The VR game was designed to give the eye muscles a workout

Monday, June 2nd, 2025

Researchers at Kwansei Gakuin University in Japan developed a VR game that aims to improve players’ eyesight:

It’s a relatively simple target shooting game developed in Unity for Meta Quest 2. The game features three lanes, each with a circular target on a stick. Pressing down the trigger button on the controller activates a virtual laser beam. Pointing this laser towards a lane highlights the lane and target and puts the player into “aim” mode. But to successfully hit the target, players have to move the controller’s stick in the direction indicated by the small Landolt C (a black ring shape with a gap used in Japanese eye tests) in the middle of the target.

VR Vision Training Game

The VR game was designed to give the eye muscles a workout, as players alternate between switching their gaze between targets at different distances and focusing on the Landolt C to see where the gap is. At the end of the game, players were treated to an arcade-style results screen, showing how many hits, misses and combos they got, as well as whether they broke a new record (apparently, some participants got very competitive about high scores).

The results showed that the game was effective in improving the vision of all the participants over the six week study period. For the severely myopic participants in particular, it was found that the more often they played the game, the more their sight improved.

The Landolt C was developed by the Swiss-born ophthalmologist Edmund Landolt:

The Landolt C consists of a ring that has a gap, thus looking similar to the letter C. The gap can be at various positions (usually left, right, bottom, top and the 45° positions in between) and the task of the tested person is to decide on which side the gap is. The size of the C and its gap are reduced until the subject makes a specified rate of errors. The minimum perceivable angle of the gap is taken as measure of the visual acuity. It is generally practised in the laboratory.

The stroke width is 1?5 of the diameter, and the gap width is the same. This is identical to the letter C from a Snellen chart. The Landolt C is the standard optotype for acuity measurement in most European countries. It was standardized, together with measurement procedures, by the German DIN, as DIN 58220 (now EN ISO 8596).

His research started with sixteen albino mice

Saturday, May 31st, 2025

Chaos by Tom O’NeillWhen he launched the Haight-Ashbury Free Medical Clinic, David Smith left a loose end dangling in his past, Tom O’Neill explains (in Chaos: Charles Manson, the CIA, and the Secret History of the Sixties) — he’d never actually received his PhD in pharmacology:

He’d completed a two-year research project on amphetamines and their effects on groups of confined mice, but he never finished his dissertation. Although he shrugged off the lapse—he’d already completed medical school, after all, and he’d taken quickly to his new life in the Haight—it surprised many of his closest friends, and in our interviews, he was reluctant to admit it. It wasn’t like him to leave something undone.

[…]

His research started with sixteen albino mice. With the assistance of other researchers, he separated these into two groups of eight in “aggregate” settings—small, closely confined communities intended to simulate crowding. Then he injected the mice with amphetamines. Over the next twenty-four hours, they transformed from docile animals into frantic combatants, fighting one another until they died either from injuries, self-inflicted wounds from overgrooming, or simple exhaustion. The violence was unremitting; Smith described “frenzied attacks of unrelenting rage.” Afterward, all that remained in the blood-spattered cages were scattered, dismembered body parts. Simply by confining the animals in close quarters, he’d increased the toxicity of the amphetamines more than four times.

In another attempt, some of the mice were dosed with other chemicals—mescaline, chlorpromazine, or reserpine—before they received amphetamine injections. The extra drugs sometimes had a sorting effect, segregating the mice that would kill from the mice that wouldn’t. Or they had a soothing effect, all but eliminating the violent tendencies.

Smith told me he’d started his research having foreseen an influx of amphetamine abusers in San Francisco. He didn’t say how he’d predicted that influx, but he was right. In the summer of ’67, as he opened his clinic, amphetamines exploded in popularity in the Haight.

“When the speed scene hit, it was a total shock to everybody,” he told me. “Suddenly, what I’d learned in pharmacology relative to amphetamines was applicable [to people].”

Throughout Love Needs Care, Smith draws parallels between the rodents he’d studied and the speed-addled hippies in the Haight. The mice on speed, he wrote, “become inordinately aggressive and assaultive… [turning] upon one another with unexpected savagery. Their violent behavior is probably intensified by confinement for it is strikingly similar to that observed in amphetamine abusers who consume the drugs in crowded atmospheres.”

In the Haight, Smith watched as people living cheek by jowl took huge doses of speed, inspiring paranoia and hallucinations. Once peaceful and well-adjusted, the “speed freaks” of San Francisco now “lashed out with murderous rage at any real or imagined intrusion,” assaulting, raping, or torturing to relieve the paranoid tension. “Cut off from the straight world, crammed together in inhuman conditions, and controlled by chemicals,” Smith concluded, “they behaved, quite naturally, like rats in a cage.”

[…]

In fact, according to Dr. Eugene Schoenfeld, who participated in a portion of Smith’s rat research in 1965, LSD was an integral component of the project. Smith and his colleagues would inject the rats with acid in hopes of making them more suggestible before he gave them amphetamines. Suggestibility was among the most prized effects of LSD from a clinical perspective. And yet Smith kept LSD out of the official documentation of his research. The article he published in the Journal of Psychedelic Drugs never mentioned acid.

I asked Smith if LSD was part of his protocol. He denied it—then, a moment later, without provocation, he reversed himself.

“Yeah, I stuck LSD in them,” he said.

But he couldn’t explain why. “I was sticking all different kinds of drugs in them,” he added. In his recollection, LSD “produced disorganized behavior, but not violent behavior.” The rats would just wander around in a daze.

If you’ve noticed that I’ve used “rats” and “mice” interchangeably, there’s a reason for that—Smith used them interchangeably, too, even though the two species have vastly different behavioral patterns, especially in groups. In his Journal of Psychedelic Drugs article, he calls them mice; in Love Needs Care and another book he published, they’re rats. Schoenfeld insisted that he’d worked with rats during his part of the research. But Smith was adamant that they were mice, and he couldn’t explain his confusion on the subject.

