Fungal infected insects were first discovered in 1859; In 1984, Janice Moore experimentally demonstrated that parasites have the ability to manipulate their hosts; A 2017 NCBI paper pointed out that nearly one-third of the world's population carries a parasite that can affect and even manipulate the human brain; In December 2021, scientists suggested that the complex molecular mechanisms of the novel coronavirus may have been manipulated by the host without being known. That same year, Musk tweeted in response to National Geographic's article that parasites were causing hyenas to lower their vigilance against lions, with Musk jokingly saying that Toxoplasma would be the true arbiter of human destiny.
With the deepening of biological research, more and more bizarre parasitic behaviors surfaced, and there are two frequently appearing phrases in these information, parasitism, manipulation, when these two keywords are spelled together, a terrifying concept emerges, parasitic behavior manipulation. Zombie fungus (Lateral Cordyceps vexus) To understand parasitic manipulation behavior, we will start with the top manipulators in nature, and audiences who like to watch biological documentaries must be familiar with it, it is Paralateral Cordyceps fungus, and some people prefer to call it a zombie fungus.
Its story begins with an ant, a fateful insect in the Thai rainforest, not only facing the threat of anteaters, but also another pair of eyes deep in the rainforest, eager to spread the breeding zombie fungus (Ophiocordyceps unilateralis). In the eyes of zombie fungi, carpenter ant species are one of the perfect hosts, in July 2014 ICB a paper on parasitic fungi mentioned that spores attach and penetrate the stratum corneum of ants, foraging ants may be infected, fungi will colonize the body of ants, infected ants will leave the colony, become a fungus transportation tool, crawling towards the trunk stems and leaves.
After carefully selecting the right location, bite the branches or leaf veins tightly, the jaw muscles atrophy to prevent themselves from falling, and then wait for the fungus to hatch in their own body, after death the fungus will grow from the corpse, and the host's body will be transformed from the fungus's transportation tool into the carbon source needed for fungal growth and reproduction. Fruiting bodies grow on the back of the neck, and when mature, sexual spores are transmitted to the colony through spores falling from the stroma, infecting more ants. From the perspective of ants, zombie fungi are no less terrifying than any horror movie.
So how exactly does the zombie fungus make ants become their own puppets? The conclusion was far more frustrating than I had imagined. David Hughes is a veteran scholar of zombie fungi, and his name appears in nine out of ten highly cited papers in this field, and in a 2014 paper he co-published in which they speculated that once the colony was large enough, the fungus hijacked the host's central nervous system.
In addition, through ex vivo ant tissue culture and metabolomics experiments, it was found that ants of independent species would only be controlled by fungi of the corresponding species. This is a fairly fine classification, almost all ants that can be naturally infected in the rainforest have a corresponding fungus, and such a detailed classification is likely to be the result of the evolution of fungi over many years. However, this evolution time is greatly beyond their imagination. In 2010, Hughes and his team found a fossilized leaf from the Eocene in Germany's Messer fossil pit, and the clear death bite on the fossil could prove that zombie fungi manipulating ants dates back 48 million years. Hughes et al. then believed that fungi had evolved over the years to produce a series of specific compounds that had an impact on the host brain.
However, as the research deepened, things took a startling turn. Just when everyone thinks, fungi deprive ants of control by controlling their central nervous system. In 2017, Hughes and other scholars again released a paper on the mechanism of zombie fungal behavior manipulation, but the content of this paper largely overturned the conclusion of brain control in 2014, and many domestic biological bigwigs have summarized it. David Hughes and others combined serial block scanning electron microscopy (SEM) and deep learning-based image segmentation algorithms to visualize the distribution, abundance, and interactions of fungi in the host, which was able to examine the 3D structure and distribution of fungal cells in the muscles of the manipulated ants.
