Category Archives: Germ Warfare

By Bartee Haile

Just when Texans started to think the Spanish Flu had finally run its course, on Feb. 4, 1920 the State Health Department reported 2,514 new cases in the past 24 hours.

The deadly strain of influenza that caused the worldwide epidemic at the end of the First World War was called the Spanish Flu because the outbreak in that country that killed eight million in May 1918 received the most attention. As a noncombatant, Spain had no wartime censorship. Interestingly enough, the Spaniards themselves named the scourge the French Flu.

The Great Pandemic was genuinely global in scope. The only place on the planet to escape the calamity was a small island deep in the Amazon jungle. No one really knows how many lives were lost, but estimates of the worldwide death toll ranged from 40 to 100 million making the twentieth-century pandemic the deadliest in human history.

The Spanish Flu struck healthy individuals, usually the young rather than the old, without warning. In a matter of hours, victims were too weak to walk and had to take to bed. Of those that died, the end often came the very next day. The stricken rarely lingered longer than three days after infection.

The symptoms were ghastly. As the lungs failed, victims turned black or blue from lack of oxygen and bled from the nose, ears and eyes. And, as one historian wrote, Patients would writhe from agonizing pain in their joints.

Although victims were advised to send for a doctor as soon as they came down with Spanish Flu, there was little a physician could do when he arrived. Penicillin would not be discovered until 1928, and it was not until 1943 that an influenza vaccine became available.

The first documented case in the United States occurred on March 11, 1918 at Fort Riley, Kansas, when army cook showed up at sick call with a temperature of 103. Forty-eight hours later, 522 soldiers were flat on their backs.

Later that summer, a more virulent form of the Spanish Flu, undoubtedly carried by returning doughboys, hit Boston. The sickness spread like wildfire through the crowded cities on the East Coast, killing 800 a day in New York City, before heading west.

In the absence of a scientific explanation for the cause and with no cure, hysteria and ignorance filled the void. One popular theory was that the Spanish Flu was part of a germ-warfare attack by the Germans, while others blamed cat hair and coal dust. The long list of useless home remedies included everything from onions and garlic to goose grease.

The Surgeon Generals antidote for such nonsense was four basic precautions: 1) Keep out of crowds. 2) Cover up each cough and sneeze. 3) Do not spit on the floor or sidewalk. 4) Shun the common drinking cup and the roller towel in public places.

Texans could only wait and hope for the best. Maybe by some sort of miracle the Spanish Flu would skip the Lone Star State. But it didnt.

The suspense ended on Sept. 23, 1918 with the first confirmed sightings of the sickness in Williamson, Kaufman and Bosque counties. Eleven days later, 35 counties were under siege, and a week after that the number had grown to 77.

Towns throughout Texas moved quickly to protect the public over the objections of local merchants and skeptics, who pooh-poohed the danger. On Oct. 9 alone the following communities closed schools, theaters and other gathering places: Lewisville, Plano, Marshall, McKinney, Bonham, Wills Point, Clarksville, Cleburne, Temple, Wichita Falls, Waxahachie, Houston and Corsicana.

By late October, the Spanish Flu had reached the Panhandle with the death of the president of Wayland Baptist College in Plainview on the 28th, and El Paso, where the number of cases neared 5,000 by the 23rd. On the 29th, the State Health Department reported 106,978 cases and 2,181 deaths and that was just in the cities.

Galvestons response to the worst public health crisis since the yellow fever epidemics of the 1800s was typical of most towns. City officials and the daily newspapers saw panic as the greatest enemy and in their efforts to keep everybody calm often painted too rosy a picture of a truly grave situation.

Any decline in the daily death toll was hailed by politicians and The Daily News as a sign the worst was over. Carried away by encouraging numbers in early November, the health commissioner lifted the ban on public places and reopened the schools.

But this unfounded optimism ignored the fact that the Spanish Flu came in waves and would hang on in Texas well into 1920. When the disease returned with a vengeance killing 65 Galvestonians between Nov. 15 and Dec. 15, the commissioner was forced to shut the city down again.

The final figures for the United States, nothing more than educated guesses, had one out of every four Americans stricken by the Spanish Flu and at least half a million fatalities in a population of 105 million. As for the four and half million Texans, 30 to 40 percent contracted the disease and five to ten percent of the afflicted perished. Thats 70,000 dead in the best case and upwards of 175,000 in the worst.

Bartee welcomes your comments and questions at barteehaile@gmail.com or P.O. Box 130011, Spring, TX 77393 and invites you to visit his web site barteehaile.com.

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This week in Texas History: Spanish flu, our ancestors' pandemic - Hays Free Press

Many of us continue to steady our steps. The germ warfare has us on a carousel going up and down and all around.

We have learned that vaccinations and good health practices make a difference. We know the high vaccination rate on Guam is a safety net for our health care system.

Emotionally, stressors come from all points. Closures, work, prices, empty shelves challenge us to be even more patient, focused and creative. Our hope for better times keeps us steady.

A lack of decorum from elected officials unsettles that hope. If the Guam Legislature has organizational issues with attendance practices, it can address that internally. If the Guam Legislature has issues with the performance of committee members and officers, it can address that in joint caucus.

As a former senator, I learned when I was present at a majority, if not all, public hearings and committee meetings, there were a variety of acceptable strategies to fully engage in legislative business. I learned that Families First should concentrate on its office and while it should certainly foster relationships with others, it should trust individual senators to be accountable for their efforts.

The people are astute enough to know who is getting the peoples work done. The people will decide, as they always do.

Do not misunderstand me. Heated discussion about policy, programs and practices is vital. Best steps result as discourse, data, research, stakeholder input and visionary sights take the stage. We elect our leaders to make the best decisions possible for all of us to live, work, pray, learn, dream and play safely, fairly and happily to our potential.

As officials live in glass houses, boundaries should be respected for private matters, especially when we already know tragedy and high-risk health issues are being addressed, especially when we already know health care being sought isnt available on Guam, especially when we know that deliverables continue to be addressed.

We have little control over many Guam decisions. We do have control over our relationships with each other. Even as we disagree, respect and regard especially as we are just healing from the health crisis are expected from our officials. Further concern hampers recovery.

Vice Speaker Tina Mua Barnes tele-working has made progress on Guam issues transshipment, COFA renegotiations, affordable homes. She continues to do her work on the Guma Mami Board. Most recently, her measure to identify haul-road highways that aims to help control Guam prices passed.

I dont know if Tina is seeking re-election. What I do know is that she continues to deliver for our families as she cares for hers. What I do know is that she is deserving of respect, regard and restraint as she steadies her footing.

We may not be able to control treatment from others, but certainly we can temper treatment among ourselves. Respect, regard, restraint standards of behavior we expect from those who call Guam home.

Aline Yamashita, Ph.D., is a teacher, single mother and former senator.

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Yamashita: Boundaries should be respected | Opinion | guampdn.com - Guam Pacific Daily News

Flickr/Roman Kruglov On June 6, 1966, a group of US Army scientists made their way into the Seventh and Eighth Avenue lines of the New York City subway. Some carried air sampling machines in boxes and on belts; others carried light bulbs.

The light bulbs were packed with about 175 grams of Bacillus subtilis bacteria, then known as Bacillus globigii approximately 87 trillion organisms in each. The plan was to shatter them and then use the sampling machines to see how they spread through the subway tunnels and trains.

This test was one of at least 239 experiments conducted by the military in a 20-year "germ warfare testing program" that went on from 1949 to 1969. These experiments that used bacteria to simulate biological weapons were conducted on civilians without their knowledge orconsent. That stands in directviolation of the Nuremberg Code, which stipulates that "voluntary, informed consent" is required for research participants.

And while the people who conducted these experiments did so under the belief that the bacterial species they used were harmless, it has since been revealed that they can cause health problems.

"They're all considered pathogens now," says Leonard Cole, the director of the Terror Medicine and Security Program at Rutgers New Jersey Medical School, who documented these experiments in his book "Clouds of Secrecy: The Army's Germ Warfare Tests Over Populated Areas."

A paper from the National Academy of Sciences analyzing military experiments notes that B. globigii is "now considered a pathogen" and is often a cause of food poisoning. "Infections are rarely known to be fatal," the report said though fatal cases have occurred.

The New York experiments were some of the most shocking ones that occurred in terms of people exposed, according to Cole.

"During peak hours, these bacteria were dropped," he says. "If you can get trillions of bacteria into a light bulb and throw it on the track as a train pulls into a station, they'll get pulled through the air as the train leaves."

The Army came to that very conclusion, whichis documented in a report titled "A Study of the Vulnerability of Subway Passengers in New York City to Covert Attack with Biological Agents."

They wrote that clouds engulfed people as trains pulled away, but that they "brushed their clothing, looked up at the grating apron and walked on." No one was concerned.

Army scientistsconcluded that it took between four and 13 minutes for train passengers to be exposed to the bacteria. Five minutes after bacteria were released at 23rd Street Station, the bacteria could be detected at every station between 14th Street and 59th, according to the report. Between June 6 and June 10, they calculated that more than a million people were exposed.

The germ warfare testing program was revealed by a news report in the early 1970s and then by subsequent Freedom of Information Act Requests. Scientists who'd been involved with the program were called to testify before Congress.

Army scientist Charles Senseney was one of those called to testify in 1975. He told a Senate subcommittee that city officials had no idea the tests occurred. According to a New York Daily News report that cites his testimony, he said that a more dangerous agent would have "put New York out of commission."

In a 1995 Newsday story(which is not available online), reporter Dennis Duggan contacted the retired Senseney, who declined to tell him anything about it.

"I don't want to get near this," Senseney said to Duggan. "I [testified], because I was told I had to by the people at the Department of Defense ... I better get off the phone."

Cole cites somedeclassified documents that discuss the New York tests in his book.

The report's conclusion is chilling: "Test results show that a large portion of the working population in downtown New York City would be exposed to disease if one or more pathogenic agents were disseminated covertly in several subway lines at a period of peak traffic."

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The Army tested 'germ warfare' on the NYC subway by ...

Biotechnology. 2016 : 687719.

Department of Microbiology, Southern Illinois University, Carbondale, Illinois, USA

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

The term biological warfare typically conjures images of medieval warriors tossing dead cattle over city walls or clandestine government agents secretly releasing mysterious microbes into enemy territory. Of course, biological warfare does encompass such activity, but the vast majority of what constitutes biological warfare is far more mundane. Ever since life evolved on earth about 3.8 billion years ago, organisms have constantly devised new ways to kill each other. Any organism that makes use of toxinsfrom bacteria to snakesis engaging in a form of biological warfare. Humans who engage in biological warfare do so by taking advantage of these toxin-producing organisms.

Keywords: bacteriocins, biosensors, Black Death, botulinum toxin, bubonic plague, checkerboard hybridization, dominant-negative mutations, ergot, high-containment laboratories, incubation time, kappa particles, lysins, phage therapy, poison sequence, quorum sensing, ricin, siderophores, smallpox, toxins, weaponization

The term biological warfare typically conjures images of medieval warriors tossing dead cattle over city walls or clandestine government agents secretly releasing mysterious microbes into enemy territory. Of course, biological warfare does encompass such activity, but the vast majority of what constitutes biological warfare is far more mundane. Ever since life evolved on Earth about 3.8 billion years ago, organisms have constantly devised new ways to kill each other. Any organism that makes use of toxinsfrom bacteria to snakesis engaging in a form of biological warfare. Humans who engage in biological warfare do so by taking advantage of these toxin-producing organisms.

An entire textbook could be filled with examples of organisms that employ toxins to kill other organisms. We therefore touch only briefly on the natural history of biological warfare.

Bacteria are particularly adept at biological warfare. While humanity finds antibiotics incredibly useful in our battle against infectious disease, bacteria did not create them for our benefit. Instead, they make antibiotics to kill off other bacteria that are competing for the same habitat or resources. Similarly, bacteria synthesize toxic proteins known as bacteriocins to kill their relatives because closely related strains of bacteria are likelier to compete with each other. For example, many strains of Escherichia coli deploy a wide variety of bacteriocins (referred to as colicins) intended to kill other strains of E. coli. The genes for colicins are normally carried on plasmids, and many of these plasmids are commonly used in molecular biology and genetic engineering (see Chapter 3). Yersinia pestis, the plague bacterium, also makes bacteriocins (called pesticins in this case) designed to kill competing strains of its own species ().

Bacteriocins Inhibit Other Bacteria

A bacteriocin-producing strain of Lactococcus in a piece of cheese can inhibit the growth of a related microorganism.

From Garde S, etal. (2011). Outgrowth inhibition of Clostridium beijerinkii spores by a bacteriocin-producing lactic culture in ovine milk cheese. Int. J Food Microbiol150, 5965.

A point of clarification: The distinction between bacteriocin and toxin has to do with the target. Bacteria deploy bacteriocins against their fellowoften closely relatedbacteria with the deliberate intention of killing them. In contrast, proteins produced by bacteria that act against higher organisms are referred to as toxins. Perhaps counterintuitively, pathogenic bacteria do not usually intend to kill the organisms they infect. Rather, they want to manipulate them long enough to survive and reproduce. The longer the host stays alive, the longer it provides a home for the infecting bacteria. Just like antibiotics, some bacterial toxins are useful to humans. The bacterium Bacillus thuringiensis produces an insect-killing toxin that is harmless to vertebrates, and this Bt toxin has been used extensively in genetically modified crops. (See Chapter 15.)

Lower eukaryotes also regularly engage in biological warfare. Paramecium, a ciliated protozoan, carries symbiotic bacteria (Caedibacter) known as kappa particles that grow and divide inside the larger eukaryotic cell ().

Killer Paramecium Uses a Bacterial Toxin

(A) The kappa particles are found in the cytoplasm of the Paramecium. (B) Kappa particles are symbiotic Caedibacter that are found in many strains of Paramecium, yet they have their own DNA and divide like typical bacteria.

Strains of Paramecium with kappa particles are known as killers and, due to unknown genetic factors and resistance mechanisms, are naturally tolerant of them. Killer strains release kappa particles into the environment, and if a sensitive Paramecium (i.e., one lacking the ability to harbor kappa particles) eats and digests just a single kappa particle, a protein toxin is released and kills the Paramecium. Interestingly, the toxin is not encoded by a gene on the bacterial chromosome, but on a plasmid derived from a defective bacteriophage. So a toxin encoded by a virus infecting the kappa particle bacterium has been commandeered for the purpose of killing other strains of Paramecium.

This phenomenon is not at all unusual. Many toxins used by pathogenic bacteria that infect humans are actually encoded by foreign DNA of nonchromosomal origin, such as viruses, plasmids, or transposons. These elements are often integrated into the chromosome of pathogenic strains of bacteria. For example, the only strains of Corynebacterium diphtheriaethe causative agent of diphtheriathat are dangerous to humans are the ones that carry a toxin-encoding virus.

Higher eukaryotes can either create their own toxinssuch as the venom produced by snakes and scorpionsor expropriate toxins produced by other species. One species of caterpillar that feeds on tobacco plants can exhale noxious nicotine at spiders, chasing them away. Other insects rely on microbes to wage biological warfare. Certain parasitic wasps inject their eggs into the maggots (i.e., larvae) of plant-eating insects. After the eggs hatch, the newborn wasps eat the living maggots from the inside ().

Wasps Use Viruses against Maggots

Certain types of wasps lay their eggs inside tobacco hornworm larvae. The wasp lands on the back of the larva and injects the eggs plus adenovirus into the maggot through the ovipositor. The adenovirus prevents the larva from eating and therefore developing into a pupa. When the eggs hatch, the young use the insides of the larva as a food source, to grow and develop into adult wasps.

The maggots are eventually killed, and a new generation of wasps is released. The secret to the wasps success is the injection of an adenovirus along with the eggs. The virus targets the maggots fat body (vaguely equivalent to the liver of higher animals) and cripples the maggots developmental control system and immune system. The maggot loses its appetite for plants and is prevented from molting and turning into a pupa, the next stage in its life cycle.

Many different kinds of organisms engage in biological warfare. Bacteria kill other bacteria with antibiotics or bacteriocins. They also make toxins that are targeted at higher organisms. Eukaryotes can either make their own toxins or commandeer those produced by lower organisms.

Although we rarely perceive it this way, infectious disease is just another manifestation of biological warfare that is ubiquitous throughout life. The evolutionary relationship between hosts and pathogens is essentially a never-ending arms race. When a pathogen evolves a new toxin, the host evolves a response to it. Humanity has taken this arms race one step further by utilizing technology such as vaccines and industrial-scale manufacturing of antibiotics. However, the microbes are fighting back.

Perhaps the biggest problem plaguing medical microbiology today is the rise of antibiotic resistance. There are many reasons why bacteria have developed this resistance, but all of the explanations have one thing in common: the proliferation and misuse of antibiotics. For instance, medical doctors often prescribe antibiotics to patients who have an infection, even if it is unknown whether the disease is bacterial. Other times, the wrong antibiotic is prescribed. In many developing countries, antibiotics can be bought over the counter without a prescription. Compounding the dilemma, patients who receive antibiotics often do not comply with the recommended dose, ending treatment as soon as they feel better. This has the effect of selecting for the survival of the bacteria that have already developed a slight resistance to the drug. When the patient propagates the infection, he unintentionally passes on these toughened survivors. The widespread use of antibiotics in animal feedwhich farmers use to fatten up livestockis also a major contributor to the problem.

Today, many experts worry about incurable infections. Methicillin-resistant Staphylococcus aureus (MRSA) gets a lot of media attention, but it is not the only worrisome microbe. There have been reports from around the world of totally drug-resistant tuberculosis, which as the name implies, appears to be resistant to all treatment. In a 2013 report, the Centers for Disease Control and Prevention (CDC) issued an urgent warning about infections from (1) Clostridium difficile, which causes diarrhea and is often acquired by patients in health-care settings who were treated with antibiotics for other infections; (2) Carbapenem-resistant Enterobacteriaceae (CRE), such as Klebsiella and E. coli, which also cause health-care-associated infections and may be resistant to all known antibiotics; and (3) Neisseria gonorrhoeae, the etiologic agent of gonorrhea, which is growing in resistance to several antibiotics.

While these developments are alarming, much research is being done to combat the rise of antibiotic resistance. Although microbes have responded to our antibiotic assault, we are developing some new weapons to regain the upper hand.

Although there has been speculation of an inevitable post-antibiotic era, there are still plenty of opportunities for the development of novel antibiotics.

