WOOY!! After decades of attempts to publish all of George Herriman’s full-page Sunday Krazy Kat comics, Fantagraphics, the Seattle comics publisher, has done it. In 13 volumes, we get all the Krazy Kat comics, dating from April 23, 1916 (when they began) to June 25, 1944 (when Herriman died), plus some pre-Krazy strips thrown in for good measure. HOOROO!!
At last, every Krazy Sunday page is between covers: from the
first, where the Kat steals away from a picnic to bring ice cream to
some “poor li’l orphan ‘kitties'” in a coal chute, to the last, where a
worried-looking Krazy floats to who-knows-where clutching a paper sail.
And what covers, and spines, they are! The quirky volumes, designed by
cartoonist Chris Ware and edited by Bill Blackbeard (with Derya Ataker,
Jeet Heer, and Kim Thompson), are a shelf to behold.
It has been a long haul. The first book of selected Krazy Kat
comics was published in 1946, just two years after Herriman’s death,
with an introduction by e.e. cummings. It was followed, forty years
later, by an excellent book, the volume that got me hooked: Krazy Kat: The Comic Art of George Herriman
edited by Patrick McDonnell, Karen O’Connell, and Georgia Riley de
Havenon. And that was followed in 2010 by Sunday Press’s grand,
oversized book, George Herriman’s Krazy Kat: A Celebration of Sundays, edited by McDonnell and Peter Maresca. But all these were selections, not the full monty.
The idea of publishing the strip’s entire life was hatched in the late 1980s. By the early nineties, a couple volumes of The Komplete Kolor Krazy Kat,
edited by Rick Marschall, had been published by Kitchen Sink Press, and
“a consortium of comics lovers comprising Eclipse Comics, Turtle Island
Press, and Bill Blackbeard” — as Kim Thompson, one of the publishers of
Fantagraphics, remembers it — had begun publishing a 29-volume set of
the Sunday Krazys. The main supplier of these comics was Blackbeard himself, one of the editors of The Smithsonian Collection of Newspaper Comics and, more recently, a hero of Nicholson Baker’s book Double Fold: Libraries and the Assault on Paper.
He had row upon row of old newspaper comics piled high in his garage
and basement, which he called the “San Francisco Academy of Comic Art.”
(I went to the “academy” myself in the eighties and bought a few
black-and-white Krazys.) Alas, though, after only nine volumes
(1916-1924) the project was ditched when, says Thompson, “intractable
(and non-Kat-related) business problems sank the good ship Eclipse in
1992.”
Ten years passed. Finally, in 2002, Blackbeard joined with
Fantagraphics to finish the job, picking up where the consortium left
off, pushing on to the end of Herriman’s career, and then wrapping back
to repeat the material already published. They finished up the series
this year, just after Blackbeard died, but only in the middle part of
Herriman’s career.
That was one Krazy plan, but it worked. As for the 32 years of daily Krazy Kat strips, they are, as Derya Ataker points out in the introduction to The Kat Who Walked in Beauty: The Panoramic Dailies of 1920, a more “elusive catch.” But that’s another story.
¤
The completion of Fantagraphics’s Krazy Sunday series also
means, quite possibly, the end of Krazy Kriticism — a brand of writing
that, as far as I can tell, only the Kat engenders. Critic Gilbert
Seldes first articulated its credo in the 1924 article “The Krazy Kat
That Walks by Himself.” After comparing Herriman to Dickens, Cervantes,
and Charlie Chaplin, Seldes threw up his hands: “It isn’t possible to
retell these pictures; but that is the only way, until they are
collected and published, that I can give the impression of Herriman’s
gentle irony, of his understanding of tragedy, of the sancta simplicitas,
the innocent loveliness in the heart of a creature more like Pan than
any other creation of our time.” Thus did the gates open to a flood of
ecstatic, mimetic writing in which every critical impulse was
mercilessly drowned in gushing praise and fervent prayers to put the
comics between covers.
Here are the marks of Krazy Kriticism, a good sampling of which can be found in Craig Yoe’s Krazy Kat & The Art of George Herriman: A Celebration. The Kritics use Ks where Cs would normally go. They explore ad nauseam
the love triangle between Krazy Kat, Ignatz Mouse, and Offissa Pupp.
They marvel at, and occasionally copy, the Kat’s linguistic habbits:
“werra” rather than “very,” “heppy” rather than “happy,” “ainjil” rather
than “angel.” They pore over the scant crumbs of Herriman’s short life.
(Did you know Herriman called himself “Garge” and cooked lamb legs for
his Scottie dogs Angus, Ginsberg, Shantie, McTavish, and Macgregor?)
They also love to compare the strip to literary classics: It’s “Don
Quixote and Parsifal rolled into one,” wrote John Alden Carpenter,
composer of the 1922 Krazy Kat ballet. And above all, they gush, gush, gush!
The earliest example of Krazy Kriticism comes from 1917. When the
Sunday strip was only a year old, Summerfield Baldwin described its
basic plot as “the perpetual chastisement of the Kat by the Mouse”
(usually in the form of a hurled brick), followed by the Kat’s “delight
in [this] forever recurring maltreatment.” He detailed the strip’s
linguistic hijinks, in which wonderful becomes “wundafil” and a flying
brick is “represented by the letters Z-I-Z-Z strewn in its wake.” He
admired the “indiscriminate mingling of the choicest of diction” with
barely comprehensible slang. He thrilled at Krazy’s tail, “a most
remarkable creation, ending very squarely indeed, and almost always
betraying one or two quite heart-rending kinks.” And he relished the
strip’s surreal, shape-shifting landscapes, including “trees with
extraordinarily large and bulging trunks crowned by the merest tuft of
foliage.”
Baldwin did quite a nice job detailing the strip’s delights. But then
he stopped and, like every Krazy Kritic after him, threw up his hands:
“I have been incompetent to devise any consistent critical theory that
would do justice to his genius … My sole purpose has been … to perform
what is really the sole function of criticism, the function of
discovering genius wheresoever it may be concealed.”
Yes, even 95 years ago the truth was as loud and clear as a pair of clapping mitten rocks rising up out of the mesa encantada: Krazy Kat
is perfect and Herriman is a genius — linguistically, graphically,
poetically, onomatopoetically, every which way. Confronted with such
perfection, most of Herriman’s critics, once they finish reciting plot,
affecting accents, and making comparisons to classics, have always
thrown up their hands and said, “Behold!” But does it have to be that
way? The genius label, after all, has never kept Shakespeare or Picasso
scholars from finding something to say.
Maybe the problem is that critics feel they must use all their air to hoist Krazy Kat
from low culture to high. Or maybe the problem is humor; analyzing why
something is funny is a sure way to kill it. Or maybe the problem is
that Krazy Kat simply lacks a basic feature required by critics to analyze a work of art: development. Krazy Kat never evolved. Indeed, in some respects, it
actually devolved. Whenever Herriman’s format was restricted to
regular-sized frames, his strips became more wooden. And color — which
crept in briefly and beautifully in 1922, then permanently and less
beautifully in 1935 — was a mixed blessing. But so what? Everything
great about the strip was present in the first few years of its
three-decade run: the radical layouts (vertical, horizontal, diagonal,
wavy); the language and accents (a mix of New Orleans Creole,
Elizabethan English, Brooklynese, Yiddish, and Spanish); the wordplay;
the weird wheel with a dot; the Navajo-inspired zig-zag (which Charles
Schulz borrowed for Charlie Brown’s shirt); the time conundrums and
gender bendings; the landscape of the Monument Valley; and the
intertwinings of species and race, of family myths and genetics, of
fabric and skin, of art and artifice, of dreams and reality, of crime
and charity. And, of course, the amazing riffs on natural events and
objects: wind, waves, mitten rocks, tumbleweeds, tule swamps, and the
old ignis fatuus.
After Herriman had finished laying out this grand picnic before him,
he didn’t really develop. He fiddled, he noodled, he rearranged, he
played. In this respect, the artist he most resembles is not Picasso,
who developed and changed constantly, but rather someone like Mark
Rothko, who, after discovering his vocabulary of colored rectangles,
spent his last 20 years exploring it.
Just because a body of work lacks development doesn’t make it boring.
It can, however, make it hard to write about. And that difficulty, in
Herriman’s case, is compounded by the fact that Krazy Kat lacks
not only stylistic development but plot development too. The plot, if
you can even call it that, is almost always the same — a brick, hurled
by a mouse, at a cat who loves it. Though the characters get deeper as
their biographies extend back in time and their families extend to the
air and sea, the plot never thickens, never develops. Indeed, it’s hard
to imagine what Krazy Kat would have become if Herriman had
ever dropped the brick and created a true plot, a long yarn that would
give his characters a chance to stretch out and change.
As luck would have it, Herriman did once drop the brick, for nearly a
year. From May 15, 1936, to March 17, 1937, Herriman used his daily
strip to spin out a single story: Krazy Kat discovers a cache of Tiger
Tea (a strong katnip tea) which gives its drinkers a tiger-like power
and ferocity — and eventually gives them stripes too. In the final pages
each animal except for Krazy rejects the Tiger Tea, preferring not to
aspire to the grandest of the Kats, but rather to the grandest animal of
its own kind. (Fish want to be like sharks, mice like rats.) For
Herriman, this is not just weirdly plot-driven and weirdly topical — the
movie Reefer Madness was made the same year — but also weirdly
didactic, with its Aristotelian message that everyone should strive for
self-realization, not self-alteration. And maybe there’s another moral
here, a hidden one, proffered unconsciously: Characters under the
influence of plot (or pot) will lose their character, becoming like
everyone else. In the end, we see Herriman returning his characters to
their pre-Tiger Tea selves, and the plot virtually eats itself, turning
into a fable about the evils of plot. Maybe Herriman learned his lesson.
After the “Tiger Tea” saga, he went back to his ur-plot — the daily
hurled brick — never to abandon it again.
¤
Now that Krazy Kritics have gotten their dearest wish — all of the Sunday Krazys published
in book form — what will happen to Kriticism? Will it yield to real
criticism? Will the endless retelling, mimicking, and gushing stop? Will
we finally be able to say, as Ignatz might, fooey to all that?
One essay in Yoe’s collection, Douglas Wolk’s “The Gift,” offers a
ray of hope. Wolk finds something new to analyze in the strip — its
peculiar pace: “The real comedy of Krazy Kat is almost always
slower than its surface humor, which is appropriate for a strip whose
central joke is miscommunication on a grand scale. The one way you can’t
read it for pleasure is quickly.” This helps explain why
Herriman, now a god among cartoonists, was never terribly popular during
his lifetime. Yes, he had plenty of high-toned fans — e.e. cummings,
Carl Sandburg, T.S. Eliot, Willem de Kooning, H.L. Mencken, and Edmund
Wilson among them — but his strip was under constant attack from
newspaper readers, editors, and especially advertisers. Readers who
couldn’t understand the strip were skipping it, so advertisers began to
worry that readers were skipping their ads too. As Blackbeard notes,
William Randolph Hearst, the strip’s key supporter, would often find
that an editor had quietly pulled it out of the lineup and have to
demand its restoration.
The problem with Krazy Kat is the same as its genius: It
cannot be consumed quickly or easily. And it is best not consumed in
great quantities all at once. The first time I read it I was stunned
and, for a while, stumped, by the verbal and visual density of the
strip. How do you get through this? Where do you start? According to
Wolk, “Everything from Herriman’s crabbed hand-lettering and batty
phonetic spellings to his habit of showing Ignatz’s brick flying from
right to left (against the flow of reading) to the way he constructs his
panels and pages — with vistas so wide the eye can’t take them in all
at once — means you need to slow down …”
To take Wolk’s analysis a step further, the strip’s slowness is
probably also due to something that has been present from the beginning
and that runs against the grain of most comics and most Western reading:
its verticality. Herriman was obsessed with matters of up and down, not
just when it came to birth and culture, but also graphically. He had a
tendency to push downward against the horizontal tide of comics, against
reading in general, and, as in the “Tiger Tea” tale, against the idea
of a linear plot. Instead, the reader’s eye wanders restlessly over the
page, up and down, back and forth, “William and Nilliam,” as Krazy would
say. It can take a long time to read one full-page comic thoroughly,
and even then you cannot be sure you’ve gotten it all.
The vertical push of the strip lies in its very origins. The first
time that Ignatz beaned Krazy (with a marble, on July 26, 1910), the cat
and mouse drama appeared as a sub-cartoon, underneath another Herriman
strip, The Family Upstairs — literally underfoot. And even when Krazy Kat had become its own strip, breaking away from the hijinks of The Dingbat Family, Herriman’s vertical proclivities continued: Wolk informs us that the first all-Kat strip, on October 28, 1913, ran in the New York Journal‘s
comics page “in a vertical, page-high stack of five tall panels beside
the horizontal rows of regularly laid-out comics.” That verticality
stuck until the end: The very last frame of Krazy Kat, the one
that shows the Kat sailing away, is a panel that lies beneath the
floorboards of the main strip, in what Herriman called “the waste
space.”
To make the eye track vertically as well as horizontally, to mess
with the very process and direction of reading, is not only a sure way
of slowing down a newspaper reader, who is, after all, used to gobbling
words and pictures easily, it is also a way of breaking down a sacred
wall. If “prose … is ordinary speech,” says Russian formalist Viktor
Shklovsky, then poetry is “the language of impeded, distorted speech.”
Of course, that’s just a fancy way of saying that Krazy Kat is
not just a low-down comic strip, but high-class poetry too. And that,
after all, is something we Kritics have known all along. So let the
parsing begin!
Frank
Jones, “Untitled (Puerto Rican German)” (circa 1960), colored pencil on
paper, 18.75 x 25 inches (all images courtesy of Shrine, New York)For
Frank Jones (1900-1969) — a Black self-taught artist who spent his life
in Texas, where he died while serving time at the state penitentiary in
Huntsville, north of Houston (home of the Lone Star State’s execution
chamber) — making art might have served as a form of spirit-lifting
escape from the monotony and tension of his long years in prison.
Although
his remarkable drawings in colored pencil on paper are well known among
informed collectors and specialists in the outsider-art field, they
still have not achieved the broad recognition enjoyed by the similarly
unique works of Bill Traylor (circa 1853-1949) or Thornton Dial, Sr.
(1928-2016), to name two other renowned, African American self-taught
artists. This might be due in part to the fact that only a few hundred
of Jones’s drawings are known to exist, and many of them have been in
private hands for many years.
As a result, although examples of
his work do routinely turn up at events like the annual Outsider Art
Fair in New York, presentations of significant quantities of Jones’s
drawings are generally less frequent than those of, say, Traylor. His
last notable showings took place at Carl Hammer Gallery in the spring of
2017 and, later that same year, at Ricco/Maresca Gallery in New York. Frank Jones, “Untitled (number 602)” (circa 1960), colored pencil on paper, 20.5 x 25 inchesNow,
though, Shrine, a gallery at the southern end of Manhattan’s Lower East
Side that often focuses on outsider art, is presenting 114591
— at nine drawings, a relatively bountiful exhibition of Jones’s
production and one brimming with some of his highest-quality, most
emblematic creations (tip to fans: there’s a tenth piece available that
is not on display). The show takes its title from the artist’s own
prisoner number. (Jones, who was illiterate, routinely marked his
drawings with that impersonal, institutional identifier.) The exhibition
remains on view through September 13.
