Zombies, Crazies, and Rage

Bub, I salute YOU!

In honor of the Halloween season I have decided to write a special post. It's hard to think about Halloween without thinking of ghouls, goblins, vampires, and Frankenstein's monster. Of course we cannot forget about the most beloved of all night-time prowlers, the zombie. I am an avid fan of horror movies and especially love those centered around hordes of flesh-eating zombies and the survivers that band together to take them down one bullet at a time. I noticed that each movie provides a subtly different explanation for why zombies have come to be and why they act as they do. This led me to an interesting thought. What would it take to make a zombie virus? Are the movies accurate in their descriptions are do they haphazardly try to bend the rules of science in order to make their scenarios plausible? I am truly excited to be digging deep into the recesses of science and bring to light the truth about zombies.

Zombies portrayed in cinema have evolved throughout the ages. The most iconic zombie would be something akin to George A. Romero's masterpiece "Night of the Living Dead." This is what most people think of when they hear "zombie." Slow moving, moaning, flesh-eating, undead ghouls that prowl the cities to satiate their hunger. But as time passes and movie effects and audiences changed, so did the zombie. Even in "Day of the Dead" which was released in the 1985, we see the zombie idea start to change. In this George A Romero classic, the zombie were not creatures of non-intellect. In fact, this movie proposed the idea that zombies could learn. They could be taught and domesticated through science. (Bub, is by far the best zombie in all of horror cinema!) In my opinion this is where we see an important paradigm shift. From then on the notion of the zombie in cinema would no longer be something that is seen as "non-human." Instead the view became that of a changed human. Fundamentally, they remain people, but somehow they have lost their humanity and they are left as something sub-human.

How did the the transformation change from radiation from a satellite (Night of the Living Dead) to the virus? I think it's because viruses offer a plausible explanation as to why people have lost their humanity. It has to do with physical effects of viruses. Viral infections have a profound effect on personality. You become lethargic and agitated. The cheerful person you are ceases to be and you are replaced by someone else...a zombie version of yourself. Of course, viruses also cause very obvious physical symptoms that movies use in full effect. Usually these involve the viruses that cause bleeding or vomiting and most other unpleasant symptoms associated with the nasty BSL 4 agents.

The evolution of zombies from non-human monster (Night) --> sub-human monster (Day) --> human monster due to viral infection is the hallmark feature of what I like to call the "modern zombie." The best example is 28 Days Later (Probably my favorite horror movie of all time). Here "zombie" transitions to "infected." They are solely the product of the virus that courses through their veins. This is also true for the infected in The Crazies. Even in Resident Evil, the zombies are the result of a virus. For the modern era the zombies are less zombie-ish (slow moving, moaning, etc) and more terrifying. The hallmark of the modern zombie is that they run, shriek, and are super scary! You outrun the traditional zombies, you get ripped to shreds by the modern zombie. What makes the infected version of these "modern zombies" so terrifying is the fact that they are truly human! They are reformed into a running vector that is controlled only by the virus' will to replicate.

This is the special T-Virus...I still get the creeps
when I look at Nemesis

Now that cinematic zombie evolution has been covered we can get into the different viruses. Let's start with T-virus. This is the fictional virus in the Resident Evil films and video game franchise. In the movie the T-virus was developed by the the infamous Umbrella Corporation which is then unleashed on Raccoon City, turning it's population into a horde of zombies. The computer Ashley tells the survivors how the virus works. She explains that the virus selectively reactivates the regions of the primitive brain and that the zombies are only driven by the simplist of needs..."The need to feed." This would imply that the T-virus is activating the brain in a few regions. The occipital region for sight, the temporal region for sound, the basal ganglia for some movement (the cerebellum controls fine movement which the staggering zombies suggest wouldn't be working), and the limbic system. The limbic system is the ancient brain region involved in desire. So basically the T-virus makes the virus think like this "See/hear human...WANT FOOD!" The science here is iffy considering that T-virus was supposed to be man-made and would be probably the most sophisticated virus in existence! Think about it...the virus selectively activates regions of the brain...That means that it overlooks everything elese and targets specific neurons in specific parts in the brain dedicated to a specific function. Certain strains of the virus can also mutate a person's entire phenotype as in the case of Nemesis! Basically, the fact that humans can actually make something so specific makes the scenario highly unlikely. Nonetheless it works well for a video game franchise that gets your blood pumping around every corner you turn.