One strategy is to attack previously unexploited vulnerable spots in a bacteriums metabolism or life cycle, preferably those that bacteria cannot easily defend by acquiring resistance. For instance, bacteria use iron chelators, known as siderophores, to bind iron and extract it from host proteins. Siderophores are excreted, bind iron, and are then taken back into bacteria by specialized transport systems. Absence of high-potency siderophores largely abolishes virulence in both plague and tuberculosis. Because mammals do not make siderophores, their unique biosynthetic pathways provide an attractive target for development of novel antibiotics. Yersiniabactin, the siderophore of several pathogenic Yersinia species, is capped by a salicyl group ().

Salicyl-AMS Inhibits the Production of Yersiniabactin

The structure of yersiniabactin shows the salicyl group in red. The precursor, salicyl-AMP, is made by activating salicylate with ATP. The sulfamoyl analog, salicyl-AMS, inhibits the incorporation of the salicyl group into yersiniabactin.

The intermediate in the pathway, produced when ATP activates salicylate, is salicyl-AMP. A chemically synthesized analog of salicyl-AMP, called salicyl-AMS, replaces the phosphate with a sulfamoyl group. The compound is highly active and specifically inhibits siderophore synthesis. This prevents the growth of Yersinia under iron-limiting conditions, such as encountered in the human body.

Another strategy is to screen novel microbes for antibiotics. As discussed earlier, bacteria produce antibiotics for the explicit purpose of killing other bacteria. Since most microbes that exist in nature have neither been cultured nor identified, it is likely that many natural antibiotics have yet to be discovered. In 2013, a new antibiotic, called anthracimycin, was isolated from an Actinomycete that lives in the ocean. The new antibiotic is active against Bacillus anthracis and MRSA, and modifying it with chlorine groups expanded its spectrum of activity.

Yet another strategy is to identify and clone potential antimicrobial biosynthetic pathways. For example, based on its DNA sequence, one research group cloned a biosynthetic gene cluster from an Actinomycete called Saccharomonospora that was predicted to produce an antimicrobial lipopeptide. Expressing the gene cluster resulted in the discovery of a new antibiotic, taromycin A. The major advantage of this technique is that it can be applied to microbes that are difficult to culture in the laboratory.

A different approach is to disrupt existing antibiotic resistance, rather than developing new antibiotics. For example bacteriophage, such as those that live in the human gut, can shuttle antibiotic resistance genes between bacteria. Consequently, developing drugs that kill or disable bacteriophage is an innovative way to combat the spread of antibiotic resistance. Additionally, disrupting bacterial quorum sensing has been suggested. Bacteria use quorum sensing as a communication system in order to coordinate behavior ().

Quorum Sensing

Bacteria can coordinate behavior by detecting the presence of a signal molecule that indicates the density of the population.

From Boyen F, etal. (2009). Quorum sensing in veterinary pathogens: mechanisms, clinical importance and future perspectives. Vet. Microbiol135, 187195.

By releasing particular chemical compounds into the environment, bacteria can detect when a threshold population density, or quorum, has been reached. Many pathogens construct antibiotic-resistant biofilms after the population has reached a particular density. Disrupting their communication system would cripple their ability to coordinate behavior and keep the bacteria more vulnerable to antibiotics.

The history of phage therapythat is, using bacteriophage (also called phage) to treat bacterial infectionsbegins in France in 1921. That year, microbiologist Felix dHrelle used phage to treat patients suffering from dysentery ().

Felix dHrelle

Microbiologist Felix dHrelle helped pioneer phage therapy.

In 1927, he also used phage therapy to treat cholera victims in south Asia. Unfortunately, many other scientists in the United States and elsewhere were unable to replicate his work, and when the widespread production of antibiotics started in 1945, the scientific community mostly lost interest in phage therapy. The French, however, enthusiastically practiced phage therapy into the 1990s and, during those seven decades, there were reports of successful treatment of typhoid fever, colitis, septicemia, skin infections, and various other bacterial diseases. Other countries that embraced phage therapy include Poland, Russia, and Georgia. Today, patients there can receive phage therapy for chronic and antibiotic-resistant bacterial infections.

Since the 1990s, the Western scientific community has renewed its interest in phage therapy. One benefit of using phage, as opposed to antibiotics, is their specificity. Antibiotics kill many different types of bacteriawhich is harmful if they destroy helpful gut bacteriabut individual phage species infect only a group of very closely related bacteria. Every bacterial infection could, in theory, be targeted by a highly specific phage.

As predicted, however, bacteria also can develop resistance to phage, mainly through thwarting viral attachment. Now, researchers are investigating the use of lysins, a class of toxins that phage use to dismantle bacterial cell walls as part of their lytic cycle (). Because lysins target conserved regions within peptidoglycan, it is believed that bacteria will be less able to develop resistance. Lysins work best against Gram-positive bacteria, but genetic engineering can expand the spectrum of activity to include Gram-negative bacteria also.

Bacteriophage Tsamsa Kills Bacillus anthracis

The lysin isolated from the bacteriophage Tsamsa kills Bacillus anthracis and other closely related species.

From Ganz HH, etal. (2014). Novel giant Siphovirus from Bacillus anthracis features unusual genome characteristics. PLoS One9(1), e85972.

As an alternative to phage, it may be possible to deploy predatory bacteria against human pathogens. Bdellovibrio, which invades other bacteria rather like a virus, and Micavibrio, which attaches to bacterial cell surfaces, have been shown to kill antibiotic-resistant pathogenic bacteria invitro.

Because of a persistent fear that we will run out of novel antibiotics, many clever new technologies have been suggested to fight bacterial infections. Some of the most promising of these antibiotics utilize genetic engineering.

For example, many pathogenic Escherichia coli use the FimH adhesin to bind to mammalian cells via mannose residues on surface glycoproteins. Several alkyl- and aryl-mannose derivatives bind with extremely high affinity to the adhesin and block its attachment to the natural receptor. Such mannose derivatives, therefore, could serve as anti-adhesin drugs. However, manufacturing pharmaceuticals is quite expensive. It would be far cheaper to genetically engineer nonpathogenic strains of E. coli to express the mannose derivatives on their cell surfaces. Pathogenic bacteria would then bind to these decoys instead of to mammalian cells. This would also avoid the need for continuous administration of sugar derivatives because the decoy strains of E. coli would multiply naturally in the intestine. Alternatively, nonpathogenic strains of E. coli could be engineered with genes for adhesins that would allow them to compete with pathogens for mammalian cell receptors. (Such engineered strains would also have the advantage of being able to deliver protein pharmaceuticals or large segments of DNA for gene therapy into mammalian cells.)

A different approach is to generate altered toxins that interfere with their natural analogs. Typical A-B bacterial toxins are made from a single active A subunit, which carries out a toxic enzymatic reaction inside a target cell, and often several binding B subunits, which serve as a delivery system by attaching to the cell surface. Because several properly functioning binding subunits are required to deliver the active subunit, one approach to antitoxin therapy relies on utilizing dominant-negative mutations in the binding subunit of the toxin. The mechanism involves the binding of a defective protein subunit to functional subunits resulting in a complex that is inactive overall. (The term dominant-negative refers to mutations in which an abnormal gene product sabotages the activity of the wild-type gene product. Consequently, most dominant-negative mutations affect proteins with multiple subunits.) Dominant-negative mutations have been deliberately isolated in the B protein (called the protective antigen) of anthrax toxin. Mixing mutant subunits with wild-type ones resulted in the assembly of inactive heptamers that bind the A subunits (called lethal factor and edema factor) of anthrax toxin. As a result, the toxic A subunits cannot be transported into target cells (). This technique has been shown to protect both cultured human cells and whole mice or rats from death by lethal levels of anthrax toxin.

Dominant-Negative Mutations

For anthrax, the B subunit (called PA63 protein or protective antigen) binds the A subunits (called lethal factor, LF, and edema factor, EF) and transports them into the target cell cytoplasm via an endocytic vesicle. The dominant-negative inhibitory (DNI) mutant of the PA63 protein (purple) assembles together with normal PA63 monomers (pink) to give an inactive complex that cannot release the LF and EF toxins from the vesicle into the cytoplasm.

Many of the advances in nanotechnology aimed at fighting pathogens involve the creation of bactericidal surfaces (see Chapter 7 for more on nanotechnology). Several metals are inherently antibacterial. For instance, silver ions kill bacteria through several mechanisms, such as generating reactive oxygen species and disrupting protein disulfide bonds. Surfaces coated with silver, selenium, and copper nanoparticles all show antimicrobial activity.

Metals are not the only option. A substance known as black silicon is made of tiny nanopillars that are able to physically destroy bacteria, including endospores, through mechanical stress (). Antimicrobial activity has also been demonstrated with stacked carbon nanotubes called nanocarpets (see Chapter 7). Additionally, polymers of esters and cyclic hydrocarbons reduce attachment of bacteria. Such discoveries could allow for improved sanitation in health-care settings and the manufacture of antimicrobial medical devices.

Antibiotic resistance is a growing concern, but contrary to popular reports, it is not necessarily an intractable problem. Novel targets for antibiotics, phage therapy, genetic engineering, and nanotechnology provide multiple possibilities for fighting antibiotic-resistant pathogens.

Nanostructures Can Kill Bacteria

Scanning electron micrograph of black silicon surface showing its hierarchical structures. (A) Periodically arranged micropillar arrays; (B) a micropillar with nanostructures; (C) nanostructures formed on the top of the micropillar.

From He Y, etal. (2011). Superhydrophobic silicon surfaces with micro-nano hierarchical structures via deep reactive ion etching and galvanic etching. J Colloid Interface Sci364, 219229.

Throughout history, humans have devised new and innovative ways to kill other humans. When technology was primitive, warriors used whatever nature provided. Burning crops was probably the easiest and earliest form of warfare aimed at undermining an enemy, as was poisoning a communitys drinking water with dead or rotting animals.

Slightly more advanced forms of biological warfare emerged when soldiers began dipping spears in feces and throwing poisonous snakes. During the Black Death epidemic of the mid-1300s, the Tartars catapulted plague-ridden corpses over the walls into cities held by their European enemies. Although this is sometimes credited with spreading the plague, rats and their fleas were far more effective at spreading bubonic plague than contact with corpses ().

Bubonic Plague

This painting by Arnold Bcklin, simply titled Plague, depicts the fear that bubonic plague provoked in antiquity.

From ET Rietschal, etal. (2004). How the mighty have fallen: fatal infectious diseases of divine composers. Infect Dis Clin North Am18, 311339.

Given the state of hygiene in most medieval towns or castles, there was little need to provide an outside source of infection. With plague, typhoid, smallpox, dysentery, and diphtheria already around, all that was usually necessary was to let nature take its course. Similarly, a widespread myth exists that European settlers purposefully infected Native Americans with smallpox. While it is true that the British military attempted this strategy during the French and Indian War in the mid-1700s, the vast majority of Native American deathsperhaps as much as 95% of the populationwere due to inadvertent infection with smallpox and other diseases.

The truth is, until very recently, humans were not particularly hygienic. Consider, for instance, that antiseptic surgeryinvented by Joseph Lister and now considered a mainstay of modern medicinewasnt widely adopted until the late 1870s. Before then, armies and civilian populations were so dirty and disease-ridden that practicing germ warfare was like throwing mud on a pig. It is only in our modern hygienic age that biological warfare has become a more meaningful threat.

Modern biological warfare began during World War I. Although the Germans refused to use biological agents against people, they did use them against animals, infecting Allied horses with glanders (Burkholderia mallei) and anthrax. The French also employed glanders against German horses. During World War II, the infamous Japanese Unit 731 experimentally infected Chinese prisoners of war with horrifying diseases, such as cholera, epidemic hemorrhagic fever, and venereal disease. It was also responsible for dropping plague-infected flea bombs on cities in China, although this likely had little effect partly because plague was already endemic to the region ().

Unit 731

Japanese military Unit 731 killed thousands of Chinese people with experimental infections and biological warfare.

Source: Figure 6 from: Lpez-Muoz F, etal. (2007). Psychiatry and political-institutional abuse from the historical perspective: the ethical lessons of the Nuremberg Trial on their 60th anniversary. Prog Neuropsychopharmacol Biol Psychiatry31, 791780.

After World War II, particularly during the Korean War, the United States ratcheted up its biological weapons program. Perhaps the most controversial aspect of the program was the purposeful release of biological agents, such as the relatively harmless Serratia marcescens, over American cities to study weapons dispersal. The military unintentionally infected 11 civilians, one of whom died. By 1969, the U.S. had weaponized anthrax and tularemia. However, in 1975, the U.S. renounced all biological weapons by signing the Biological Weapons Convention (BWC).

The Soviet Union also signed the BWC but then deceitfully enlarged its efforts. The scope of the Soviet program was astonishing. The Soviets manufactured several hundred tons of anthrax, and an accidental release in 1979 killed 66 people. The former USSR also made thousands of pounds of smallpox and plague, and in 1989, they supposedly managed to weaponize Marburg virus, which causes a deadly hemorrhagic fever similar to Ebola. These allegations remain unconfirmed. Finally, under President Boris Yeltsin in 1992, Russia ended its biological weapons program, but the fate of the weapons stockpiles remains unclear.

Today, biological warfare is feared less from nations and more from terrorist groups or lone wolves. But there is disagreement over just how much of a threat this poses. Many believe that terrorists would be incapable of carrying out an effective, large-scale biological attack. For instance, in 1984, the Rajneesh cult gave food poisoning to about 750 citizens of a small Oregon town for political purposes by adding Salmonella to salad bars. Aum Shinrikyo, a Japanese cult that perpetrated a sarin gas attack in the Tokyo subway in 1995, experimented with biological weapons, but to no avail. The 2001 U.S. anthrax attack (discussed in more detail in the following section) killed only 5 people. Skeptics point to incidents like these as evidence that bioterrorists are incapable of inflicting widespread damage. Other analysts disagree ().

Bioterrorism

Some experts believe that a large-scale bioterrorist attack will occur in the not-too-distant future, but others say bioterrorism is an ineffective tactic. Attack methods include contamination of food and water supplies (A), bombs (B), using the mail (C), contamination of water (F), spraying aerosolized agents (E, G), direct injection (D), or the infiltration of suicide infectees (H).

From Osterbauer PJ, Dobbs MR (2005). Neurobiological weapons. Neurol Clin 23, 599621.

Some biological agents, such as anthrax, require little expertise to grow or weaponize. With microbiological information universally available on the Internet, some experts believe that it is just a matter of time before a large bioterrorist attack occurs. A small crop duster airplane loaded with anthrax and flown over a major city could potentially kill hundreds of thousands if not millions of people. Exacerbating the problem is the fact that a 2010 federal commission found the United States to be completely unprepared in the event of a bioterrorist attack.

During the Vietnam War, the Viet-Cong guerillas dug camouflaged pits as booby traps. Inside, they often positioned sharpened bamboo stakes or splinters smeared with human waste. Although it was possible to contract a nasty infection from these, the main purpose was psychological. The tactic worked. The response of American troops was to alter their movements in a way that was disproportionate to the actual threat. An analogous scenario played out following the 2001 anthrax attack in the United States in which there was a colossal disruption of postal services and massive new expenses. Yet, only 5 people died in the attack. (Compare that to the roughly 62,000 Americans who died from influenza and pneumonia that same year.)

Both of these examples serve to underscore two important points: First, biological warfare will almost certainly have a far greater psychological impact than direct impact; and second, protective measures against biological attacks are costly and inconvenient. For instance, giving soldiers vaccines against all possible biological agents would be impractical and possibly dangerous if they have been developed under emergency conditions without thorough testing. Also, vaccines have side effects. Consider the anthrax vaccine used by the U.S. army that was approved in 1971. Vaccination requires six inoculations plus annual boosters. It produces swelling and irritation at the site of injection in 5% to 8% and severe local reactions in about 1% of those inoculated, although major systemic reactions are rare. Although it works against natural exposure, it is uncertain whether it would protect against a concentrated aerosol of anthrax spores.

Or consider the smallpox vaccine (). For every 1 million people vaccinated, the CDC estimates that 1,000 people will have serious side effects, 14 to 52 people will have life-threatening side effects, and 1 or 2 people will die. Is it worth vaccinating an entire army or nationknowing ahead of time that many will die or become sickto protect them against an unlikely threat? From an epidemiological standpoint, the answer is clearly no, which explains why citizens do not receive smallpox vaccinations. The general rule in public health is to vaccinate only if the risk of the disease is greater than the risk of vaccination.

Smallpox Vaccine

How the normal skin reaction to smallpox vaccination progresses in two patients.

Source: Centers for Disease Control and Prevention.

Even if widespread vaccination is forgone in favor of other measures, such as protective clothing or respirators, there is still the financial cost. A nation that invests heavily in bioterrorism preparedness could have spent that money in more productive ways. Dressing troops in special clothing and equipment could promote heat stress or make them easier targets for conventional weaponry. Additionally, medications taken prophylactically to prevent infectious diseases are expensive, rarely 100% effective, and may have long-term negative health consequences.

Biological warfare has been practised since ancient times. However, it has only rarely been effective. Naturally occurring infectious diseases have killed far more people. Still, bioterrorism may pose a serious threat today. Even if an attack kills relatively few people, the psychological impact could be enormous.

Biological warfare is used to kill, injure, and psychologically intimidate enemies. Many naturally occurring diseases are effective agents, although it might be possible to improve them with genetic engineering, as discussed later.

What makes for an effective biological agent? Five major factors need to be considered.

Preparation. Some pathogenic microorganisms are relatively easy to grow in culture, whereas others are extremely difficult or expensive to manufacture in sizeable quantities. Viruses, for instance, can grow only inside host cells, and culturing animal cells is more complex than growing bacteria. Similarly, pathogenic eukaryotes such as Plasmodium (malaria) or Entamoeba (amoebic dysentery) are difficult to culture on a large scale, although some pathogenic fungi can be grown relatively easily. Bacteria are generally the easiest to manufacture on a large scale, but most bacterial infections can be cured with antibiotics. Viruses, though more difficult to grow, have the advantage of being largely incurable despite a small and growing range of specific antiviral agents.

Another factor is weaponization. The disease agent must be prepared in a manner that facilitates storage and dispersal. Because bacterial cells and spores tend to clump together spontaneously, they must be weaponized to allow effective delivery.

