by Daniel Keays

Mind Control

Rabere, Rabhas

Creeps up the nerve-cell highway.

Bullet to the brain.

 

            Fred Gipson was an American journalist who grew up on a farm in Texas in the early 1900s. The first part of his writing career was devoted to newspaper reporting, but in the 1940s he began writing short stories, eventually novels. He had several published, but his most memorable work was the book “Old Yeller,” the story of a stray dog a Texas pioneer family adopts in the mid-1860s. The book won the prestigious Newbery honor and was made into a successful motion picture by the Walt Disney Company in 1957. 

            While young Mr. Gipson was growing up in Texas hill country, his grandfather told him a story about a dog that was attacked and bitten by a wolf. The dog went on to contract the dreaded disease rabies. This incident stayed with him and became a central part of the book “Old Yeller.” Fortunately for most of us, the fictional story of Old Yeller and its dramatic depiction in the book and film is the closest we will ever get to this most horrible disease. Modern practices of vaccination and animal husbandry have seen to that. But in some parts of the world, rabies is still a scourge, just as it has been for millennia.

           For some serious infectious diseases, the torment comes from the physical manifestations of the ailment. In rabies, while the physical pain is formidable, the horrific nature of the illness is the mental terror accompanying the physical signs, including fear, panic, and the frightening reality that another entity controls our thoughts. The rabies virus makes its way into the victim’s brain and objectively redirects their thoughts to suit its own needs. It directs the infected person to bite other people. This is true of animals as well as humans. The rabies virus spreads through the introduction of infected saliva into another mammal's body, and it can alter the mind of the host animal to achieve its purpose.

            In “Old Yeller,” two portrayed facts tell a lot about the disease. The ailment is called hydrophobia, the fear of drinking water or other fluid. Another classic sign is “foaming at the mouth.” The two are related because the inability to swallow causes the symptoms. Swallowing water cannot be controlled, and it is likely to “go down the wrong pipe” directly into the lungs. The infected individual is acutely aware of this and avoids drinking fluids, including their saliva, which appears as “foam” as it collects around the exterior of the mouth.  

            The other is that the locals recognized “hydrophobia” in the area, referring to the siting of several animals diagnosed as rabid by their characteristic wild, savage, out-of-control appearance. This behavior is typical of the infected animal or person and foreshadows the unique symptom of the disease, the overwhelming urge to bite. In Old Yeller’s tale, the mention of local hydrophobia comes up several times, and the index case is a wolf that suddenly appears on the scene of the ranch where the family lives. Wolves were known to avoid human camps and communities, but this one came in and attacked. Old Yeller rises to the occasion and saves the family but becomes infected. The wolf’s strange actions, going decidedly against its nature, raise high suspicion that he was rabid. As is the case today, Yeller was put into quarantine and checked daily for symptoms. When they unmistakably appear, he must be put down, sadly, by the 14-year-old boy who loves him, as the father is away. For the boy, Travis, it is an unenviable rite of passage.     

 

           Rabies is an ancient disease, one affecting animals primarily, humans incidentally. It may be the first infectious disease for which the epidemiology was fully known to ancient people: an animal that has the disease bites another animal, and that animal or human becomes rabid. The infected animal’s wild, deranged behavior is usually unmistakable, and infected animals need to be destroyed before they can spread the infection. The first known writing about rabies comes from ancient texts from the Middle East in the area we now call Iraq. (It is sometimes referred to as Mesopotamia, mesos, meaning in the middle or between, and potamos, or river; between the Tigris and Euphrates rivers). In the mid-1940s, a pair of tablets from the area, written about 4,000 years ago, were recovered from a site about 30 miles northeast of Baghdad. They were a set of laws from the community of Eshnunna and are known as the Laws of Eshnunna. The laws are written in a very simple form, as if they were meant to be memorized. One of the laws states, “If a dog becomes rabid and the ward authority makes that known to its owner, but he does not watch over his dog so that it bites a man and causes his death, the owner of the dog shall pay forty shekels of silver; if it bites a slave and causes its death, he shall pay fifteen shekels of silver.” (The word for “rabid” can also be translated as either “furious” or “vicious.” As a reference, the near-contemporary Code of Hammurabi states that a small boat costs two shekels, so 40 or even 15 must have been a tidy sum).

