Pathogens are disease producing agents and they include bacteria, viruses, funguses, protozoa, worms, and prions (potential pathogenic proteins).
Of the 1,500 pathogens known to cause disease in humans, the CDC (Center for Disease Control) formed a list of the ones which are most likely to be used as biological agents. The list is separated into three categories, depending on how easily the pathogens can be spread and their lethality. Category A agents are considered the highest risk and Category C agents are those that are considered emerging threats of diseases.
Biological agents that are highly lethal and quickly spread or transmitted from person to person. Category A agents are:
- Anthrax (Bacillus Anthracis) (Bacteria)
- Botulism (Clostridium Botulinum Toxin) the toxin of C. botulinum Bacteria
- Plague (Yersinia Pestis) (Bacteria)
- Smallpox (Variola Major) (Virus)
- Tularemia (Francisella Tularensis) (Bacteria)
- Viral Hemorrhagic Fevers (Filoviruses such as Ebola and Marburg, and Arenaviruses such as Lassa and Machupo)
Biological agents that are moderately easy to disseminate, and have lower mortality rates.
The Category B agents are:
- Brucellosis (Brucella species) (Bacteria)
- Epsilon Toxin of Clostridium Perfringens (Bacteria)
- Food Safety Threats (Bacteria such as Salmonella species, E. Coli O157:H7, Shigella)
- Glanders (Burkholderia Mallei) (Bacteria)
- Melioidosis (Burkholderia Pseudomallei) (Bacteria)
- Psittacosis (Chlamydia Psittaci) (Bacteria)
- Q fever (Coxiella Burnetii) (Bacteria)
- Ricin Toxin from Ricinus Communis (Castor Beans) (Bacteria)
- Staphylococcal Enterotoxin B (Bacteria)
- Typhus Fever (Rickettsia Prowazekii) (Bacteria)
- Viral Encephalitis (Alphaviruses [e.g., Venezuelan Equine Encephalitis, Eastern Equine Encephalitis, Western Equine Encephalitis])
- Water Safety Threats (Bacteria such as Vibrio Cholerae and Cryptosporidium Parvum)
Biological agents which might be engineered for mass dissemination because they are easy to produce and have potential for high morbidity or mortality.
The Category C agents are:
- Nipah Virus
- Multi-Drug Resistant Tuberculosis (MTB)
- Tick-Borne Encephalitis Viruses
- Yellow Fever (Virus)
Aiming at human extinction, the initial intuition is probably to look for the quickest most lethal pathogen in these kinds of lists, and focus on it. However, we don’t think this should be the research guideline. First of all since the quickest most lethal pathogen is not necessarily the most suitable for human extinction. Second, since we believe we shouldn’t think in terms of finding the one single magic bullet. And third and most important, because we should not focus on what currently exists naturally, but on what can exist. In other words, instead of focusing on current pathogens which hold desirable relevant traits, the main aim should be how desirable relevant traits can be engineered into existing organisms.
The type of pathogens that may drive their hosts to the brink of extinction and beyond, may surprisingly not be the more intuitive ones. When thinking of pathogens with a major impact on the human population, what comes to mind is acute highly contagious pathogens that cause sudden and major epidemics, such as smallpox or pandemic flu. Such swift agents may significantly reduce the human population size, however they are not highly likely to cause the extinction of humanity. This is due to the inherently self-limiting nature of such pathogens.
Epidemics start when an infectious individual enters a population of susceptible individuals. This sparks a chain of transmission that initially exponentially increases the number of cases. At the beginning, all people are susceptible, and so the disease spreads rapidly. However, the initial exponential increase also leads to a decrease in the number of susceptible individuals (as those that were already infected are no longer susceptible – they either died or became immune). As the number of susceptible humans is decreasing through the pandemic, the transmission slows down. This natural deceleration increases the chances that the chain of transmission will be broken by some susceptible individuals who now have smaller chances to get infected since there are less and less infectious humans around. Thus, the quickest most lethal pathogen may leave a share of the human population unharmed even if it kills each individual it infects, since it might "burn out" too soon, even in the absence of any behavioral changes of the population such as quarantines or vaccinations.
The inherent self-limitation of these pathogens comes about because the force of infection acting on a susceptible population drops since at some point the hosts die before they get the chance to infect as many humans as possible.
Another factor which limits pathogens is an inverse relationship between their lethality and their transmissibility. This is a result of an evolutionary pressure which generally constrains the lethality of pathogens, as the swiftest highly lethal pathogens often don’t get the chance to spread far before killing their hosts.
There are several potential ways to overcome self-limiting.
The first one, is trying to use the rapid and immense advances in the field of biotechnology. Biotechnology has the potential to tackle the natural decline in lethality of some pathogens due to the mentioned evolutionally pressure, and more importantly, it can slow the process down so the pathogens would have enough time to spread before killing their hosts. It also has the potential to improve and refine pathogens’ transmissibility and resistance.
In the last Global Catastrophic Risks report, which is published by the Global Challenges Foundation, two examples of significant modifications of this sort were reported. The first one occurred in 2001, as Australian researchers accidentally created a highly lethal and vaccine resistant form of mousepox, and they claim that "similar techniques could potentially be applied to smallpox". And the second example is that "two recent controversial papers have shown how to create a version of H5N1 which is potentially transmissible between humans".
Both cases are obviously not sufficient to totally overcome self-limiting, but they do exemplify the potential biotechnology has in modifying existing pathogens in relation to some of the required traits which are crucial for potentially overcoming self-limiting (one regarding overpowering the natural decrease in lethality as well as increasing resistance, and the other regarding transmissibility).
Besides pathogens engineered to be extraordinarily transmissible and more resistant, another crucial part in overcoming self-limiting, is modifying the length of the infectious period. The pace of pandemics is not only a product of the pathogen’s lethality and transmissibility, it is also highly influenced by the duration of the infectious period (since obviously, the longer the hosts remain contagious, the greater the chances they infect the rest of humanity), and also by whether during the infectious period symptoms start to appear (the period before symptoms appear or become obvious is called the incubation period). The latter is a significant factor because if there are no symptoms during most of the infectious period, unaware of their infection, humans are highly likely to move around freely while infecting many others.
