Rabies, a virus, but oh what a virus

Rabies, a virus, but oh what a virus

The specific ways that rabies affects the nervous system, its sole target, can tell us volumes about human behavior, normal and abnormal, and human development, from infant to the fully socialized, highly civilized beings we are expected to become as adults.  It can show us the extent to which humans act as vampires and werewolves, and the meaning of such behavior.  Yet, the rabies virus has not given up its knowledge, although it has been part of our written history since writing began. 

So what is this rabies, this lyssavirus that I am rabid to understand?  Briefly, it is a virus, meaning it contains a long string of RNA (ribonucleic acid) molecules whose.  The specific order of these different RNS molecule makes a code on how to make various proteins. The RNA is packaged inside a protective shell that also contains a specific chemical motif that will provide attachment to the cell it will infect.  Viruses do not have the machinery to gather the necessary material – amino acids – nor the assembly lines to actually construct proteins or RNA.  Therefore, replication of viruses is dependent on the virus’s ability to enter and take over the machinery of a cell that is self-replicating.  Entry must be made into a host cell, that is, a cell whose protein-making capabilities can be manipulated by the viral RNA.  This entry primarily occurs via attachment of the virus to a receptor molecule on the outside surface of the host cell.  Once anchored to the outside of a host cell, the virus may have its own machinery for injecting its RNA through the cell’s membrane (its ‘skin’).  More often, the receptor is internalized into the host cell as part of the normal replacement of that receptor.  In this case, the virus just hitches a ride into the cell.  Lyssavirus uses this method, hitchhiking, to enter its host cells.

The receptors used by many viruses are fairly common across many types of cells or the cells having the necessary receptor are fairly frequent.  The rabies virus is unique in the level of specificity of its target.  Rabies can only infect (enter and take over) neurons.  And, it can only infect neurons of the brain and spinal cord, that is, the central nervous system (CNS).  Neurons wholly outside of the CNS, in the peripheral or autonomic nervous systems or sensory neurons, apparently do not have the appropriate receptor molecule.  Nor does any other cell in our body!  Among other things this means that just because one is bitten by a rabid animal, even having virus-laden saliva in the bloodstream, does not mean that one is infected.  At this stage the victim is simply exposed.  While this is true of any virus, for most viruses the time from exposure to infection is very short.

The CNS is well-protected from many kinds of unwanted material, be it bacteria, toxins, even the body’s own immune cells.  This is a result of the blood-brain barrier.  This consists of very tight junctions – very tiny spaces -- between cells of the blood vessels in the CNS.  The CNS maintains a stringent regulation over what is allowed to enter, or leave, the CNS.  Rabies viral particles are too large to slip between the cells of the cerebral blood vessels.  The virus also cannot infect the cells of the blood vessel walls and thus cannot enter the CNS in that way. 

There are a few CNS neurons that extend out of the CNS.  One type is the neuron that controls skeletal muscle movement, called skeletal motorneurons.  Almost without exception it is the endings, nerve terminals, of these CNS neurons, which are located in our skeletal muscles that are the target for rabies infection. 

Rabies is the only tool for understanding lyssants

Rabies is the only tool for understanding lyssants

We glibly talk about the brain regions and circuits of the rage circuit as givens, but they cannot be effectively studied at the present time.  The risks of working with rabies-infected animals as well as the cruelty of forcing experimental subjects to experience the lethal effects of rabies infection render this approach unacceptable.  We must, instead, be able to work with the native target for the virus, able to turn on, and off, the effects that the virus would produce, without the fear of actual infection and death. 

Early on in the study of animal psychology investigators stimulated various regions of the brain to see what would result.  In some cases they induced behaviors, in cats especially, that had characteristics of attack or of defensive rage.  However, without an object to fully express these behaviors upon, it was difficult to say what was being produced; aggression, defense, rage, or simply a collection of muscle movements.  In light of the uncertainty of what these collections of behaviors meant, they were termed “sham rage” and investigation of them stopped. 