            The first reported description of rabies transmitted by a dog’s saliva is attributed to the Roman scholar Celsus in the first century AD. He also recommended a cure, holding the patient underwater. The logic behind such a remedy escapes us today, but it may have sounded like a good idea at the time. Without knowledge as to the microbial cause of the disease, much assignment for the nature of the condition went to supernatural causes, often something akin to demonic possession. Numerous incantations and ceremonies were developed to dispel the disorder, and some may have seemed effective to those present at the time. The fact is, being bitten by a rabid dog doesn’t mean a bitten person will develop rabies. The bite must be deep with enough tissue damage to introduce the virus. Wounds that bleed excessively are more likely to expel the virus, lessening the chance of infection. It’s also possible the dog was just plain mean, not rabid, so no virus transmission occurred. If a preventative measure had been taken, it may have seemed effective, and its tale of wonder spread.

            Besides the supernatural, there was historically a school of thought that the dog’s saliva was poisoned, like that of a poisonous snake or insect. There were “cures” proposed for that as well, such as a preparation from the skull of a hanged man, cutting out a portion of the patient’s tongue, various poultices and herbal dressings, and hanging a calcified hairball from the stomach of a ruminant (known as a “madstone”) around your neck. A phrase that survives today, but in an entirely different context, is “the hair of the dog,” short for the original “hair of the dog that bit you.” It refers to the thought that “like cures like” (the Latin phrase is Similia similibus curentur):  placing hairs from the animal that bit you on the wound so rabies would not ensue. Today, of course, it refers to taking a drink of the alcohol that caused a hangover, hoping that a small amount of the drink will relieve the pains brought on by the large amount.  

            Clearly, none of the historic remedies had any effect on the unfortunate rabies victim. Even today, there is no cure for a person who develops the disease. One procedure that was a somewhat effective attempt at preventing the disease immediately after the bite is cauterization, using a red-hot iron to kill the tissue in and around the bite site. The procedure is first known to have been proposed by the Greek physician and pharmacologist Pedianius Dioscorides, who lived in Asia Minor and had close ties to the Romans. He wrote the time-honored volume De Materia Medica, a series of books containing information about herbal and other treatments and remedies. It remained “in print” for over 1500 years, and the cauterization technique for the prevention of rabies following an animal bite became something of a standard procedure. Getting one such burn is horrifically painful, but rabies victims are usually bitten several, sometimes dozens of times. The pain and horror of this preventative treatment are indescribable, but the other option was most likely an even worse death. Today we have very effective vaccines available, and the lag time from the bite to symptoms of the infection is at least a month, so there is time to administer vaccination soon after the rabid bite, a much better idea than burning flesh. But once the disease takes hold, the mortality rate approaches 100%. At one time, euthanasia, by smothering the victim between two mattresses, was a not uncommon practice once the symptoms were in full severity.

 

            The origin of the term rabies is interesting. Interesting in that the two languages to which it may be ascribed are not related. The Latin term rabere means to “rave” and would seem to be the logical source of the term rabies. But there is a Sanskrit word, rabhas, which means “violence.” Perhaps there was a confluence of terms during cultural interaction through early trade routes. The Greek word for madness is lyssa, which has become the technical name of the genus of the virus causing the disease, Lyssavirus.  

            It seems appropriate that the deadliest infectious disease is caused by a virus that physically resembles a bullet. The virus can enter the body in several ways, but in the vast majority of cases it enters by way of an animal bite introducing viral-containing saliva into the wound. The deeper the wound, the better for the virus. After a few weeks, the virus enters the axon of a nearby neuron, attaches itself to the internal transit system of the nerve cell, and progresses rather rapidly to the body of the nerve cell located in the spinal column. It can enter either motor or sensory neurons. From the spinal cord, it makes its way into the brain, then proceeds to infect an enormous number of brain cells, yielding a very high number of virions. Next, it progresses down a neuron into the tissues of the throat area, especially the parotid (salivary) glands. The activity in the brain results in the production of more virions and a profound effect on the infected person or animal’s thought processes. Namely, the infection causes the infected individual to have an overwhelming desire to bite another creature. There are also changes in the mental status of the infected individual. Death nearly always ensues. One might say that rabies, with the shape of the virus, is like a “bullet to the brain.”

            

            The rabies virus contains only five proteins, plus its genetic material in the form of single-stranded RNA. The key to the virus’ profound ability to infect and kill is a remarkable substance, the G-protein. (The G stands for glycoprotein, a combination of sugar and protein). It is present as the “fuzz” that projects out from the virus's surface. The G-protein is remarkable in that it is responsible for not just one but several vital operations in getting the virus into and through cells and into the brain. It also is chiefly responsible for reducing the immune system’s response to the invasion of the virus.  