So, a long infectious period, which is as symptomless as possible, can play a very crucial role in overcoming self-limiting.
Another option worth investigating, considering the self-limiting issue, is thinking about a pathogen which doesn’t cause a disease that kills its host, but attacks the immune system, and so makes it easier for other pathogens to kill the host (immunosuppression).
Two other key traits that reduce pathogens’ self-limiting and increase the chance of extinction, are that the pathogens would also be vector-borne (transmitted by an agent), and that they would have a reservoir (a species of some insect or warm-blooded animal in whom the pathogen harmlessly resided and quietly reproduces).
Having a blood-feeding vector (Arthropod-borne viruses) can secure a robust circulation as the hosts become rarer, and so overcome self-limiting. That is since the vectors need their blood meal and will increase their focus on the remaining humans.
Vector-borne transmissions can also overcome quarantines. So far in history it was hard for humanity to successfully quarantine members of its own species, so having a vector borne pathogen would make what is already challenging, far from being sufficient.
Mechanisms that ensured the mutual survival of vectors and pathogens have evolved over millions of years. Studies of genetic relationships between particular microbes and their most common insect vectors suggest that the species had co-evolved, developing capabilities that were primarily advantageous to the microbes. When the female mosquitoes for example bit into human flesh they spit into the site a fluid that contains among other things a variety of factors that destroy immune system cells and chemicals. This ensures the mosquitoes a steady flow of food, without toxic human immune system chemicals or cells, and allows the pathogen a relatively safe invasion to the host.
Furthermore, since only female mosquitoes feed on blood, to ensure a plentiful supply of females, some microbes made their way to the insect’s ovaries, where they genetically manipulated the male chromosomes, ensuring that the offspring would be female. The organisms would then be passed on to the adult insect’s female offspring, which would be born already infected.
Vector-borne transmissions are usually endemic and spread much slower than human to human infections, so it is unlikely to be a sufficient alternative method for transmission. However, since human to human transmission holds the inherent self-limiting element, vector-borne transmission combined with human to human transmission, is highly crucial to insure, or at least to increase, the chances to overcome this issue and allow the continuance of the pathogen spread.
Similar to the vector-borne factor, having an alternative and resistant host (reservoir), also means that the pathogen can still circulate robustly even when the susceptible population is depleted. It insures that the pathogen couldn’t be eradicated easily, not by natural means such as killing its human hosts quicker than spreading itself to other humans, or by unnatural means such as human quarantines and etc. When there is an alternative and resistant host, even after a pandemic loses momentum (since the number of potential susceptible hosts at some point drops), the pathogens are still out there ready to infect humans.
However, none of the elements we have just covered can assure the infection of the entire human population in the case of natural immunity of some of them to the pathogen. That is one of the main reasons we don’t think we should focus on searching for one omnipotent pathogen. Unfortunately humanity may be genetically diverse enough, so a single pathogen is not sufficient for extinction. Therefore we shouldn’t look for one magic bullet but for a combined effort.
Another reason for that strategy is that multiple pathogens can cause co-infections. Co-infections, as the term suggests, are when hosts are infected with more than one pathogen, and these cases are often harder to deal with for a number of reasons:
1. Greater susceptibility to other infections – once hosts are challenged with one pathogen they can become more susceptible to other pathogen species that are circulating the environment. For example pathogens which have trouble infecting healthy individuals are more prone to infect once the hosts are infected with other pathogens.
2. Triggers Pathogenicity – sometimes a pathogen can trigger the pathogens already living in the hosts, which until then had only a mild effect.
3. The presence of one pathogen can interfere with the treatment of another pathogen.
But probably the main motive behind not focusing on developing the one ultimate pathogen is that humans would obviously try to stop it, and obviously facing one pathogen is easier than several ones.
It is easier but still, it’s possible to envision an exception. HIV, for example is around since the beginning of the 80’s and there is still no vaccination. One may appear in the next few years but even if so, it took humanity almost 40 years to make it. If HIV’s incubation period were about two years instead of several ones, and if it were airborne, there is a high chance that humanity was brought to the verge of extinction by a natural pandemic. If us activists can engineer a highly complex pathogen which undergoes constant mutation and so it is extremely complicated to vaccinate against, such as HIV, make it airborne, and with a shorter incubation period but long enough to not burn itself out too fast, that can be as close as it can get to a magic bullet. Facing not one but several kinds of such pathogens, all the more so if they can be novel (meaning no human is naturally immune to them, and obviously being unknown there would be no vaccines or treatments for them), then with all of humanity’s medical progression, it might be too much for humans to deal with, and can be nonhumans’ salvation. Finally.
D. A Henderson, the epidemiologist who had once led efforts to eradicate smallpox, said in a World Health Organization convention in Geneva that "there is a growing belief that mankind’s wellbeing, and perhaps even our survival as a species, will depend on our ability to detect emerging diseases… where would we be today if HIV were to become an airborne pathogen? And what is there to say that a comparable infection might not do so in the future? "
David Quammen, author of Spillover: Animal Infections and the Next Human Pandemic, strengthen Henderson’s statement: "If HIV could be transmitted by air, you and I might already be dead. If the rabies virus — another zoonosis — could be transmitted by air, it would be the most horrific pathogen on the planet."
An airborne, as well as vector borne pathogen, with a reservoir, highly mutative like HIV but with a shorter incubation period in which the infected are contagious, brings us to the third point earlier mentioned, which is examining desirable traits and not existing pathogens.
This kind of observation, which was imaginary a few decades ago, is possible thanks to extreme and rapid advances in biotechnology, genetic engineering, and particularly in the novel scientific field – synthetic biology, which basically means that by manipulating the genetic code, it is possible to create engineered pathogens.