Another tool that held promise was a result of damaging a brain region known as the septal nucleus, an area in the heart of the rage circuit.  Damage to this area sometimes produced a syndrome very much like furious rabies where sudden noises or movements would result in a sudden, full-blown attack on whatever happened to be near.  I can personally vouch that the attack rabbit from Monty Python and the Holy Grail is no fiction!  The speed and ferocity of a raging rabbit flying out of its cage and aiming itself directly at one’s throat is terrifying.  Unfortunately, for our understanding of the basis of rage, this syndrome disappears fairly quickly after the septal area is damaged and is therefore not useful for study. 

Some instances of human rage, like that of Charles Whitman’s murder spree from the University of Texas Tower, can be traced to specific trauma to the brain; in his case a tumor pushing on another structure in the rage circuit called the amygdala.  However, most lyssants, like animals infected with rabies, show no signs of structural damage in the brain.  We know that the amygdala is activated during very stressful events, like those that result in PTSD (post-traumatic stress disorder).  This activation appears to be necessary for making the emotional memories so strong.  We can presume that this type of activation of the amygdala is important for the amazing feats of strength, etc. that can occur in emotional situations.  On the other hand the amygdala is largely absent in some people.  These people do not feel fear.  The understand that certain situations are dangerous, but they do not express fear in the situation.  They don’t exhibit lyssantic behaviors.  We can expect that pharmacological manipulation of the amygdala or brain regions connected with it will allow us to induce rage.  However, this hasn’t occurred yet, strongly suggesting that the critical neuronal circuits, the critical neurotransmitter receptors, are not known.  But we do know that rabies virus, its targeting motif, can produce rage behaviors, so we can presume that it is affecting the critical receptors. 

Experimental neurobiologists have also studied aggressive behavior, but aggression by itself overlaps only partially with rage.  Even the studies of aggressive behavior have had limited success, in large part because we did not/do not have pharmacological tools to selectively stimulate and block all the subtypes of serotonin receptors that appear to be the most promising underlying mechanisms.  Even when these tools do become available, it is already clear that aggressive behavior is quite different from rabidity.  Aggressive behavior, bullying is one aspect, has a large component of voluntary control with positive reinforcement of past occurrences that lead an individual to continue to use these behaviors.  On the other hand one of the hallmarks of lyssantic behavior is that it does not appear to care whether it is likely to result in a win or a loss, it just rages.  Of course, we presume that lyssantic behavior has been successful in keeping individuals alive and therefore has been kept as an important part of our genetic heritage.  I expect it is possible for people to learn the triggers that can release a lyssant’s rage, but there is still a large difference from aggressive pushiness and impulsive aggression.  Reports about the changes in demeanor of people like Al Capone going beyond their being aggressive to becoming a ‘monster’ with a baseball bat are probably good examples of lyssantic behavior in action.

Our most promising avenue to pursue understanding lyssants and their behavior is still the rabies virus.  However, as long as we have only the lethal virus itself, we will be unable to fulfill our need to understand rage.  We must, and we have the tools to do this, discover the target of the rabies virus; the only psychologically important part of the virus.  Being a virus has largely distracted us from learning the secrets it holds to our own inner selves.  The behaviors it unlocks in its victims are not the result of it being a virus, only its targeting motif is necessary to produce these behaviors.  So, we need to discover the target.  And, as a major added bonus, discovering the target, the CNS receptor, will also provide us the means to discover post-infection treatments for rabies itself.  It’s a win-win-WIN BIG situation.

Lyssants – incidence & prevalence – anyone willing to be census-takers?

Lyssants – incidence & prevalence – anyone willing to be census-takers?

Just how prevalent are lyssants?  At some time we have all been lyssants even if only when we were toddlers and having a temper tantrum.  It is a natural part of our behavioral repertoire.  It plays a critical role when it occurs as defensive rage and allows us to overcome or frighten away an assailant.  And the playful frenzy during sexual relations can serve to strengthen interpersonal attraction, and can help overcome external pressures.  But, for teens and adults, becoming a lyssant often produces more trouble than it solves.  Lyssant behavior is not tolerated in most societies and is quickly punished.  An exception occurs to some regulated degrees in various sports.  Even here, there is increasing recognition of progressive neural damage from multiple physical traumas.  This suggests these outlets for our innate lyssantic behaviors need continual monitoring and improvement in safety equipment and health surveillance. There is no chance, certainly no wish by this author, to try to curtail these means of ‘letting off steam’.  I fully believe this would be disastrous to us as a species and would just move such behaviors further into underground fight clubs and the like.