Like the San Francisco Project and Roger Smith’s Amphetamine Research Project (ARP), some of David Smith’s research, according to his academic papers, was funded by the National Institute of Mental Health (NIMH), which, as mentioned earlier, later acknowledged that the CIA used it as a front for LSD research. And though David never mentioned it in his writing, his work owed a clear debt to the landmark research of another NIMH psychologist, John B. Calhoun, who’d studied rat populations since 1946.

Calhoun reported that rats in confined groups—even without drugs—became uncharacteristically aggressive. They’d erupt in rape, murder, cannibalism, and infanticide. A dominant male rat emerged in the “behavioral sink”—Calhoun’s term for his aggregated rat cultures—subjugating other males into a tribe of cowering, enfeebled followers and organizing female rats into a “harem” of sex slaves. The strangest group to emerge was “the probers”: “hypersexualized” male rats that stalked and raped both males and females, and often cannibalized their young. The probers would commit “frenzied” and “berserk” attacks against rat families sleeping in their burrows, leaving the remains of half-eaten victims. Again, no drugs were involved here; the probers emerged simply as a result of their confinement. They deferred only to the dominant male rat, fleeing if he caught sight of them.

Calhoun’s study was a watershed. In the midsixties, amid growing concerns about population density, social scientists, politicians, and journalists cited him to explain the riots in America’s overcrowded ghettos. His term “behavioral sink”—defined as “the outcome of any behavioral process that collects animals together in unusually great numbers… aggravating all forms of pathology that can be found within [the] group”—entered the scientific lexicon almost right away. David Smith used it extensively in his writing and in interviews with me.

[…]

Plus, the more interesting subtleties of Calhoun’s research—the emergence of a dominant male, a harem of subservient females, and an underclass of “probers,” all of which, it had to be said, sounded a lot like the Family—had gone entirely unnoted in Smith’s project. I wondered if amphetamines, with or without LSD, had increased the dominant male’s grip on his followers.

Given how eerily Smith’s research prefigured the creation of the Family—under David’s nose, in the Haight, during the summer of ’67—I wondered if he had deliberately underreported it. I’ve never come close to proving that he did, but I haven’t been able to explain the holes in it, either. Why would he use LSD to induce suggestibility in rats before injecting them with amphetamines and making them berserk?

[…]

The reams of record keeping you’d expect from clinical experimentation simply weren’t there. Stephen Pittel, a forensic psychologist who’d worked with both Smiths at the HAFMC, volunteered a stunning bit of information that Roger and David had neglected to share with me.

“The only thing I remember about ARP was that it got burglarized one night and Roger lost all of his files,” Pittel told me. Their disappearance had been jarring, in part because Roger was “an unusually paranoid guy to begin with.”

[…]

The HAFMC’s original chief psychiatrist, Dr. Ernest Dernburg, remembered the theft of the ARP files, too. As he recalled, they’d gone missing right after the announcement of Manson’s arrest for the Tate–LaBianca murders and that “Roger, understandably, was pretty upset.” Nothing else was taken from the HAFMC, which led the staff to believe that the police or some federal agency might’ve removed the files. These were research papers, he reminded me: “It didn’t make sense for someone to steal these things when they didn’t inherently have any value to the average individual. It seemed to have a more nefarious purpose.”

The Smiths both denied that the theft had ever happened. “You’re dealing with aging memories,” David said. But Dernburg and Pittel—full-time doctors, and credible sources, I thought—stood by their stories. “They were absolutely stolen,” Pittel said. Dernburg, perturbed by David’s insinuation about his faculties, told me more that he remembered. “It was a considerable amount of research—the premier amphetamine research conducted at a street level. It would have been very important to the clinic… and it disappeared. Call David. Ask Roger if he has the files or knows where they are.”

[…]

David Smith had studied these same phenomena, formulating an idea that he called “the psychedelic syndrome,” first articulated in 1967 or early ’68. The gist was that acid, when taken by groups of like-minded people, led to a “chronic LSD state” that reinforced “the interpretation of psychedelic reality.” The more often the same group of “friends” dropped acid, the more they encouraged one another to adopt the worldview they’d discovered together on LSD, thus producing “dramatic psychological changes.”

Usually the psychedelic syndrome was harmless, but regular LSD use could cause “the emergence of a dramatic orientation to mysticism.” And in people with “prepsychotic personalities,” Smith wrote, LSD precipitated “a long-term psychological disorder, usually a depressive reaction or a schizophrenic process.”

Had Smith seen this “syndrome” in the Family? After Manson had been arrested for the murders, David wrote, “Charlie could probably be diagnosed as ambulatory schizophrenic.” He said the same thing when I asked about Manson: “I felt that he was schizo.” It was Roger Smith who’d had the better diagnosis, and the earlier one, David maintained: “Roger said that he knew from day one that Charlie was a psychopath.”

But Roger apparently never thought it was necessary to intervene—to send his parolee back to prison or to get him proper psychiatric care. Instead, he sent him to the Haight and watched him drop acid every day, accruing suggestible young followers as he went. Meanwhile, David was studying the exact psychological conditions that gave rise to the Manson Family while he treated them at his clinic.

The subterranean humanity was nonsense

Friday, May 30th, 2025

Invented to make beef last through a long voyage, Bovril became a famous British kitchen staple:

Less well-known is its link to an odd, pioneering science fiction novel.

A stout black jar of Bovril with a cheery red top lurks in many a British kitchen, next to tins of treacle and boxes of tea. The gooey substance, made of rendered-down beef, salt and other ingredients, can be spread on toast or made into a hot drink, but what many people don’t realise is that this old-fashioned comfort food has a surprising link to science fiction.

The “Bov” part of the name is easy enough to decipher — from “bovine”, meaning associated with cattle. But the “vril” bit? That’s a different story, literally.

In 1871, an anonymous novel was published about a race of super-humans living underground. The narrator of The Coming Race, who has fallen into their realm during a disastrous descent into a mine shaft, is shocked to learn that they are telepathic, thanks to the channeling of a mysterious energy called vril.