            After entry into the body of the victim, the virus enters muscle fibers near the bite. Entry into the muscle cell is facilitated by the G-protein, which binds to a receptor on the outside of the cell. The virus is then actively transported into the muscle cell and resides inside an endosome. Because of the change in pH from neutral outside the cell to acid inside, the shape of the G-protein changes, allowing the virus to adhere to the endosome's membrane, causing the endosome to break apart and release the virus into the cell’s cytoplasm. During this process, the virus disassembles, and its RNA is released and available to be copied by the host cell’s ribosomes. Rabies virus RNA is “negative sense,” so it has to be copied by its own polymerase to make “positive sense” RNA, which is able to bind to host cell ribosomes and produce protein.  

            The rabies virus is a marked exception to the aphorism “more is better.” While very efficient at making copies of itself within the host cell, it is designed to curtail its numbers: enough to get the job done, but not too many to trigger the death of its host cell or signal the immune system as to its presence. Rabies is a “stealth” virus, creeping inside peripheral neurons until it reaches its targets, the brain and the salivary glands. Rather than acting like a powerful infantry, marching along with a great show of force, it assumes the role of a small unit of commandoes, much smaller in size but highly efficient and capable of great destruction.

            After replicating and producing suitable numbers in the muscle fibrils, the virus escapes into the space (synapse) between the muscle cell and the adjacent neuron. It then binds to a receptor on the neuronal surface and enters the neuron’s axon in much the same way it entered the muscle cell, using the G-protein. After entering the nerve cell axon, it attaches to the “fast-track” transport system, which carries molecular material from the axon's tip back to the nerve cell body in the spinal cord. Tetanus and botulism toxins utilize this same mechanism of transport.

            Again, the G-protein is responsible for this adhesion and transport. While the explanation is not clearly known, the virus can speed up its transport up the neuron, proceeding more rapidly than usual. It still takes a while, with an estimated rate of about 3 millimeters per hour. Axons can be up to a meter long, so it can take a couple of days for the virus to journey to the spinal cord. But being inside a cell protects the virus from the antibodies, macrophages, and lymphocytes the immune system uses to detect and eliminate invaders.

            After trekking up the nerve cell’s axon to the spinal cord, the virus enters the neuron cell body, replicating as it did in the muscle fibrils. Again, the number of virions produced is minimal, resulting in three favorable outcomes for the virus. First, the infected cell is much less likely to destroy itself through apoptosis. Apoptosis is often precipitated by viral proteins bumping against the cell membrane. Since there isn’t that much G-protein to adhere to the membrane, the apoptosis signal is not easily sent. Second, the chemical signals that are usually sent to the host cell genome to produce interferons a and b are muted, so very little of that protective substance is produced and transferred to nearby cells. This allows the virus a smoother trip along the neurons of the spinal cord on its journey to the brain because each cell on the way is more receptive to its entry. Third, chemical distress signals normally sent to the cell surface to alert natural killer lymphocytes are muted, and the cell appears perfectly normal and is spared. These three abilities of rabies, keeping the host cell intact, reducing interferon production, and mitigating against host cell destruction by killer lymphocytes, allow the rabies virus to trudge along nearly unmolested en route to its ultimate destination, the brain.

            After entering the brain, the virus no longer relies on the nerve cell transport system to carry it along. It is free to enter any and all of the brain's nerve cells. And it does. Virtually every cell in the brain is infected during a typical case of rabies, with obvious devastating consequences. The virus is especially good at infecting brain cells of the amygdala, the hippocampus, the thalamus, and the hypothalamus, key members of what has been called the limbic system. Just why it seems to strike these areas so virulently isn’t known; they rest on the top of the brain stem, so ascending viruses will likely encounter this area of the brain first. Perhaps these cells have more receptors on their surface for the virus to latch onto. Whatever the reason, attacking these specific areas results in marked behavioral changes. The infected patient becomes openly hostile and combative. They are also restless and agitated, and small sounds or other stimuli can send them into a hyperactive state. There is also the overwhelming urge to bite someone.  Paranoia is extreme, and patients lash out at the slightest thing in fear for their lives. 

            Meanwhile, the virus has infected brain neurons and neurons leading away from the brain and into the peripheral tissues. It becomes especially concentrated in the parotid, or salivary, glands. The mouth and throat muscles become paralyzed, and there is a loss of control over swallowing. Hence, the onset of hydrophobia and “foaming at the mouth.” This all plays into the virus's plan, enabling it to spread to another individual so it may propagate itself.