Given the lack of a specific accepted definition or test, calculating the prevalence of uncontrolled lyssant behavior is presently impossible.  However, some insights into its prevalence may be gained from comorbidity studies.  For example, the occurrence of oppositional defiant disorder and/or conduct disorder in people with ADHD is commonly reported to be 30-50%. Certainly not all are lyssant, but some are.  The rage cycle in people with an autism spectrum disorder is well-recognized.  Some of this behavior is surely lyssantic. The prevalence of Intermittent Explosive Behavior has been estimated to be from 3-7% of the population.  What is crystal clear is that rage that “comes out of nowhere” is common, and more so among people with other conditions that make generating accepted social behavior difficult.  It is also clear that ADHD, autism disorders, bipolar disorder, and others are not synonymous with lyssantic behavior.  Lyssants need to be uniquely defined and specific treatments found for when their behavior interferes with the conduct of their lives.  Specific means to draw it out, like sodium lactate for panic disorder, must be found.  And, as much as I admire the accomplishments of cognitive-behavioral therapy (CBT), I simply do not believe that overt reinforcements or ‘mindfulness’ can address the true measure of lyssantic behavior.  I know a number of people that can recognize they are heading toward having a migraine headache, but they still need pharmacological treatments to blunt or block the migraine headache itself.  Lyssantic behavior is much, much more powerful than that.

there be monsters… actually, they’re lyssants

there be monsters… actually, they’re lyssants

If, as I proclaim, rabidity is a natural part of human behavior that emerges in a number of situations, then we need a single, general term to refer to a person or animal affected in this way.  I introduce a new word, lyssant, to refer to a person or animal exhibiting rabid behavior, however it is induced.  The word derives from the Greek word, lyssa, which refers to rabies, certain kinds of madness, and is the goddess (daimona, i.e. spirit or demon) of rage, fury, and rabies (ref).  Indeed, the formal name for the rabies virus is Lyssavirus.  The Roman equivalent of Lyssa was variously called Ira, Furor, and Rabies.  Although this narrative will continue to use terms such as rabid, vampire, werewolf, intermittent explosive behavior, road rage and others, all refer to a lyssant, a person or animal exhibiting these behaviors.  This term also allows us to dissociate temporarily our discussion from a second set of symptoms of rabies, the so-called dumb or paralytic form.  Lyssa clearly refers to the rage aspect, i.e., furious rabies, and for now, lyssant does also.

Lyssantic behavior is found throughout psychiatry and clinical psychology.  However, its appearance is fragmented, inserted piecemeal into a wide array of behavioral disorders.  Behaviors that include rage are clustered with Impulse Control Disorders where they are uselessly clumped together with kleptomania and compulsive gambling.  Lyssantic behavior is couched in a variety of terms including Impulse Control Disorder, Intermittent Explosive Disorder, Conduct Disorder, Emotional Dysregulation, Impulsive Aggression, and others.  Lyssants and their behaviors are listed among the myriad of symptoms of broader diseases including Attention Deficit/Hyperactivity Disorder (ADHD), for example ADHD with Conduct Disorder, and in various subclasses of autism spectrum disorders.  Disorders such as road rage and domestic violence are shunted into corners of Personality Disorders that have no meaningful therapeutic approaches. 

This jumble is clearly the result of a lack of a specific physiological or pharmacological means of categorizing lyssants and their specific set of neuropsychiatric characteristics.  At best it is likened to the temper tantrums of toddlers.  While temper tantrums are surely lyssantic behavior, psychoanalytic analysis of regression to some unconscious psychological trauma is of no use in describing or in treating lyssants.  Given the lack of a specific definition, lyssants are bombarded with anxiolytics, antipsychotics, and antidepressants.  Essentially the full range of psychotherapeutics is thrown at them simply hoping the lyssant will obtain some relief or be controlled.  Maybe also a full dose of sunlight or a stake through the heart for good measure.

