The Epidemiology of Greyscale

[Obvious warning is obvious: potential spoilers for A Song of Ice and Fire novels/Game of Thrones TV series below].

While no one will claim that George R.R. Martin’s epic series, “A Song of Ice and Fire,” is historically accurate, there are a number of historical parallels that can be drawn from the characters and plotline–particularly from medieval Europe. While most of those relate to epic battles or former monarchs or other royalty, another of Martin’s characters, so to speak, is the disease greyscale (1).

Greyscale is a contagious disease that seems to come in at least two distinct forms: greyscale, an endemic and slow acting, highly contagious illness that can affect either adults or children; and the grey plague, a rapidly-spreading epidemic that can wipe out entire swaths of cities in a short period of time. Both versions of the illness have a high fatality rate (no exact details are given, but it seems to be close to 100%, especially in adults). Recovery from greyscale makes one immune to outbreaks of grey plague, so they seem to be caused either by the same microbe or ones which are very closely related.

The Epidemiology of Greyscale

Greyscale is a disfiguring disease. As its name suggests, it transforms the skin into a hardened, scaly tissue. As the skin dies, it becomes grey in color with permanent cracks and fissures. Infection that spreads across the face can cause blindness.

Like many diseases we consider to be “childhood” diseases (measles, mumps, smallpox, chickenpox, etc.), children seem to be spared the worst of the disease and are the most likely to recover from the illness, though recovery still appears to be quite rare. The disease is most common in Essos, but can also be found occasionally throughout Westeros, including north of the Wall (more on that below).

Greyscale is believed to be transmitted primarily person-to-person via direct skin contact. We see this in the books with the infection of Jon Connington and on the TV show with Jorah Mormont, as both characters are transporting/protecting Tyrion Lannister and apparently are exposed to the pathogen during a battle with the Stone Men (2, 3). The Stone Men are victims in the last stage of greyscale infection, where the skin is entirely calcified and there is involvement of muscle, bone, and internal organs, including the brain. Late signs of greyscale infection include violent insanity, leading sufferers to violently attack anyone who comes near. As these Stone Men are highly feared as sources of the disease, greyscale appears to be contagious for the entire duration of infection, from the development of symptoms to near-death.

A Stone Man with late-stage greyscale infection.

If a person has been exposed to greyscale, but is not yet showing symptoms, they can check for impending infection by pricking their toes and fingers each day. Once they’re no longer able to feel the knife, that’s bad news–greyscale infection is likely, as insensitivity to touch is one of the early signs. Once the scaling begins, the victim no longer feels any pain in the affected areas, making the Stone Men essentially invulnerable to pain.

The incubation period of greyscale seems to be very short. As soon as Jorah and Tyrion realize they are safe and the Stone Men are defeated, Jorah rolls up his sleeve and we see that the initial small patch of greyscale has already appeared.

First appearance of Jorah’s greyscale following fight with Stone Men.

Another prominent victim of greyscale, Shireen Baratheon, is thought to have acquired greyscale via contact with a fomite (an inanimate object that serves as a vehicle to transmit an infectious agent between people)–in her case, a beloved wooden doll clothed in Baratheon House colors from when she was an infant. Her father, Stannis, implies that this may have been a form of bioterrorism–that Stannis received the doll from a Dornish trader on Dragonstone. He tells his daughter, “No doubt he’d heard of your birth, and assumed new fathers were easy targets” (S05E04). “I still remember how you smiled when I placed that doll in your cradle, and you pressed it to your cheek,” where evidence of greyscale is still present (4).

Shireen Baratheon with facial greyscale.

Treatment

A number of remedies have been proposed to treat greyscale, but none of them are proven effective. They include treating it with boiling water containing limes; chopping off of the infected limbs; religious means/magic; and maybe fire–in A Dance with Dragons, Tyrion touches a Stone Man with his torch, and the Stone Man shrieks in pain (even while having bone showing through his skin, which apparently doesn’t bother him).  Whether fire could be a cure is unclear.

Also in A Dance with Dragons, we read of Tyrion’s musings on treating greyscale: “He had heard it said that there were three good cures for greyscale: axe and sword and cleaver. Hacking off afflicted parts did sometimes stop the spread of the disease, Tyrion knew, but not always. Many a man had sacrificed one arm or foot, only to find the other going grey. Once that happened, hope was gone.” As such, the infectious agent seems to enter into the bloodstream and spread throughout the body at some point during the infection, and at this point, local measures such as amputation are no longer useful. Other home remedies, such as cleansing the infected area with vinegar, are also employed. In fact, Jon Connington, once he realizes he’s been infected, soaks his hand in bad wine instead of vinegar, because he believes that if he asks for vinegar, it will be an obvious “tell” that he has the disease.

In the TV series (S05E04), Stannis says to Shireen regarding her infection, “I called in every Maester in this side of the world, every healer, every apothecary. They stopped the disease and saved your life.” However, no details are given on the show regarding how it was stopped (medicine? magic?), or if a mechanism exists that could be used on an adult instead of an infant. When Daenerys asks Jorah if there is a cure, he tells her simply that he doesn’t know, and she directs him to leave, find one, and return to her.

Cultural response

Largely, those with greyscale are shunned and sent elsewhere, especially to the ruins of Valyria (5) where a whole colony of Stone Men live. Shireen asks Stannis, “Are you ashamed of me, Father?”, understanding that her obvious greyscale scars are a sign of stigma for their entire family. Stannis tells his daughter, “Everyone advised me to send you to the ruins of Valyria to live our your short life with the Stone Men before the sickness spread throughout the castle. I told them all to go to hell.” (Father of the Year before that whole burning stuff, Stannis!)