            The symptoms of rabies were elegantly chronicled by the eminent British neurologist Sir William Gowers, referred to by some as the founder of the science of neurology. Between 1886 and 1888, he wrote a classic two-volume reference, Manual of Diseases of the Nervous System. It is still used in some form today. In his chapter on rabies, he was very clear and thorough in his description:

            “Early symptoms show some discomfort about the throat, and occasional sense of choking, or a little difficulty in swallowing liquids. The attempt to drink occasions some spasms in the pharynx, which increases in the course of a few hours, and spreads to the muscle of respiration, causing a short, quick inspiration, a “catch in the breath.” This increases in severity to a strong inspiratory effort, in which the extraordinary muscles of respiration, sterno-mastoid, scaleni, etc., and even the facial muscles take part; the shoulders are raised, and the angles of the mouth drawn outwards. As the intensity of the spasm increases, so does the readiness with which it is excited. It may be caused by a mere contact of water with the lips, and a state of cutaneous hyperaesthesia (increase in sensitivity of the sensory organs) develops, so that various impressions, so that a draught of air, which normally excite the respiratory effort, bring on the spasm. The mere movement of air caused by raising the bedclothes may be sufficient. The patient is often unable to swallow the saliva, which is usually abundant and viscid, so that it hangs about the mouth and is expelled with difficulty. Vomiting is common. The spasm attacks are very distressing to the patient; the mental state which they occasion increases the readiness with which they are produced; in some cases, the mere sight of water or the sound of dropping water will cause an attack. It may even be excited by visual impressions that cause a similar sensation, as the reflection from a looking glass or a strong light. The sufferer’s horror and dread of these excitants becomes intense. Thus the disturbance in the act of swallowing liquids, which constitutes the first symptom and keynote of the disease, spreads on the one hand, to mental disturbance, and on the other to extensive muscular spasm. In each of these directions further symptoms develop. The spasm, at first confined to the muscles of swallowing and respiration, spreads to the other muscles of the body, and the paroxysms, at first respiratory, afterward become general, and assume a convulsive character, although still excited by the same causes. The convulsions may consist of general muscular rigidity. Actual delusions occasionally supervene, and there may even be wild delirium. The mental derangement is most intense during the paroxysms of spasms, and the frenzied patient may spit his saliva at those about him, and often attempts to bite them with his teeth, making occasional strange sounds in his throat which have been thought to resemble the barking of a dog.”

            

            After several days of this horrible experience, the patient invariably lapses into a coma and dies. Once the disease enters this late symptomatic stage, there is no cure. The patient may be placed in an induced coma in developed countries, but death is still inevitable.  

            The description above is known as “furious” rabies. In about 25% of cases, the disease takes another path initially, causing general paralysis. Why the disease progresses this way is not known, but just as with furious rabies, paralytic rabies results in death.

            

            For thousands of years, the fight against rabies was a losing one. Like in the novel Old Yeller, destroying an animal suspected of having the disease was the only recourse, along with cauterizing the wound(s). Most people were painfully aware of the consequences of a bite by a rabid animal, and one can only imagine the horror felt if a member of your family were bitten. For thousands of years, rabies plagued not only humans but their livestock, creating terror and sometimes food shortages, even though the disease was not primarily human or domestic animal by nature. People lived close to the land, and the wild mammals that inhabited it were continually subject to becoming infected by the very efficient and lethal rabies virus.

            German physician Georg Gottfried Zinke presented in 1804 the first scientific evidence of what was suspected for centuries, that the saliva of an infected animal spread rabies. He took the saliva from an infected dog, injected it by syringe into a healthy dog, and produced the disease. He also produced the disease in rabbits by the same method. An enormous breakthrough came in 1882 when French veterinary microbiologist Pierre-Victor Galtier injected rabies-laden saliva into sheep, but not into their skin. He injected it into their veins. Much to his surprise, this did not give them rabies. On the contrary, it protected them from the virus he subsequently inoculated into their skin. Galtier’s research laid the groundwork for the historic discovery made a few years later, a vaccine against the dread disease.

            Many people consider science boring—repetition after repetition, written in words that resemble a foreign language. But sometimes science can present compelling, suspenseful, emotional dramas that rival the best of books, plays, or motion pictures. Such was the case with the development of the first anti-rabies vaccine by a team led by Louis Pasteur in 1885. Pasteur, of course, was familiar with the smallpox vaccine, which used a virus that was similar but different from the one that caused the severe disease. He himself had produced a vaccine protective against chicken cholera bacteria (now called Pasteurella multocida) and the often-fatal animal bacterium Bacillus anthracis, the cause of anthrax. He used old, dried-out cultures of chicken cholera bacteria. And he and grew the anthrax bacterium at higher and higher temperatures.  In both situations, the microbe was changed or “attenuated.” This way, they could be inoculated into animals without causing the disease but still inducing the formation of immunity. (The word attenuate, meaning to weaken or lessen, comes from the Latin tenuis, to “make thin”). By 1885 Pasteur had made two other extremely important discoveries: gently heating wine and beer to prevent spoilage (later called Pasteurization), and isolating diseased silkworms from healthy ones to allow the more abundant formation of silk, a major industry in France at the time. In doing all this, he gained notoriety and was well-known to the average Frenchman. Arguably, his greatest accomplishment was still to come: developing a vaccine for the terrifying disease rabies.

