When watching or reading science fiction, we always wonder, what if it was real. Then we think, how could we make it real. Be it that fancy space wrap drive, or driving through a worm hole, or be it uploading your brain to a computer. Sounds like fun right? But have you ever thought destructively and wondered, how to make the nightmares come to life? How would you design a Zombie virus if you had to?
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Life is going good, you are shopping at a mall; except you notice this freak looking person in the mall, who looks like s/he is dressed for the Halloween. You pass by, but seconds later you hear screams. You turn back and see that this person is biting someone. If you have watched zombie movies, it would be a smart thing to run while there is still time. However, if you are a cat that died because of curiosity, you stand there and watch. A few minutes later, the person who was bitten, becomes a freak too, and bites someone else. And for that moment onwards it is a chain reaction, until majority of world population turns into a freak.
Well, that's the common theme is most zombie stories out there. Though, I think it's not the best way for infection to spread, but let's work with that for now. Let's get as close as possible for bringing it to life. To get there, we are going to first look at the most optimal infectious agents, we can use. Then we will look at the symptoms of the zombie disease, and from where we can get the genes for making them real. And finally the best strategy for spreading it. So, let's start with picking the pathogen.
CV by mohamed_hassan.
Phage by sbtlneet.
Hired by geralt.
I mean, there is a bucket list of pathogens to pick from - bacteria, fungi, worms, virus. For instance, Last days on Mars, shows that a bacteria on Mars turns the mars explorers into zombie-like creatures. One of my favourite movie in this theme - The girl with all the gifts, shows that infection by a fungus turned people into the undead. I specifically like the fact that fungus developed its own network with the neurons in the brain, doing the thinking for the infected. Moreover, in the second generation of infected kids, fungus developed a symbiotic relationship with the young ones. And, finally they kept in the mind that fungal spores are the best way to spread the infection in air.
In Santa Clarita diet, the infection spread by eating the undead clams. Though they do not focus on which pathogen can be spreading the infection - it can be anything from a toxin in the clans to a virus. I like the virus. And, I will tell you why.
The host pathogen friendship.
I mean what could be worse than losing your home. If you think of humans as a pathogen of the planet, then humans would die, if they destroy the environment on earth. Well, unless they find a way to spread to other habitable planets, before they make a mess here. We are a planet to the pathogens. The pathogens don't intent to kill us(if they had any intentions at all). They just want to use our resources for their selfish benefits. But a war between them and own cells for this territory, ends up killing us. Best pathogens are those, that evade our immune system and build a home in our bodies, hardly causing any symptoms1. They grow and build up their population slowly. Then one day they sprout out, infecting other people we come in contact with. The milder the symptoms they can cause during sprouting out, the better. The longer their host survives, the more probability for them to spread. Some pathogens, even make their home inside our cells or even DNA and are passed on to our future generations. And no one, I mean it, no one does it better than a virus.
I mean sure there are bacteria, like Mycobacterium tuberculosis, which can lie latent inside our macrophages for years without causing any symptoms and spread. But, they can be easily detected by our immune system. On the other hand you have Herpes family of viruses, which has, as you read this made their home in almost, every human on the planet. Then you have lentiviruses, like HIV, a retrovirus, which can add its genes into your DNA, makes its copies for years, infect new hosts, before causing its first symptoms. In fact, during the course of evolution many retroviruses have infected us and our ancestors. They have dropped their disease causing genes all together, and have become an integral part of us. The worst these ancient viruses in our DNA, called retrotransposons, or jumping genes, do is jump around our DNA causing unwanted mutations. However, cells usually tame them and don't let them cause a mutational overload. But at times they have been helpful too. Like in elephants, they carried tumor suppressor genes and made multiple copies of it throughout its genome, giving elephants a brilliant resistance to cancer2. Even our neurons sometimes use them as pets3.
The power of stealth
Image showing Alberto Del Rio mocking John Cen by Feedback.
CC BY-SA 3.0
I mean sure living inside the host DNA and dividing with the cells themselves, is a good stratedgy to stay hidden. But, before you can reach that stage you need to hide from the immune system. Plasmodium archives this by infecting the liver cells and then taking the shelter in your red blood cells. But, it is exposed when red blood cells are destroyed as a normal cycles causing symptoms of malaria. Rabies virus, on the other hand don't care much about the blood cells. It inserts itself into your peripheral neurons, and travels its way up the the Nevers to the brain. That's not where your immune system would even be looking for it. If not for the excessive neuropathology it causes it can keep the host alive longer and spread slowly. And other features of rabies are going to important for our recipie as well.
But, before we design the recipient, we need to ask - what do we need to make? What are the symptoms that this virus needs to develop in the host?
Differential diagnosis for Zombie disease and ingridents.
White board by mnplatypus
So, what are the symptoms most zombie movies portray? How many of them are feasible to make a functional zombie?
Biting and Cannibalism
The importance of the symptom
Most movies show zombies as these undead creatures, which want to bite and even eat other people of their own species. They love meat and blood. So biting is what we need for sure, that will be important for starting the pandemic, even though eating the target to death isn't really compulsory. However, if induced by hunger biting can be amplified to a good extent. So it won't hurt if our zombies eat some of its victim completely, while spreading the infection in failed attempts.
Ingridents for the symptoms
Controling biting behaviour needs the pathogen to infect the brain. It needs the loss of ability to supress the apetite. This can be achieved if the virus destroys the leptin receptors in neurons or kills the neurons containing the leptin receptor in the hypothalamus. Alternatively, we can co-infect the fat cells to make a lot of hunger producing hormone, Ghrelin. In fact it wont hurt to just pack a Ghrelin producing gene or Ghrelin receptor gene in our virus, and target it straight to the brain4.