In recent years it’s becoming easier and easier for more and more people to work with different types of organisms, including pathogens, and it’s becoming easier and easier to modify them. Some of these changes are due to rapid technological advances as well as falling costs of gene sequencing and synthesis. Gene synthesisers for example, can turn digital sequence data into physical genetic sequences, enabling individuals to create viruses from digital files. Genome editing technology such as the CRISPR (Clustered, Regularly Interspaced, Short Palindromic Repeat) – which enables to cut off and replace a DNA sequence with a new sequence or code that codes for a particular protein or characteristic – is now cheap enough to be accessible for practically anyone, not just official facilities but privet individuals as well.
And CRISPR doesn’t only significantly cut financial costs, it also significantly cuts the waiting time. While other methods take months or years to edit gene sequences, CRISPR speeds that time up to weeks.
And it also cuts much of the complexity. The process is so straightforward, one scientist said that a grad student can master it in an hour, and produce an edited gene within a couple of days.
This tool also seems to work on nearly every organism, and also in every cell type. Some researchers have compared CRISPR to a word processor, capable of effortlessly editing a gene down to the level of a single letter.
The ability to cut and splice genes so quickly and so precisely has potential applications for creating new life forms. This isn’t just a theory, bioengineered viruses have been created.
As mentioned earlier, in 2001, Australian researchers attempting to make a contraceptive vaccine for “pest” control inserted a "good" gene into mousepox virus and accidentally created a lethal new virus that is resistant to vaccination. And two recent controversial papers have shown how to create a version of H5N1 which is potentially transmissible between humans (as opposed to the natural strains).
In 2004, scientists at the University of Wisconsin-Madison used a technique called reverse genetics to create a virus closely resembling the 1918 Spanish flu strain (only about 3% different) that killed an estimated 50-100 million humans. The scientists combined it from fragments of wild bird flu strains. They then mutated the virus to make it airborne to spread more easily.
In 2002, the virologists Eckard Wimmer and Aniko Paul have used synthetic biology to produce polio. They downloaded the genetic makeup of the polio virus from the internet and acquired the DNA sequences by mail order. Using standard university lab equipment they were able to bring the polio virus back to life.
David Evans, an orthopox researcher in Canada has created horse pox, which was a previously extinct virus. Pox virologists and others have speculated for years that orthopox viruses like horsepox and smallpox can be recreated from scratch now.
As gene synthesis becomes routine, the tools enabling such actions become widely accessible. Online available genetic data information of pathogens, such as in the case of smallpox, is becoming more relevant and applicable.
There are already many DNA synthesis companies which offer people synthesized DNA according to a required sequence. There are limitations on the complexity of the ordered organism, and these firms are supposed to screen the orders, but there can be loopholes that can be used, and anyway it’s surely an indication of the immense advances and possibilities held in biotechnology.
For several decades advances in biotechnology have paved the way allowing the modification of naturally occurring pathogens into a new generation of genetically engineered pathogens. These new pathogens could be potentially developed into extremely deadly biological agents that could be untreatable and uncontrollable.
Genetically engineered virus that is as contagious as the Spanish Flu, but deadlier, and which could spread for years undetected, is a tool with the destructive power of nuclear weapons, but far harder to prevent from being used. Needless to mention, nuclear weapons require huge facilities and obtaining rare materials, while engineered pathogens are possible to create in a lab with a couple of biology PhDs.
James R. Clapper, the director of National Intelligence, said in his Worldwide Threat Assessment testimony to the Senate Armed Services Committee, that genome editing had become a global danger. The new technology, he said, could open the door to "potentially harmful biological agents or products," with "far-reaching economic and national security implications."
Major scientific breakthroughs regarding pathogens were already made more than half a century ago, in times when biotechnology was in its nascent.
Both Britain and the U.S have weaponized Tularemia and Brucellosis, while Britain had also weaponized Yersinia Pestis (Plague) and even Equine Encephalomyelitis, and the U.S had also weaponized Anthrax, and Q-Fever.
But the most extensive research, development and stockpile of biological agents was made by the USSR. The Soviets are known to have weaponized Anthrax, Yersinia Pestis, Tularemia, Brucellosis, Glanders, Q-Fever, Venezuelan Equine Encephalitis Virus, Botulism, Staphylococcal Enterotoxin B, Smallpox, and Marburg virus.
In the 80’s and 90’s, many of these agents were even genetically altered to resist heat, cold, and antibiotics as well as being made airborne, which was done even earlier.
Much of this was revealed by the former Soviet bio-weapons expert Ken Alibek, who defected to the United States in 1992, and worked there as biodefense consultant. Alibek said in an interview that: "People don't realize biological weapons could be the most sophisticated weapons. Biological weapons could be used covertly. There are a lot of different deployment scenarios. There are a lot of different techniques to manufacture biological weapons. And a lot of different agents could be used in biological weapons.
One of the problems is biotechnology is moving fast. We see a lot of changes in biotechnology in general—in microbiology, genetic engineering. And all the developments will give more and more information about how to develop and manufacture sophisticated types of biological weapons…
…This knowledge exists, this knowledge is, let me say, widely published, and there is no significant problem to developing genetically engineered pathogens."
Sergei Popov is another former Soviet bio-weapons expert who now lives in the U.S, and works in the field of biological weapons.
Here is a short description of his former work:
"Initially I was involved in the production of synthetic genes. That means we created in tubes, in vitro, [gene] constructs that did not exist in nature. The hope was, making those constructs, it would be possible to provide bacterial agents and viruses completely new properties which they did not have in natural conditions. So, for example, a virus could produce something absolutely difficult to imagine in natural circumstances, like peptides which destroy the immune system in a very special way.
My most successful research was the finding that a bacteria called Legionella could be modified in such a way that it could induce severe nervous system disease. And the symptoms of nervous disorders would appear several days after the bacterial disease was completely "cured." So there would be no bacterial agent, but symptoms—new and unusual symptoms—would appear several days later.
The idea was that a new weapon has to have new and unusual properties, difficult to recognize, difficult to treat. And finally, it has to be a more deadly weapon. Essentially I arranged the research towards more virulent agents causing more death and more pathological symptoms."He mentions antibiotic-resistant strains of bacteria research: "It was found that it was possible to create, say, plague microbe resistant to almost 10 antibiotics. And a recombinant strain of anthrax had resistance to 10 different antibiotics. In addition, some research resulted in an anthrax strain which was resistant to existing vaccine, and that seems to me even more dangerous. So, essentially, it is impossible to treat that kind of strain."