Dispersal. Dispersal is a particular challenge for biological weapons. The most likely option would be some form of airborne delivery. However, if applied outdoors, this tactic would be vulnerable to the whims of the weather. Not only is a pleasant breeze required, but also the wind needs to blow in the right direction! During the 1950s, the British government conducted field tests with harmless bacteria. When the wind blew them over farmland, many of the airborne bacteria survived the trip and reached the ground alive. In contrast, when the wind blew the bacteria over industrial areas, especially oil refineries or similar installations, the airborne bacteria were almost all killed. Ironically, air pollution may help protect an urban population from a bioterrorist attack. To aerosolize a biological agent for an indoor attack, a buildings ventilation system or a medical nebulizer could be used ().

Nebulizer

A medical nebulizer could be used to aerosolize a biological agent for an indoor attack. Two general types of nebulizer are in use: the jet nebulizer that uses pressurized gas and the ultrasonic nebulizer that relies on ultrasonic vibrations.

Persistence. Persistence may be the most difficult factor to consider. On the one hand, the biological agent should be able to persist in storage until it is ready to be deployed, and it must survive long enough in the environment to infect the enemy. On the other hand, it should not persist so long that the victor is unable to invade and conquer enemy territory.

Many infectious agents are sensitive to desiccation and become inactive if exposed to air for significant periods of time. Moreover, natural UV radiation from the sun also inactivates many bacteria and viruses. Thus, most biological warfare agents must be protected from this open air factor before use and then dispersed as rapidly as possible. For instance, many viruses last only a few days, if even that, outside their animal or human hosts. (However, infections due to these agents may persist among the local population.)

Anthrax is often chosen as a biological weapon because of its ability to persist for long periods of time. The bacterium Bacillus anthracis, which causes the disease, spreads by forming spores that are tough and difficult to destroy (). When suitable conditions return, for example, inside the lungs of a human, the spores germinate and resume growth as normal bacterial cells, releasing life-threatening toxins.

Spores of Bacillus anthracis

Anthrax spores, which are seen here forming inside bacterial cells, are difficult to destroy and last a very long time.

From Ringertz SH, etal. (2000). Injectional anthrax in a heroin skin-popper. Lancet356, 15741575.

Incubation time. A problem unique to biological warfare, compared to conventional weapons, is that death or incapacitation from infectious disease is a relatively slow process. Even the most virulent pathogens, such as Ebola virus or pneumonic plague, can take a few days to kill. An infected enemy would therefore still be capable of fighting for a significant period. Yet, a biological agent that kills too quickly may not have time to spread among the enemy population.

High-containment laboratories. High-containment laboratories are needed for research and development of infectious biological agents. Biological containment is rated on a scale with four levels. Biosafety level 1 (BSL-1) microbes are mostly harmless, such as nonpathogenic E. coli. BSL-2 organisms are human pathogens, but not easily transmitted in the laboratory, such as Salmonella. BSL-3 organisms are dangerous and often can be transmitted via aerosol, such as tuberculosis and SARS. BSL-4 laboratories are for extremely dangerous and easily transmissible microbes, such as Ebola.

Read the rest here:

Biological Warfare: Infectious Disease and Bioterrorism

Photo illustration by The Globe and Mail

Norman Doidge, MD, is a psychiatrist, psychoanalyst and author of The Brain That Changes Itself. He is executive director of Health and the Greater Good.

Just before Christmas, without much fanfare, Ontario became the first province to approve fluvoxamine a decades-old drug few had heard of for the early treatment of COVID-19. The December 20 announcement, coming at a time when Canadians were preoccupied with Omicron, and the fear hospitals would soon be overwhelmed, received hardly any news coverage.

Fluvoxamine is a repurposed drug, and comes from what might seem like a most unlikely source psychiatry. It is an antidepressant used most commonly to treat obsessive-compulsive disorder. The drug has had two randomized control trials, or RCTs (the highest level of evidence) and four observational studies showing it keeps people with COVID out of hospital, from requiring intubation, and helps prevent death. The discovery of its anti-COVID properties came after impressive sleuthing in France and the United States. Then a partnership co-led by a team of Canadians conducted the large randomized trial that proved what it could do.

This is a good news story, about our public-health officials doing something right, and showing flexibility, at a time when we are learning the limits of our vaccines and accompanying strategies. Reappraisal is in the air, driven by everyones two-year-experience with the pandemic scientists included.

Philanthropist Bill Gates.Arnd Wiegmann/Reuters

Consider how things appeared in April, 2020, when Bill Gates, whose foundation is the largest private contributor to the World Health Organization, said: The ultimate solution, the only thing that really lets us go back completely to normal and feel good is to create a vaccine. His only meant, that in practice, our chief hope and focus in research, policy, in the media, and even emotionally, for many became the vaccines. Mr. Gates articulated what became our master narrative: Public health would stop the spread with extemporizing measures such as lockdowns, discouraging social functions and travel, and closing schools and businesses until the vaccines arrived, all of which would protect us until we achieved vaccine-induced herd immunity everywhere, which, we were told, would eliminate the virus. We put our faith in the vaccines, while other approaches such as drugs for early treatment, or a role for our natural immunity, or lowering our personal risk factors, for instance got comparatively less attention.

Key individuals predicted half promised, really wed be done with COVID, at least in the West, by the summer of 2021. In February, 2021, Pfizers CEO, Albert Bourla, said the vaccine was still offering strong protection at the six-month mark and indicators right now are telling us that there is a protection against the transmission of the disease. That April, Dr. Ugur Sahin, the CEO of BioNTech (which developed the vaccine for Pfizer), told reporters, Europe will reach herd immunity in July, latest by August. It wasnt a tough sell. Who would not want it to be true? Having no pandemic experience, we took them at their word. Politicians fostered the idea that our proper aim for handling COVID would be to eliminate it everywhere, as Prime Minister Justin Trudeau said. Early treatment doesnt promise that, though it might lower death rates. Eradication had more psychological appeal: lets get it out of our lives forever.

Yet, in dismal December, 2021, two years in, with cases soon to reach record highs, and another lockdown looming and vaccines waning, it wasnt working out that way. Perhaps if we hadnt been so focused on one tool things might have gone differently. And perhaps if certain voices hadnt been silenced, and others handed a megaphone, our pandemic tool kit, and mindset, would have been different too.

People applaud health-care workers from their balconies on the second day of France's first pandemic-related lockdown in Paris, 2020. Paris is home to a psychiatric hospital where COVID-19 questions raised theories about the antiviral properties of antidepressants.THOMAS COEX/AFP via Getty Images

Early in the pandemic, at the Sainte-Anne site of the Parisian mental hospital, Psychiatrie & Neurosciences, something mysterious occurred. The staff started contracting COVID in high numbers, but their patients, gravely mentally ill, did not. Three staff got COVID for every patient, despite the patients having more risk factors, such as being overweight, or having cardiovascular disease.

Someone wondered, could it be that the patients psychiatric medications were protecting them? The staff homed in on chlorpromazine, a common antipsychotic medication, and learned it had antiviral properties against SARS-Cov-1 and MERS-CoV (the predecessors to SARS-CoV-2). In a May, 2020, publication, they proposed repurposing it for treating COVID-19.

French psychiatrists and scientists next did a multicentre study, looking at 7,230 patients who had been hospitalized in Paris for severe COVID-19. Coincidentally, 300 of the patients were taking antidepressants. The data showed that those on Selective Serotonin Uptake Inhibitors (SSRI) a kind of antidepressant were less likely to require intubation or die. Not all SSRIs worked equally, but those that did reduced major inflammatory problems (the COVID cytokine storm that often kills). Lab research showed that the SSRI fluvoxamine had an antiviral effect, and a salutary effect on blood platelets that might protect patients from blood clots.

A sample of SARS-CoV-2, the virus that causes COVID-19.NIAID-RML via AP

Meanwhile, back in the U.S., in parallel process, a child psychiatrist, Dr. Angela Reirson, caught COVID in early 2020. Sick at home, she started doing research. She recalled a study on mice she had read the previous year. The mice had sepsis a dangerous response to infection that can kill. Something akin to sepsis can happen in serious COVID. In the 2019 study, mice with sepsis were given fluvoxamine, which halted the condition. So, in March, 2020, Dr. Reirson contacted another psychiatrist, Eric Lenze, a colleague of hers at Washington University in St. Louis. Dr. Lenze was a specialist in repurposing drugs. Realizing fluvoxamine had a great safety record, he launched its first small randomized control trial of COVID patients. Not one of the 80 volunteers who got fluvoxamine deteriorated or got COVID lung damage, whereas 8 per cent of the 72 who got a placebo did deteriorate. The findings were published in JAMA in November, 2020.

Next came the Together Trial, the worlds largest placebo study of COVID drugs, co-led by McMaster researcher Edward Mills and Brazilian physician Gilmar Reis. To do large trials you need a lot of cases, and Brazil had two million. The study was published Oct. 27, 2021, in the Lancet. It studied about 1,500 unvaccinated patients with COVID-19 who also had another serious illness and were at high risk for hospitalization. Half were given fluvoxamine, half a placebo. In those who took the fluvoxamine as prescribed it reduced the odds of hospitalization or emergency care by 66 per cent and death by 90 per cent.

Ontario Premier Doug Ford and government officials give a news conference in 2020 about the pandemic.Nathan Denette/The Canadian Press

The Ontario Science Table noticed these findings and on Dec. 20 it put fluvoxamine in the guidelines, for doctors to prescribe on an outpatient basis if needed, recognizing the need for outpatient treatment options with a reasonable safety profile during an anticipated spike in COVID-19 cases due to the Omicron variant.

That was significant, because early treatment of COVID measures we can take to avoid symptomatic cases from worsening, requiring hospitalization has been so minimal. In Ontario, treatment includes monoclonal antibodies (now only one works with Omicron) for specific people at risk, and steroids. Otherwise outpatients were told to rest, drink fluids, and hope their immune system would handle the virus.

True, there was much talk of brand-new, non-repurposed drugs for early treatment. Pfizers Paxlovid, just approved by Health Canada on Monday, is very new. But repurposed drugs have a track record, and thus often a safety advantage. And the generic ones are cheap. Fluvoxamine costs about $15 for a course of treatment. Repurposed drugs are used by poorer countries that cant afford vaccines or expensive early treatment drugs such as Paxlovid ($500) or Molnupiravir (US$700 and not yet approved in Canada).

So why hasnt treatment focused more on repurposed drugs?

First, because the master narrative, once it took hold, directed our attention away from this possibility. Second, in North America, the first repurposed drug that came to public attention was hydroxychloroquine. When it was endorsed by then-president Donald Trump it became highly politicized. Peoples opinions about it often had more to do with their political affiliation than whether they had read any of the (now) 303 studies. Third, agencies that regulate drugs, such as the U.S. Food and Drug Administration and Health Canada, mandate that any drug they evaluate have a sponsor, usually a drug company agreeing to assume liabilities for the drug. Its an extremely expensive process. If an old, cheap generic drug shows promise for repurposing, it still needs a sponsor to get approved for that. But drug companies have no financial incentive to do so. So usually there are no sponsors, and the drugs languish.

A person walks past a mural honouring health-care workers in Toronto. Imagery of war and communal struggle became a big part of the COVID-19 narrative: This mural, for instance, uses the pose and bandana of Rosie the Riveter, a Second World War icon.Nathan Denette/The Canadian Press

Of all the reasons that we didnt focus on repurposed drugs, I would argue, the master narrative was the most important, because of the way it organized so many peoples thoughts, attention and emotions.

The narrative would not have been nearly as problematic had it not been so tied into something else: the military metaphor that has defined our COVID experience from the beginning. This master narrative was our battle plan and this was a war to eradicate the enemy virus.

This military metaphor seems second nature in medicine. We are always in a war against cancer, or combatting heart disease, Alzheimers, and AIDS. But this way of thinking only became common in medicine several hundred years ago, after the philosopher Francis Bacon argued the goal of science should change from what it had been the study of nature to the very practical conquest of nature. Soon physicians were speaking of conquering disease, with magic bullets. We increasingly left behind the original Hippocratic mindset of medicine as an extension of nature, which involved working with it, as an ally, wherever possible not to conquer, but to heal, often with the help of the patients own healing capacities.

Scientists were to be soldiers in this new army. And here a problem arose. Despite some similarities, science (and medicine) is really best not construed as warfare and the kind of virtues that may suit soldiers in an army (following an authority without questioning), are vices in science, which is a mode of critical inquiry. Modern science arose because the world was filled with too many dogmas and orthodoxies that were not to be questioned. That is why the motto of the Royal Society, the first national scientific institution, became Nullias in verba, Take Nobodys Word For It. Its the role of scientists, as Nobel Prize-winning physicist Richard Feynman said, to question the experts, and fellow scientists, and debate each experimenters conclusions, which are based on human judgments and interpretations of data, until there is certainty the conclusion can resist all onslaughts.

Reappraisal of any prevailing narrative requires taking in new insights, which, by definition, arise from a minority viewpoint. When a military metaphor sweeps through a society or a bureaucracy beset by fear, all-or-nothing, you-are-with-us-or-against-us thinking follows. We become more prone to see someone who doesnt go along with the majority view including scientists who spot problems with the reigning narrative as putting the rest of us at risk, and a traitor, rather than as someone doing their job. They are attacked, censored or self-censor to survive. In war, you shut up and follow orders, or get court-martialed.

We are especially suspicious of other people during contagion, because our brains are fired up by a primitive circuit that protects us by making us obsessively preoccupied with the purity of those around us. Will this person get me sick? It even fires if we think their actions, or even policy proposals might be risky. The circuit, called the behavioural immune system, causes us to fear, loathe and feel rage toward the impure germ bearer. It results in many false alarms (think of someone driving alone with a mask on). Its one reason debates about vaccines are emotionally radioactive. Some vaccinated people feel all the unvaccinated bear germs, while some unvaccinated people feel vaccine may put germs or toxins in their bodies.

A nurse administers a COVID-19 vaccine in Orange, Calif., this past summer.Jae C. Hong/The Associated Press

This past summer, as news broke that there were breakthrough infections and vaccine protection against infection was waning, the North American media began to advise us to lower our expectations for them: Vaccines Can Only Do So Much, read a headline in The Washington Post. Many readers were caught completely off guard. In part they were surprised, because the censorship of scientists who held dissenting views and had been warning this might happen was much more widespread than many are aware of.

According to an Amnesty International report published in October, censorship and harassment of health professionals, and others, has been a problem across the world, during the pandemic. Most singled out are those who express critical opinions of their governments policies (e.g. restrictions of movement, lockdown, or criticisms of government dispensing with civil liberties).

The censors justified these actions as simply banning misinformation and prevent[ing] panic. In North America people were not imprisoned, but many brilliant scientists and physicians with proper credentials from places such as Harvard, Oxford and Stanford, were under fire. Physicians were vilified for questioning government policies on lockdowns, masks, aspects of vaccines, mitigation or unproven treatments the very things that were, of course, the subject of serious continuing scientific debate. In some jurisdictions in North America physicians are threatened by their regulating boards with suspension or revocation of their medical licenses for spreading misinformation, forcing some doctors to have to choose between what they rightly or wrongly see as their patients best interests, and their own livelihood. But as the Amnesty report states, Winning the battle against the virus includes not just government led actions and top-down diktats, but also bottom-up approaches which can only come about if the rights to freedom of expression and access to information are fully enabled.

Warning signs are seen at a COVID-19 testing lab in Ingelheim, Germany.Kai Pfaffenbach/Reuters

There were snake oil claims on the internet, yes, but generally when scientists and health care workers were party to these quarrels, it was because there was a scientific debate. In such a case, to accuse ones opponent of spreading misinformation is to pre-emptively ascribe to oneself an unjustified certainty and to ones opponent bad faith. At times no one really knew what was more harmful e.g. keeping children out of school, or sending them in. There was incorrect information aplenty in our novel situation, and that included some spread by officials who flip-flopped multiple times on masks, or who, claiming to follow the science, differed with officials in similar jurisdictions, based on changing data.

This, in medicine, is called the problem of medical reversal. An approach thought to be helpful is proven to be harmful, and vice versa. Sometimes two studies can contradict each other even on the same day. Physician-scientist Vinayak Prasad, of UC San Francisco, argues it is the most important problem facing medicine today. The problem of medical reversals didnt disappear the day the virus landed on our shores. We had not only a virus problem, but a medical reversal problem.

The medical boards were in an unusual situation, torn between once-cherished traditions of scientific debate, and the atmosphere of crisis and their wish to do their part in the war. After all, it is vital that public health, and its officials, in a crisis, be able to convey consistent messages as they ask citizens to change their behaviours, and undergo various privations. But if those messages are to be persuasive, and the requests for such privations scientifically arguable and legitimate, the actions must be based on a full, open, unhampered scientific process solid enough to withstand scientific criticism and debate. Why else should the public go along? Censorship, by giving the public the false impression there are no medical controversies, undermines the censors own claim to speak in the name of science and public safety. Ironically, it guarantees the public will be left misinformed.

People light a display of about 1,500 candles in memory of COVID-19 victims in Greifswald, Germany. After the original virus spread around the world, more contagious variants like Delta and Omicron superseded it, and researchers scrambled to understand how effective vaccines would be against them.Stefan Sauer/dpa via AP

The authors of the master narrative tend to say the main reason that things have not gone as they predicted is because variants arose. But if anything could have been predicted, it is that viruses mutate. Columbia virologist Vincent Racaniello described how fellow scientists were worried that the new mRNA technology, by focusing on only a small portion of the virus, the spike protein, would make it easy for the virus to get around or escape the vaccine through mutations. Thats partly why, he said in May, all the variants are arising now, because we have only the spike epitopes in there. That view didnt get much of a hearing.

It wasnt just the variants role in declining vaccine efficacy that surprised people. There was something about the execution of the original clinical trials, conducted by the pharma companies themselves, on their own products that also led to this surprise. Its worth going back for a moment and looking at how the problem unfolded.

In December, 2020, the new mRNA vaccines were rolled out, and were, according to the randomized clinical trials, 95 per cent (Pfizer) and 94.5 per cent (Moderna) efficacious in stopping infection. Physician-scientist Eric Topol, head of Scripps Labs, said these vaccines will go down in history as one of science and medical researchs greatest achievements.

But by the time summer 2021 arrived, real world experience contradicted Mr. Bourlas and Dr. Sahins claims of potency at six months, no transmission by the vaccinated, and imminent herd immunity. Pfizers Mr. Bourla, in his February interview, had called Israel the worlds lab, because it was vaccinated with the Pfizer extensively and several months ahead of other countries, giving the world a glimpse of its future. But when Israeli public health released its six-month data, they showed that vaccine effectiveness had dropped to 39 per cent, and Delta was surging. (The FDA had originally said it would not approve a vaccine less than 50-per-cent effective.) A Mayo clinic study showed that after six months, protection granted by the two Pfizer doses dropped from the original 95 per cent to 42 per cent. Another Israeli study showed it had dropped to 16 per cent. That huge discrepancy couldnt be attributed just to the new variant, Delta, because protection was already fading at five months for the earlier variants too.