            Pasteur hypothesized that a changed microorganism similar to but distinct from the disease-causing agent could induce immunity but not cause the disease. He sought to produce such a change in the microorganism responsible for rabies. The animal model he used was the rabbit, in which it was possible to induce rabies by injecting them with rabid dogs' saliva, as Zinke showed many years before. As one can imagine, rabid rabbits are much easier to work with than rabid dogs. Since rabies takes a long time to develop when it is injected into muscles, Pasteur short-circuited the natural route by injecting the material directly into the rabbit’s brain, a technique called trepanation. Rather than waiting months to harvest the virus, it could be done in a few days. When injected this way, the virus spreads through the rabbit’s brain and into its spinal cord. This was the objective of Pasteur’s investigations. He harvested the spinal cord of the dead rabbits and put each into a sealed container containing a tiny bit of potassium. The potassium removed the water from the air, giving a dry environment. By experiment, Pasteur found that rabid rabbit spinal cords dried this way were not infectious after about two weeks. Those freshly put into the dry air containers were highly infectious for one to two days. There was a clear spectrum, showing more virulence with shorter time periods and little or no virulence after two weeks, with time periods in the middle showing some but markedly reduced ability to infect.  

            The work was arduous, and it was dangerous. Imagine being assigned the job of securing saliva from a rabid dog. When the test animals were inoculated, the virus was just as virulent as the wild type, and any slip-up in handling the animals would be deadly. And not just a simple death, but a brutal, torturous one. Pasteur, of course, gets the credit for the theory and the experiments, but the nameless laboratory assistants who did the work also deserve much adulation.

            The telling experiments began once the attenuated virus was obtained in ground-up rabbit spinal cords. Fifty dogs were immunized, first by giving them two-week-old, or non-virulent, spinal cord material. A few days later, more material was given, this time from material that was thirteen days old. Then twelve-day-old material, and so on, down to spinal cord material only a couple of days old. The dogs were observed for two weeks, and none developed rabies. Then the real test: the fifty dogs were each inoculated with fresh saliva from rabid dogs. Much to the elation of the Pasteur team, none of the dogs developed rabies. All were immune.

            

            Alsace, France, is a picturesque area in the mountain region bordering France, Germany, and Switzerland. It is on the western bank of the Rhine River, and the area's culture shares the traditions of both French and German history. Known for its lush valleys and scenic mountains, the quaint Alsatian region and lifestyle are the stuff of tourist brochures and quiet getaways. In 1885 it was part of Germany. In this quiet mountain area began one of the epic tales of medical history.  

            One morning in early July 1885, Alsatian baker Joseph Meister sent his nine-year-old son, also named Joseph, to a neighboring village to get yeast from the brewery there. From out of nowhere came a large, viscous dog, clearly mad, who caught and attacked the helpless boy in the most savage fashion. A policeman shot the dog. Joseph received 14 severe wounds from the dog, whom neighbors saw and clearly identified as rabid. The dog’s owner, Monsieur Theodore Vone, knew his dog had recently changed dramatically and thought him rabid. Joseph’s wounds could be bound up and possibly healed, but the boy’s parents knew they were not the primary concern: the dog was rabid, which was a death sentence for their young son—a most horrible one at that.

            The town physician, Doctor Eugene Weber, came to treat Joseph’s wounds that evening, about 14 hours after the attack. He treated them with carbolic acid and sutured those that he could.  Dr. Weber was honest and blunt in his conversation with Joseph’s parents. While not every bite by a rabid dog results in rabies, many do, especially when there are multiple wounds. The prognosis was grave.

            Some locals had heard reports, even way out here in the far reaches of the German/French countryside, that scientists in Paris were working on a preventive cure for rabies. The dog’s owner, Monsieur Vone, had stopped by a pub on his way home after visiting Joseph’s family, and he listened intently as the conversation centered on the Paris scientists’ work. He rushed back to the Meister home to relay what he had heard. Without hesitation, Mademoiselle Meister took her son on the three-hundred-mile train ride, even though she didn’t know anyone in Paris and didn’t know the name of the scientists. The dog’s owner accompanied them. When the mother and boy arrived in Paris, she immediately went to a hospital, explained her situation to a doctor, and inquired about the scientist working on rabies treatment. The doctor knew right away about the work of Pasteur and his associates and escorted them to his laboratory. It was July 4, 1885, when the Meisters met Louis Pasteur.