In other words, the ants were cut into 1200-2400 pieces of tissue, and after using fluorescence confocal microscopy, the test found that the fungal cells were concentrated only outside the brain, and no fungal cells were observed in the brain, which also means that the fungal control of the behavior of ants occurs in the outer layer of the brain. The fungus does not attack the host central nervous system, but other tissues of the body, so where exactly does the fungus control?
The next experiment sent chills down the spine, and fungal cells connected neighboring cells through the conidia anastomosis (CAT), forming a spiderweb-like structure around the host's muscle fibers. The mycelium network allows the fungus to obtain resources from the muscle and distribute these resources to other fungal cells in the network but away from the muscle, thereby cutting off the connection between the peripheral nerves of ants and the myofilament, achieving precise control of the jaw muscle.
Simply put, the fungus did not attack the ant's brain, but forcibly used mycelium to control the ant's muscles and occupy its body. This control is like a puppet in a puppet show. Compared with manipulating the central nervous system to achieve the control effect of the body, this barbaric way of manipulating muscles is obviously more direct and effective. Ants are likely to clearly perceive that they are going to death step by step but cannot redeem themselves, and eventually die a painful death. Fungi create optimal living conditions for themselves by controlling ants, thereby maximizing reproduction. The victims are not only ant colonies, but also other insects in the rainforest, and this terrifying ability has been used by video games after it was discovered, in "Pokemon", it is a large mushroom on Parast, and in "The Last of Us 2", it is a lateral snake cordyceps that mutates enough to infect humans and turn the host into a zombie. Back to reality, who was this terrible fungus discovered in the first place? How was this phenomenon first documented? How many years it took humanity to roughly grasp the mystery, these questions surrounded me and forced me to dig a little deeper. A Google search for who first discovered Cordyceps hemilateral snakes will come up with a not-so-unfamiliar name, Alfred Russell Wallace, a skilled British naturalist, geographer, anthropologist, biologist and illustrator.
If there was to be a simple word to sum him up, it was the man who pushed Darwin to publish the theory of evolution. However, Wiki only mentions that he discovered zombie fungi, but does not record any articles about zombie fungi, but the year is mentioned in the data, 1859 is the fifth year of Wallace's expedition to the Malay Archipelago. In 1854, Wallace set sail from England to the Malay Archipelago to collect specimens of various plants and animals for study and sale. In 8 years, he collected a total of 110,000 insects, 7,500 shells, 8,050 bird skins and 410 specimens of mammals and reptiles in the Malay Archipelago, of which more than 5,000 were new species he discovered. Wallace collected and recorded almost everything he saw, and 2% of all birds known today were recorded by Wallace. During his expeditions, he refined his ideas about evolution and summarized his insights on natural selection, and in 1858 he wrote a paper summarizing his theoretical summary and sent it to Darwin, which promoted the publication of Darwin's "On the Origin of Species". Later, in 1869, he published The Malay Archipelago, a book that has been in circulation since its publication and is still in circulation today, and can be said to be a sacred book of scientific exploration.
If Wallace has described a lateral snake from a grass fungus, then it is most likely in this book. In my experience, locating content in such lengthy books requires first looking at the title, and then searching for keywords in the electronic version of the document, but it didn't work out, and only one paragraph of fungal keywords appeared in the entire Malay Archipelago, and this paragraph is not describing the lateral snake cordyceps, but Wallace is describing a butterfly that imitates the fungal spots that grow on the leaves to camouflage itself.
I've been stuck here for a long time because there are only two possibilities for this, one is that Wikipedia went wrong and Wallace really didn't record zombie fungi. The second is that I missed or found the wrong book, because I didn't have much confidence in myself, so I assumed that I was wrong, but if Wallace did not record the lateral snake cordyceps, who was the first person to record this phenomenon? In the process of verification, I stumbled upon another article about Wallace, written by a retired biologist - Susan.
