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Kindle Notes & Highlights
by
Tom Ireland
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September 11 - October 12, 2023
Some scientists believe that all life may have evolved from self-replicating entities more akin to viruses than cells.
Bacteria are also essential to all life on Earth.
Anywhere and everywhere a bacterial strain has evolved to exploit an ecological niche, there will be viruses that have evolved to exploit that bacteria. This makes these seemingly obscure viruses easily the most abundant biological entity on Earth.
For a few decades in the early twentieth century, the world went mad for phages, and phage therapy was everywhere – from chemists’ shops in Britain to Brazilian public hospitals.
And, most crucially, we will see why we need phages more than ever before: the escalating threats posed by antibiotic-resistant bacteria.
in 2019 alone, almost two million people had died from infections with bacteria that were resistant to frontline antibiotics, and a further three million died from causes associated with a drug-resistant infection.7 That puts drug-resistant infections up there with killers like diarrhoeal diseases and dementia on the World Health Organization’s (WHO) list of the ten leading causes of death globally.8
If we could design the perfect antidote to this crisis, what would it look like?
Bacteriophages are all of these things.
The Ganges’ holiness is, as the scholar Rijul Kochhar puts it, a result of the remarkable confluence of ‘faith, filth and phage’.13
By 1907, d’Herelle had been hired by the government in nearby Mexico (again, as he wrote later, ‘where anyone could be a doctor, no degree was required’)
d’Herelle made his first major breakthrough as a scientist in Mexico.
The idea of using nature itself to fight nature – an epidemic to fight a plague – was really rather pioneering, and would become a feature of d’Herelle’s work.
Now in his forties, perhaps he felt a pressure to come up with a big idea – perhaps to keep his ‘life plan’ on track, or perhaps just to keep the questions about who he was, and his right to be working as a scientist at the Pasteur Institute, at bay.
And now for the really neat part: the components spontaneously self-assemble, pushed and pulled into shape by the tiny attractive and repellent forces of the molecules they are made up of, while other special proteins encoded in the phage’s genes act as scaffolds or guide the various components into place. A molecular motor at the top of the tail packs the long length of DNA – which doesn’t naturally want to coil or fold into a tight space – so tightly into the phage’s heads that scientists estimate the pressure inside them to be thirty times higher than a car tyre.38 It’s both a meticulous
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This technique even allowed d’Herelle to start to quantify the number of virus particles he was dealing with; by counting the spots and working backwards through the dilutions of the solution, he could work out how many individual phages were in his original sample. The elegantly simple techniques he developed for detecting and counting phages remain, to this day, the standard way to find and isolate bacterial viruses.
At one point d’Herelle roped none other than Albert Einstein into the debate, asking him to review the maths of the experiments showing that phages were individual particles not a liquid. Einstein sided with d’Herelle.46
It was still early days – just five patients – yet it’s hard to overstate how important this result was. No clinic or hospital in the world at the time had access to reliable treatments for treating acute bacterial disease.
The Australian phage researcher Jeremy Barr, one of the leading experts in this emerging field, now calls phages the body’s ‘third immune system’,
he believed his scientific upbringing in the wilds of Guatemala and Mexico was a ‘school of hard knocks’ that had made him more daring and fearless than others.
D’Herelle would later write of Calmette: ‘Of him I will say nothing: he was my declared enemy, he pursued me with his enmity for the rest of his life.’
Thanks to commercial interest in his ideas he was able to found a private lab in Paris, the Laboratoire du Bacteriophage, which manufactured at least five phage-based medicines for different types of infection, named Bacté-coli-phage, Bacté-rhino-phage, Bacté-intesti-phage, Bacté-pyo-phage and Bacté-staphy-phage – the profits of which allowed him to fund further research. (The laboratory was later acquired by French company L’Oréal.)
By 1926, d’Herelle had accurately deduced the life history of a bacterial virus, including the attachment of the phage particle to the susceptible bacterium, multiplication of phages within the bacterial cell and the bursting of the bacterium to set free the progeny virus particles – decades before the technology required to actually see any of this was available.
It is believed d’Herelle was nominated for a Nobel Prize at least twenty-eight times,65 possibly more, but the campaign to sow confusion and distrust in his work ensured he never won it.