“Through vril conductors, they can exercise influence over minds, and bodies animal and vegetable, to an extent not surpassed in the romances of our mystics,” the narrator realises. Vril gives them strength, as well, rendering them capable of incredible feats. The people call themselves the Vril-Ya, and their society seems in many ways superior to that of the surface dwellers.

The Coming Race was a runaway bestseller. It eventually became clear that the anonymous author was Edward Bulwer-Lytton, the prominent politician and writer (and, to give you a sense of his prose, the first person to start a novel: “It was a dark and stormy night…”). It became such a cultural touchstone that 20 years later, the Royal Albert Hall in London played host to the Vril-Ya Bazaar and Fete, to raise money for a school of massage “and electricity”.

In 1895, a writer for The Guardian newspaper started a review of a new novel with this statement: “The influence of the author of The Coming Race is still powerful, and no year passes without the appearance of stories which describe the manners and customs of peoples in imaginary worlds, sometimes in the stars above, sometimes in the heart of unknown continents in Australia or at the Pole, and sometimes below the waters under the earth.” The work under review? The Time Machine, by H G Wells.

And so you can see how, in the 1870s, when John Johnston, Scottish meat entrepreneur, was coming up with a name for his bottled beef extract, “vril” was a tip-of-the-tongue reference.

[…]

Johnston and other makers of the substance were responding to a demand for beef products in Europe, where raising cattle was prohibitively expensive, and the growth of cattle ranches in South America, Australia and Canada.

There was no way to get fresh meat from these far-flung places to Europe. But rendering the meat down into a paste and sealing it in jars yielded a shelf-stable product that could make the long journeys involved. (Johnston was not the only player in the meat extract game — Justus von Liebig, one of the founders of organic chemistry, founded Leibig’s Extract of Meat Company to commercialise his process. The company later went on to produce Oxo bouillon cubes and Fray Bentos pies.)

How do you make a salty meat paste sound nourishing? By linking it to a fantastical substance with great powers. An excitable advert for Bovril in the program from the Vril-Ya Bazaar reads, “Bo-VRIL is the materialised ideal of the gifted author of ‘The Coming Race’… it will exert a marvellous influence on the system, exhilarating without subsequent depression, and increasing the mental and physical vitality without taxing the digestive organs. It is a tonic as well as a food, and forms the most Perfect Nourishment known to Science.”

[…]

Members of the theosophy movement, including the spiritualist medium Madame Blavatsky, claimed that vril was real. Willy Ley, a German rocket enthusiast writing about conspiracy theories in Germany during the rise of the Nazis in the magazine Astounding Science Fiction, said there was a society in Berlin that believed in vril: “They knew that the book was fiction, Bulwer-Lytton had used that device in order to be able to tell the truth about this ‘power’.

“The subterranean humanity was nonsense, Vril was not. Possibly it had enabled the British, who kept it as a State secret, to amass their colonial empire.”

I have discussed the pursuit of the almighty vril before.

That burning feeling is real

Monday, May 12th, 2025

The first scientist to draw the connection between exercise and lactic acid was Jöns Jacob Berzelius, Alex Hutchinson explains, the Swedish chemist who devised the modern system of chemical notation (H2O, etc.):

Sometime around 1807, he noticed that the chopped-up muscles of dead deer contained lactic acid, a substance that had only recently been discovered in soured milk. Crucially, the muscles of stags that had been hunted to death contained higher levels of lactic acid, while deer from a slaughterhouse who had their limbs immobilized in a splint before their death had lower levels, suggesting that the acid was generated by physical exertion.

A century later, physiologists at the University of Cambridge used electric stimulation to make frogs’ legs twitch until they reached exhaustion, and observed high lactic acid levels. The levels were even higher if they performed the experiment in a chamber without oxygen, and lower if they provided extra oxygen. That finding helped establish the prevailing twentieth-century view: your muscles need oxygen to generate energy aerobically; if they can’t get enough oxygen, they switch to generating energy anaerobically, which produces lactic acid as a toxic byproduct that eventually shuts your muscles down.

Athletes going lactic feel the burn and typically back off a bit:

In interviews with athletes who’ve begun using baking soda, a common theme is that they’re able to push harder for longer before feeling that burn in their legs, which in turn enables them to race faster.

One theory about the feeling of going lactic is that you’re literally starving your brain of oxygen. If you push hard enough, it’s not just your muscles that go more acidic; your whole bloodstream follows. Thanks to a phenomenon called the Bohr effect, rising acidity reduces the ability of your red blood cells to ferry oxygen from your lungs to the rest of your body, including your brain. In one study, all-out rowing caused oxygen saturation to drop from 97.5 to 89.0 percent, which is a big drop—big enough, perhaps, to slow you down and contribute to the out-of-body feeling at the end of hard races.

We also have nerve sensors that keep the brain informed about the metabolic status of the muscles. These group III/IV afferents, as they’re known, keep tabs on the real-time levels of molecules like lactate and hydrogen ions. If you block these nerves with spinal injections of fentanyl, exercise feels great—too great, in fact, because you’ll lose all sense of pacing, go out too hard, then hit the wall.

The most telling finding about the lactic burn, in my view, was a 2013 study where they injected various molecules into the thumbs of volunteers in an attempt to reproduce that familiar feeling. Injecting lactate didn’t do it. Neither did injecting hydrogen ions, or ATP, a fuel molecule whose levels are also elevated during hard exercise. Injecting them in pairs didn’t do it either. But injecting all three at the levels you’d experience during moderate exercise produced a sensation of fatigue in their thumbs, even though they weren’t moving them. And injecting higher levels turned fatigue into pain.

That’s a distinction I try to keep in mind in the late stages of hard workouts, and at the crux of races. That burning feeling is real, and it’s associated with lactate and acidity and muscular fuel levels. But it’s just a feeling.