She mentioned her admiration for Wallace and read almost all the manuscripts and even letters Wallace had written. Because she is a doctor of biology, she was also curious about zombie fungi, so she wanted to get inspiration from Wallace's book, but she was also disappointed that not only did "Malay Archipelago" not record zombie fungus, but there were no zombie fungus-related topics in other Wallace's biographies and books. But Susan's article also proves that my thinking is not wrong, not only that, Susan also provides an important clue, biologist David Hughes of the University of Pennsylvania and others cited an ancient document from 1886 in a paper on the mechanism of zombie ant behavior. So I found this paper, Article 30 is exactly the article that Susan mentioned, and at this moment I had to lament the convenience of the Internet, even if it was an article from 136 years ago, I can find the original text in the BHL (Biodiversity History Library). And this document from 136 years ago is the first orthodox article to record the phenomenon of zombie fungi, written by William Fawcett.
The article chronicles an ant collector named Lloyd who found an ant with fungi growing in its body, and the original text describes the phenomenon as follows:
The ant seems to have been attacked by a fungus while alive, and the fine filial mycelium growing in the body will continue to squeeze its life until the mycelium finally grows at the joints of the chest and abdomen and attaches to the leaves where the ants are located, while the cephalic matrix grows between the head and the thorax.
And because Lloyd was the first to actually propose the phenomenon, the fungus is also named after him. However, looking down, a familiar name appeared - Wallace.
The article writes that in the collection of the British Museum, Wallace's bowback ants (Camponotus atriceps), black spiny ants (Echinopoa melanarctos) and polyrachis merops found in the village of Tondano in Brazil all have traces of Hemizos, and the Formica sexguttata from Brazil has also been attacked by a fungus, but this fungus is too incomplete , which could not be identified.
The ant Lloyd found was almost identical to the one Wallace found in the British Museum, and it dawned on me that Wikipedia was not wrong. According to time estimates, Wallace first discovered Cordyceps hemifolia in 1859, but Wallace himself was not interested in fungi, and only brought back ant specimens infected by fungi, and did not record this phenomenon of fungal infection.
In 1886, this phenomenon happened to be discovered again by ant lover Lloyd, and was recorded by Fawcett, so the first person to discover the zombie fungus was indeed Wallace, but the first to record this phenomenon was not him but Fawcett.
The article ends with a brief description of fungal infections in ants, and it's clear that 136 years ago, biologists had a vague idea of zombie fungi. This phenomenon could not be further explained at the time, and in the following 100 years, there was no breakthrough in the research of zombie fungi, and it disappeared from the public eye as expected.
It wasn't until 1986 that Janice Moore first threw that terrible concept to the scientific community through experimental proof, parasitic host behavior control. Zombie fungi have gradually returned to the biologists' research list with this concept, and the whole manipulation mechanism became clear only a few years ago.
But how does mycelium coordinate ant muscles for movement and bite?
Is there a network of information exchange between the hyphae?
How chemicals and molecular signals released during this period are regulated is still a mystery. Our understanding of fungi is only a small step, but the experiences along the way seem so distant.
Parasitic behavior manipulated by the brain - Toxoplasma gondii
When I was glad that zombie fungi could not control humans, I found that 1/3 of the earthlings were infected by another parasite. What's even more frightening is that when the doctor who studied him said this sentence in an interview: "We used to think that ideas belong to us, but..." It is another master of manipulation in nature, Toxoplasma gondii.
In August 2000, Joanne Webster and other scholars at the University of Oxford used a simple experiment to prove that Toxoplasma gondii greatly affected the behavior of rodents, its intermediate host. They placed mice infected with and without Toxoplasma gondii in enclosures with four different odors. Contains the smell of the mouse itself, the neutral smell of water, the smell of cat urine, and the smell of rabbit urine. The results of the experiment shocked scholars, and mice not infected with Toxoplasma were extremely disgusted with cat urine and avoided it, but mice infected with Toxoplasma were obsessed with cat urine and spent most of their time hovering around cat urine. Science has proven decades ago that mice have evolved an innate defense response to predator odors, and even after hundreds of generations of laboratory mice that have not been exposed to cats, they still show an averse response to cat odors. But Toxoplasma gondii single-handedly changed the long-evolved protective mechanism of mice, which caused all infected mice to lose their fear of cats and eventually send themselves into the mouth of natural enemies step by step.