Similarly, both the books and show note the existence of greyscale beyond the wall among the Wildlings–and that the free folks’ response to greyscale infection is exile and/or death. In the books, a wildling named Val sees Shireen, and notes Shireen has a condition they call “the grey death,” which is always fatal in children–because they’re given either hemlock, a pillow, or a blade rather than be allowed to live. She also suggests that greyscale may become quiescent and return later, saying “The grey death sleeps, only to wake again. The child [Shireen] is not clean.”

On the TV version, the wildling Gilly takes the place of Val, and while she is not as frightened of Shireen’s greyscale, she notes she’s also had experience with the illness.  She tells the tale of two of her sisters, who contracted greyscale (exactly how, we’re not told). Though he did not kill them as Val suggested, Gilly noted that her father “made them move out of the keep, into the hut outside. None of them were allowed to go near them, but we heard them, especially at night. They started to sound not like themselves.” Gilly saw them again “only once, at the end. They were covered with it. Their faces, their arms. They acted like animals. My father had to drag them out to the woods on a rope.” Shireen doesn’t find out what happened to them after that, but we can guess it’s not good.

Gilly and Shireen at Castle Black.

What are some real-life parallels?

Clearly greyscale is another invention of Martin’s that doesn’t quite match up to any real infectious disease (6), and I’ll leave that linked article to summarize some of the pros and cons of the alternative diagnoses. But given the other historical parallels, leprosy (Hansen’s disease) is probably the closest real-life affliction to greyscale, due to the route of transmission (I’ll elaborate on that below), symptoms, incubation period, and particularly the cultural response to those who are affected.

Like those with leprosy, sufferers of greyscale can become disfigured, are considered “unclean” and shuffled off to the far corners of the map, feared and then ignored by their family and friends. Connington, when hiding his infection, noted that “Queer as it seemed, men who would cheerfully face battle and risk death to rescue a companion would abandon that same companion in a heartbeat if he were known to have greyscale”–a similar phenomenon to what still can happen today with stigmatized diseases such as leprosy. A case of greyscale is a source of stigma for both the sufferer (even if they survive, like Shireen) and for the family, as there will always be those who fear contagion.

Though evidence is gathering that leprosy is actually transmitted via the respiratory route (like its cousin, tuberculosis), for centuries people believed it could be spread by touch, as greyscale is. So even though the transmission route for the two diseases really isn’t the same, the *presumption* that leprosy can be spread by touch is still incredibly common. The lengthy period between infection and outward symptoms of the affliction is also similar, taking years from exposure to the final stages of infection that we see in the Stone Men. Leprosy can also take years or decades to progress, and while untreated leprosy is not typically a cause of death itself, it can lead to death indirectly due to secondary infections and other issues.

One of the early signs of leprosy is also numbness in an affected area as nerves are damaged by the infection, as Tyrion tried to evaluate after his exposure to the Stone Men, as well as a general thickening and stiffness of the skin. It doesn’t get to the level that’s seen with the Stone Men–one of the biggest problems with leprosy is actually secondary infections, which can lead to loss of digits or even whole limbs rather than a whole-body calcification of the skin–but many of the hallmarks of greyscale are very similar to leprosy.

While leprosy is now treatable with antibiotics, it wasn’t all that long ago that we had our own leper colonies in the U.S. (you can read about one of them here, also on a near-deserted island where the afflicted were largely left to fend for themselves with some occasional governmental assistance, similar to Valyria/the Sorrows). Martin himself even notes that Valyria is “like a leper colony.” Leprosy, and its stigma, remains an issue in some countries still today, and the purposeful isolation of those who have leprosy and exclusion from society persists.

Image of the U.S. leper colony at Molokai, Hawaii, circa 1900.

However, while there are many similarities, leprosy doesn’t have an epidemic form equivalent to the grey plague. Described in A Dance with Dragons, it’s suggested that the grey plague wiped out half of Oldtown in the southwest of Westeros, and was only stopped by closing the gates and preventing anyone from entering or leaving. And like the Black Plague, the grey plague’s arrival in Pentos (a city in Essos) came by ship, and its spread into the city was possibly aided by rats. So is there an airborne form of greyscale that causes the grey plague? Could it be similar to Yersinia pestis, the bacterium that causes the Black Plague: transmitted by rats and fleas (or skin to skin in the case of greyscale) in its more mild form, but occasionally ending up in the lungs of an unfortunate victim and spread via the air after that, causing massive epidemics? Is it zoonotic, spread via rats? Will we see the grey plague on the TV series or not?

Lingering Questions

While comparisons to other real infections are interesting, my real question is–what is Martin going to do with greyscale? How does it feature into the larger end game, when we move beyond just a human “Game of Thrones” into the battle for humanity itself against the White Walkers and their army of undead wights? With all the time spent on the affliction in both the books and particularly in the show, there has to be some payoff somewhere, right?

In some ways, the wights beyond the wall and Stone Men are similar–undead, or nearly-dead, aggressive hunters of humans, with no sense of humanity left. When we last saw Jorah in the TV version, he had confessed his affliction to Daenerys, and she sent him off to find a cure. Will he find Dany after her arrival in Westeros and bring with him an army of (now healthy?) Stone Men–healed by fire perhaps, to fight against those brought back to life by ice? Will he return to Valyria–an area largely abandoned except as a place of exile for the Stone Men since The Doom a thousand years ago–and learn the truth of what happened there? Could Valyria provide a key to ending both greyscale and perhaps also the White Walkers? Or is the haunting poem Tyrion and Jorah recited as they rowed down the Rhoyne toward the ruins of the city foreshadowing what’s going to happen to Westeros?