Pfizer doses are prepared at a temporary vaccination centre in London.DANIEL LEAL/AFP via Getty Images

So why such a discrepancy? The original studies were clinical trials. The Pfizer study followed about 38,000 people without COVID who were divided in two groups half got the vaccine, and half a placebo. The investigators asked the question: could the vaccines prevent symptomatic cases of COVID-19? But, as Peter Doshi, senior editor at the British Medical Journal, warned, None of the trials currently under way are designed to detect a reduction in any serious outcome such as hospital admissions, use of intensive care, or deaths. He explained that, Because most people with symptomatic COVID-19 experience only mild symptoms, even trials involving 30,000 or more patients would turn up relatively few cases of severe disease. Susanne Hodgson of the University of Oxford agreed: The current [randomized control trials] that are ongoing are not powered to assess efficacy against hospital admission and death.

The Moderna report to the FDA on Dec. 17, 2020, confirmed there were no deaths due to COVID-19 at the time of the interim analysis to enable an assessment of vaccine efficacy against death due to COVID-19. Moderna followed about 30,000 people. When asked by the British Medical Journal, why the trial had not been designed to assess if the vaccine could prevent hospitalization and death, Moderna answered: You would need a trial that is either 5 or 10 times larger or youd need a trial that is 5-10 times longer to collect those events. In the Pfizer study of 38,000 people, not a single person in the placebo or the vaccine group died of COVID. By publication date, only one person had died of COVID in the Moderna study. To state it clearly: One person out of about 70,000 in the combined studies of Pfizer and Moderna actually died of COVID. In the real world, at the time, about 60 per cent of COVID deaths were in people over 75 years of age. But only 4.4 per cent of that age group were in the Pfizer study. The sample chosen was not appropriate to answer the publics most pressing question: Could the vaccines save lives?

And how long had the Moderna and Pfizer vaccines been studied, when released for mass use in the winter of 2021? Two months.

These studies looked at the vaccines at their most potent, in a low risk population, and gave us a flattering snapshot. But COVID-19 is a movie.

In contrast, the Mayo study, and the Israeli data, were looking at data over a more realistic time course to test effectiveness.

The waning created a crisis in Israel. Dr. Sharon Alroy-Preis, director of Israels Public Health Services, told the FDA Vaccine Advisory Committee on boosters, why the country became the first to roll out a third shot: What we saw prior to our booster campaign was that 60 per cent of people in severe and critical condition were immunized, doubly immunized, fully vaccinated and as I said, 45 per cent of the people who died in the fourth wave were doubly vaccinated. Most breakthrough infections are indeed mild, but she was describing life-threatening ones in the vaccinated. As breakthrough infections became commonplace throughout the world, noted Harvard epidemiologist Michael Mina said, the message that this is only an epidemic of the unvaccinated is falling flat.

A newly vaccinated patient takes a selfie with the nurse at the Sheba Medical Center in Ramat Gan, Israel.Tsafrir Abayov/The Associated Press

As for Dr. Sahins claim that we were on the brink of vaccine-induced herd immunity and being rid of COVID altogether, experts such as Larry Brilliant (who had helped eradicate smallpox with vaccines) and five other scientists wrote in Foreign Affairs in July, 2021, Among humans, global herd immunity, once promoted as a singular solution, is unreachable. They explained in precise detail why COVID-19 was unlike smallpox, and it could not be eradicated, such as the fact it is growing in a dozen animal species already. If we are forced to choose a vaccine that gives only one year of protection, said Dr. Brilliant, then we are doomed to have COVID become endemic, an infection that is always with us That vaccines would get us to a vaccine-based herd immunity had been one of the two main scientific justifications for vaccine mandates. Now it was gone.

The other justification for mandates had been that the vaccinated dont transmit the virus.

Most of us had presumed, when we got our first doses, that we couldnt pass the virus on to others. Public statements repeatedly praised people for doing your part to stop the spread. But in August, CDC director Rochelle Walensky told CNN, when asked why the vaccinated must wear masks, Our vaccines are working exceptionally well. They continue to work well for Delta; with regard to severe illness and death, they prevent it. But what they cant do any more is prevent transmission.

In fact, the original randomized clinical trials for Pfizer and Moderna did not test if the vaccines stop transmission. Now our best hope was that the vaccinated might transmit less than the unvaccinated. Several studies could be interpreted as showing this. But others found the vaccinated likely had equal transmission. One study, conducted in a prison, concluded that the vaccinated prisoners had as much transmission potential as the unvaccinated prisoners, adding, clinicians and public health practitioners should consider vaccinated persons who become infected with SARS-CoV-2 to be no less infectious than unvaccinated persons. Dr. Cyrille Cohen, head of the immunotherapy lab at Bar-Ilan University, and adviser to the Israeli government on vaccine trials, said that with respect to transmission with Omicron, we dont see virtually any difference between people vaccinated and nonvaccinated, adding both get infected with the virus, more or less at the same pace. The rancour that we, the vaccinated, are increasingly directing against the unvaccinated, fuels itself by remaining wilfully oblivious of this later painful truth: we too spread, to ourselves, and to the unvaccinated, as they to us and each other.

The master narrative was silent about natural immunity and its relationship to vaccination status. Many scientist-physicians, from prominent universities in the U.S. with specialties in public health, argue that one can be for the use of the COVID vaccine, but also against mandating it for unvaccinated people who are already immune.

These scientists maintain what matters is not whether a person is vaccinated or not, but whether they are immune or not. Thus, the European Union recognizes natural immunity in its Digital COVID Certificate, which is in lieu of a vaccine passport, and is not limited to proof of vaccination. You could get a passport and travel if you have been vaccinated or if you have recovered from COVID-19 or if you have a recent test saying you are negative. For air and train travel, Canada has also acknowledged recovery from COVID as an exemption, if one presents a recent negative test but, inconsistently, natural immunity is not recognized in most other quasi-mandate situations here. Such scientists think it irrational that government calls for mass mandates are escalating just as the core original justifications for them that the vaccinated dont transmit the virus, and the vaccine will bring us to herd immunity have collapsed.

A mobile phone shows a European Union digital vaccine certificate.OLIVIER MORIN/AFP via Getty Images

Those unvaccinated people who were exposed to the virus, make up a huge number. For instance, in the U.S., according to a Columbia University study, by Jan. 31, 2021 (before many vaccines had been given) 10 months into the pandemic, 120 million Americans had natural immunity. Now, 12 months later, with the much more infectious Delta and Omicron variants, it is likely a highly significant majority of the unvaccinated now have natural immunity.

A recent pivotal study from South Africa not yet peer reviewed shows that in poor communities, where there was modest vaccination (39 per cent of adults), more than 70 per cent of people had already been exposed to the virus in previous waves, going into Omicron. The twice vaccinated had more protection than those who were unvaccinated and never had COVID. But the unvaccinated who had COVID and recovered had more protection from severe disease than the vaccinated. One Israeli study showed that the unvaccinated who recovered from COVID have 27 times less risk of reinfection compared with the vaccinated, and nine times less risk of hospitalization.

In a recent Munk Debate, Harvards Dr. Martin Kulldorff, an epidemiologist and vaccine safety specialist, argued that mandating vaccines for the naturally immune actually creates problems because when people see that they are forced to take a vaccine that they dont need because they already are immune, that causes a lot of distrust in public health. And we have seen during this last year and a half that all the hard work weve done over many decades to build trust in vaccines is now disappearing because were making these mandates that make no sense from a scientific or public health perspective.

Public health moves at the speed of trust, as physician Rishi Manchanda wrote. Of the two main approaches to public health the participatory, and the coercive the coercive usually makes enemies, and tears society apart. Its like a hare: it has quick victories. The participatory approach, is a tortoise; when it fails to persuade, instead of blaming those it serves, it asks, as a scientist might, where have I fallen short, and aims to do better.

People are seen through a frame that reads 'third dose reinforcement' at a mass vaccination clinic for people over 60, in Mexico City. Third doses proved very effective against Delta, and are still important at preventing hospitalization and death in Omicron cases.Luis Cortes/Reuters

Israels third booster helped beat back the Delta wave. Then Omicron hit. On Dec. 19, The New York Times headlined an article, Most of the Worlds Vaccines Likely Wont Prevent Infection from Omicron. Thankfully, the vaccines still seemed like they would prevent those infections from becoming severe the key point. A Kaiser study showed that two doses, over time, fell to zero efficacy against Omicron. Then Danish data showed that a booster offered protection against severe disease, but only to those over 70 years. But would boosters wane too? The U.K. Health Security Agency study showed the protection from the Pfizer booster (third shot) had dropped to 45-per-cent coverage at only 10 weeks.

Then on Jan. 1, 2022, a study of vaccine effectiveness against getting infection in Ontario not yet peer-reviewed showed a trend that had already shown up in Denmark. It examined provincial data and was authored by members of Public Health Ontario, ICES, the Dalla Lana School of Public Health, UHN, and other major Ontario university and health programs.

They found two things of note. The first was that VE [vaccine effectiveness against getting infection] against Omicron was only 37% > 7 days following a third dose. That doesnt mean that those in the other 63 per cent who did get the infection might not have got some protection from severe infection, but the authors were unable to measure protection from severity from the data that had.

The second finding was more dramatic:, We also observed negative VE against Omicron among those who had received 2 doses compared to unvaccinated individuals. Translation: Negative VE means that the vaccinated got more infections than the unvaccinated.

That negative finding they noted, had already been observed elsewhere. In the Danish study, there was no significant protection against Omicron infection beyond 31 days after the second dose of the Pfizer. The Danes also found significant negative VE estimates 91-150 days after the second dose. The Danish study showed those vaccinated with the Pfizer had a 76.5 per cent greater chance of getting infected than unvaccinated people. With the Moderna, the vaccinated had a 36.7 per cent greater chance of getting infected than the unvaccinated after 90 days.

The authors discuss how negative vaccine effectiveness finding might arise. It may not mean that the vaccine actually decreases the persons immunity. There could be confounding factors. One possible explanation they raise is that in Ontario, a vaccine certificate system was introduced in the fall of 2021, and only those who had two doses could travel by air, rail, go to bars, gyms, etc., and so they may have had more social contacts than the unvaccinated who were shut in. But even if true it would still mean that the vaccines are not protecting us as much as wed like, which is nothing to celebrate.

Another possible explanation the authors raise is the possibility that antigenic imprinting could impact the immune response to Omicron. It had been observed in the past that the immune system is highly influenced by the first exposure to a microbe (antigen) that it encounters. Its called original antigenic sin. When a second exposure occurs, to a similar but not identical microbe, the immune system reacts as though it is targeting the original microbe. But the new invader isnt the original, and so the immune system is actually less effective in dealing with this. In essence the immune system is weakened for a microbe too similar to its first similar exposure. This phenomenon was originally described as occurring in influenza on occasion. This is only a theoretical possibility here, not proven for COVID, but now a matter of scientific discussion. The negative vaccine efficacy has since shown up in Iceland, and the U.K. as well. The Ontario authors are to be applauded for thoughtfully laying out some possibilities to think through, so as to determine what might be the cause.

A COVID-19 mural in Vancouver urges people not to worry.Jonathan Hayward/The Canadian Press

Weve had so many mood swings. We had been through a year of defining vaccine success as eliminating the virus, then as lowering infection and stopping the spread, to discovering there were breakthrough infections and transmission to other people, but that they still lowered our risk of hospitalization and death thats worth a lot though not always in the most vulnerable. In the West, many have responded to waning vaccine protection with time by doubling down, proposing ever more boosters. What is the scientific evidence for frequent boosters? Thats a matter of scientific debate.

The original Pfizer study submitted to the FDA booster meeting was shockingly tiny a mere 306 patients were given the section, and they had been followed for only a month, and, again, most of the subjects were younger than those at risk (18-55). Pfizer wanted it on that basis rolled out to millions. That was enough to get FDA officials asking hard questions. Crucially, nobody had studied the long-term effects of multiple mRNA boosters there hasnt been time. The FDA refused Pfizers recommendation to approve the booster for the entire U.S. population, with the top two heads of its Vaccine Research and Review Committee, Dr. Marion Gruber, (the head, and former acting chief scientist at the FDA), and Philip Krause (deputy director), and international colleagues, writing in the Lancet:

There could be risks if boosters are widely introduced too soon, or too frequently, especially with vaccines that can have immune-mediated side-effects (such as myocarditis, which is more common after the second dose of some mRNA vaccines, or Guillain-Barre syndrome, which has been associated with adenovirus-vectored COVID-19 vaccines [like the AstraZeneca or Johnson & Johnson]). If unnecessary boosting causes significant adverse reactions, there could be implications for vaccine acceptance that go beyond COVID-19 vaccines.

When the head scientists of the FDA Vaccine Review committee and colleagues raise such questions, it cant be dismissed as fringe fear-mongering. Shortly after, Dr. Gruber and Dr. Krause quit the FDA because the Biden administration was putting pressure on them to approve boosters before the vaccine committee had even met. The standard practice for approval is for the agencies to convene panels of outside experts to review the data openly, weigh risks and benefits, and take votes. But in December, the FDA and CDC leadership three times took the extraordinary step of not convening those experts for key booster meetings, in essence going around them because committee members had warned that the science supporting boosters for younger people was weak to non-existent, and they had safety concerns. Dr. Paul Offit, perhaps the most high profile provaccine physician-scientist in America, who was on the FDA panel told The Atlantic, he wouldnt advise a booster for his healthy son in his 20s, or a healthy male in his teens, because the risks of myocarditis (higher in males) outweigh the benefits. Dr. Offit rejects the CDCs and FDAs all-or-nothing approach to childrens vaccination.

Vinayak Prasad, the UCSF epidemiologist, says if you put the Danish, Ontario, U.S., and Kaiser studies about Omicron together, its time to face the reality about the vaccines.

Two doses of vaccine does nothing or almost nothing to stop symptomatic SARS-CoV-2, he says. Three doses barely does anything, and the effect will likely attenuate over time. He says, Booster mandates make no sense. Boosting should happen in populations where it further reduces severe disease and death a.k.a. older and vulnerable people.

With Omicron surging, Israeli public health met to discuss a fourth booster. The New York Times reported that some scientists on the Israeli government booster advisory panel, warned that the plan could backfire, because too many shots might cause a sort of immune system fatigue, compromising the bodys ability to fight the coronavirus. This immune system fatigue was, perhaps, not inconsistent with negative vaccine efficacy. Its not proven, but the fact that public-health officials were voicing such concerns shows that the doubling down strategy on boosters is being reappraised on safety lines. The EU, in a reversal, has just come out against regular, continuing boosters, saying they are afraid it will weaken the immune system.

People at a private nursing home dance before getting their fourth vaccine doses in Netanya, Israel. Israelis are eligible to get Pfizer as a fourth dose if they're over 60, immunocompromised or work in health care.Ariel Schalit/The Associated Press

From the very beginning, some scientists have wondered whether our goal the conquest and eradication of the virus was the right one. As Michael Cordingley reminds us in his book Viruses, in each millilitre of seawater there are about 10 to 100 million viruses, and this was a respiratory virus, free-floating, all around us, likely to shape shift and mutate. Could we, conquerors of nature, really overwhelm an enemy so omnipresent and agile?

As we have seen, as part of the reappraisal, theres an increasingly new goal being articulated by most public-health experts, that its not eradication of the virus, but it is keeping hospitalizations and deaths down, but also, working with the virus. The chairman of the Israeli Association of Public Health Physicians, professor Hagai Levine, said, Because Omicron is so contagious, our efforts to stop its spread are probably pretty futile. We are not going to stop this wave. Then he dared to say, We have been trying to dodge the bullet for two years, and in Israel we have been successful to some extent. But most of humanity is still alive after contracting COVID.

The Jerusalem Post reported, that in Israel some health experts believe the magic bullet this time around will actually be widespread infection. It cited Dr. Cohen, saying, The fifth wave might end when a large number of people will be infected.

Just as deaths have decoupled from cases with Omicron, our COVID mandates have decoupled from the science originally used to justify them. But the goalposts are moving, and now it is argued that only mandates will keep hospitals free of high-risk unvaccinated patients. What are the numbers? As of Jan. 20, there are 740 unvaccinated, and 2,091 fully vaccinated people in hospital for COVID (but not the ICU). In the ICUs there are 208 unvaccinated and 263 fully vaccinated people. True, there are fewer unvaccinated than vaccinated people in Ontario, but if surgeries are delayed, it is clearly because both groups are occupying beds. Portraying the unvaccinated as the sole cause is inaccurate, and deflects from the painful fact that Canada has fewer ICU and acute care beds per capita than almost any country in the developed world, and that the current vaccines are not working as well as hoped. What is called for is not more scapegoating and coercion, but healing, and more early treatment for both groups, now that we have it. Honouring the bedrock of medical ethics, no treatment without consent, is humane, preferable and possible.

Also reappraising is Bill Gates himself. He admitted this past November, We need a new way of doing the vaccines. He also accepted that our focus had been too narrow. We didnt get much in the way of therapeutics way less than should have been the case.

Consider how different our narrative is now. More and more officials are saying openly what the authors of the Great Barrington Declaration the ridiculed view of 60,000 public health scientists and physician signatories said some time ago: Our goal is not eradication of the virus, or a one-size-fits-all policy, but lessening of deaths in the vulnerable through focused protection, and focused vaccination. The immunity we have will be a mix of vaccine immunity and natural immunity, depending on the person. The new plan to live with the virus and get back to living a normal life is a departure from the pure Baconian conquest of nature, and hearkens back to the ancient, Hippocratic, notion that we must work with nature as an ally, in a kind of collaboration.

Since nature can indeed be both the enemy, but also is our very foundation, and potential ally and friend, no narrative that excludes either side of this friend and foe duality can ever do justice to medicine and healing. If the abandonment of Hippocrates was the first medical reversal, we are seeing in its return, a reversal of a reversal.

Its been a blow to our Baconian narcissism to be upended by nature these past two years. That thin-skinned Baconian within seems almost offended to admit that protection has come not only from scientific advances, but from natural immunity. Others might see this as a reassuring reminder that natural processes are not always and only the enemy. We shall find out, as we observe the unvaccinated, to what extent natural immunity, accumulating in waves of infection over time, does or does not protect, for the current or future variants.

