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.
  

Contagion: Fiction or Reality?

So, last weekend I spent some quality time with my brother. Both movie fans we decided to check out "Contagion." I recently heard that this new bio-thriller was actually the #1 movie in the box office in its opening weekend.  Apparently people found the movie genuinely scary because the monster of the movie isn't anything that can be seen with the naked eye. It was a good representation of a viral pandemic so I won't spoil the movie for those of you that want to see (I highly suggest it because it is pretty awesome), but I thought the idea behind the movie was worth examining. Can such a situation really happen? How real is the threat of a vial pandemic? A million people have written similar things on this topic but I would like to let everyone know that my explanation is best! (I'm joking, but seriously...) Let's turn to some history and science for the answers.


The movie follows the outbreak of a virus as it spreads throughout the human population. The key here is that the virus was new. Throughout history the appearance of novel viruses has resulted in pandemics. For example, the Spanish Influenza pandemic of 1918 was a novel type of flu and the result was the worst pandemic in the history of the world. A dramatic phrase, but true nonetheless. What makes novel virus outbreaks so debilitating to humans is the simple fact that the human body have never experienced the virus, therefore the body has no way of figuring out what to do. The Spanish Influenza (which deserves its own post at a later time) had surface antigens that the body could not recognize and the result was a quick spreading outbreak that swept around the world.

The 1918 pandemic influenza was not the only time a novel virus has emerged which threw the CDC into a frenzy. Remember SARS? Well, the onset of SARS was a bigger deal than we actually know. It started in one hotel in Hong Kong and within a week it was in Canada knocking on our door. This is a perfect representation of how technological advances have acted as a double-edged sword when it comes to viral epidemics. All it takes is one infected person to board a plane and infect a group of people at an airport and then the virus could be world wide in no time. The end result of SARS was nearly 9000 individuals infected and 900 deaths.



A key component of "Contagion" is the work of doctors to track down the path of the virus. This is also based on fact. The CDC has a special branch called the Epidemic Intelligence Service (EIS) whose job is to travel abroad and see outbreaks first-hand, interview patients, and uncover the epidemiology of the disease. On a side-note, my goal is to one day work for the EIS because they are basically the most BA doctors in the world! The single goal of these "virus hunters," as they call themselves, is to find out any information they can that can lead to the containment and possible treatment of the disease. This includes the pathways by which the virus is spread, the amount of people that can potentially be infected from one contagious individual (a term called the R-naught which is referred to many times in "Contagion"), and to find out if the virus is on its way to the US.


These guys also have had a huge role in some serious biological incidences, one of the most notable involving a novel virus in the mid seventies that began an epidemic in Zaire. Those infected displayed a horrific hemorrhagic pathology and the virus was given the name "Ebola." Another involved a mysterious viral outbreak in New Mexico that resulted in similar symptoms to Ebola. This one was more related to a virus called Hantavirus only this particular strain of Hantavirus caused renal failure in its victims. The EIS doctors discovered that the virus which they called "Sin Nombre" was spread like other Hantviruses, through the urine of mice and by getting rid of the mice the virus outbreak ended. The EIS doctors come face-to-face with the worst types of viruses with scant regard for their own safety. If an outbreak of a virus on the scale of "Contagion" were to occur these investigative doctors would be the first to the scene. They're awesome!

So the CDC is just overreacting right? In "Contagion" the media makes the point that most people believe the CDC overreacts to such threats. The truth is that they do, but with good reason. I think that it highlights a serious flaw in our own philosophy. People don't think epidemics abroad can effect them. Individually they are probably right, but the more people that hold this view, the less prepared we are to face it when a threat emerges. If an entire town doesn't vaccinate their children then the result can be the recurrence of disease such as Whopping Cough which was reported in California last year. The problem isn't only for your own safety. It is....but the CDC has more important reasons for you to get vaccinated. By reducing the amount of people susceptible to disease, you can cut off the route of a potential epidemic quicker. It's a statistical thing. So when the CDC freaks out and says to get your vaccine even if you're healthy what they're really asking is for you to help reduce the threat of an epidemic.

What should trouble is how the virus acts. As I've mentioned before viruses want to spread. It's all they care about. They wait for millions of years until one susceptible host comes along and triggers a cascade of biochemical events that ultimately lead to replication of the virus. They can mutate their genome and give slight changes to their surface which could allow them to infect new species or evade an immune response. This was what happened with novel H1N1. A bird harboring the virus gave it to a pig which itself was infected with another virus. The pig acting like a mixing vessel then generates a new virus capable of infecting a human and...bang, the gun goes off and it's off to the races.

Should a pandemic ensue I think the most powerful driving force would be fear. Assuming people recognize the virus as a very real threat, fear will become its own plague. The media propagates stories about the virus and people start to freak out. The novel H1N1 pandemic of 2009 showed that. Every day I heard stories about how new people were infected and more people died.  With images like these constantly bombarding the public it's easy to see why a virus with very real effects could transform the American public through fear. "Contagion" obtains maximum effect from this field!

Imagine hearing a town next to yours now has the virus. You're walking down the street not knowing if your town is still safe and if anyone is infected with a lethal virus. Every cough, sneeze, and sniffle would make you wonder if the person next to you is infected and if its possible that the agent has breached your city walls. There would be a palpable fear. So strong was this kind of fear that in the 14th century towns literally gated themselves off from one another to prevent the entrance of Plague. This was also the case in Poe's short story "Masque of the Red Death" but not even closed doors could stop the Red Death from gaining entrance to the castle... The movie very accurately portrayed the social aspect of a pandemic in that people will become restless and hostile. Seeking the well being for one's own family becomes priority and people would achieve this by any means necessary including force. It's at this point that the military intervenes and cities start to look more like a scene from "Outbreak."