"I'm not crazy...I'm A crazy!"

The next movie I'm interested in is The Crazies. Here the inhabitants of a small town start acting a little...crazy! They become very angry and seek to kill other people with whatever means necessary. Here, they actually give a reasonable explanation. It's overheard that the virus is a mutated form of Rhabdoviridae which to the casual viewer would just sound like made up gobbilty-gook. However, since you are all trained microbiologist by know you know that Rhabdoviridae is actually the Rabies virus! The Rabies virus is unique in that it alters the behavior of the infected host in order to prpagate itself. It does this through infection of neurons that make the host aggresive and infection of the salivary glands. So Agitation + infected saliva + bite+ new host = infection. This is a scenario that holds some merit.

I WANT CANDY NOW! Seriously, [REC] is an amazing
horror movie! WATCH IT!

The Crazies is not the only movie to use Rhabies virus as the basis for a zombie infection. Quarantine ( the American version of a much better Spanish movie called [REC] ) also uses this virus to explain the paranormal events occurring within the apartment building. Mutated Rhabies may look something akin to the infected in this movie. Rhabies is a very interesting virus because it can alter behavior to propagate infection, so it is an acceptable explanation to the beginning of the zombie virus. Plus the CDC is in the Quarentine so I have to agree with it! Compared to T-virus, mutated Rabies is definitely a more plausible scenario to a zombie outbreak. It lets a real virus found in nature to be the source which avoids the problem of humans making a virus that is far too sophisticated for humans to ever make.

The only image of Rage Virus as seen
in 28 Weeks Later

Finally, we arrive at the Rage Virus. This is the causative agent for the events in 28 Days and Weeks Later, two of the most awesome horror-movies ever. Here the science is a bit ambiguous but the special feature in 28 Days Later does shed more light on the origin of the Rage Virus. Of course, it begins as a monkey virus, the stereotype for every bad virus infection scenario! Two researchers at Cambridge University were studying the effects at neurotransmitters that control aggression and rage. Their goal was to develop an inhibitor to these chemicals in order to help people with anger issues. They decide to use chimps as the test subjects. Unable to get results utilizing pills or aerosols, the scientist decide to use a contagion as a vector for their inhibitor. They discover that the Ebola virus has the specific genome sequence they need in order to deliver the drug into the CNS. Because EVERY lab just has tons of Ebola laying around they make their vector and administer it into the chimp. Somehow, the vector changed in the chimp and the chimp became fueled by rage. The scientists developed a Rage Virus. One of the researchers is disgusted with the work and leaves and notifies an animal rights eco-terrorism group about it. They break into the lab and seek to free the caged monkey. The scientists tries to explain that the monkey is highly contagious and is infected with Rage. They attempt to free the monkey when the monkey bites one of the group members...the rest you'll have to see for yourself!



The result is a post-apocalyptic nightmare with the Infected at its heart. Again, the key point is that now the monsters are human, but they have become enslaved to the behavioral changes brought about by the virus. This is very similar to the Rabies scenario but what I like about Rage is that it provides the most plausible scenario for a zombie apocalypse. The Rage Virus is man-made but unlike the T Virus which is almost overly perfect, the Rage Virus was generated using very real techniques in molecular biology. Believe it or not, viruses make wonderful laboratory tools especially in experiments that require the insertion of genetic material into a host.

This technique is called Transfection and basically what you do is use a viral vector to insert your gene of interest into a host. Small pieces of DNA called plasmids are used very highly in genetic research in order to allow for expression of the gene you want. It's easier to have a virus do your job instead of trying to fadangle your genetic material into bacteria which can be a pain in the butt and may yield crappy return. Viruses do everything very efficiently and you get a ton of bacteria with your gene of interest.