Till then, lets give infallibility the day off. We have some ingenuity and some tools in our tool kit, none perfect, but if we use the whole kit, instead of just the hammer, we might be better for it. That goes for how we treat the virus, and how we treat each other. And for those scientists among us those strange creatures, always reappraising! there is comfort in knowing that after two years of hard work, we have a new narrative, or picture of our situation, which though imperfect, is more nuanced and likely closer to the truth.

How are scientists tracking the mutations of COVID-19 variants like Omicron to learn what they might do to populations next? Globe science reporter Ivan Semeniuk explains. Subscribe for more episodes.

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The SARS pandemic spread around the world in 2003 and we can see how, even as far back as 20 years ago, world health is a priority for air travel which relies on health information and government guidelines to restrict travel to stop the virus spreading.

SARS: A New Blow

In 2002 airlines were affected by the war on terrorism, the war in Iraq and what reporter Frances Fiorino wrote on page 59 of the April 7 issue of the magazine, germ warfare, against severe acute respiratory syndrome (SARS), a deadly atypical pneumonia that is spreading rapidly worldwide.

As such, the World Health Organisation (WHO) issued emergency travel advisory postponing travel to Hong Kong and Chinas Guangdong province where the virus was believed to have originated. Read more about this in our archive.

SARS In Europe

By April 28, we were reporting on news that European airlines were trying to allay potential passengers fears about the danger of air travel, and that WHO had conducted aggressive research and had confirmed the SARS virus as a member of the coronavirus family.

French health epidemiologist Jean-Baptiste-Brunet said: Medical detectives should be aware that SARS, which was carried from Asia to most of the world, is, of course, directly tied to air transportation, he added. But commercial transports are not the cause, just the conduit.

Read more of this article in which it discusses the effect of air conditioning and pressurized cabins.

SARS Redux

By 2005, we were reporting on having weathered the severe economic blows of SARS but the world is about to battle another new enemy, avian influenza virus, which while the strain causes severe illness in fowl, is now being transmitted from birds to humans, according to a WHO report. And it is spreading, with the fear that the vaccine may not necessarily work against the latest strain.

The image in the article shows that infrared monitors had been installed in Taiwan's Chiang Kai-shek International Airport to scan travelers for fever, a symptom of SARS.

Read more on this analysis.

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SARS: A Mystery Illness To Impact Air Travel - Aviation Week

The Earth needs to be ready for invasion from other planets, scientists have warned, but the danger is not so much intelligent, malevolent aliens coming to conquer us. Instead, the danger we face is more in the form of microbes that could cause diseases for which we, and everything else on Earth, have no immunity. Likewise, we need to watch out for our own organisms hitchhiking on space missions to threaten any life that may exist on the worlds we visit.

The idea of interplanetary germ warfare goes back at least as far as HG Wells' War of the Worlds. However, the Univerity of Adelaide's Dr Phill Cassey and Dr Andrew Woolnoughargue in BioSciencesthat it is time we moved it from the pages of science fiction to treating the problem as a serious concern.

In addition to government-led space missions, the arrival of private companies such as SpaceX has meant there are now more players in space exploration than ever before, Cassey. said in a statement. We need to take action now to mitigate those risks. Risks that have low probability of occurrence, but have the potential for extreme consequences, are at the heart of biosecurity management. Because when things go wrong, they go really wrong.

It's possible the rest of the Solar System is lifeless, with nothing to threaten us or be threatened. However, if there is life on (or in) Mars, Europa or Enceladus, we face what economists might consider the largest externality problem of all time. If any one country or company's mission to space were to return carrying a deadly virus (known as backward contamination) the consequences would be felt by everyone. Yet currently the costs of prevention fall only to those undertaking the mission, creating an enormous financial incentive to cut corners on sterilizing or containing anything brought back.

Similarly, if some future corporate exploration of Mars carries Earth-based bacteriathat ends up displacing the local life forms (forward contamination)with them,the loss is to all of us but the price of avoidance falls only to the explorers.

To illustrate the dangers the authors point to the way humans have spread organisms to some of the most remote and hostile places on Earth. They note it is the isolated ecosystems with little experience of the outside world or in this case Solar System that are most vulnerable to new arrivals.

Australia, having suffered self-inflicted disasters such as the arrival of rabbits and cane toads has plenty of valuable lessons to teach the world about biosecurity, the authors argue. It is far cheaper to prevent biological contamination by implementing protocols on Earth than it is on Mars, for example, Casey said.

Nevertheless, the international Committee on Space Research Planetary Protection has yet to call on the experience of invasion biologists, Australian or otherwise, raising the question of whose expertise they think is useful.

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We Need To Protect Earth (And Space) From Interplanetary Invaders - IFLScience

Louis Pasteur (18221895) is revered by his successors in the life sciences as well as by the general public. In fact, his name provided the basis for a household wordpasteurized.

His research, which showed that microorganisms cause both fermentation and disease, supported the germ theory of disease at a time when its validity was still being questioned. In his ongoing quest for disease treatments he created the first vaccines for fowl cholera; anthrax, a major livestock disease that in recent times has been used against humans in germ warfare; and the dreaded rabies.

Pasteur was born in Dole, France, the middle child of five in a family that had for generations been leather tanners. Young Pasteurs gifts seemed to be more artistic than academic until near the end of his years in secondary school. Spurred by his mentors encouragement, he undertook rigorous studies to compensate for his academic shortcomings in order to prepare for the cole Normale Suprieure, the famous teachers college in Paris. He earned his masters degree there in 1845 and his doctorate in 1847.

While waiting for an appropriate appointment Pasteur continued to work as a laboratory assistant at the cole Normale. There he made further progress on the research he had begun for his doctoral dissertationinvestigating the ability of certain crystals or solutions to rotate plane-polarized light clockwise or counterclockwise, that is, to exhibit optical activity. He was able to show that in many cases this activity related to the shape of the crystals of a compound. He also reasoned that there was some special internal arrangement to the molecules of such a compound that twisted the lightan asymmetric arrangement. This hypothesis holds an important place in the early history of structural chemistrythe field of chemistry that studies the three-dimensional characteristics of molecules.

Pasteur secured his academic credentials with scientific papers on this and related research and was then appointed in 1848 to the faculty of sciences in Strasbourg and in 1854 to the faculty in Lille. There he launched his studies on fermentation. Pasteur sided with the minority view among his contemporaries that each type of fermentation is carried out by a living microorganism. At the time the majority believed that fermentation was spontaneously generated by a series of chemical reactions in which enzymesthemselves not yet securely identified with lifeplayed a critical role.

In 1857 Pasteur returned to the cole Normale as director of scientific studies. In the modest laboratory that he was permitted to establish there, he continued his study of fermentation and fought long, hard battles against the theory of spontaneous generation. Figuring prominently in early rounds of these debates were various applications of his pasteurization process, which he originally invented and patented (in 1865) to fight the diseases of wine. He realized that these were caused by unwanted microorganisms that could be destroyed by heating wine to a temperature between 60 and 100C. The process was later extended to all sorts of other spoilable substances, such as milk.

At the same time Pasteur began his fermentation studies, he adopted a related view on the cause of diseases. He and a minority of other scientists believed that diseases arose from the activities of microorganismsgerm theory. Opponents believed that diseases, particularly major killer diseases, arose in the first instance from a weakness or imbalance in the internal state and quality of the afflicted individual. In an early foray into the causes of particular diseases, in the 1860s, Pasteur was able to determine the cause of the devastating blight that had befallen the silkworms that were the basis for Frances then-important silk industry. Surprisingly, he found that the guilty parties were two microorganisms rather than one.

Pasteur did not, however, fully engage in studies of disease until the late 1870s, after several cataclysmic changes had rocked his life and that of the French nation. In 1868, in the middle of his silkworm studies, he suffered a stroke that partially paralyzed his left side. Soon thereafter, in 1870, France suffered a humiliating defeat at the hands of the Prussians, and Emperor Louis-Napolon was overthrown. Nevertheless, Pasteur successfully concluded with the new government negotiations he had begun with the emperor. The government agreed to build a new laboratory for him, to relieve him of administrative and teaching duties, and to grant him a pension and a special recompense in order to free his energies for studies of diseases.

In his research campaign against disease Pasteur first worked on expanding what was known about anthrax, but his attention was quickly drawn to fowl cholera. This investigation led to his discovery of how to make vaccines by attenuating, or weakening, the microbe involved. Pasteur usually refreshed the laboratory cultures he was studyingin this case, fowl choleraevery few days; that is, he returned them to virulence by reintroducing them into laboratory chickens with the resulting onslaught of disease and the birds death. Months into the experiments, Pasteur let cultures of fowl cholera stand idle while he went on vacation. When he returned and the same procedure was attempted, the chickens did not become diseased as before. Pasteur could easily have deduced that the culture was dead and could not be revived, but instead he was inspired to inoculate the experimental chickens with a virulent culture. Amazingly, the chickens survived and did not become diseased; they were protected by a microbe attenuated over time.

Realizing he had discovered a technique that could be extended to other diseases, Pasteur returned to his study of anthrax. Pasteur produced vaccines from weakened anthrax bacilli that could indeed protect sheep and other animals. In public demonstrations at Pouilly-le-Fort before crowds of observers, twenty-four sheep, one goat, and six cows were subjected to a two-part course of inoculations with the new vaccine, on May 5, 1881, and again on May 17. Meanwhile a control group of twenty-four sheep, one goat, and four cows remained unvaccinated. On May 31 all the animals were inoculated with virulent anthrax bacilli, and two days later, on June 2, the crowd reassembled. Pasteur and his collaborators arrived to great applause. The effects of the vaccine were undeniable: the vaccinated animals were all alive. Of the control animals all the sheep were dead except three wobbly individuals who died by the end of the day, and the four unprotected cows were swollen and feverish. The single goat had expired too.

Pasteur then wanted to move into the more difficult area of human disease, in which ethical concerns weighed more heavily. He looked for a disease that afflicts both animals and humans so that most of his experiments could be done on animals, although here too he had strong reservations. Rabies, the disease he chose, had long terrified the populace, even though it was in fact quite rare in humans. Up to the time of Pasteurs vaccine, a common treatment for a bite by a rabid animal had been cauterization with a red-hot iron in hopes of destroying the unknown cause of the disease, which almost always developed anyway after a typically long incubation period.

Rabies presented new obstacles to the development of a successful vaccine, primarily because the microorganism causing the disease could not be specifically identified; nor could it be culturedin vitro (in the laboratory and not in an animal). As with other infectious diseases, rabies could be injected into other species and attenuated. Attenuation of rabies was first achieved in monkeys and later in rabbits. Meeting with success in protecting dogs, even those already bitten by a rabid animal, on July 6, 1885, Pasteur agreed with some reluctance to treat his first human patient, Joseph Meister, a nine-year-old who was otherwise doomed to a near-certain death. Success in this case and thousands of others convinced a grateful public throughout the world to make contributions to the Institut Pasteur. It was officially opened in 1888 and continues as one of the premier institutions of biomedical research in the world. Its tradition of discovering and producing vaccines is carried on today by the pharmaceutical company Sanofi Pasteur.

Pasteurs career shows him to have been a great experimenter, far less concerned with the theory of disease and immune response than with dealing directly with diseases by creating new vaccines. Still it is possible to discern his notions on the more abstract topics. Early on he linked the immune response to the biological, especially nutritional, requirements of the microorganisms involved; that is, the microbe or the attenuated microbe in the vaccine depleted its food source during its first invasion, making the next onslaught difficult for the microbe. Later he speculated that microbes could produce chemical substances toxic to themselves that circulated throughout the body, thus pointing to the use of toxins and antitoxins in vaccines. He lent support to another view by welcoming to the Institut Pasteur lie Metchnikoff and his theory that phagocytes in the bloodwhite corpusclesclear the body of foreign matter and are the prime agents of immunity.

The information contained in this biography was last updated on December 14, 2017.

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Louis Pasteur | Science History Institute

1763 war launched by Native Americans against the British Empire in North America

Pontiac's War (also known as Pontiac's Conspiracy or Pontiac's Rebellion) was launched in 1763 by a loose confederation of American Indians dissatisfied with British rule in the Great Lakes region following the French and Indian War (17541763). Warriors from numerous tribes joined in an effort to drive British soldiers and settlers out of the region. The war is named after Odawa leader Pontiac, the most prominent of many Indian leaders in the conflict.

The war began in May 1763 when Native Americans, alarmed by policies imposed by British General Jeffrey Amherst, attacked a number of British forts and settlements. Eight forts were destroyed, and hundreds of colonists were killed or captured, with many more fleeing the region. Hostilities came to an end after British Army expeditions in 1764 led to peace negotiations over the next two years. The Natives were unable to drive away the British, but the uprising prompted the British government to modify the policies that had provoked the conflict.

Warfare on the North American frontier was brutal, and the killing of prisoners, the targeting of civilians, and other atrocities were widespread. In an incident that became well-known and frequently debated, British officers at Fort Pitt attempted to infect besieging Indians with blankets that had been exposed to smallpox. The ruthlessness of the conflict was a reflection of a growing racial divide between British colonists and Native Americans. The British government sought to prevent further racial violence by issuing the Royal Proclamation of 1763, which created a boundary between colonists and Natives.

The conflict is named after its most well-known participant, the Odawa leader named Pontiac. An early name for the war was the "Kiyasuta and Pontiac War," "Kiaysuta" being an alternate spelling for Guyasuta, an influential Seneca/Mingo leader. The war became widely known as "Pontiac's Conspiracy" after the 1851 publication of Francis Parkman's The Conspiracy of Pontiac. Parkman's book was the definitive account of the war for nearly a century and is still in print.

In the 20th century, some historians argued that Parkman exaggerated the extent of Pontiac's influence in the conflict, so it was misleading to name the war after him. Francis Jennings (1988) wrote that "Pontiac was only a local Ottawa war chief in a 'resistance' involving many tribes." Alternate titles for the war have been proposed, such as "Pontiac's War for Indian Independence," the "Western Indians' Defensive War" and "The Amerindian War of 1763." Historians generally continue to use "Pontiac's War" or "Pontiac's Rebellion," with some 21st century scholars arguing that 20th century historians had underestimated Pontiac's importance.

You think yourselves Masters of this Country, because you have taken it from the French, who, you know, had no Right to it, as it is the Property of us Indians.

Nimwha, Shawnee diplomat, to George Croghan, 1768

In the decades before Pontiac's War, France and Great Britain participated in a series of wars in Europe that involved the French and Indian Wars in North America. The largest of these wars was the worldwide Seven Years' War, in which France lost New France in North America to Great Britain. Most fighting in the North American theater of the war, generally called the French and Indian War in the United States, or the War of Conquest (French: Guerre de la Conqute) in French Canada, came to an end after British General Jeffrey Amherst captured French Montral in 1760.[24]

British troops occupied forts in the Ohio Country and Great Lakes region previously garrisoned by the French. Even before the war officially ended with the Treaty of Paris (1763), the British Crown began to implement policy changes to administer its vastly expanded American territory. The French had long cultivated alliances among Indian tribes, but the British post-war approach essentially treated Indians as a conquered people. Before long, Indians found themselves dissatisfied with the British occupation.

American Indians involved in Pontiac's War lived in a vaguely defined region of New France known as the pays d'en haut ("the upper country"), which was claimed by France until the Paris peace treaty of 1763. Indians of the pays d'en haut were from many different tribes. These tribes were linguistic or ethnic groups rather than political units; no chief spoke for an entire tribe, and no tribe acted in unison. For example, Ottawas did not go to war as a tribe: some Ottawa leaders chose to do so, while other Ottawa leaders denounced the war and stayed clear of the conflict.

The tribes of the pays d'en haut consisted of three basic groups. The first group was composed of tribes of the Great Lakes region: Ottawas, Ojibwes, and Potawatomis, who spoke Algonquian languages, and Hurons, who spoke an Iroquoian language. They had long been allied with French habitants with whom they lived, traded, and intermarried. Great Lakes Indians were alarmed to learn they were under British sovereignty after the French loss of North America. When a British garrison took possession of Fort Detroit from the French in 1760, local Indians cautioned them that "this country was given by God to the Indians." When the first Englishman reached Fort Michilimackinac, Ojibwe chief Minavavana told him "Englishman, although you have conquired the French, you have not yet conquered us!"

The second group was made up of tribes from eastern Illinois Country, which included Miamis, Weas, Kickapoos, Mascoutens, and Piankashaws. Like the Great Lakes tribes, these people had a long history of close relations with the French. Throughout the war, the British were unable to project military power into the Illinois Country, which was on the remote western edge of the conflict. The Illinois tribes were the last to come to terms with the British.[30]

The third group consisted of tribes of the Ohio Country: Delawares (Lenape), Shawnees, Wyandots, and Mingos. These people had migrated to the Ohio valley earlier in the century to escape British, French, and Iroquois domination. Unlike the Great Lakes and Illinois Country tribes, Ohio tribes had no great attachment to the French regime, though they had fought as French allies in the previous war in an effort to drive away the British. They made a separate peace with the British with the understanding that the British Army would withdraw. But after the departure of the French, the British strengthened their forts rather than abandoning them, and so the Ohioans went to war in 1763 in another attempt to drive out the British.

Outside the pays d'en haut, the influential Iroquois did not, as a group, participate in Pontiac's War because of their alliance with the British, known as the Covenant Chain. However, the westernmost Iroquois nation, the Seneca tribe, had become disaffected with the alliance. As early as 1761, Senecas began to send out war messages to the Great Lakes and Ohio Country tribes, urging them to unite in an attempt to drive out the British. When the war finally came in 1763, many Senecas were quick to take action.

General Jeffrey Amherst, the British commander-in-chief in North America, was in charge of administering policy towards American Indians, which involved military matters and regulation of the fur trade. Amherst believed with France out of the picture, the Indians would have to accept British rule. He also believed they were incapable of offering any serious resistance to the British Army, and therefore, of the 8,000 troops under his command in North America, only about 500 were stationed in the region where the war erupted. Amherst and officers such as Major Henry Gladwin, commander at Fort Detroit, made little effort to conceal their contempt for Indians; those involved in the uprising frequently complained that the British treated them no better than slaves or dogs.

Additional Indian resentment came from Amherst's decision in February 1761 to cut back on gifts given to the Indians. Gift giving had been an integral part of the relationship between the French and the tribes of the pays d'en haut. Following an Indian custom that carried important symbolic meaning, the French gave presents (such as guns, knives, tobacco, and clothing) to village chiefs, who distributed them to their people. The chiefs gained stature this way, enabling them to maintain the alliance with the French. The Indians regarded this as "a necessary part of diplomacy which involved accepting gifts in return for others sharing their lands." Amherst considered this to be bribery that was no longer necessary, especially as he was under pressure to cut expenses after the war. Many Indians regarded this change in policy as an insult and an indication the British looked upon them as conquered people rather than as allies.