Hendra and Nipah virus, two very
unfriendly looking pathogens

The viruses that can cause such an event do exist even if we aren't fully aware of them. These agents are termed Emerging Infectious Diseases and these are the ones that are downright scary. These are viruses that are new to the human population even though they may have been circulating in the wild for a long time. Nipah, Hendra, Ebola, Lassa Fever, and Hanta Virus are a few of this class and all cause a horrific display of symptoms ranging from encephalitis to renal failure and hemorrhaging (all very bad things). Worse, these agents have no treatment and no cure. Given that these viruses aren't endemic to the US there is no need for alarm. However, the director of the CDC said in an interview with CBS that a new pathogen is discovered everyday so it looks like the odds of an outbreak occurring is higher than we expect and it may only be a matter of time before luck runs out and one poor individual harboring a new virus boards a plane and crosses boarders.

So is "Contagion" more real than fiction? In truth, it is. This is why the movie creates fear. Whether or not we want to admit it, there is something frightening about the human race being overwhelmed by an enemy that can't be seen, smelled, heard, or felt. Worse, "Contagion" holds very true to the events that would commence once the outbreak began. The science of the movie, although ambiguous in parts, is pretty good in explaining the course of viral infection and why it is easy to lose control over the situation unless it is handled immediately. All in all, it is a very good and exciting movie that is sure to make you pause when the person next to you sneezes.

The Philosophy of the Virus

Sorry for such a hiatus everyone. I've had serious changes I've had to adapt to, the chief being the first few weeks of medical school! In order to get away from the books that I have become slave to in the past couple of weeks, I am back. This time the topic of discussion is the virus. I've already written a short spiel about viruses that provided a brief theory about how viruses came to be (I encourage all readers to look at it again because it's awesome!) so I won't go there. This time I want to tackle an even bigger question that has grown more along the lines of philosophical debate than scientific inquiry. The question is simple "Do viruses think?"



The short answer to this question is "No." Okay great so post over, right? Not quite. There is more to the story of viruses that makes them seem more like living, thinking creatures more than they really are. So much so that the lines of biology start to blur the more you learn about them. Viruses are to the field of biology what black-holes are to physics. Once you closely inspect the underlining principles of the virus, the rules of biology start to break down and some really weird things happen that basically make you question the fabric of existence... Ok, so viruses aren't that crazy, but they do take part in some pretty crazy things.

Let's take for instance a virus we've all heard of before Rhabdoviridae...more commonly called Rabies. These things look like bullets, maybe its a grim premonition of what's to come once you've become infected. I think Rabies provides one of the most interesting examples of how viruses "think." Basically, Rabies virus has the unique ability among other virus to travel up neurons. This is pretty cool in itself because the cell actually transports it without ever knowing it's being infected! Eventually the virus reaches the blood-brain barrier which it breeches and infects the spinal cord and brain. This is where the virus starts to do something very strange. It starts to infect the cells of the salivary glands in the mouth, the cells that produce saliva. Not only this, but the infection of the neurons in the brains leads to severe agitation which can lead to an infected host biting an individual which can then spread the virus! So this is a case where the virus has evolved a mechanism of infection that plays off of a behavioral change caused by an earlier stage of the infection cycle.

This is such a profound manipulation of the host that movies like "The Crazies" have used Rabies virus as the basis for their viral outbreak. In fact there's a direct mention of Rhabdoviridae in the newest version of the movie. I laughed when I heard this and my friends had no clue what they were talking about. Authors and movie-makers even take this to another level by using the idea of "mutated Rabies" for the creation of zombies! Rabies on steroids would probably look something akin to those infected in the movies. It is the unique property of the virus to change the behavior of the host in order to continue its propagation that makes it the target of anyone wanting to create a fictional virus that has some basis in science...but more on that later... ;)


Is this virus really "thinking" about the best way to continue its own propagation? Of course you can just say "no," but then you'd fail to appreciate the true power of the virus. It's obvious to anyone that viruses can't think like us, but I think they have replaced "cognition" with the sheer power of evolution and biochemistry. Driven solely by these two processes viruses have developed their own way of "thinking" over billions of years.

Another example of these two processes at work can be found in the unique ways viruses replicate their genomes. Each class of virus has ways of achieving this in different ways, but I'll be general just to get the point across. Some viruses based on +RNA (essentially a coding strand of mRNA; the simplest virus possible) have built in genetic sequences that can form loops due to repeating sequences of bases. For instance a sequence of CAGCUG in RNA could potentially fold over in on itself and base pair to form a loop. Some viruses use these types of sequences to form loops which act on elongation initiation factor 4G (eIF 4G) within the host cell. The elongation factor recognizes the loop as a sequence that needs to be bound, completely unaware that it doesn't belong to the host. The elongation factor can then recruit the ribosome to begin translation of the viral genome. Basically the cell is translating the very proteins that are going to end up killing it! And let's not forget that coded within the genome are factors that essentially eliminate host cell translation and enhance viral translation even more!



