresses a few key genes that identify its cells, so that another cell, say a nerve cell migrating through the area, can tell exactly where it is. Each protein is expressed in a gradient within its zone, allowing the next regulator in the process to detect which end of that gradient it lies in, and thus whether to turn on or not. Late in this genetic series are the Hox genes, which are notorious for the complexity of their own regulation, for their ability, when mutated, to transform the identity of some segments entirely into other ones, and for the linear relationship between their chromosomal position and the locations on the body where they are individually expressed.

Progressive genetic specification of the fly embryo body plan, dividing it up into segments.  Gradients of one gene product allow the next gene product to detect the sides of its compartment and thus refine its cellular and body identity to a finer level.

A recent paper took up this adventure in the area around the head and neck, asking how embryonic nerve cells (neuroblast stem cells) originating in segments 4 to 6 know who they are and where to go. While one might not think that an animal head has segments at all, in embryological and molecular terms, heads encompass about 7 segments, (in the fly), which go through very messy convolutions into the complex mature structure. In comparison, body segments are far more orderly. Indeed, the central thoracic segment appears to be the default state, needing no Hox gene expression to develop normally:
"While thoracic identities seem to represent a ground state (T2, no input of Hox genes), identities of consecutive posterior segments are established by adding the function of Bx-C Hox genes Ultrabithorax (Ubx), abdominal-A (abdA) and Abdominal-B (AbdB), an evolutionary highly conserved phenomenon described as posterior dominance or prevalence of Hox genes. The terminal abdominal neuromeres A8-A10 exhibit a progressively derived character regarding size and composition. In these segments, NB [neuroblast, or neuronal stem cell] patterns and segmental identities are controlled by combined action of the Hox gene AbdB and the ParaHox gene caudal."

Map of the Drosophila head region, stained to show the Engrailed gene product. This is a homeotic segment polarity gene, expressed on one side of each segment throughout the embryo at this stage. At bottom is a map, coding the different segments accounted for within the head: red- antenna segment; purple- ocular segment; orange- intercalary segment; brown- labral segment; black- mandibular segment; green- maxillary segment; blue- labial segment; gray- first thoracic segment. In ensuing figure, the embryo is squashed to lay out the segments better.

The head segments likewise require extensive input from the Hox genes to keep their identities distinct. The researchers use a series of mutants to figure out how the local (segments 4 to 6) neuronal stem cells respond to missing genetic homeotic inputs. To do this, they use a few morphological characteristics and gene markers (assays for a gene whose expression is restricted to a certain lineage or cell type, in this case antibodies specific to the respective proteins) to identify the neuroblasts or stem cells they are interested in.

Stem neurons in three segments are stained with a combination of gene expression probes: Eagle in green, Runt in red, and Engrailed in blue. Note how combined expression renders some key cells aqua (green + blue) or yellow (green + red). Other diagnostic genes used for cell identification, which are all known to have developmental roles, are Deadpan, Deformed, Repo, Even-skipped, Eyeless, Sex combs reduced, Proboscipedia, and Gooseberry. The segments, from front [top] to back, are mandibular (mad), maxillary (max) and labial (lab). In back of the labial segment is the first thoracic segment. This stage of development (12) is quite early, well before the first larva forms.

Many figures of embryos later, stained for the expression of various proteins, in flies mutated for various key homeotic genes, and analyzed for the presence of notable cells at various stages, the authors draw several conclusions about the genetic influences that determine the identity and existence of neurons in these head segments, some of which will go on to contribute to the adult fly's brain. First, the maxillary segment, including its neuronal stem cells, expresses Deformed and Sex combs reduced from the Hox genes, while the next labial segment expresses Labial, but not in its neuronal cells. These seem to be the principal determinants of segmental identity. Yet when Deformed is mutated, only about half the cells are transformed from maxillary identity to a labial or thoracic identity. Only when another homeotic gene is also mutated, either Antennapedia or Labial, is the transformation more complete.

The curious thing about this is that neither Antennapedia nor Labial are normally expressed in the maxillary head segment, so the effect of their mutation must not be what the resarchers term cell-autonomous. These other genes must be acting from some distance away, instead of directly via their own expression in the cells being affected. This gets these researchers quite excited, and they track down some of the mechanism behind this extra cell fate specification.
"We identify the secreted molecule Amalgam (Ama) as a downstream target of the Antennapedia-Complex Hox genes labial, Dfd, Sex combs reduced and Antennapedia. In conjunction with its receptor Neurotactin (Nrt) and the effector kinase Abelson tyrosine kinase (Abl), Ama is necessary in parallel to the cell-autonomous Dfd pathway for the correct specification of the maxillary identity of NB6-4. Both pathways repress CyclinE (CycE) and loss of function of either of these pathways leads to a partial transformation (40%), whereas simultaneous mutation of both pathways leads to a complete transformation (100%) of NB6-4 segmental identity."