Currently, interesting studies are being conducted in trying to use toxins to treat cancers and neurological conditions. Basically, if a toxin can target a specific cell, why not use it's toxicity to KILL cancer? There are also other labs that are exploring the use of the tetanus neurotoxin in order to introduce therapeutics past the blood-brain barrier. This is something that is notoriously difficult to do and if these test succeed then there can be a new wave of therapeutic opportunities for patients suffering from neurological conditions!

The Infected with the red sclera...That chick had
better start praying!

Alright back to the Rage Virus. Besides from a semi-realistic development schema, the Rage Virus also has a basis in real viral infection. The most obvious is the dreaded Ebola virus. This virus causes massive hemorrhaging and one of the signs is a red, bloody sclera (the "white of the eye"). This is also a portrayed in the Infected. Just like Ebola, the Rage Virus is also blood-bourne. However, the difference is that in the movies it seems as if the virus causes symptoms that will propagate its own survival. Namely the projectile vomiting of Rage infected blood into the mucosal membranes of victims. But curiously, the time it takes to show symptoms of Rage is VERY short...like seconds. Seriosuly, one second your normal and the next your puking blood into your victim's face. SUPER FUN TIME! This suggest that somehow Rage Virus has the ability to bypass the blood brain barrier and directly infect the regions of the brain affecting rage, most likely the amygdala. This combined with Ebola's hemorraging manifestations can lead to the profuse bloody vomit that further propagate the virus. I guess what I like about Rage virus is that it combines the man-made virus hypothesis with the natural course of viral infections.


Thinking about the ways viruses work and the scenarios proposed by movies a probable scenario for such a virus emerging would be like this. The virus would probably be man-made. Scientists seeking a cure for something like neural cancer use Rhabdovirus as a vector for its ability to enter the CNS. Using fancy molecular biology techniques,they manipulate the genome of Rhabdovirus and allow it to express a cytotoxin like Diphtheria toxin in order to kill the cancer cells, a real technique called "Molecular Bullet Therapy". The problem is that Rabies is notoriously slow in its movement up to the brain so the brilliant scientists decide to make it a blood-borne pathogen, thereby circumventing the long and torturous road up the neurons and spinal cord. In order to do this the researchers decide to try to use a blood-borne virus in order to increase the efficiency at which the virus is spread through the blood.

Ebola...Totally NOT Marburg...

"Wonderful! I went to college for 9 years so I know that viral hemorrhagic fevers are blood-borne pathogens that can help us! Let's use Marburg because it's not Ebola but can pretty much do the same thing!" Isn't science fun!?

Marburg...Totally NOT Ebola...

So they once again use molecular biology techniques to have the Rhabdovirus express the genes necessary for blood transfer. Now everything is working perfectly. The concoction of genes successfully enters the blood, and quickly by-passes the blood-brain barrier, targeting neural tumors and expressing the toxin which kills the cancer! Before the scientists can get their Nobel Prize for curing brain cancer there is a problem...Nothing is EVER 100%, especially biology. One of their vector viruses maintains the ability to infect the brain which causes severe aggression. The virus also maintains the deadly hemorrhagic genes of Marburg, causing blood filled with billions or virus particles to flow out of every orifice. Now, we have a true "zombie" virus. The Index patient is taken over by the virus and only wishes to infect others. Grab your shotguns, because the zombie apocalypse has started!

There you have it my vision of how a zombie outbreak can happen. Yesterday, I saw a History Channel special entitled "Zombies: A Living History." It chronicled the idea of a zombie apocalypse using the plague, spanish flu, and other viruses as models for what it would look like. More importantly, it underscored the fact that zombies have become part of our culture now more than ever. This is so true that he CDC has actually posted a Zombie Preparedness page on their website! Not matter how fictional the scenarios may be it is very clear that zombies have become a large part of our culture so just appreciate that zombies are here to stay in our minds and in our hearts. I hope you found this post fun because I've had fun writing it! Now go watch all of the movies I used in this post! MUAHAHAHAHAHA! >:D

For more information on how to prepare for the zombie apocalypse visit the CDC website.
http://www.bt.cdc.gov/socialmedia/zombies_blog.asp

The Flu Ends With...