By defining a specific term, lyssant, and the behaviors it encompasses, we have the opportunity to untangle this mess.  We can apply the full weight of neuroscience research tools to discover and study the pathways and actions of rabies.  Most usefully, we can discover and study its native target in the central nervous system.  We can already expect this to be successful because our knowledge of the emotional centers of the brain, exemplified by the Papez circuit, are exactly the result of Dr. Papez’s work in determining the avidity of the rabies virus for various regions of the brain.  These regions and their connections are sometimes referred to as the Rage Circuit, and it is in modulating this circuit that we will be able to treat lyssantic behavior gone awry (psychological disorders as well as the actions of mad-men) and to come to understand our own inner vampires and werewolves, that is, come to understand what it means to be a complete human.

Human vampiric virus…. no, it’s much scarier

Human vampiric virus….  no, it’s much scarier

We are, in a revolting sense, lucky that rabies-infected, rabid, victims do not survive long.  Death comes quickly, though not at all mercifully.  One can wonder what would happen if humans could survive infection by rabies, or, if not rabies itself, then a closely related virus.  Even more, perhaps this related virus is what produces real vampires and werewolves!  Thanks to our extraordinary imaginative capacity, a Human Vampiric Virus (HVV to make it sound like a real medical term) has been dreamed up.  The reader can see and hear about it on Animal Planet’s website in its section on Freak Encounters.  This imaginary virus might have been first written about in 1616 in a Treatise on Vampires, written by an Italian scientist Ludovico Fatinelli.  He could have speculated on the role of an invisible pathogen to induce vampirism.  Of course, this is a modern hoax -- thanks to an Amateur Vampirologist for seeing through it [http://doaav.blogspot.com/2011/09/ludovico-fatinelli-exposed.html].  Still, it makes good starting material for a blog.

In order to produce true vampires and werewolves, the virus would have to induce the rapid and reversible growth of our canine teeth and other such bodily transformations as are beyond any biology that we can even conceive.  The painful changes that Prof. Lupin [thanks to J.K. Rowling] and other movie and TV werewolves go through are easily indicative of the utter impossibility.  [And yet, these painful, difficult movements do resonate with the difficult movements of the paralytic (dumb) form of rabies.]  No, we are stuck with rabies itself, producing all the behaviors of our avatars of rage, but without the bodily transformation.

Potentially more likely is that some people may be able to survive rabies infection and then be in a constant state of bloodthirsty, biting behavior.  Although not outside the realm of possibility, this wouldn’t be very useful for the survival of the rabies virus itself.  And, we’ve already noted that humans are poorly designed to pass the virus on to other victims, however much biting is a natural, prepotent behavior for us.  We just can’t sink our teeth into it.  The virus would likely simply die off as its human carrier dies.  Perhaps this is more plausible to occur in carnivores, like wolves.  Still, my guess is that the incessant attempt to bite other members of the pack would result in the, in this case, timely death of the infected victim.  And yet...

What would a living rabid person be like?  They would be the embodiment of several psychological disorders including intermittent explosive behavior, impulsive aggression, extremely prone to road rage, having hair-trigger tempers.  The primary danger wouldn’t be whether one is turned and could pass on the virus.  It is enough that they would maim, mutilate, and murder.  Imagine the ability to produce true ‘dog soldiers’, a movie I still have nightmares about.  The greatest threat probably wouldn’t be an attack by a force of dog soldiers – like Tolkien’s orcs they would probably kill as many of their own kind as any enemy.  The real threat is spreading the rabidity among our own friends and neighbors and the havoc it would wreak on our own people turned and caught up in the madness that is rabies infection.  But this wouldn’t happen by using the rabies virus itself; we’ve seen that it takes weeks or longer to infect its victim.  Not a very efficient weapon.