It’s interesting that most stories open with an infection that ushers in the apocalypse: The Stand; The Passage series; The Walking Dead; World War Z; I Am Legend; the MaddAddam trilogy; the Planet of the Apes reboot; The Last of Us video game; even back a century or two to the Scarlet Plague or The Last Man. I could go on and on. Martin is known for taking many fantasy tropes and turning them on their heads, so instead of having a plague begin the downfall of society, could greyscale serve to save it somehow? With reportedly two seasons left in the TV series after Sunday’s Season 6 finale, we’ll have less time to wait and find out than it takes a newly-infected greyscale patient to turn into a Stone Man.

Notes

(1) The information provided on greyscale in this article is a mix of literature from the books and the show. Note that the show, to my recollection, hasn’t delved into the grey plague, so information on that malady comes exclusively from the books. Also note some of the victims of greyscale differ in the books versus in the show (eg Jorah Mormont taking Jon Connington’s place in the TV version).

(2) Though Jorah denies any contact with the Stone Men initially, and it isn’t 100% clear if he was touched during the scene, he does back off from Daenerys when she moves toward him in S06E05, when he discloses his condition (which is now all the way up his forearm). This suggests he does believe he acquired it through direct contact with a Stone Man.

(3) Though these sufferers are uniformly called Stone Men, and the ones seen on-screen appear to be male, presumably there are also Stone Women. Possibly loss of hair as the skin calcifies could lead to a more androgynous look.

(4) I should note there are some alternative views about exactly how Shireen’s greyscale infection was acquired, and about the use of greyscale as a biological weapon.

(5) Or on “the Sorrows” in the novels.

(6) I don’t agree with several things in that article, written by a dermatologist. It concludes based mainly on symptoms and a bit on epidemiology that greyscale is something more like smallpox or HPV and largely rules out a leprosy-like illness. It also notes the potential for an infectious agent that’s only infectious to those with an underlying genetic susceptibility, but I don’t think there’s much evidence to suggest that.

Find other posts in today’s carnival on the science of Game of Thrones!

One Reason Scientists and Science Writers Want to Talk About Game of Thrones by Matt Shipman

Biology Would Leave the Game of Thrones Dragons Grounded by David Hone

Dire Wolves Were Real by Brian Switek

Winter is coming: climate change and biodiversity beyond the Wall by Jacquelyn Gill

White Walkers: a warning letter from north of The Wall by Michelle LaRue

Tales from a Westeros Geologist by Miles Traer

A Storm of Chemistry by Raychelle Burks

The Heating Engineers of Winterfell by Jesse Emspak

The microbiology of zombies, part V: beware the bite?

Now that seemingly the flu outbreak storyline has been wrapped up on The Walking Dead (unsurprisingly, but disappointingly, with their ineffective treatments proving to be miracle cures), there’s still one more zombie microbiology topic I’d like to cover: what’s up with the bite, and is it the cause of death? I said previously:

“We know the pathogen can certainly be spread by bites and then cause zombification that way…”

but one commenter disagreed, noting:

“I don’t think we have evidence for that from the show. I think it clearer that zombie bites cause death, and there doesn’t seem to be evidence that the agent that causes death also causes zombieism (or vice versa). In Walking dead, any death is a sufficient condition for becoming a zombie. I would guess that zombies cause death because of a massive polymicrobial infection/sepsis.”

So, could death be due to massive sepsis (an overwhelming immune response to infection, which can lead to organ failure and death) via the bite, rather than the introduction of a specific zombie pathogen? It’s certainly not the first time I’ve seen that argument. Even the Zombie Research Society has put that forth as a hypothesis (and Matt Mogk has written of it in his book as well). However, I don’t buy it for a few reasons.

First and foremost, human bites simply aren’t that deadly. Even in a study of patients presenting to emergency rooms (which are probably the most serious of bites), none were found to have sepsis. Well, you might say, maybe more would have had this if antibiotics weren’t available, which would be the case with TWD (well, except now they have them, but I digress…) A Medscape article addresses this, noting that prior to the antibiotic era, up to 20% of bites caused amputation of a finger–but still, a local nasty infection, not necessarily sepsis. Even in a 1936 NEJM paper studying bites, only 2 deaths are noted, and both are in “delayed cases”–individuals who waited 5 days post-bite to present to the hospital. In these cases, the cause of death is indeed listed as “extensive sepsis.”

However, it should be noted that hand bites in particular—the subjects of those papers and articles above– seem to be rather nasty. Per Medscape again, “… most human bite injuries occur on the hands, and hand wounds from any cause have higher infection rates than do similar wounds in other anatomic locations.” So, these papers focus on the worst types of bites (hand injuries) at the most severe locations (presenting to emergency rooms), and thus should be considered likely a worst-case scenario for our potential infectees: that, even if bitten, a minority of them would have serious complications, and a minority of those might perish of sepsis. This doesn’t match up with what we see in the show.

You might argue that the process of zombification would modify/increase the nasty bugs living in the mouth. I agree–rotting in this manner certainly could alter the presence and types of organisms that would be present in the mouth, and therefore possibly make them more deadly and more likely to result in a sepsis death of the bitten. However, even accounting for rapid reproduction rates for microbes (mostly bacterial when you’re talking about sepsis and oral germs), this doesn’t seem to be a satisfactory answer, as one can quickly die and be reanimated and immediately have the potential for a deadly bite. It could also be argued then that therefore *everyone*, living or dead, would also possess this quality in that case–it shouldn’t matter if the bite is from a zombie or from a living person; the result should be the same (sepsis and zombification).