Every year as we go into clinics or pharmacies to receive an annual flu vaccine we have a reminder of what was arguably the deadliest pandemic this world has ever seen. It wasn't from Ebola virus or yersinia perstis. It was from a much more common pathogen that that most people shrug off as never a serious threat. Maybe it's that the disease symptoms are so general that it seems mundane or maybe it's that the youth disregard influenza as something to fear, but every year when my peers are asked if they received a flu vaccine only a few people raise their hand. Admittedly I was not included in this group on more than one occasion. So what's the deal this virus? Is it sheep or is it a wolf?  Let's take a look and you can decide for yourself.

I can't imagine what the world must have felt like in 1918. No internet, no Facebook!? Such a time actually existed!? All joking aside, the world was at war. Out of this war would be the seeds that would grow into a second war. But something that is generally accepted is that out of World War I also came the flu. As soldiers marched from town to town, so to did the flu. With such a wide movement of people it's no surprise that disease followed, but what was extraordinary was that this wasn't an ordinary flu virus. This one was different and it would become known as the Spanish-Influenza. Modern virologist and epidemiologist today agree that the Spanish Influenza was a plague which remains unmatched in mortality and force.

Like nearly every other virus the origins of the flu are a mystery. I heard a very interesting theory recently wherein it was believed that the flu was caused by extraterrestrial forces in order to bolster our immune systems for some awful plague that would befall us in the future. The weak were killed, ideally leaving only those who are immune left...kind of like artificial selection on a global level. Does this have any validity? Of course not, but given the wierd-ness that is the virus it wouldn't surprise me if it were true! What we do know is that it has probably been around for as long as we have silently passing from birds into the human population without much effect. It wasn't until 1918 that the flu began to come under our radar as a serious health threat.

Influenza belongs to a class of virus called Orthomyxoviridae. Fun to say isn't it? The flu also has three subclasses A, B, and C. But we're only focusing on A because that's what caused every pandemic influenza in recorded history. Influenza A is a minus sense single-stranded RNA virus which willed be designated as         -ssRNA from here on out. It also has an envelope which it steals from the infected host cell...tricky little thief. On this envelope are two absolutely essential proteins called hemagglutinin and neuraminidase. Influenza virus particles are designated based on the differences in these proteins. Ever thought of what the "H" and the "N" meant? Well that's it! To give you an idea of how variable this virus can be (Assuming I recall my virology class correctly) Influenza A can have 29 different hemagglutinin and 16 different neuraminidase, all of which can intermix (So you can have H1N1, H1N2...H1N16 and everything else!). The point is that Influenza A can be extremely variable in its form. These two surface antigens are how the CDC decides how to immunize people for the coming flu season.

Hemagglutinin binds sialic-acid which are found on the plasma membranes of cells. This is why certain types of flu can't infect humans. Certain species of animals contain certain variants of sialic-acid residues that are recognized by specific hemagglutinin molecules. So this is why a flu that infects a horse cannot jump to humans, because the flu that is infecting the horse CAN'T infect a human to begin with! The virus particle binds to the host cell and it is taken up in a phagocytic vesicle. The vesicle is then brought to a lysosome within the host cell to be destroyed. The virus is pretty much hiding and waiting...Fusion to the lysosome releases the virus particle into the lumen of the lysosome. Right now the cell is thinking "I'm going to kill whatever this thing is." The high concentration of acid in the lysosome flows through another protein on the viral envelope called M2. The flow of hydrogen ions down M2 causes the ribonucleoproteins that are covering the genome of the virus to dissociate. BINGO! It's all the virus's game now...

An RNA polymerase that comes with the virus particle can then begin to copy the -RNA. This is necessary because without this RNA polymerase, the virus can't copy it's genome! The reason is because the cell can only recognize +RNA so it wouldn't know what to do if it saw minus sense! The genome is divided into eight seperate segments of -ssRNA. This is pretty unique to viruses which usually only have one segment of genetic material. These segments are transported to the nucleus and this is when they start a devious biochemical cycle. The -RNA is copied into +RNA. One of the segments is the RNA polymerase that the virus needs to make more of itself. The virus makes a lot of this enzymes and thus makes a load more of the +RNA.