Again we see that the virus is able to manipulate multiple ares of the cell in order to produce the biggest effect on its own replication cycle. Crazier still is that this virus would only be able to infect one specific type of cell, so the mechanism that I described is very selective for its target. This all comes from specific receptors that recognize certain host cells that the virus can exploit. It's incredible that such specificity can be achieved and so many ways of manipulation have been created by the virus.

Our cells are not stupid to the threat of viral infection either. As discussed in my very first post about the Red Queen Hypothesis, we have evolved a powerful set of immune system regulators. Our cells recognize some of the molecules produced by these viruses which are called Pathogen Associated Molecular Patterns or PAMPs. If one our immune cells binds a PAMPs it immediately begins a cascade of other signals that bring in nasty Natural Killer cells (yes, that is what they're called and they are pretty BA!), neutrophils, and plasma cells which produce antibodies. So what's the effect of the virus? They, in turn, evolve new ways of trying to evade these signals. They mask of their PAMPS by slightly altering their shape or eliminating the signals released by the cells. And back and forth the battle goes...



The complexity of viruses really makes you ask "How do they do that?" Yet they are still as primitive as they were billions of years ago. At their core they are only genetic material wrapped up in protein. Everything else about viruses, from the envelopes they use to shield themselves from recognition to the destructive signals they produce to kill their host are all the result over years of evolutionary change. So do viruses think? Or are they simply a byproduct of evolution? Either way it is for certain that they have developed ways of fundamentally changing our views of biology. This brings about a whole new meaning to a "smart" virus!

I C a DIFFicult Situation With That Treatment

If you didn't get my failed attempt at being clever, this post regards the common Gram-positive bacteria clostridium difficile, commonly referred to in the medical community as C diff. I have a friend that just completed nursing school and she mentioned seeing a patient with an infection of C diff. So, that gave me the brilliant idea of having a post about this pathogen.

What is important here is that C diff is primarily a nosocomial infection, that is to say that it is most commonly acquired in a hospital setting. This is a very good reason why it is crucial to get out of a hospital as soon as possible in order to avoid an infection like C diff or a variety of other pathogens that lead to a whole host of problems. To give you an idea, a hospital worker simply put their used glove on an agar plate and growth was detected for C Diff...the picture speaks for itself!


I had the pleasure (? I don't know if that's the right word to use, but I thought it was cool) of seeing C. diff under the microscope in my bacterial pathogenesis lab at U of I. (This is basically the best class ever!) Aside from making the lab being VERY stinky, this anaerobe had a unique drumstick like shape that made its identification pretty simple. As a side not, the awful smell from these anaerobic bacteria comes from the fact that they produce sulfides as a course of metabolism. The text book smell for these chemicals is "rotting eggs," but I always thought they had more of a pleasant vomit odor.


Okay, too much information. So, C. diff often occurs in hospitals but not for the reasons you may be thinking. These infections happen because of antibiotic treatment usually for some other infection. Most often a class of antibiotics called quinolones is the medicine that leads to C. diff infection. These drugs kill the bacteria of the main infection that probably brought the patient into the hospital in the first place but also causes the C. diff to overgrow leading to this infection instead.

Like the other gram-positive clostridia (the more interesting ones in my opinion), C. diff can sporulate. Under harsh environmental stress they can go metabolically dormant and become a spore in which they wait until the stressor goes away. They are also resistant to antibiotics in this state giving an explanation as to how they can selectively survive a regimen of antibiotic therapy for a different infection.

C. diff causes diarrhea and a dangerous condition called pseudomembranous colitis. This happens after C. diff enters the colon. The bacteria is initially ingested and is usually killed immediately by the harsh stomach acid. This is good and prevents an infection before it can begin. However, if the bacteria are in a spore form, they can survive the stomach and enter the small intestines. Here the body does what it normally does in the process of digestion. The duodenal cells of the small intestine secrete cholecystokinin (entomologically defined as "A chemical that moves the gallbladder;" It stimulates the gallbladder to release other digestive good-ness) and bile salts. Normally, the bile salts kill any of the lucky bacteria that survive the stomach and enter the intestine. But in the case of C. diff the bile salts stimulate the spores to germinate into the replicative form. Now a growing and metabolically active bacteria the C. diff moves throughout the intestinal tract.

Here the bacteria secrete two toxins called Toxin A and Toxin B (oh you clever scientists...) Toxin A is an enterotoxin while B is a cytotoxin. These terms nearly mean the same thing but "enterotoxin" is more specific to cells of the GI tract. Anyway, Toxin A and Toxin B kill the cells of the intestinal tract by the inactivation of a set of proteins called the RhoGTPases. I think I mentioned them somewhere before, but if not then the only thing worth mentioning about these proteins is that they function to maintain the cell membranes and are used as regulators of other molecular stuff we're not too interested in. Toxin B specifically depolymerizes the host cell actin which destabilizes the mebrane which will inevitably lead to cell death. It also causes the cells to lose their association with each other. These cells or usually very tightly associated with each other in order to keep a strong barrier between the cells and the lumen of the intestines. By breaking these associations, the lumen becomes more "leaky" and the result is diarrhea from the inability to absorb material.

These toxins cause the cells to burst and release their contents among which are enzymes that function in digestion. The release of these enzymes leads to destruction of the surrounding tissue which then brings in inflammatory cells to clean up the mess. The problem with the inflammatory cells is that...they're inflammatory! So now the patients will have inflammation in the stomach which also leads to diarrhea.