Further, in the human bite literature, there are two types of bites typically described: occlusive bites and clenched-fist injuries. The former is probably what you think of when you think zombie bites: mouth open, teeth coming together on the skin, chomp, chomp, chomp. Clenched-fist injuries are what happens when someone strikes another person’s teeth with, as the name suggests, their clenched fist, often scraping the knuckles: basically, a punch that strikes the teeth/mouth. While on the Walking Dead the former universally mean death (except in the case of really quick amputation of the bitten part, like we saw with Hershel’s leg), we’ve seen many examples of the latter—how many fistfights has Rick alone gotten into now? Not to mention, scenes like this:

 So if one is going to support the “polymicrobial infection as a result of bites” scenario for zombification, the issues of living biters need to be explained away as well.

Others have argued along similar lines regarding bites and sepsis, suggesting that the zombie bite is analogous to what happens to the prey of the Komodo dragon:

“Animals that escape the jaws of a Komodo will only feel lucky briefly. Dragon saliva teems with over 50 strains of bacteria, and within 24 hours, the stricken creature usually dies of blood poisoning. Dragons calmly follow an escapee for miles as the bacteria takes effect, using their keen sense of smell to hone in on the corpse.”

The problem with that analogy is that it’s based on a myth. That’s not what really happens: the dragon actually has venom, as I noted way back in 2005 (and Ed Yong updated recently, both based on the work of Bryan Greig Fry). It’s not their bacteria that kill their prey, but their venom. Do zombies suddenly become venomous? Doubtful. So, another idea shot down.

To me, the most convincing scenario, and the one that seems to jibe with both the idea that everyone is infected and with the little we know about the epidemiology of the outbreak, is that the immune system keeps the “zombie virus” under control while one is still alive and healthy. When one dies, the virus is allowed to replicate unchecked, resulting in both zombification/reanimation as the infection proceeds unabated throughout the body. The virus would also replicate (probably within the salivary glands) in order to enable transmission to the next bite victim. A zombie bite then introduces a large amount of this virus right into the bloodstream of the target, which overwhelms the body’s defenses and is responsible for both death and subsequent zombification—like rabies virus on steroids—and the cycle perpetuates itself.

Bottom line is that with the sepsis model, you have to explain more anomalies than with a virus-death model. You’d need to postulate immediate changes in the oral microbiome that aren’t readily accounted-for, but would be responsible for the 100% fatality rates upon receiving a bite (but ONLY a zombie bite, and not a live-human bite), while with the novel zombie virus model you get a bit more carte blanche to account for the transmission and certain death. That seems a much better explanation to me.

 Works Cited:

Welch CE. Human bite infections of the hand. NEJM, 215:901. 1936.

Talan DE et al. Clinical Presentation and Bacteriological Analysis of Infected Human Bites in Patients Presenting to Emergency Departments. CID, 37:1481. 2003.

See also:

Part I: the microbiology of zombies

Part II: ineffective treatments and how not to survive the apocalypse

Part III: “We’re all infected”

Part IV: hidden infections

The microbiology of zombies, part IV: hidden infections

(As previously, spoilers abound)

So on this week’s Walking Dead soap opera, we find that Daryl/Michonne’s group is still out and about searching for medical supplies. Back at the prison, the food situation is dire (apparently all the food stores were in the cell block where the infection broke out), so Rick and Carol head out to look for both medicines and food from the local ‘burbs. During their outing, discussion ensues of Carol’s attempt to stop the prison’s apparent influenza outbreak by killing two people who, at that point, were the only ones showing symptoms of disease. Rick decides he can’t trust her, and ends up banishing her from the group.

Carol said multiple times that she was trying to do the right thing, to protect the rest of the group from those who were sick and was only trying to end the outbreak. However, here’s where some knowledge of infectious disease would have helped her. Every disease has an incubation period: the time when the microbe is multiplying in your body, but you’re not showing any physical disease symptoms yet. This can be short–as little as perhaps a few hours for something like Salmonella food poisoning. It can be extremely extended, as I mentioned with rabies virus in my previous post, where the incubation period can be months to years. With influenza, the typical incubation period is 2 days, but it can be as short as 1 or as long as 4-5. The kicker is that a person who’s incubating flu can still spread it even before they show symptoms of the illness. So just because Karen and David were the only ones actively coughing and looking miserable, Carol was mistaken in her assumption that they were the only ones infected, and that she could stop the outbreak by snuffing them.

This is the difference between two similar concepts, quarantine and isolation. People who have been *exposed* to an infectious agent, but are not yet showing any signs of illness, can be quarantined to keep them away from others due to their *potential* to spread a disease. Those who are already showing signs and symptoms are placed into *isolation* to keep them from spreading it–they’re a known quantity. The prison group has used primarily isolation to keep the infection from spreading: they’re putting the ill in the Death Row cell blocks as an isolation area, and those who are well can roam around as they choose. (Maggie, for instance, hasn’t been sent to quarantine even though she clearly was exposed to the illness by being in such close contact with Glenn).

However, one thing that the group hasn’t yet determined (probably because no one has recovered as of yet) is how long they’re going to keep anyone who gets better in the isolation area. Though adults usually stop releasing influenza virus even before their symptoms are completely gone, kids can shed the virus for a long time: up to two weeks after their symptoms started according to one study (and others have found similar results). So while right now they have the healthy young children segregated from everyone else for their own protection, in theory, if Lizzie (the flu-infected child currently in held in isolation) gets well and is released back to the healthy kid’s room, she could simply re-start the outbreak there, among the most susceptible. 