Also, Popov details other Soviet projects: "they successfully produced several cell combinations of different viruses. And they also continued research in terms of putting certain viruses inside bacterial cells—so that a double agent, like plague and encephalomyelitis virus, could be combined in one. Imagine a bacterial agent which contains inside its cells a virus. The virus stays silent until the bacterial cells get treated. So, if the bacterial disease gets recognized and treated with an antibiotic, there would be a release of virus. After the initial bacterial disease was completely cured, there would be an outbreak of a viral disease on top of this."
"Essentially, whole genomes of different viruses were being combined together to produce completely new hybrid viruses. They wanted to combine two microorganisms in one, say, a combination of encephalomyelitis virus and smallpox.
There could be numerous advantages of that. First of all, it is a completely artificial agent with new symptoms, probably with no known ways to treat it. Essentially, the major feature would be a kind of surprise effect. Nobody would recognize it. Nobody would know how to deal with it."
Dr. William C. Patrick III who spent over three decades at Fort Detrick, Maryland – the U.S. Army's base for biological weapons research, and was one of Alibek’s investigators when he defected to the U.S, said that: "The new technology is certainly out there to be exploited if you want to exploit it for purposes of biological warfare. Through DNA technology, you could improve stability. You could reduce the number of cells required for infection by the respiratory route. It is all out there."
Karl Johnson, the notable virologist from the American Society of Tropical Medicine and Hygiene, said: "I worry about all this research on virulence. It’s only a matter of months – years, at most – before people nail down the genes for virulence and airborne transmission in influenza, Ebola, Lassa, you name it. And then any crackpot with a few thousand dollars’ worth of equipment and a college biology education under his belt could manufacture bugs that would make Ebola look like a walk around the park."
Martin Rees of the Centre of Existential Risk at Cambridge said "My worst nightmare is the lone weirdo ecofanatic proficient in biotech, who thinks it would be better for the world if there were fewer humans to despoil the biosphere."
The philosopher Nick Bostrom, who also extensively deals with existential risks and human extinction, and is the founding director of the Future of Humanity Institute at Oxford University, said that "With the growing technological powers, particularly DNA synthesis machines and other technics. We are right now going down a path where these kinds of capabilities will become available to anyone who wants to buy them. So 10-15-20 years from now, unless something is done to stop this, anybody can able to print out their own version of smallpox virus or Ebola virus."
Anthony Fauci, the Director of the National Institute of Allergy and Infectious Diseases said regarding the chance of human extinction by engineered pathogens: "Would you end up with a microbe that functionally will … essentially wipe out everyone from the face of the Earth? … It would be very, very difficult to do that"
While this particular quote may sound depressing at first, consider that the answer would have been a definitive "NO!" just a few years ago. Now it is not no but "very very difficult". In just a few years from now, probably one of the "very"s would be omitted from this answer, and not long after, that answer might be something like “well it is not going to be easy but yes it is possible…"
Future Threats And Uses Of Advanced Biological Warfare Agents
The accessibility of biotechnological information in the public domain is already relatively extensive, and this is just a preview of what’s to come in the future. According to Global Trends 2025: "For those terrorist groups active in 2025, the diffusion of technologies and scientific knowledge will place some of the world’s most dangerous capabilities within their reach. The globalization of biotechnology industries is spreading expertise and capabilities and increasing the accessibility of biological pathogens suitable for disruptive attacks."
Several years ago a study to identify future threats and uses of advanced biological warfare agents was conducted by scientists who served as technical advisers to the U. S. government. Their study generated several classes of genetically engineered pathogens that could pose serious threats to society. The following are two of the main existing classes, and two of the main futuristic classes.
Binary Biological Weapons: This bioweapon is made up of a two-component system with independent elements that are safe to handle separately but when mixed together form a lethal combination. This system consists of a virus and a helper virus, or a bacterial virulence plasmid.
The earlier mentioned Ken Alibek, revealed that the former Soviet Union had researched a new and improved “super-plague” (Yersinia Pestis) that would be more resistant to multiple antibiotics and would be made with a special new process described as follows: "In its initial form, the plague would not be virulent – so it would be safe to handle and store…Russian Scientists had found a way to convert this non-toxic plague back into a deadly, antibiotic-resistant form as soon as it was needed for weaponization." (Because of its properties and ability to be stored in large volumes for a long period without causing any harm, it is presumed that Russia still maintains this bioweapon).
Binary biological weapons are good candidates for future use because of their benign properties making them easy to store and handle. Because the components are not independently dangerous or hazardous they can be relatively easily obtained and transported, requiring less confirmations and verifications.
Designer Genes and Life Forms: The successful completion of the human genome project paved the way to understanding the nature and content of complex genetic information that could be used to create new biological life forms, or alter old ones. Using the technique of gene splicing, a single gene can be inserted in an organism to alter its genetic properties by design.
Designer genes could become the most lethal form of bioweapon of the future. Those who are interested in developing lethal weapons can openly use the genomic sequence databases to choose the genes they want to design. One assessment noted, "The ever-expanding microbial genome databases now provide a parts list of all potential genes involved in pathogenicity and virulence, adhesion and colonization of host cells, immuneresponse evasion and antibiotic resistance, from which to pick and choose the most lethal combinations." With this wealth of information it would be possible to create diseases using synthetic viruses that could wipe out the entire species.
Stealth Viruses: The basic concept of this potential bioweapon is to "produce a tightly regulated, cryptic viral infection that can enter and spread in human cells using vectors" and then stay dormant for a period of time until triggered by an internal or external signal. The signal then could stimulate the virus to cause severe damage to the system.