            In the 19^th century, there were no government oversight committees on medical treatments as we have today. Doctors and scientists were guided by their sense of ethics and morality, and therapeutic trials were based on what was seen as the wisest options available. Pasteur listened intently and with sympathy to the tearful woman explaining her son’s situation, but he was naturally concerned. His treatment had successfully prevented rabies in dogs, but the jump to humans, using a known killer virus, was disturbing. What if the virus wasn’t fully attenuated and injected directly into a human? Certainly, it would mean a horrible death to the injected individual. Pasteur would have preferred more animal trials and time to evaluate the data, but the case before him couldn’t wait. Young Joseph had already received a death sentence and was likely to die a wretched death. One prominent physician-scientist in the laboratory, Emile Roux, reportedly refused to participate in the therapy on ethical grounds. Pasteur reluctantly decided to go ahead and allow the administration of his anti-rabies emulsions.

 

            “As the death of this child appeared inevitable, I decided, not without deep and severe unease, as one can well imagine, to try on Joseph Meister the procedure which had consistently worked in dogs.”

                        —Louis Pasteur

            

           Pasteur was not a medical doctor. A physician was required to oversee the injections, and two volunteered, Drs. Alfred Vulpian and Jacques-Joseph Grancher.  On July 6^th, young Joseph received his first injection, material taken from a 15-day-old emulsion of a rabbit spinal cord. Over the following ten days, Joseph received 13 doses of younger and younger emulsions. At ten days, he received an emulsion that was only two days old, clearly enough to induce rabies.  

            Waiting can be excruciating, especially when the outcome may be horrific. But after two months, it became clear: Joseph Meister was rabies-free! The treatment had been a tremendous success, and the world was on its way to at least partially containing this most terrible disease. Much work remained to be done to advance from these crude beginnings, but the prophylactic rabies treatment performed in Paris in July of 1885 was one of the great accomplishments of human history.           

            Of course, scientific experiments need to be confirmed, and another case presented in October of the same year. Fifteen-year-old Jean-Baptiste Jupille was tending sheep in the farming community of Villers-Farlay in eastern France, not too far away from Alsace. He was also watching over five young children. A rabid dog appeared, threatening all, but Jean-Baptiste threw himself into direct contact with the dog, fighting it until the children could run away. He sustained multiple deep bites in his act of heroism, and his future was in grave peril. But he was able to travel to Paris to receive the new therapy at the Pasteur Institute, and, like Joseph Meister, his life was spared.  

            Word of the success of the post-exposure rabies treatment traveled fast. Soon bite victims from all around Europe were coming to Paris to be treated. Nineteen people traveled from Russia after being attacked by a rabid wolf. This created an enormous problem, as the vaccine material was in short supply and was very difficult to make. Also, it didn’t travel well and could not be shipped to remote locations, requiring bite victims to make their way to Paris. Adding to the difficulty was what is known today as the “worried well.” Not every dog that bites a person is rabid, and not every wound from a rabid animal will result in rabies. Given the limited supply of vaccination material, difficult decisions had to be made based on the time elapsed from the bite, the nature of the wounds, and the veracity of accounts as to the condition of the animal involved. But the workers in Paris did the best they could, and in one year after the first trial, over a thousand patients were treated with rabies post-exposure treatment. Most survived, although there were a few deaths.  

            Following the dramatic success of the Pasteur rabies treatment in Paris, clinics sprang up worldwide. Elie Metchnikoff led the first one in Odessa, Ukraine, in 1886, with many to follow. Some were directly associated with the Pasteur Institute in Paris, but many were not, though they still carried the name. 

            Advances to the treatment came incrementally, with the most significant breakthrough at the hands of a British doctor, David Semple, who served as a lieutenant colonel in the British army in India. In 1911 he perfected the means of giving live rabies virus to rabbits, letting them develop the disease, then harvesting their brains with the intact virus. He killed the virus by subjecting the “brain soup” to phenol. This created a vaccine that could be stored and transported and didn’t have the chance of giving a patient rabies instead of preventing it. Later the virus was grown in sheep instead of rabbits. To be effective, the Semple vaccine had to be administered by injection into the patient’s abdomen, a painful event. And one shot was not enough; a half dozen injections were necessary.  The fact that the patient was receiving not just a killed virus but emulsified sheep brain was a big concern, as a few patients developed a hyperimmune disease. It was better than the original rabies post-exposure prevention, but it was clearly not ideal. Still, the Semple method was the preferred rabies prevention therapy for nearly half a century.  