This is why disease eradication is so difficult, and why it’s been accomplished for so few pathogens to date: many pathogens can spread on the sly, even when people don’t know they’re sick. For influenza, even if it’s knocked down in this group (and of course, it soon will be one way or another–at some point, the susceptible hosts in the prison will be exhausted, either by infection & recovery or by death), there is always another reservoir of disease out there. It may be other humans. Darryl/Michonne’s group finally made it to the veterinary school mentioned two episodes ago, and the zombies they ended up fighting there had clinical signs that looked an awful lot like the survivors had seen at the prison: blood that had come from the eyes and nose. Had flu been circulating there as well? It’s a vet school, pigs could certainly be housed (there were a number of animal cages, and could easily be an outdoor space for livestock somewhere). So pigs could be serving as a reservoir. Flu can also come from a number of other animals–most notably, birds, who don’t even have to appear sick to transmit the infection to people.

Infections can be sneaky and unseen, as this group should well know.

See also:

Part I: the microbiology of zombies

Part II: ineffective treatments and how not to survive the apocalypse

Part III: “We’re all infected”

The microbiology of zombies, part III: “We’re all infected”

Warning: here be spoilers

In many latter-day zombie movies, books, and TV shows, zombie-ism has a biological cause. In 28 Days Later, the infection is caused by the “Rage” virus, which escaped from a lab when animal rights activists break in and release a group of infected chimpanzees. Of course, one of the animals promptly bites one of its “liberators,” and the infection spreads rapidly throughout Great Britain. In Zombieland, it’s a mutated form of “mad cow” disease. The Crazies, it’s the Trixie virus; World War Z, the Solanum virus; Resident Evil, the T virus. I could go on and on. Zombie causation has clearly evolved from the early days of radiation or curses, and has become a biological phenomenon in most modern zombie tales.

The Walking Dead is no exception. Though the claim is made in season 1, episode 6 (“TS-19”) that the outbreak could be caused by just about anything–bacteria, virus, parasite, act of God–I call shenanigans. In the previous episode (“Wildfire”), Jenner, the CDC scientist, is processing tissue taken from Test Subject 19, and the visualization under his microscope looks very viral. Of course, take this with a few pounds of salt, since he’s using a light microscope and can also see the nice alpha-helical DNA strains within the pathogen (in real life, things just don’t look like this) and unless you’re one of the giant viruses, you can’t see viruses, much less DNA, under the microscope Jenner uses anyway. But still, it looks pretty viral-y to me, which is why I typically refer to it that way:

screenshot wildfire virus

Microbial zombification makes sense in today’s culture. My colleague Brooks Landon notes: “…zombies represent a better monster for the modern, post-9/11 world. They provide a release for feelings of being overwhelmed by abstract and intractable events like global economic crises, terrorism, and pandemics.” In the past decade or so, we’ve seen the emergence of SARS, multiple outbreaks of influenza including a new pandemic strain, the continuing HIV crisis, Nipah, Hendra, more Ebola, just to name a handful. Infectious diseases are commonly in the news, and many times are unfortunately over-hyped, leading to a collective nervousness of all things microbial.

The infected zombie is further boosted by a number of recent studies, largely in insects, that demonstrate a type of pathogen-directed “mind control:” zombie ants, zombie grasshoppers, and zombie cockroaches, just to name a few. A recent video game has exploited the ant fungus idea, mutating it into a form that infects humans. Even rodents (and possibly humans) can have their behavior apparently influenced by a parasite called Toxoplasma gondii, which makes rodents lose their fear of cat scents and may influence the development of schizophrenia in humans, or more controversially, even affect sexual inhibitions. If germs are already controlling our minds–why couldn’t they turn us into zombies?

And certainly, there are some candidate microbes which could, in theory, cause at least the “living” form of zombie-ism, even if they couldn’t necessarily raise you from the dead. The Trixie virus, for example, is supposed to be a weaponized rhabdovirus–the family of viruses that includes rabies. Rabies virus infection certainly causes aggression and biting. The virus is spread via saliva, so biting is the main way it is transmitted between animals. In a recent book, Rabid, the authors trace rabies through history, and note that it may be at the root of many zombie (and vampire) tales. Rabies can also hide out in the body for awhile before showing symptoms, as the virus travels up the nerves toward the brain. This is why a bite near the head progresses to symptoms much faster than, say, one to the foot. Typical time from bite to symptoms is in the neighborhood of 6 weeks, depending on the location of the bite and dose of virus one receives, but extreme cases have been documented, with symptoms not showing up for as long as 8 years. And, like has been done on The Walking Dead, one of the ways that bitten victims would try to avoid symptoms would be to cut off the affected limb before the infection spread. (Ouch).

Could something like the “we’re all infected” scenario used in the Walking Dead occur in real life? Maybe. With rabies, victims could appear physically fine for months to years. Even more extreme, there are a number of germs which can remain with people throughout their entire life. The virus that causes chicken pox, for example, doesn’t ever really go away. Your body fights it off enough to keep it in check after the initial rash, but it hides out  in your nerves and can come back in later years as shingles. Other herpes family viruses have a similar lifestyle: symptoms can come and go, but the virus never really leaves. The human papilloma virus (HPV) can also persist for years in some people (most infected people appear to clear this one, though). A bacterium called Helicobacter pylori can live very happily in a person’s stomach–sometimes causing ulcers, but going completely undetected and causing no symptoms in most people. And of course, HIV, which does not go away except in a few notable and high-profile cases. So the concept is, as they say, biologically plausible.

The problem isn’t necessarily with the microbiology, then, but with the epidemiology. How did everyone get infected so quickly? We know that the plague took an incredibly short time to spread (Jenner says less than 200 days in the first season, and “less than 63 days” since it went pandemic)–but how? That’s a missing link in this scenario. We know the pathogen can certainly be spread by bites and then cause zombification that way, but other forms of inoculation (such as getting sprayed in the eyes or nose with zombie blood) don’t seem to have that effect. Is it in the water? If so, that would be some damn rapid spread, since early on Jenner noted that this appeared to be a true pandemic–present around the world. How would that happen?