Then for infection we need virus to slowly accumulate in the saliva. So when zombie bites, it transfers the infection. It would also be a good idea to make these people fear swallowing. This will concentrate the virus in the saliva if they don't drink water. Plus, to hunt the victim the zombies should be agressive. Well guess which virus already have all these features? Rabies.
So, rabies is going on our ingridient list. We are going to take genes from rabies that will help infect the nervous system, causes it to accumulate in saliva, plus make swallowing painful. We will also add a leptin receptor inhibitor gene or a Ghrelin gene, to make these people hungry. However we will drop the genes that causes excessive neuropathology, so our host lives longer. We can use promoters that causes slower gene expression, so virus will replicate really smooth and slow.
The undead behaviour
The importance of being undead.
"What is dead may never die."
-Followers of drowned God(Game of Thrones).
Image by ErikaWittlieb.
Zombies have this important feature - you can't kill them unless you shoot them in the brain. Now, this is really important. Because, if not for this feature, you may just shoot the zombie trying to target you. Then zombie pandemic would never happen and our umbrella corporation would fail.
Ingridents for making the undead
Now, zombies become undead because they don't have blood circulation, heartbeat or pain. However, unless our virus can convert blood into some sort of thick hemolymph, which allows passive diffusion of oxygen, it's not going to be very helpful. Without oxygen, there won't be much energy for neurons and muscles to function. A fungus would have been a better candidate to supply alternative network for oxygen supply, but we ain't using fungus. And creating new organs is tedious. But we can do something else. We can make sure that our zombies don't feel pain.
We can make the virus to either kill or inhibit pain sensing neurons. We can derive example of genetic mutations from people who don't feel pain5. Such as, target neurons or gene itself, which produces a voltage gated sodium channel SCN9A. Alternatively, you can add a gene in the virus which causes overexpression of endorphins(the endogenous opids body uses to dull the pain). At least without feeling the pain, our zombie will have longer time for attacking the person shooting it.
But, what about blood loss, you ask. That can be slowed down. We can add genes to the virus which will overexpression coagulants. So blood can quickly form a clot when wounded. We can also make skin a little thicker by causing dermal fibrosis and increasing the fat pad. Though, you will need to add skin specific expression of TGF-beta gene6.
However, in order to achieve this we will need a systemic infection. So, we run the risk of exposing our virus to immune system. But don't worry, we can borrow some stealth from Herpes virus or HIV here. For instance, you can kill the cells of immune system and make the host immunocompromised before launching the symptoms. Well that's HIV. Herpes on the other hand, has in built mechanism to evade interferon signalling, and mellow down the immune response. So genes from both of them can come handy for us.
The cosmetic features of zombies
Importance of rotting and looking undead
Zombie movies show that zombies have rotting skin, and body parts. Well, not surprising if you have ischemic death of cells all over your body. However, in my opinion, that's not in the best for interest of zombies. I mean, why would you want our zombies to be easily spotted. Won't it be better, if they look like normal people, like in Santa Clarita Diet. Though lesions on the body could help spread the virus by contact. Which would be nice, but let's just keep the lesions minimalistic, just to stay away from the spotlight.
Ingridents for the Zombie skin.
However, if you still want them to be there for asthetic purposes, the dermal fibrosis and genes from Herpes virus, we just talked about, would give you that. However, I am going to recommend using slow acting gene promoters, to still keep our zombies look pretty and human.
Maximizing the spread of infection.
Globe by geralt
Biohazard sign by Clker-Free-Vector-Images
When talking of a zombie outbreak, it won't be a great idea to have acute, localised outbreaks. Virus needs to spread globally, over years, without causing any major symptoms. Herpes and HIV are both good at evading immune system. For instance HIV don't try to infect too many cells very fast. It causes a localised infection and infect cells with CD4+ receptors in its surroundings. Once inside the cell, it not only incorporates its genes in the host genome, but it also supress the antiviral interferon response of the cell7. Plus it already have mechanisms in place to evade detection of cytosolic viral genome in the cells8. Plus, given we would choose most of the expressed genes of secreted proteins, such as hunger hormones, of human origin, that would reduce the immune reaction. Moreover, the fact that main target would be neurons
Nevertheless, only issue with using, a HIV like virus is that it may need a long waiting time for it to become pandemic. Moreover, the outbreaks would be unpredictable. For our zombies apocalypse, the rise of the zombie needs to be synchronised. One can think of a stratedgy, such as that exist in some plant viruses. In this case, your first virus is a strain that spreads slowly and asymptomatically. While the second strain is an activator of virulence and can be fast airborne strain like flu. What this stratedgy would do is make sure that everybody has virulent genes in the cells, while the release of the activator will synchronise the rise of zombies. So, in terms of resident evil, it's not just T-virus, but T1 and T2 viruses.
If you have an evil mind, dreaming to be a supervillian, you can also own a pharma company and launch a drug that can turn on zombie virulence. That's upto you. So what do you think? What stratedgy would you use to design most optimal zombie outbreak?
A game you might love to play
Check out if you can infect the world.
For purposes of national security, I will keep the information on assembling virus genome secret. Also I won't give away the antidote.
Ok, just kidding it's just that, I feel that the article is too long now. And it was suppose to be a fun virology read. However, if you are interested in knowing how to design a virus with genes of your interest, I already did a blog on that. So now it's just a matter of deciding, how you would organize all the genes I mentioned, in the viral genome. And, as far as antidote is concerned, keep some CRISPR Cas handy(read my blog on CRISPR).
Brainstorm your strategy, for making a pandemic zombie virus. 2 SBI shares for cool comments in this context.
Enjoy the Song
Doehle BP, Gale M Jr. Innate Immune Evasion Strategies of HCV and HIV: Common Themes for Chronic Viral Infection. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.