Could rabies virus be changed to get into the central nervous system (CNS) more quickly?  Possibly, but not likely.  As we will see, it is the targeting vector in the rabies virus that produces its effects.  It does not produce its deadly effects as do most viruses, by multiplying and then destroying the cells it has infected.  We really must stop focusing on the virus aspect of rabies.  It is a virus, obviously, but that’s neither the menace, nor the hope that it represents.  Rabies is cleverer, more insidious than that.  The behaviors it releases are the result of it binding to, presumably blocking (but that also awaits the discovery of its target), the activity of specific types of neuronal receptors – selectively modulating lines of neuronal communication and control.    It takes advantage of what we already are – closet vampires and werewolves – and uses our own behavioral repertoire to get us to pass the virus on to new victims.  In the long run, the multiplication of these receptor ‘blockers’ does overwhelm essential functions of the nervous system resulting in the death of the victim.  But, as it initially infects the CNS, it selectively ratchets up our rage defense attack system, by enhancing it or dampening our social inhibitions, or both.  Luckily for us humans, we generally become exposed to it from short-toothed, clean wounding animals resulting in the paralytic, muscle-weakening effects rather than furious rabies, or perhaps the ataxia and paralysis just limit the victim from being able to actively engage potential new victims.

Getting the rabies virus into the CNS faster would require changing its targeting motif so that it attaches to something more common, something found on many types of neurons or cells in general.  But, that would destroy its specificity, its ability to induce a unique and frightening set of behaviors; it would just kill us.  No, dog soldiers and bioterror weapons will be the result of a pharmacological agent that modulates the receptors that are targeted by rabies.  It may be good theater to continue to have a virus be the means of producing werewolves and vampires, even zombies, but it will be straight-forward chemistry that makes these horrific visions come alive.  Civilized people and nations need to ensure that we understand how to defend against this before someone does turn it loose.  Is anybody listening?!

it's rabies, plain as the claws on your paws

Authors before me have hypothesized that rabies is at the root of werewolves and vampires.  Certainly many of the modern tales at least allude to a viral infection.  Specifically, Dr. Gomez-Alonso published a report (Neurology, 1998, 51:856-9.) drawing the link between rabies infection and the vampire legends.  He proposed “that rabies may have played a key role in the development of the vampire legend, given the coincident time of the phenomena and the striking similarities between them.”

Ian Woodward in his comprehensive analysis The Werewolf Delusion states “But I have no doubt that, because of the shared symptoms, a vast proportion of history’s dreaded “werewolves” were in fact either rabid wolves or their rabid human victims.  The facts seem to speak for themselves” (p. 168).

Yet, some authors discount this connection, although still noting the similarity over and over.  Most recently the book Rabid sought to sever the link.  Rabid is a wonderful compilation of information about rabies and other zoonotic diseases.  The authors give a number of reasons why rabies does not produce vampires and werewolves.  One possible anomaly is that vampires and werewolves can give long accounts of their behavior, seemingly in contrast to the short lifespan of the infected individual.  Yet, only a few pages earlier they note the case of Charles Lennox, governor-general of Canada in 1819.  He was bitten by a fox and contracted rabies.  He became lucid at various times during his madness, in one case dictating “a lengthy letter to his eldest daughter” (p.10).  And later, discussing the possibility that Edgar Allen Poe died from rabies, they again state “Rabies sufferers, by contrast, are prone to just these sorts of swings between delirium and lucidity” (p.108). As these authors note, this cycling is a notable, and perhaps one of the most heart-wrenching, aspects of rabies infection.  A person with rabies will have periods when they are fully aware of what’s been happening to them, and fully aware of what’s to become of them! 

It also seems to the authors of Rabid and many other investigators that the fact that victims of rabies infection die quickly once symptoms appear is at odds with the longevity of some imprisoned self-confessed vampires and werewolves.  However, not one of those self-confessed monsters turned into a vampire or werewolf while in the presence of authorities.  These people were certainly mentally ill, but they were not true vampires or werewolves, and they did not have rabies.  Moreover, especially in times before hospitals patients would have been treated at home.  As noted, many victims of rabies do, at times, understand what their fate will be and the danger they pose to family and friends.  This knowledge, coupled with rabies’s urges for the victim to escape any confines (real or apparent) and to roam resulted in many victims running away, into the forest, from which they might never be seen again.  Who’s to say they died… although almost certainly they did die from the rabies itself or from a foolish encounter with another predator.

Tuberculosis and porphyria are two other disorders often tried to be linked with vampires (but not werewolves).  In the case of tuberculosis the link is really to revenants with their sickly, ghostly appearance.  There is no room for werewolves, nor vampires, in this scenario. 