In the air? Possibly, but even most airborne microbes don’t hang out indefinitely; they’re dispersed by wind to levels below those able to cause infection, or killed by sunlight or other environmental conditions. So even if you had a herpes- or HIV-like virus that could hide out in the body for an extended period of time without causing symptoms, how did *everyone* get it in such a short timeframe? Some scenarios in other books and movies put the blame on bioterrorism. The above-mentioned Trixie virus, for example, was a bioweapon which was only accidentally released when the plane carrying it crashed. Spread of Trixie in the movie ended up being only local, but transmission beyond that is hinted at the end. A true bioterrorist attack could, theoretically, account for simultaneous outbreaks all over the world.

Finally, though the “infected zombie” is now the most common type, it should be noted that this isn’t really new. George Romero, widely recognized as the grandfather of the modern zombie, acknowledges that he “ripped off” his idea for Night of the Living Dead from Richard Matheson’s I am Legend–a vampire story from 1954. The cause of that vampirism?

Bacillus vampiris–a bacterium.

 

See also:

Part I: the microbiology of zombies

Part II: ineffective treatments and how not to survive the apocalypse

Part IV: hidden infections

The microbiology of zombies, part II: ineffective treatments and how not to survive the apocalypse

(Spoilers. And things.)

After the start of season 4 of the Walking Dead and the introduction of a new nemesis: a fast-spreading, deadly infectious disease that seems to be a strain of influenza, I was looking forward to the plot arc of this season.

And then episode 3, “Isolation”, happened. From an infectious disease standpoint, I say, bah.

At the end of the previous episode, “Infected”, the group had decided to lock up anyone who was showing signs of the infectious disease within the death row cellblock, so that they would not further spread the disease, and to put the children and elderly (as the most vulnerable population) in another area to keep them safe from the infection. Quickly it was seen that this wasn’t working well, as people were becoming sick all over and more and more were moving into the isolation cellblock.

So, a council meeting was called of the leaders of the group. One of the decisions which was made, on the advice of Hershel the veterinarian, was to try to scavenge supplies from a college of veterinary medicine approximately 50 miles away from their location at the prison. What supplies?

ANTIBIOTICS.

For the micro people reading, you’ll see why my rage started boiling a bit at this point. Hershel was the one who’d suggested this was an influenza outbreak (and therefore, caused by a virus) in the prior episode. He is familiar with the disease (and there is another physician, Dr. Subramanian, who has been treating the ill and has seen the rapid course of the disease–of course, he is now sick himself). It is true that influenza can be complicated by a secondary bacterial infection: that those sick with the flu could develop pneumonia due to Staphylococcus aureus or other bacteria, and that these bacterial infections would respond to antibiotic treatment. But, when the course of disease is as rapid as it appears to be during this outbreak, it’s more likely that people are dying from primary influenza infections, which are most certainly NOT treatable with antibiotics. There are antiviral drugs that can treat influenza infections if given early in the disease course (such as oseltamivir or zanamivir ), but I think the odds of those being stocked at a veterinary school would be pretty slim.

So, rather than at least try for some kind of medically plausible scenario (is that really too much to ask?), Daryl, Michonne, Tyreese and Bob the medic take off in search of completely ineffective antibiotics,and run into an enormous zombie horde on the way. Hershel, in the interim, leaves the relative safety of the prison (he was ensconced with the children as a “high risk” individual) and wanders out into the woods to pick berries and leaves to brew elderberry tea. A folk remedy, there are a few peer-reviewed publications which suggest that elderberries or elder flower might have some properties that do work to treat influenza, so at least here Hershel is, well, sucking somewhat less here when it comes to proposing medical interventions to help those suffering than he did with his terrible antibiotics idea.

Hershel does end up with his tea, taking it into the isolation cell block and distributing it to the infected. This includes Dr. Subramanian, who repays the favor by coughing bloody sputum all over Hershel’s face. (Seriously, he doesn’t even know how to cough into his elbow? Even the little girl talking to Carol did that correctly).

From the previews of next week’s episode, “Indifference”, it appears there will be more searches for drugs, while presumably the horde advances toward the prison. I anticipate a miracle cure of some kind for Glenn at the least, but remain annoyed that the writers are touting antibiotics for a viral infection when flu season is upon us.

See also:

Part I: the microbiology of zombies

Part III: “We’re all infected”

Part IV: hidden infections

The microbiology of zombies, part I

(Spoilers below!)

For Walking Dead fans and readers of this blog, you probably know why I was all excited about some of the plot elements that have been included thus far this season: possible zoonotic disease, and in particular, a potential influenza outbreak that may have originated in pigs. I muse about this and other infections in an article for Slate.com, and will have additional thoughts about zombies and infectious disease more generally in the coming days.

See also:

Part II: ineffective treatments and how not to survive the apocalypse

Part III: “We’re all infected”

Part IV: hidden infections

Interview with “Warm Bodies” author Isaac Marion

And now for something a bit different. I’ve mentioned before that I’m a big fan of zombies. So, I was intrigued when I started seeing press for Warm Bodies, a book by Isaac Marion about a zombie who is, well, not your typical zombie. Recently released as a feature film, I read the book a few weeks ago, and last weekend took my 13-year-old daughter to see the movie. I enjoyed both (as did my daughter), and asked Isaac if he’d be willing to answer a few questions for the blog. His interview is below (a few spoilers, take note):

Tara: Your take on zombies is a bit different than most stories. Obviously there’s the central idea that they can be “cured”–and they also talk and have friends. I saw in a previous interview that you said you’d kind of “stumbled” into the zombie genre and were not always a zombie geek. Can you describe your experience emerging as a bona fide zombie author, and what has the reaction to the book/movie been from the hard-core zombie community?