Jones was born in
northeastern Texas, near the border with Oklahoma. His enslaved
ancestors had labored on cotton plantations. Young Frank grew up in a
rural environment in which generations-old African traditions helped
shape his aesthetic-spiritual sensibility and worldview.
Jones was
born with a caul: part of the fetal membrane covered his left eye. In
the society in which he grew up, this unusual physical feature was known
as a “veil,” and children born with such cauls were regarded as
“double-sighted.” It was believed that they could communicate with the
spirit world. Throughout his life, Jones claimed that he could see
supernatural beings — animated objects, animal-like creatures, demons —
which he called “haints” (“haunts”), “devils,” or “haint devils.” Frank Jones, “Untitled (number 112)” (circa 1960), colored pencil on paper, 12 x 18 inchesJones,
who worked as a farm laborer and did odd jobs to eke out a living,
spent roughly two decades in and out of Texas jails; he was sent to the
prison in Huntsville to serve a life sentence for a murder he insisted
he had not committed. In the 1960s, as an inmate, he began making
drawings on found scraps of paper with the stubs of blue-and-red
accountants’ pencils. In them, he developed his “devils’ houses” motif —
wiry-looking structures depicted in cross-section, in which his
omnipresent, horned, bird-like “haints” resided.
Through his
depictions of the demons he claimed to be able to see, and that, he
explained, were always eager to cause mischief, Jones not only gave
visible form to his spirit sightings, but also contained or curtailed
what he perceived to be their hurtful powers. His winged devils’
grinning faces belie the harm he believed they could cause. Clocks often
appear in Jones’s drawings, too, alluding to the marking of time and
sense of mortality that, inevitably, are on many a prisoner’s mind.
In
the early 1960s, Murray Smither, a young employee of the now-defunct
Atelier Chapman Kelley, then an important gallery in Dallas specializing
in modern and contemporary art, traveled back to Huntsville, his
hometown, to judge a competitive exhibition of art made by inmates at
the state penitentiary. There, he chose Jones as the winner of the
contest. He shared his discovery with his boss, Chapman Kelley, whose
gallery began offering the self-taught draftsman’s works for sale at a
time when the market for what would become known as “outsider art” was
still in its infancy in the United States. Frank Jones, “Untitled (Whiskey Drunken Devil House CFA 692)” (1964), colored pencil on paper, 8.5 x 11 inchesSmither
went on to become a collector, curator, and respected authority on folk
art and outsider art from Texas and the American South. Today, at the
age of 83, he is bringing his large, renowned collection to market
through a year-long series of exhibitions
at the Webb Gallery in Waxahachie, a small town south of Dallas.
(Seekers of Jones’s works take note: one of his iconic drawings is among
the Webb Gallery’s offerings, and Smither is in the process of donating
a second work to a Texas museum.)
In the works on view at Shrine,
some of Jones’s houses are so packed with fluffy demons that they seem
ready to teeter or wobble. In some of these drawings, which are rich in
decorative detail, Jones’s devilish spirits seem to emerge right out of
the crossbeams of the houses they inhabit. In one elaborately shaped
structure, they appear only symbolically, integrated into the artist’s
form-giving, decorative patterning.
In this group of drawings,
Jones’s houses are also at times exuberantly non-rectilinear, with
appendages or protuberances providing quirky charm. (The artist’s
cathartic intentions notwithstanding, another way to appreciate his
works is to view them as intriguing examples of fantasy architecture.)
Notable here, too, are the drawings in which Jones’s colored-pencil
palette expands beyond blue and red to include green, orange, and
purple. Frank Jones, “Untitled” (circa 1964-69), colored pencil on paper, 25.5 x 30.5 inchesOf
special interest among the works at Shrine are five that the gallery’s
founder-director, Scott Ogden, a longtime outsider-art collector,
managed to find from a private source who had owned them for many years
and was ready to bring them to market.
These drawings offer vivid
evidence of the expressive range of Jones’s draftsmanship and
compositional skill, and several still bear, on the backs of their
frames, labels from the galleries through whose inventories they passed
over the years. For collectors interested in such artworks’ provenances —
the records of those who have owned them over time — the collective
history of these drawings mirrors the development of the outsider art
field in the U.S.
Admirers of drawing in all its forms have plenty
to savor in Jones’s mysterious — and mysteriously elegant — delicacies.
Those who are already familiar with his art will find some gems in
Shrine’s presentation. Newcomers may find them devilishly alluring. Frank Jones – 114591continues at Shrine (179 East Broadway, Lower East Side, Manhattan) through September 13.
To place Jonathan Swift and the Marquis de Sade
next to each other looks at first like setting up hero and antihero.
Jonathan Swift is the fierce but righteous satirist; the Marquis de Sade
is, as Henry James
put it, the “unnameable” pornographer. Swift was the consummate Church
of England man who had no shortage of invective to lob against libertine
freethinkers like the Earl of Wharton and advocated for theater censorship to stave off vice. Sade was reported to the police by a prostitute for masturbating on a crucifix.
Their characters may never have been clearer than at the end of their
lives. Swift’s self-penned Latin epitaph for his burial site at St.
Patrick’s Cathedral in Dublin, where he was a dean, translates as
“Fierce indignation can no longer injure the heart. Go forth, voyager,
and copy, if you can, this vigorous (to the best of his ability)
champion of liberty.” Sade, who died in prison sixty-nine years after
Swift, struck a more defiant and grandiose tone in an oft-cited passage
said to be from his will: “Imperious, choleric, irascible, extreme in
everything, with a dissolute imagination the likes of which has never
been seen, atheistic to the point of fanaticism, there you have me in a
nutshell, and kill me again or take me as I am, for I shall not change.”
Their parting words left an imposing, almost abstract, impression of
these authors on subsequent generations. They had become monuments,
examples, ghosts. Whether they were benevolent or malevolent depended on
what those conjuring chose to see. At times Swift’s writings were
obviously the work of a lunatic, while Sade’s writing was capable of
driving people to lunacy and even fits of epilepsy. At other times Swift
was lionized by the likes of Irish president Eamon de Valera as “one of
the [Anglo-Irish] pioneers…who realized that they ought not to permit
themselves to be governed by ministers from England.” William Butler Yeats offered a more grandiloquent, un-Swiftian translation of Swift’s epitaph, claiming that “he served liberty.” In 2014, on the bicentennial of Sade’s death, the scroll manuscript of The 120 Days of Sodom Sade had spent thirty-seven days in the Bastille writing was put on public display in Paris; in 2017 it was declared a national treasure by the French government, which ordered it to be withdrawn from private auction.
Treating the manuscript as an object of admiration was likely
preferable to trying to actually finish it. Neither author made for easy
reading. Sade’s best-known novels are huge bricks alternating between
philosophical digressions and sexual depravity that are both comically
grotesque and repetitively vulgar. “One of the most fascinating things
about Sade’s writing,” Maggie Nelson writes, “is its immense capacity to
shock, and its equally immense capacity to bore.” The challenges of
Swift are more temporal. His writings are filled with conflicts,
controversies, and people long abandoned by posterity. Much of the
potency of his language is flattened and the sharpness of his irony
dulled because the subjects being ridiculed proved so ephemeral. “He has
written miscellaneously,” John Boyle, the fifth earl of Orrery, fairly
assessed in his otherwise unfair account of Swift, “and has chosen
rather to appear a wondering comet than a fixed star.”
Reading them, we see why Swift biographer John Stubbs calls his
subject Sade’s “satirical cousin” with a “technique…classified above all
as the art of upsetting people” and whose “determination to vex…prevents any political group from conscripting him.” We see why Swift and Sade are the first two entries in André Breton’s Anthology of Black Humor. And we follow why, in Simone de Beauvoir’s
words, Sade rejected the idea of submission as “hypocritical
resignation which is adorned in the name of virtue” that aims “to
destroy the individual by imposing upon him a stupid conformism.” All
dissidents would admire such attributes, especially at the height of the
twentieth-century obscenity trials, when both Sade and Swift could be
cast as patron saints of extremism in the pursuit of liberty. Whatever
their pursuits, they were extremists who created literature that wasn’t
so much great as it was relentless. Even now they make passive reading
impossible.
The “projection” or “project”—a
pitch made to the public for the improvement of their welfare—was a
popular way of getting noticed in a burgeoning media environment of
cheap, fast printing. Projects could be written by anyone and ranged
widely in quality from outright scams to substantial, pathbreaking
policy proposals. Defoe gained notoriety with an entire book of projects
for the reform of mental health care, bankruptcy, the education of
women, and other ideas. Not all projects were humanist, of course; Swift
also wrote pamphlets in support of suppressing the opposition press and flogging beggars.
With his satire exposing the condition of Ireland’s poor and the
negligence of their imperial managers, Swift turned the projection on
its head. The result is an authorial voice who, in the words of Swift
biographer David Nokes, tilts between “nervous” reticence and
“lip-smacking relish” over his one neat trick. The first eight hundred
words of the Proposal are innocuously grandiloquent:
I think it is agreed by all parties that this
prodigious number of children in the arms, or on the backs, or at the
heels of their mothers, and frequently of their fathers, is in the
present deplorable state of the kingdom a very great additional
grievance; and, therefore, whoever could find out a fair, cheap, and
easy method of making these children sound, useful members of the
commonwealth would deserve so well of the public as to have his statue
set up for a preserver of the nation.
The invocation of “sound, useful members” is perhaps the first red
flag. Without further warning, the proposer gets to his point: “I have
been assured by a very knowing American of my acquaintance in London
that a young healthy child well nursed is at a year old a most
delicious, nourishing, and wholesome food, whether stewed, roasted,
baked, or boiled; and I make no doubt that it will equally serve in a
fricassee or a ragout.” The selling of Ireland’s poor children for food
will ensure a reduction of the noxious Catholics, he argues, and poor
tenants will have children as currency to pay rent. “Constant breeders”
will make “eight shillings sterling per annum by the sale of their
children” and will be relieved from caring for them after a year. The
author then makes the famous declaration of his own charitable
disinterest: “I have no children by which I can propose to get a single
penny.”
Like Swift’s previous efforts, however, A Modest Proposal had
little practical effect. Ireland would continue to be seen as a burden
to its neighbor. A famine came in 1740 that killed at least 300,000
people. One million died in the Great Famine a century later. Instead
his proposal took on greater relevance the further it drifted from its
intended context and came to indict humanity at large. Philosopher John Gray writes: “The final effect of the Modest Proposal is to leave the human story a dark and senseless farce.” This effect is best demonstrated by the reading Peter O’Toole gave
in Dublin in 1984. He began by noting that the essay had “a little
something to offend everybody,” and his appropriately lackadaisical
reading did just that. O’Toole was heckled, people walked out, and the
reading, broadcast live on Irish public broadcast station RTÉ, was cut
short, setting forth a flock of ironies that would have delighted the
dean in his nearby resting place.
Swift did succeed in his desire to “vex” his readers—some say far too much. Edward Said
noted a “discomfort” in all of Swift’s work, “that we have before us a
show of freaks and horrors: a mad writer, an astrologer being murdered,
an absurd and impossible war…a gallery of raving freethinkers, men
burrowing in dung, and so on.” Leavis went further, contrasting Swift’s
cruel irony against what he saw as the less abrasive variety practiced
by Edward Gibbon.
“Gibbonian prose insinuates solidarity with the reader,” whereas the
“ironical” solidarity of Swift is a “betrayal.” To Leavis, Swift’s irony
“is a matter of surprise and negation,” as he implies that “this is the
only argument that appeals to you. Here are your actual faith and
morals. How, on consideration, do you like the smell of them?” It is a
small blessing that Leavis lived only one year into punk.
If Jonathan Swift were a wandering
comet, then the Marquis de Sade was the fixed star—or the black hole. He
never moved very far, with the second half of his life spent shuffling
around the French penal system for various sex scandals and blasphemies.
Sade’s writing, begun in earnest once he reached middle age, was not a
tool for raising his social station, as with Swift, but a by-product of
his decline. Restricted from pursuing his orgiastic and blasphemous
hobbies, Sade undertook several writing projects across different forms:
philosophical dialogues, short stories, a Candide-esque novel
of morals, and drama. In 1783 he wrote his wife from the Château de
Vincennes that he had begun a “great novelistic labor” requiring six
hundred pages of manuscript paper thin enough to be rolled. The result
was, in his words, “the most impure tale ever written since the world
began.” Few have been inclined to disagree. From the manuscript of The 120 Days of Sodom, by the Marquis de Sade, 1785. Photograph by ActuaLitté. Flickr (CC BY-SA 2.0).
As with A Modest Proposal, The 120 Days of Sodom
describes the utmost lengths of human depravity. In Sade’s case, the
audience (predominantly four libertine men of eminent rank but
grotesquely low character) is an active part of the sprawling narrative.
It is an unfinished tale, written after he was incarcerated in the
Bastille, then abandoned when Sade was transferred elsewhere for yelling
that prisoners were being murdered, and seemingly lost when the prison
was stormed just days later. The manuscript was discovered by a man
named Arnoux de Saint-Maximin, who sold it to the Marquis de
Villeneuve-Trans. Villeneuve-Trans’ family kept it until the early
twentieth century, when it was sold first to a German collector, and
then to Sade’s descendants in 1929. Of the four parts, only the first is
near completion; the remaining three are in outline form, some largely
just telegrammic lists of obscene acts. Sade replicated the novel’s tone
in his subsequent works Justine, Juliette, and Philosophy in the Bedroom, but 120 Days remains the quintessential and most criticized and cited of Sade’s works.
“Any decent pleasures, or any prescribed by that beast…that you call
Nature…shall be expressly excluded from this collection,” Sade wrote in
his introduction, “and should you stumble across them by chance it shall
only be in cases where they shall be accompanied by some crime, or
tainted by some infamy.” The narrative, such as there is one, is
double-layered. Inside a castle in the Black Forest four prostitutes
regale the four noblemen with stories of past exploits. The men, eager
to explore the “six hundred passions,” then imitate the remembered
debauchery with the adolescent boys and girls they have kidnapped and
brought to the castle for sexual exploitation along with older male
studs, or “fuckers.”
Sade’s most salacious novels lead the reader to question how much of
it is meant to be read as a litany of straightforward sexual fantasies.
He rejected the speculative “wizardry” of the gothic novels of Ann
Radcliffe and Matthew Lewis, but he had a gift for black comedy that won
the appreciation of the surrealists. He described one of the
storytellers as “the very image of crime incarnate. Her withered arse
resembles marbled paper.” One of the libertines, in a test of his
strength, “wagered he could suffocate a horse between his legs, and the
beast breathed its last at the very moment he had predicted.”