If the infection occurs in the colon then the inflammation and presence of the immune cells results in a mass of dead cell debris, bacteria, and other fun things leading to a condition called psuedomembranous colitis seen right. Basically, the colon becomes inflamed and covered by these psudeomembranes. The danger is when the psudeomembranes rupture and spill the colonic contents into the abdomen. This can lead to sepsis and death.

Lister-who, Mono-what!?

I recently heard that the Dole food company had packages of pre-made salads that were contaminated with a Gram-positive bacteria called Listeria Monocytogenes. Alright, all together now... List-ear-e-uh Mono-sight-ah-gen-ease. This immediately paved the way for a new blog post. One of my favorite things to do is to entymologically break down these latin words to a nifty new definition. In this case Monocytogenes would be defined as something to the effect of "Produced in Monocytes" which we'll see why later. Interesting tidbit of info. The bacteria has a flagella which it can use to propel itself around but it only works at room temperature at not at the body's temperature.


Anyway this pathogen was originally discovered in the 1920s but somehow they deemed the bacteria of this genus worthy of the named Lister, a British surgeon from the early 1900s that became famous for the advocacy of sterilization of hospitals and clinics including the tools they use. He's pretty awesome in his own right so maybe whoever named this species found it fitting that this awesome bacteria also be named after an equally awesome guy.

It terms of evolutionary adaptiveness l. moncytogenes wins by a landslide in my book. This is primarily a GI pathogen so it gets ingested into your system. Normally the harsh environment of the stomach would kill anything that gets it, but everey once and awhile some bacteria may get through and be introduced into the small intestines. Here the story gets pretty cool. The bacteria has a virulence factor on its cellular surface called Internalin and these proteins caused M cells to take up the bacteria. These M cells in the intestines function to move foriegn material from the intestinal lumen to a collection of monocytes on the other side. This is good because the Monocytes in this region called the Peyer's Patch (The deep purple region on the pic left) initiate all sorts of immune responses that kill anything else that's around.  The bacteria are shuttled to the monocytes in the Peyer's Patches in the small intestines like everything else. And like everything else the bacteria is taken up by the monocytes.


Now the bacteria is sitting in a phagolysosome which is targeted for destruction. Here's where the bacteria turns nasty. The bacteria secretes another virulence factor called Listeriolysin O. LLO (AHAHA...wait that's not LOL >_< ) creates very large holes in the phagolysosome by physically implanting itself within the membrane. When I say these pores are large I mean it. They're are so big that the entire bacteria can actually fit through! So now l. monocytogenes has a free pass into the cytoplasm of the cell. It prevented it's own death and now has access to the cell from the inside. This is a true cellular invasion is I ever saw one.

Now, listeria produces yet another virulence factor called ActA. This protein acts as a "seed" for host actin polymerization. Wait what creates a what for what??? Ok sorry, I get super excited! Every human cell has a small protein called actin that gathers together and forms long chains. These actin chains, or filaments, act as structural support for cell structure and have roles in mediating cell division, so they're pretty important. So ActA looks kind of like actin and as a result actin starts to form these chains from ActA. The bacteria strategically places the ActA at the end of its body and the polmerization of the actin propels the bacteria forward! So it utilizes the host cells own actin in order to "drive" around via what scientists call the "comet tail." The listeria will eventually push itself against the host cell membrane, and if this happens it can potentially reach into a neighboring cell! So cool! The pic on the right shows the bacteria in orange within the cell cruising along inside using the actin tails which are florescent in green. The green is the tagged actin as as you can see it's all along the border of the host cell which helps the cell hold its shape. If you look near the middle-left of the pic you can even see several bacteria pushing out from the inside of the cell! TOO COOL!

Great, so what? Well what happens is that by using this methods of pathogenesis the bacteria can gain access to whole host of cells (ha that was a pun). It can be transported around the body and can gain access to nerve tissue leading to meningitis or even, as the University of Illinois College of Medicine has shown, invade heart tissue leading to acute endocarditis. It can also arise in the bloodstream and produces severe septicemia leading to shock. Worse yet, this is one of the few pathogens that can actively invade and breach the placental barrier. Sadly 22% of listeria infections in pregnant women lead to the death of the fetus. The wide variety of sever diseases that the bacterial infection can cause make it one of the most dangerous pathogens around. In fact, although infections of l. monocyotgenes is rare it leads to death in a quarter of cases!

Evolutionary this bacteria has taken advantage of several things in order to survive. The first, and by now what I hope is seen as a recurring theme in my posts, is that it directly invades immune cells breaching a very powerful innate barrier in human hosts. Not only that but it also high-jacks a normal cellular response and uses it for its own ends. In this case, the uptake by M cells and the target for degradation are used for the benefit of the bacteria in order to gain full access to the host cell cytoplasm. Listeria is an incredible and effective pathogen because of how versatile it is. The interesting way it works intracellularly makes it one of my favorite pathogens.

The Black Death

...And with those two words we begin the tale of one of the most feared pathogens in the world. We've all heard of the times of the Black Death. How it claimed the lives of an estimated 30-60% of the European population during the 14th century. How it caused the disturbing symptoms of painful necrotic swelling. How it was feared throughout Europe. But behind this story there is another. It's here that we come face to face with the culprit and see why it is so deadly. So let us delve deeper into the world of yersinia pestis better known as The Plague. The cartoon on the right is a bacterium singing "Ring Around the Rosy," a poem written in response to the Plague, one of the many legacies the scourge passed onto the human race.