            In the late 1950s, scientists at the Eli Lilly pharmaceutical company succeeded in growing the rabies virus in duck eggs. That freed the vaccine of most contaminating material. More recently, the virus has been successfully propagated in cell culture, and it can now be administered with very few side effects. The current regimen for people exposed to a suspected rabid animal in developed countries is straightforward. The virus and the infection it causes are unique, so preventative therapy must be tailored to combat the disease most advantageously. Nothing in medicine is one hundred percent effective, but the current therapeutic regimen is reliable for the most part.

            

            The rabies virus, known technically as Lyssavirus, does not normally enter the bloodstream. In fact, it doesn’t enter body cavities or intercellular spaces. During its early phases, it enters muscle cells, then jumps to neurons. Unlike most viruses, it doesn’t produce large quantities of itself while reproducing. It makes just enough to get its travel job done, and until it gets into the brain, very few virions are loose in the body. Thus, the immune system doesn’t encounter the virus enough to build an immune response. The virus proceeds to the brain by traversing the synaptic spaces, a very small area, and traveling up the nervous system, moving from one cell to another. The synaptic space for us is very small, but it is quite a distance for a tiny virus. The synaptic space is the only location where the virus is exposed to the immune system and its many weapons. Cellular immunity is ineffective since the virus is very good at suppressing the host cell’s signaling and self-destructing mechanisms. Humoral immunity, antibodies produced by B-lymphocytes, is the only effective means of thwarting the virus’ advance. Flooding the synaptic space with antibodies prevents the viral G-protein from adhering to its nerve cell receptor, and the virus cannot advance.

            Since the virus normally doesn’t inhabit areas in the body that would illicit contact by dendritic cells or lymphocytes, antibody production is minimal to non-existent. Indeed, people with full-blown rabies don’t have their own naturally occurring antibody until it’s too late. It is only in the very late stages of the disease, when death is imminent, that antibodies produced by the patient begin to appear, too late to do any good. 

            Following the bite of a dog or other animal that may have rabies, the wound(s) must be thoroughly cleansed. Soap and water are a good start, along with an antiseptic. Povidone iodine has proven effective. Topical antibiotics, of course, do no good for rabies since a virus causes it. Still, other diseases may occur following a dog or cat bite, and a topical antibiotic would be useful in preventing them.  

            The key to preventing the onset of rabies after the bite exposure is to get as much antibody into the patient as possible. This is done by two means: Administering an antibody already made in another person or animal (passive immunity), and administering large quantities of dead virus to stimulate the patient’s immune system to stimulate a strong response (acquired immunity). For passive immunity, the so-called hyperimmune serum is administered on the first day of treatment, preferably in the vicinity of the bite wound. The dead virus-containing vaccine is administered over a period of several days. The two injections must be given in different parts of the body, as the pre-formed antibody would quickly inactivate both itself and the dead virus if given in close proximity. In the days of the Semple vaccine, the one using killed virus mixed with the brains of infected sheep, the inoculation had to be given into the abdomen over the course of around seven injections, a very painful process. Today, the virus is prepared in cell culture, and it usually only takes four injections into the arm, and they are relatively pain-free. The Centers for Disease Control in the U.S. recommends that the vaccine be given on days 0, 3, 7, and 14.

            The prevention of rabies by this method is unique. The disease incubation time is so long that it is preferable to quarantine the offending animal for ten days to determine its status before initiating treatment. But that still leaves enough time to begin therapy. If the animal remains healthy, there is no need to proceed. If the animal is unavailable or is determined to be rabid, the vaccine is given in a short time. For most other diseases, multiple doses of vaccines are administered over months, often years.  With rabies, it’s four doses in just two weeks. The plan is to induce the formation of much specific antibody in a short amount of time. 

            The diagnosis of rabies is usually very easy or very difficult. It’s obvious when the patient is known to have been bitten by a rabid animal and goes on to display classic symptoms. It is difficult if the animal bite is not apparent. In the developed world, most rabies cases arise from the bite of a mammal other than a dog, such as a bat. The disease may take months to develop, and the patient may not comment on the event, especially if it’s a child. In such cases, the diagnosis is problematic.  