“Written down, shit does not smell,” Roland Barthes
wrote of Sade with a reassurance similar to a parent telling a
frightened child that no monster hides under the bed. One salient
criticism of pornography is that it glosses over the less pleasant
physical rigors and secretions that accompany the acts depicted: sweat,
stench, intrusions of the digestive process, exhaustion, vomit (when
applicable), etc. Sade, quite famously, invites and revels in these
by-products, which appear with such frequency, and are recounted in such
detail, that the pungency of his prose is difficult to tolerate. The
reader is ceaselessly confronted with the scents and sounds of Sade’s
players and their playthings. Sade lacks the willingness or the ability
to keep up the pornographic pretense of serving the reader’s pleasure.
Instead the reader is beset with examples of pleasure he is certain they
have never thought possible, performed with a sprightly energy that is
almost more discomfiting than the acts themselves. One storyteller
recalls:
“The first, whom I frigged as we stood naked, wanted
floods of nearly boiling water to stream over our bodies through a hole
in the ceiling as long as our session lasted…One cannot imagine the
pleasure he felt as it washed over him; as for me…I screamed out like a
scalded tomcat—my skin peeled from this, and I firmly promised myself
never to return to that man’s house.”
“Oh my God,” said the Duc. “I feel the urge to scald the love Aline
like that.” “My lord,” the latter humbly replied, “I am not a pig.” At
once everyone laughed at the innocent candor of her childish response.
That is probably the most representative Sadean exchange that
one can respectably reprint, wherein “pleasure” is a top-down decree.
“The idea of seeing another person experience the same pleasure,” Sade
wrote, “reduces one to an equality which spoils the unutterable charms
that comes from despotism.” If there is any cogent idea to extract from
Sade’s filth, it is the lure of anarcho-tyranny. That was given full
expression in Pier Paolo Pasolini’s Salò, the equally infamous 1975 film adaptation of 120 Days,
set in Fascist Italy. “We Fascists are the only true anarchists,
naturally, once we’re masters of the state,” the duke declares in the
film. “In fact, the one true anarchy is that of power.” Sade’s worldview
combined hostile atheism, might-makes-right determinism, and madcap
nihilism, cutting against the humanist and deist grain of the
Enlightenment philosophes: when God is absent, man will sooner re-create
hell in His stead, not heaven. The Marquis de Sade and the King of Diamonds, by Jose Luis Cuevas, 1965. Smithsonian American Art Museum, gift of the Tamarind Lithography Workshop, Inc., 1973.
As much as he tried to instill his work with philosophical heft and
authorial ambition, Sade was not a writer of ideas—he was a writer of
sensory overload. Even in his more thematically and compositionally
complete novels, he could not stop pushing beyond the bounds of good
taste or sense. Sade remained preoccupied with release at the expense of
tension. The only option that leaves for a reader is simply to endure.
Those who do endure likely get by on the faint traces of better, more
concise narratives that Sade could have wrung out of his excesses.
If there is an irony in Sade, it is that, rather than scandalize and
draw the reader into his morass, he incites them to flee as far away as
possible—anything to escape Sade’s tedious and putrid garden of
damnation.
Considering these texts sometimes
leads me to wonder about a literary history where things turned out
differently for their authors. What if Sade had somehow evaded prison?
Doubtless he’d have kept on with his libertine extracurricular
activities. His writing might have been a more gentlemanly or
remunerative pursuit, producing bawdy but harmless stories and
pedestrian infidel tracts. What he channeled into his novels might have
been redirected into his letters—indeed, he might have become, as Gore
Vidal thought him to be, one of the great letter writers of his age.
What if Swift had managed to stay in England, never returning to
Ireland—and even managed to attain a much-desired bishopric? More
pamphlets and polemics, to be sure, and more banter in coffeehouses with
his equals. But also likely a deepening involvement in sectarian
issues, leading him to become a more rigid Tory and a more committed
High Churchman. He might even have followed his colleagues Bolingbroke
and Francis Atterbury into Jacobitism, and hence into exile in France.
Something like Gulliver’s Travels would still have been possible, but one that had more in common with the bloody-minded Hobbes than with the anarchic Rabelais.
What is more certain is that The 120 Days of Sodom and A Modest Proposal
have no place in these alternate histories, so wedded as they are to
the circumstances their authors encountered at the time of writing.
The extremes of Sade’s novel would have been less possible if he had
been free from the contradictory extremes of prolonged incarceration.
The social and sensory deprivation, the regimentation of time and the
elasticity of the experience of time, the total absence of freedom and
the fluid morality of mere survival, the myopia of living with your own
thoughts—all were necessary elements for the creation of The 120 Days.
Sade obsessively kept track of the patterns and frequency of letters
and visits to make sense of how long he’d been in prison and how long
he’d have until he was released. By the time he wrote The 120 Days,
Sade had been in prison for seven years; he remained imprisoned for
five more before the Revolution freed him, if only for a time. “Prison
is bad,” Sade wrote to his wife, “because solitude gives added strength
only to ideas, and the disturbance that results therefrom becomes all
the greater and ever more urgent.”
Similarly, Swift’s tract would never have been written if he had
remained on the other side of St. George’s Channel, remote from the toll
British policy exacted on its nearest colony. Gone would be the vision
of a consumer economy taken to its most literal conclusion and of
industrialism taken to its logical extreme. Swift makes several
references to the overly fecund Catholics, the shameful waste of babies
who are aborted, and the equally if not more shameful waste of resources
by those babies who are not. At its heart, A Modest Proposal
is a coldly concise plan for bodily control, rendered with the greatest
simplicity, that comes with the dehumanization of one population by
another. Swift never had a perfectly benevolent attitude toward the
Irish as a mass, but he found them redeemable enough to conjure the
great Swiftian image of a baby leaving an Irish womb only to enter an
English mouth.
Both Swift and Sade created works with tenacious wills to survive.
Their legacies now seem to cast them as more beast than ghost at first.
Subsequent artists have tried to leash the anger of Swift or the
depravity of Sade, taming them for their own transgressive ends. But in
truth they are more like warnings. Swift’s and Sade’s literature was
neither the literature of majestic vision nor of pure shock. They are
not examples of a certain method of execution but of conditions that
made other methods impossible. In considering the heirs of this kind of
art, we move away from the provocative fantasies of Salò or Naked Lunch and toward the nightmare reportage of Elem Klimov’s film Come and See and Curzio Malaparte’s novel Kaputt.
The result is a double-edged critique of humanism, which dredges the
enduring capacity for cruelty out from beneath an enlightened, noble
surface and shows the mind not as a parent to an idea but under the
dictatorship of an idea.
Contributor
Chris R. Morgan
Chris R. Morgan writes from New Jersey. His Twitter is here and his blog is here.
When two neutron stars merge, they always produce a gravitational wave signal. However, dependent on a variety of factors, with mass being especially important, these neutron star mergers may or may not produce an electromagnetic signal as well. When they do, it does not arrive simulatenously with gravitational waves, but slightly later. (NATIONAL SCIENCE FOUNDATION/LIGO/SONOMA STATE UNIVERSITY/A. SIMONNET)
Ask Ethan: Why Don’t Light And Gravitational Waves Arrive Simultaneously?
There was less than a 2 second delay between gravitational waves and light, but that’s incredibly meaningful.
There’s an important rule in relativity that — as far as we know — all objects must obey. If you have no rest mass as you travel through the vacuum of space, you absolutely are compelled to travel exactly at the speed of light. This is exactly true for all massless particles, like photons and gluons, approximately true for particles whose mass is tiny compared to their kinetic energy, like neutrinos, and should also be exactly true for gravitational waves. Even if gravity isn’t inherently quantum in nature, the speed of gravity should be exactly equal to the speed of light if our current laws of physics are correct. And yet, when we saw the first neutron star-neutron star merger in both gravitational waves and with light, the gravitational waves got here first by almost 2 seconds. What’s the explanation? That’s what Mario Blanco wants to know, asking:
“I read your articles and found the one on gravitational waves very interesting. […] What would account for the 2s delay of gravitational waves over light waves?”
If everything traveled at the same speed, and both are generated at the same time, then why would one arrive before the other? It’s a great question. Let’s investigate.
Illustration of a fast gamma-ray burst, long thought to occur from the merger of neutron stars. The gas-rich environment surrounding them could delay the arrival of the signal, but the mechanism that produces like could also cause a delay in the emission of the signal. Light and gravity should both travel, through the vacuum of space, at the same speed. (ESO)
On August 17, 2017, the signal from an event that occurred 130 million light-years away finally arrived here on Earth. From somewhere within the distant galaxy NGC 4993, two neutron stars had been locked in a gravitational dance where they orbited one another at speeds that reached a significant fraction of the speed of light. As they orbited, they distorted the fabric of space owing to both their mass and their motion relative to the curved space through which they traveled.
Whenever masses accelerate through curved space, they emit tiny amounts of invisible radiation that’s invisible to all telescopes: gravitational, rather than electromagnetic, radiation. These gravitational waves behave as ripples in the fabric of spacetime, carrying energy away from the system and causing their mutual orbit to decay. At a critical moment in time, these two stellar remnants spiraled so close to one another that they touched, and what followed was one of the most spectacular scientific discoveries of all-time.
This three-panel illustration of the inspiral and merger of two neutron stars shows how the amplitude and frequency of the gravitational waves both increase as the merger becomes imminent. At the critical moment of merger, the signal spikes, and then disappears behind the event horizon as a black hole is formed. Optical and other electromagnetic light may or may not be emitted as part of this process. (NASA)
As soon as these two stars collided, the gravitational wave signal came to an abrupt end. Everything that the LIGO and Virgo detectors saw was from the inspiral phase up until that moment, followed by total gravitational wave silence. According to our best theoretical models, this was two neutron stars inspiraling and merging together, likely resulting in a remarkable end result: the formation of a black hole.
But then it happened. 1.7 seconds later, after the gravitational wave signal ceased, the first electromagnetic (light) signal arrived: gamma rays, which came in one enormous burst. From the combination of gravitational wave and electromagnetic data, we were able to pin down the location of this event better than any gravitational wave event ever: to the specific host galaxy in which it occurred, NGC 4993.
Over the coming weeks, light began to arrive in other wavelengths as well, as close to 100 professional observatories monitored the spectacular afterglow of this neutron star merger.
For the 2017 neutron star-neutron star merger, an electromagnetic counterpart was robustly seen immediately, and follow-up observations, such as this Hubble image, were able to see the afterglow and remnant of the event. For GW190425, the only other neutron star-neutron star merger seen in gravitational waves, that has not been possible. (P.K. BLANCHARD / E. BERGER / HARVARD-CFA / HST)
On the one hand, this is remarkable. We had an event occur some 130 million light-years away: far enough away that light took 130 million years to travel from the galaxy where it occurred to our eyes. Back when the merger took place, planet Earth was a vastly different place. Feathered birds had been around for only 20 million years; placental mammals for 10 million. The first flowering plants were just beginning to emerge, and the largest dinosaurs were still 30 million years in Earth’s future.
For all that time, from then until the present, both the light and the gravitational waves from this event were journeying through the Universe, traveling at the only speed they could — the speed of light and the speed of gravity, respectively — until they arrived at Earth after a journey of 130 million years. First the gravitational waves from the inspiral phase arrived, moving the mirrors on our gravitational wave detectors by an incredibly small amount: less than a ten-thousandth of the size of an individual proton. And then, just 1.7 seconds after the gravitational wave signal ended, the first light from the event arrived as well.
An illustration of a very high energy process in the Universe: a gamma-ray burst. These bursts can arise when two neutron stars merge, and one was detected just 1.7 seconds after the gravitational wave signal from GW170817 ceased. (NASA / D. BERRY)
Immediately, this gave us the most impressive physical measurement of the speed of gravity ever: it was equal to the speed of light to better than 1 part in a quadrillion (1015), as it takes around four quadrillion seconds to make up 130 million years, and they arrived less than two seconds apart from one another. Prior to that, we had excellent theoretical reasons for knowing that the speed of gravity ought to equal the speed of light, but only had indirect constraints that the two were equivalent to within 0.2% or so.
Does this mean that the speed of gravity and the speed of light aren’t quite equal, then? That perhaps either gravity moves slightly faster than c, the speed of light in a vacuum, or that light itself might actually move a tiny bit slower than c, as though it had a tiny but non-zero rest mass to it? That would be an extraordinary revelation, but one that’s highly unlikely. If that were true, light of different energies (and wavelengths) would travel at different speeds, and the level at which that would need to be true is much too large to be consistent with observations.
The longer a photon’s wavelength is, the lower in energy it is. But all photons, regardless of wavelength/energy, move at the same speed: the speed of light. The number of wavelengths required to cover a certain, specified distance may change, but the light-travel-time is the same for both. (NASA/SONOMA STATE UNIVERSITY/AURORE SIMONNET)
In simpler terms, if light had a non-zero rest mass, and that mass were heavy enough to explain why gravitational waves arrived 1.7 seconds earlier than light after traveling 130 million light-years across the Universe, then we’d observe radio waves traveling significantly slower than the speed of light: too slow to be consistent with what we’ve already observed.
But that’s okay. In physics, we don’t have any problem considering all possible explanations for an observed puzzle. If we’re doing our jobs correctly, every explanation except for one will be incorrect. The challenge is to find the correct one.
And we think we have! The key is to think about the objects that are merging together, the physics at play, and what signals they’re likely to produce. We’ve already done this for the gravitational waves, detailing how they’re produced during the inspiral phase and cease once the merger takes place. Now, it’s time to go a little deeper and think about the light.
During an inspiral and merger of two neutron stars, a tremendous amount of energy should be released, along with heavy elements, gravitational waves, and an electromagnetic signal, as illustrated here. (NASA / JPL)
Up until these two neutron stars touched, there was no “extra” light produced. They simply shone as neutron stars do: faintly, at high temperatures but with tiny surface areas, and completely undetectable with our current technology from 130 million light-years away. Neutron stars aren’t like black holes; they aren’t point-like. Instead, they’re compact objects — typically somewhere between 20 and 40 kilometers across — but denser than an atomic nucleus. They’re called neutron stars because they’re about 90% neutrons by composition, with other atomic nuclei and a few electrons at the outer edge.
When two neutron stars collide, there are three possibilities that can result. They are:
you can form another neutron star, which you’ll do if your total mass is less than 2.5 times the mass of the Sun,
you can form a new neutron star briefly, which then collapses into a black hole in under a second, if your total mass is between 2.5 and 2.8 solar masses (dependent on the neutron star’s spin),
or you can form a black hole directly, with no intermediate neutron star, if your total mass is greater than 2.8 solar masses.
We knew that when two neutron stars merge, as simulated here, they can create gamma-ray burst jets, as well as other electromagnetic phenomena. But perhaps, above a certain mass threshold, a black hole is formed where the two stars collide in the second panel, and then all the additional matter-and-energy gets captured, with no escaping signal. (NASA / ALBERT EINSTEIN INSTITUTE / ZUSE INSTITUTE BERLIN / M. KOPPITZ AND L. REZZOLLA)
From the gravitational wave signal that arose from this event, officially known as GW170817, we know that this event falls into the second category: the merger and post-merger signal existed for a few hundred milliseconds before disappearing entirely all in an instant, which indicates that a neutron star formed for a brief time before an event horizon formed and engulfed the entire thing.
But nevertheless, light still got out. The next question was, simply, how?
How was the light that we observed generated? Again, there were three possibilities that we could think of.