Isaac: The reaction has been pretty much split between two camps. Camp 1 is people who understand that a zombie is a fictional creature that has been portrayed differently, with different origins and different behavior, in pretty much every iteration and remains open to interpretation depending on the goals of the story in which it appears. That camp thinks its a great new idea and welcomes the unexpected shift in perspective that explores a lot of the unaddressed questions in zombie lore, while using the mythology to explore other, more human themes. Camp 2 is people who I don’t understand at all, who seem to think that zombies are real creatures that have been studied and defined by science, and that there are immutable “rules” to how they should function in fiction. These people tend to ignore the fact that every major work in the canon of zombie mythology has redefined what zombies are. First, they were regular people brainwashed by Haitian voodoo powder. (White Zombie.) Then they were corpses reanimated by mysterious cosmic radiation. (Night of the Living Dead.) Then they were regular people driven insane by a virus. (28 Days Later and onward.) In the midst of all this, we saw zombies with lingering consciousness who responded to music and speech (“Bub” in Day of the Dead) self-aware zombies capable of independent thought and even leadership (Land of the Dead) and yes, zombies who fall in love. (Fido.) I don’t really know what it means to be part of a “zombie community” but I’m certainly well familiar with the “genre” if all stories about a certain creature can be lumped into one genre. (Why is “Dragon” not a genre? Why is there no “Robot genre”? I don’t even think “Vampire” is considered its own genre.) My roots run pretty deep into geekdom, so it’s not like I just decided “I think I’ll write a zombie novel” and then had to research what the fuss was all about.

Tara: Each zombie story also seems to come up with their own terminology for zombies: “walkers,” “skels,” “Z’s,” “stragglers,” “biters,” etc. Yours are “corpses”, “the Dead,” and “Boneys,” though you do occasionally break the unwritten rule and refer to them as zombies. Was it important to you to try to differentiate your Dead from those that had come before in other movies/books?

Isaac: I think Warm Bodies is kind of a mashup of all the zombie fiction that came before it. I wasn’t trying to create a new “version” of zombies to add to the canon, I was trying to use all the tropes of that canon for satirical and metaphorical purposes. So I just combined everything–R doesn’t know where zombies came from, but he references every well known origin story in his musings. One of the unusual things about Warm Bodies’ universe is that it’s actually our universe. These people knew about zombies in fiction before they became reality. They’ve seen the George Romero films. So when zombies first started to appear, it wasn’t just “Oh my God there are corpses coming to life!” it was, “Oh my God, our collective cultural nightmares are becoming reality!” This is only briefly referenced in the movie (Julie holds up a copy of the 1979 film “Zombie” next to R’s face at one point) but it’s a little more explicit in the book and will be explored further in the sequel.

Tara: Zombie stories run the spectrum from trying to create very scientifically legitimate zombies (“Neuropathology of Zombies,“The Zombie Autopsies”–even “Zombieland” suggested the outbreak had resulted from a mutated “mad cow” infection) to not even trying to justify them scientifically. In the book, R can’t remember anything about how the world ended or the zombie plague may have begun, while Julie muses that it started when humans “buried themselves under greed and hate” until they hit the bottom of the universe, and then kept on digging–an idea more along the lines of a curse rather than an infection. And of course, The Dead eat the brains of the living and by doing so, gain their memories–so yours swings pretty far to the “not even trying” end of the spectrum. Were you worried about how that would be received when so many recent zombie stories have tried to be a bit more rooted in reality?

Isaac: The stories that root it in reality do so because they aren’t really about the zombies themselves, they aren’t using zombies for any thematic purpose beyond maybe some light social commentary, they’re mostly just props to menace the characters and create action. Obviously, with a zombie narrator, Warm Bodies is much more about the Dead themselves, and what it means to be in that state vs. fully alive. I didn’t use any science because this is a metaphorical story. In the sequel I’m writing now, it will go deeper into the actual metaphysical causes of the plague and the way human consciousness influences reality, but it definitely won’t reveal some random virus to explain everything. Most zombie stories use something like that because it’s quick and easily understood and clears the field for all the action and visceral thrills. That’s not really what these books are about.

Tara: When I first read the description of “Warm Bodies,” I admittedly cringed a bit. Like many others, I was a bit apprehensive that it was going to be a “Twilight” for zombies. Thankfully, R wasn’t sparkly like Edward and Julie wasn’t a pathetic wimp like Bella, and I was pleasantly surprised with how much I liked the book and the movie. Like much great zombie fiction, your book is entertaining but also has a bigger message about the state of society–very Romero-esque, even if your zombies are much different than his. How did the novel evolve from your initial short story, just musing about what a zombie might think about, to the richer allegory of the finished product?

Isaac: It had a lot to do with the state of my own life at the time I was inventing this story. I had moved from my small hometown to Seattle a couple years before and had left behind my conservative religious upbringing in the process. It was a weird moment in life, where I was trying to understand who I was and what my purpose was outside of this very small-minded, limiting, ultimately pessimistic worldview that I had grown up with. And beyond that, I was getting older, feeling the loss of energy and passion that comes with age and experience and trying to find a way to fight it off. So I started to notice a lot of parallels between my life and this unhappy corpse living in the wreckage of civilization, and my transformation started to connect with his. The story kind of just exploded out of me in a short period. I think it was a therapeutic experience for me as a person. Writing it helped me figure out some of my own struggles.