Researchers flipped the position of just two atoms in LSD’s molecular structure

Monday, April 21st, 2025

University of California, Davis, researchers have developed a new, neuroplasticity-promoting drug closely related to LSD with reduced hallucinogenic potential:

To design the drug, dubbed JRT, researchers flipped the position of just two atoms in LSD’s molecular structure. The chemical flip reduced JRT’s hallucinogenic potential while maintaining its neurotherapeutic properties, including its ability to spur neuronal growth and repair damaged neuronal connections that are often observed in the brains of those with neuropsychiatric and neurodegenerative diseases.

[…]

JRT exhibited powerful neuroplastic effects and improved measures in mice relevant to the negative and cognitive symptoms of schizophrenia, without exacerbating behaviors and gene expression associated with psychosis.

[…]

Olson said that it took his team nearly five years to complete the 12-step synthesis process to produce JRT. The molecule was named after Jeremy R. Tuck, a former graduate student in Olson’s laboratory, who was the first to synthesize it and is a co-first author of the study along with Lee E. Dunlap, another former graduate student in Olson’s laboratory.

[…]

Key findings included:

  • JRT and LSD have the exact same molecular weight and overall shape, but distinct pharmacological properties.
  • JRT is very potent and highly selective for binding to serotonin receptors, specifically 5-HT2A receptors, the activation of which are key to promoting cortical neuron growth.
  • JRT promoted neuroplasticity, or growth between cellular connections in the brain, leading to a 46% increase in dendritic spine density and an 18% increase in synapse density in the prefrontal cortex.
  • JRT did not produce hallucinogenic-like behaviors that are typically seen when mice are dosed with LSD.
  • JRT did not promote gene expression associated with schizophrenia. Such gene expression is typically amplified with LSD use.
  • JRT produced robust anti-depressant effects, with it being around 100-fold more potent than ketamine, the state-of-the-art fast-acting anti-depressant.
  • JRT promoted cognitive flexibility, successfully addressing deficits in reversal learning that are associated with schizophrenia.

Joe Lonsdale presents a blueprint for FDA reform

Sunday, April 13th, 2025

The new FDA report from Joe Lonsdale and team is impressive, Alex Tabarrok says, as he shares a few of the recommendation which caught his eye:

In the U.S., anyone running a clinical trial must manufacture their product under full Good Manufacturing Practices (GMP) regardless of stage. This adds enormous cost (often $10M+) and more importantly, as much as a year’s delay to early-stage research. Beyond the cost and time, these requirements are outright irrational: for example, the FDA often requires three months of stability testing for a drug patients will receive after two weeks. Why do we care if it’s stable after we’ve already administered it? Or take AAV manufacturing—the FDA requires both a potency assay and an infectivity assay, even though potency necessarily reflects infectivity.

This change would not be unprecedented either. By contrast, countries like Australia and China permit Phase 1 trials with non-GMP drug with no evidence of increased patient harm.

[…]

With modern AI and digital infrastructure, trials should be designed for machine-readable outputs that flow directly to FDA systems, allowing regulators to review data as it accumulates without breaking blinding. No more waiting nine months for report writing or twelve months for post-trial review. The FDA should create standard data formats (akin to GAAP in finance) and waive documentation requirements for data it already ingests. In parallel, the agency should partner with a top AI company to train an LLM on historical submissions, triaging reviewer workload so human attention is focused only where the model flags concern. The goal is simple: get to “yes” or “no” within weeks, not years.

[…]

When negative results aren’t published, companies duplicate failed efforts, investors misallocate capital, and scientists miss opportunities to refine hypotheses. Publishing all trial outcomes — positive or negative—creates a shared base of knowledge that makes drug development faster, cheaper, and more rational. Silence benefits no one except underperforming sponsors; transparency accelerates innovation.

The FDA already has the authority to do so under section 801 of the FDAAA, but failed to adopt a more expansive rule in the past when it created clinicaltrials.gov. Every trial on clincaltrials.gov should have a publication associated with it that is accessible to the public, to benefit from the sacrifices inherent in a patient participating in a clinical trial.

[…]

We need multiple competing approval frameworks within HHS and/or FDA. Agencies like the VA, Medicare, Medicaid, or the Indian Health Service should be empowered to greenlight therapies for their unique populations. Just as the DoD uses elite Special Operations teams to pioneer new capabilities, HHS should create high-agency “SWAT teams” that experiment with novel approval models, monitor outcomes in real time using consumer tech like wearables and remote diagnostics, and publish findings transparently. Let the best frameworks rise through internal competition—not by decree, but by results.

The Return of the Dire Wolf?

Monday, April 7th, 2025

Time magazine announces the return of the dire wolf:

The dire wolf once roamed an American range that extended as far south as Venezuela and as far north as Canada, but not a single one has been seen in over 10,000 years, when the species went extinct. Plenty of dire wolf remains have been discovered across the Americas, however, and that presented an opportunity for a company named Colossal Biosciences.

Relying on deft genetic engineering and ancient, preserved DNA, Colossal scientists deciphered the dire wolf genome, rewrote the genetic code of the common gray wolf to match it, and, using domestic dogs as surrogate mothers, brought Romulus, Remus, and their sister, 2-month-old Khaleesi, into the world during three separate births last fall and this winter—effectively for the first time de-extincting a line of beasts whose live gene pool long ago vanished. TIME met the males (Khaleesi was not present due to her young age) at a fenced field in a U.S. wildlife facility on March 24, on the condition that their location remain a secret to protect the animals from prying eyes.

The dire wolf isn’t the only animal that Colossal, which was founded in 2021 and currently employs 130 scientists, wants to bring back. Also on their de-extinction wish list is the woolly mammoth, the dodo, and the thylacine, or Tasmanian tiger. Already, in March, the company surprised the science community with the news that it had copied mammoth DNA to create a woolly mouse, a chimeric critter with the long, golden coat and the accelerated fat metabolism of the mammoth.

If all this seems to smack of a P.T. Barnum, the company has a reply. Colossal claims that the same techniques it uses to summon back species from the dead could prevent existing but endangered animals from slipping into extinction themselves.

