Alexander Wilson, Ornithologist

Curiosity drove Wilson to study, describe, and paint birds- founding scientific ornithology in America.

What makes birds so compelling? Birding can be a matter of fanticism, with competitive list making, and expensive and arduous travels. They are both beautiful and talented, endowed with the magic of flight, which humans have only learned laboriously over the last century. They are cheerful and communicative, singing and chattering in notes we can relate to, if not understand. And they are extremely diverse, and turn out to be the successors of some of the charismatic animals of all time- the dinosaurs.

But in colonial times, birds were more appreciated for food than for watching. Countless wild birds ended up sold at market, one fate that sealed the doom of the passenger pigeon. Alexander Wilson (1766-1813) was no slouch in the hunting department, as a crack marksman who shot countless specimens, and dined on many of them. But for his time, he was also a pioneer in sensitivity towards birds, perhaps not surprising as ornothology was his second career choice, after poetry. A recent biography, though rather disorganized, is an excellent introduction to his work and times.

Wilson was a weaver and poet in Ireland, and then a schoolmaster in America, but finally found his calling when he came in contact with William Bartram, the leading naturalist of the newly minted US. Bartram was just the gentle, dedicated, and respected lover of nature that Wilson needed as a mentor. His gardens were extensive and his travels through much of the Southern countryside a model for Wilson's future years of tramping through all areas east of the Mississippi in search of birds ... and also customers.

One plate from Wilson's work. Note the phenomenal detail and realistic poses.

For publishing in Wilson's time was on the kickstarter model. The 9-volume American Ornithology was accepted by the publisher only on condition of Wilson collecting sufficient subscriptions to fund its production, which was lavish. Each volume had about nine plates, engraved and over-painted with color, in addition to Wilson's text describing the features and habits of the  pictured birds. Wilson therefore went on long trips to drum up interest and subscriptions, focusing on the wealthy elite of each region, who would be most likely to have the means to buy his expensive production. The subscribers would then receive copies of Wilson's columes as they came off the press in subsequent years.

Notably, Wilson had very little luck with the tight-fisted New Englanders. But he had much better luck at the President's House, paying a visit to Thomas Jefferson. Jefferson had himself published a guide to the birds of Virginia, and was keenly interested in Wilson's work and book. Indeed, he made his cabinet officers take out subscriptions as well! It was in a related vein that Jefferson later ordered the Lewis and Clark expedition to study the geography and biology of the vast Louisiana Purchase territory and points west to the Pacific. Imagine such intellectual depth and engagement in our current age!

Wilson's portrayal the the Pileated, Red-headed, and Ivory-billed woodpeckers.

Wilson studied as many of his specimens in their natural habitat as he could, and took many captive for further study. His detailed descriptions and paintings were, at their best, far more realistic and accurate than anything that had come before. He asked penetrating questions and resolved mysteries with detailed investigation, creating new species or uniting badly named and split species as needed. In his intense curiosity and willingness to pursue evidence and experiments he is reminiscent of that great naturalist to come, Charles Darwin. In one episode, Wilson wounded and captured an ivory-billed woodpecker, the largest woodpecker of all and a species now sadly extinct.

"Not far from Wilmington [North Carolina], he shot and killed two Ivory-billed woodpeckers and slightly wounded a third. With the two specimens in his pack, he wrapped the injured bird in his coat, placed it in front of him on the saddle where he could keep hold of it, and rode into Wilmington where he planned to spend the night. As he rode through the streets and up to the hotel, the piteous cries of the woodpecker attracted a worried crowd. They joined the landlord in a relieved laugh when Wilson dismounted and unfolded his coat, revealing the furious woodpecker. 

After he registered, Wilson took his pack and his woodpecker to his room, then left to tend his horse. Upon his return, ho could hear chopping sounds as he ascended the stairs to his room. He opened the door and the woodpecker cried out, possibly in frustration at being discovered in its effort to escape. It had climbed the window frame and cleared a fifteen inch square section of plaster that now lay in chunks on the bed. It had also cut a hole larger than a man's fist through the lathing and begun chiseling on the back side of the exterior weatherboards. In less than an hour it would have escaped."