Immediately, as soon as the neutron stars touch, by processes that occur on their surfaces.
Only after material gets ejected, where it collides with any surrounding material and produces light from that.
Or from the interior of neutron stars, where reactions generate energy that only gets emitted once it propagates to the exterior.
In each scenario, gravitational waves travel unperturbed once the signal is generated, but light takes an extra amount of time to get out.
In the final moments of merging, two neutron stars don’t merely emit gravitational waves, but a catastrophic explosion that echoes across the electromagnetic spectrum. The arrival time difference between light and gravitational waves enables us to learn a lot about the Universe. (UNIVERSITY OF WARWICK / MARK GARLICK)
If it’s the first option, and neutron star mergers generate light as soon as they touch, the light gets emitted immediately and therefore must be delayed by passing through the environment surrounding the neutron star. That environment must be rich in matter, as each fast-moving neutron stars, with charged particles on their surfaces and intense magnetic fields, is bound to strip and eject material from the other one.
If it’s the second or third option, merging neutron stars generate light from their mergers, but that light only gets emitted after a certain amount of time has passed: either for ejected material to smash into the circumstellar material or for the light generated in the neutron star interiors to reach the surface. It’s also possible, in either of these cases, that both “delayed emission” and “slowed arrival by surrounding material” are at play.
Any of these scenarios could easily explain the 1.7s delay of light’s arrival with respect to gravitational waves. But on April 25, 2019, we saw another neutron star-neutron star merger in gravitational waves, which was more massive than GW170817. No light was emitted of any type, disfavoring the first scenario. It looks like neutron stars don’t generate light as soon as they touch. Instead, the emission of light comes after the emission of gravitational waves.
Neutron stars, when they merge, should create an electromagnetic counterpart if they don’t create a black hole right away, as light and particles will be expelled due to internal reactions in the interior of these objects. However, if a black hole forms directly, the lack of an outward force and pressure could cause total collapse, where no light or matter escapes at all to the outside observers in the Universe. (DANA BERRY / SKYWORKS DIGITAL, INC.)
With only two direct detections of merging neutron stars through the emission of gravitational waves, it’s a testament to how incredibly precise the science of gravitational wave astronomy has become that we can reconstruct all we have. When you add in the electromagnetic follow-up observations from the 2017 event that also produced light, we’ve definitively shown that a large fraction of the elements in our Universe — including gold, platinum, iodine and uranium — arise from these neutron star mergers.
But not, perhaps, from all neutron star mergers; perhaps it’s only the ones that don’t immediately form a black hole. Either ejected material or reactions in the neutron star’s interior is required to produce these elements, and hence, the light associated with a kilonova explosion. That light is only produced after the gravitational wave signal has ended, and may further be delayed by having to pass through the circumstellar material. This is why, even though light and gravity both travel exactly at the speed of light in a vacuum, the light we saw didn’t arrive until nearly 2 seconds after the gravitational wave signal ceased. As we collect and observe more of these events, we’ll be able to confirm and refine this picture once and for all!
The Universe is: Expanding, cooling, and dark. It starts with a bang! #Cosmology Science writer, astrophysicist, science communicator & NASA columnist.
Early in the coronavirus pandemic, a survey
of the world’s frontline physicians showed hydroxychloroquine to be the
drug they considered the most effective at treating COVID-19 patients.
That was in early April, shortly after a French study showed it was safe
and effective in lowering the virus count, at times in combination with
azithromycin. Next we were told hydroxychloroquine was likely
ineffective, and also dangerous, and that that French study was flawed
and the scientist behind it worthy of mockery. More studies followed,
with contradictory results, and then out came what was hailed by some as
a definitive study of 96,000 patients showing the drug was most
certainly dangerous and ineffective, and indeed that it killed 30% more
people than those who didn’t take it. Within days, that study was retracted, with the editor of one of the two most respected medical journals in the Western world conceding it was “a monumental fraud.” And on it went.
Not
only are lay people confused; professionals are. All that seems certain
is that there is something disturbing going on in our science, and that
if and when the “perfect study” were to ever come along, many won’t
know what to believe.
We
live in a culture that has uncritically accepted that every domain of
life is political, and that even things we think are not political are
so, that all human enterprises are merely power struggles, that even the
idea of “truth” is a fantasy, and really a matter of imposing one’s
view on others. For a while, some held out hope that science remained an
exception to this. That scientists would not bring their personal
political biases into their science, and they would not be mobbed if
what they said was unwelcome to one faction or another. But the sordid
2020 drama of hydroxychloroquine—which saw scientists routinely attacked
for critically evaluating evidence and coming to politically
inconvenient conclusions—has, for many, killed those hopes.
Phase
1 of the pandemic saw the near collapse of the credible authority of
much of our public health officialdom at the highest levels, led by the
exposure of the corruption of the World Health Organization.
The crisis was deepened by the numerous reversals on recommendations,
which led to the growing belief that too many officials were
interpreting, bending, or speaking about the science relevant to the
pandemic in a politicized way. Phase 2 is equally dangerous, for it
shows that politicization has started to penetrate the peer review
process, and how studies are reported in scientific journals, and of
course in the press.
Those
who have their doubts about hydroxychloroquine rightly point out that
the public is scared, and we are longing for a magical potion to rescue
us. The history of plagues is rife with such potions and the charlatans
who sold them were well documented in Daniel Defoe’s Journal of a Plague Year. A pandemic is not a remedy for the innate tendency toward wishful thinking.
What
is unique about the hydroxychloroquine discussion is that it is a story
of “unwishful thinking”—to coin a term for the perverse hope that some
good outcome that most sane people would earnestly desire, will never
come to pass. It’s about how, in the midst of a pandemic, thousands
started earnestly hoping—before the science was really in—that a drug,
one that might save lives at a comparatively low cost, would
not actually do so. Reasonably good studies were depicted as sloppy
work, fatally flawed. Many have excelled in making counterfeit bills
that look real, but few have excelled at making real bills look
counterfeit. As such, as we sort this out, we shall observe not only
some “tricks” about how to make bad studies look like good ones, but
also how to make good studies look like bad ones. And why should anyone
facing a pandemic wish to discredit potentially lifesaving
medications? Well, in fact, this ability can come in very handy in this
midst of a plague, when many medications and vaccines are competing to
Save the World—and for the billions of dollars that will go along with
that.
So
this story is twofold. It’s about the discussion that unfolded (and is
still unfolding) around hydroxychloroquine, but if you’re here for a
definitive answer to a narrow question about one specific drug (“does
hydroxychloroquine work?”), you will be disappointed. Because what our
tale is really concerned with is the perilous state of vulnerability of
our scientific discourse, models, and institutions—which is arguably a
much bigger, and more urgent problem, since there are other drugs that
must be tested for safety and effectiveness (most complex illnesses like
COVID-19 often require a group of medications) as well as vaccines,
which would be slated to be given to billions of people. “This
misbegotten episode regarding hydroxychloroquine will be studied by
sociologists of medicine as a classic example of how extra-scientific
factors overrode clear-cut medical evidence,” Yale professor of
epidemiology Harvey A. Risch recently argued. Why not start studying it now?
This
inquiry concerns a molecule that has had so many accusations directed
against it that it now has more than a whiff of scandal. As such, it
might be thought of as a miniature of those eponymous 18th-century
novels of reputation named after a single protagonist, such as Tom
Jones, or Moll Flanders, where the hero’s good name is besmirched early
in life and they must spend the rest of the story hoping to retrieve it.
These adventures are really every bit as much about the societies that
surround the protagonist who, though no angel, has some redeeming
features, and the writer has invented these imperfect, roguish heroes
for the pleasure of seeing them abused and tormented chapter after
chapter, often falsely accused. We are held in suspense, watching the
hero’s rises and falls, waiting to see whether fair play wins out in the
end—or whether he or she is a scoundrel after all, who has pulled the
wool over our eyes. So they are also morality tales.
A
morality tale must have a central character that can arouse some of our
sympathy. When the lead character’s name is the unapproachable and
unpronounceable “C18H26C1N3O,” we are off to a bad start. That it often
goes by “hydroxychloroquine sulfate” doesn’t help. So, like those
English men and women of a certain era with embarrassing names who hid
them behind initials or contemporaries so well known to their audiences
that all one needs are a few letters to recognize them—like FDR or OBL
or DMX—we shall call our protagonist simply: HCQ.
HCQ was first synthesized in 1946,
but came from a distinguished European line. Its esteemed forebear,
“quinine,” made from cinchona bark, had been used to treat malaria
since at least the 1600s. In the 1700s, the Scottish physician and
chemist William Cullen, an important Enlightenment figure, friend of
David Hume, and physician to both Hume and the Scottish king, published
his theory of how quinine cured malaria. Another physician, Cullen’s
near contemporary, Samuel Hahnemann,
translated Cullen’s medical text, and decided to try some quinine
himself, and found it gave him malaria-type symptoms. This so intrigued
him, that it launched him on a new theory of his own—that diseases can
sometimes be cured by substances that, if given to healthy
individuals, give symptoms that are similar to the disease, but if given
to people with the disease, they for some reason get better, such that
“like cures like.” Thereby, homeopathy was born, an approach that
continues to be widely used in Europe and is considered a sign of
insanity by many Western physicians—mature skeptics who prefer to
champion effective and safe medications, like opioids.
For
300 years, quinine, which is not rare—it is in tonic water, for
instance—was the only known remedy for malaria, albeit an imperfect one.
In 1934, German chemists at Bayer synthesized chloroquine in the lab,
and during World War II, that drug was widely used by American forces,
and found more effective than quinine, for both preventing the disease,
and for its treatment. Chloroquine was used widely until the 1960s, when
malaria—Plasmodium falciparum—cleverly had become resistant to
it. But malaria couldn’t resist HCQ, which is nothing but chloroquine
with a slight modification of its chemical structure, an added hydroxyl
group. HCQ was approved for use in 1955, and found to be both more
effective and less toxic than chloroquine, especially when taken for
longer periods. As time passed, both chloroquine and HCQ were found to
be helpful in treating autoimmune diseases like lupus and rheumatoid
arthritis.
Early
in the pandemic, in February and March, I was in Italy, where the death
rate from corona (as it was then called) was astronomical, especially
in the elderly and in frontline medical workers who had sustained
contact with it (in what turned out to be infected hospitals), so I paid
a lot of attention to what the Italian physicians and nurses and
respiratory techs were doing for patients, and to protect themselves.
Stories emerged that often they, and the Chinese frontline physicians
and health care workers, were treating corona patients with HCQ, hoping
it would help, and similarly hoping that by taking it prophylactically,
it would stop them from getting sick. But why?
While
the Chinese Communist Party and government were engaged early in the
pandemic in a well-documented deception of the naive West—withholding
information about the virus, and even banning their physicians from
publishing research on the corona outbreak—behind the scenes many brave
Chinese physicians were nonetheless communicating with Western
colleagues. Wuhan was the epicenter, and the Chinese physicians at the
People’s Hospital of Wuhan University told their Western counterparts
that they got the idea of using HCQ because none
of the 178 patients they had admitted for COVID-19 had lupus—a
surprise, since lupus is an immune disease, and some thought it might
have made these patients especially vulnerable. They wondered why this
might be, and whether HCQ, which these patients had been taking for this
preexisting condition, might in some way be protecting them against
COVID-19.
Even
in an age smitten by the idea that “Big Data Is Our Savior,” many of
medicine’s greatest discoveries begin with precisely these kinds of
chance observations, made by perspicacious frontline physicians looking
at patients, and not from data sets or models, which can often be so
abstract, that they generate only exalted nonsense. The question was:
Could one extrapolate from these few patients—who might have been
protected so far—to others?
A
study in 10 Chinese hospitals was initiated, beginning as early as
January 2020. When they found that 100 Chinese patients did better on
chloroquine than controls, a conference was held on the subject on Feb.
15, in China. The preliminary results were published
as a letter to an English-language journal, claiming they found the
drug was effective against COVID-19-associated pneumonia. Chloroquine
was included in the guidelines for the treatment of COVID-19 issued by
the National Health Commission of the People's Republic of China. By
Feb. 23, seven Chinese studies of chloroquine or HCQ and COVID-19 had
been added to the Chinese Clinical Trial Registry.
There
was another reason studies were necessary. HCQ, though less toxic than
chloroquine, can be dangerous in overdose, and for some people causes
fatal heart arrhythmias, and it can cause retinal problems and blindness
with long-term use (after 10 years of daily use, in 1% of patients),
hearing loss, and even psychosis. Luckily, having been around so long, physicians had come to understand
it very well, knew its dangers, how to screen for the approximately 1%
of people who were vulnerable to these side effects, and also what drugs
it interacted with that might trigger problems (such as
antidepressants). And so, despite all of that, it had been considered
safe enough—if patients were properly screened and monitored by
physicians or trained health care providers, and it was taken in the
right amounts for the proper period of time—to be used throughout the
world. They were still careful: COVID patients were poorly understood
and being administered many new combinations of medications; rather than
just giving HCQ and hoping for the best, scientists began carefully
documenting their observations.
By March, there was evidence from China, published in Nature,
that showed HCQ blocked not only malaria but also the COVID-19 virus in
a test tube. The study showed that HCQ was effective at inhibiting
COVID infections when the scientists put cells (stand-ins for our own)
in culture, in a petri dish, then added the COVID-19 virus, and watched
what happened. Compelling photos
showed how the drug inhibited the development of COVID-19 infections in
the cells, making it a potent “antiviral.” It also decreased
inflammation, which wasn’t that big of a surprise since this property
was the reason HCQ was used to treat autoimmune diseases like lupus and
rheumatoid arthritis, where the body’s inflammatory processes get out of
control and attack its own cells. It was already clear by March that
COVID-19 causes a wild autoimmune response in patients—the “cytokine
storm”—which was often what killed them. But HCQ blocked cytokines, and
moreover, it didn’t damage the cells in the process.
The lab scientists writing in Nature
concluded that HCQ had three things going for it: It seemed safe for
the cells (at least in the short term), was a promising antiviral
against SARS-CoV-2 virus, and an anti-inflammatory compound that had
potential for treating these patients. (It was soon learned that
COVID-19 causes thrombosis or clots, which lead to stroke, and that HCQ
also helped prevent these.)
Then on March 9, there was another Chinese study, published in Clinical Infectious Disease, which showed that HCQ was more effective in inhibiting the COVID virus in the test tube than chloroquine.
Did this mean the drug would cure COVID?
No,
and the study wasn’t designed to demonstrate that. These tests done in
the labs were what are called “proof of concept” studies: Preliminary
studies designed to see if the “concept” that HCQ is an antiviral has
any merit. To prove the drug could cure COVID would require studies in
human beings, which followed patients for significant periods until they
were better, or died, or left with aftereffects of the infection.
Especially influential in much of the world in the early days (if not
the U.S., which often, focuses, it seems, mostly on studies from the
Anglosphere) were studies commissioned by the French government and led
by the microbiologist, physician, and professor of infectious disease
and virology, Didier Raoult,
from l’Institut hospitalo-universitaire (IHU), which he directs in
Marseille, and which had assembled one of the largest datasets in
Europe.