Tara: Still, it is a romance, complete with “R and Julie” and even a balcony scene. Like the play, R and Julie brought about change and a healing in their respective populations, even if that was not their intent. Why did you decide to incorporate that story and those references into your novel?

Isaac: It kind of just happened by accident, actually. I was fairly deep into plotting it when I noticed the ways my story had assembled itself around that classical arc, and I decided to run with it. To me, the Shakespeare allusions are just another layer, not really the central theme of the story, although people are quick to call it “Romeo and Juliet with Zombies.”

Tara: There seems to be a rash of first-person zombie stories lately–Hugh Howey’s “I, Zombie”, “Brains” by Robin Becker, or “Zombie, Ohio” by Scott Kenemore, in addition to “Warm Bodies.” Do you see this as a new trend–a humanization of the zombie?

Isaac: I’m not familiar with any of those. I would imagine people probably have similar thoughts to the one that first inspired my short story: “Why hasn’t this been done yet?” Villains are almost always more interesting than heroes. It’s always fascinating to get inside the mind of the bad guy and try to understand them. For thousands of years we’ve been watching the pure white knight slay the monster, and it’s getting old. People are starting to understand that morality and motives are complex and we want to know more about what goes on in the darker half that’s been hidden away from us for most of the history of fiction. I think as society becomes more and more comfortable with moral ambiguity, these kinds of perspective swaps will become more and more common.

Tara: Can you tell readers a bit about “The New Hunger” and your anticipated sequel to “Warm Bodies”? Any other writing projects you’re kicking around?

Isaac: “The New Hunger” is a novella that takes place seven years before Warm Bodies, involving a formative early encounter between Julie, Nora, and a newly undead R. It illuminates their histories and expands the scope of the world a bit, while foreshadowing a lot of what’s going to happen in the sequel. The sequel is going to be a lot bigger and more complex than Warm Bodies, less about zombies than death itself and the forces, human and inhuman, that make our world a dark place when it doesn’t have to be. It will explore some more metaphysical, even cosmic themes, and veer more toward modern fantasy than zombie horror. I’m pretty excited about it.

Many thanks to Isaac for participating! You can find out more about him via his website, or follow him on Twitter.

Using zombies to teach science

With my colleague Greg Tinkler, I spent an afternoon last week at a local public library talking to kids about zombies:

The Zombie Apocalypse is coming. Will you be ready? University of Iowa epidemiologist Dr. Tara Smith will talk about how a zombie virus might spread and how you can prepare. Get a list of emergency supplies to go home and build your own zombie kit, just in case. Find out what to do when the zombies come from neuroscientist Dr. Greg Tinkler. As a last resort, if you can’t beat them, join them. Disguise yourself as a zombie and chow down on brrraaaaiiins, then go home and freak out your parents.

Why zombies? Obviously they’re a hot topic right now, particularly with the ascendance of The Walking Dead. They’re all over ComicCon. There are many different versions so the “rules” regarding zombies are flexible, and they can be used to teach all different kinds of scientific concepts–and more importantly, to teach kids how to *think* about translating some of this knowledge into practice (avoiding a zombie pandemic, surviving one, etc.) We ended up with about 30 people there: about 25 kids (using the term loosely, they ranged in age from maybe age 10 to 18 or so) and a smattering of adults. I covered the basics of disease transmission, then discussed how it applied to a potential “zombie germ,” while Greg explained how understanding the neurobiology of zombies can aid in fleeing from or killing them. The kids were involved, asked great questions, and even taught both of us a thing or two (and gave us additional zombie book recommendations!)

For infectious diseases, there are all kinds of literature-backed scenarios that can get kids discussing germs and epidemiology. People can die and reanimate as zombies, or they can just turn into infected “rage monsters” who try to eat you without actually dying first. They can have an extensive incubation period, or they can zombify almost immediately. Each situation calls for different types of responses–while the “living” zombies may be able to be killed in a number of different ways, for example, reanimated zombies typically can only be stopped by destroying the brains. Discussing these situations allows the kids to use critical thinking skills, to plan attacks and think through choice of weapons, escape routes and vehicles, and consider what they might need in a survival kit.

Likewise, zombie microbes can be spread through biting, through blood, through the air, by fomites or water, even by mosquitoes in some books. Agents can be viral, bacterial, fungal, prions or parasitic insect larvae (or combinations of those). Mulling on these different types of transmission issues and asking simple questions:

“How would you protect yourself if infection was spread through the air versus only spread by biting?”

“How well would isolation of infected people work if the incubation period is very long versus very short?”

“Why might you want to thoroughly wash your zombie-killing arrows before using them to kill squirrels, which you will then eat?” (ahem, Daryl)

can open up avenues of discussion into scientific issues that the kids don’t even realize they’re talking about (pandemic preparedness, for one). And the great thing is that these kids are *already experts* on the subject matter. They don’t have to learn about the epidemiology of a particular microbe to understand disease transmission and prevention, because they already know more than most of the adults do on the epidemiology of zombie diseases–the key is to get them to use that knowledge and broaden their thinking into various “what if” situations that they’re able to talk out and put pieces together.

It can be scary going to talk to kids. Since this was a new program, we didn’t know if anyone would even show up, or how it would go over. Greg brought a watermelon for some weapons demonstrations (household tools only–a screwdriver, hammer and a crowbar, no guns or Samurai swords) which was a big hit. Still, I realize many scientists are more comfortable talking with their peers than with 13-year-olds. Talking about something a bit ridiculous, like an impending zombie apocalypse, can lessen anxiety because it takes quite a lot of effort to be boring with that type of subject matter; it’s entertaining; and kids will listen. And after all, what you don’t know, might eat you.