Yersinia pestis was discovered in 1894 during an outbreak of Plague in Hong Kong. By now, Koch's postulates were regarded as the experimental way scientists found the agents of disease and Alexandre Yersin used them in order to discover that this simple gram-negative (turns pink during a gram stain) rod shaped bacterium was the source of Plague.  Over one-hundred years later modern scientists in 2010 used bodies from England, France, and the Netherlands to experimentally prove one and for all that y. pestis was the bacteria that was the source of the Black Death, a fact that was under serious debate my bacteriologist throughout history

So the commonly held theory is that during the 14th century the reservoir (the organism that harbors the agent without displaying symptoms itself)  of the bacteria, rodents, took a sailing trip to Europe on trading ships from Asia. The blood of these rodents were then taken as a blood-meal for the common flea ingesting the bacteria with it. Due to the unsanitary conditions of the 14th century the fleas were able to leap onto humans. The bacteria coagulates the blood meal within the flea literally starving it. As the flea bit the human for another meal it regurgitated the blood and injected the bacteria into the human host. It's at this point that the Black Death would make history not only for the lethality of the disease it caused but for the changes it would bring to the practice of medicine.

One such change was what would become known to us as quarantine. As knowledge of the Black Death spread across Europe, cities had to take their own measure in order to protect their citizens. One instance was in 1377 in the town of Dubrovnik, Croatia. Here the town decreed that travelers and ships had to be isolated for 40 days in order to see if symptoms would appear. They called this practice "quaranta giorni," meaning "forty days" in the Venetian dialect of Italian. This was then simplified to "quarantine." Needless to say that the practice of quarantine exist as one of the simplest and most effective ways to prevent an infection in health care professionals, friends, and family.

Aren't the similarities between this and the next pic uncanny!?

Another major change came to medicine out of a misinterpreted view of disease. Like so many other diseases doctors during the Black Death era saw the pestilence in the form of a miasma (see the cholera post...it's awesome you won't regret it!). As a result doctors fitted themselves with garments that would prevent the miasma from entering their bodies which would prevent the disease when they were working with patients infected with the plague. What they ended up with was a long overcoat that covered them from head to foot and a beak-like mask that was filled with herbs and flowers. Essentially, this strange looking costume became a biohazard suit! It was an airbourne pathogen, so the mask acted as a respirator similar to what would see today. You can see the similarities right? I like to think that this tradition continued and became not only the first biohazard suits but also the first lab coats! But, I have no proof of this claim, it'd just be cool!


Finally, the Plague began a very dark practice in science. This was the first instance in recorded history that people used disease in warfare. Invading armies would hurl Plague infected corpses over castle walls spreading the disease by force. Obviously this idea persisted and became Biowarfare. Today y. pestis is listed as a class 3 BSL agent (Biohazard Safety Level) meaning that it can cause a severe and lethal infection of humans if inhaled but for which treatment exist. In modern times y. pestis infected fleas were released with wheat and rice by Japan over China in 1940 killing 120. It's clear that because of its history y. pestis is viewed highly by individuals seeking militaristic ends via biological means.

Alright, now that we have a bigger view of yersinia pestis as it pertains to history let's talk biology. The lethality of this bacteria comes from its unique pathogenic cycle in humans. Like I said the accepted cycle is rat --> flea --> human. After the flea injects the bacteria into the human host's bloodstream it immediatly disemminates to a nearby lymph node. Here, the bacteria does something that we will see again and again with severe infections. It invades a macrophage and dampens the inflammatory response.

In order to achieve these ends, yersinia uses one of those fancy syringe-like structures (called a Type III secretion system) to inject the macrophage with a series of proteins called Yops. These Yops all vary in their function but the common theme is that they function in cleaving proteins necessary for the inflammatory response. This is the go-to response for infection. It signals immune cells to proliferate and communicate with other cells that produce antibodies. This is all accomplished by signalling molecules called cytokines. By preventing phagocytosis and the release of cytokines, yersinia essentially has a free ride in both its replication cycles and its entrance into the bloodstream. Of course while in the lymph node it kills the cells which causes the black and swollen lymph nodes from which Bubonic Plague gets its name.

Now that y. pestis is in the bloodstream of the human it will eventually disseminate into the lungs thanks to the circulation of blood. If the overload of bacteria in the blood doesn't kill the host due to shock then the disease becomes Pneumonic Plague (the white blotch seen on the x-ray right) when the bacteria reaches the lungs. It's this stage that really ends up killing the most people. The bacteria can survive in the lungs and when the host coughs they release the bacteria into the air which can be breathed in and infect another person. By becoming airbourne, the bacteria vastly increases the probability that it will infect another host. As you will see in other posts, transmission via aerosols is by far the most advantageous method used by pathogens.


I hope you have seen the similarities between y. perstis and b. anthracis (second post! Read it!). Both pathogens have evolved the unique ability to evade the immune response and disseminate into the blood. What's interesting is that they both use different methods to achieve the same end. Anthrax toxin kills the macrophages in the lungs while Yops kill them in the lymph nodes. Both Anthrax toxin and Yops also inhibit phagocytosis, but again the location is different. Evolution has pushed these organisms to infect a specific location even though they have mechanisms that do the same thing. Different evolutionary stresses have caused these pathogens to infect a different location, but the functions of these protein have been beneficial to the organism in its replication and survival.