Raoult is the most highly cited microbiologist in Europe, recognized for having identified 468 novel species of bacteria,
most in humans, and for his team having discovered the largest virus
ever documented at the time (so large it had been mistaken for an
intracellular bacterium). He has boldly asserted that viruses—which had
been classified as nonliving—are alive. He has published over 2,000
papers, many of them through the IHU, with him as a contributing or lead
author. He has been given major awards, the French Legion d’honneur,
and perhaps the most important one for a microbiologist, having a
bacteria genus, “Raoutella,” named in his honor.
Raoult
is a fascinating, eccentric, theatrical figure. He couldn’t be more
colorful—a maverick who delights in opposing conventional thinking, his
peers, and followership in science. He has hair to his shoulders, a
long, pointed beard, and looks like a medieval knight in a lab coat. He
loves a fight. At 68 years of age, he rides a Harley to work. He still
treats patients. He sees himself as more like a philosopher or
anthropologist than a typical French scientist, and teaches
epistemology, the study of how we know that we know things, to his lab
scientists, He believes an ever-increasing homogeneity is ruining
scientific thought. He told Paris Match:
I
am Nietzschean, I am looking for contradiction, trouble to strengthen
myself. The worst is the comfort: It makes you silly ... The more humans
you have, the less they think differently. The “politically correct,”
the “compliant thinking” are only a mass effect, to be avoided, even if
it is difficult to resist! ... To follow the herd no brain is needed,
legs are sufficient ... I don’t like movements, I run in the opposite
direction. In general, that is where there are nuggets.
As a young man, he was, by his own account a poor student,
and dropped out of school to join the French merchant marine. He
eventually returned to the family trade, conventional medicine, but as
is clear from his work on the interface of bacteria and viruses, the
boundaries drawn by others are not his thing. His frank contempt for
conformity is, not surprisingly, refreshing: He is a kind of Nassim
Taleb of infectious disease. He is brilliant, doesn’t feign false
humility, and claims rather persuasively that he is indifferent to many
of his critics.
Raoult
was the one in his lab who came up with the idea of combining the two
older drugs, HCQ and azithromycin, for COVID-19. A contrarian specialty
of his has been “repurposing” or “repositioning” inexpensive generic and
already available medications to fight infections. Repurposing has huge
advantages. If a drug can be repurposed as an antiviral in an outbreak,
it provides an already approved drug on hand, one with which we have
had years of experience, so we know its drug interactions, how to
monitor its effects on the major organs, how to test for blood levels,
as well as its “posology,” or the science of how a drug’s dosing changes
in different situations, and its safety profile and side effects.
Moreover, old drugs have huge advantages over new ones in this area,
because often bad effects don’t show up for years after the drug is
brought to market. For instance, we now know that methotrexate, which is
used for certain kinds of arthritis, can cause cancer years later;
certain chemotherapies for cancer can cause heart problems
years later. New psychiatric drugs, often heralded to have better side
effect profiles than the current ones on the market, turn out, as time
passes to be far worse, and cause diabetes. The only way to learn about
long term effects of anything is via time.
For many, hydroxychloroquine became viewed as a marker of political identity, on both sides of the political spectrum.
Copied link
But
drug companies are big businesses, and when they bring a drug to
market, they do studies that display an aptitude for not asking
questions they don’t want the answer to. Relatively little attention is
paid to documenting even short-term side effects in studies. How little?
A recent review
of 192 randomized control trials, in seven different areas of medicine,
showed most randomized control trials for drugs (61%-71%) didn’t deal
adequately with short-term drug toxicity, and those that dealt with it
devoted the same amount of page space, in the published articles, as was
taken up by listing the author’s credentials. And of course we can only
learn of the long-term side effects decades later.
Repurposed
drugs are often generics, and so if one worked during an epidemic, a
society would not have to spend hundreds of millions on developing new
ones, which may or may not work, and may or may not be safe in the long
term. The cost of HCQ for a course of COVID treatment is under $10, and
the cost of another new medication, being evaluated now, remdesivir, is
about $3,500 (which is an entire year’s annual income in some developing
countries, and will not be affordable). So, repurposing also has the
effect of pissing off Big Pharma and those academic courtiers who make
their living from its untold generosity to them.
The
public has almost been trained to think that drugs can only be used for
the purpose for which they are primarily known. People who get cold
viruses and ask their physicians if they can have an antibiotic are told
that old adage: “Antibiotics kill bacteria, not viruses.” And that is
true for most antibiotics. But Raoult’s team was able to show that azithromycin,
classically described as “an antibiotic that fights bacteria,” was
effective in protecting cells that were infected with the Zika virus.
His team also had 20 years of experience of repurposing HCQ for the
long-term treatment of a kind of Q fever—another infectious disease.
Sometimes
drugs developed for noninfectious disease turn out to fight infection.
Some antihypertensives, for example, have antiviral properties, it turns
out. By investigating these relationships systematically—simply
trying old drugs on new conditions and seeing what happened—Raoult was
making a career of, or increasing the probability of, making the kinds
of “chance” observations that the Chinese physicians had made when they
saw that lupus patients on HCQ seemed not to be getting COVID-19. He was
making his luck.
The
idea of studying HCQ as part of a “drug cocktail” to treat COVID-19 had
a personal resonance for Raoult. Part of his childhood was spent in
French Senegal (in Dakar) where his father, a military physician, was
stationed, and as a kid Raoult took chloroquine to prevent malaria. He
had a realistic sense of its long-term side-effect profile, and didn’t
take at all seriously the media characterization of its safer version,
HCQ, as especially dangerous, if taken for several weeks to treat
COVID-19, if patients were properly monitored.
When
the pandemic broke, the first thing that Raoult studied was the effects
of HCQ and azithromycin on “viral load,” or how much COVID-19 virus a
given patient had. Leaving aside other factors—including the patient’s
general health, immune system, diet, Vitamin D status, age, and
more—Chinese physicians knew the amount of virus present correlated with
severity of symptoms
in sick patients, and doctors were beginning to think that “how much
virus” the patient has to deal with was likely a factor in how they
would ultimately fare. The longer that virus had to replicate in the
body, especially in a vulnerable person, the harder it might be to
defeat. So, early in the battle against the virus physicians realized
that if a medication was to work, the earlier it was given to an
infected person the better.
The first small study
by Raoult’s group was begun with 36 COVID-19 patients divided into
three groups: 14 who got HCQ and six who got HCQ and azithromycin for 10
days. (The azithromycin was only added when patients were showing signs
of a lower respiratory tract infection). The third was a control group
of 16 people. These patients were from another hospital that didn’t
offer the new treatment, or people who were offered the treatment but
refused. As we shall see, this approach is very important to Raoult: On
moral grounds he refuses to set up a control group that withholds a
possibly effective treatment from a patient with a lethal illness.
Patients who might be vulnerable to the potential cardiac side effects
were screened and not included in the study, and EKGs were done as
required. It too was a kind of “proof of concept” study, like the
studies of HCQ in the test tube, but taking it to the next level, to see
if the drugs might work to lower the amount of virus in an infected
person’s nasopharynx. COVID-19 was seen as primarily a respiratory
disease at that time, so it made sense to measure the virus there. This
study was answering questions like: Would the drug actually lower the
viral load in the respiratory tract? What would be the appropriate
dose? Would the drugs in combination work synergistically? Lowering
viral load in the nasopharynx alone would not prove that these drugs
would save lives. But without it happening, it would be hard to imagine
saving lives with the drugs would be possible.
The
patients’ noses were swabbed every day, to check for presence of the
virus. By day six, 70% of the HCQ group no longer tested positive for
the virus in the nasopharynx, versus only 12.5% of the control group who
were virus-free. 100% of those who were on both drugs had no virus by
day five. That sounded very good, and seemed to “prove” that the drugs
lower viral load in most patients, in a short time.
Some
criticized the study. While the combination of HCQ and azithromycin’s
effect was dramatic, there were only six patients in that group—not a
big number. Another criticism was that there were six dropouts in the
treatment arm, and they were not included in the final analysis, which
weakened the results. This was not hidden in the paper but discussed and
explained. Studies usually have dropouts. One dropout stopped taking
the medication because of nausea. One person died on day three of
getting the medication. One was transferred to the ICU on the second day
of medication, one on the third day, and one on the fourth day. In
fact, there was nothing original in this discovery of dropouts, since
the authors had pointed them out. These patients had a lethal disease,
and it is not surprising some couldn’t complete the trial. Those who
went to the ICU would then be getting other treatments, which would
confuse the analysis, not clarify it, had they been included.
In
a case of “unwishful thinking,” some people said, in a knee-jerk way,
that the dropouts were obviously a fatal flaw in the study. But, in
fact, the only way to know that would be to check the actual numbers.
Epidemiologist Harry Risch from Yale reanalyzed the raw data—this time
including the dropouts in the analysis. Risch found that their inclusion
“does not much change the 50-fold benefit.”
His analyses also reconfirmed that the drug had to be given earlier in
the illness, to patients with a lower viral load, and that Raoult’s drug
combination did indeed seem to help many patients lower their viral
load.
So:
Those dropouts were not a “fatal flaw” for the study, nor was the
sample size, given its purpose. These “proof of concept studies” are
often small when human beings are involved. Where no effective treatment
exists, you have to start somewhere. And “where” you start—i.e., in
which country or ecology—may also be relevant. Raoult, also an expert in
the history of epidemics, believes that that scholarly discipline
teaches us that ecology—local environmental factors that we don’t
completely understand such as climate, or the presence of other
organisms in a region—influence epidemics, and affect when the peaks
occur and when they recede. Different strains of the coronavirus have
arisen in different parts of the world, for instance. Indeed, sometimes
epidemics do recede, as happened before humanity had medications or
vaccines, again for reasons we don’t totally understand. We also know
genetic factors in different groups can influence differential responses
to medications and perhaps even resistance. Thus it is important to do
studies in different countries, and in different ecological situations.
This was a French beginning, done at the point when there were only
4,500 COVID-19 patients in the country, but already the team had enough
very promising results to be gearing up for the next study of over 1,000
treated patients. A larger and longer follow-up
clinical trial—what is known as an outcome study— would now definitely
be worth the effort, and might show whether lowering the virus in the
nasopharynx correlated with a lasting benefit, such as saving lives, at
least in some patients.
What
the proof of concept study didn’t do was what so many desperate people,
including those in the media who were also personally scared of
COVID-19, wanted it to do: declare that we had a medication combo that
would entirely defeat virus in any and all who were infected. They
wanted a study that would declare that all our troubles were over.
Those
people were skipping steps. In fact, they were skipping science,
because science is about just this kind incrementalism. So here then is a
lesson: When scientific competitors, politicians, and the media, dump
on a study for not showing X, make sure you know whether that study was
even designed with the primary purpose of showing X to begin with.
Raoult’s
clinical group found that for the medications to work, they had to be
given early—something since replicated. This happens with anti-flu drugs
as well—there is a need to stop the virus in its tracks before it
overwhelms the body. This was not only a viral load issue. It had to be
given, it seemed, before the cytokine storms got fully underway.
COVID-19 is almost like two illnesses—one before the storm, and one
after. Any evidence about the use of HCQ and azithromycin given after
the storm starts might well be irrelevant to its effectiveness before
the storm. As well, HCQ is cleared out of the body in significant part
by the kidneys. But the COVID-19 disease process can attack small blood
vessels, and seriously harm the kidneys (and other organs, including the
heart and brain). Basic physiology suggests that giving HCQ after the
kidneys are destroyed would likely mean they would not be able to filter
and clear many of the medications the patients were on, including HCQ,
and so those patients would be more vulnerable to overdose
complications.
Meanwhile,
some American physicians and specialists in infectious disease working
on the frontlines began reporting to American media that they were
seeing HCQ benefits in their own patients too, from some large groups of
physicians at the Henry Ford Health Systems in Detroit, to ones in
private clinics. Two physicians with decades of experience with
epidemics—Drs. Jeff Colyer and Daniel Hinthorn—wrote in theWall Street Journal, “the
therapy [HCQ plus azithromycin] appears to be making a difference. It
isn’t a silver bullet, but if deployed quickly and strategically the
drug could potentially help bend the pandemic’s ‘hockey stick’
curve.” Given that the American political class and pharmaceutical
industry had outsourced the making of essential medications abroad,
chiefly to China and India, Colyer and Hinthorn publicly asked for
federal help to secure the supply.
Hydroxychloroquine
was not yet a household word. It was just another molecule, making its
way through the world, with a good-enough reputation.
On March 21, President Donald Trump, referring to Raoult’s group’s study (which had appeared just days before), tweeted:
“HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real
chance to be one of the biggest game-changers in the history of
medicine... Hopefully they will BOTH (H works better with A,
International Journal of Antimicrobial Agents)..... be put in use
IMMEDIATELY...”
A
week later, Trump announced that he was going to make sure that the
United States had a huge stockpile of HCQ. He quickly made a deal with
India—which produced most of the world’s supply, and which had hoped to
keep it for its own citizens—and stockpiled 29 million tablets.
This would make it available for Americans if it turned out it was as
effective as hoped, and also protect supplies for patients with lupus
and rheumatoid arthritis.
Trump
was clearly very excited (and would, according to reports, ultimately
take the drug prophylactically himself), and like many a politician,
wanted to be the bearer of good news in a frightening time. But as so
many had, he slid into seeing Raoult’s very hopeful proof of concept
study as an outcome study.
Let usleave
aside that the biggest game-changer in the history of medicine probably
occurred on the day that physicians and surgeons learned to wash their
hands between patients, and thus stopped killing them while curing them,
and leave aside considerations of how to best convey such information
to a frightened populace as the last few pages show. There was a very
serious line of reasoning, and a case to be made for:
1. Allocating resources to study HCQ and azithromycin in early cases of COVID-19 on a large scale
2.
Making both drugs available on compassionate grounds for an illness
that had no other effective treatment, as was already now routine in
other countries
3. Securing the national supply in case the combo turned out to be as effective as hoped, for COVID-19 patients and for those with lupus and other conditions where it was needed
4. Making clear that the current studies were as of yet small
5.
Making clear these studies were not of HCQ for prophylaxis (studies
that take a lot of time, because the subjects must take the drug and
then be exposed to the virus), but instead that they were of its use in
treating people already infected
Trump’s
political base cheered for HCQ and his opponents booed and accused him
of practicing medicine without a license—and began dredging up any
evidence, or “experts,” they could find, who might emphasize that HCQ
was dangerous, or useless, or both, and thus they responded to his hyperbole with their own, and then some. As Risch observed in Newsweek, for many HCQ became “viewed as a marker of political identity, on both sides of the political spectrum.”
CNN
began a nonstop campaign criticizing the safety of the drug, holding
Trump responsible for three people who overdosed on it in Nigeria.
Rivals went after Raoult, now tainted because Trump had mentioned his
work. A New York Timesprofile
depicted the scholar-physician as a Trump doppelganger, with his,
“funny hair” and, being a man “who thinks almost everyone else is
stupid,” who “is beloved by the angry and the conspiracy-minded.”