Summary of findings, where Deformed is the main, local homeotic specifier for the maxillary segment neurons. But additional help comes from the next-door labial segment which expresses the homeotic gene Sex combs reduced, which influences expression in turn of the diffusible protein Amalgam, which helps the nearby maxillary segment keep its identity, via repression of the gene cyclin E. Interestingly, the Amalgam gene is located in the homeotic cluster right next to Deformed.

Summary of findings, where Deformed is the main, local homeotic specifier for the maxillary segment neurons. But additional help comes from the next-door labial segment which expresses the homeotic gene Sex combs reduced, which influences expression in turn of the diffusible protein Amalgam, which helps the nearby maxillary segment keep its identity, via repression of the gene cyclin E. Interestingly, the Amalgam gene is located in the homeotic cluster right next to Deformed.

So what had originally been though of as a fully cell-autonomous system, whereby each homeotic gene or combination thereof dictates the identity of cells in each respective segment where it is itself expressed, turns out to be a bit more messy, with neighbor effects that refine the identity code. Obviously this is getting into the deep weeds of developmental biology, but at the same time is an outstanding example of where the field is today, filling in ever-finer details of how development happens, using sophisticated techniques and backbreaking amounts of work.



Saturday, April 2, 2016

We Have Been Energy Hogs For a Billion Years

Mitochondria and the origins of eukaryotes.

Last week, we read about the origins of one important characteristic of eukaryotic cells- sex. But there are many more properties that distinguish eukaryotic cells from their bacterial forebears. These include the compartmentalized organelles like mitochondria, chloroplasts, nuclei, golgi, lysozomes, and the endoplasmic reticulum, a vastly expanded and junk-laden nuclear genome with introns, numerous new families of proteins, larger ribosomes, linear DNA with telomeres, separated transcription and translation, and centrosomes / cilia, among others. The mystery is how these many innovative characters all came to happen in one lineage that left no other discernable branches or traces, making the divide between the two forms of life truly gaping and hard to reconstruct. A paper from 2011 provides an illuminating attempt to explain some of these mysteries. Incidentally, it is well-written, and rewards a direct read.

Perhaps one of the most complex, yet at the same time simple, characteristics, is the mitochondrion. Though some eukaryotes live without them, such lineages all are known to have evolved from mitochondrion-containing ancestors. Thus mitochondria are truly part of the original equipment of eukaryotes as far as we currently know. Mitochondria are the descendents of bacteria completely distinct from the proto-eukaryotic host cell, (whether archaeal or something else), and became endosymbionts, whether by some dramatic engulfment / phagocytosis or something more cooperative and intricate. Thus the origin of the mitochondrion is simple- just take in a bacterial partner- even as the organelle and its effects on the host are highly complex. Indeed, mitochondria still have a tiny residual genome, encoding, 37 genes in humans, most of which are tRNAs. While the vast majority of its proteins are encoded far away in the nucleus, it runs its own replication, transcription, and translation apparatus complete with tRNAs and charging enzymes to make 13 proteins of its own, using a genome 1/200,000 the size of the host cell.

Mammalian cell with its nucleus labelled "N" and mitochondria labeled "M".

The current paper proposes that the partnership with mitochondria was the first step on the long road to the eukaryotic cell. The reason is that it is the one enabling change that unleashes all the others, by vastly increasing the energy available to the combined entity. The author goes through a lengthy calculation of the DNA carrying capacity of bacteria, which is clearly limiting and causes a ceaseless competition among bacteria to shorten and streamline their genomes, which account for roughly 2% of cellular metabolism simply for DNA replication, quite apart from all the other costs of gene expression, repair, etc.  Once the host cell convinced the endosymbiont to give up its excess energy (ATP) in return for safety and free food, the race was on to a very profitable division of labor.

If in the combined cell, each mitochondrion supplies the energy equivalent of a bacterium, but with only the genome of an influenza virus, the efficiencies of scale are substantial, perhaps transformative, enabling much larger cells and much larger central genomes. On the other hand, the eukaryotic cell has just as much protein, mRNA and other gene expression apparatus (by mass and energy) as the bacterial cell, (if not more), so the author's focus on the energy available per gene, which results in starting quantitative contrasts between the two domains, is not terribly persuasive.