This gave me 3 questions about Toxoplasma gondii. The first question is: How does Toxoplasma control mice from falling in love with cat smell? The second question is: why does Toxoplasma go to the cat's body when it wades through mountains and waters? The third and most important question: How does Toxoplasma affect people? Back in 2007, Webster published another paper. The article suggests that neuromodulation may be an ideal mechanism because Toxoplasma gondii can affect at least some of the host's behavioral expression. Experiments have shown that blocking the *N-* methyl-D-aspartate receptor in the amygdala of mice that controls normal anxiety and providing serotonin antagonists to mice will make these mice lose their fear of cats like mice infected with Toxoplasma gondii. The researchers also observed significant increases in levels of high vanillic acid, norepinephrine, and dopamine, which are substances that regulate motor activity, mood, learning, memory, and cerebral blood flow, in mice infected with Toxoplasma gondii. Robert Sapolsky's lab at Stanford University also found that Toxoplasma gondii cuts off fear circuits in the brain, which may help explain why infected mice lose their aversion to cat smell.
He also found that Toxoplasma gondii was also "able to hijack some of the sexual arousal-related circuitry in male rats," which he speculated could be achieved by raising dopamine levels in the brain's reward-processing portion. That said, Toxoplasma makes cat scent sexy for male mice. This answers my first doubt. On the second question, a major turning point came in 1970. Scientists have shown that cats are the ultimate hosts of Toxoplasma gondii, and that they can only reproduce sexually in the feline gut. But at this time, the researchers are not sure, why did they only choose felines as the final host. Until 2019, scholars such as Matorell discovered that while Toxoplasma gondii can reproduce asexually in any warm-blooded mammal, linoleic acid is required for sexual reproduction. Delta-6-desaturase is required for linoleic acid metabolism, and felines are the only mammals that lack delta-6-desaturase activity in the intestine, and the lack of this metabolite leads to a systemic linoleic acid excess in felines, which promotes sexual reproduction of Toxoplasma gondii. This means that Toxoplasma gondii is immature in intermediate hosts, and it must be eaten by its predatory final host before reaching maturity and completing its life cycle. So it manipulates the behavior of intermediate hosts to enhance propagation to the final host.
Speaking of the third problem, as early as the early 90s, a Czech parasitologist Jaroslav Fleg began to suspect that his personality was manipulated by a single-celled creature, resulting in his strange behavior and self-destructive tendencies. But his views were rejected by mainstream society in his early years, and he persisted in research and experimentation with little support. It took 15 years to finally conclude in 2007 that latent toxoplasmosis affects not only the behavior of rodent hosts, but also humans. His findings showed infection with Toxoplasma gondii. Men are more likely to ignore rules and become suspicious and more jealous. Women are more enthusiastic, outgoing and conscientious.
He once described himself in an interview: "I am very unhappy to be infected by some parasite, but... It's fun at the same time. I mean this idea could explain some of my behavior patterns. For example, I am not very afraid in situations where I should be afraid, which is a very strange behavior. For example, I was in Kurdistan, there were a lot of shootings around and I was calm. This wasn't the only case, and my startle reflex was also a bit unusual. My instinctive behavior in imminent personal danger situations is rather slow or passive. In situations where others might be frightened and don't look around or think deeply, my reaction will be slower and later. When a car rushes at me or a horn sounds behind me, I'm more likely not to dodge. "While looking through official sources, I discovered that Toxoplasma was first discovered and defined in 1908, but it wasn't long before I saw some more mysterious records. In some ancient civilizations, it seems that there have long been more magical descriptions of it.