The report suggests to visualize the following scenario – a cancer causing virus enters a human cell and lay dormant until an external signal triggers the disease. When the signal gets activated the cells become abnormal and could rapidly generate abnormal cell growth leading to a tumor and ultimately, death. Now, apply this concept to a population where rabies – a 100% lethal disease – gets disseminated within it. At a specific time chosen by the activators, the signal would be triggered to harm an entire population all at once.
Stealth Viruses are currently futuristic, but not at all improbable and deserve to be examined according to the study’s authors.
Designer Diseases: The knowledge of cellular and molecular biology has progressed nearly to a point where it may be possible to conceptually design a disease first and then create the pathogen to produce the desired effect of that disease. These designer diseases might work by attacking the immune system to affect the cells’ natural ability to fight diseases, or it might reactivate dormant genes to cause destruction of cells, or simply instruct cells "to commit suicide" (programmed cell death mechanism called apoptosis). Apoptosis can be used to activate “death pathways” that could kill all cells at once.
Designer Diseases are also currently futuristic, but by no means inconceivable and deserve to be examined, according to the study’s authors.
In conclusion, biotechnology, particularly genetically engineered pathogens, will be more attractive to individuals and groups because of the high degree of ease, expertise, low costs, and widespread information.
The developmental trends in biological sciences indicate there is an abundance of possibilities regarding the study of microorganisms and its applicability in creating new biological agents with desirable traits. And the plenitude of properties and capabilities of the various current natural pathogens is very encouraging and inspiring.
Various pathogens have various ways to penetrate hosts, overpower their immune system, and multiply within them. Some do some of these tasks better than others, and the idea is not to find the one with the best average score in all the relevant factors, but to try and implement the better ways into the more relevant pathogens.
Let’s take one of the most crucial parts in pathogens life – Immune Evasion.
Pathogens’ very existence depends on whether they are able to break into hosts, overpowering or outsmarting the immune system. They do that in several ways:
Trying to avoid being detected by the immune system by camouflaging themselves chemically.
Hiding in cells and organs where the immune system is poor. Some even do that in the immune system cells themselves.
Others are constantly changing their outer surface glycoproteins so that the immune system would fail to recognize them.
Some are able to set off false alarms that would occupy the system while the pathogens slip into safe hiding places.
There are pathogens which actively interfere with the immune system’s commanding control system. They produce molecules or even induce their host to produce molecules which interfere with the complex process involved in regulating an immune response.
Lastly, some attack the immune system cells by engulfing them or making them commit suicide, or produce toxins that kill them.
Host defense systems have to distinguish self from nonself. They do that by recognizing the molecules on the surface of pathogens, or on the surface of the cells the pathogens are in. The molecules which are recognized by the T-cells and antibodies are called epitopes. Therefore some pathogens change their coat, and once they do, the antibodies don’t connect to them to disable them and define them as dangerous. These pathogens have a large number of genes coding for these coats and they can turn them on or off. They can even create new gene sequence during the course of an infection so the coat types can continually be generated. That is why it is hard to produce a vaccine against them specifically.
Less than 0.64 micron is all the distance between the air environment in the lungs and the human bloodstream. All a pathogen has to do to gain entry to the human bloodstream is get past that 0.64 micron of protection. Viruses accomplish the task by accumulating inside epithelial cells in the airways and creating enough local damage to open up a hole of less than a millionth of an inch in diameter. Some viruses, such as those that cause common colds, are so well adapted to the human lung that they have special proteins on their surfaces which lock on to the epithelial cells. Larger pathogens, such as the tuberculosis bacteria, gain entry via the immune system’s macrophages. They are specially adapted to recognize and lock on to the large macrophages that are distributed throughout pulmonary tissue. Though it is the job of the macrophages to seek out and destroy such invaders, many pathogens had adapted ways to fool the cells into ingesting them. Once inside the macrophages, the pathogens get a free ride into the blood or the lymphatic system, enabling them to reach destinations all over the human body.
Overpowering the immune system is only one part of the pathogen lifecycle. Various viruses have various ways for each step in their life. The virus’ first mission is obviously to make an attachment to a host cell. After attachment the virus must penetrate the host’s cell. The third step is uncoating in which the virus must release its capsid (which contains its nucleic acid). The fourth step is macromolecular synthesis in which the virus starts to replicate. The last stage is the release of the virus from the cell. Some, like polio virus, blast the host cell and thus are released from it to infect other cells. Other viruses, enveloped ones, push through the host cell membrane, making it their own envelope, in a process called budding.
There can be many ways for viruses to kill cells: they can be cytopathic (causing a change in the cell’s morphology that kills it), they can kill the cell as they replicate by apoptosis (programmed cell death) , necrosis (cell injury resulting in unregulated digestion of cell components), pyroptosis (when immune cells recognize foreign danger signals within themselves, swell, burst and die), many viruses make proteins which punch holes in cell membrane called viroporins causing the content of the cell to leak out, many viruses inhibit host proteins and RNA synthesis (as they steal the cells system to replicate themselves) which leads to loss of membrane integrity, leakage of enzymes from the lysosomes, cytoplasmic degradation, some enveloped viruses can cause syncytium by causing fusion of neighboring cells together which leads to cell killing.
Each virus makes at least one protein that recruit the cellular synthetic apparatus so that it is the virus genome which is replicated and not the cell’s. For example, one such protein is T protein, which binds a number of cell proteins that are part of the cellular synthetic apparatus, and by that the virus gets priority in replication over cell genome. Another thing T protein does to allow the virus to replicate (other viruses may do this with different proteins), is making cells that don’t normally replicate genomes, as they don’t divide (in fact most of our cells don’t divide), to start replication. It does that by binding with a cell protein that is in charge of inhibition of synthesis of proteins.
The attachment of a virus determines its host range. Viruses bind to cells through specific interactions between components on the host cell surface, and specific surface proteins of the viruses. These interactions determine the host range and the tissue specificity. Some viruses can replicate in a limited variety of tissues (some only in one) and some can replicate in almost all tissues, those are called pantropic viruses (Ebola is such virus). What determines which tissues a virus can replicate in are: susceptibility – whether the cell has the receptors the virus needs to enter the cell, permissivity – whether the virus can do all the steps of replication in that cell, accessibility – can the virus reach the cell, and defensibility – can the virus overcome the immune system.