Headlines such as, “Why does Trump call an 86-year-old unproven drug a game-changer against coronavirus?”
were common. Stories began equating HCQ with Trump (“Trump’s drug”) and
emphasized not only that it was dangerous, but that HCQ was old. And
old was definitely not good. The implication was that far better than
old was some new drug—that wasn’t yet invented, never mind tested—that
might be in the utopian “pipeline” to the always better medical future.
What
the media, and public health officials, did not report at the time was
how poor people’s chances were should they go to hospital and need
intensive care for the illness. Hospitals were finding that 80% of
people put on mechanical ventilators died. All the commentators who
railed that HCQ was “unproven” because there had been no randomized
control trials (RCTs) didn’t mention that standard ventilation treatment
for COVID-19, which had become treatment-as-usual overnight for severe
cases, had no RCTs supporting it either. There was a double standard as
far as HCQ was concerned.
Our
poor protagonist, HCQ, could now go nowhere in a hyperpoliticized
America without being hectored and called “Trump’s drug.” In the media,
HCQ was now “touted,” “hyped,” and not “recommended” or “prescribed,” by
the physicians who advocated for it. If someone took the do-it-yourself
approach, as in the sad story of the Arizona man who, terrified out of
his wits of the coronavirus, along with his wife, drank fish tank cleaner
mixed with soda, because she had noticed it had among its ingredients,
“chloroquine phosphate.” His death was blamed on “a chemical that has
been hailed recently by President Trump ...”
This
was all happening at a moment when clinicians working 12- to 15-hour
shifts, seven days a week with COVID patients, probably had more
knowledge of the disease and its treatment than any studies could yet
provide. During this first-wave HCQ-chastisement by the American media, a survey study of 6,200 frontline physicians
in 30 countries showed that, worldwide, HCQ was chosen by the
physicians, from among 15 options, as what they thought was the most
effective treatment for patients (37% chose HCQ). The other drug the
physicians thought highly of was azithromycin.
But
in the United States, HCQ was embroiled in the Republican-Democratic
rivalry. On March 12, Michigan state Rep. Karen Whitsett, a Democrat
representing the 9th Michigan House District in Detroit, went into
quarantine for cornavirus symptoms, and by March 31 got her test results
and was diagnosed with such a serious case of COVID-19 that she thought
she was dying. She and her physician, Dr. Mohammed Arsiwala, sought
permission to use HCQ but could not get it, because the Michigan
Department of Licensing and Regulatory Affairs, under Democratic Gov.
Gretchen Whitmer, had issued an order prohibiting the use of HCQ for
COVID-19.
What
an interesting twist: Plagues always give rise to new customs,
practices, and regulations. If the state can give a medication to some
poor decent citizen on compassionate grounds, indeed why can’t it withhold it on vindictive grounds from a traitor and a fool (as someone who wanted the Trump drug must obviously be)?
In
response, her Michigan Democratic colleagues voted unanimously to
censure her, the resolution stating she had “misrepresented the needs
and priorities” of the Michigan Democratic leadership to the president
and public “in contradiction with the scientifically based and
action-oriented response” of themselves—i.e., the Michigan
leadership—thereby “endangering the health, safety and welfare of her
constituents, the city of Detroit, and the state of Michigan.”
On
April 9, Dr. Raoult’s French center released the initial abstract
reporting their team had now put 1,061 patients on HCQ (for 10 days) and
azithromycin (for five days), and it was ultimately published in Travel Medicine and Infectious Disease
on May 1. All the patients had had viral tests, to establish the
diagnosis, and had electrocardiograms. Genetic analysis of their viruses
was also performed. By publication time 91.7% of those patients had a
good clinical outcome and a virological cure. Eight patients (0.75%)
died, ranging from 74-90 years of age, often having several other
complicating illnesses. These were far better results than in most
centers. They also found that only 5% of the patients were shedding the
virus after the first week of treatment. They reported that none of the
patients had the dreaded cardiac side effects that were being discussed
by some.
Was
this the last word on HCQ? No. According to Raoult’s own scholarly
interest in how epidemics are expressed differently in different
locales, other studies would have to be done. For instance, in
Marseille, Raoult found hardly any obesity in his study population. But
in America, the COVID-19 epidemic was happening on top of another
epidemic: According to the CDC,
71.6% of American adults are overweight, and 39.8% are overweight to
the point of being obese; and obesity, often associated with diabetes,
are two huge risks factors for COVID-19. They might somehow lower the
drug’s effectiveness. One couldn’t assume that because a study showed
the drugs worked in Marseille, they would work in the United States. By
the same token, just because an American study might get poor results
for the combo, wouldn’t mean the Marseille study was inaccurate.
This
study also wasn’t a randomized control trial, intentionally. As noted,
Raoult doesn’t believe in them during a pandemic (nor at some other
times). As he told the Times: “We’re not going to tell someone, ‘Listen, today’s not your lucky day, you’re getting the placebo, you’re going to be dying.”
What
was emerging in scientific circles now was a debate about
“methodology,” or what kind of scientific study of HCQ was appropriate
in an emerging, lethal pandemic.
We
tend to think of methodology as a dry question that has nothing to do
with morality. The methodologist asks what is the best technique to get
at the most certainty most quickly, and usually answers: a randomized
control trial, or RCT. But in medicine, moral concerns can’t be humanely
divorced from methodology. Early in a pandemic, when we know little,
there is a moral imperative to start gathering data. While RCTs are
often (but not always, see below) the best kind of study, they take more
time, and involve randomly assigning, say, half the patients to a new
unknown but promising treatment, and half to either a placebo (sugar
pill) or treatment-as-usual (which might be nothing). They are a type of
experiment. With a milder disease, slow to overtake its victims, with
some viable treatments to compare, one would perform RCTs sooner rather
than later. If the disease is slow to kill, and patients don’t get
better in the study, they might try another treatment or two after the
study ends. But COVID-19 is lethal, kills within weeks when it does, and
there was no good standard treatment for very sick patients, which
meant that in a randomized study, some people would most likely get no
effective treatment, and no second chance with another treatment after
the study was done. Raoult was saying those people were being randomly
assigned to death.
That
is one reason why so many researchers, like Raoult, opted for
observational studies, in which as many patients as possible are
treated. This is not a matter of choosing a design that is “fatally
flawed,” it is a matter of choosing a design that is not unnecessarily
fatal to the patients. It’s is not sloppiness (as some of his critics
would allege), but being true to the study question as he saw it: How
can we save as many lives as possible. These observational studies could
begin almost immediately, and didn’t require the slow approval process
that RCTs require, in part because of the moral dilemmas they raise.
Still,
given that pandemics kill tens of thousands, if not millions, why not
favor the cold-hearted methodologist, who is willing to stand back on a
high hill, like a general in a war, and take some casualties to get a
win sooner? Isn’t that more moral in the long run?
Not
necessarily. It is a common conceit of methodologists that they alone
can improve the quality of medicine, which, without them, would be
hopelessly unscientific. But diseases are very complicated. I know, from
personal experience, that pure methodologists—like “armchair
generals”—i.e., researchers who have perhaps have never treated a single
patient with the relevant illness—often make very elementary errors in
design because they don’t understand how people react to illness, the
illnesses themselves, or the burden of side effects, but rather work
from models. Here is just one kind of such elementary methodological
error. The kind of Russian Roulette RCT I described above, which
involves withholding a possible treatment from a lethal disease, is a
methodologist’s dream design. But you won’t likely volunteer yourself or
loved ones for it if there is a more direct access to a promising
treatment in a dire situation. Almost no sane, nonsuicidal person will,
if properly informed about what is going on (which doesn’t always
happen).
This
is why the role of the “clinician-researcher” developed. A union of
humane medicine with the certitude-seeking scientific researcher, these
people don’t solve all research design problems; rather their role is,
ideally, not to lose sight of the inherent tension of the enterprise.
Anyone who has performed both sides of that compound discipline in good
faith knows there are profound ongoing moral conflicts between the good
doctor, who thinks of the patient in front of him or her, and the
scientist who thinks of the ideal methodology, which—it is hoped—might
benefit other patients in the future. The randomization conflict almost
always exists in serious illness, because we don’t generally study
treatments on dying people that we think have no chance of working. Any
clinician-researcher deserving the name knows that being a researcher
does not cancel out the clinician’s Hippocratic oath to do no harm, or
give them permission not to do what is best for the patient.
So,
how does one sort out what kind of study is appropriate for testing a
new treatment for a lethal disease? Let’s take a little detour to
discuss the models.
Once
a proof of concept study has established that a treatment has a chance
of being effective, then one goes on to do an “outcome study.” Of these,
there are two major kinds: observational studies and randomized control
trials.
The
aim in RCTs, as we’ve said, is to compare those who get that new
medication to those who don’t (or who get another medication). It is
especially important that the two groups are very similar. If the two
groups are very different, it is impossible to tell if the group that
did better did so because of the medication, or perhaps because
of some other characteristic. For instance, we know that advanced age
is a huge risk factor for COVID-19 death. Say one group got the drug,
and the other got placebo, and the group that got the drug had a better
survival rate, but on closer look, was also younger on average. It would
be hard to know if they survived because of the drug or their relative
youth.
Age,
here, is considered a “confounding factor.” It is called a confounding
factor because a naive researcher might think that in the above study,
he or she was measuring “the power of the medication to protect one from
COVID-19 death,” but may actually have also been measuring the role of
youth in protecting the patient from a COVID death. Other confounding
factors we know about now could include how advanced the illness is at
the time of the study, heart disease, diabetes, obesity, or the person’s
vitamin D levels. There could easily be many other confounding factors
we don’t yet know about.
This is where randomization can be very helpful. In a randomized control trial, one takes a large group of patients and randomly
assigns them to either the treatment group, or the nontreatment
“placebo” control group, for instance. It is hoped that by randomly
assigning this large number of patients to either the treatment or
nontreatment condition, that each of the confounding factors will have an equal chance of appearing in both groups.
Observational
studies don’t randomly assign patients to another group. Sometimes they
take people with a chronic illness (which by definition doesn’t
improve) and give them a treatment, and see if they improve. They
compare the patients before the medication and after they got it.
Sometimes they find a control group too. One way they might do so is by
comparing patients in two different settings, where one setting provides
the treatment, and the other setting doesn’t. (This is what Raoult
did). This is a way to get around the moral problem of “withholding”
treatment from the control group—they weren’t going to get it anyway.
Care can (hopefully) be taken to make sure the patients in both groups
are as similar as possible, and are “matched” (say in terms of severity
of illness), but the risk of yet-unknown confounding factors is higher.
For such reasons, many scientists confidently assert that RCTs are
generally better, and many researchers often say—about HCQ for
instance—that we will only know if it works when we get the results of a
large number of large RCTs.
This
implies two things. First, that they are not as confident in the RCT
design sorting out the HCQ problem as they say they are: If the design
is so unshakable and so bias resistant, why would we need to repeat it
many times over? Why wouldn’t one good study be sufficient? Which brings
us to the second implication—namely, that there is safety in numbers:
The more studies show a similar outcome, the more comfortable scientists
will be with it.
Except,
sometimes more studies create more confusion, and are part of a
bandwagon going in the wrong direction. In 2005, Dr. John Iaonnides
published a paper called “Why Most Published Research Findings Are False”
that became the most downloaded paper in the journal PLOS’s history,
and demonstrated that all study designs can, and often do, have
problems—including replication problems, meaning that in a disturbing
number of cases when one group repeats a study or experiment of another
group, they do not get the same findings. He proposed that this was due
to various kinds of bias sneaking in. He also showed there is often a
tendency for a first study to be biased in a certain way, and for that
bias to be picked up and repeated in subsequent studies so that they all
have the same flaw. In this way, a massive library of falsity can build
up, until it is exposed, and overthrown. So, we can’t assume just
because many studies show a particular outcome, that it is true.
One
might think frontline physicians would have protested Ioannides’
findings. But many were not at all surprised, since they too had
witnessed the many reversals of major findings. This is now called the
“replication crisis” in science, or what Nature calls a crisis of “reproducibility,”
and is widely accepted to be a crisis in many fields, but particularly
in the life sciences, psychology, and in medicine—and much less so in
engineering, physics, and astrophysics.
In medicine, it is a problem that is found even in the most respected and cited journals. For instance, a study in The Journal of the American Medical Association
in 2014, also by the Ioannidis group, showed that 35% of the
conclusions of the finest RCTs, assessed by peer review and published in
the most respected medical journals, could not be replicated on reanalysis
of their raw data. Meaning that when researchers gave over their
original data sets to another group, they could not come up with the
same results 35% of the time—in the very best, most-cited journals.
RCTs
are an ingenious tool, a blessed but imperfect gift to humanity, but
the “RCT fundamentalist” is practically a monist, exemplified by the
statement in the text Evidence Based-Medicine: How to Practice and Teach EBM,
which says that when searching for evidence, “If you find the study was
not randomized, we would suggest that you stop reading it and go on to
the next article.”
We now have studies
that show one of the weaknesses of RCTs is that in the quest to
eliminate confounding factors, they end up, in a majority of cases,
excluding patients who are typical of those in the population. The RCT
evangelist focuses only on the RCT strengths, and forgets their
weaknesses. A typical RCT describes several data points about hundreds
of patients. It can be helpful in determining what treatment might work for most people
in a large population. A typical case history describes perhaps
hundreds of data points about a single patient. Its focus might be on
what treatment might work best for this patient. Sometimes we
need all that information about a patient, to choose a proper treatment,
because individual patients differ, often in decisive ways. Patients
are not “several data points.” There are multiple good reasons that the
medical curriculum and major journals and texts publish RCTs,
observational studies, case histories, and other designs, and why most
physicians with experience will use what I would call the
“all-available-evidence” approach and take, as appropriate, what they
can learn from different kinds of studies, and of course everything they
know about their own patient in front of them, to decide on a
treatment. That is what personalized medicine is about. RCT
fundamentalists—who believe only in their randomized data and
essentially argue for throwing away everything else—pose as people
simply expressing the conventional view: All you need is one tool. But
in practice, they are way outside it.
When the teacher tells you to quit paying so much attention to the
fullness of your experience, pay more attention to why he might be
saying so.
For
more on the controversy around “Randomized Control Trials,” why “RCT”
shouldn’t mean “rigidly constrained thinking,” and on the strengths and
weaknesses of different types of studies, see Medicine’s Fundamentalists.
Back
to the world of plague and our poor protagonist, HCQ, who was about to
undergo some extraordinary new trials and adventures in humiliation.
On April 21, the American Veteran’s Administration released a study,
funded by the National Institutes of Health. The authors pointed out
that this was not a randomized clinical trial, there was not a “group
matched design,” and it was not peer reviewed. It was a retrospective
analysis of patients who did and did not get HCQ, in all U.S. Veterans
medical centers until April. It was very reasonable for a large system
to release the best available data they had at the moment, until other
kinds of studies, including RCTs and careful observational studies,
might be released. They reported that 158 patients got standard
management (neither HCL or azithromycin), 97 patients received HCQ, and
113 patients received a combo of HCQ and azithromycin. They followed
these patients and found that of those who got standard care, 11% died,
of those who got HCQ, 28% died, and of those who got HCQ and
azithromycin, 22% died.