[…]

It takes surprisingly few genetic changes to spell the difference between a living species and an extinct one. Like other canids, a wolf has about 19,000 genes. (Humans and mice have about 30,000.) Creating the dire wolves called for making just 20 edits in 14 genes in the common gray wolf, but those tweaks gave rise to a host of differences, including Romulus’ and Remus’ white coat, larger size, more powerful shoulders, wider head, larger teeth and jaws, more-muscular legs, and characteristic vocalizations, especially howling and whining.
The dire wolf genome analyzed to determine what those changes were was extracted from two ancient samples—one a 13,000-year-old tooth found in Sheridan Pit, Ohio, the other a 72,000-year-old ear bone unearthed in American Falls, Idaho.

[…]

Colossal’s dire wolf work took a less invasive approach, isolating cells not from a tissue sample of a donor gray wolf, but from its blood. The cells they selected are known as endothelial progenitor cells (EPCs), which form the lining of blood vessels. The scientists then rewrote the 14 key genes in the cell’s nucleus to match those of the dire wolf; no ancient dire wolf DNA was actually spliced into the gray wolf’s genome. The edited nucleus was then transferred into a denucleated ovum. The scientists produced 45 engineered ova, which were allowed to develop into embryos in the lab. Those embryos were inserted into the wombs of two surrogate hound mixes, chosen mostly for their overall health and, not insignificantly, their size, since they’d be giving birth to large pups. In each mother, one embryo took hold and proceeded to a full-term pregnancy. (No dogs experienced a miscarriage or stillbirth.) On Oct. 1, 2024, the surrogates birthed Romulus and Remus. A few months later, Colossal repeated the procedure with another clutch of embryos and another surrogate mother. On Jan. 30, 2025, that dog gave birth to Khaleesi.

[…]

“The idea that we could just take a vial of blood, isolate EPCs, culture them, and clone from them, and they have a pretty high cloning efficiency, we think it’s a game changer,” says George Church, Colossal co-founder, and professor of genetics at both Harvard University and the Massachusetts Institute of Technology. The less invasive cell-sampling process will make the procedure easier on animals, and the fact that Colossal’s methods worked on this early go-round boosts company confidence that they are on track for much broader de-extinction and rewilding.

Borrowing a name from Game of Thrones for a dire wolf makes perfect sense, but Khaleesi? The actual (fictional) dire wolves in the stories are:

Grey Wind, adopted by Robb Stark.
Lady, adopted by Sansa Stark.
Nymeria, adopted by Arya Stark.
Shaggydog, adopted by Rickon Stark.
Summer, adopted by Bran Stark.
Ghost, adopted by Jon Snow.

Scientific purists will note that the “dire wolves” created by Colossal are merely ordinary wolves with a few gene edits. Previous “dire wolves” have been dogs bred to look like wolves.

Artificial sweetener shows surprising power to overcome antibiotic resistance

Sunday, April 6th, 2025

Professor Ronan McCarthy, at Brunel University of London’s Antimicrobial Innovations Center, and his team have found that saccharin shows surprising power to overcome antibiotic resistance:

“Saccharin breaks the walls of bacterial pathogens, causing them to distort and eventually burst, killing the bacteria. Crucially, this damage lets antibiotics slip inside, overwhelming their resistance systems.”

[…]

The international team found that saccharin both stops bacterial growth and disrupts DNA replication and stops the bacteria from forming biofilms—sticky, protective layers that help them survive antibiotics.

They also created a saccharin-loaded hydrogel wound dressing that, in tests, outperformed market-leading silver-based antimicrobial dressings currently used in hospitals.

“This is very exciting,” Prof McCarthy added. “Normally it takes billions of dollars and decades to develop a new antibiotic. But here we have a compound that’s already widely used, and it not only kills drug-resistant bacteria but also makes existing antibiotics more effective.

“Artificial sweeteners are found in many diet and sugar-free foods. We discovered that the same sweeteners you have with your coffee or in a ‘sugar-free’ drink could make some of the world’s most dangerous bacteria easier to treat.”

What does saccharin do to benign bacteria?

Beginning in 1957, massive tunnel complexes were drilled into the volcanic rock and granite by hard-rock miners working twenty-four hours a day, seven days a week

Friday, March 21st, 2025

Area 51 by Annie JacobsenUnderground tunnels, called N-tunnels, P-tunnels, and T-tunnels, have been drilled next door to Area 51, Annie Jacobsen explains (in Area 51), for decades:

The 1,150-foot-long tunnel at Jackass Flats, drilled into the Calico Mountains, through which NERVA scientists and engineers like T. D. Barnes accessed their underground workstations is but one example of an underground tunnel at the Nevada Test Site. The NERVA complex in Area 25 has since been dismantled and “deactivated,” according to the Department of Energy, but elsewhere at the test site dozens of tunnel complexes exist. In the 1960s, one tunnel dug into the granite mountain of Rainer Mesa, in Area 12, reached down as far as 4,500 feet, nearly a mile underground. There are many such government tunnels and bunkers around America, but it was the revelation of the Greenbrier bunker by Washington Post reporter Ted Gup in 1992 that set off a firestorm of conspiracy theories related to postapocalypse hideouts for the U.S. government elite—and since 1992, these secret bunkers have been woven into conspiracy theories about things that go on at Area 51.

The Greenbrier bunker is located in the Allegheny Mountains, 250 miles southwest of the nation’s capital. Beginning in 1959, the Department of Defense spearheaded the construction of a 112,544-square-foot facility eight hundred feet below the West Virginia wing of the fashionable five-star Greenbrier resort. This secret bunker, completed in 1962, was to be the place where the president and certain members of Congress would live after a nuclear attack. The Greenbrier bunker had dormitories, a mess hall, decontamination chambers, and a hospital staffed with thirty-five doctors. “Secrecy, denying knowledge of the existence of the shelter from our potential enemies, was paramount to all matters of operation,” Paul Bugas, the former onsite superintendent at the Greenbrier bunker, told PBS when asked why the facility was kept secret from the public. Many citizens agree with the premise. Conspiracy theorists disagree. They don’t believe that the government keeps secrets to protect the people. Conspiracy theorists believe the leaders of government are only looking to protect themselves.