A human influenza virus for example, can only replicate in the respiratory tract. This is because while the virus can enter cells in other tissues (the virus enters the cell in an endosome) only in the respiratory tract there are cells called club cells that produce proteases (type of enzymes) that cleave the hemagglutinin (HA) of the virus which allows it to fuse the endosome membrane and release its genome into the cell. On the other hand, the H5N1 influenza virus for example, due to a difference in the hemagglutinin, can replicate in every tissue because it requires proteases that every cell in the body has, for the cleavage of the hemagglutinin. That’s one of the reasons why this strain is much more lethal as it can replicate in many different organs.
Another example of how a change in the hemagglutinin (and so in the virus’s target cells) can make a big difference is that while human influenza viruses prefer to bind to receptors that exist in cells that are up in the respiratory tract so they infect humans easily, avian influenza viruses, prefer to bind to receptors that mostly exist deep in the lungs of humans (and also in the eyes), and that is why humans don’t usually get avian flu. But if the hemagglutinin protein of a pathogenic avian influenza virus would change so it would bind to humans upper repertory tract cells, then this pathogenic strain would spread easily among humans (as human influenza does), and would be very virulent as the population would not be immune to it.
Some viruses remain localized to the infection site, but there are viruses that spread beyond that primary site. To do that the virus must breach physical and immune barriers. In the respiratory tract or in the gut, for example, a virus may enter the cells from the apical side (the side that faces out), and after replication, it can exit the cell at the same side (like influenza) and be transmitted from there to infect other hosts. Another options is that it can get out of the cell on the other side – the basolateral side (the side that faces the inside of the body) and spread to other parts of the body. Some viruses can do both, and sometimes a virus can be genetically altered to change the side of the cell it would get out of.
The following is a typical description of the stages when a virus is released from the cell on the basolateral side – along the basolateral side there is a layer called the basement membrane, which is not really a membrane but it is a barrier made up of various components which is very difficult to get through. The virus causes an infection in the cell layer. As a result the immune system causes a disruption in the basement membrane so that immune cells could transfer to the infection area to clear the infection. The viruses use that disruption to get into the host. Once the virus passed the basement membrane there are blood capillaries and lymph capillaries the virus can enter. From there the virus can get to the blood stream (a state called viremia). And once the virus is in the blood it can move around the entire body within minutes.
Some viruses that infect lymphocytes and monocytes cells, like HIV, can move with them from the blood to the central nervous system. Generally, this barrier is not easy to pass, and these viruses can do it since they infect those cells which travel in and out of the brain and so overcome the barrier (which many other viruses cannot pass). Another two methods some viruses use to enter the CNS (central nervous system) are – by entering peripheral nerve ending and traveling through it straight into the CNS, and also by passing from capillaries in the brain, through the basement membrane into the CNS (as was just described regarding entering blood vessels – by causing a disruption in the basement membrane by an infection and then passing throw that disruption).
The sturdiness of the pathogens is obviously a very important trait. Despite that the intuition is that enveloped viruses are much sturdier than naked ones (viruses that have only a capsid without a second layer – the envelope), it seems that it is the other way around. That is because the virus’s envelope is derived from the host cell (its membrane), so it is as sturdy as the host cell. Enveloped viruses are very sensitive to what the host’s membrane is sensitive to. For instance, if an enveloped virus gets ingested, the stomach acids chew up the envelope and then the virus loses the attachment proteins that are necessary to bind to the host cell. Naked viruses can withstand the acid.
Another example of sturdiness, this time of bacteria, is their ability to defend themselves by forming a very strong mechanism called biofilm. This is a coherent cluster of bacterial cells embedded in a matrix of various components. Biofilms provide effective protection against many decontamination techniques both inside and outside the body. The advantage of the biofilm is that it is extremely tolerant to outside threats and this tolerance seems to be dependent on physiological properties rather than genetic ones. Antibiotics seem not to work that well against biofilms since the dense matrix structure and the outer layer of cells protect the interior of the community. Antibiotics may kill some of the outer and middle layers of the biofilms, but some bacteria stay inside the inner layers. Some recent studies suggest that the inner subpopulation of the biofilm form a unique, and highly protected spore like formation, which further protects it.
The physiology of biofilm enables bacteria embedded in them to survive long term exposure to antibiotic, which allows the bacteria to acquire specific resistance to the particular antibiotic agent and so biofilms are a favorable environment for development of anti-bacterial resistance. Furthermore, the frequency of mutations in bacteria growing in biofilms is significantly higher in comparison to bacteria growing in planktonic environment.
Another reason for antibiotic resistance of bacterial biofilms is the ability of bacteria to adapt itself to stress conditions. Bacterial biofilms can switch themselves to more tolerant phenotypes upon facing prevalent environmental stresses such as temperature alterations, alterations in osmotic concentration, pH, cell density, and nutritional quality by turning on stress-response genes.
Biofilms are also quite protected against host defenses. One of the reasons is that the host doesn’t detect the true scale of the bacteria when it is in biofilm and so the response is not intense enough. That is in addition to that the biofilms protect themselves for example by producing a substance which lessens the effectiveness of the immune system.
Furthermore, since the host immune system uses receptors on the bacteria to identify threats, some bacteria can mimic the extra-cellular host's receptors and so be recognized as non-dangerous. This ability also means that any drug that targets them will also target the same metabolic pathways in the host.
Another main characteristic of the cells that are found in a biofilm is their ability to communicate with one another, using different chemical signals. These chemicals are produced and passed by outer membranes of these cells and can be interpreted by members of the same cell species as well as other microbial species present in the same biofilm community. These chemical signals can induce different behavior of neighboring cells due to occurring of different genetic expression in those cells. This type of interaction produces behavioral changes because in biofilms the population is numerous enough to initiate genetic activity (although the same signals are produced in planktonic populations they are not concentrated enough to cause genetic expression change). The coordinated behavior of biofilm is responsible for the survival strategies against host immune system as well as antimicrobial agents.