In 610 AD, the Sui Dynasty's "Treatise on the Origin of Diseases", volume 23, recorded in the corpse and disease syndrome: "There are three corpse worms in the human body, born with people, and this worm is jealous of evil, can communicate with ghosts, often attract external evils, and cause harm to people." The three corpse insects here refer to Toxoplasma. The seizure mentioned in the article is very similar to the symptoms of a parasitic infection now in medicine. However, because the Sui Dynasty established the Imperial Medical Department, its facilities and medical system were not perfect, so people could not explain the cause of this disease. Therefore, Taoists attribute such illnesses to ghosts and gods. But it can be seen that the ancients have long been aware of this creature that cannot be observed with the naked eye. This makes me very curious, when exactly did nature create Toxoplasma gondii? Is there any record older than the Three Corpse Worms? If you want to ask when Toxoplasma was born, think from another angle. Since it can sexually reproduce in cats, does that mean that as long as it is known how long cats have existed, the history of Toxoplasma gondii can be traced?
The earliest recorded cat is the protocat, a prehistoric creature that lived in the Oligocene and Miocene, nearly 55 million years ago. But at present, archaeological excavations have yielded very little from it, let alone research data. If there is information to prove that evidence of Toxoplasma gondii has been found in protocat fossils, then it is certain that Toxoplasma gondii has a long history like zombie fungi. Unfortunately, there was no literature to provide such evidence, so I began to try to find some older information and documents to see if there were any more ancient related records other than the three corpse insects. According to the information about the three corpse insects, the three corpse insects were first proposed by Taoists, and Taoism was born in the Eastern Han Dynasty, more than 1700 years ago. Before this, there were not many large civilizations, and the civilizations with a large number of cat elements were easy to lock, one of the four ancient civilizations more than 7400 years ago - ancient Egypt.
So, I put my energy into articles related to ancient Egypt, and sure enough, I found some information. During the search, one word quickly caught my eye - mummy, the most representative symbol of Egyptian culture. The article mentioned that in 2013, scientists used NGS technology to find for the first time the DNA sequences of malignant Moreworm and Toxoplasma gondii in ancient Egyptian human mummies, which indicates that Toxoplasma has existed in ancient Egypt. To understand ancient Egypt is to understand its culture, and cats were important in ancient Egyptian religion about 2800 BC, and ancient people showed respect and loyalty to it. It is believed that the sun god Ra, who can transform into a pharaoh cat, travels to the underworld every night to fight against the snake demon Apophis, and only by killing the snake demon will the sun rise the next day. Cats were especially common in art around 1000 BC, and Egyptian archaeologists found hundreds of thousands of cat mummies with intact fur during excavations. They were taken to the capital of Bubastis, embalmed, mummified and buried in sacred cemeteries, expecting their owners to escort them into eternal life.
And these cat mummies are the same as the contemporary Egyptian pharaoh cat MUA, which proves that the ancient Egyptian pharaoh cat is the oldest domestic cat.
In this way, the frequent contact between domestic cats and humans can explain why the DNA sequence of Toxoplasma gondii was present in ancient Egyptian human mummies. The history of Toxoplasma gondii dates back at least to ancient Egypt, but I think its story is far older than we think. Under its simple physiological structure, it has really been studied by scientists for hundreds of years, but it is only a mystery that does not know why. Today, it can parasitize almost all mammals and infect 1/3 of the world's population. Perhaps, as Musk said, he is the real winner on the blue planet. But there is no need to be anxious about this, because Toxoplasma gondii is almost permanently dormant in healthy people. After all, human knowledge is its intermediate host, and it only poses a threat to humans when the immune system is destroyed or weakened.
Viruses (rabies virus, influenza virus, new coronavirus) As more and more parasites capable of controlling host behavior were discovered, I gradually began to accept this phenomenon. But when I saw this article, I was shocked again because it was so close to our lives. The article mentioned that the key to the successful spread of the new crown virus around the world may be related to the behavior manipulation of the virus, and perhaps the new crown still hides an unknown side.