Evolution functions to tweak ever so slightly what the bacteria already have. Over time bacteria can develop new ways of infection. Perhaps in the case of yersinia it was once strictly an infection of the flea's GI tract. But somewhere in its evolution it developed the ability to infect humans. This jump probably didn't happen overnight. It may well have just been a simple mutation that went overlooked for thousands of years until it finally came in contact with the human host. Many pathogens can change for its benefit and the end result is a pathogen that is all the more frightening.



   

Don't Drink That Water!!!

I'm sure everyone remembers the powerful earthquake that struck Haiti in 2010. The 7.0 magnitude earthquake ravaged the Haitian landscape leaving cities and people in ruin. Beside the obvious destruction the earthquake produced it also brought about serious health risks. I remember watching the news and seeing these families in tent cities. Anderson Cooper, of course, interviewing the people and giving the world a view of unimaginable poverty (his infamous black shirt is depicted right being given a medal for spreading fear). At the same time I thought, "these people are going to get sick. It may not happen today, or tomorrow, but at some point an outbreak of something will occur." In December 2010 an outbreak of cholera began, marking the beginning of the one of the worst cholera epidemics in modern times.

The story of cholera has its origins way back in history. Like many other illnesses, people in the 19th century knew the disease cholera. In fact it was the first reportable disease in U.S. history. In 1854, the world changed with the use of keen observation. Throughout history, diseases like the plague were thought to have two sources. One was God and the other was the miasma theory. The first being that God punishes humanity by means of disease and the second being that the deadly fumes from swamps and the dead bring about disease. A English physician named John Snow was skeptical to the miasma theory of disease and being the good physician he was decided to investigate the clusters of cholera outbreaks in England.  He used a map and plotted the locations are those infected. Then he placed this map over a map showing the drinking water system throughout London. He saw that every infected area drew its water from a single well. After debate with authorities, Snow finally got them to close the well and like magic the incidence of cholera dropped. It's because of this simple observation that Snow became the father of epidemiology, a path that I would like to follow some day myself.

From the observation that sewage contaminated water was the source of disease, Robert Koch (the man! see the first post. He's the one with the sweet beard!) used his own methods to show that cholera was in fact caused by a bacteria. Just like anthrax, cholera was not transmitted by a miasma but a bacillus that named vibrio cholerae. Together Snow and Koch developed the fundamentals of bacteriology and epidemiology: Infectious diseases are caused by bacteria and each one was a particular route of infection.

If yersinia pestis is the Black Death then vibrio cholerae is surely the White Death. The reason is simple enough, it causes a sever diarrhea that is white. Yes I'll say that again it's white, like rice water, hence the condition called Rice Water stool. It doesn't have a smell nor a color. Essentially it's just water that is leaving the body. If left untreated it will probably kill the host. This is why many cartoons were made in the early 20th century that portray cholera as Death or Death spreading cholera. I love the top of that picture the most, it made me laugh.

The pathogenesis of vibrio cholerae begins with its two plasmids. These plasmids contain two pathogenicity islands (clusters of genes coding for virulence traits) coding for the toxin and an adhesin respectively. Interestingly, the clusters of genes coding for the toxin are now believed to have been derived from a bacteriophage that injected its genes into a harmless virbio. The bacteria is initially ingested and then adheres to the epithelial lining of the intestinal tract. This is why it has the adhesins. The next thing that occurs is the secretion of the cholera toxin.

So, vibrio cholerae secretes the toxin into the environment. This toxin has a ton of individual components but can be broken down into two main parts. The first is the receptor binding domain (B domain), which is a series of five peptide subunits that act together for the toxin to bind to the GM1 ganglioside on the surface of the intestinal epithelial cell. I know, I know...a ganglio-wha? It's essentially a sugar molecule that extends off the host which it uses for signalling with other cells. Anyway, once it binds the GM1 ganglioside the cell takes the toxin up via endocytosis like it would to anything else that gets bound. Inside the vesicle, the receptor binding domain releases from the catalytic domain (A domain), the part of the toxin that ends up doing the damage. The A domain passes through the B domain which releases the A part into the cellular cytoplasm. The picture to the left shows the cholera toxin with the B domain on the bottom and the A domain on the top.

Now the story get's cool. If you read the e. coli post this'll sound familiar. So, the toxic A domain ADP-ribosylates a G protein on the inside surface of the cell membrane. By adding this small molecule the G protein can no longer regulate the enzyme adenylate cyclase by turning it off. The result is that this enzyme stays on, and makes a large amount of the molecule cAMP. This molecule acts on ion channels causing ions within the cell like K+, Ca 2+, and Na+ to leave the cell. Due to osmotic force, water inevitably follows and leaves the cells. The water goes into the intestinal lumen and this is the source of the "rice water stool" seen left. Not pretty...

The result of this drop in water volume leads to hypovolemic shock which leads to kidney failure and death. It's for this reason that physicians use a series of ions including sugar as treatment. Interestingly, the sugar channels are not effected by the toxin, so by bringing sugar into the cell water will follow and flow back into the cell hopefully stopping the watery diarrhea. Super clever! We can use osmolarity against the disease which is ruled by osmolarity! What's important is that they replace the amount of water that is lost. In order to do this clinics use the so called "cholera cot." It's a cot with a hole in it with a bucket that measures the amount of water that is expelled from the body. Very simple but super effective!