Biofilms are much sturdier than the bacteria that form them. They can usually last for long periods outside a host. This ability makes sterilization incredibly difficult and allows the bacteria to popup again at a later time to reinfect a host.
Another trait relating to sturdiness that bacteria have is a number of stress proteins (or genes that code for them) which are activated when the bacterium cell faces a range of stimulus such as heat, fevers, some human hormones, and arachidonic acid (an immune system activator). When activated, these proteins, termed "molecular chaperones", rapidly act to protect vital biochemical functions inside the microbe.
Some bacteria have Invasins which are proteins that allow them to bind to and invade non phagocytic cells (as phagocytic cells are designed to take up bacteria). In these cases the bacterium doesn’t have to escape being killed since these cells, being non phagocytic ones, don’t have the mechanisms to kill it, so once the bacterium is in, it is safe.
An even more remarkable feature of bacteria is that bacterial genetic traits can commonly jump from place to place within their own genome, or between different bacteria. These scrabble tiles of movable genes could be in the form of discrete packages of DNA that move about along the bacterial genome called transposons. They could be singular genes that appear to leap about almost at random, designated "jumping genes". Or they could be highly stable rings of DNA, called plasmids, that sit silently in the bacterial cytoplasm waiting to be stimulated into biochemical action. Bacteria use this constant game of genetic scrabble to their advantage creating new features. And they can even occasionally undergo a process called sexual conjugation, stretching out portions of their membranes to meet one another and pass plasmids, transposons, or jumping genes – including for example genes that conferred resistance to antibiotics.
Some bacteria have plasmids which their function is drug resistance, and toxin production. Since relevant plasmids can be implanted in the genome of other bacteria, ones with other relevant and necessary traits, it is possible to improve them and make them more relevant for our causes.
So far we have specified some general and rudimentary examples of pathogens traits, the following are more specific ones:
Specific cases of sturdiness can be found in Anthrax and the Marburg virus for example. Anthrax is capable of protecting itself by becoming endospore. When a bacterium is not in the right environmental conditions, it forms a spore which is very tough, and is very hard to kill. The genetic material of the bacteria is in the center and it is circled with layers that protect it. Endospore helps the organism with resistance to radiation, chemicals, desiccation, freezing, and excessive heat.
The Marburg virus can be found in two different forms. The first looks like a caterpillar, with its long, thin, tubular shape coated with “fuzz”. Inside the tube is RNA, the genetic blueprint of the virus. The “fuzz” along the outside of the virus’s protein tube is a constellation of extruding protein receptors the virus uses to gain entry into target cells.
In its more mature and dangerous form, the viral tube is rolled up into a tight round coil that appear virtually invulnerable to assaults from the host’s immune system.
Picornaviridae is a family of small and naked viruses, which are very sturdy. They are stable at pH3 and are resistant to alcohol and detergents since they have no envelope.
Another example of a tough pathogen is Legionella, the bacterium that causes Legionnaires’ Disease. It could survive over a year inside pipes as a biofilm, emerging in wholly infections form once the faucet was turned on full force. It thrives in temperatures from ice cold to steamy hot. Even distilled water samples occasionally contain small numbers of legionella organisms.
Specific example of an invader prodigy is the bacterium Borrelia Burgdorferi (causes Lyme disease). After entering the human blood-stream, it quickly embeds itself in muscles, the heart, and brain tissue or in any part of the body that antibiotics have difficulty reaching. The bacterium then changes its shape from a corkscrew spirochete to a cyst, making it adapt at avoiding the body’s immune system as well as most blood tests (the serologic blood test for Lyme is highly insensitive, missing 40% of the cases). So, Lyme can hide, reappear, and mess with the brain in a number of ways over a long period of time (the same happens with syphilis). Borrelia Burgdorferi is also highly diverse with five subspecies and nearly 300 strains worldwide. In addition, live Borrelia Burgdorferi spirochetes have been recovered not only from ticks but also from gnats, fleas, mosquitoes, and various human bodily fluids such as urine, tears, semen, and blood.
And a specific example of an evasive prodigy is the Dengue-2 virus.
Usually when people develop strong antibody immune responses against a virus they are protected against future exposure to the microbe. But Dengue-2 virus had evolved an extraordinary ability to exploit human antibodies to its advantage. When the human antibodies attach to the outer envelope of the Dengue-2, it can perform stealth, allowing the antibodies to send their signals to the large immune system macrophage cells. In a process that is usually lethal to the pathogens, the macrophages would then engulf the viruses, but instead of dying, the Dengue takes control of the immune system’s primary killer cells.
Thus, Dengue-2 evades the immune system defenses and gain entry to every organ in the body, carried by macrophages that act as Trojan horses for the virus. As the immune system struggles to overcome this stealthy invasion, various biochemical reactions are triggered producing soaring fevers – as high as 107 degrees Fahrenheit – convulsions, classic allergy like shock, and death.
Another way to outmaneuver the immune system is to inhibit phagolysosome fusion (which is, as the name implies, a reaction of the phagosome and the lysosome which is a cytoplasmic cell organelle that holds enzymes that destroy cellular matter). M. tuberculosis gets into the macrophages, inhibits this fusion and so escapes the immune system. The macrophages recognize there is an infection and that it is inside the macrophages, but they can’t kill it.
Listeria is another bacterium which escapes the phagosome before phagolysosome fusion, and so can replicate in the immune cell. Once it does this, Listeria can also polymerize actin (a type of protein) and it can propel itself into neighboring cells without getting out of the cell. Both listeria and tuberculosis are bacterial agents that get inside a phagocytic cell which are designed to kill these very cells.
Many pathogens, among them E.coli, Salmonella species, Yersinia species, P. Aeruginosa, and Chlamydia, can use a tunnel they create to the host cell that delivers bacterial toxins directly and without having to get into the cells or to have to bind to an extracellular receptor. These are like a molecule syringe.