In
other words, one would be forgiven for thinking that the people who got
HCQ were much more likely to die, according to this study—if the groups
that got HCQ and those who didn’t were similar.
The
left-leaning media now took up cheering remdesivir the way the
right-leaning media had taken up bashing HCQ. America, I always say, is a
team sport.
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But wait: “[H]ydroxychloroquine, with or without azithromycin, was more likely to be prescribed to patients with more severe disease,
as assessed by baseline ventilatory status and metabolic and
hematologic parameters,” wrote the authors (emphasis is mine). The point
should be clear: The HCQ patients were sicker and were more likely to
get the drug as a last resort—just the thing Raoult had warned against.
It was given too late to work.
The
authors had a mathematical way of trying to correct for the problem
that the two groups were not matched on severity by accounting for some
confounding factors after the fact, but ultimately they admitted that
they may have missed some key ones. Though the study didn’t document
cardiotoxicity in the patients, they nonetheless speculated that the
increased cause of death might be related to cardiac toxicity (and not,
for instance, advanced COVID). How did they justify the speculation?
Because a study of chloroquine had found this problem. But chloroquine
and HCQ are different drugs. It was guilt by association.
CNN pounced, and its correspondents and announcers shared the same message. Anderson Cooper
framed it this way: “The President had been out there touting
hydroxychloroquine saying, ‘What do you have to lose?’” The question was
answered by the headline crawler running underneath him: “No Benefits,
Higher Death Rate.” What you have to lose is your life, the network
warned its millions of viewers.
Now
Raoult pounced, and pointed out that there were also objective blood
measures in the study tables, that the authors had not commented on,
showing that those who got HCQ were much sicker than those who
didn’t. Early on, physicians realized that a patient’s white blood cell
count could indicate how close they are to death, as a study eventually published in Nature
made clear. White blood cells are the soldiers in our immune system. As
their numbers collapse, late in COVID, the person’s chances of dying
are vastly increased, meaning that a low white cell count (called
lymphopenia) correlates with a high fatality rate. The reason
for this is being sorted out now; one possibility is those white cells,
or their supportive organs, become infected with the COVID virus and
die. Raoult noted that the pathologically low white count was twice as common in the patients who were given HCQ, so they were much closer to death.
This had not been sufficiently taken into account in the severity
ratings of patients. Secretary of Veteran Affairs Robert Wilke made it clear
that the study “was done on a small number of veterans, sadly those of
whom were in the last stages of life, and the drug was given to them. We
know that the drug has been working on middle aged and younger veterans
... In stopping the progression of the disease.”
He also pointed out that a number of the patients who got HCQ and azithromycin were given the medications after
they had been intubated, so mostly after the cytokine storm had begun,
when organs throughout the body were often already destroyed—way too
late to be effective. Of course it would now tie HCQ into death—and
could be used to falsely suggest those patients were harmed by HCQ, and
not their illness. Raoult also pointed out that the so-called untreated
group had at times received azithromycin in 30% of the cases, so it was
really a “treated” group.
This
same limitation—conducting a study where doctors were more likely to
give HCQ to sicker patients and then comparing how they did with the
less sick group that didn’t get it—would be repeated in several studies
over the next months.
You’ve
heard of cherry-picking evidence or results, when advocating for an
argument, or product or invention. What followed was a torrent of what
could best be called “rotten cherry picking”—media, politicos, and
rivals, scouring the internet for any sign that HCZ would kill masses of
people. For instance, on the same Anderson Cooper show
mentioned above, Dr. Sanjay Gupta listed only the studies that
supposedly showed HCQ didn’t work, and none of the studies that showed
it did.
“A lot of people have gone crazy,” says Raoult,
“claiming that we were dealing with the most dangerous drug in the
world, when almost 2 billion people have already taken it.” HCQ, he
points out, has been given safely for decades, even to pregnant women,
but is being made to look dangerous—even when properly monitored by
cardiologists. In a study,
his team wrote, “There have probably been more than a billion
azithromycin prescriptions around the world since it was first
discovered. The toxicity of each of these two drugs does not, therefore,
pose a major problem. Their possible toxicity in combination has been
suggested in a few anecdotal reports but, to our knowledge, has never
been demonstrated.” As he said in an interview, “It is bizarre, but it is part
of something, you know, that people are completely turned mad about one
of the medics [sic] that have been most prescribed medications in the
history of humanity.”
Meanwhile,
interest was growing in another drug, remdesivir, that had been
developed for Ebola. Dr. Anthony Fauci, head of the U.S. National
Institute of Allergy and Infectious Diseases was enthusiastic—unlike as
he was with HCQ. Even though the early study showed modest gains, Fauci said
“the data show that remdesivir has a clear-cut significant positive
effect in diminishing the time of recovery. This is really quite
important.” The study had shown that those on remdesivir had a mortality
rate of 8.0% vs. 11.6% mortality in the placebo group—statistically
significant, more than a glimmer of hope, less than a cure-all.
Additionally, a not widely reported study
leaked by WHO by accident, showed that remdesivir had no benefits and
that it caused serious side effects to some. But, nonetheless, the
left-leaning media now took up cheering remdesivir the way the
right-leaning media had taken up cheering HCQ. America, I always say, is
a team sport, and each team needs its mascot—or in this case, its med.
On
May 1, the NIH’s COVID-19 Treatment Guidelines panel members allowed
for the emergency use of remdesivir and started pulling away from HCQ,
saying it could only be used in hospital or in studies. Investigative
journalist Sharyl Attkisson looked into the financial links of the
members of that group that was suddenly restricting HCQ and giving the
edge to remdesivir. When she and her team examined the ties of those on
the committee, she found
that a large number had ties with Gilead, the company that makes
remdesivir, which costs $3,500 for several days' worth, and was emerging
as the chief rival to HCQ. It was not just a few members either: “We
found that of 11 members reporting links to a drug company, nine of them
named relationships to remdesivir’s maker Gilead. Seven more, including
two of the committee’s leaders, have ties to Gilead beyond the 11
months they had to disclose. Two were on Gilead’s advisory board. Others
were paid consultants or received research support and honoraria.
Nobody reported ties to hydroxychloroquine, which is now made by
numerous generic manufacturers and is so cheap, analysts say even a
spike in sales would not be a financial driver for the companies.”
Attkisson’s
team also found that one of the authors of the VA study that claimed
HCQ caused increased deaths had received research funding from Gilead,
“including a $247,000 grant in 2018.”
One didn’t have to be an expert in
medical research, or chemistry, to ascertain that the opposition to HCQ
at times was confused and contradictory. Those who opposed it often
gave as their first reason for opposition that “we can’t have
people using HCQ for COVID-19 because we need to keep supplies for
people with rheumatoid arthritis and lupus, who are dependent upon it,”
but adding, sometimes in the same breath, “besides, the drug is a
dangerous killer.”
This
was reminiscent of the initial media messaging around masks, which were
said both to not work and to be desperately needed by medical
professionals. It was a clear case of “both those things can’t be true,” and yet here was Harvard Medical School cardiologist Haider Warraich in the New York Times:
“The bottom line is that even as we are in the midst of a pandemic with
a climbing death toll, hydroxychloroquine has potentially added to the
body count because of its serious possible side effects—like liver and
kidney damage, heart failure and cardiac arrest—and by creating a
shortage of the drug for patients with lupus, whose disease flares when
they don’t take hydroxychloroquine.”
It’s
worth lingering on Dr. Warraich’s statement. It is subtle. By beginning
with the words “the bottom line” and leading to “body count,” the
sentence’s emotional tone suggests we have established definitive evidence that HCQ, even if
prescribed properly by physicians, screening out or at least carefully
monitoring people with heart problems, is a killer. But on closer
inspection, he hedges on that decisive point, and writes HCQ “has potentially added to the body count,” (i.e., it really isn’t certain), and the side effects of which he speaks, are “serious possible
side effects.” He doesn’t quantify how common these side effects are
compared to how many lives might be saved by the drug—a crucial point in
any cost-benefit analysis. By mixing a compound of two “maybes”
(“potential,” and “possible”), he has nonetheless come up with a far
more definite “bottom line.” The article goes on to plead for more
protections for the public from the FDA, a sentiment with which I
completely agree, given the far greater danger posed by many other
drugs.
Warraich
deserves credit for one fact he did express entirely correctly: There
was indeed a serious shortage of HCQ in the United States that was
threatening supply for people with autoimmune disease. It had to be
addressed. But part of the reason it was so hard to get was because
other countries (including Switzerland, India, Brazil, and Israel, among
others) were using it because their public health officials considered
it safe and promising enough, and so they were buying, protecting, even
hoarding it, and by now there were also reports from all over the world
reaching America that physicians were using it prophylactically for ...
themselves.
Anyway, let’s get back to our story—and the moment things took another dramatic turn.
In
May we got two more publications, this time in the two most respected
medical journals in the Western world, that showed that HCQ and
chloroquine increased the death rate of COVID patients by 30%, and
caused heart problems.
The first study was published in the Lancet, and claimed that HCQ and chloroquine caused cardiac arrhythmias and 30% increased deaths
in COVID-19 patients. The study was supposedly based on data taken from
96,000 patients—quite impressive. The same data set was used, in part,
in the New England Journal of Medicine study,
which reiterated that heart disease was a risk factor for COVID-19
death in hospitals, and that certain medications, like ACE inhibitors,
were not a risk. Neither was a randomized control trial, but those were
huge numbers: The kind of “big data” that American computer-smitten
advocates have been insisting would change health care forever for the
better.
Reaction around the world couldn’t have been swifter. As soon as the Lancet study was published, WHO suspended
its own clinical HCQ trial; the United Kingdom’s regulators suspended
all their studies of HCQ, and even France reversed its policy that had
allowed the use of HCQ. On June 15, the FDA revoked the emergency status
use of HCQ with patients (so, perhaps President Trump’s physician, who
is prescribing it for him, should lose his license too now). It seemed
all over for HCQ. Physicians, like Dr. Jon Giles, a rheumatologist at
Columbia University who had used HCQ safely for years, complained that
his research group could no longer get patient recruits
for their HCQ study because they were had been so frightened, and so
they had to abandon it altogether. The Oxford University study of HCQ in
40,000 people for prophylaxis frontline health workers may never get
completed for the same reason. Once drugs are discussed as dangerous,
the lawyers smell business, then physicians smell the lawyers and back
off using it. Licensing bodies now got excited, too, and made hints that
physician outliers could be accused of malpractice and negligence for
using it. HCQ was having a bad week.
Then
two things happened, one on June 4, and one on July 1. One event
illustrated perfectly much that is wrong with modern medicine, and the
other, pretty much everything that is right with it and worth
preserving.
One would figure that the Lancet and the New England Journal
studies must have been very powerful if they were able to slay all the
other HCQ studies in the cradle—including preempting the much awaited
RCTs—and to so impress the scientists at the world’s major public health
organizations, the FDA, and the science-literate writers at the major
newspapers of record.
But fairly suddenly, the studies were retracted.
The
retraction was set in motion when HCQ researchers around the world
noticed all sorts of problems. And these were problems that the study
authors, who were using a big-data approach, seemed not really aware of.
For example, data, supposedly from Australia, was very different from
what was known about Australia’s COVID-19 numbers. The study also
claimed to include cases from Africa, based on extensive electronic
records, and which had testing using advanced medical equipment, that
were not known to exist in many areas of Africa. I myself have worked in
hospitals in Africa, and the scope and kinds of electronic record
keeping they described seemed unlikely.
Over 100 knowledgeable scientists with relevant expertise then signed a letter to the Lancet highlighting the irregularities. In it, they asked the Lancet to have the authors share their raw data.
In
response, the study authors said sorry, they could not identify the
hospitals from which they got their data, or even name the countries
from which they got it, because, they claimed, it was protected by
confidentiality agreements that prohibited them from doing so. You read
that correctly: The researchers hadn’t seen any of these 96,000
patients, or even gathered data from them; it was supposedly all turned
over to their computers, by other computers, in a magnificent data dump.
It
turned out the study authors—the first author was Dr. Mandeep R. Mehra,
of Harvard (that old place again!)—had got their data holus-bolus from
an organization called Surgisphere, which, alas, could not share it
externally. But Surgisphere, it turned out, was all about sharing
internally, because it was run by a vascular surgeon named Dr. Sapan
Desai, who happened to be the brother-in-law of another of the study
authors, Dr. Amit Patel, who was himself a tenured professor of cardiac
surgery. Surgisphere had only a few employees, which included a science
fiction writer and an adult model.
Cornered, the three authors, excluding Sapan Desai, wrote to the Lancet
they were very sorry, but they did an internal investigation of
Surgisphere, and discovered that that entity (which one of the authors
had been in charge of) just couldn’t turn over the records to them,
apologized, and requested their paper be withdrawn. They signed it
listing the dozen companies they had been paid by—mostly drug companies
but some medical equipment makers as well— as a sign of good faith and
transparency. The sister study was retracted from The New England Journal of Medicine an hour after the first was pulled from the Lancet.
Richard Horton, editor of the Lancet, did not pull his punches, and it was he who called it a “monumental fraud.” By focusing on the fraud perpetrated against the Lancet,
he deftly deflected attention away from the monumental inadequacy of
the peer review process at the esteemed journal. Consider that
multitalented crew from Surgisphere claimed that they had somehow
gathered data on 96,000 patients from 1,200 hospitals throughout the
world, and would have been expected to check all 96,000 records, and
analyzed all that data, and done all of this almost overnight. Could
anything have been more implausible? Have you ever tried to get your own medical record from your own local hospital in a jiffy?
And,
if you are a physician, have you ever tried to get medical record
systems, from different hospitals, in the same city, to talk to each
other easily?
There
were other oddities. Though the studies claimed HCQ was toxic, they
often didn’t make clear the what doses of HCQ were administered, and
mixed together patients getting low doses of HCQ with high doses. 66% of
doses it discussed were significantly higher than the FDA recommended
dose. How in the world could the study claim that it was HCQ that was
dangerous, and not the physicians who were overdosing the patients? A
study that didn’t exclude these overdoses seemed almost designed to show
HCQ was unsafe. And the studies didn’t adjust for disease severity as a
confounding variable—so it again blurred together patients too sick to
benefit from HCQ with those for whom it was indicated. It blurred
together people who had COVID-19 induced heart problems with those that
might be caused by the medication. And there was also no ethics review.
The sheer cumulative weight of these flaws—whether the data was
fraudulent or not—should have disqualified the study.
So, is HCQ combined with azithromycin dangerous? The better question to ask is: compared to what?
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But
it wasn’t. Perhaps because the study came to the “right” conclusion:
HCQ was dangerous. Far be it for Richard Horton to be accused of mixing
politics and medicine—though he wasn’t all that shy about calling Trump’s defunding of WHO “a crime against humanity.” Perhaps even more revealing: The same week the Surgisphere study came across the esteemed Lancet desk, so did the Raoult study of 1,061 actual patients—but that one was refused.