Cholera remains as a disease exacerbated by poverty. Indeed cholera is a disease not commonly found in the modern world, but runs rampant through underdeveloped nations where human waste contaminates the drinking water. Luckily, it's an easily treatable disease and if treatment is given promptly and effectively it should be cleared on its own. Antibiotics are usually not prescribed unless it is severe. 

Vibrio cholerae has played a serious role in history effectively shaping how epidemiologist started to understand how bacterial diseases are spread. Importantly, in modern times Horizontal Gene Transfer has resulted in the transfer of the cholera toxin to previously avirulent types of bacteria like e. coli. Likewise, this same process resulted in vibrio's acquisition of the toxic genes in the first place! In the wondrous world of biology we have to appreciate how these bacteria evolve so quickly. We also have to recognize that in order to address the spread of these diseases we need to help nations with simple necessities like clean drinking water. 

So You Have A Virus...Some Antibiotic Should Clear That Right Up

I was watching the news tonight and was taken aback by a very small phrase. As we are all well aware, the Center for Disease Control and Prevention (the CDC, the holy grail of work places for me) has been tracking the course of deadly e. coli that has recently surfaced in the U.S. The news was covering this story when the anchorman said "This virus..." I cringed.  He had implied the e. coli, a bacteria, was a virus. This is the sin amongst all sins in the microbiology world. Thinking about it I realized that many people see the terms "bacteria" and "virus" as interchangeable. More importantly, this habit would lead one to believe that they are the same. This post intends to draw a clear distinction between a bacteria and virus and examine how evolution had played a role in the persistence of each.


I'll begin with the virus. Let's take a trip back to the beginning of life. I'm not talking about primitive amoeba, I'm taking further back than that. The story of the virus may well begin at the beginning of life itself. At some point in time a layer of fat was able to surround a randomly attached molecule of base pairs. Thanks to Carl Woese (UI ftw!) it is now plausible to believe that this molecule was RNA as it is much more primitive than our double stranded DNA, hence what he called the RNA World.We'll skip a few million years until this thing ("life" sounds like a stretch for a fat covered bubble) somehow gained the ability to replicate its own genetic component. This is another piece of evidence for the RNA World because RNA can use itself as a mechanism to replicate its own sequence. Anyway, at some point the RNA in this thing somehow left its original sequence by an unknown cause (if you thought transposon, the jumping gene from a previous post, then you deserve a cookie). More importantly this RNA could no longer be replicated unless it is within its parent. This rouge RNA, by the laws of physics, buds off the thing and the result is a separate fat covered bubble that now has a bit of RNA that can be replicated only when its back inside of the host. This is a very murky description of the creation of the primitive virus. In case you're wondering, "The Thing" in John Carpenter's horror movie replicated and disguised itself much live a virus in nature, hence my word choice.

Protein Capsid of Herpes Simplex Virus-A which
 houses the genome of the virus

Note that for viruses I used the word "persist" and not "survive." "Survive" implies that viruses are a living organisms. This is not the case for several reasons. They do not replicate on their own. That's a biggie. The other big one is that they do not produce their own energy. A lot of scientists disagree and do consider viruses to be alive, but by the biological definition they are in their own grey area of existence.

Viruses can come in many flavors which are based on the genetic material they have. They can be single stranded (ss) RNA, double stranded (ds) DNA, ssDNA, and dsRNA. Interestingly, viruses are the only things on Earth that have dsRNA and your cells have evolved a receptor that specifically bind this molecule. If dsRNA gets bound the cell knows its being attacked by something really foreign and really bad, so it usually kills itself right away to prevent viral replication. Sorry, I get so excited about viruses that I can get sidetracked! They can also have a lipid envelope or they could be "naked" and only have a protein capsid that holds the genome inside.

Evolution has done something pretty crazy with these guys. They pack their genomes full of genes in extraordinary ways. Unlike us, viruses can have multiple coding regions of genetic material that overlap with each other. Basically, by starting the process of translation in a different spot, they can make fully functional proteins. If we tried that we'd end up with junk! For instance take the phrase "The Fat Cat Ate The Rat." All three letter words that make a perfect little message we can all understand. Let's say hypothetically instead of started at the first T you start at the H instead. Try reading it in the same sequence of three letters...of course you can't because it doesn't make any sense. But in the viral world such a message would make perfect sense. Because of this phenomenon, viral genomes are can be very small but pack a ton of different genes. Pretty cool, huh?

Now for bacteria. Unlike viruses, bacteria are alive. They replicate on their own and they produce their own energy through super fun metabolic pathways that become not so fun when you're taking a biochemistry class. Bacteria are far more complex than a virus, with genomes that are much larger and produce many more different kinds of proteins. In order of complexity the progression is virus << bacteria< eukaryote. That being said, bacteria were probably the first complex forms of life on Earth. And as long as they've been around, a virus has been around to infect and replicate inside. So as history progressed and cells became more specialized, the virus also had to adapt in order to be able to infect these new kinds of cells.

This is the bare bones of it. I'll do a much more expansive examination of viruses later because I realized I have a lot to say about them because they are super primitive but can do things that make the heads of scientists explode. The point to all of this is that bacteria and viruses are not the same. So if you have a bacterial infection, antibiotics will hopefully take care of the problem. However if a doctor prescribes antibiotics to you after diagnosing you with a virus, you are wasting your time because you can't kill what isn't alive.