The underground tunnels and bunkers at the Nevada Test Site may be the most elaborate underground chambers ever constructed by the federal government in the continental United States. The great majority of them are in Area 12, which is located approximately sixteen miles due west of Area 51 in a mountain range called Rainier Mesa. Beginning in 1957, massive tunnel complexes were drilled into the volcanic rock and granite by hard-rock miners working twenty-four hours a day, seven days a week. To complete a single tunnel took, on average, twelve months. Most tunnels ran approximately 1,300 feet below the surface of the earth, but some reached a mile underground. Inside these giant cavities, which averaged one hundred feet wide, the Atomic Energy Commission and the Department of Defense have exploded at least sixty-seven nuclear bombs. There, the military has tested nuclear blast and radiation effects on everything from missile nose cones to military satellites. A series called the Piledriver experiments studied survivability of hardened underground bunkers in a nuclear attack. The Hardtack tests sought to learn how “to destroy enemy targets [such as] missile silos and command centers” using megaton bombs. Inside the T-tunnels, scientists created vacuum chambers to simulate outer space, expanding on those dangerous late-1950s upper atmospheric tests code-named Teak and Orange. And the Department of Defense even tested how a stockpile of nuclear weapons inside an underground bunker would hold up to a nuclear blast.

Richard Mingus has spent many years inside these underground tunnel complexes, guarding many of the nuclear bombs used in the tests before they were detonated. In Mingus’s five decades working at the test site, these were his least favorite assignments. “The tunnels were dirty, filthy, you had to wear heavy shoes because there was so much walking on all kinds of rock rubble,” Mingus explains. “The air was bad and everything was stuffy. There were so many people working so many different jobs. Carpenters, welders… There were forty-eight-inch cutting machines covering the ground.” Most of the equipment was hauled in on railroad tracks, which is at least partially responsible for inspiring conspiracy theories that include trains underneath Area 51—though the conspiracy theorists believe they’re able to ferry government elite back and forth between Nevada and the East Coast. In reality, according to Atomic Energy Commission records, the Defense Department built the train system in the tunnels to transport heavy military equipment in and out. If employees wanted to, men like Richard Mingus could ride the train cars down into the underground tunnel complexes, but Mingus preferred to walk.

They were speaking from a very motivated standpoint, trying to shut down something that they thought would hurt their interests

Sunday, March 16th, 2025

Viral by Alina Chan and Matt RidleyFive years ago, the SARS-CoV-2 virus shut down the world and changed it forever:

While initial reports suggested that the virus had jumped from wild animals to humans at a market in Wuhan, China, others pointed to the Wuhan Institute of Virology — the only lab actively experimenting with closely related viruses. Since these viruses have never been found naturally within 1,000 miles of Wuhan, a local outbreak made little sense — yet questioning this brought swift political and institutional backlash from scientists worried about risking their careers and their work. But while working at the Broad Institute in Cambridge, scientist Alina Chan kept publicly questioning the official story, despite attempts from influential scientists and the media to cast the hypothesis as a conspiracy theory.

[…]

So back in 2020 when I interviewed you for Boston, you were basically a postdoc with a Twitter account. Since then, you’ve published a book as well as influential opinion pieces in Science magazine and the New York Times, and have shifted to work on the challenges relating to research that can cause pandemics. How has your life changed?

My gosh, five years, that’s a lot to cover. I mean, almost everything has changed.

[…]

Has your confidence that the pandemic resulted from a lab incident changed since 2020?

Back then, I was pretty agnostic. I was about 50/50. To the rest of society, that seemed insane because all of the top scientists were saying that this was a racist, anti-scientific conspiracy theory.

Yes, and now we know, thanks to the Freedom of Information Act, that they were colluding to suppress discussion of the lab-leak theory and were secretly trying to get you disciplined or fired. How did that make you feel?

Scientists are people. They have a lot of different pressures in their lives. Pressures to keep their labs running, to publish, to advance in their career. These virologists were not speaking scientifically. They were speaking from a very motivated standpoint, trying to shut down something that they thought would hurt their interests. Even in a situation where millions of people were dying. That shocked me.

What finally convinced you that the Wuhan Institute of Virology was the likely cause of the pandemic?

For me, the thing that really shifted the balance of evidence was the discovery of a 2018 research proposal called Defuse that was submitted by the Wuhan Institute of Virology and their U.S. collaborators that specifically said, “We’re gonna look for novel SARS-like viruses in the wild, we’re gonna put in these novel furin cleavage sites and see what happens, and we’re gonna test these viruses in human cells to see how these features can impact their ability to replicate and cause disease.” And then, barely two years later, exactly such a virus causes an outbreak in their city, very far away from where these viruses are found naturally. To me, that extreme coincidence was too much to ignore.

They hiked inside several atomic craters

Friday, March 14th, 2025

Area 51 by Annie JacobsenA little-known fact, Annie Jacobsen explains (in Area 51), is that to prepare for what it would actually be like to walk around on the geology of the moon, the astronauts visited the Nevada Test Site:

There, they hiked inside several atomic craters, learning what kind of geology they might have to deal with on the lunar surface’s inhospitable terrain.

[…]

“I was with them in 1965, and again five years later when they came back,” Williams recalls. This time the astronauts arrived with a lunar roving vehicle to test what it might be like driving on the moon.

[…]

The lunar roving vehicle was not a fast-moving vehicle, and the astronauts took turns driving it. “NASA had built it and had driven it in a lot of flat places,” Williams explains. “But before it came to the test site and drove on the craters, the vehicle had no real experience on inhospitable terrain.