What
was the reaction of those so skeptical of HCQ to this revelation of the
fraud? Not much. I heard colleagues say just because a study showing it
is dangerous and doesn’t work turns out to be a fraud, doesn’t mean it
is safe and effective—which is of course true—but there was not a lot of curiosity about how easy it had been to dupe the two premier medical journals—or
why. Or whether a growing confirmation bias was now sweeping through
the journals, such that the reviewers could not see through ludicrous
exaggerations, and seemed more impressed by techno-computer-fetishism
and big numbers than simple logic.
On July 1, the cheap, eternally unproven drug seemed, finally, to catch a big break. A large peer-reviewed study of 2,541 patients by the Henry Ford Health Center in Detroit was published in the International Journal of Infectious Diseases.
It showed that HCQ lowered mortality in hospitalized COVID-19 patients
by over 50%. This was a very large effect, in line with the robust
findings Raoult was claiming. Luckily, that study managed to get done
between March 10 to May 2—just before the scare tactics about HCQ made
it harder to get hold of and had all but eliminated people’s willingness
to enroll in such inquiries.
The
Henry Ford study of HCQ was very large, and performed in a hospital
system, consisting of six hospitals. Fifty-six percent of participants
were African Americans, who a number of studies had shown were at higher
risk from COVID than other racial groups, for reasons that are still
being analyzed. It was not a randomized control trial, but was superior
to earlier studies that lumped all patients together and didn’t
effectively distinguish how sick different patients were. This study
took into account 19 different risk factors, and illness severity. So,
unlike the earlier VA study, they did a better partial workaround to
make sure that the patients who received medication, and those who
didn’t, had similar severity of illness. They were also able to match
many of the patients in terms of illness severity of their COVID, and
then compare 190 patients who received HCQ, to 190 matched patients that
did not. HCQ gave a mortality hazard ratio decrease of 51% for those
closely matched patients. Overall, treatment with HCQ decreased the
mortality hazard ratio (the risk of death in the defined time period of
the study) by 66%.
In
that health care system, 26.4% of all patients who had COVID-19, and
got the standard treatment but not the study medications, died. Of those
who received HCQ, only 13.5% died. So, HCQ cut the death rate in half.
As of Aug. 12, over
744,649 people have died of COVID, according to Johns Hopkins
University. If this rate held, in other studies, over 350,000 of those
people might be alive. Worldwide it might save a million or more people
before COVID is tamed.
The
Henry Ford study also studied HCQ in combination with azithromycin to
improve outcomes, and it did. It specified all doses, seemed to get them
right, and gave them at the proper time, early, right after admission,
which as we’ve seen, is crucial to precede the cytokine storm. The study
followed the patient’s electrocardiograms (ECGs), and heart status
throughout, checking for any of the alleged cardiac problems, to make
sure the HCQ didn’t cause harm. It found that with early prescription of
HCQ (82% within 24 hours of hospitalization, 91% within 48 hours), the
patients had far fewer cardiac problems than are usually seen
in later stages of COVID. Since this study, multiple studies have come
out showing that HCQ, when properly monitored, is not
associated with increased cardiac fatalities. The authors made the very
sensible point, that it is probably the case that we will have to work
with several drugs to treat this disease, and the combinations will
likely be different for different patients. Imagine.
CNN called it “a surprising study,” then invited experts to tear it apart, mentioning Trump’s tie to HCQ repeatedly. Anthony Fauci told a House subcommittee
dismissively, “That study is a flawed study, and I think anyone who
examines it carefully [will see] is that it is not a randomized
placebo-controlled trial.” He said it, as though the fact it wasn’t an
RCT had been deliberately buried, and had to be unearthed.
One even-handed critique
of the study—rare in this debate—noted both its strengths and its
weaknesses. One weakness was that patients who got HCQ had received
dexamethasone twice as often as the controls. Dexamethasone is a common
steroid (with a lot more side effects than HCQ) that is used when
inflammation gets out of control. It was good medical practice to not
withhold that drug, but it would likely have been a confounding factor.
If one’s only goal is to determine if HCQ and azithromycin are helpful,
this must be considered a study flaw, as Fauci said. But if one’s goal
is to help people survive, a 66% reduced mortality rate is something to
celebrate, even if it means that the cocktail for COVID-19 might involve
three drugs, for a while. But Fauci didn't seem excited about that. A study
published July 29, from Milan, which also tested HCQ and azithromycin
vs. controls, and which eliminated some of the Henry Ford study
weaknesses, got a 66% reduction of risk compared to controls with the
drug combo.
So, is HCQ combined with azithromycin dangerous? The better question to ask is: compared to what?
When
its foes speak of frightening side effects they do so without ever
quantifying how common they are. Risch did though. He found that of 300,000 people with multiple illnesses,
who had been tried on the medication combination worldwide, the number
of cardiac arrhythmias was 47 per 100,000 and the number deaths (the key
figure) was 9 per 100,000. This was at a time when 10,000 Americans
were dying every week from COVID-19. If the drug combo was able to halve
that number of deaths, as the Ford study suggested, it is easy to see
that the relative risks of the medications are small, and the potential
gain astronomical.
It
is one thing for the HCQ skeptics to have challenged the studies that
said it worked, saying they were imperfect and flawed because they were
not RCTs. But what they really needed in order to put the molecule out
of its misery once and for all were some top notch RCTs to show it
didn’t work. That would finish the job. And that is what happened
next. Official opinions began to morph from, “let’s wait for the RCTs to
settle the matter,” to “it’s already been settled by the RCTs.”
When an RCT by Skipper and colleagues was published in the Annals of Internal Medicine, it came with an editorial accompanying, claiming that this study, along with a few others, were now “strong evidence” against HCQ being more effective than placebo in mild COVID-19 patients. The editorial
then argued that the “the sad saga” of HCQ had almost come to an end.
But, then, “almost at an end” wasn’t soon enough, because the editorial
concluded, “It is time to move on from hydroxychloroquine.”
The
author made no mention of the studies that found the HCQ to be
effective and safe—and instead used only the RCTs that he claimed showed
it was ineffective.
One such RCT was done in China and published in the British Medical Journal.
Yet, once again, the patients were given the medication late—on average
16.6 days after the first symptoms. That guaranteed the HCQ wouldn’t
work well: We already knew HCQ was not for late cases. As well, no
azithromycin was given. Despite that, the HCQ group actually gave more symptomatic relief than the non-HCQ group, but it did not do so at a statistically significant level, But the authors wrote that their study was not
definitive proof HCQ didn’t work—“The results of our main prespecified
outcomes are not entirely conclusive, being based on an underpowered
sample size.” This means they didn’t have enough subjects to make
definitive claims. But that didn’t stop the editorialist, and others,
from claiming more than the authors. On top of that, mysteriously,
sentences that had been in the first preprint version that had been
posted online, were removed in the second version. All the removed sentences spoke to the benefits
of HCQ in more rapidly diminishing symptoms. The Raoult group caught
this covering up of significant pro-HCQ evidence. This, arguably, is a
second scandal in a British medical journal in so many weeks.
Interestingly,
the other RCT cited by the editorial as part of the “strong evidence”
that put the nail in the coffin for the usefulness of HCQ for saving
lives, itself had significant problems, if that was the claim being made
for it (the study authors were not making that claim). It was
not a study to see if HCQ saves lives (though it began so, it was
changed mid-course), but to see if it reduces symptoms. No azithromycin
was used. The patients were given the medication for between a third and
half of the days it is normally given in a typical study to see if the
drug saves lives. (They were given the HCQ for five days, when most
studies use it for 10-14 days, and 21 days in severe cases.) The placebo
used, folic acid, may well not be a placebo at all. There is evidence that in certain forms, folic acid actually can be used to diminish COVID-19, by inhibiting the virus.
Additionally, the patients were not seen
by the investigators—their symptoms were assessed by sending email
surveys to subjects asking them how they felt. This is different than
having them assessed in person, as the French group did. Medication was
mailed to the patients, which meant that some likely got it too late for
it to be effective with weekend delays. In addition, one quarter of
patients reported they didn’t take the medication they did get
as prescribed. Almost half the patients did not have a viral test
confirming the diagnosis. This was early in the pandemic, and they were
in short supply at the time in the United States, and had a long
turnaround time. The lack of early rapid testing, and thus quick
diagnosis, also suggests that many patients may have got their
medication too late to be effective. Even so, the HCQ group, despite all
these obstacles, had more diminishment of their symptom severity
compared to the placebo group—i.e., HCQ did better, just not to the
point of being statistically significant. Half as many in the HCQ group
had to be hospitalized. It leaves one wondering how HCQ would have
performed in terms of saving lives (the most important question), if all
the patients who took it did so promptly and actually got a standard
amount, and not half to a third, and were properly monitored to take it
as prescribed. It is one of three RCTs that actually show, in their
results sections, that HCQ did better than placebo, but which
in their conclusions, the authors claim the opposite. This is based on a
confusion about how to draw conclusions from statistics. This error is
clearly explained in an international letter,
signed by medical statisticians and mathematicians who are disturbed by
the use to which these studies are being put, given their actual
results.
The
evidence from these RCTs for the assertions that HCQ, combined with
azithromycin doesn’t work in the early cases is astoundingly weak—looked
at closely, a few of those studies actually are closer to supporting
HCQ. Yet, when Assistant Secretary for Health Admiral Brett Giroir,
M.D., who is also a member of the White House Coronavirus Task force, appeared on Meet the Press
on Aug. 2, he seemed not to know that, or any of the evidence in its
favor. Host Chuck Todd asked the admiral: “I know you’re not a political
person, but the president continues to advocate for hydroxychloroquine,
is that a danger to public health? The admiral replied, parroting the
recent editorial: “I think we need to move on from that ...” He
elaborated, saying: “At this point in time we don’t recommend that
[hydroxychloroquine] as a treatment. There’s no evidence to show that it
is ... Most physicians and prescribers are evidence-based and they are
not influenced by whatever is on Twitter or anything else.”
His
assertion implied that anything that had been said in favor of HCQ was
the product of Twitter and not serious studies; it was a claim tone deaf
to the fact that the clinicians and researchers in whose name this
assertion was made, were some of the very ones who knew of these
positive studies—who, in some cases, were the ones who conducted them, and who still stand by them.
Indeed,
at this point confirmation bias against HCQ has been so intense,
especially among those who don’t have experience prescribing it, that
the bias-holders simply ignore large studies like Ford and brush aside
the fact that the drug had been safe enough to be a standard of care for
decades. They have even ignored studies that are broadly negative,
including an RCT from the United States and Canada combined
that showed that HCQ did not work as a prophylactic to people who had
high risk exposures to COVID-19 contacts, but which also showed that
“there were no serious intervention related adverse reactions or cardiac
arrhythmias.” It has begun to seem like, unless a study justifies a
visceral and comprehensive skepticism for HCQ, it won’t get
attention—let alone be taken seriously. And what does “moving on from
HCQ” even mean? Banning it? Closing down the RCTs that are ongoing? One
thing 'moving on' means is that the FDA is now overriding large
organizations that had access to HCQ, and want that access to continue.
On Aug. 13, it was revealed that the large Henry Ford Hospital System,
based on their study and the requests of their frontline physicians, had
asked the FDA to let them continue using HCQ for their patients, though
the study had ended. The FDA refused.
So
this is likely how it’s going to be. Poor HCQ will remain a kind of
Rorschach inkblot test, saying more about one’s projections than itself.
Or, to switch metaphors, it seems destined to carry an orange T on its
forehead, a warning to sensible people to steer clear.
Lots
and lots of COVID-19 studies will come out—several hundred are in the
works. People will hope more and more accumulating numbers—and more big
data—will settle it. But big data, interpreted by people who have never
treated any of the patients involved can be dangerous, a kind of exalted
nonsense. It’s an old lesson: Quantity is not quality.
On
this, I favor the all-available-evidence approach, which understands
that large studies are important, but also that the medication that
might be best for the largest number of people may not be best one for
an individual patient. In fact, it would be typical of medicine that a
number of different medications will be needed for COVID-19, and that
there will be interactions of some with patient’s existing medications
or conditions, so that the more medications we have to choose from, the
better. We should be giving individual clinicians on the front lines the
usual latitude to take account of their individual patient’s condition,
and preferences, and encourage these physicians to bring to bear
everything they have learned and read (they have been trained to read
studies), and continue to read, but also what they have seen with their
own eyes. Unlike medical bureaucrats or others who issue decrees from
remote places physicians are literally on our front lines—actually
observing the patients in question, and a Hippocratic Oath to serve
them—and not the Lancet or WHO or CNN.
As
contentious as this debate has been, and as urgent as the need for
informed and timely information seems now, the reason to understand what
happened with HCQ is for what it reflects about the social context
within which science is now produced: a landscape overly influenced by
technology and its obsession with big data abstraction over concrete,
tangible human experience; academics who increasingly see all
human activities as “political” power games, and so in good conscience
can now justify inserting their own politics into academic pursuits and
reporting; extraordinarily powerful pharmaceutical companies competing
for hundreds of billions of dollars; politicians competing for
pharmaceutical dollars as well as public adoration—both of which come
these days too much from social media; and the decaying of the
journalistic and scholarly super-layers that used to do much better
holding everyone in this pyramid accountable, but no longer do, or even
can. If you think this year’s controversy is bad, consider that
hydroxychloroquine is given to relatively few people with COVID-19, all
sick, many with nothing to lose. It enters the body, and leaves fairly
quickly, and has been known to us for decades. COVID vaccines, which
advocates will want to be mandatory and given to all people—healthy and
not, young and old—are being rushed past their normal safety precautions
and regulations, and the typical five-to-10-year observation period
is being waived to get “Operation Warp Speed” done as soon as possible.
This is being done with the endorsement of public health officials—the
same ones, in many cases who are saying HCQ is suddenly extremely
dangerous.
Philosophically, and psychologically, it is a fantastic spectacle to behold, a reversal, the magnitude and the chutzpah
of which must inspire awe: a public health establishment, showing
extraordinary risk aversion to medications and treatments that are
extremely well known, and had been used by billions, suddenly throwing
caution to the wind and endorsing the rollout of treatments that are
entirely novel—and about which we literally can’t possibly know
anything, as regards to their long-term effects. Their manufacturers know this well themselves, which is why they have aimed for, insisted on, and have already been granted indemnification—guaranteed,
by those same public health officials and government that they will not
be held legally accountable should their product cause injury.
From
unheard of extremes of caution and “unwishful thinking,” to unheard of
extremes of risk-taking, and recklessly wishful thinking, this double
standard, this about-face, is not happening because this issue of public
safety is really so complex a problem that only our experts can
understand it; it is happening because there is, right now, a much
bigger problem: with our experts, and with the institutions that we had
trusted to help solve our most pressing scientific and medical problems.
Unless these are attended to, HCQ won’t be remembered simply as that
major medical issue that no one could agree on, and which left
overwhelming controversy, confusion, and possibly unnecessary deaths of
tens of thousands in its wake; it will be one of many in a chain of such
disasters.
* Update, Aug. 14: This
article has been updated with new information on the aftermath of the
peer-reviewed HCQ study conducted by the Henry Ford Health System in
Detroit. * Update, Aug. 15: This article originally described a study published in May in the Lancet
that claimed to show COVID patients given the drug HCQ experienced
increased health risks. The article has been updated to reflect that the
study examined both HCQ and the drug chloroquine.