Some birds are not the cheerful songsters around the yard, but ferocious and spirited. But whatever their temperament, between habitat destruction, rampant pesticide use and other pollution, light pollution, the introduction of invasive species, and now global warming, we have fewer species and individuals now than Wilson experienced, in a steady rain of ecological destruction.

• A culture of complete white collar impunity.
• Whatever happened to freedom of religion?
• Optimists are at fault!
• Why the east side is the bad side.
• Treason? Yes, it is obvious.
• Vietnam all over again.. a delusional military.
• Taxes affect income. They do not affect propensity to work.
• Do sleazy people make better capitalists and capitalism? No.

Blood Tests For Cancer

"Liquid biopsies" for cancer are coming to the clinic.

Cancer remains the winner in the war on cancer. New molecularly-driven precision treatments have improved outcomes for a few types of cancer, and the reduction in smoking has provided substantial improvements in death rates, but the overall statistics remain grim, most treatments are dreadful, and early detection is more a mirage than reality. One promising, though still experimental, area of progress is in detecting cancers using blood samples.

Cancer trends in the US, overall.

Early detection has been a holy grail, with enormous resources devoted to mammography and PSA tests, among much else, which have turned out to be of marginal utility, or far less than touted. I do not believe there is currently any cancer for which a reliable medical test of any kind provides detection before symptoms or manual / visible detection is possible. After the various reliable and unreliable methods of detection, assessment of cancers involves biopsy, which is far more invasive and disruptive than it sounds, piercing the putative site / organ with a large sampling needle which can cause permanent damage. Biopsy should be regarded as a full surgical procedure in its own right.

Both of these problems could be alleviated with effective blood tests for cancer presence, type, and progression. A significant development in the research field over the last decade or two has been the realization that cancers shed material constantly. Cells are sloughed off in live and dead form, and DNA from tumors is generally in circulation. One corollary is that metastasis is more a matter of these cells finding a congenial home than of their dispersal from their primary source. A second is that blood tests can detect these DNAs and cells on a routine basis.

The root method for doing so is PCR- that revolutionary method in molecular biology that harnesses DNA replication to amplify nucleic acids exponentially, allowing detection of infinitesimal amounts. One of the papers under review in this post claims that a single molecule of cancer cell DNA can be detected in 5 ml of blood. This is astonishing, but also puts bounds on the ultimate utility of this method, since they also say that less than half of grade 1 cancers provide even such a tiny signal. It turns out that, as one might expect, earlier and smaller cancers shed less material than later ones do.

Early stage cancers are hard to detect, but not impossible. The lowest Y-axis levels correspond to one molecule in the sample.

This landmark paper tests patients with many different types of cancer to evaluate the possibility of a relatively blood test for certain known cancer mutations. They find that brain cancers are particularly poorly represented- their shed materials are likely to be confined due to the blood-brain barrier system, plus the glymphatic system. But other cancers are quite amenable to blood testing, at least when in an advanced state. This would at least be a boon to recurrence tracking, and treatment monitoring, for which (repeated) biopsy is either impractical or impossible.

Which cancers give usable blood-born DNA samples?

"... 47% of patients with stage I cancers of any type had detectable ctDNA, whereas the fraction of patients with detectable ctDNA was 55, 69, and 82% for patients with stage II, III, and IV cancers, respectively."

For early screening, blood testing is not, as of this paper in 2014, truly reliable. On the other hand, it finds half of stage 1 cancers, which otherwise might not be found at all, raising the question of how such a cancer should diagnosed and found if a blood test finds, for example, that a common mutation (for example, in the gene TP53) is found to be afoot in a patient. Such mutations, which drive many different cancers, could come from virtually any organ. Some more sleuthing would be in order.

One such approach came up recently, in studies of regulatory markings on DNA, which some call "epigentic" marks. C nucleosides in DNA can be methylated and then derivitized from there to 5-hydroxymethyl 5-formyl, 5-carboxyl, and finally identified by the DNA repair pathway and excised / replaced. Typically, methylation is a repressive signal, part of the cellular machinery that turns off gene expression. In contrast, 5-hydroxymethy modified C residues seems to be associated with higher gene expression. At any rate, both modifications are dramatically reduced in cancer cells, and their patterns can be informative about the cancer's tissue of origin and prognosis/stage. There is even the possibility that the relative positions of 5-methyl-C and 5-hydroxymethyl-C in very small segments of DNA (detected by FRET, no less) could be informative on these issues, though that is more esoteric.