Another segment encodes a protein which basically shuts down host cell RNA synthesis and induces apoptosis. The cell's toast at this point, so the virus moves quick. It ships the +RNA back out of the nucleus where it is translated with a high affinity by host ribosomes. Basically, instead of host RNA the ribosomes of the host cell are recognizing viral RNA more. The virus produces more proteins called nucleocapsid proteins which wrap themselves around the newly made -RNA. The RNA segments move toward the cell membrane and push the membrane outward. Neuraminidase then jumps into action. It cleaves nueraminic acid, another cell membrane protein, which releases the new virus particle and allows the virus to continue the process over again.

Now that the bio is covered let's get to what makes this virus so crazy. The RNA polymerase that it uses is prone to mistakes so the virus produces small alterations in the genome with each replicatative cycle. As I said before in a previous post the viral cycle is a game of numbers. The goal is to make as much as you can as fast as you can. In the case of influenza the inherent mutability of the genome has an evolutionary advantage especially if it alters the hemagluttinin and neuraminidase proteins in the envelope. This process is called antigenic drift and basically it's a fancy way of saying "mutations." Antigenic drift is the basis for annual flu vaccines. Even if the same strain of flu is circulating, the current variant of that strain is just slightly different than the year before. These mutations produce variants of the flu that aren't recognized by the human immune system because the antibodies that the body produces can't efficiently recognize the altered hemagluttinin and neuraminidase proteins. This is bad...

The second reason why Influenza A is such a powerful foe is because of antigenic shift. This is a higher level process that involves something called a "superinfection." What happens here is that one species of host is infected at the same time by two different types of Influenza. Take for example H1N1 and H5N1. If these two viruses infect a single cell then what we have is a situation where there are now 16 unique segments of RNA in the same cell. What can happen is that the segments can sort around and the first virus can pull other pieces of the genome from the second virus. The result can be a completely new type of virus. It's widely believed that the start of H1N1 in 1918 was the result of this process.

Hold the phone. How does it spread to humans then!? This goes back to the sialic acid that is specific to each species. What can happen with the flu is a case where a bird infects a pig. The pig contains both sialiic residues common to birds AND humans. The result is that a strain of Influenza from birds can coinfect a pig that has already been infected with a strain of flu from humans! So what happens? You guessed it, a superinfection! The bird and human Influenza can reassort their genomes and the result can be a hybrid that has the capability of infecting humans with a novel type of virus! I'm still amazed by this...Seriously, it's a biological mastermind!

The Influenza scares like "Bird Flu" and "Swine Flu" are the result of antigenic shift. The reason why the CDC places so much emphasis on these outbreaks are because these viruses had an atypical infection pattern. These strains targeted and killed young, healthy people. This is abnormal for the flu which primarily causes mortality in the very young and the very old. It's for this reason that the CDC strongly advises for a yearly flu shot. I recently saw a sign that read "The Flu Ends With U" and this is the most important reason for vaccinations. If the virus cannot replicate in a host then it is cut of from spreading anymore which dramatically reduces infections rate in the entire population. But in cases when the young and healthy who aren't supposed to be getting sick start to get sick and die a red flag is raised. 

I've always been amazed by the flu. Evolutionarily it does everything right. Antigenic drift and shift produce a wide variety of viruses that continuously permeate throughout the population. This is exactly what a good virus  should do. If the sole purpose of the virus is to replicate its genome, then influenza has achieved this end perfectly. Unlike small pox which was a strictly human virus we can never hope of ever eliminating influenza because it crosses over between animal species. This is a logistically impossible task! Antigenic shift is also a nasty weapon in the arsenal of the virus because it widens the range of host that can potentially be infected. The more hosts that can potentially be infected the more the virus can replicate its genome. It's incredible to think that such a primitive structure can be so sophisticated in evolutionary adaptation.