Amherst also began to restrict the amount of ammunition and gunpowder that traders could sell to Indians. While the French had always made these supplies available, Amherst did not trust Indians, particularly after the "Cherokee Rebellion" of 1761, in which Cherokee warriors took up arms against their former British allies. The Cherokee war effort had failed due to a shortage of gunpowder; Amherst hoped future uprisings could be prevented by limiting its distribution.[43] This created resentment and hardship because gunpowder and ammunition helped Indians provide food for their families and skins for the fur trade. Many Indians believed the British were disarming them as a prelude to war. Sir William Johnson, the Superintendent of the Indian Department, warned Amherst of the danger of cutting back on presents and gunpowder, to no avail.

Land was also an issue in the coming of Pontiac's War. While the French colonists had always been relatively few, there seemed to be no end of settlers in the British colonies. Shawnees and Delawares in the Ohio Country had been displaced by British colonists in the east, and this motivated their involvement in the war. Indians in the Great Lakes region and the Illinois Country had not been greatly affected by white settlement, although they were aware of the experiences of tribes in the east. Dowd (2002) argues that most Indians involved in Pontiac's War were not immediately threatened with displacement by white settlers, and that historians have overemphasized British colonial expansion as a cause of the war. Dowd believes that the presence, attitude, and policies of the British Army, which the Indians found threatening and insulting, were more important factors.

Also contributing to the outbreak of war was a religious awakening which swept through Indian settlements in the early 1760s. The movement was fed by discontent with the British as well as food shortages and epidemic disease. The most influential individual in this phenomenon was Neolin, known as the "Delaware Prophet," who called upon Indians to shun the trade goods, alcohol, and weapons of the colonists. Melding Christian doctrines with traditional Indian beliefs, Neolin said the Master of Life was displeased with Indians for taking up the bad habits of white men, and that the British posed a threat to their very existence. "If you suffer the English among you," said Neolin, "you are dead men. Sickness, smallpox, and their poison [alcohol] will destroy you entirely." It was a powerful message for a people whose world was being changed by forces that seemed beyond their control.

Although fighting in Pontiac's War began in 1763, rumors reached British officials as early as 1761 that discontented American Indians were planning an attack. Senecas of the Ohio Country (Mingos) circulated messages ("war belts" made of wampum) calling for the tribes to form a confederacy and drive away the British. The Mingos, led by Guyasuta and Tahaiadoris, were concerned about being surrounded by British forts. Similar war belts originated from Detroit and the Illinois Country. The Indians were not unified, and in June 1761, natives at Detroit informed the British commander of the Seneca plot. William Johnson held a large council with the tribes at Detroit in September 1761, which provided a tenuous peace, but war belts continued to circulate. Violence finally erupted after the Indians learned in early 1763 of the imminent French cession of the pays d'en haut to the British.

The war began at Fort Detroit under the leadership of Pontiac and quickly spread throughout the region. Eight British forts were taken; others, including Fort Detroit and Fort Pitt, were unsuccessfully besieged. Francis Parkman's The Conspiracy of Pontiac portrayed these attacks as a coordinated operation planned by Pontiac. Parkman's interpretation remains well known, but later historians argued there is no clear evidence the attacks were part of a master plan or overall "conspiracy."[note 1] Rather than being planned in advance, modern scholars believe the uprising spread as word of Pontiac's actions at Detroit traveled throughout the pays d'en haut, inspiring discontented Indians to join the revolt. The attacks on British forts were not simultaneous: most Ohio Indians did not enter the war until nearly a month after Pontiac began the siege at Detroit.

Early historians believed French colonists had secretly instigated the war by stirring up the Indians to make trouble for the British. This belief was held by British officials at the time, but subsequent historians found no evidence of official French involvement in the uprising.[note 2] According to Dowd (2002), "Indians sought French intervention and not the other way around." Indian leaders frequently spoke of the imminent return of French power and the revival of the Franco-Indian alliance; Pontiac even flew a French flag in his village. Indian leaders apparently hoped to inspire the French to rejoin the struggle against the British. Although some French colonists and traders supported the uprising, the war was launched by American Indians for their own objectives.

Middleton (2007) argues that Pontiac's vision, courage, persistence, and organizational abilities allowed him to activate an unprecedented coalition of Indian nations prepared to fight against the British. Tahaiadoris and Guyasuta originated the idea to gain independence for all Indians west of the Allegheny Mountains, although Pontiac appeared to embrace the idea by February 1763. At an emergency council meeting, he clarified his military support of the broad Seneca plan and worked to galvanize other tribes into the military operation he helped to lead, in direct contradiction to traditional Indian leadership and tribal structure. He achieved this coordination through the distribution of war belts, first to the northern Ojibwa and Ottawa near Michilimackinac, and then to the Mingo (Seneca) on the upper Allegheny River, the Ohio Delaware near Fort Pitt, and the more westerly Miami, Kickapoo, Piankashaw, and Wea peoples.

Pontiac spoke at a council on the banks of the Ecorse River on April 27, 1763, about 10 miles (15km) southwest of Detroit. Using the teachings of Neolin to inspire his listeners, Pontiac convinced a number of Ottawas, Ojibwas, Potawatomis, and Hurons to join him in an attempt to seize Fort Detroit. On May 1, he visited the fort with 50 Ottawas to assess the strength of the garrison. According to a French chronicler, in a second council Pontiac proclaimed:

It is important for us, my brothers, that we exterminate from our lands this nation which seeks only to destroy us. You see as well as I that we can no longer supply our needs, as we have done from our brothers, the French.... Therefore, my brothers, we must all swear their destruction and wait no longer. Nothing prevents us; they are few in numbers, and we can accomplish it.

On May 7, Pontiac entered Fort Detroit with about 300 men carrying concealed weapons, hoping to take the stronghold by surprise. The British had learned of his plan, however, and were armed and ready.[note 3] His strategy foiled, Pontiac withdrew after a brief council and, two days later, laid siege to the fort. He and his allies killed British soldiers and settlers they found outside of the fort, including women and children. They ritually cannibalized one of the soldiers, as was the custom in some Great Lakes Indian cultures. They directed their violence at the British and generally left French colonists alone. Eventually more than 900 warriors from a half-dozen tribes joined the siege.[79]

After receiving reinforcements, the British attempted to make a surprise attack on Pontiac's encampment. Pontiac was ready and defeated them at the Battle of Bloody Run on July 31, 1763. The situation remained a stalemate at Fort Detroit, and Pontiac's influence among his followers began to wane. Groups of Indians began to abandon the siege, some of them making peace with the British before departing. Pontiac lifted the siege on October 31, 1763, convinced that the French would not come to his aid at Detroit, and removed to the Maumee River where he continued his efforts to rally resistance against the British.

Before other British outposts had learned of Pontiac's siege at Detroit, Indians captured five small forts in attacks between May 16 and June 2. Fort Sandusky, a small blockhouse on the Lake Erie shore, was the first to be taken. It had been built in 1761 by order of General Amherst, despite the objections of local Wyandots who warned the commander they would burn it down. On May 16, 1763, a group of Wyandots gained entry under the pretense of holding a council, the same stratagem that had failed in Detroit nine days earlier. They seized the commander and killed 15 soldiers and a number of British traders, among the first of about 100 traders who were killed in the early stages of the war. They ritually scalped the dead and burned the fort to the ground, as the Wyandots had threatened a year earlier.

Potawatomis captured Fort St. Joseph (site of present Niles, Michigan) on May 25, 1763, using the same method as at Sandusky. They seized the commander and killed most of the fifteen-man garrison. Fort Miami (present Fort Wayne, Indiana) was the third fort to fall. On May 27, the fort commander was lured out by his Indian mistress and shot dead by Miamis. The nine-man garrison surrendered after the fort was surrounded.

In the Illinois Country, Weas, Kickapoos, and Mascoutens took Fort Ouiatenon, about 5 miles (8.0km) west of present Lafayette, Indiana, on June 1, 1763. They lured soldiers outside for a council, then took the 20-man garrison captive without bloodshed. These Indians had good relations with the British garrison, but emissaries from Pontiac had convinced them to strike. The warriors apologized to the commander for taking the fort, saying "they were Obliged to do it by the other Nations." In contrast with other forts, the Indians did not kill their captives at Ouiatenon.

The fifth fort to fall, Fort Michilimackinac (present Mackinaw City, Michigan), was the largest fort taken by surprise. On June 4, 1763, Ojibwas staged a game of stickball with visiting Sauks. The soldiers watched the game, as they had done on previous occasions. The Indians hit the ball through the open gate of the fort, then rushed in and seized weapons that Indian women had smuggled into the fort. They killed about 15 of the 35-man garrison in the struggle; they later tortured five more to death.

Three forts in the Ohio Country were taken in a second wave of attacks in mid-June. Senecas took Fort Venango (near present Franklin, Pennsylvania) around June 16, 1763. They killed the entire 12-man garrison, keeping the commander alive to write down the Seneca's grievances, then burned him at the stake. Possibly the same Senecas attacked Fort Le Boeuf (present Waterford, Pennsylvania) on June 18, but most of the 12-man garrison escaped to Fort Pitt.

The eighth and final fort to fall, Fort Presque Isle (present Erie, Pennsylvania), was surrounded by about 250 Ottawas, Ojibwas, Wyandots, and Senecas on June 19. After holding out for two days, the garrison of 30 to 60 men surrendered on the condition that they could return to Fort Pitt. The Indians agreed, but then took the soldiers captive, killing many.

Colonists in western Pennsylvania fled to the safety of Fort Pitt after the outbreak of the war. Nearly 550 people crowded inside, including more than 200 women and children. Simeon Ecuyer, the Swiss-born British officer in command, wrote that "We are so crowded in the fort that I fear disease the smallpox is among us." Delawares and others attacked the fort on June 22, 1763, and kept it under siege throughout July. Meanwhile, Delaware and Shawnee war parties raided into Pennsylvania, taking captives and killing unknown numbers of settlers. Indians sporadically fired on Fort Bedford and Fort Ligonier, smaller strongholds linking Fort Pitt to the east, but they never took them.

Before the war, Amherst had dismissed the possibility that Indians would offer any effective resistance to British rule, but that summer he found the military situation becoming increasingly grim. He wrote the commander at Fort Detroit that captured enemy Indians should "immediately be put to death, their extirpation being the only security for our future safety." To Colonel Henry Bouquet, who was preparing to lead an expedition to relieve Fort Pitt, Amherst wrote on about June 29, 1763: "Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them."[105] Bouquet responded that he would try to spread smallpox to the Indians by giving them blankets that had been exposed to the disease.[note 4] Amherst replied to Bouquet on July 16, endorsing the plan.[note 5]

As it turned out, officers at Fort Pitt had already attempted what Amherst and Bouquet were discussing, apparently without having been ordered by Amherst or Bouquet.[111][note 6] During a parley at Fort Pitt on June 24, Captain Ecuyer gave representatives of the besieging Delawares two blankets and a handkerchief that had been exposed to smallpox, hoping to spread the disease to the Indians and end the siege.[114] William Trent, the fort's militia commander, wrote in his journal that "we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect." Trent submitted an invoice to the British Army, writing that the items had been "taken from people in the Hospital to Convey the Smallpox to the Indians." The expense was approved by Ecuyer, and ultimately by General Thomas Gage, Amherst's successor.

Historian and folklorist Adrienne Mayor (1995) wrote that the smallpox blanket incident "has taken on legendary overtones as believers and nonbelievers continue to argue over the facts and their interpretation." Peckham (1947), Jennings (1988), and Nester (2000) concluded the attempt to deliberately infect Indians with smallpox was successful, resulting in numerous deaths that hampered the Indian war effort. Fenn (2000) argued that "circumstantial evidence" suggests the attempt was successful.

Other scholars have expressed doubts about whether the attempt was effective. McConnell (1992) argued the smallpox outbreak among the Indians preceded the blanket incident, with limited effect, since Indians were familiar with the disease and adept at isolating the infected. Ranlet (2000) wrote that previous historians had overlooked that the Delaware chiefs who handled the blankets were in good health a month later; he believed the attempt to infect the Indians had been a "total failure."[note 7] Dixon (2005) argued that if the scheme had been successful, the Indians would have broken off the siege of Fort Pitt, but they kept it up for weeks after receiving the blankets. Medical writers have expressed reservations about the efficacy of spreading smallpox through blankets and the difficulty of determining if the outbreak was intentional or naturally occurring.[note 8]

On August 1, 1763, most of the Indians broke off the siege at Fort Pitt to intercept 500 British troops marching to the fort under Colonel Bouquet. On August 5, these two forces met at the Battle of Bushy Run. Although his force suffered heavy casualties, Bouquet fought off the attack and relieved Fort Pitt on August 20, bringing the siege to an end. His victory at Bushy Run was celebrated by the British; church bells rang through the night in Philadelphia, and King George praised him.

This victory was followed by a costly defeat. Fort Niagara, one of the most important western forts, was not assaulted, but on September 14, 1763, at least 300 Senecas, Ottawas, and Ojibwas attacked a supply train along the Niagara Falls portage. Two companies sent from Fort Niagara to rescue the supply train were also defeated. More than 70 soldiers and teamsters were killed in these actions, which colonists dubbed the "Devil's Hole Massacre," the deadliest engagement for British soldiers during the war.

The violence and terror of Pontiac's War convinced many western Pennsylvanians that their government was not doing enough to protect them. This discontentment was manifested most seriously in an uprising led by a vigilante group known as the Paxton Boys, so-called because they were primarily from the area around the Pennsylvania village of Paxton (or Paxtang). The Paxtonians turned their anger towards American Indiansmany of them Christianswho lived peacefully in small enclaves in the midst of white Pennsylvania settlements. Prompted by rumors that an Indian war party had been seen at the Indian village of Conestoga, on December 14, 1763, a group of more than 50 Paxton Boys marched on the village and murdered the six Susquehannocks they found there. Pennsylvania officials placed the remaining 14 Susquehannocks in protective custody in Lancaster, but on December 27, the Paxton Boys broke into the jail and killed them. Governor John Penn issued bounties for the arrest of the murderers, but no one came forward to identify them.

The Paxton Boys then set their sights on other Indians living within eastern Pennsylvania, many of whom fled to Philadelphia for protection. Several hundred Paxtonians marched on Philadelphia in January 1764, where the presence of British troops and Philadelphia militia prevented them from committing more violence. Benjamin Franklin, who had helped organize the militia, negotiated with the Paxton leaders and brought an end to the crisis. Afterwards, Franklin published a scathing indictment of the Paxton Boys. "If an Indian injures me," he asked, "does it follow that I may revenge that Injury on all Indians?"

Indian raids on frontier settlements escalated in the spring and summer of 1764. The hardest hit colony was Virginia, where more than 100 settlers were killed. On May 26 in Maryland, 15 colonists working in a field near Fort Cumberland were killed. On June 14, about 13 settlers near Fort Loudoun in Pennsylvania were killed and their homes burned. The most notorious raid occurred on July 26, when four Delaware warriors killed and scalped a school teacher and ten children in what is now Franklin County, Pennsylvania. Incidents such as these prompted the Pennsylvania Assembly, with the approval of Governor Penn, to reintroduce the scalp bounties offered during the French and Indian War, which paid money for every enemy Indian killed above the age of ten, including women.

General Amherst, held responsible for the uprising by the Board of Trade, was recalled to London in August 1763 and replaced by Major General Thomas Gage. In 1764, Gage sent two expeditions into the west to crush the rebellion, rescue British prisoners, and arrest the Indians responsible for the war. According to historian Fred Anderson, Gage's campaign, which had been designed by Amherst, prolonged the war for more than a year because it focused on punishing the Indians rather than ending the war. Gage's one significant departure from Amherst's plan was to allow William Johnson to conduct a peace treaty at Niagara, giving Indians an opportunity to "bury the hatchet."[138]

From July to August 1764, Johnson conducted a treaty at Fort Niagara with about 2,000 Indians in attendance, primarily Iroquois. Although most Iroquois had stayed out of the war, Senecas from the Genesee River valley had taken up arms against the British, and Johnson worked to bring them back into the Covenant Chain alliance. As restitution for the Devil's Hole ambush, the Senecas were compelled to cede the strategically important Niagara portage to the British. Johnson even convinced the Iroquois to send a war party against the Ohio Indians. This Iroquois expedition captured a number of Delawares and destroyed abandoned Delaware and Shawnee towns in the Susquehanna Valley, but otherwise the Iroquois did not contribute to the war effort as much as Johnson had desired.

Having secured the area around Fort Niagara, the British launched two military expeditions into the west. The first expedition, led by Colonel John Bradstreet, was to travel by boat across Lake Erie and reinforce Detroit. Bradstreet was to subdue the Indians around Detroit before marching south into the Ohio Country. The second expedition, commanded by Colonel Bouquet, was to march west from Fort Pitt and form a second front in the Ohio Country.

Bradstreet left Fort Schlosser in early August 1764 with about 1,200 soldiers and a large contingent of Indian allies enlisted by Sir William Johnson. Bradstreet felt that he did not have enough troops to subdue enemy Indians by force, and so when strong winds on Lake Erie forced him to stop at Fort Presque Isle on August 12, he decided to negotiate a treaty with a delegation of Ohio Indians led by Guyasuta. Bradstreet exceeded his authority by conducting a peace treaty rather than a simple truce, and by agreeing to halt Bouquet's expedition, which had not yet left Fort Pitt. Gage, Johnson, and Bouquet were outraged when they learned what Bradstreet had done. Gage rejected the treaty, believing that Bradstreet had been duped into abandoning his offensive in the Ohio Country. Gage may have been correct: the Ohio Indians did not return prisoners as promised in a second meeting with Bradstreet in September, and some Shawnees were trying to enlist French aid in order to continue the war.

Bradstreet continued westward, unaware his unauthorized diplomacy was angering his superiors. He reached Fort Detroit on August 26, where he negotiated another treaty. In an attempt to discredit Pontiac, who was not present, Bradstreet chopped up a peace belt Pontiac had sent to the meeting. According to historian Richard White, "such an act, roughly equivalent to a European ambassador's urinating on a proposed treaty, had shocked and offended the gathered Indians." Bradstreet also claimed the Indians had accepted British sovereignty as a result of his negotiations, but Johnson believed this had not been fully explained to the Indians and that further councils would be needed. Bradstreet had successfully reinforced and reoccupied British forts in the region, but his diplomacy proved to be controversial and inconclusive.

