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Pharma’s broken business model — Part 2: Scraping the barrel in drug discovery – Endpoints News
According to the Human Protein Atlas, there are 19,613 proteins encoded by the human genome. Of these, 14,545 (74%) have no known link or relationship with disease, which rules them out as potential new drug targets because they fail to meet criterion 1 above. Perhaps these proteins are non-essential, as any deficiencies can be compensated by other proteins or pathways; or perhaps they are essential, however any deficiencies are lethal before birth so they never have the chance to cause any disease. In any case, we have no reason to believe that targeting these proteins will do anything for any known human disease.
Now of the 5,068 proteins that have any link to disease, 3,131 (16% of all human proteins) are considered to be “undruggable”, either because they have no obvious pocket capable of binding small molecule drugs, or because they are intracellular and thus inaccessible to large proteins that cannot penetrate the cell membrane. We must rule out these proteins as potential new drug targets because we currently have no way to target them, so they fail to meet criterion 2 above.
The Dark Side of the Enlightenment - WSJ
This astonishing arrogance is based on a powerful idea: that mathematics can produce universal truths by beginning with self-evident premises—or, as Rene Descartes had put it, “clear and distinct ideas”—and then proceeding by means of infallible deductions to what Kant called “apodictic certainty.” Since this method worked in mathematics, Descartes had insisted, it could be applied to all other disciplines. The idea was subsequently taken up and refined by Thomas Hobbes, Baruch Spinoza, John Locke and Jean-Jacques Rousseau as well as Kant.
This view of “reason”—and of its power, freed from the shackles of history, tradition and experience—is what Kant called “Enlightenment.” It is completely wrong. Human reason is incapable of reaching universally valid, unassailably correct answers to the problems of science, morality and politics by applying the methods of mathematics.
The first warning of this was Descartes’s 1644 magnum opus, “The Principles of Philosophy,” which claimed to reach a final determination of the nature of the universe by moving from self-evident premises through infallible deductions. This voluminous work is so scandalously absurd that no unabridged English version is in print today. Yet Descartes’s masterpiece took Europe by storm and for decades was the main textbook of the Cartesian school of science. Kant followed this dubious example with his “Metaphysical Foundations of Natural Science” (1786), in which he claimed to have deduced Newton’s laws of motion using pure reason, without empirical evidence.
The Cultural Axis | by Robert O. Paxton | The New York Review of Books
The word “international” acquired a special meaning in its usage by Nazi and Fascist cultural officials. The Allies’ international cultural associations had rested on a set of liberal democratic assumptions: that works of art and literature should be evaluated by universal standards of quality; that masterpieces were the product of individual creativity; and that no national culture deserved hegemony over another. The Nazi and Fascist dictators reversed all of these assumptions. They measured the merit of works of art and literature by their significance within unique national cultural traditions. Masterpieces, in their view, grew out of community roots. And national cultural traditions were ranked in a natural hierarchy, with the German and Italian ones at the top.
Hitler concerned himself with cultural matters as soon as he became chancellor of Germany in January 1933. He purged the German section of PEN International of “leftist” and Jewish writers. When PEN International protested, Hitler dissolved the German section altogether at the end of 1933. During this dispute the president of the Italian PEN club, the provocateur Futurist intellectual Filippo Tommaso Marinetti, supported the German position. Thus from the earliest days, Nazi cultural projects proved capable of enlisting foreign support.
Recentering the universe
It was this hierarchy—so central to Western cosmology for so long that, even today, a ten-year-old could intuitively get much of it right—that was challenged by the most famous compendium of all: Denis Diderot and Jean le Rond d’Alembert’s eighteen-thousand-page Encyclopédie. Published between 1751 and 1772, the Encyclopédie was sponsored by neither the Catholic Church nor the French monarchy and was covertly hostile to both. It was intended to secularize as well as to popularize knowledge, and it demonstrated those Enlightenment commitments most radically through its organizational scheme. Rather than being structured, as it were, God-down, with the whole world flowing forth from a divine creator, it was structured human-out, with the world divided according to the different ways in which the mind engages with it: “memory,” “reason,” and “imagination,” or what we might today call history, science and philosophy, and the arts. Like alphabetical order, which effectively democratizes topics by abolishing distinctions based on power and precedent in favor of subjecting them all to the same rule, this new structure had the effect of humbling even the most exalted subjects. In producing the Encyclopédie, Diderot did not look up to the heavens but out toward the future; his goal, he wrote, was “that our descendants, by becoming more learned, may become more virtuous and happier.”
Why do people in medieval art look bored or indifferent when being killed? (cross-post from /r/Art) : AskHistorians
I've been amused by this trait in pre-1600's european paintings all my life; people going through the most horrific injuries imaginable look as if they were bored with life anyway and their killer did them a service. It would have been easier to draw open, panicked eyes and flailing arms than just laconic, Eeyore-like pawns that die on command and without fuss.
Dostoyevsky and Russia's soul
Dostoevsky, who traveled widely in Europe but was suspicious of it, despised passionately the revolutionaries and their desired revolution. He spent the 1860s and 1870s obsessing over Russia’s looming confrontation with itself. His four most important works (Crime and Punishment, The Idiot, Devils, and The Brothers Karamazov) are not simply novels, but rather dystopian warnings about what would happen if Russia did not return to its pre-Petrine origins.