Nor does porphyria explain the primary behaviors of vampires and werewolves, that is, rage and blood-lust.  Porphyria produces a hypersensitivity to sunburn and therefore a healthy avoidance of direct sunlight.  This simply doesn’t compare with the active startle and apparent fearfulness of bright light, and sounds, associated with vampires and werewolves, and very prominent in people infected with rabies.  Porphyria may have provided people with the hope of a defense against vampires - that they would burn up in sunlight - but the message certainly didn’t get across to rabid bats and wolves (and beavers) that are notable for being seen openly during the daylight that they normally avoid.

There really is no doubt that rabies infection is the model for the behavior of vampires and werewolves.  Whether true vampires and werewolves exist may be another story, but it is clear that their behavior closely mimics that of rabies infection as well.  More intriguing, more frightening, and truly more hopeful, is that rabies infection allows us to understand that this behavior is a normal aspect of every human being – we each carry our own vampire and werewolf inside our own brains, and in some of us, they come out to romp at times of their own choosing.  This realization gives us hope to understand, and when necessary to treat our inner monsters.  That rabies infection is linked to our legends is very satisfying, but it is the fact that rabies draws out, in a consistent and predictable way, the set of rage behaviors that otherwise seem to be the work of some supernatural, at least subconscious, power over which we have no control.  We need to understand the workings of the rabies virus because then we will be able to obtain control, and understanding, of all that it means to be completely human.

Which came first, rabies or rabid creatures?

Which came first, rabies or rabid creatures?

In terms of when they first appeared, rabies is at least as old as vampires and werewolves.  Of course, this only means that they both appear in the earliest of human writings.  Rabies makes its way into our earliest books of law, not long after the advent of writing.  Rabies may be referred to in the Codex Eshnunna of ancient Mesopotamia (1930 B.C.E.).  A more definitive reference, specifically noting a mad dog, is found in the code of Hammurabi (1750 B.C.E.), still nearly 4,000 years ago.  To be specifically mentioned when writing was considered an essentially mystical creation meant only for demigod-like royalty strongly indicates that rabies infection was already a very prominent fear and a fairly common occurrence!

Rabies is well-documented within the pantheon of gods and goddesses of the earliest written European cosmologies.  Lyssa, the Greek goddess of rage - who has a rabid dog crowning her head - certainly dates from earliest Olympian cosmology.  The Romans had their own counterparts -- Ira, Furor, and Rabies.  Lyssa is perhaps best known for driving Hercules (Heracles) to madness during which he murdered his wife and child.  Many cosmologies have wolf gods, Fenrir in Norse mythology and Wepwawet in Egyptian, but their raging characters are a given rather than a unique excess that might be due to rabies infection. Of course, with wolves it’s best to presume they are rabid.

We have already noted that a werewolf, King Lycaon, is mentioned in Ovid’s Metamorphoses from around 1 C.E.   This story almost certainly followed the lead of earlier oral traditions.  Humans living and behaving like animals are fairly common in Greek tales – Circe certainly did a number on Odysseus’s crew.  But this jumbles lycanthropy into the mix.  Tales of werewolves exist, but are generally just added in to tales of shape-shifting in general.  Still, as King Lycaon’s tale attests, transformation into a werewolf has a specific character, and a specific implication, that is, the loss of social, civilized behavior, and of killing or turning new victims

Vampires, in their earliest form as revenants, are clearly noted in folktales from earliest times.  For historical purposes, these folktales were perhaps best kept alive in Eastern Europe where pantheistic, pre-Christian beliefs were still common at the same time the printing press was invented making preservation of oral traditions a reality.  As the modern (since the Americas were discovered) view of vampires did not coalesce until Europeans observed vampire bats (1600’s), it is difficult to directly or simply trace the early conceptions of vampires.  Many of the words from which vampire has been derived may originally have referred to witches.  Witches could turn people mad, or drove themselves into madness in search of mystical knowledge.  A deeper analysis of the origin may not be fruitful since vampires as we understand them almost certainly required the discovery of vampire bats to take on their distinctive, singular persona.

In summary, rabies, werewolves, and vampires have coexisted as far back as we can trace.  This doesn’t prove they are one and the same, but it is definitely consistent with that notion.  In concert with the similarity of behaviors and the commonality of how they are passed from one victim to another, it is almost impossible to deny their unity.