Colonel Bouquet, delayed in Pennsylvania while mustering the militia, finally set out from Fort Pitt on October 3, 1764, with 1,150 men. He marched to the Muskingum River in the Ohio Country, within striking distance of a number of Indian villages. Treaties had been negotiated at Fort Niagara and Fort Detroit, so the Ohio Indians were isolated and, with some exceptions, ready to make peace. In a council which began on October 17, Bouquet demanded that the Ohio Indians return all captives, including those not yet returned from the French and Indian War. Guyasuta and other leaders reluctantly handed over more than 200 captives, many of whom had been adopted into Indian families. Not all of the captives were present, so the Indians were compelled to surrender hostages as a guarantee that the other captives would be returned. The Ohio Indians agreed to attend a more formal peace conference with William Johnson, which was finalized in July 1765.

Although the military conflict essentially ended with the 1764 expeditions, Indians still called for resistance in the Illinois Country, where British troops had yet to take possession of Fort de Chartres from the French. A Shawnee war chief named Charlot Kask emerged as the most strident anti-British leader in the region, temporarily surpassing Pontiac in influence. Kask traveled as far south as New Orleans in an effort to enlist French aid against the British.

In 1765, the British decided that the occupation of the Illinois Country could only be accomplished by diplomatic means. As Gage commented to one of his officers, he was determined to have "none our enemy" among the Indian peoples, and that included Pontiac, to whom he now sent a wampum belt suggesting peace talks. Pontiac had become less militant after hearing of Bouquet's truce with the Ohio country Indians. Johnson's deputy, George Croghan, accordingly traveled to the Illinois country in the summer of 1765, and although he was injured along the way in an attack by Kickapoos and Mascoutens, he managed to meet and negotiate with Pontiac. While Charlot Kask wanted to burn Croghan at the stake, Pontiac urged moderation and agreed to travel to New York, where he made a formal treaty with William Johnson at Fort Ontario on July 25, 1766. It was hardly a surrender: no lands were ceded, no prisoners returned, and no hostages were taken. Rather than accept British sovereignty, Kask left British territory by crossing the Mississippi River with other French and Native refugees.

The total loss of life resulting from Pontiac's War is unknown. About 400 British soldiers were killed in action and perhaps 50 were captured and tortured to death. George Croghan estimated that 2,000 settlers had been killed or captured, a figure sometimes repeated as 2,000 settlers killed.[note 9] [note 10] The violence compelled approximately 4,000 settlers from Pennsylvania and Virginia to flee their homes. American Indian losses went mostly unrecorded, but it has been estimated at least 200 warriors were killed in battle, with additional deaths of germ warfare initiated at Fort Pitt was successful.

Pontiac's War has traditionally been portrayed as a defeat for the Indians, but scholars now usually view it as a military stalemate: while the Indians had failed to drive away the British, the British were unable to conquer the Indians. Negotiation and accommodation, rather than success on the battlefield, ultimately brought an end to the war. The Indians had won a victory of sorts by compelling the British government to abandon Amherst's policies and create a relationship with the Indians modeled on the Franco-Indian alliance.

Relations between British colonists and American Indians, which had been severely strained during the French and Indian War, reached a new low during Pontiac's War. According to Dixon (2005), "Pontiac's War was unprecedented for its awful violence, as both sides seemed intoxicated with genocidal fanaticism." Richter (2001) characterizes the Indian attempt to drive out the British, and the effort of the Paxton Boys to eliminate Indians from their midst, as parallel examples of ethnic cleansing. People on both sides of the conflict had come to the conclusion that colonists and natives were inherently different and could not live with each other. According to Richter, the war saw the emergence of "the novel idea that all Native people were 'Indians,' that all Euro-Americans were 'Whites,' and that all on one side must unite to destroy the other."

The British government also came to the conclusion that colonists and Indians must be kept apart. On October 7, 1763, the Crown issued the Royal Proclamation of 1763, an effort to reorganize British North America after the Treaty of Paris. The Proclamation, already in the works when Pontiac's War erupted, was hurriedly issued after news of the uprising reached London. Officials drew a boundary line between the British colonies and American Indian lands west of the Appalachian Mountains, creating a vast "Indian Reserve" that stretched from the Appalachians to the Mississippi River and from Florida to Quebec. By forbidding colonists from trespassing on Indian lands, the British government hoped to avoid more conflicts like Pontiac's War. "The Royal Proclamation," writes Calloway (2006), "reflected the notion that segregation not interaction should characterize Indian-white relations."

The effects of Pontiac's War were long-lasting. Because the Proclamation officially recognized that indigenous people had certain rights to the lands they occupied, it has been called a Native American "Bill of Rights," and still informs the relationship between the Canadian government and First Nations. For British colonists and land speculators, however, the Proclamation seemed to deny them the fruits of victorywestern landsthat had been won in the war with France. This created resentment, undermining colonial attachment to the Empire and contributing to the coming of the American Revolution. According to Calloway, "Pontiac's Revolt was not the last American war for independenceAmerican colonists launched a rather more successful effort a dozen years later, prompted in part by the measures the British government took to try to prevent another war like Pontiac's."

For American Indians, Pontiac's War demonstrated the possibilities of pan-tribal cooperation in resisting Anglo-American colonial expansion. Although the conflict divided tribes and villages, the war also saw the first extensive multi-tribal resistance to European colonization in North America, and the first war between Europeans and American Indians that did not end in complete defeat for the Indians. The Proclamation of 1763 ultimately did not prevent British colonists and land speculators from expanding westward, and so Indians found it necessary to form new resistance movements. Beginning with conferences hosted by Shawnees in 1767, in the following decades leaders such as Joseph Brant, Alexander McGillivray, Blue Jacket, and Tecumseh would attempt to forge confederacies that would revive the resistance efforts of Pontiac's War.

Originally posted here:

Pontiac's War - Wikipedia

Aspect of Japan's military history

Beginning in the mid-1930s, Japan conducted numerous attempts to acquire and develop weapons of mass destruction. The 1943 Battle of Changde saw Japanese use of both bioweapons and chemical weapons, and the Japanese conducted a serious, though futile, nuclear weapon program.

Since World War II, the United States military based nuclear and chemical weapons and field tested biological anti-crop weapons in Japan.

Japan has since become a nuclear-capable state, said to be a "screwdriver's turn" away from nuclear weapons; having the capacity, the know-how, and the materials to make a nuclear bomb. Japan has consistently eschewed any desire to have nuclear weapons, and no mainstream Japanese party has ever advocated acquisition of nuclear weapons or any weapons of mass destruction. There are controversies on whether such weapons are forbidden by the Japanese constitution or not. Japan has signed many treaties prohibiting these kinds of weapons.

Japan is the only nation that has been attacked with atomic weapons. Prior to 1946 Japan carried out many attacks using weapons of mass destruction (chemical and biological), principally in China. In 1995, Japanese citizens released chemical weapons in Tokyo in a domestic terror attack.

Japan became interested in obtaining biological weapons during the early 1930s.[1] Following an international ban on germ warfare in 1925 by the Geneva Protocol Japan reasoned that disease epidemics must make effective weapons.[1] Japan developed new methods of biological warfare (BW) and used them on a large scale in China.[2]During the Sino-Japanese War (19371945) and World War II, Unit 731 and other Special Research Units of the Imperial Japanese Army conducted human experimentation on thousands, mostly Chinese, Korean, Russian, American, and other nationalities as well as some Japanese criminals from the Japanese mainlands.[3] In military campaigns, the Japanese army used biological weapons on Chinese soldiers and civilians.[4]

Japan's infamous biological warfare Unit 731 was led by Lt. General Shir Ishii.[2]Unit 731 used plague-infected fleas and flies covered with cholera to infect the population in China.[2]The Japanese military dispersed insects by spraying them from low-flying airplanes and dropping ceramic bombs they had developed that were filled with mixtures containing insects and diseases that could affect humans, animals, and crops.[5]Localized and deadly epidemics resulted and an estimated 200,000[1] to 500,000 Chinese died of disease.[2][6]Recent additional firsthand accounts testify the Japanese infected civilians through the distribution of plague-infested foodstuffs, such as dumplings and vegetables.[4]During the Changde chemical weapon attacks, the Japanese also employed biological warfare by intentionally spreading infected fleas.[1] In Zhejiang Province cholera, dysentery, and typhoid were employed.[1] Harbin also suffered Japanese biological attacks.[1] Other battles include the Kaimingye germ weapon attack in Ningbo.[1]

Japan sent a submarine with unspecified biological weapons early in 1944 to defend the island of Saipan from American invasion; however the submarine was sunk.[1]

Another attack against American troops with biological weapons was planned during the invasion of Iwo Jima. The planned involved towing gliders laden with pathogens over the American lines. However, this plan never took shape. Had it succeeded, thousands of American soldiers and marines may have died, and the operation as a whole may very well have failed.

Japan's biowarfare experts had hoped to launch biological attacks on the U.S. in 1944 with balloon bombs filled with bubonic plague, anthrax, rinderpest, and smut fungus.[1] A 1945-planned kamikaze attack on San Diego with I-400-class submarine aircraft carriers that would deploy Aichi M6As floatplanes and drop fleas infected with bubonic plague was code-named Operation Cherry Blossoms at Night.[1] The plans were rejected by Hideki Tojo who feared similar retaliation by the United States.[1]

Japanese scientists from Unit 731 provided research information for the United States biological weapons program in order to escape war crimes charges.[1] Bob Dohini, a former war crimes prosecution team lawyer, recently claimed that there was no mention of germ warfare in the investigation of war Japanese crimes.[7] The fact was not well known until the 1980s. Japan's emperor was unable to be tried. Later revelations indicated his knowledge of the program.[7]

Japan's employment of BW was largely viewed as ineffective, due to the absence of efficient production or delivery technology.[4] The U.S. government provided a stipend to the Japanese BW military scientists and researches.[1] Japanese biological warfare information provided to U.S. authorities after World War II remained a secret and was eventually returned to Japan.[8]

Right-wing Japanese officials claim that no proof of Japan's wartime atrocities exists.[7]

In August 2002, a Japanese court ended decades of official denials and acknowledged, for the first time, that Japan had used germ warfare in occupied China in the 1930s and 1940s.[8] The court acknowledged the existence of Japan's biological warfare program but rejected the plaintiffs' demands for compensation, saying the issue was covered under postwar treaties.[8] Following the court decision, Japanese officials announced that their government would send a delegation to China to excavate and remove hundreds of abandoned chemical weapons, including bombs, shells, and containers of mustard gas and other toxins left over from the Second World War.[8]

Japan's biological warfare experts and scientists from WWII, were alleged to have assisted the US in employment of BW in the Korean War.[4]

The Japanese used mustard gas and the blister agent Lewisite against Chinese troops and guerillas in China, amongst others during the Changde chemical weapon attack.

Experiments involving chemical weapons were conducted on live prisoners (Unit 516). As of 2005, sixty years after the end of the war, canisters that were abandoned by Japan in their hasty retreat are still being dug up in construction sites, causing injuries and allegedly even deaths.

Several chemical attacks on various people using VX gas and sarin and the Tokyo subway sarin attack on the Tokyo subway on March 20, 1995, were perpetrated by members of the cult movement Aum Shinrikyo in acts of domestic terrorism. A large stockpile of other chemical agents and precursor chemicals were later found in raids on their facilities.

In 1995, JGSDF admitted possession of sarin samples for defense purposes.[citation needed]

Japan had signed the Chemical Weapons Convention in December 1993. Japan ratified The Chemical Weapons Convention in 1995 and was thus a state party upon it entering into force in 1997.[9]

A Japanese program to develop nuclear weapons was conducted during World War II. Like the German nuclear weapons program, it suffered from an array of problems, and was ultimately unable to progress beyond the laboratory stage before the atomic bombings of Hiroshima and Nagasaki and the Japanese surrender in August 1945.

The postwar Constitution forbids the establishment of offensive military forces, but not nuclear weapons explicitly. In 1967 it adopted the Three Non-Nuclear Principles, ruling out the production, possession, or introduction of nuclear weapons. Japan signed the Treaty on the Non-Proliferation of Nuclear Weapons in February 1970.[10]

While there are currently no known plans in Japan to produce nuclear weapons, it has been argued that Japan has the technology, raw materials, and the capital to produce nuclear weapons within one year if necessary, and some analysts consider it a de facto nuclear state for this reason.[11] For this reason Japan is often said to be a "screwdriver's turn"[12][13] away from possessing nuclear weapons.

During the 2016 U.S. presidential election it was proposed by GOP candidates to allow both Japan and the Republic of Korea to develop nuclear weapons to counter a North Korean missile threat.[14]

Solid fuel rockets are the design of choice for military applications as they can remain in storage for long periods, and then reliably launch at short notice.

Lawmakers made national security arguments for keeping Japan's solid-fuel rocket technology alive after ISAS was merged into the Japan Aerospace Exploration Agency, which also has the H-IIA liquid-fueled rocket, in 2003. The ISAS director of external affairs, Yasunori Matogawa, said, "It seems the hard-line national security proponents in parliament are increasing their influence, and they aren't getting much criticismI think were moving into a very dangerous period. When you consider the current environment and the threat from North Korea, its scary."[15]

Toshiyuki Shikata, a government adviser and former lieutenant general, indicated that part of the rationale for the fifth M-V Hayabusa mission was that the reentry and landing of its return capsule demonstrated "that Japan's ballistic missile capability is credible."[16]

At a technical level the M-V design could be weaponised quickly (as an Intercontinental ballistic missile) although this would be politically unlikely.[17]

In response to the perceived threat from North Korean-launched ballistic missiles, Japanese government officials have proposed developing a first strike capability for Japan's military that includes ballistic and cruise missiles.[18]

The threat of North Korea-based ballistic missiles that are within range of Japan have guided Japanese and U.S. defense and deterrence strategies.[18]

South Korean interest in developing an atomic bomb began in 1950. The interest was partially a result of the rapid surrender of Korea's then-enemy Japan following use of atomic bombs in World War II. Post-war aggression from the North and from the People's Republic of China solidified that interest. A South Korean nuclear facility began to reprocess fuel and enrich plutonium based on the observation that Japan was also producing it.[14]

In late 1958, nuclear weapons were deployed by the U.S. from Kadena Air Base in Okinawa to Kunsan Air Base in South Korea in order to oppose military actions by the People's Republic of China during the Second Taiwan Strait Crisis.[19]

Okinawa has long been viewed as a stepping-stone to force open the remainder of Japan and Asia. Commodore Perry's gunboat diplomacy expedition to open Japan to U.S. trade began in Okinawa in 1852.

By the early 1950s and the outbreak of the Korean War, Okinawa was seen as America's Gibraltar of the Pacific.[20]

In 1939, the U.S. State Department reported that a Japanese Army physician in New York City had attempted to obtain a Yellow fever virus sample from the Rockefeller Institute for Medical Research. The incident contributed to a sense of urgency in the United States to research a BW capability. By 1942 George W. Merck, president of Merck and Company, was made chairman of the War Research Service which was established to oversee the U.S. development of BW-related technology at Camp Detrick.[21]

After World War II ended, a U.S. War Departments report notes that "in addition to the results of human experimentation much data is available from the Japanese experiments on animals and food crops".[22]The technical information of Japan's BW program participants was transferred into U.S. intelligence agencies and BW programs in exchange for immunity for war crimes charges.[1][21]

In 1951, the first of many allegations were made against the United States by the communist belligerent nations in the Korean war of employing biological warfare using various techniques in attacks launched from bases on Okinawa.[4]

In 1945 Japan's rice crop was terribly affected by rice blast disease. The outbreak as well as another in Germany's potato crop coincided with covert Allied research in these areas. The timing of these outbreaks generated persistent speculation of some connection between the events however the rumors were never proven and the outbreaks could have been naturally occurring.[23]

Sheldon H. Harris in Factories of Death: Japanese Biological Warfare, 19321945, and the American Cover Up wrote:

This was at least one year prior to the creation of Project 112. The Okinawa anti-crop research project may lend some insight to the larger projects Project 112 sponsored. BW experts in Okinawa and "at several sites in the Midwest and South" conducted in 1961 "field tests" for wheat rust and rice blast disease. These tests met with "partial success" in the gathering of data, and led, therefore, to a significant increase in research dollars in fiscal year 1962 to conduct additional research in these areas. The money was devoted largely to developing "technical advice on the conduct of defoliation and anti-crop activities in Southeast Asia."[4]:232233

During the Second World War limited test use of aerial spray delivery systems was employed only on several Japanese-controlled tropical islands to demarcate points for navigation and to kill dense island foliage. Despite the availability of the spray equipment, herbicide application with aerial chemical delivery systems were not systematically implemented in the Pacific theater during the war.[24]

At the close of World War Two, the U.S. planned to attack Japan's food supply with anti-crop chemical agents and by July 1945 had stockpiled an amount of chemicals "sufficient to destroy one-tenth of the rice crop of Japan."[25] However, logistical problems would have reduced that estimate.[25]

In addition to work done in the anti-crop theater during the Cold War, the screening program for chemical defoliants was greatly accelerated. By the end of fiscal year 1962, the Chemical Corps had let or were negotiating contracts for over one thousand chemical defoliants.[26] "The Okinawa tests evidently were fruitful."[4] The presence of so-called rainbow herbicides such as Agent Orange has been widely reported on Okinawa as well as at other locations in Japan. The U.S. government disputes these assertions and the issues surrounding the subject of military use anti-plant agents in Japan during the 1950s through the 1970s remains a controversy.