            In the early stages of the disease, the virus can’t be cultured or detected by molecular methods from easily obtainable specimens like blood or spinal fluid. It doesn’t induce antibody formation early in the infection, so serology to detect antibodies is fruitless. No known chemical substances can be detected in the blood or other body fluids that can serve as a marker to raise suspicion about the presence of the virus. And early abnormalities of vital signs are non-specific.  

            In 1903 an Italian pathologist, Adelchi Negri, reported finding material within the brain cells of dogs that had died of rabies. The material was seen as round, red-staining (acidophilic) dots about the size of bacteria. They were only seen in cases of rabies, and for a good part of the 20^th century, these Negri bodies, as they came to be called, were a diagnostic hallmark of rabies. For a long time, there was debate about what Negri bodies were. Dr. Negri insisted they were a tiny parasite that caused the disease. Others maintained that was not the case, as the agent was filterable, that is, able to pass through a very tiny sieve. These “filterable agents” were later called viruses, and the Negri theory of a parasitic cause of rabies was erroneous. Nevertheless, finding Negri bodies in biopsy and autopsy material was a useful diagnostic tool for many years.

            (It is interesting to note that another scientist, American Dr. Anna Wessels Williams, also discovered the cellular inclusions of rabies around the same time as Dr. Negri. But since the Italian scientist published his data first, they came to bear his name. Dr. Wessel’s staining technique, though, is the one that became the standard).

            Today we have a much better technique for diagnosing rabies, the fluorescent antibody test. Antibody to rabies is attached to a molecule that will fluoresce when exposed to ultraviolet light. When the suspected infected cell is flooded with this agent, the antibody will adhere to the virus and be seen under a fluorescent microscope. Detecting the Negri body is very suspicious for rabies, but false negatives exist. The fluorescent antibody test is much more sensitive and specific. It is the method of choice today. Unfortunately, both tests require cellular material obtained by either biopsy or autopsy. Quite often, the diagnosis comes too late.

            

            Other infectious diseases can result from a dog bite or exposure to dog saliva. The most common is the bacterium Pasteurella multocida. The organism was first described by Louis Pasteur as the cause of fowl cholera and was the organism he attenuated to induce immunity in chickens. While more common in house cats, P. multocida often exists as normal bacterial flora in the dog’s mouth. It doesn’t make the dog sick, but when transferred to a human in an open wound, the bacteria can set up an infection within the bite area. The wound becomes inflamed and red, often draining pus. It is usually cured with appropriate antibiotics. Less common is the human infection caused by the dog bacterium Capnocytophaga canimorsus. While less common than Pasteurella multocida, it is often more serious. It usually doesn’t infect people with intact immune systems but those with underlying medical problems. Alcoholics are the most vulnerable, as well as the elderly. The organism doesn’t have to enter the body by a bite. Sometimes the dog merely licking the individual is enough. The organism can cause sepsis, and vigorous antibiotic therapy is required.

            Both organisms are bacteria, and neither is related to the virus rabies.  As with rabies, proper cleansing and decontamination of the wound, if there is one, is important to ward off a possible infection.

 

            To many in the developed part of the world, rabies is a remnant of a bygone era. We read about it in stories or see a newspaper account of a rare case being described somewhere in a rural area. Unfortunately, though, rabies is by no means extinct. The World Health Organization reports at least 55,000 cases of rabies occurring in humans annually, all fatal. Many of the afflicted are children. That’s the number officially reported. Undoubtedly, many cases in rural areas of underdeveloped countries go unreported. Part of the reason for the virus’ persistence in causing human infections is the cost of vaccines. Costs vary over time, but some approximations:  

            The Semple vaccine, prepared crudely in the brains of sheep or goats, costs about $5 per course of post-exposure treatment. The vaccine is administered abdominally and is quite painful.  This is the vaccine most used in underdeveloped areas of the world.

            The human diploid cell human vaccine used in the U.S. costs about $500 per course. It is administered in the arm and feels like any other shot.

            Access to good medical care is also essential, of course. Proper cleaning and disinfecting of a wound are essential in preventing rabies and more common bacterial infections. Many people in the world don’t have access to even that.

 

            Most people wish for a dignified death. Perhaps a quiet room in our home, with family and friends in attendance. The horror of rabies steals that away. Death from rabies is inevitable, and its terror is unrelenting. Fear, anxiety, paranoia, and combative behavior. Hardly the makings of a peaceful death. In developed countries, it is possible to induce a coma so that the patient slips away quietly.  But rabies is a dreadful curse in areas without access to quality health care. With control measures well known, it is a very sad affair.

Dogs infected by rabies show signs of restlessness, uncharacteristic aggressive behavior, and impaired walking, eating and drrinking. (PHIL)

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