So far, these methods are plumbing the blood samples for specific DNA mutations in specific genes known to drive cancer, and thus have high specificity, but limited utility as general screening tools for patients who have not yet been diagnosed and could have any (or several) of thousands of different mutations. To do that, a far larger panel of genes needs to be assayed, possibly even whole genome sequencing, with an unbiased analysis of their mutations. But that begs the question of how to separate the cancer-derived DNA from all the other junk floating around in a blood sample. Methylation marks may be biased in cancer-derived DNA in useful ways, but they do not have categorically different characteristics usable for separating the wheat from the chaff. This is the big problem right now in cancer blood testing. On a practical level, it will start being used for already-diagnosed patients, to track their treatment and relapse. The cancer selection problem will likely be solved in a brute-force way by sequencing everything in the blood sample and sifting through that data using a growing catalog of cancer-causing mutations. But if some mark or characteristic can be found that is specific to cancer DNA, then general and convenient cancer screening via blood tests will come much sooner.

• Rules are for little people.
• Such as immigrants. Who are Christians, right?
• Does Amazon need to be split up?
• Go ahead and stretch ... every day.
• Skateboard therapy.
• More bullying and sleaze.
• Studies in groveling and sycophancy. What causes this temperament?
• Remember Martha Mitchell?
• The Taliban is winning.
• Meanwhile, Japan has a problem of not asking questions.
• Capitalism is so not working.
• Aretha on piano.
• In California, old-money landlords make out like bandits.

Was Jung an Atheist?

Short answer: yes. Understanding religion, and believing in it, are two different things.

Jung was highly sympathetic to religion- Christianity in particular- seeking to explain its psychology and origins, and even to replicate it. There is an old joke among Jungians. A child asks her Analyst parent.. are we Christians? And the parent answers: "heavens no, we are Jungians!" While Freud was a rather vociferous atheist, Jung took a much more ambiguous, understanding approach to religion. Rather than a pack of lies, it was a truth, just not about the cosmos. What makes Jungians distinct is their respect for the power and psychology of religion, which they are generally obsessed with, and devoted to understanding. They are more anthropologists of religion than disparagers.

It is common for god and religion in general to embody the psyche of its practitioners. Even atheists take god's name in vain, to express strong emotions. Intellectuals customarily make of god whatever most interests them. Einstein and Spinoza took god to be the universe. Jung took it to be the self. While religion touches on many archetypes and psychic complexes, the nexus around which it all revolves is the self. Am I saved? Will I live ever after? Am I good? Is anyone? What is the meaning of my life? Jung took these questions to be significant and deep, not just the superficial reflections of repressed sexuality. Indeed, his view of the unconscious was much more positive than Freud's, seeing it as a fount of deep insight and healing, whose therapeutic power is not just the exposure and extinguishing of childhood traumas and instinctive conflicts. The unconscious has its own perceptual apparatus and methods of communcation (symbols, images) which can be seen as an autonomous entity within ourselves. I.e. god.

This is why symbology and ritual are so much more important in religion than is theology. All the Western attempts to rationalize the concept of god are so much wasted effort, not only because they are intellectually bankrupt due to the non-existence of the cosmic god they posit. They operate on a typically intellectual level that is totally inappropriate to the subject at hand.

An image painted by Jung, from his Red Book. The unconscious holds dark shadows as well as  compassion.

God is indeed real and an autonomous thing, at the same time it is a psychological construct, arising from our own selves and depths. The psychological concepts that Jung fostered, about an immense and fertile unconscious, which partakes not only of individual concerns, but of communal and cosmic ones, represents a significant and irreversible step in our understanding of religion and its panoply of symbols, motivations, gods, and other artistic paraphernalia.