[…]

The craters Williams was talking about are subsidence craters—geologic by-products of underground bomb tests. When a nuclear bomb is placed in a deep vertical shaft, as hundreds were at the test site (not to be confused with tunnel tests), the explosion vaporizes the surrounding earth and liquefies the rock. Once that molten rock cools, it solidifies at the bottom of the cavity, and the earth above it collapses, creating the crater. The glass-coated rock, giant boulders, and loose rubble that remain resemble the craters found on the moon. So similar in geology were the atomic craters to moon craters that in voice transcripts sent back during the Apollo 16 and Apollo 17 missions, astronauts twice referred to the craters at the Nevada Test Site. During Apollo 16, John W. Young got specific. A quarter of a million miles away from Earth, while marveling at a lunar crater laden with rocks, Young asked fellow astronaut Charles M. Duke Jr., “Remember how it was up at that crater? At Schooner.” He was referring to the atomic crater Ernie Williams took the astronauts to in Area 20. During Apollo 17, while looking at the Haemus Mountains, Harrison H. Schmitt can be heard talking about the Buckboard Mesa craters in Area 19. For Ernie Williams, hearing this comparison was a beautiful moment. For lunar-landing conspiracy theorists, of which there are millions worldwide, the feeling was one of suspicion. For these naysayers, Schmitt’s telemetry tapes, the moon photographs, the moon rocks—everything having to do with the Apollo moon missions would become grist for a number of ever-growing conspiracies that have been tied to man’s journey to the moon.

The medieval house might have been built to specifications approved by a rodent council

Sunday, February 23rd, 2025

Dozens of rodents carry plague, Ed West notes, but it would only become deadly to humans when Yersinia pestis infected the flea of the black rat (Rattus rattus):

Black rats are sedentary homebodies and don’t like to move more than 200 metres from their nests; they especially like living near to humans, which is what makes them so much more dangerous than more adventurous rodents. Black rats have been our not-entirely-welcome companion for thousands of years, and were living near human settlements in the Near East from as far back as 3000 BC; the Romans and their roads helped them spread across the empire and brought them to Britain, the oldest rat remains here being found from the fourth century, underneath Fenchurch Street in London.

Black rats were especially comfortable in the typical medieval house, and while stone buildings became a feature of life in the 12th century, most were still made of wood and straw. In the words of historian Philip Ziegler, ‘The medieval house might have been built to specifications approved by a rodent council as eminently suitable for the rat’s enjoyment of a healthy and care-free life.’ This type of rat is also a very good climber, so could easily live in the thatched roofs which were common then.

Because of its preferred home, the black rat is also called the house rat or ship rat, while the brown rat prefers sewers. On top of this, the animals are fecund to a horrifying degree; one black rat couple can theoretically produce 329 million descendants in three years. So the typical medieval city had lots of rats, and with them came lots of fleas.

Fleas are nature’s great survivors. They can endure in all sorts of conditions, and some have developed the ability to live off bits of bread and only require blood for laying eggs. The black rat flea, called Xenopsylla cheopis, is also exceptionally hardy, able to survive between 6-12 months without a host, living in an abandoned nest or dung, although it is only active when the temperature is between 15-20 centigrade. As John Kelly wrote in The Great Mortality, the Oriental rat flea is ‘an extremely aggressive insect. It has been known to stick its mouth parts into the skin of a living caterpillar and suck out the caterpillar’s bodily fluids and innards’. What a world.

There are two types of flea: fur fleas and nest fleas, and only the former travels with its host rather than remaining in the nest. The rat flea is a fur flea, and while it prefers to stay on its animal of choice, they will jump on to other creatures if they’re nearby – unfortunately, in the 14th century that happened to be us. (In fact, they will attach themselves to most farmyard animals, and only the horse was left alone, because its odour repulses them, for some reason.)

As part of the great and disgusting chain of being, the rats inadvertently brought the plague to humans, but it wasn’t fun for the rats either, or the fleas for that matter. When the hungry flea bites the rat, the pestis triggers a mutation in the flea guts causing it to regurgitate the bacteria into the wound, so infecting the rat. (Yes, it is all a bit disgusting). Y. pestis can be transmitted by 31 different flea species, but only in a rodent does the quantity of bacillus become large enough to block the fleas’s stomach.

The flea therefore feeds more aggressively as it dies of starvation, and its frantic feeding makes the host mammal more overrun with the bacterium. The fleas also multiply as the plague-carrying rat gets sick, so that while a black rat will carry about seven fleas on average, a dying rat will have between 100 and 150. Rats were infected with the disease far more intensely than humans, so that ‘the blood of plague-infected rats contains 500-1,000 times more bacteria per unit of measurement than the blood of plague-infected humans.’

When the disease is endemic to rodents it’s called ‘sylvatic plague’, and when it jumps to humans it’s called ‘bubonic’ plague. For Y pestis to spread, there will ideally be two populations of rodents living side by side: one must be resistant to the disease so that it can play host, and the other non-resistant so the bacteria can feed on it. There needs to be a rat epidemic to cause a human epidemic because it provides a ‘reservoir’ for the disease to survive. Robert Gottfried wrote: ‘Y pestis is able to live in the dark, moist environment of rodent burrows even after the rodents have been killed by the epizootic, or epidemic. Thus as a new rodent community replaces the old one, the plague chain can be revived’. The rat colony will all be dead within two weeks of infection and then the fleas start attacking humans.

The first human cases would typically appear 16-23 days after the plague had arrived in a rat colony, with the first deaths taking place after about 20-28 days. It takes 3-5 days after infection for signs of the disease to appear in humans, and a similar time frame before the victim died. Somewhere between 20-40 per cent of infected people survived, and would thereafter mostly be immune.

What happened next would have been terrifying. ‘From the bite site, the contagion drains to a lymph node that consequently swells to form a painful bubo,’ or swelling lump, ‘most often in the groin, on the thigh, in an armpit or on the neck. Hence the name bubonic plague.’