The Plague of Our Generation

My generation has seen a couple of pandemics and pandemic scares. From H5N1 influenza (the dreaded bird flu which never came to fruition) to H1N1 (the swine flu which did spread across the world) and from SARS to anthrax the media has time and again presented the danger that these agents have on world health. But truth be told none of these have had the impact from both a social and medical perspective than has the HIV pandemic. This year marks the 30th anniversary of the first reported instances of HIV in the US and I thought I would take a little time to remind everyone what this virus has done not only to those infected but how it has also been a pandemic with great social implications.

The story of HIV and AIDS begins fifty years ago in Africa. This virus has great similarity to a similar virus called the Simian Immunodeficiency Virus and it is widely agreed that fifty years ago, a virus similar enough to SIV evolved the ability to infect humans. Thus, some poor human in Africa came in contact with simian blood and with it came a new virus that would begin the worst pandemic in human history. Twenty years later on June 5th, 1981 doctors in the US started to note something very strange. In LA there were five patients with a peculiar case of pneumonia caused by a bacteria that wouldn't normally infect a human with a healthy immune system. Immune titers from these patients confirmed that all of those with the pneumonia had a severely compromised immune system, with white blood cell counts as low as 200 per uL, only 14% of what a normal count should be.

As media spread coverage of this strange new virus one thing started to stand out amongst the patients infected: they were gay. Not knowing what this new disease was it gained the name GRID, gay-realted immune deficiency, however later it became clear that the virus didn't only effect the homosexual population and the name was changed again. Still, the gay population became stigmatized for harboring this virus and the true face of HIV emerged. Freddy Mercury, the singer of Queen, literally took the knowledge of his infection to his death bed in 1991. Even today, thanks to the media, HIV infection has become synonymous with homosexuality, drug use, and sexual misconduct the end result of of which is invariably the contraction of HIV.


In the 80's the infection also became a death sentence. With no treatment available for this disease those infected could only wait until they became infected with a normally harmless bacteria and the body was overrun. Because of this, partners would leave each other once HIV was diagnosed seeing it as a mark of imminent demise given from the person they loved. Luckily, miracle drugs emerged that could prolong the life-span of the infected for years and years and HIV. Now, HIV is no longer a death sentence and has turned into something more of a chronic illness.

The human immunodeficiency virus  infects CD 4+ T cells, also called T helper cells. These cells are charged with the responsibility of helping clear foreign agents from the blood. The virus binds to the cell and fuses its membrane with the host cells, causing the virus to release a protein capsid into the cell's cytoplasm. The capsid falls apart and releases the true monster into the cell, it's RNA. The RNA genome is reverse trasncribed by a unique enzyme called reverse transcriptase and becomes DNA. Worse, the DNA is taken to the host genome and another enzyme called integrase inserts the genome into the host cell's. As the cell replicates, it unknowingly produces more virus particle by the constant replication of the host genome which now houses the virus's genome too.


The wonder drugs target reverse trasncriptase prevent the production of DNA, and thus any step that comes after. The identification of this enzyme proved a leap forward in the field of biology. The central dogma has always been DNA--> RNA --> Protein. That's the way life works. It's the schema that makes you you and makes me me. From skin to hair, every organism on Earth is under the influence of this genetic process. This is why when researchers said they found an enzyme that makes RNA into DNA (RNA --> DNA) the scientific community scoffed at it, unable to believe that the central dogma which rules all of biology at the level of the gene could possibly be broken. However, the scientists prevailed and would be rewarded with the Nobel Prize.

This enzyme also proves the be the necessary driving force behind the evolution of the virus. The problem is that reverse transcriptase does not have a proofreading mechanism like the DNA polymerases in your cells. In humans, mutations in DNA are bad so the machines that make DNA have methods of checking their work and fixing mistakes. But, in microbes eliminating this mechanism can proove beneficial. Since the replication rate of microbes is so much more frequent than any other organism, if you eliminate the proof-reading, you can potentially cause mutations that allow the pathogen to produce functional proteins but with slightly altered attributes. This could mean the ability to bind a different receptor or in the case of HIV, the evasion of drugs. This is why new drugs are constantly developed for HIV. Reverse Transcriptase can mutate the genome and prevent it from being recognized by the drugs.

Today in the US, the infection rate of HIV is down thanks to the scientific understanding of the virus and education of students about sexual health. However, we cannot hope to solve the pandemic unless we help those that truly need help. No region needs more than the countries in Sub-Saharan Africa which show higher rates if infection than any other region. It's up to the WHO to develop a plan to deliver the aid and drugs necessary to help. Not only that but we need education in the region too. South Africa employs a HIV positive Sesame Street character named Kami in order to achieve this end. Even here though there is a great divide between the rich and poor. 80% of the citizens in South Africa receive treatment from public clinics which are understaffed and not equipped to help all those in need. In a region that is skeptical about the actions of western culture, we must also be mindful of how we would instigate such an intervention.

Although we have the medical means necessary to fight the disease what it really comes down to is money. Poor people and poor countries cannot afford the drugs, a point satirized in South Park where the cure to HIV is "concentrated cash." Also, drug users that don't have access to clean needles are also at risk of contracting HIV and other blood-bourne pathogens. There needs to be an investment in the research for a vaccine to the virus as well as preventative care not only here in the U.S. but worldwide. It's only with this amount of cooperation that we can ever hope of nearing a day where the infection rate and mortality rate of HIV is 0.