Late in his career, Jung offered an interpretation of the evolution of Christianity, in "Answer to Job". God, as the manifestation of Israel's unconscious longings and strivings, is in the Pentateuch a thin-skinned, and fickle tyrant. He is immature, and when Job calls him to moral account for the Trumpian way he has toyed with his devoted subject, all god can do is blow up in an insulting twitter-esque rage. This exchange raises to consciousness the primitive nature of the god-concept in this culture, and rankles for several hundred years, at which point the solution becomes to make a better man of god by making him (notionally) into a real man. So, Pinocchio-like, he comes to Earth as Jesus, does good deeds, expresses some compassion, (though unimaginable ego seeps through in the commands for followership and claims of overlordship), and then ritually offers his self-sacrifice to assure us that he has really changed his ways and is now meek as a lamb.

Another self-explanatory image from the Red Book.

Obviously, this made a pretty modest impression on Jews at the time and since. But the combination of monotheism and a quasi-charitable, egalitarian form of god, leavened by Greek gnosticism and other intellectual additions, spread like wildfire through a West enervated by the relentless brutality of Roman civilization, and its fractured spiritual resources.

Many gods have come and gone, as cultures evolve and elaborate new images of themselves and their ideals. While Jung dabbled in some mysticism along the way, and was frustratingly ambiguous and unscientific in his writings on the subject, he laid what we can take as a very trenchant foundation for understanding religion as a psychological phenomenon. In this he followed the lead of William James, who recognized that it is a special area, so heavily subjective that philosophy has little hold. Like other freelance religious practitioners, Jungian analysts today split their time between writing books of uplift and psychological insight, and listening to clients bring up their difficulties, whether shallow or deep. They provide spiritual solace to the lost, while trying to heal the larger culture by bringing to consciousness the powers, compassion, and insight that lie within.

• The planet is burning.
• Workers, citizens, unite!
• An emotion in every chord.
• How China beat the recession- classic Keynes.
• What makes unemployed farmers so much better than other unemployed people?
• And why is the Labor party giving up on labor?
• Resignation- an excellent precedent!
• A difference between just desserts and business models.

Where RNA Goes to Die

The exosome, which exorcises aged, defective, and short-lived RNAs, and also plays a part in maturation of ribosomal RNAs.

Much of the excitement in biology focuses on biosynthesis- the duplication of DNA, the growth of cells and organisms. But intrinsic to a dynamic, complex system like our cells are mechanisms to get rid of trash, which we produce in abundance. Trashy chemicals (like drugs and other complex toxins) are broken down by special enzymes in the liver. Old and broken-down proteins are sent to a cellular structure called the proteosome. And RNA also has a life cycle, which ends up at a small structure called the exosome.

RNA is intrinsically an unstable molecule, less chemically stable than DNA, which as archeologists, even paleotologists, have been finding, can survive for millions of years. But on a cellular time span, the spontaneous decay of RNA is hardly fast enough to provide critical regulation over key messages, which may need to be turned down in a matter of minutes. On the other hand, sometimes RNAs start out badly, with errors that jam up the translational machinery- there are several mechanisms in cells to figure out which RNAs should have short half-lives, are damaged, and are causing havoc, which generally send them to the exosome for degradation.

Human cells are full of RNA, much of it junk. By far the vast majority of RNA in a cell (90%) is ribosomal RNA and tRNA- the structural and functional cores of protein translation. Since translation is a rather slow and inefficient process, (as inherited from some extremely early ancestor), cells need tons of ribosomes, which typically make up a fair fraction of the dry mass of cells- up to 30% in bacteria. Exosomes are key processing centers that trim the ribsomal RNA and degrade excess bits. But other classes of cellular RNA are more diverse and interesting. Indeed, the encode project and similar projects have found that most of our genomes are transcribed to RNA. Some of these newly found RNAs are functional, but most is junk- junk RNA transcribed by a smart, but rather promiscuous transcription process, into junk RNA. Which does little harm if it gets sent right into the trash can.

A recent paper extended a lengthy trail of work into the structure of the exosome, reconstituting the full complexes from human and from yeast, and obtaining a new structure from the human form. Reconstitution means that the complex was not purified from cells or tissues as a whole, but that the individual proteins composing it were purified, here from bacterial cells or human cells carrying the encoding genes, and then later mixed to produce the full complex of about nine proteins.