Example of bacteria (Clostridium) in size comparison to human epithelial cells. The bar is 20 micrometers.

More persuasive is the advantage in membrane area. Bacteria, like mitochondria, manage their short-term energy via a proton motive force over their plasma membranes. Food sources are oxidized, generating electrons which power the pumping of protons out of the cell/organelle. That power, stored much like a battery, is used as needed by ATP-synthesizing machines that run off the power of letting those protons back in. Making a bacterium larger is a losing proposition since the cytoplasmic volume rises by the cube as the surface area rises by the square. While elongation is one solution, and many bacteria are filamentous, spiral, and other long-ish shapes, this poses other obvious problems of safety and internal management. The eukaryotic cell escaped all that by making of the mitochondrion an endlessly replicable internal energy unit, limited only by the host's ability to gather dinner on whatever scale it chooses to operate. And sometimes, operating on a large scale is very profitable.

This hypothesis leads to an interesting theory about the early phases of the symbiosis. However it happened, the earliest mitochondria were fully bacterial, conferring the membrane area advantage, but not the genome streamlining advantage. Given that many mitochondria can exist in each eukaryotic cell (up to several thousand), the advantage of minimizing the infrastructure and energy needed for the maintenance of each one is clear. In the first place, many of the free-living functions would have quickly become unnecessary. Mitochondria today have a complement of about 1000 proteins, far less than the ~ 5,000 proteins found in free-living bacteria. Getting rid of those and the DNA encoding them is a huge savings.

Second, this early mitochondrion would be constantly exposing the host to its own DNA, and the combined entity would gain a streamlining advantage every time the mitochondrion lost a gene that was integrated into the host genome. Putting aside the challenges of transporting all the proteins needed in the mitochondrion back from the host's expression apparatus, which are substantial, every time the mitochondrion lost a gene and had that function supplied externally instead, it became that much more efficient in terms of the genome it was carrying around, in addition to regulatory advantages from being centrally managed by the host.

Comparison of genome sizes, on a log scale. All eukaryotes have larger genomes than all bacteria. Mitochondria, at 16Kb, now fall into the viral range rather than the bacterial range.

Thus a sort of snow-balling process of mitochondrial genome miniturization took place, which had wide-ranging effects. The author speculates that controlling this exposure to external (mitochondrial) DNA, especially its primitive introns, may have led to the nuclear membrane as a form of protection and process management, which in turn created the space for new forms of eukaryotic regulation, like the spliceosomal processing that takes place during exit from the nucleus, and the myriad proteins that are specifically shuttled in and out of the nucleus for regulatory control. Overall, the union of a tiny mitochondrion and a central host genome provides a quantum leap of efficiency, compared to what is possible by scaling up single bacteria in any conceivable way (whether by invaginating their membranes, and / or multiplying their genomes to serve larger surfaces and volumes).

This in turn allowed energetic room for all sorts of new innovations and what a bacterium would regard as waste. A host genome full of introns and other junk DNA, a cytoplasm full of new cytoskeletal proteins devoted to shape control and internal cargo carrying, systems for internal membrane and vesicle management, and diploidy: carrying a full extra copy of its nuclear genome around, as part of the new sexual reproduction cycle. Also:
" The last eukaryotic common ancestor (LECA) had already increased its genetic repertoire by some 3000 novel gene families [over that of the presumed ancestral bacteria]."

Finally, the fact that this series of innovations seems to have happened only once and left no other lineages from along the way makes for a remarkable gap in the evolutionary record, far more profound than that observed around the Cambrian explosion of metazoan life. This paper is very eloquent about the many ways that prokaryotes are trapped in what might be called a version of fiscal austerity, always cutting spending, scrimping on infrastructure, and seeking efficiency ├╝ber alles. That is no way to live! That any of them found a way out, to the endless vistas of higher complexity and cooperation that now cover the earth with beautiful, rich life, is worthy of wonder and gratitude.

  • smORFs, another genomic frontier.
  • But he's a winner, right?
  • What is an undue burden? Who knows? And does the state have an interest in unused sperm?
  • Whom do investment bankers work for?
  • Let's make the FIRE sector pay its way.
  • Corporate profits are sky-high. Is that investment, or rent?
  • What defines the middle class?
  • Is suffering an excuse for being  gullible?
  • No one seems to understand national debt, after all this time.
  • Green tip of the week: let's have fewer conferences.
  • Barney Frank: You have to vote.
  • Work is fundamentally important, perhaps more than trade.
  • Republicans in the forefront of bad government.