Some pathogens have the ability to enhance themselves by themselves. Studies of Neisseria Gonorrhoeae and Hemophilus showed that these bacteria have special proteins on the outer surface of their cell walls, which look for useful genetic sequences. When something of interest drifts past them, the proteins grab it and pull the DNA into the bacterium. Another bacterium called Pneumococci has a special internal enzyme system that scans genetic material and rejects useless chunks of DNA.
Rhinoviruses have hundreds of serotypes (distinct variations within the same species, classified together based on their cell surface antigens), so humans never actually develop immunity for it, because the next time a human will get infected by the virus, it would probably be from a different serotype. Another interesting thing about this family is that even one single virion is enough to cause a disease.Another virus which overpowers the immune system and actually uses it to spread, is measles. This virus infects and replicates in immune cells and is spread by them to the blood stream and from there to a variety of organs. Since the virus infects the immune cells it suppresses the body’s immune response and so leaves the infected more vulnerable to other pathogens.
Another interesting thing about this virus is that it is one of the most contagious human viruses. It is transmitted like the flu by inhalation of respiratory secretions, with nearly all infected individuals showing signs of disease. Humans are infectious for 2-3 days before a typical rash appears and discloses their sickness, but during these days there can be only mild nonspecific symptoms (like mild fever) or none at all, while they are highly contagious. Of course this period is way too short, but even with this short period this is a highly contagious virus.
Of course, the short infectious period is not the only reason why this virus specifically is not relevant for us, as measles has a vaccine. The reason we mention it anyway is its efficient immune evasion technique, and its efficient technique of spreading between humans. These are very important traits that can be very beneficial if are integrated in other pathogens.
Variola major, the virus which causes smallpox (and a member of a wider pox family), is known to be particularly easy to produce, highly contagious and airborne. Via inhalation, the virus enters upper respiratory tract and disseminates via lymphatic capillaries to the lymph node and from there to the blood causing viremia (a state in which a virus is in the blood). After the second viremia (a state in which the presence of the virus in the blood is higher as it reaches the blood after it replicated in other parts of the body), the virus infects all dermal tissues and internal organs. This virus can be dried and then it is very stable. Another advantage of this agent is that it requires only two or three virions (a virion is a single virus particle) to produce a respiratory infection, and each infected person spreads millions of infectious viruses into the environment.
There are only about 100 antiviral drugs nowadays. The reason there are so few is that viruses are using a lot of the host machinery in order to replicate, and it is hard to find functions which are unique to the virus. So when trying to inhibit something in the virus life cycle to affect it, it is likely to affect the cell as well, causing side effects.
Another very important reason there are few antiviral drugs, is that partial inhibition of the virus replication is not good enough, because it would allow resistant mutations to arise, therefore the antiviral drug must have 100% inhibition of virus replication. And in any case, any antiviral drug would get resistance to it, because viruses replicate very efficiently and also their mutation frequencies are quite high.
Something important to consider regarding viruses’ resistance to drugs is that in all genome replication there are errors, creating mutations. But in RNA viruses there is no error correction mechanism therefore these viruses develop much more mutations than DNA viruses. So DNA viruses evolve more slowly than RNA viruses, and therefore develop resistance more slowly compared to RNA viruses.
Of course, mutations can be counterproductive, however, sequence comparisons of several RNA virus genomes have demonstrated that well over half of all nucleotides can accommodate mutations. So the virus would still be active and replicating even if half of its nucleotides are changed, meaning that these viruses are very stable but they are also very diverse.
Probably the best example of being very stable but also very diverse is Retroviruses. Retroviruses are viruses that carry two copies of plus stranded RNA and as they infect the cell their genome is translated into DNA and then inserted into the cell’s own DNA. This group of viruses has high frequency of mutation in the process of translating the RNA to DNA so it allows them to overcome antiviral drugs for instance (as in the case of HIV). In addition, since they have 2 copies of RNA, they have genetic robustness against mutations that can make the virus nonfunctional, that is because when the RNA is copied to DNA, both strands are being used during the translation process, and that increases the chances of overcoming damaged parts along the strands, and so ultimately the DNA is more likely to be functional.
The fact that Retroviruses are inserting their DNA into the cell’s DNA makes them permanent, since there is no mechanism to delete them from there. The viral DNA segments that are integrated in the host DNA are called Proviruses. Once the virus inserted its DNA into the cell, it stays there, and is translated into making more viruses.
If the virus infects cells that are germ cells (sexual reproductive cells) then the virus can pass on to the offspring. And if the virus infects cells that live as long as their host does, like HIV that infects long lived cell populations like T memory cells and hematopoietic progenitor cells (the cells that give rise to all the immune cells), then the virus cannot be eradicated, as even if the antiviral drugs work well and get rid of the virus, the provirus still stays in those cells so the virus can be made again.
FinallyThe variety of methods held by the various pathogens combined with the extreme and rapid advances in biotechnology are very encouraging. Listing desirable traits of engineered pathogens, something which would have sounded totally delusional up until recently, now sounds much more realistic.
Ideal characteristics of the pathogens which can potentially cause human extinction are: being novel – so humans’ natural immune system and medical science wouldn’t know it, be rapidly and easily transmitted from human to human, but also be vector borne, have a reservoir, a long incubation period, be contagious during the incubation period and long before symptoms occur (or are obvious) to enable maximum infections, be able to avoid the common medical diagnostic and detection tools, appear usual in terms of symptoms which would preferably be typical of known diseases, be highly stable in various environments, be able to make spore or biofilms in the case of bacteria, be highly resistant to vaccines and antibiotics or antiviral drugs, and of course be highly lethal.
That is a lot of requirements with each being extremely complicated. We realize how intimidating it sounds, but every other option currently doesn’t even manage to decrease the growing numbers of victims per year. Nothing else can ever stop all the suffering humans are causing.
We all have one life. We can use it to be another activist who tries to help some animals by convincing some humans to stop hurting them, or we can decide to devote our singular life to the super pretentious and low chance effort of stopping all humans from making all the harms combined, and forever. Obviously, once, we were also conventional activists. That was until we realized that we can’t think of a better bet than putting everything we have on the chance that all the suffering humans cause and will ever cause, will end.