Straight from the bench. Proteins are stained/displayed in blue, sorted by their molecular size by being electrophoresed (driven by an electric voltage) through a gel, from top to bottom. Smaller proteins (markers on left, marked in kilo Daltons) head toward the bottom. The middle lane is the yeast reconstituted exosome, the right lane is the human complex. The ten proteins of each complex are marked on the far right.

The complexes were then put into an electron microscope to get detailed pictures, which through the magic of superposition, averaging, and atomic modeling, can infer atomic-scale structures. The also created inactive mutatants of key proteins in the complexes, and then could add RNA to them to visualize where the RNA lies in the complex.

They found, as you can see, that the human and yeast complexes are very similar. The paths that the RNA takes within them is similar, but a bit longer in the human form, due to some accessory proteins like hMMP6, which protects a bit more of the RNA threaded through the middle from outside access. The active ribonucleases in all this are hRRP6, positioned towards the top right of the shown complexes, in red, and hDIS3, at the bottom in pink. hDIS3 is a processive RNAse, working from the 3' end to the 5' end and is also an endonuclease, meaning that it can cut in the middle of an RNA if necessary, while hRRP6 is less processive, and can nibble when needed. Also in the complex is a helicase (hMTR4) that can unwind double-standed RNAs, which is a frequent natural condition. One can see that these activities make up a directional machine, with RNAs getting fed into the top and consumed at the bottom (and side, if there is a second strand). The helicase opens the possibility of extracting jammed RNAs from polymerases and ribosomes, as though they were office printers. Enhancer RNAs, a recently-recognized class of junky RNA made at gene regulatory elements accumulates in hybrids to the enhancer DNA if not rapidly pulled off and degraded by exosomes.

Exosome structures from yeast (right) and human (left and middle). RNA is in black on right, and in schematic turquoise on left. The main digesting nuclease is at bottom in pink, while the unwinding helicase is in blue at top.

As mentioned above, chopping up RNA is not very chemically difficult. The hard part is controlling this process to separate the sheep from the goats. There is lots of good, even essential, RNA that needs to be kept around in the cell for as long as possible. All that ribosomal and rRNA is expensive to produce and should not be recycled until absolutely necessary. What regulates access to the exosome?

• Normal RNA processing prevents degradation. For example, as protein-coding mRNAs are made, they are spliced (introns removed) and polyadenylated and 5' O-methyl capped. The latter two processes protect them from degradation. Indeed, the length of the poly-A tail is in rough terms a timer for the livespan of that RNA, with longer tails on longer-lived mRNAs. Any problem in transcription and subsequent processing delays the addition of these markers and opens that RNA to attack by proteins that find uncapped and under-adenlyated RNAs and ferry them to exosomes.
• Exosomes are part of normal RNA processing in some cases. Ribosomal RNAs are trimmed by exosome versions, up to a point, where they are released and then modified and further processed into the pre-ribosomal structures, all in the nucleosome. The same goes for other small stable RNAs. Their mature structures are evidently stable enough to prevent excessive degradation. Special protein factors may facilitate this regulation as well, preventing, instead of encouraging, exosome activity beyond a certain point.
• Other special features of RNAs may be recognized by helper proteins that bring such RNAs to the exosome for degradation. For example, a complex called "PPC" recognizes short poly-A sequences, as would be common for timed-out normal mRNAs and many other RNA polymerase II transcripts that are not fully processed or stabilized by other means. It plays a big role in degrading lots of the junky RNA made from miscelleneous regions of the genome.

The cell is a sustainable chemical system, and part of that means having ways to dispose of trash. The exosome is the primary RNA disposal unit in eukaryotic cells, and has enabled the rather promiscuous transcription that has misled some people to think that we have far more genes or functional genetic elements than are actually there.

• Stories about abortion.
• What's it like to be a liberal Catholic?
• Our treatment of migrants is unlawful and cruel.
• Let's exempt Russia from sanctions.
• Denuclearize? Whoever said denuclearize?
• It's starting to feel like Georgian England around here.
• Should we have bailed out Lehman? No.
• Hey, who cares about the minus sign when you're talking about trillions of dollars?