Just a few months ago, in December 2021, the Journal of Biological Theory published Steven Macy's article on the mechanisms of coronavirus host manipulation, which discussed the ability of SARS-CoV-2 hosts to manipulate behavior. He mentioned that the new coronavirus uses a series of molecular mimicry strategies to manipulate the host molecular system, including adding cap mimicking structures to viral mRNA to mimic cellular mRNA, using replicating organelles to avoid innate immune surveillance, glycosylation of its surface spike protein to shield the epitope of the immune system, and a multi-base cleavage site spike protein located on its surface, simulating endogenous protease cleavage sites, tricking host neurofibrin into binding to it into cells, producing pain inhibition (analgesia) effects. It has a positive effect on the mood of infected people, alleviates social fear, and leads to an increase in the number and duration of social interactions of infected people. At the same time, a decline in the sense of smell in people infected with the new crown may increase risky behaviors like rats infected with Toxoplasma gondii, but it is not clear whether this increase in dangerous behaviors increases the likelihood of transmission. The spread of the virus usually requires only one cough or one sneeze, which is partly triggered by lung sensory neurons, and although the mechanism of cough induction in the new crown is still to be determined, it has been proposed that the infection is related to the production of the pro-inflammatory peptide bradykinin, which activates lung myelinated sensory neurons to induce cough.
Professor William Osler once said: "Mankind has only three great enemies: fever, famine and war. The biggest enemy of the three, and by far the most terrible, is fever. "Fever is also a useful indicator of the early coronavirus, but only 38.9% of the new crown infections evaluated in Puerto Rico last January had a fever, indicating that 60% of infected people are asymptomatic infections, and the article also mentions that asymptomatic carriers or mild patients may represent virus-induced human mimics." In other words, asymptomatic infected people may be manipulated by the virus, allowing patients to effectively imitate healthy people, reducing the vigilance of others when in contact with others, and contacts are less likely to take preventive measures and be infected with the new coronavirus without knowing it. All of the above phenomena are proving to us that the new crown virus is a smart and cunning enemy, we cannot take it lightly, it will use all the conditions of the host itself to seek benefits for itself, in order to maximize the spread of the virus. Coincidentally, in a 2010 study by Dr. Charles et al., they found that influenza viruses also increase human social behavior before symptoms appear, and although the adaptive significance of this finding needs further study, this behavioral change may increase the chance of virus transmission. At present, the research on virus manipulation is still in its early stages, and there is no reliable conclusion that the new crown has the ability to manipulate the host, but there is another virus in history that has been confirmed to have this ability, it is the rabies virus.
In 2017, Carsten Hugh et al. found that rabies virus can alter host behavior through a snaketoxin-like region of its glycoprotein that inhibits nicotinic acetylcholine receptors in the central nervous system (CNS), which leads to structural changes in the central nervous system, resulting in hyperactivity, increased bite frequency (and increased saliva flow) and more frequent social contact, which is thought to be rabies virus altering host behavior in order to maximize transmission.
There are many other parasitic manipulations in nature, but this is a vast and complex topic, and in Chapter 8 of Planet of Parasites, author Carl Zimmer compares humans to parasites, and Earth as the host.
He wrote in the original text: "When there is nothing shameful about parasites, we join a historic guild, which was born in the infancy of this planet and is already the most successful life form on Earth. However, we are still clumsy in terms of parasitic life. Parasites can shape hosts with extreme precision, changing them for specific goals. Parasites are also experts at causing necessary harm, because evolution has taught them that meaningless harm will eventually hurt themselves. If we, as parasites, want to succeed, we must learn from these masters. ”
Looking back at the entire history of parasitic behavior research, it is not difficult to find that today's research on parasitism has only taken a small step, and human beings have just lit a faint light in this field. But at the same time, humans are also the most incredible creatures on the planet, from scientists like Hughes and Flegg who spend half their lives working on a study, to explorers like Wallace who spend their lives exploring new species. It is believed that one day, mankind will solve all the mysteries of parasitism. As the Latin proverb goes, follow this hard journey to reach the stars!