At Kadena Air Force Base, an Entomology Branch of the U.S. Army Preventive Medicine Activity, U.S. Army Medical Center was used to grow "medically important" arthropods, including many strains of mosquitoes in a study of disease vector efficiency.[27] The program reportedly supported a research program studying taxonomic and ecological data surveys for the Smithsonian Institution."[27]The Smithsonian Institution and The National Academy of Sciences and National Research Council administered special research projects in the Pacific.[28] The Far East Section of the Office of the Foreign Secretary administered two such projects which focused "on the flora of Okinawa" and "trapping of airborne insects and arthropods for the study of the natural dispersal of insects and arthropods over the ocean."[28]:59 The motivation for civilian research programs of this nature was questioned when it was learned that such international research was in fact funded by and provided to the U.S. Army as requirement related to the U.S. military's biological warfare research.[29][30]

Operation Pop Eye / Motorpool / Intermediary-Compatriot was a highly classified weather modification program in Southeast Asia during 1967-1972 that was developed from cloud seeding research conducted on Okinawa and other tropical locations.A report titled Rainmaking in SEASIA outlines use of silver iodide deployed by aircraft in a program that was developed in California at Naval Air Weapons Station China Lake. The technique was refined and tested in Okinawa, Guam, Philippines, Texas, and Florida in a hurricane study program called Project Stormfury.[31][32]

The chemical weather modification program was conducted from Thailand over Cambodia, Laos, and Vietnam. The program was allegedly sponsored by Secretary of State Henry Kissinger and the Central Intelligence Agency without the authorization of Secretary of Defense Melvin Laird. Laird had categorically denied to Congress that a program for modification of the weather existed.[33] The program employed cloud seeding as a weapon which was used to induce rain and extend the East Asian Monsoon season in support of U.S. government strategic efforts related to the War in Southeast Asia. The use of a military weather control program was related to the destruction of enemy food crops.[34] Whether the use of a weather modification program was directly related to any of the chemical and biological warfare programs is not documented. However, it is certain that some of the military herbicides in use in Vietnam required rainfall to be absorbed.

In theory, any CBW program employing fungus spores or a mosquito vector would have also benefited from prolonged periods of rain. Rice blast sporulation on diseased leaves occurs when relative humidity approaches 100%. Laboratory measurements indicate sporulation increases with the length of time 100% relative humidity prevails.[35]The Aedes aegypti mosquito lays eggs and requires standing water to reproduce. Approximately three days after it feeds on blood, the mosquito lays her eggs over a period of several days. The eggs are resistant to desiccation and can survive for periods of six or more months. When rain floods the eggs with water, the larvae hatch.[36]

U.S. chemical weapons in Japan were deployed to Okinawa in the early 1950s. The Red Hat mission deployed additional chemical agents in three military operations code named YBA, YBB, and YBF. The operation deployed chemical agents to the 267th Chemical Platoon on Okinawa during the early 1960s under Project 112.[37]The shipments, according to declassified documents, included sarin, VX, and mustard gas. By 1969, according to later newspaper reports, there was an estimated 1.9 million kg (1,900 metric tons) of VX stored on Okinawa.[38] The chemical weapons brought to Okinawa included nerve and blister agents contained in rockets, artillery shells, bombs, mines, and one-ton (900kg) containers. The chemicals were stored at Chibana Ammunition Depot. The depot was a hill-top installation next to Kadena Air Base.[38]

In 1969, over 20 servicemen (23 U.S. soldiers and one U.S. civilian, according to other reports) were exposed to low levels of the nerve agent sarin while sandblasting and repainting storage containers.[38] The resultant publicity appears to have contributed to the decision to move the weapons off Okinawa.The U.S. then government directed relocation of chemical munitions. The chemical warfare agents were removed from Okinawa in 1971 during Operation Red Hat. Operation Red Hat involved the removal of chemical warfare munitions from Okinawa to Johnston Atoll in the Central Pacific Ocean.[39]An official U.S. film on the mission says that 'safety was the primary concern during the operation,' though Japanese resentment of U.S. military activities on Okinawa also complicated the situation. At the technical level, time pressures imposed to complete the mission, the heat, and water rationing problems also complicated the planning.[39]

The initial phase of Operation Red Hat involved the movement of chemical munitions from a depot storage site to Tengan Pier, eight miles away, and required 1,332 trailers in 148 convoys. The second phase of the operation moved the munitions to Johnston Atoll.[40] The Army leased 41 acres (170,000m2) on Johnston. Phase I of the operation took place in January and moved 150 tons of distilled mustard agent. The USNSLt. James E. Robinson(T-AK-274) arrived at Johnston Atoll with the first load of projectiles on January 13, 1971. Phase II completed cargo discharge to Johnston Atoll with five moves of the remaining 12,500 tons of munitions, in August and September 1971.[41]Units operating under United States Army Ryukyu Islands (USARYIS) were 2nd Logistical Command and the 267th Chemical Company, the 5th and 196th Ordnance Detachments (EOD), and the 175th Ordnance Detachment.

Originally, it was planned that the munitions be moved to Umatilla Chemical Depot but this never happened due to public opposition and political pressure.[42] The Congress passed legislation on January 12, 1971 (PL 91-672) that prohibited the transfer of nerve agent, mustard agent, agent orange and other chemical munitions to all 50 U.S. states.[43]In 1985 the U.S. Congress mandated that all chemical weapons stockpiled at Johnston Atoll, mostly mustard gas, Sarin, and VX gas, be destroyed.[44] Prior to the beginning of destruction operations, Johnston Atoll held about 6.6 percent of the entire U.S. stockpile of chemical weapons.[45]The Johnston Atoll Chemical Agent Disposal System (JACADS) was built to destroy all the chemical munitions stored on Johnston island.[46] The first weapon disposal incineration operation took place on June 30, 1990. The last munitions were destroyed in 2000.

The intensity of the fighting and the high number of casualties during the Battle of Okinawa formed the basis of the casualty estimates projected for the invasion of Japan that led to the decision to launch the atomic bombing of Japan. Atomic bombs were deployed in order to avoid having an[nother] Okinawa from one end of Japan to the other.[47]

The atomic age on Japan's southern islands began during the final weeks of the war when the U.S. Army Air Force launched two atomic attacks on Hiroshima and Nagasaki from bases on Tinian in the Marianas Islands. Bockscar, the B-29 that dropped the Fat Man nuclear weapon on Nagasaki, landed at Yontan Airfield on Okinawa on August 9, 1945.[48] The U.S. military immediately began constructing a second B-29 base and a facility for atom bomb processing in Okinawa to be completed in September 1945 that would open more targets in mainland Japan.[49]

Japanese naval warships captured by the U.S. after Japan's surrender in World War II, including the Nagato, were used as target ships and destroyed in 1946 in nuclear testing at Bikini Atoll during Operation Crossroads. The atomic testing was conducted in the Marshall Islands group that U.S. forces captured in early 1944 from the Japanese.[50]

The first hydrogen bomb detonation, known as Castle Bravo, contaminated Japanese fisherman on the Daigo Fukury Maru with nuclear fallout on March 4, 1954. The incident further rallied a powerful anti-nuclear movement.

Article 9 of the Japanese Constitution, written by MacArthur immediately after the war, does not explicitly prohibits nuclear weapons. But when the U.S. military occupation of Japan ended in 1951, a new security treaty was signed that granted the United States rights to base its "land, sea, and air forces in and about Japan."[51]

It is true that Chichi Jima, Iwo Jima, and Okinawa were under U.S. occupation, that the bombs stored on the mainland lacked their plutonium and/or uranium cores, and that the nuclear-armed ships were a legal inch away from Japanese soil. All in all, this elaborate strategem maintained the technicality that the United States had no nuclear weapons "in Japan."[51]

In 1959, Prime Minister Nobusuke Kishi stated that Japan would neither develop nuclear weapons nor permit them on its territory".[51] He instituted the Three Non-Nuclear Principles--"no production, no possession, and no introduction."

But when these non-nuclear principles were being enunciated, Japanese territory was already fully compromised, in spirit if not in letter. Although actual nuclear weapons were removed from Iwo Jima at the end of 1959, Chichi Jima, which had the same legal status, continued to house warheads with their nuclear materials until 1965. And Okinawa, of course, was chock-a-block full of nuclear weapons of all types until 1972. Nuclear-armed ships moored at U.S. Navy bases in Japan, and others called at Japanese ports without restriction...Yet, as compromised as it was, Japan's non-nuclear policy was not wholly fictitious. The Pentagon never commanded nuclear storage rights on the main islands, and it had to withdraw nuclear weapons from Okinawa in 1972...Undoubtedly, Japanese rulers firmly believed that the compromises they made with Washington were necessary for Japanese security during the dark days of the Cold War. Through it all, nonetheless, "non-nuclear Japan" was a sentiment, not a reality.[51]

A 1960 accord with Japan permits the United States to move weapons of mass destruction through Japanese territory and allows American warships and submarines to carry nuclear weapons into Japan's ports and American aircraft to bring them in during landings.[52][53][54] The discussion took place during negotiations in 1959, and the agreement was made in 1960 by Aiichiro Fujiyama, then Japan's Foreign Minister.[53]"There were many things left unsaid; it was a very sophisticated negotiation. The Japanese are masters at understood and unspoken communication in which one is asked to draw inferences from what may not be articulated."[53]

The secret agreement was concluded without any Japanese text so that it could be plausibly denied in Japan.[51][53] Since only the American officials recorded the oral agreement, not having the agreement recorded in Japanese allowed Japan's leaders to deny its existence without fear that someone would leak a document to prove them wrong.[53] The arrangement also made it appear that the United States alone was responsible for the transit of nuclear munitions through Japan.[53] However, the original agreement document turned up in 1969 during preparation for an updated agreement, when a memorandum was written by a group of U.S. officials from the National Security Council Staff; the Departments of State, Defense, Army, Commerce and Treasury; the Joint Chiefs of Staff; the Central Intelligence Agency; and the United States Information Agency.[52][53][54]

A 1963 Central Intelligence Agency National Intelligence Estimate stated that: '...US bases in Japan and related problems of weapons and forces will continue to involve issues of great sensitivity in Japan-US relations. The government is bound to be responsive to the popular pressures which the left can whip up on these issues. We do not believe that this situation will lead to demands by any conservative government for evacuation of the bases.'[55]

During the early parts of the Cold War the Bonin Islands including Chichi Jima, the Ryukyu Islands including Okinawa, and the Volcano Islands including Iwo Jima were retained under American control. The islands were among "thirteen separate locations in Japan that had nuclear weapons or components, or were earmarked to receive nuclear weapons in times of crisis or war."[51] According to a former U.S. Air Force officer stationed on Iwo Jima, the island would have served as a recovery facility for bombers after they had dropped their bombs in the Soviet Union or China. War planners reasoned that bombers could return Iwo Jima, "where they would be refueled, reloaded, and readied to deliver a second salvo as an assumption was that the major U.S. Bases in Japan and the Pacific theater would be destroyed in a nuclear war." It was believed by war planners that a small base might evade destruction and be a safe harbor for surviving submarines to reload. Supplies to re-equip submarines as well as Anti-submarine weapons were stored within caves on Chichi Jima. The Johnson administration gradually realized that it would be forced to return Chichi Jima and Iwo Jima "to delay reversion of the more important Okinawa bases" however, President Johnson also wanted Japan's support for U.S. Military operations in Southeast Asia." The Bonin and Volcano islands were eventually returned to Japan in June 1968.[51]

Prime Minister Eisaku Sat and Foreign Minister Takeo Miki had explained to the Japanese parliament that "the return of the Bonins had nothing to do with nuclear weapons yet the final agreement included a secret annex, and its exact wording remained classified." A December 30, 1968, cable from the U.S. embassy in Tokyo is titled "Bonin Agreement Nuclear Storage," but within the same file "the National Archives contains a 'withdrawal sheet' for an attached Tokyo cable dated April 10, 1968, titled 'Bonins Agreement--Secret Annex,'".[51]

On the one year anniversary of the B-52 crash and explosion at Kadena Prime Minister Sato and President Nixon met in Washington, DC where several agreements including a revised Status of Forces Agreement (SOFA) and a formal policy related to the future deployment of nuclear weapons on Okinawa were reached.[56]

A draft of the November 21st, 1969, Agreed Minute to Joint Communique of United States President Nixon and Japanese Prime Minister Sato was found in 1994. "The existence of this document has never been officially recognized by the Japanese or U.S. governments." The English text of the draft agreement reads:[56]

United States President:

As stated in our Joint Communique, it is the intention of the United States Government to remove all the nuclear weapons from Okinawa by the time of actual reversion of the administrative rights to Japan; and thereafter the Treaty of Mutual Cooperation and Security and its related arrangements will apply to Okinawa, as described in the Joint Communique. However, in order to discharge effectively the international obligations assumed by the United States for the defense of countries in the Far East including Japan, in time of great emergency the United States Government will require the re-entry of nuclear weapons and transit rights in Okinawa with prior consultation with the Government of Japan. The United States Government would anticipate a favorable response. The United States Government also requires the standby retention and activation in time of great emergency of existing nuclear storage locations in Okinawa: Kadena, Naha, Henoko, and the Nike Hercules units...

Japanese Prime Minister:

The Government of Japan, appreciating the United States Government's requirements in time of great emergency stated above by the President, will meet these requirements without delay when such prior consultation takes place. The President and the Prime Minister agreed that this Minute, in duplicate, be kept each only in the offices of the President and the Prime Minister and be treated in the strictest confidence between only the President of the United States and the Prime Minister of Japan.

Complete information surrounding U.S. nuclear accidents is not generally available via official channels.[52][56][57][58] News of accidents on the island usually did not reach much farther than the islands local news, protest groups, eyewitnesses and rumor mills. However, the incidents that were publicized garnered international opposition to chemical and nuclear weapons and set the stage for the 1971 Okinawa Reversion Agreement to officially ending the U.S. military occupation on Okinawa.[59][60][61][62][63][64]

32 Mace Missiles were kept on constant nuclear alert in hardened hangars at four of the island's launch sites.[19] The 280mm M65 Atomic Cannon nicknamed "Atomic Annie" and the projectiles it fired were also based here.[66] Okinawa at one point hosted as many as 1,200 nuclear warheads.[67] At the time, nuclear storage locations existed at Kadena AFB in Chibana and the hardened MGM-13 MACE missile launch sites; Naha AFB, Henoko [Camp Henoko (Ordnance Ammunition Depot) at Camp Schwab], and the Nike Hercules units on Okinawa.[56]

In June or July 1959, a MIM-14 Nike-Hercules anti-aircraft missile was accidentally fired from the Nike site 8 battery at Naha Air Base on Okinawa which according to some witnesses, was complete with a nuclear warhead.[68] While the missile was undergoing continuity testing of the firing circuit, known as a squib test, stray voltage caused a short circuit in a faulty cable that was lying in a puddle and allowed the missile's rocket engines to ignite with the launcher still in a horizontal position.[68] The Nike missile left the launcher and smashed through a fence and down into a beach area skipping the warhead out across the water "like a stone."[68] The rocket's exhaust blast killed two Army technicians and injured one.[68] A similar accidental launch of a Nike-H missile had occurred on April 14, 1955, at the W-25 site in Davidsonville, Maryland, which is near the National Security Agency headquarters at Fort George G. Meade.[69]

On October 28, 1962, during the peak of Cuban Missile Crisis U.S. Strategic Forces were at Defense Condition Two or DEFCON 2. According to missile technicians who witnessed events, the four MACE B missile sites on Okinawa erroneously received coded launch orders to fire all of their 32 nuclear cruise missiles at the Soviets and their allies. Quick thinking by Capt. William Bassett who questioned whether the order was "the real thing, or the biggest screw up we will ever experience in our lifetime delayed the orders to launch until the error was realized by the missile operations center. According to witness John Bordne, Capt. Bassett was the senior field officer commanding the missiles and was nearly forced to have a subordinate lieutenant who was intent on following the orders to launch his missiles shot by armed security guards. No U.S. Government record of this incident has ever been officially released.[70][71] Former missileers have refuted Bordne's account.[72]

Next, on December 5, 1965, off of the coast of Okinawa, an A-4 Skyhawk attack aircraft rolled off of an elevator of the aircraft carrier the USS Ticonderoga (CV-14) into 16,000 feet of water resulting in the loss of the pilot, the aircraft, and the B43 nuclear bomb it was carrying, all of which were too deep for recovery.[73] Since the ship was traveling to Japan from duty in the Vietnam war zone, no public mention was made of the incident at the time and it would not come to light until 1981 when a Pentagon report revealed that a one-megaton bomb had been lost.[74] Japan then formally asked for details of the incident.[75]

Last, In September 1968, Japanese newspapers reported that radioactive Cobalt-60 had been detected contaminating portions of the Naha Port Facility, sickening three. The radioactive contamination was believed by scientists to have emanated from visiting U.S. nuclear submarines.[76]

Finally, on November 19, 1968, a U.S. Air Force Strategic Air Command (SAC) B-52 Stratofortress (registration number 55-01030) with a full bomb load, broke up and caught fire after the plane aborted takeoff at Kadena Air Base, Okinawa while it was conducting an Operation Arc Light bombing mission to the Socialist Republic of Vietnam during the Vietnam War.[62][77] The plane's pilot was able to keep the plane on the ground and bring the aircraft to a stop while preventing a much larger catastrophe.[59] The aircraft came to rest near the edge of the Kadena's perimeter, some 250 meters from the Chibana Ammunition Depot.[59][77]

The fire resulting from the aborted takeoff ignited the plane's fuel and detonated the plane's 30,000-pound (13,600kg) bomb load, causing a blast so powerful that it created a crater under the burning aircraft some thirty feet deep and sixty feet across.[77] The blast blew out the windows in the dispensary at Naha Air Base (now Naha Airport), 23 miles (37km) away and damaged 139 houses.[59][62] The plane was reduced "to a black spot on the runway"[62] The blast was so large that Air Force spokesman had to announce that there had only been conventional bombs on board the plane.[63] Nothing remained of the aircraft except the landing gear and engine assemblies, a few bombs, and some loose explosive that had not detonated.[59][77] Very small fragments of aircraft metal from the enormous blast were "spread like confetti," leaving the crew to use a double entendre to refer to the cleanup work, calling it, "'52 Pickup."[59] The planes Electronic Warfare Officer and the Crew Chief later died from burn injuries after being evacuated from Okinawa.[59][77] Two Okinawan workers were also injured in the blasts.[62]

Had the plane become airborne, only seconds later it would have crashed farther north of the runway and directly into the Chibana Ammunition Depot,[59] which stored ammunition, bombs, high explosives, tens of thousands of artillery shells, and warheads for 19 different atomic and thermonuclear weapons systems in the hardened weapon storage areas.[66] The depot held the Mark 28 nuclear bomb warheads used in the MGM-13 Mace cruise missile as well as warheads for nuclear tipped MGR-1 Honest John and MIM-14 Nike-Hercules (Nike-H) missiles.[66] The depot also included 52 igloos in the Red Hat Storage Area containing Project Red Hat's chemical weapons and presumably Project 112's biological agents.[56][57][78][circular reference][79]

The crash led to demands to remove the B-52s from Okinawa and strengthened a push for the reversion from U.S. rule in Okinawa.[62][64] The crash sparked fears that another potential disaster on the island could put the chemical and nuclear stockpile and the surrounding population in jeopardy and increased the urgency of moving them to a less populated and less active storage location.

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