The bacteria continue to grow exponentially only within tumors

Tuesday, February 18th, 2025

A University of Massachusetts Amherst-Ernest Pharmaceuticals team has developed a non-toxic bacterial therapy to deliver cancer-fighting drugs directly into tumors:

The team has been finetuning the development of non-toxic, genetically engineered strains of Salmonella to target tumors and then control the release of cancer-fighting drugs inside cancer cells. In addition to sparing healthy tissue from damage, this cancer treatment platform is able to deliver orders of magnitude more therapy than the administered dose because the simple-to-manufacture bacteria grow exponentially in tumors.

[…]

Early on in the research, the scientists discovered that it was the bacterial flagella – part of the cell that aids in movement – that enables the bacteria to invade cancer cells. So they engineered a genetic circuit in the bacteria that turns on the production of flagella with a simple, over-the-counter dose of aspirin. Without the turn-on switch provided by salicylic acid, the active metabolic product in the blood after a person takes an aspirin, the bacteria remain dormant in the tumor.

“One core part of this technology is the controlled activation of flagella,” Raman explains. “And the other core part is once the bacteria go inside cancer cells, we engineered them with a suicide circuit. So they rupture on their own and deliver the therapy inside the cancer cell.”

In pre-clinical research with mouse models, the bacteria is injected intravenously. “It goes everywhere, but then the immune system rapidly clears the attenuated bacteria from healthy organ tissue within two days. The bacteria continue to grow exponentially only within tumors during that time. On the third day, we give an over-the-counter dose of aspirin to trigger the bacteria to invade the cancer cells and then deliver the therapy,” Raman says.

Why are female intellectuals crazy?

Saturday, February 15th, 2025

Emil Kirkegaard presents his speculative model of sex differences among people with extreme beliefs, which explains why female intellectuals are crazy:

Women are more centrist in their personality and thus their beliefs than men. They hold views that are more common, or statistically speaking, their standard deviation is smaller for beliefs and their strength of belief. This is just a special case of the nearly universal greater male variance finding.

To move a person to adopt views that are very unlike those held by the rest of society, some kind of psychological push-factor is needed. The main push-factors are intelligence, open-mindedness, or craziness (psychopathology, P factor).

Thus, statistically speaking, women with extreme views need a stronger push factor than men do to attain those views.

Thus, statistically speaking, women with extreme views will average higher open-mindedness, intelligence, and craziness.

5% is about the base rate for pandemic flus per year

Wednesday, February 5th, 2025

Flu, Scott Alexander reminds us, is a disease caused by a family of related influenza viruses:

Pandemic flu is always caused by the influenza A virus. Influenza A has two surface antigen proteins, hemagglutinin (18 flavors) and neuraminidase (11 flavors). A particular flu strain is named after which flavors of these two proteins it has – for example, H3N2, or H5N1.

Influenza A evolved in birds, and stayed there for at least thousands of years. It crossed to humans later, maybe during historic times – different sources give suggest dates as early as 500 BC or as late as 1500 AD. It probably crossed over multiple times. Maybe it died out in humans after some crossovers, stuck around in birds, and crossed over from birds to humans again later.

During historic times, the flu has followed a pattern of big pandemics once every few decades, plus small seasonal epidemics each winter. The big pandemics happen when a new strain of flu crosses from animals into humans. Then the new strain sticks around, undergoes normal gradual mutation, and once a year immune response decays enough / mutations accumulate enough to cause another small seasonal epidemic (Why is this synced to the calendar year? See here for more).

Let’s digress to visit his piece on “diseasonality”:

The most common theories for disease seasonality are:

  1. Pathogens like the cold
  2. Pathogens like low humidity
  3. People are cramped indoors during the winter
  4. People have low vitamin D during the winter, and vitamin D helps fight pathogens

None of these are really satisfactory on their own.

[…]

Deprived of seasons, a place doesn’t just have a slow burn of flu cases all year. It has a big epidemic, then dies down for a while, then has another big epidemic. In retrospect, this is an obvious consequence of how diseases work (eg the SIR model of transmission). Some people get the disease, it spreads exponentially until lots of people are immune, and then it stops until something changes.

[…]

So in the tropics, Florida, and Alaska, epidemics “want” to follow a cycle of coming approximately once a year. In the tropics, nothing is giving them that cycle, so they come at a random time once a year, or twice a year, or whatever. In Florida, UV light, temperature, etc provide that cycle, and they come once a year. In Alaska, UV light, temperature, etc also provide that cycle, and they come once a year independent of what’s going on in Florida.

Back to the original piece:

The severity of any given flu epidemic depends both on the innate severity of the virus, and on how closely the human population’s circulating flu antibodies match the epidemic strain. People usually have good antibodies to the seasonal flu, because it’s only slightly different from last year’s seasonal flu. For the big new animal crossovers, the level of protection provided by existing antibodies is unpredictable. Older people may have antibodies left over from the last time that particular flu crossed over from animals to humans; younger people probably won’t. In some cases, people’s immune systems will be permanently synced to the first flu they encounter, with less protection against subsequent versions.

So for example, the Spanish Flu of 1918 was an H1N1 strain that killed about 2% of the world population. But the exact mortality pattern was surprising; people between 18 and 28 were especially likely to die, and people older than 88 especially likely to survive. Why? Because an H1N1 flu went pandemic in 1830; anyone who first encountered the flu around then had an immune system synced to H1N1. But an H3N8 flu went pandemic between 1890 and 1900; anyone who first encountered the flu then had an immune system synced to that strain and was unprepared for H1N1.

[…]

Interestingly, 5% is about the base rate for pandemic flus per year: five in the past century = one per twenty years = 5% chance per year.

[…]

Third, maybe mortality would be between 0.01% and 0.2%. The argument here is looking at normal (ie not 1918) flu pandemics of the past century. The least bad among these, the 2009 swine flu, had CFR of 0.01%. The worst, Hong Kong flu, was somewhere around 0.2%. If H5N1 is a normal pandemic flu — and right now there’s not much that differentiates it — it will probably be somewhere in that range.

Fourth, maybe mortality will be 2-10%. This was the mortality rate of the 1918 Spanish Flu. It seems to be an outlier: as far as we know, no other flu in the past 500 years was nearly as bad.