By the late 1920s and early 1930s, injudicious use of any old phages to treat any old infection – with predictably poor results – meant their reputation as a wonder drug was starting to fade in most countries.
the head of the latest iteration of the Russian super-state was another Georgian – Ioseb Besarionis dze Jughashvili, better known in the West as Joseph Stalin.
a Pulitzer Prize-winning novel, Sinclair Lewis’s 1926 Arrowsmith, which went on to be a huge hit, adapted for stage, radio and film.
All that is clear is that by 1937, just as the main buildings of Eliava’s enormous institute were being finalised, he was suddenly arrested in front of his family while hosting a dinner party.
The same fate would eventually meet almost all of Eliava’s famous and intellectual friends,FN00 and hundreds of thousands of others, in a spasm of paranoid violence that year that became known as the Terror, or Great Purge.
He died of pancreatic cancer in 1949. Despite d’Herelle’s remarkable breakthroughs on the nature of viruses, his name soon faded, and his work is largely unknown and uncelebrated outside of the virology community. (Frederick Twort died a year later, in 1950.)
The heroic efforts of Zinaida Yermolyeva, brewing anti-cholera phages in siege conditions in a bunker below the flattened city, helped keep Stalingrad and its defenders free from the cholera outbreaks
Yermolyeva went on to become known as ‘Madame Penicillin’ for
The insecure Stalinist regime could not accept its failure to provide such important medicines and began a propaganda drive to sow distrust in these scandalous Western chemicals. A campaign encouraged citizens to use home-grown, ‘natural’ Soviet products – including phages and all manner of dubious herbal remedies that were better for the Soviet people because they were nashi, meaning ‘ours.’
As none other than Sir Alexander Fleming wrote: ‘The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.’
This crisis threatens to dwarf the impact of any pandemic caused by a single bacterium or virus, and the Western world’s scramble to find effective alternatives to the traditional chemical antibiotic are becoming increasingly desperate.
As the menace of antibiotic resistance became more serious across the globe, few if anyone in the West knew anything about the massive operation at Tbilisi and their alternative antibiotics.
up to half of the institute’s collection – some gathered and studied since d’Herelle and Eliava’s time – may have been lost.
Professor Elizabeth ‘Betty’ Kutter
In 1996, the science magazine Discover ran an article by the Russian-American journalist Peter Radetsky entitled ‘The Good Virus’.FN00 This seminal piece of reporting was the first to reveal to the American public that in a small pocket of the former Soviet Union, doctors were using a long-forgotten treatment that involved injecting patients with live viruses dredged from dirty water.
the Sunnyside Collaborative Clinic is also one of the tiny number of places in the world where you can receive phage therapy.
Given federal regulations in the US forbade any extraneous material in vaccines at all, efforts to maintain the status quo ended with President Richard Nixon signing an executive order, remarkably, to allow vaccines to be contaminated with bacteriophages.32 For all the wrong reasons, both the FDA and the US President had just essentially declared it safe to inject phages directly into the human body.
He repeatedly selected these long-lasting phages over and over until he had bred two variants of super-phage that could escape the RES for days. He named them Argo1 and Argo2, after Jason and the Argonauts.
he wrote a paper setting out his vision for what needed to happen to make phage therapy a reality in the West, published in the journal Nature Drug Discovery, in 2003.35
Clause 37 of the Helsinki Declaration has been virtually the only way of getting phages into the arms of patients outside of Georgia or Poland.
Do doctors really understand what will happen when phages are injected into the body,
They are already there. Wherever there are bacteriae, there are bacteriophages...
He and Delbrück not only agreed to join forces then and there over dinner, but like new lovers in the throes of new passion, immediately travelled to New York on New Year’s Day 1941 for a ‘forty-eight-hour bout of experimentation’ in Luria’s lab. Using dishes of bacterial viruses as their biological looking glass, the pair of immigrant phageophiles began to seek answers to some of the most intractable questions of the century.
Delbrück and Luria’s findings also helped put to bed the idea that organisms can acquire the genetic adaptations they need during their lifetimes,
But Hershey added yet more experimental creativity and clout to the great mind of Delbrück and the sponge-like brain of Luria.
German physicist called Ernst Ruska
The electron microscope was born.
The images, first published in 1940, were grainy and blurry, but remarkable. They show round phages, club-like phages, phages with heads and tails, some surrounding their bacterial prey, others spilling out from broken cells, whole tableaus of microbial warfare magnified by 25,000 times their natural size.
